Expert Interview

Q1: How do/can fibroids influence fertility?

When considering how uterine fibroids influence fertility, it's important to understand that uterine fibroids are very common. Uterine fibroids are the most common pelvic tumor in women, and they're non-cancerous tumors that are developed from the muscle cells of the uterus. The lifetime risk, before the age of 50, of a woman having fibroids varies by race and ethnicity, but in general, about 80% of Black women and 70% of Caucasian women will have at least one uterine fibroid diagnosed before the age of 50.

It's also important to understand when considering fertility that the prevalence of uterine fibroids increases as someone gets older. So uterine fibroids are much less common in younger women in their 20s as they are in women in their upper 30s and 40s. That's important to understand when looking at fertility because we also know that with age, fertility decreases. Thus, uterine fibroids also can impact fertility. There's also this age-related factor, which makes it difficult to really look at fibroids as far as being a causative agent for infertility.

We do know that approximately 10% of women with infertility will be diagnosed with uterine fibroids during their evaluation, and there's multiple ways that uterine fibroids impact fertility. In general, it's going to depend on the location of the uterine fibroids, the size and the bulk or the number of uterine fibroids that a woman has.  But when we look at the ways that uterine fibroids can impact fertility, what they can do is they distort the uterine cavity. This is the most common for submucosal fibroids or fibroids that have a component that's present inside the uterine cavity. Fibroids that are submucosal or intramural fibroids  are in the muscle of the uterus and have an intracavitary component. They're well-known to distort the uterine cavity and that can impact implantation of an embryo. There's also thought that it can impact an ongoing pregnancy.

There's speculation that uterine fibroids can impact the blood flow to a pregnancy as well and they may impact fertility. Depending on the size of the uterine fibroid, they may block the fallopian tubes. And so, if you have a uterine fibroid that's in the corner of the uterus, that could cause a tubal factor type of infertility where there's occlusion of the fallopian tube. But in general, the most concern we have for uterine fibroids is how those fibroids impact the uterine lining and implantation of an embryo, and it's thought that those are most likely due to submucosal fibroids, or some intramural fibroids that may be particularly large, or that have a component that's inside the cavity.

Q2. Several studies have attempted to clarify the influence of fibroids on fertility, however, there have been various, sometimes contradictory findings and a lack of well-designed trials. Why is this?

One of the challenges in counseling patients regarding uterine fibroids is that there's really a lack of  high-quality studies assessing uterine fibroids and fertility. And we all know that the gold standard research study is a randomized control trial, as they provide the highest level of evidence, but those are very difficult to conduct especially for women with uterine fibroids, as many women will decline randomization.

It's difficult to design a study where there's one treatment that can be beneficial versus no treatment. That's one challenge. Because of that, the study designs that we've had to date have mostly been retrospective, and there's been some observational studies. But even those studies, unfortunately, are complicated by the fact that fibroids themselves are very heterogeneous. It's a very heterogeneous condition. There's a lot of difference between the size of the uterine fibroids, the location and the bulk of the fibroid, and then there's also going to be the issue with age. If you have a woman who's older with uterine fibroids, obviously her age is also going to impact her fertility. We know that women with uterine fibroids tend to be older and that also impacts fertility. So that's going to have an impact on any research as well.

What we do know from some of the research to date is that it's well-known that submucosal fibroids impair fertility, that's well established. We do know that subserosal fibroids or the fibroids on the surface of the uterus do not impact uterine fibroids. The question that really hasn't been answered because there hasn't been adequate research and there's just not enough data of high quality is, whether intramural fibroids or fibroids inside the uterine muscle, whether they impact fertility.

Many women who have intramural uterine fibroids are asymptomatic. They don't have symptoms at all. So, the question is whether a woman should undergo an invasive procedure to remove that fibroid and if it’s going to help or not? That's one of the questions that we just don't have enough adequate research on because there are some limitations in the literature.

Q3. What are the current treatments, both surgical and nonsurgical, for patients with fibroids who may want to become pregnant?

I think if there's a patient, a woman with uterine fibroids who's interested in fertility, she may be a patient who is diagnosed with symptomatic fibroids, who wants to preserve her fertility, or she may be a patient who's an infertility patient who during her fertility evaluation discovers she has fibroids. It is important to determine whether treatment is appropriate for that patient, and as we just discussed, there's not a lot of answers in the literature for some patients. I think the most important thing to do first before deciding on a treatment is  to determine the best type of treatment. At Johns Hopkins, for many of our patients with uterine fibroids, they'll undergo a pelvic MRI because the pelvic MRI can provide the most detailed information regarding the size and exact location of the uterine fibroids.

We then have a multidisciplinary conference every two weeks where we review the MRIs with a group of minimally invasive surgeons, interventional radiologists, and fertility specialist where we can really decide the best treatment for the individual patient. In deciding on a patient, it's important to make the right decision and have the most information. So as far as treatments that are available, for women who are wanting to preserve their fertility or planning to get pregnant very soon, the most common options are going to be surgical.

The least invasive surgical treatment would be a hysteroscopic myomectomy where we would do a hysteroscopy and remove the uterine fibroids by either shaving the pieces of the submucosal fibroid or we can remove it with a hysteroscopic morcellator. There are various techniques. But for the submucosal fibroids that are inside the uterine cavity, hysteroscopic myomectomy is very minimally invasive. It's an outpatient procedure. It's very safe and it's something that we will typically offer to patients who have submucosal fibroids.

For patients who have symptomatic uterine fibroids and may have bulk symptoms, or have numerous uterine fibroids, we typically would recommend either a laparoscopic robotic-assisted myomectomy, sometimes just a laparoscopic myomectomy, or for women who have the most severe, a very large fibroid uterus, let's say greater than 20 centimeters, they may actually need to undergo an exploratory laparotomy or abdominal myomectomy. For patients who have symptomatic subserosal fibroids and large intramural fibroids that need to be removed, it really depends on the size, location, and bulk of the uterine fibroids. And that's where the pelvic MRI becomes very useful.

I would say that for the majority of my patients that have a large amount of fibroids, are still able to undergo a robotic-assisted laparoscopic hysterectomy which oftentimes can be an outpatient procedure just because we've had this improvement in technology with robotic and laparoscopic surgery. But surgery can be very beneficial as far as removing the bulk of the uterine fibroids. And so that is typically our treatments that we would recommend for those who want future fertility or who are imminently trying to get pregnant.

There are medical treatments as well or non-surgical treatments such as GnRH analogs that can shrink the size of the uterine fibroids. Unfortunately, the uterine fibroids are still there and typically will still impact fertility. So that's not something that we do often for those that are actively trying to get pregnant. The same for uterine artery embolization or uterine fibroids embolization. We will not recommend that for patients who want to have future fertility because the fibroids will still be in that location and they're typically in a location that's impairing fertility.

Q4. How long do patients have to wait after a fibroid treatment to try to get pregnant?

The length of time that a patient needs to wait after having fibroids removed for surgical treatment typically depends on the type of surgery the patient undergoes as well as the size of the fibroids and the extent of the surgery. For a patient who's undergoing a hysteroscopic myomectomy, they typically only must wait a month or two. Once they're assessed that there's no residual fibroid that's left, then they can try to conceive.

For patients who need to undergo abdominal myomectomy or laparoscopic myomectomy, those are much more extensive procedures. Typically, surgeons will recommend a patient wait three to six months to try to conceive. It's also important for the surgeon to discuss with the patient the extent of the myomectomy and whether that patient, when she does become pregnant, will require a c-section because typically if the uterine cavity is entered or if there are multiple incisions on the uterus during the myomectomy surgery, surgeons will recommend a c-section for that patient when she does become pregnant to decrease the risk of uterine rupture. And typically, that will be documented in the operative note, but the surgeon will also counsel the patient regarding this.

Q1: How do/can fibroids influence fertility?

When considering how uterine fibroids influence fertility, it's important to understand that uterine fibroids are very common. Uterine fibroids are the most common pelvic tumor in women, and they're non-cancerous tumors that are developed from the muscle cells of the uterus. The lifetime risk, before the age of 50, of a woman having fibroids varies by race and ethnicity, but in general, about 80% of Black women and 70% of Caucasian women will have at least one uterine fibroid diagnosed before the age of 50.

It's also important to understand when considering fertility that the prevalence of uterine fibroids increases as someone gets older. So uterine fibroids are much less common in younger women in their 20s as they are in women in their upper 30s and 40s. That's important to understand when looking at fertility because we also know that with age, fertility decreases. Thus, uterine fibroids also can impact fertility. There's also this age-related factor, which makes it difficult to really look at fibroids as far as being a causative agent for infertility.

We do know that approximately 10% of women with infertility will be diagnosed with uterine fibroids during their evaluation, and there's multiple ways that uterine fibroids impact fertility. In general, it's going to depend on the location of the uterine fibroids, the size and the bulk or the number of uterine fibroids that a woman has.  But when we look at the ways that uterine fibroids can impact fertility, what they can do is they distort the uterine cavity. This is the most common for submucosal fibroids or fibroids that have a component that's present inside the uterine cavity. Fibroids that are submucosal or intramural fibroids  are in the muscle of the uterus and have an intracavitary component. They're well-known to distort the uterine cavity and that can impact implantation of an embryo. There's also thought that it can impact an ongoing pregnancy.

There's speculation that uterine fibroids can impact the blood flow to a pregnancy as well and they may impact fertility. Depending on the size of the uterine fibroid, they may block the fallopian tubes. And so, if you have a uterine fibroid that's in the corner of the uterus, that could cause a tubal factor type of infertility where there's occlusion of the fallopian tube. But in general, the most concern we have for uterine fibroids is how those fibroids impact the uterine lining and implantation of an embryo, and it's thought that those are most likely due to submucosal fibroids, or some intramural fibroids that may be particularly large, or that have a component that's inside the cavity.

Q2. Several studies have attempted to clarify the influence of fibroids on fertility, however, there have been various, sometimes contradictory findings and a lack of well-designed trials. Why is this?

One of the challenges in counseling patients regarding uterine fibroids is that there's really a lack of  high-quality studies assessing uterine fibroids and fertility. And we all know that the gold standard research study is a randomized control trial, as they provide the highest level of evidence, but those are very difficult to conduct especially for women with uterine fibroids, as many women will decline randomization.

It's difficult to design a study where there's one treatment that can be beneficial versus no treatment. That's one challenge. Because of that, the study designs that we've had to date have mostly been retrospective, and there's been some observational studies. But even those studies, unfortunately, are complicated by the fact that fibroids themselves are very heterogeneous. It's a very heterogeneous condition. There's a lot of difference between the size of the uterine fibroids, the location and the bulk of the fibroid, and then there's also going to be the issue with age. If you have a woman who's older with uterine fibroids, obviously her age is also going to impact her fertility. We know that women with uterine fibroids tend to be older and that also impacts fertility. So that's going to have an impact on any research as well.

What we do know from some of the research to date is that it's well-known that submucosal fibroids impair fertility, that's well established. We do know that subserosal fibroids or the fibroids on the surface of the uterus do not impact uterine fibroids. The question that really hasn't been answered because there hasn't been adequate research and there's just not enough data of high quality is, whether intramural fibroids or fibroids inside the uterine muscle, whether they impact fertility.

Many women who have intramural uterine fibroids are asymptomatic. They don't have symptoms at all. So, the question is whether a woman should undergo an invasive procedure to remove that fibroid and if it’s going to help or not? That's one of the questions that we just don't have enough adequate research on because there are some limitations in the literature.

Q3. What are the current treatments, both surgical and nonsurgical, for patients with fibroids who may want to become pregnant?

I think if there's a patient, a woman with uterine fibroids who's interested in fertility, she may be a patient who is diagnosed with symptomatic fibroids, who wants to preserve her fertility, or she may be a patient who's an infertility patient who during her fertility evaluation discovers she has fibroids. It is important to determine whether treatment is appropriate for that patient, and as we just discussed, there's not a lot of answers in the literature for some patients. I think the most important thing to do first before deciding on a treatment is  to determine the best type of treatment. At Johns Hopkins, for many of our patients with uterine fibroids, they'll undergo a pelvic MRI because the pelvic MRI can provide the most detailed information regarding the size and exact location of the uterine fibroids.

We then have a multidisciplinary conference every two weeks where we review the MRIs with a group of minimally invasive surgeons, interventional radiologists, and fertility specialist where we can really decide the best treatment for the individual patient. In deciding on a patient, it's important to make the right decision and have the most information. So as far as treatments that are available, for women who are wanting to preserve their fertility or planning to get pregnant very soon, the most common options are going to be surgical.

The least invasive surgical treatment would be a hysteroscopic myomectomy where we would do a hysteroscopy and remove the uterine fibroids by either shaving the pieces of the submucosal fibroid or we can remove it with a hysteroscopic morcellator. There are various techniques. But for the submucosal fibroids that are inside the uterine cavity, hysteroscopic myomectomy is very minimally invasive. It's an outpatient procedure. It's very safe and it's something that we will typically offer to patients who have submucosal fibroids.

For patients who have symptomatic uterine fibroids and may have bulk symptoms, or have numerous uterine fibroids, we typically would recommend either a laparoscopic robotic-assisted myomectomy, sometimes just a laparoscopic myomectomy, or for women who have the most severe, a very large fibroid uterus, let's say greater than 20 centimeters, they may actually need to undergo an exploratory laparotomy or abdominal myomectomy. For patients who have symptomatic subserosal fibroids and large intramural fibroids that need to be removed, it really depends on the size, location, and bulk of the uterine fibroids. And that's where the pelvic MRI becomes very useful.

I would say that for the majority of my patients that have a large amount of fibroids, are still able to undergo a robotic-assisted laparoscopic hysterectomy which oftentimes can be an outpatient procedure just because we've had this improvement in technology with robotic and laparoscopic surgery. But surgery can be very beneficial as far as removing the bulk of the uterine fibroids. And so that is typically our treatments that we would recommend for those who want future fertility or who are imminently trying to get pregnant.

There are medical treatments as well or non-surgical treatments such as GnRH analogs that can shrink the size of the uterine fibroids. Unfortunately, the uterine fibroids are still there and typically will still impact fertility. So that's not something that we do often for those that are actively trying to get pregnant. The same for uterine artery embolization or uterine fibroids embolization. We will not recommend that for patients who want to have future fertility because the fibroids will still be in that location and they're typically in a location that's impairing fertility.

Q4. How long do patients have to wait after a fibroid treatment to try to get pregnant?

The length of time that a patient needs to wait after having fibroids removed for surgical treatment typically depends on the type of surgery the patient undergoes as well as the size of the fibroids and the extent of the surgery. For a patient who's undergoing a hysteroscopic myomectomy, they typically only must wait a month or two. Once they're assessed that there's no residual fibroid that's left, then they can try to conceive.

For patients who need to undergo abdominal myomectomy or laparoscopic myomectomy, those are much more extensive procedures. Typically, surgeons will recommend a patient wait three to six months to try to conceive. It's also important for the surgeon to discuss with the patient the extent of the myomectomy and whether that patient, when she does become pregnant, will require a c-section because typically if the uterine cavity is entered or if there are multiple incisions on the uterus during the myomectomy surgery, surgeons will recommend a c-section for that patient when she does become pregnant to decrease the risk of uterine rupture. And typically, that will be documented in the operative note, but the surgeon will also counsel the patient regarding this.

Q1: How do/can fibroids influence fertility?

When considering how uterine fibroids influence fertility, it's important to understand that uterine fibroids are very common. Uterine fibroids are the most common pelvic tumor in women, and they're non-cancerous tumors that are developed from the muscle cells of the uterus. The lifetime risk, before the age of 50, of a woman having fibroids varies by race and ethnicity, but in general, about 80% of Black women and 70% of Caucasian women will have at least one uterine fibroid diagnosed before the age of 50.

It's also important to understand when considering fertility that the prevalence of uterine fibroids increases as someone gets older. So uterine fibroids are much less common in younger women in their 20s as they are in women in their upper 30s and 40s. That's important to understand when looking at fertility because we also know that with age, fertility decreases. Thus, uterine fibroids also can impact fertility. There's also this age-related factor, which makes it difficult to really look at fibroids as far as being a causative agent for infertility.

We do know that approximately 10% of women with infertility will be diagnosed with uterine fibroids during their evaluation, and there's multiple ways that uterine fibroids impact fertility. In general, it's going to depend on the location of the uterine fibroids, the size and the bulk or the number of uterine fibroids that a woman has.  But when we look at the ways that uterine fibroids can impact fertility, what they can do is they distort the uterine cavity. This is the most common for submucosal fibroids or fibroids that have a component that's present inside the uterine cavity. Fibroids that are submucosal or intramural fibroids  are in the muscle of the uterus and have an intracavitary component. They're well-known to distort the uterine cavity and that can impact implantation of an embryo. There's also thought that it can impact an ongoing pregnancy.

There's speculation that uterine fibroids can impact the blood flow to a pregnancy as well and they may impact fertility. Depending on the size of the uterine fibroid, they may block the fallopian tubes. And so, if you have a uterine fibroid that's in the corner of the uterus, that could cause a tubal factor type of infertility where there's occlusion of the fallopian tube. But in general, the most concern we have for uterine fibroids is how those fibroids impact the uterine lining and implantation of an embryo, and it's thought that those are most likely due to submucosal fibroids, or some intramural fibroids that may be particularly large, or that have a component that's inside the cavity.

Q2. Several studies have attempted to clarify the influence of fibroids on fertility, however, there have been various, sometimes contradictory findings and a lack of well-designed trials. Why is this?

One of the challenges in counseling patients regarding uterine fibroids is that there's really a lack of  high-quality studies assessing uterine fibroids and fertility. And we all know that the gold standard research study is a randomized control trial, as they provide the highest level of evidence, but those are very difficult to conduct especially for women with uterine fibroids, as many women will decline randomization.

It's difficult to design a study where there's one treatment that can be beneficial versus no treatment. That's one challenge. Because of that, the study designs that we've had to date have mostly been retrospective, and there's been some observational studies. But even those studies, unfortunately, are complicated by the fact that fibroids themselves are very heterogeneous. It's a very heterogeneous condition. There's a lot of difference between the size of the uterine fibroids, the location and the bulk of the fibroid, and then there's also going to be the issue with age. If you have a woman who's older with uterine fibroids, obviously her age is also going to impact her fertility. We know that women with uterine fibroids tend to be older and that also impacts fertility. So that's going to have an impact on any research as well.

What we do know from some of the research to date is that it's well-known that submucosal fibroids impair fertility, that's well established. We do know that subserosal fibroids or the fibroids on the surface of the uterus do not impact uterine fibroids. The question that really hasn't been answered because there hasn't been adequate research and there's just not enough data of high quality is, whether intramural fibroids or fibroids inside the uterine muscle, whether they impact fertility.

Many women who have intramural uterine fibroids are asymptomatic. They don't have symptoms at all. So, the question is whether a woman should undergo an invasive procedure to remove that fibroid and if it’s going to help or not? That's one of the questions that we just don't have enough adequate research on because there are some limitations in the literature.

Q3. What are the current treatments, both surgical and nonsurgical, for patients with fibroids who may want to become pregnant?

I think if there's a patient, a woman with uterine fibroids who's interested in fertility, she may be a patient who is diagnosed with symptomatic fibroids, who wants to preserve her fertility, or she may be a patient who's an infertility patient who during her fertility evaluation discovers she has fibroids. It is important to determine whether treatment is appropriate for that patient, and as we just discussed, there's not a lot of answers in the literature for some patients. I think the most important thing to do first before deciding on a treatment is  to determine the best type of treatment. At Johns Hopkins, for many of our patients with uterine fibroids, they'll undergo a pelvic MRI because the pelvic MRI can provide the most detailed information regarding the size and exact location of the uterine fibroids.

We then have a multidisciplinary conference every two weeks where we review the MRIs with a group of minimally invasive surgeons, interventional radiologists, and fertility specialist where we can really decide the best treatment for the individual patient. In deciding on a patient, it's important to make the right decision and have the most information. So as far as treatments that are available, for women who are wanting to preserve their fertility or planning to get pregnant very soon, the most common options are going to be surgical.

The least invasive surgical treatment would be a hysteroscopic myomectomy where we would do a hysteroscopy and remove the uterine fibroids by either shaving the pieces of the submucosal fibroid or we can remove it with a hysteroscopic morcellator. There are various techniques. But for the submucosal fibroids that are inside the uterine cavity, hysteroscopic myomectomy is very minimally invasive. It's an outpatient procedure. It's very safe and it's something that we will typically offer to patients who have submucosal fibroids.

For patients who have symptomatic uterine fibroids and may have bulk symptoms, or have numerous uterine fibroids, we typically would recommend either a laparoscopic robotic-assisted myomectomy, sometimes just a laparoscopic myomectomy, or for women who have the most severe, a very large fibroid uterus, let's say greater than 20 centimeters, they may actually need to undergo an exploratory laparotomy or abdominal myomectomy. For patients who have symptomatic subserosal fibroids and large intramural fibroids that need to be removed, it really depends on the size, location, and bulk of the uterine fibroids. And that's where the pelvic MRI becomes very useful.

I would say that for the majority of my patients that have a large amount of fibroids, are still able to undergo a robotic-assisted laparoscopic hysterectomy which oftentimes can be an outpatient procedure just because we've had this improvement in technology with robotic and laparoscopic surgery. But surgery can be very beneficial as far as removing the bulk of the uterine fibroids. And so that is typically our treatments that we would recommend for those who want future fertility or who are imminently trying to get pregnant.

There are medical treatments as well or non-surgical treatments such as GnRH analogs that can shrink the size of the uterine fibroids. Unfortunately, the uterine fibroids are still there and typically will still impact fertility. So that's not something that we do often for those that are actively trying to get pregnant. The same for uterine artery embolization or uterine fibroids embolization. We will not recommend that for patients who want to have future fertility because the fibroids will still be in that location and they're typically in a location that's impairing fertility.

Q4. How long do patients have to wait after a fibroid treatment to try to get pregnant?

The length of time that a patient needs to wait after having fibroids removed for surgical treatment typically depends on the type of surgery the patient undergoes as well as the size of the fibroids and the extent of the surgery. For a patient who's undergoing a hysteroscopic myomectomy, they typically only must wait a month or two. Once they're assessed that there's no residual fibroid that's left, then they can try to conceive.

For patients who need to undergo abdominal myomectomy or laparoscopic myomectomy, those are much more extensive procedures. Typically, surgeons will recommend a patient wait three to six months to try to conceive. It's also important for the surgeon to discuss with the patient the extent of the myomectomy and whether that patient, when she does become pregnant, will require a c-section because typically if the uterine cavity is entered or if there are multiple incisions on the uterus during the myomectomy surgery, surgeons will recommend a c-section for that patient when she does become pregnant to decrease the risk of uterine rupture. And typically, that will be documented in the operative note, but the surgeon will also counsel the patient regarding this.

Loretta J. Colvin, APRN, ACNP-BC, is a Nurse Practitioner at Sleep Services, SSM Health Medical Group, specializing in the treatment of sleep disorders. Her focus is on insomnia, narcolepsy, obstructive sleep apnea, parasomnias, periodic leg movement disorder, restless leg syndrome, sleep disorders, snoring and telehealth.  

Q: As a nurse practitioner and a specialist at a clinic focused on identifying sleep related disorders, what do you feel is the overall value of such a clinic as a therapeutic need for patients?

Ms. Colvin: Well, for us in sleep, we've experienced a growth in our field, and anticipate further growth. We know that many people remain undiagnosed with their sleep disorders. So, we see our role as filling a need for the public in providing more personalized and specialized care for those that have a sleep problem.

Patients get to us via many routes, including self-referral or referral by their primary care provider or specialist.  We help these patients identify their sleep problems, guide them in testing and treatment decisions, and provide on-going treatment support.

Currently, there are two areas in which there is a particular need. With current stressors impacting our society, there is an increased need for patients to discuss their insomnia or sleep difficulty concerns with a healthcare provider.  We are seeing more patients bring up insomnia concerns to their primary care providers or coming directly to our sleep clinic for discussion of these concerns.   As the recognition of the importance of diagnosing and treatment sleep apnea continues to grow, we see more patients coming to us for care, including those with less obvious symptoms but high risk of sleep apnea due to their comorbid diseases.     

Q: Given current predictions that the outpatient health care structure will change and the number of APRNs and PAs will increase, what is your perspective on role and utilization of APPs, as well as the need to plan for the future care of patients with sleep disorders?

Ms. Colvin: First, let me talk about the national landscape with regards to structure. Nationally, the APP role and the number of professionals in that role is growing, so that's going to help meet some of the needs of our society for providing health care, whether it be primary care or specialty care, like I do, or acute care in the hospital. At present, there are a significant number of places where we fill a needed role but within the area of sleep, there is a likely to be an  increase in need for APPs as a result of attrition in the field as well as a shift in how many physicians are available to provide care in our ever-expanding specialty. What we then need to do is figure out how do we train these Providers in a specialty? This is not a specialty that is a large part of our basic education, so how do we train people into that specialty? And how do we prepare them for their role and ensure that we are offering opportunities to expand their capabilities over time?

An example of this can be seen with regards to the opportunities now being offered in telehealth in behavioral sleep medicine and in working with conditions like insomnia, or with people who have difficulty in trying to adjust to Continuous Positive Airway Pressure (CPAP) therapy and might need additional assistance and coaching.

Within my organization, physicians will refer patients directly to me who have struggled to use PAP in the past.  With specialized guidance, these past struggles can often be overcome thanks to improvements in our equipment and technology, patient knowledge and acceptance combined with personalized specialty care. I have had good success with helping patients who were not successful using PAP 10 or 20 years ago to become successful through guidance and coaching.  When we encounter anxiety or claustrophobia with PAP, we can incorporate behavioral sleep principles into the patient’s care to help them better acclimate to PAP therapy or consider alternative therapies.

Q: With more than 70 million US adults affected by sleep disorders and a growing number of clinicians and sleep practitioners gaining expertise in virtual models for diagnosis and treatments, what is your approach to using the telehealth to provide the same level of support, education, and therapy at home versus in the office?

Ms. Colvin: The pandemic definitely pushed us farther along in how we use telehealth. Before the pandemic, I was utilizing it in small increments, but there were some limits as a result of either regulation or reimbursement that caused it to not be included as a larger part of our program. However, now that we've experienced this shift with the pandemic, our health system has invested more in technology, and exposed more patients to the experience, I think telehealth and our usage of it will be different once we come out on the other side of this public health crisis. So, now we must decide, how are we going to use this mode as an alternative model of care?

I see two main focuses for us in sleep—expanding patient access and patient convenience. As technology improves, it will expand access for patients with less accessibility to technology and the internet, such as those in rural areas. And with smartphones becoming even more readily available and more capable of doing virtual care, we see potential to reach out and treat patients who we would otherwise not be able to offer treatment to.

Patient convenience is also very important. With virtual visits, we may be able to keep patients from having to leave work as they may be able to just ‘pop out’ at lunch, have a visit, and then go right back to work. Doing so also helps if patients have care giving responsibilities as they don't have to, for example, find a babysitter to come in for an office visit as they can make the necessary arrangements from home.

In lockstep with patient access and convenience, I am interested to see how telehealth, over time, manifests for patients with disabilities but we are already seeing the benefits of its application within this population.

I have a patient who is confined to a wheelchair so for this patient to get to a visit requires significant planning time to get into the van and be driven to the clinic by his caregiver, who has to schedule time off from work. So, it is not an easy process for this patient to come in and see me for a quick visit. With telehealth, this simple visit doesn’t have to be a whole- or half-day affair as it can be a quick check-in. If an in-person visit is warranted, we can always arrange that but usually we can accomplish what we need to on video and audio.

Another example is with those patients with hearing impairments. Depending on the impairment, certain patients may be able to use Bluetooth or audio enhancement with their hearing aids and can actually hear me better in a video environment than they can in the clinic; especially at this point in time as we are masked when in the office.

Q: In what ways do you think the telemedicine diagnosis process might be impacted post-pandemic?

Ms. Colvin: At-home sleep testing became available several years ago, but it has a limited role as it is specifically for the diagnosis of sleep apnea in the uncomplicated patient. Telehealth offers some convenience in enabling patients to be tested in their home and it is also more affordable for the patient and for insurance. In fact, this is seen as one of the disruptors in our field that will continue to expand in the appropriate patient populations. But we will always have to acknowledge that it won't serve all patient needs because our more complex patients still need to come in for in-person testing.

Q: Overall, in what ways do sleep professionals support the value of having a specialist care model versus a generalist PCP model to perform patient care within the US as well as other countries?

Ms. Colvin: From my view, I see that our PCPs are already stretched thin in their ability to provide easily accessible care and I think it would be difficult for them to also provide the specialty care that patients with sleep disorders need. Some of the less complex patients might be able to stay within a primary care environment but as technology, as well as the software training that is required to be able to communicate with the devices our patients use for treatment or for diagnosis, continues to become more complex, it can become difficult to manage through the primary care environment.

The question then goes back to, how can we be as accessible as possible in an underserved area or where the specialty clinic is not easy to access? I think this is where telehealth may give us new options for expanding access to patients who can use the technology that is available.

Loretta J. Colvin, APRN, ACNP-BC, is a Nurse Practitioner at Sleep Services, SSM Health Medical Group, specializing in the treatment of sleep disorders. Her focus is on insomnia, narcolepsy, obstructive sleep apnea, parasomnias, periodic leg movement disorder, restless leg syndrome, sleep disorders, snoring and telehealth.  

Q: As a nurse practitioner and a specialist at a clinic focused on identifying sleep related disorders, what do you feel is the overall value of such a clinic as a therapeutic need for patients?

Ms. Colvin: Well, for us in sleep, we've experienced a growth in our field, and anticipate further growth. We know that many people remain undiagnosed with their sleep disorders. So, we see our role as filling a need for the public in providing more personalized and specialized care for those that have a sleep problem.

Patients get to us via many routes, including self-referral or referral by their primary care provider or specialist.  We help these patients identify their sleep problems, guide them in testing and treatment decisions, and provide on-going treatment support.

Currently, there are two areas in which there is a particular need. With current stressors impacting our society, there is an increased need for patients to discuss their insomnia or sleep difficulty concerns with a healthcare provider.  We are seeing more patients bring up insomnia concerns to their primary care providers or coming directly to our sleep clinic for discussion of these concerns.   As the recognition of the importance of diagnosing and treatment sleep apnea continues to grow, we see more patients coming to us for care, including those with less obvious symptoms but high risk of sleep apnea due to their comorbid diseases.     

Q: Given current predictions that the outpatient health care structure will change and the number of APRNs and PAs will increase, what is your perspective on role and utilization of APPs, as well as the need to plan for the future care of patients with sleep disorders?

Ms. Colvin: First, let me talk about the national landscape with regards to structure. Nationally, the APP role and the number of professionals in that role is growing, so that's going to help meet some of the needs of our society for providing health care, whether it be primary care or specialty care, like I do, or acute care in the hospital. At present, there are a significant number of places where we fill a needed role but within the area of sleep, there is a likely to be an  increase in need for APPs as a result of attrition in the field as well as a shift in how many physicians are available to provide care in our ever-expanding specialty. What we then need to do is figure out how do we train these Providers in a specialty? This is not a specialty that is a large part of our basic education, so how do we train people into that specialty? And how do we prepare them for their role and ensure that we are offering opportunities to expand their capabilities over time?

An example of this can be seen with regards to the opportunities now being offered in telehealth in behavioral sleep medicine and in working with conditions like insomnia, or with people who have difficulty in trying to adjust to Continuous Positive Airway Pressure (CPAP) therapy and might need additional assistance and coaching.

Within my organization, physicians will refer patients directly to me who have struggled to use PAP in the past.  With specialized guidance, these past struggles can often be overcome thanks to improvements in our equipment and technology, patient knowledge and acceptance combined with personalized specialty care. I have had good success with helping patients who were not successful using PAP 10 or 20 years ago to become successful through guidance and coaching.  When we encounter anxiety or claustrophobia with PAP, we can incorporate behavioral sleep principles into the patient’s care to help them better acclimate to PAP therapy or consider alternative therapies.

Q: With more than 70 million US adults affected by sleep disorders and a growing number of clinicians and sleep practitioners gaining expertise in virtual models for diagnosis and treatments, what is your approach to using the telehealth to provide the same level of support, education, and therapy at home versus in the office?

Ms. Colvin: The pandemic definitely pushed us farther along in how we use telehealth. Before the pandemic, I was utilizing it in small increments, but there were some limits as a result of either regulation or reimbursement that caused it to not be included as a larger part of our program. However, now that we've experienced this shift with the pandemic, our health system has invested more in technology, and exposed more patients to the experience, I think telehealth and our usage of it will be different once we come out on the other side of this public health crisis. So, now we must decide, how are we going to use this mode as an alternative model of care?

I see two main focuses for us in sleep—expanding patient access and patient convenience. As technology improves, it will expand access for patients with less accessibility to technology and the internet, such as those in rural areas. And with smartphones becoming even more readily available and more capable of doing virtual care, we see potential to reach out and treat patients who we would otherwise not be able to offer treatment to.

Patient convenience is also very important. With virtual visits, we may be able to keep patients from having to leave work as they may be able to just ‘pop out’ at lunch, have a visit, and then go right back to work. Doing so also helps if patients have care giving responsibilities as they don't have to, for example, find a babysitter to come in for an office visit as they can make the necessary arrangements from home.

In lockstep with patient access and convenience, I am interested to see how telehealth, over time, manifests for patients with disabilities but we are already seeing the benefits of its application within this population.

I have a patient who is confined to a wheelchair so for this patient to get to a visit requires significant planning time to get into the van and be driven to the clinic by his caregiver, who has to schedule time off from work. So, it is not an easy process for this patient to come in and see me for a quick visit. With telehealth, this simple visit doesn’t have to be a whole- or half-day affair as it can be a quick check-in. If an in-person visit is warranted, we can always arrange that but usually we can accomplish what we need to on video and audio.

Another example is with those patients with hearing impairments. Depending on the impairment, certain patients may be able to use Bluetooth or audio enhancement with their hearing aids and can actually hear me better in a video environment than they can in the clinic; especially at this point in time as we are masked when in the office.

Q: In what ways do you think the telemedicine diagnosis process might be impacted post-pandemic?

Ms. Colvin: At-home sleep testing became available several years ago, but it has a limited role as it is specifically for the diagnosis of sleep apnea in the uncomplicated patient. Telehealth offers some convenience in enabling patients to be tested in their home and it is also more affordable for the patient and for insurance. In fact, this is seen as one of the disruptors in our field that will continue to expand in the appropriate patient populations. But we will always have to acknowledge that it won't serve all patient needs because our more complex patients still need to come in for in-person testing.

Q: Overall, in what ways do sleep professionals support the value of having a specialist care model versus a generalist PCP model to perform patient care within the US as well as other countries?

Ms. Colvin: From my view, I see that our PCPs are already stretched thin in their ability to provide easily accessible care and I think it would be difficult for them to also provide the specialty care that patients with sleep disorders need. Some of the less complex patients might be able to stay within a primary care environment but as technology, as well as the software training that is required to be able to communicate with the devices our patients use for treatment or for diagnosis, continues to become more complex, it can become difficult to manage through the primary care environment.

The question then goes back to, how can we be as accessible as possible in an underserved area or where the specialty clinic is not easy to access? I think this is where telehealth may give us new options for expanding access to patients who can use the technology that is available.

Loretta J. Colvin, APRN, ACNP-BC, is a Nurse Practitioner at Sleep Services, SSM Health Medical Group, specializing in the treatment of sleep disorders. Her focus is on insomnia, narcolepsy, obstructive sleep apnea, parasomnias, periodic leg movement disorder, restless leg syndrome, sleep disorders, snoring and telehealth.  

Q: As a nurse practitioner and a specialist at a clinic focused on identifying sleep related disorders, what do you feel is the overall value of such a clinic as a therapeutic need for patients?

Ms. Colvin: Well, for us in sleep, we've experienced a growth in our field, and anticipate further growth. We know that many people remain undiagnosed with their sleep disorders. So, we see our role as filling a need for the public in providing more personalized and specialized care for those that have a sleep problem.

Patients get to us via many routes, including self-referral or referral by their primary care provider or specialist.  We help these patients identify their sleep problems, guide them in testing and treatment decisions, and provide on-going treatment support.

Currently, there are two areas in which there is a particular need. With current stressors impacting our society, there is an increased need for patients to discuss their insomnia or sleep difficulty concerns with a healthcare provider.  We are seeing more patients bring up insomnia concerns to their primary care providers or coming directly to our sleep clinic for discussion of these concerns.   As the recognition of the importance of diagnosing and treatment sleep apnea continues to grow, we see more patients coming to us for care, including those with less obvious symptoms but high risk of sleep apnea due to their comorbid diseases.     

Q: Given current predictions that the outpatient health care structure will change and the number of APRNs and PAs will increase, what is your perspective on role and utilization of APPs, as well as the need to plan for the future care of patients with sleep disorders?

Ms. Colvin: First, let me talk about the national landscape with regards to structure. Nationally, the APP role and the number of professionals in that role is growing, so that's going to help meet some of the needs of our society for providing health care, whether it be primary care or specialty care, like I do, or acute care in the hospital. At present, there are a significant number of places where we fill a needed role but within the area of sleep, there is a likely to be an  increase in need for APPs as a result of attrition in the field as well as a shift in how many physicians are available to provide care in our ever-expanding specialty. What we then need to do is figure out how do we train these Providers in a specialty? This is not a specialty that is a large part of our basic education, so how do we train people into that specialty? And how do we prepare them for their role and ensure that we are offering opportunities to expand their capabilities over time?

An example of this can be seen with regards to the opportunities now being offered in telehealth in behavioral sleep medicine and in working with conditions like insomnia, or with people who have difficulty in trying to adjust to Continuous Positive Airway Pressure (CPAP) therapy and might need additional assistance and coaching.

Within my organization, physicians will refer patients directly to me who have struggled to use PAP in the past.  With specialized guidance, these past struggles can often be overcome thanks to improvements in our equipment and technology, patient knowledge and acceptance combined with personalized specialty care. I have had good success with helping patients who were not successful using PAP 10 or 20 years ago to become successful through guidance and coaching.  When we encounter anxiety or claustrophobia with PAP, we can incorporate behavioral sleep principles into the patient’s care to help them better acclimate to PAP therapy or consider alternative therapies.

Q: With more than 70 million US adults affected by sleep disorders and a growing number of clinicians and sleep practitioners gaining expertise in virtual models for diagnosis and treatments, what is your approach to using the telehealth to provide the same level of support, education, and therapy at home versus in the office?

Ms. Colvin: The pandemic definitely pushed us farther along in how we use telehealth. Before the pandemic, I was utilizing it in small increments, but there were some limits as a result of either regulation or reimbursement that caused it to not be included as a larger part of our program. However, now that we've experienced this shift with the pandemic, our health system has invested more in technology, and exposed more patients to the experience, I think telehealth and our usage of it will be different once we come out on the other side of this public health crisis. So, now we must decide, how are we going to use this mode as an alternative model of care?

I see two main focuses for us in sleep—expanding patient access and patient convenience. As technology improves, it will expand access for patients with less accessibility to technology and the internet, such as those in rural areas. And with smartphones becoming even more readily available and more capable of doing virtual care, we see potential to reach out and treat patients who we would otherwise not be able to offer treatment to.

Patient convenience is also very important. With virtual visits, we may be able to keep patients from having to leave work as they may be able to just ‘pop out’ at lunch, have a visit, and then go right back to work. Doing so also helps if patients have care giving responsibilities as they don't have to, for example, find a babysitter to come in for an office visit as they can make the necessary arrangements from home.

In lockstep with patient access and convenience, I am interested to see how telehealth, over time, manifests for patients with disabilities but we are already seeing the benefits of its application within this population.

I have a patient who is confined to a wheelchair so for this patient to get to a visit requires significant planning time to get into the van and be driven to the clinic by his caregiver, who has to schedule time off from work. So, it is not an easy process for this patient to come in and see me for a quick visit. With telehealth, this simple visit doesn’t have to be a whole- or half-day affair as it can be a quick check-in. If an in-person visit is warranted, we can always arrange that but usually we can accomplish what we need to on video and audio.

Another example is with those patients with hearing impairments. Depending on the impairment, certain patients may be able to use Bluetooth or audio enhancement with their hearing aids and can actually hear me better in a video environment than they can in the clinic; especially at this point in time as we are masked when in the office.

Q: In what ways do you think the telemedicine diagnosis process might be impacted post-pandemic?

Ms. Colvin: At-home sleep testing became available several years ago, but it has a limited role as it is specifically for the diagnosis of sleep apnea in the uncomplicated patient. Telehealth offers some convenience in enabling patients to be tested in their home and it is also more affordable for the patient and for insurance. In fact, this is seen as one of the disruptors in our field that will continue to expand in the appropriate patient populations. But we will always have to acknowledge that it won't serve all patient needs because our more complex patients still need to come in for in-person testing.

Q: Overall, in what ways do sleep professionals support the value of having a specialist care model versus a generalist PCP model to perform patient care within the US as well as other countries?

Ms. Colvin: From my view, I see that our PCPs are already stretched thin in their ability to provide easily accessible care and I think it would be difficult for them to also provide the specialty care that patients with sleep disorders need. Some of the less complex patients might be able to stay within a primary care environment but as technology, as well as the software training that is required to be able to communicate with the devices our patients use for treatment or for diagnosis, continues to become more complex, it can become difficult to manage through the primary care environment.

The question then goes back to, how can we be as accessible as possible in an underserved area or where the specialty clinic is not easy to access? I think this is where telehealth may give us new options for expanding access to patients who can use the technology that is available.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Anna Suk-Fong Lok, M.D., is assistant dean for clinical research, a post she has held since March 2016. She also is the Alice Lohrman Andrews Research Professor in Hepatology and director of clinical hepatology. Her research focuses on the natural history and treatment of hepatitis B and C, and the prevention of liver cancer.

Q: Are there any unique operative or preparation steps required for this type of transplant regarding the donor, recipient, or both? Walk us through any differences from standard transplant procedures.

Dr. Lok: There’s nothing special about the surgical operation itself other than the surgeon’s need to remember that the organs came from an HCV+ donor, so they should be a little bit more careful. This procedure should only be done within a protocol where the possibility of putting in an organ from an HCV+ to HCV- recipient is being discussed ahead of time and agreed to by both the transplant team within the institute, and with the potential recipients.

Currently, all donors in the U.S. are tested for hepatitis C antibody and also for hepatitis C RNA using what we call nucleic acid (NAT or PCR) test. It is important to differentiate between a donor who is anti-HCV+ but NAT negative, versus someone who is anti-HCV+ and NAT positive. Someone who is anti-HCV+ and NAT or PCR positive is capable of transmitting the infection, whereas someone who is anti-HCV+ but NAT or PCR negative, had a prior infection, is no longer infected, and is not going to transmit the infection.

It is important to have a discussion with the recipient ahead of time. The recipients will most likely be HCV-, so we are going to be giving them an infection, because we are transplanting an organ from an HCV-infected donor. It is best to have the discussion at the time of listing, with written consent, and rediscuss as the patients get closer to the top of the list.  It can be several years before they move to the top and receive a transplant. What was discussed and agreed on with the patient 2 or 3 years ago might be forgotten, and it is important to bring it up again as the patients get closer to their transplant date. In addition, we need to reverify the consent when it is time for the actual transplant. The surgery itself is similar, whether the donor is HCV+ or HCV-, but the transplant center needs to have a protocol ahead of time. There are several ways to minimize the impact on the recipient. How do we monitor for infection in the recipient? When do we start HCV direct-acting antiviral (DAA) therapy? Who is going to pay for it? What about insurance coverage? The answers to all these questions need to be in place.

During the early post-transplant period, doctors place patients on many different medications, which can cause interference with the DAAs, so we need to be cautious about potential drug-drug interactions. Some programs start in the first few days post-transplant, others start the day before transplant and continue through the transplant period, yet others start only after the patient is stable post-transplant, which can vary from a few days to a few weeks. Some patients are not ready to take oral medications right after the transplant because they just had a major operation. Debate continues over whether we can crush these pills and put them down a feeding tube. The manufacturers of these medications have not provided the data to show how well these drugs are absorbed when crushed. Still, limited data appear to suggest that some DAAs can be crushed and are effective when put down the feeding tube. 

Q: In addition to increasing the donor pool, what are other benefits of this manner of transplantation?

Dr. Lok: Some patients may be sick, going in and out of the hospital because of the underlying end-organ damage, and it is getting worse. The willingness to accept an HCV+ organ might mean that they can get transplanted sooner. There are also some data to suggest that HCV+ donors tend to be younger, with fewer comorbidities, and potentially the organ quality could be better.

Q: Do the risks and possible side effects outweigh the potential benefits of this type of transplantation?

Dr. Lok: Overall, the benefits outweigh the risk, in my opinion. There are several reasons: 1) it allows the recipient to have an earlier transplant. So, they do not have to continue to suffer from the end-organ damage; and 2) the success rate of HCV cure with the DAA drugs is very high. And we certainly know that even when we administer it post-transplant, most of the regimens have been 95% to 100% successful.

A wide range of regimens are currently in practice. Many transplant centers use the classical regimen of 8 to 12 weeks of treatment. We know that some transplant programs have shortened the duration of treatment to 4 weeks or even shorter. But some of the ultra-short regimens may be associated with a lower rate of success. And that is why it is important for people to really think through what protocols would be most cost-effective.

The key thing here is to really ensure success. We are introducing a new infection; many of us would consider even a drop from a success rate of 98% to 90% to be unacceptable. There are times when a success rate is lower because patients encounter complications after the transplant operation that results in interruption of treatment. This is one reason why, I think, that if the patients cannot take the pills by mouth, we should consider administering the medications through the feeding tube rather than stopping the treatment.

We certainly know that when we start, DAAs can affect the success rate. If we wait until the patient is truly stable post-transplant, and if the patient did have postoperative complications lasting more than a couple of weeks, the delay would be too long. There have been occasional reports of these patients suffering adverse consequences, including kidney injury related to HCV glomerulonephritis, or Fibrosing cholestatic hepatitis (FCH)—a severe and rapidly progressive form of liver damage.

Thus, it is very important to make sure that we start the treatment as soon as possible and that is why some of the programs have moved to starting one day before a patient has transplant surgery.

Another aspect that should be considered is that some of the HCV+ donors might have underlying liver disease. When HCV+ livers are being used, a liver biopsy should be performed to ensure there is no significant liver damage. This is, generally speaking, not a problem because many of the HCV+ donors are young and likely have been infected for a short period of time. The use ofHCV+ organs in HCV- recipients is relatively new. We know that the risk is short-term, but we do not know what the long-term risk is. The data we have so far extends to one-year post-transplant and shows no negative impact, but a longer follow-up is needed.

Q: How reluctant have insurance companies been to lower treatment barriers, such as cost and coverage approvals?

Dr. Lok: There were many concerns early on, but now this procedure has become more common. This is an accepted practice within the transplant community and has been endorsed by professional societies. We also know that the cost of the DAAs has been greatly reduced. And it is certainly shown to be cost-effective and cost-saving. If it allows us to get these patients transplanted sooner, if we can save one hospital admission because of cirrhosis complications prior to transplant, it is a win for the patient, who will save money as a result.

Q: This transplantation method started with kidneys. How have other organs fared such as liver, heart, and lungs?

Dr. Lok: Yes, this procedure started with the kidneys, but is now widely accepted for liver, lung, heart, pancreas, and even some of the combined transplants such as kidney and pancreas. The good news is that the success rate of the DAA is similar whether you had a kidney or heart transplant. The willingness to accept HCV+ organs in 2018 had increased by about 30% to 40% for all organs compared to 2015, except for intestines, but intestinal transplant is rare. So, the increase has occurred for all organs.

Deep endometriosis, including bowel endometriosis, happens in more than 10% of all women with endometriosis. Because it can be debilitating and difficult to diagnose, how is it identified?

Dr. Kho: Diagnosing deep infiltrating endometriosis (DIE) is one of the biggest challenges in the field. Currently, the gold standard is still histologic confirmation of endometriosis lesions, but I think the paradigm is shifting significantly. Advanced centers are now moving towards the use of imaging to visualize suspected endometriosis better. In skilled hands, ultrasonography and MRI can accurately detect DIE. The advantage of visualizing suspected deep endometriosis before surgery is that we can offer better counseling to patients and offer medical or surgical treatments or a combination of both. When the patient chooses surgery, we can be better prepared with a multidisciplinary team to remove the lesions completely.

The treatment of deep endometriosis can be challenging because it does not always respond to medical therapy, such as oral contraceptive pills or GnRH agonists. What treatment options have shown effectiveness?

Dr. Kho: It should be understood that we need to manage the symptoms and not the lesions. Just because there are endometriosis lesions identified does NOT mean that they need to be removed. The decision should be based on what the treatment goals are. A good discussion with the patient is important to determine what the treatment objectives are. Are we managing pain? Are we surgically treating infertility? Are we treating something else, such as bowel obstruction or blood in the urine? These questions and their answers should be first and foremost in the clinician’s mind.

Different medical treatment therapies are available and have been shown to be effective in managing endometriosis symptoms without having to immediately resort to surgery as with certain cases of suspected DIE. These medical management options include combined estrogen and progesterone contraceptive formulations, progesterone-only formulations, and GnRH agonists and antagonists. Patients should be counseled about the different options and their associated risks. Often, patients need to switch from one form to another when side effects encumber them. 

If imaging or an exam reveals incidental findings of suspected deep endometriosis, it does not mean that treatment is required because some patients can be without symptoms or have no issues. But when the indication for pain or desire to achieve a pregnancy is clear, and the decision is to proceed with treatment, there are some guidelines: 

• If the pain is severe and affects the patient’s daily quality of life, for example, with large, deep lesions, surgical excision appears to be effective in improving the patient’s quality of life. 
• If infertility is the main indication, then other factors need to be considered. Has she had previous surgeries? What is her age? What is her ovarian reserve? What is the condition of the tubes? Is the use of artificial reproductive technology, or ART, an option for the couple? What is her cancer risk? 
• Lastly, what is the extent of the lesion(s)? Both medical and surgical approaches for treatment carry risks. For surgery, complications can be severe with long-term consequences. Therefore, it is important to discuss all of this in detail with the patient. 

When we understand what the main goal of the treatment is for endometriosis—such as either to treat pain or to achieve pregnancy, or both—we can tailor our surgical approach to achieve the goal(s). For example, in a patient who wants to achieve a pregnancy in the future, we may opt to do only what is necessary to remove endometriosis and relieve pain without impairing the patient’s fertility potential and overall quality of life.   

Post-operatively, if the patient does not desire to become pregnant, medications to suppress the ovaries are an option to reduce the chance of disease recurrence.  

What pearls can you provide when it comes to surgical techniques available and benefits for short- and long-term risks and limitations?

Dr. Kho: The surgeon should tailor his or her level of radicality to excise endometriosis to achieve the treatment goals that are mutually agreed on with the patient. For the surgeon bringing the patient into surgery, go in prepared. I strongly believe in preoperative imaging to provide the best mapping of the disease and in having other specialists or surgeons available—whether it be a urologist, a colorectal surgeon, a thoracic surgeon, a vascular surgeon, or an orthopedic surgeon (if needed)—depending on where the lesions are located.  

Because we know that the best surgical outcomes come from surgeons with the highest volume, providers should be willing to refer patients with advanced disease to centers that specialize in the treatment of endometriosis. Many providers with this expertise undergo additional training to advance their skills. Advanced centers in endometriosis also provide patients with a multidisciplinary team to provide the best care.  

What is the most optimal setup for a multidisciplinary team treating deep infiltrating endometriosis?

Dr. Kho: You will find that advanced centers for endometriosis will have in place a multidisciplinary team that includes a pain specialist, a surgical specialist, a pain psychologist, physical therapy, urologist, colorectal surgeon, and other sub-specialty surgeons to be able to look at the patients from all the different aspects. Often a reproductive endocrinologist or REI specialist would also be part of the group. 

At our center, we have what we call a “benign tumor board,” where we discuss complex cases with representatives from different areas. This allows us to discuss the case, review what is known in the literature, and collectively develop a treatment plan.

Is there anything that was not covered in this discussion that you would like to mention?

Dr. Kho: Something that should be mentioned is that ovarian endometriosis is often associated with advanced endometriosis, often Stage 3 or 4. Clinicians should be aware that when imaging suggests the presence of ovarian endometriosis, studies show that the disease is isolated in the ovary in only 15% of cases—meaning that there is an 85% chance that endometriosis is present elsewhere in the pelvis. Therefore, the surgeon should be prepared for more extensive dissection when they bring the patient into surgery.

Deep endometriosis, including bowel endometriosis, happens in more than 10% of all women with endometriosis. Because it can be debilitating and difficult to diagnose, how is it identified?

Dr. Kho: Diagnosing deep infiltrating endometriosis (DIE) is one of the biggest challenges in the field. Currently, the gold standard is still histologic confirmation of endometriosis lesions, but I think the paradigm is shifting significantly. Advanced centers are now moving towards the use of imaging to visualize suspected endometriosis better. In skilled hands, ultrasonography and MRI can accurately detect DIE. The advantage of visualizing suspected deep endometriosis before surgery is that we can offer better counseling to patients and offer medical or surgical treatments or a combination of both. When the patient chooses surgery, we can be better prepared with a multidisciplinary team to remove the lesions completely.

The treatment of deep endometriosis can be challenging because it does not always respond to medical therapy, such as oral contraceptive pills or GnRH agonists. What treatment options have shown effectiveness?

Dr. Kho: It should be understood that we need to manage the symptoms and not the lesions. Just because there are endometriosis lesions identified does NOT mean that they need to be removed. The decision should be based on what the treatment goals are. A good discussion with the patient is important to determine what the treatment objectives are. Are we managing pain? Are we surgically treating infertility? Are we treating something else, such as bowel obstruction or blood in the urine? These questions and their answers should be first and foremost in the clinician’s mind.

Different medical treatment therapies are available and have been shown to be effective in managing endometriosis symptoms without having to immediately resort to surgery as with certain cases of suspected DIE. These medical management options include combined estrogen and progesterone contraceptive formulations, progesterone-only formulations, and GnRH agonists and antagonists. Patients should be counseled about the different options and their associated risks. Often, patients need to switch from one form to another when side effects encumber them. 

If imaging or an exam reveals incidental findings of suspected deep endometriosis, it does not mean that treatment is required because some patients can be without symptoms or have no issues. But when the indication for pain or desire to achieve a pregnancy is clear, and the decision is to proceed with treatment, there are some guidelines: 

• If the pain is severe and affects the patient’s daily quality of life, for example, with large, deep lesions, surgical excision appears to be effective in improving the patient’s quality of life. 
• If infertility is the main indication, then other factors need to be considered. Has she had previous surgeries? What is her age? What is her ovarian reserve? What is the condition of the tubes? Is the use of artificial reproductive technology, or ART, an option for the couple? What is her cancer risk? 
• Lastly, what is the extent of the lesion(s)? Both medical and surgical approaches for treatment carry risks. For surgery, complications can be severe with long-term consequences. Therefore, it is important to discuss all of this in detail with the patient. 

When we understand what the main goal of the treatment is for endometriosis—such as either to treat pain or to achieve pregnancy, or both—we can tailor our surgical approach to achieve the goal(s). For example, in a patient who wants to achieve a pregnancy in the future, we may opt to do only what is necessary to remove endometriosis and relieve pain without impairing the patient’s fertility potential and overall quality of life.   

Post-operatively, if the patient does not desire to become pregnant, medications to suppress the ovaries are an option to reduce the chance of disease recurrence.  

What pearls can you provide when it comes to surgical techniques available and benefits for short- and long-term risks and limitations?

Dr. Kho: The surgeon should tailor his or her level of radicality to excise endometriosis to achieve the treatment goals that are mutually agreed on with the patient. For the surgeon bringing the patient into surgery, go in prepared. I strongly believe in preoperative imaging to provide the best mapping of the disease and in having other specialists or surgeons available—whether it be a urologist, a colorectal surgeon, a thoracic surgeon, a vascular surgeon, or an orthopedic surgeon (if needed)—depending on where the lesions are located.  

Because we know that the best surgical outcomes come from surgeons with the highest volume, providers should be willing to refer patients with advanced disease to centers that specialize in the treatment of endometriosis. Many providers with this expertise undergo additional training to advance their skills. Advanced centers in endometriosis also provide patients with a multidisciplinary team to provide the best care.  

What is the most optimal setup for a multidisciplinary team treating deep infiltrating endometriosis?

Dr. Kho: You will find that advanced centers for endometriosis will have in place a multidisciplinary team that includes a pain specialist, a surgical specialist, a pain psychologist, physical therapy, urologist, colorectal surgeon, and other sub-specialty surgeons to be able to look at the patients from all the different aspects. Often a reproductive endocrinologist or REI specialist would also be part of the group. 

At our center, we have what we call a “benign tumor board,” where we discuss complex cases with representatives from different areas. This allows us to discuss the case, review what is known in the literature, and collectively develop a treatment plan.

Is there anything that was not covered in this discussion that you would like to mention?

Dr. Kho: Something that should be mentioned is that ovarian endometriosis is often associated with advanced endometriosis, often Stage 3 or 4. Clinicians should be aware that when imaging suggests the presence of ovarian endometriosis, studies show that the disease is isolated in the ovary in only 15% of cases—meaning that there is an 85% chance that endometriosis is present elsewhere in the pelvis. Therefore, the surgeon should be prepared for more extensive dissection when they bring the patient into surgery.

Deep endometriosis, including bowel endometriosis, happens in more than 10% of all women with endometriosis. Because it can be debilitating and difficult to diagnose, how is it identified?

Dr. Kho: Diagnosing deep infiltrating endometriosis (DIE) is one of the biggest challenges in the field. Currently, the gold standard is still histologic confirmation of endometriosis lesions, but I think the paradigm is shifting significantly. Advanced centers are now moving towards the use of imaging to visualize suspected endometriosis better. In skilled hands, ultrasonography and MRI can accurately detect DIE. The advantage of visualizing suspected deep endometriosis before surgery is that we can offer better counseling to patients and offer medical or surgical treatments or a combination of both. When the patient chooses surgery, we can be better prepared with a multidisciplinary team to remove the lesions completely.

The treatment of deep endometriosis can be challenging because it does not always respond to medical therapy, such as oral contraceptive pills or GnRH agonists. What treatment options have shown effectiveness?

Dr. Kho: It should be understood that we need to manage the symptoms and not the lesions. Just because there are endometriosis lesions identified does NOT mean that they need to be removed. The decision should be based on what the treatment goals are. A good discussion with the patient is important to determine what the treatment objectives are. Are we managing pain? Are we surgically treating infertility? Are we treating something else, such as bowel obstruction or blood in the urine? These questions and their answers should be first and foremost in the clinician’s mind.

Different medical treatment therapies are available and have been shown to be effective in managing endometriosis symptoms without having to immediately resort to surgery as with certain cases of suspected DIE. These medical management options include combined estrogen and progesterone contraceptive formulations, progesterone-only formulations, and GnRH agonists and antagonists. Patients should be counseled about the different options and their associated risks. Often, patients need to switch from one form to another when side effects encumber them. 

If imaging or an exam reveals incidental findings of suspected deep endometriosis, it does not mean that treatment is required because some patients can be without symptoms or have no issues. But when the indication for pain or desire to achieve a pregnancy is clear, and the decision is to proceed with treatment, there are some guidelines: 

• If the pain is severe and affects the patient’s daily quality of life, for example, with large, deep lesions, surgical excision appears to be effective in improving the patient’s quality of life. 
• If infertility is the main indication, then other factors need to be considered. Has she had previous surgeries? What is her age? What is her ovarian reserve? What is the condition of the tubes? Is the use of artificial reproductive technology, or ART, an option for the couple? What is her cancer risk? 
• Lastly, what is the extent of the lesion(s)? Both medical and surgical approaches for treatment carry risks. For surgery, complications can be severe with long-term consequences. Therefore, it is important to discuss all of this in detail with the patient. 

When we understand what the main goal of the treatment is for endometriosis—such as either to treat pain or to achieve pregnancy, or both—we can tailor our surgical approach to achieve the goal(s). For example, in a patient who wants to achieve a pregnancy in the future, we may opt to do only what is necessary to remove endometriosis and relieve pain without impairing the patient’s fertility potential and overall quality of life.   

Post-operatively, if the patient does not desire to become pregnant, medications to suppress the ovaries are an option to reduce the chance of disease recurrence.  

What pearls can you provide when it comes to surgical techniques available and benefits for short- and long-term risks and limitations?

Dr. Kho: The surgeon should tailor his or her level of radicality to excise endometriosis to achieve the treatment goals that are mutually agreed on with the patient. For the surgeon bringing the patient into surgery, go in prepared. I strongly believe in preoperative imaging to provide the best mapping of the disease and in having other specialists or surgeons available—whether it be a urologist, a colorectal surgeon, a thoracic surgeon, a vascular surgeon, or an orthopedic surgeon (if needed)—depending on where the lesions are located.  

Because we know that the best surgical outcomes come from surgeons with the highest volume, providers should be willing to refer patients with advanced disease to centers that specialize in the treatment of endometriosis. Many providers with this expertise undergo additional training to advance their skills. Advanced centers in endometriosis also provide patients with a multidisciplinary team to provide the best care.  

What is the most optimal setup for a multidisciplinary team treating deep infiltrating endometriosis?

Dr. Kho: You will find that advanced centers for endometriosis will have in place a multidisciplinary team that includes a pain specialist, a surgical specialist, a pain psychologist, physical therapy, urologist, colorectal surgeon, and other sub-specialty surgeons to be able to look at the patients from all the different aspects. Often a reproductive endocrinologist or REI specialist would also be part of the group. 

At our center, we have what we call a “benign tumor board,” where we discuss complex cases with representatives from different areas. This allows us to discuss the case, review what is known in the literature, and collectively develop a treatment plan.

Is there anything that was not covered in this discussion that you would like to mention?

Dr. Kho: Something that should be mentioned is that ovarian endometriosis is often associated with advanced endometriosis, often Stage 3 or 4. Clinicians should be aware that when imaging suggests the presence of ovarian endometriosis, studies show that the disease is isolated in the ovary in only 15% of cases—meaning that there is an 85% chance that endometriosis is present elsewhere in the pelvis. Therefore, the surgeon should be prepared for more extensive dissection when they bring the patient into surgery.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Joseph K. Lim, MD, is the Director of Clinical Hepatology and Professor of Medicine in the Department of Medicine, Section of Digestive Diseases, Yale Liver Center, at the Yale University School of Medicine in New Haven, Connecticut. Dr. Lim's primary clinical and research interests are focused on viral hepatitis and non-alcoholic steatohepatitis.

What are some of the reasons for first line direct-acting antiviral (DAA) regimen failures in hepatitis C virus (HCV)?

Dr. Lim: In clinical practice, approximately 5% to 10% of patients will fail to achieve sustained virologic response (SVR). The most common reason is incompletion of treatment as a result of non-adherence, intolerance, adverse effects, or other medical/logistical factors that interfere with treatment. Another reason is reinfection, in which an individual who achieves viral eradication is re-exposed to HCV and develops a new infection. Each scenario warrants a careful evaluation to help identify which factors contributed to treatment failure.

Regarding incomplete treatment, it is important to identify other issues that require attention before considering retreatment. If there are other potential medications with potential drug-drug interaction (DDI) which influence the absorption of the DAA medications, that is important to identify (e.g. proton pump inhibitors).
 

Finally, if there are other non-medical reasons—psychosocial reasons, substance use reasons, or psychiatric reasons—that may prevent a patient from completing a full treatment course, it is important to identify and manage these before reconsidering DAA therapy.

What is the current standard of care for patients who failed a first line DAA regimen?

Dr. Lim: Fewer than 5% to 10% of patients treated with a first-line regimen fail to achieve a sustained virologic response (SVR). A significant proportion may develop resistance-associated substitutions (RASs) which may affect susceptibility to other DAA regimens, but fortunately, multiple studies have confirmed that retreatment of these patients with a contemporary DAA treatment regimen is associated with similarly high rates of SVR exceeding 90%.
 

The current guidelines by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) suggest retreating these patients with a triple combination regimen of sofosbuvir, velpatasvir, plus voxilaprevir (also known as SOF/VEL/VOX) or glecaprevir plus pibrentasvir (GP).

Both are viable options for those who fail first line regimens, but with important nuances: 1) for patients who are genotype 1, either of these options is considered a valid regimen strategy; 2) for patients with genotype 2 through 6, the SOF/VEL/VOX combination is recommended; 3) for patients who have signature mutations for either the protease or the nonstructural protein 5A (NS5A), an individualized approach is needed to determine which strategy will be most efficacious; 4) for patients who have cirrhosis, and particularly those with decompensated cirrhosis, protease inhibitor-based combinations are contraindicated because of the risk of liver toxicity and/or hepatic decompensation, which is associated with an FDA black box warning.

Treatment of the very small number of patients who fail the second-line regimen with either GP or SOF/VEL/VOXis an area of significant controversy, and for which the evidence-based guidance in 2021 is quite limited. However, the AASLD and the IDSA recommend 2 potential regimens, including SOF/VEL/VOX plus weight-based ribavirin for 24 weeks, or sofosbuvir plus GP plus weight-based ribavirin for 16 weeks.

Why can it be difficult to differentiate true virological failure from relapse caused by non-adherence or from reinfection?

Dr. Lim: When I speak with patients who have failed DAAs, the majority state that they took every single pill. And although that leaves us in a conundrum where we cannot chalk it up to possible non-adherence, we do wish to determine whether the timing of when they took the medications was consistent.

We ask about whether there are other medications that may interact with these medications. Before we start treatment, we work with a pharmacist and online drug interaction websites to make sure that we do our best to avoid other medications that may interact with DAAs and impact the chance of achieving sustained virologic response (SVR). Despite those efforts, on occasion, patients report that they forgot they were taking a drug or supplement that could interfere with DAA absorption.

Lastly, in patients who offered no history of taking other medications and a report of 100% adherence, we make a presumption that this is probably true virological failure with development of virologic resistance. In 2021, AASLD/IDSA guidelines do not routinely recommend resistance testing for all patients who fail a first-line regimen because it frequently does not influence our decision on retreatment and may not always impact susceptibility to SOF/VEL/VOX or GP. However, in patients who have a history of multiple lines of treatment failure, some of whom have failed 4 or more previous treatment regimens, I do perform resistance testing on an individualized basis to inform our retreatment strategy.

With regards to the question about reinfection, there is no routine way this is assessed in clinical practice. From a public health perspective, we can perform phylogenetic testing, which can help distinguish the very specific viral strains to connect individuals in terms of the root of the infection. But in clinical practice, we do not use phylogenetic testing because if a patient’s initial genotype was genotype 1 and then they get reinfected, and their genotype was genotype 3, you do not need any special testing. At that point you know it is a different virus than what you initially had, and so that is the easiest way to make a distinction. If they have a different genotype of HCV the second time around, we generally will conclude that it represents reinfection rather than virologic relapse, although conversely, the discovery of the same genotype does not exclude reinfection.

Ninety-five percent of individuals treated with DAA agents are cured of HCV infection. Of the 5% who failed first line DAA regimens, what are their options and chances for being cured?

Dr. Lim: Again, retreatment with either SOF/VEL/VOX or GP is associated with a very high rate of SVR. Specifically, for SOF/VEL/VOX, there are two phase 3 clinical trials. One is POLARIS-1 for genotypes 1 through 6 and the other is POLARIS-4 for those with genotype 1 through 4. In both of those clinical trials, they reported a 96% to 97% chance of achieving SVR.^{1, 2}  For GP, the MAGELLAN-1 protocol looked at patients, specifically genotype 1, and found that GP was associated with a 96% chance of SVR.³ As such, there is robust prospective RCT evidence validating the safety and efficacy of both SOF/VEL/VOX and GP for patients who fail first line DAA regimens.

How do people with HIV and persons who use drugs factor into DAA failures, and how does it affect them? How can their unique needs be met, and what special considerations can be made for them going forward?

Dr. Lim: Historically, HIV was viewed within our community as a “special population.” And the reason why was that with some older regimens, including those requiring pegylated interferon, the chance of achieving SVR was about 20% lower than those who had HCV monoinfection. But with our contemporary DAA regimens, that differential has washed away. The expected sustained virologic response rates of those with HCV alone or with coinfection of HIV is identical, around 95%. However, from a reinfection perspective, the available data suggests no difference in rates of virologic relapse or virologic failure or treatment failure or the risk of reinfection in HIV coinfected individuals. However, patients with HIV are taking antiretroviral therapy (ART) regimens that are associated with potential DDIs, which require special attention. On occasion, modification of the ART is needed to permit safe administration of HCV DAAs. In contrast, persons who inject drugs (PWID) remain a special population because of unique challenges and considerations required in the decision of who to treat, when to treat, and how to treat.

In terms of who to treat, there has been a paradigm shift. In the past, we would want to delay treatment until patients were drug-free for 6 months or greater. Many of our current insurance policies still mandate that patients be confirmed to be drug-free for a required amount of time before they will authorize the drug's release from the pharmacy. But at this time, that paradigm has shifted to where we, as a liver community, view HCV treatment as prevention. The concept is that within injection drug communities, if we can treat and eradicate HCV in super users of injection drugs, not only does it benefit that individual patient, but it may also benefit their community of injection drug users and prevent spread to others.

It is a high priority in 2021 that clinicians within the GI, liver, and infectious disease communities are willing to treat patients who are actively injecting drugs or in the process of going through relapse prevention, and/or rehabilitation. We must accept that persons who inject drugs may experience relapse to substance use which may be associated with HCV reinfection rates as high as 10% to 15% of cases. While these numbers are significant in my view, from a public health perspective and a clinical perspective, this should not dissuade clinicians from considering an individualized approach to offering DAA therapy to all patients, including those who are PWID.

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

Can you provide some background on endometriosis and the importance of early diagnosis?

Dr. Goldstein: Endometriosis is an inflammatory condition, characterized by endometrial tissue at sites outside the uterus—this definition comes from the World Endometriosis Society.

Endometriosis is said to affect about 10% of women of reproductive age, and if you look at a group, a subset of women with pelvic pain or infertility, the numbers rise to the range of 35% to 50%. It can present in a multitude of locations, mainly in the pelvis, although occasionally even in places like the lung. When it occurs in the uterus, it is known as adenomyosis; when it occurs inside the ovary, it can cause an endometrioma (or what is sometimes referred to as chocolate cyst of the ovary), but you can see endometriotic implants anywhere in the peritoneum—along the urinary tract, rectum, uterosacral ligaments, rectovaginal septum, and even the vaginal wall occasionally.

What I am really interested in is an earlier diagnosis of superficial endometriosis, and it should be apparent to the reader why this is important—the quality of life from pain from endometriosis can be debilitating. It can be a source of infertility, a source of menstrual irregularities, and a source of not only quality of life but also economic consequences. Many women can also undergo as much as a 7-year delay in diagnosis, so the need for a timely diagnosis and initiation of treatment is extremely important.

What is the role of ultrasound in endometriosis diagnostics?

Dr. Goldstein: In an article that I authored 31 years ago, I wrote that there was a difference between an ultrasound examination by referral and examining one’s patients with ultrasound. I coined a phrase: the “ultrasound-enhanced bimanual exam.” I believed that this term should become a routine part of the overall gynecologic exam. I wanted people to think about the bimanual that we had done for at least half a century, which, in my opinion, consists of 2 components:

1. An objective component: Is this uterus normal? Is it enlarged or irregular in contour, suggesting maybe fibroids? Is an ovary enlarged? If so, does it feel cystic or solid?
2. A subjective component: Does this patient have tenderness through the pelvis. Is there normal mobility of the pelvic organs?

Part of the thesis was that the objective portion could be replaced by an image that could be produced in seconds, dependent on the operator’s training and availability of equipment. The subjective portion, however, depended on the experience and, often, nuance of the examiner. Lately, I have been seeking to expand that thesis by having the imager use examination as part of their overall imaging—this is the concept of dynamic imaging.

Can you expand on the concept of dynamic ultrasound in this setting?

Dr. Goldstein: Presently, most imagers take a multitude of pictures, what I would call 2-dimensional snapshots, to illustrate anatomy. This is usually done by a sonographer, or a technician, who collects the images for viewing by the physician, who then often does so without holding the transducer. Increasing utilization of remote tools like teleradiology only makes this more likely, and for a minority of people who may use video clips instead of still images, they are still simply representations of anatomy. The guidelines for pelvic ultrasound are the underpinning of the expectation of those who are scanning the female pelvis. With dynamic imaging, the operator uses their other hand on the abdomen as well as some motion with the probe to see if they can elicit pain with the vaginal probe, checking for mobility, asking the patient to bear down. Whether you are a sonographer, a radiologist, or an ObGyn, dynamic imaging can bring the examination process into the imager’s hands.

Can you tell us more about the indications for pelvic sonography for endometriosis and what data can you give to support this?

Dr. Goldstein: There is a document titled “Ultrasound Examination of the Female Pelvis,” that was originally developed by the American Institute of Ultrasound in Medicine (AIUM). In this document, there are about 19 different indications for pelvic sonography (in no defined order), and it is interesting that the first indication listed is evaluation of pelvic pain. Well, I would ask you, how do you evaluate pelvic pain with a series of anatomic images? If you have a classic ovarian endometrioma, or you have a classic hydrosalpinx, you can surmise that these are the source of the pain that the patient is reporting. But how do you properly evaluate pain with just an anatomic image? Thus, the need to use dynamic assessment.

There was a concept first introduced by my colleague, Dr. Ilan Timor, known as the sliding organ sign, that was mainly used to determine if 2 structures were adherent or separate. This involved use of the abdominal hand, liberal use of the probe moving in and out, and under real-time vision, examining the patient with the ultrasound transducer; this is the concept of dynamic ultrasound. This practice can be expanded to verify if there is pelvic tenderness and can be a significant part of the nonlaparoscopic, presumptive diagnosis of endometriosis, even when there is no ovarian endometrioma.

To support this theory, I would point you toward a classic article by E Okaro and colleagues in the British Journal of OB-GYN. This study took 120 consecutive women with chronic pelvic pain who were scheduled for laparoscopy, but performed a transvaginal ultrasound prior, and they looked for anatomic abnormalities and divided this into hard markers and soft markers. Hard markers were obvious endometriomas and hydrosalpinges, while soft markers included things like reduced ovarian mobility, site-specific pelvic tenderness, and presence of loculated peritoneal fluid in the pelvis. These were typical of chronic pelvic pain patients that ranged from late teens to almost menopausal, as the average age was about 30 years old.

Patients had experienced pain for anywhere from 6 months to 12 years, but the average was about 4 years. At laparoscopy, 58% of these patients had pelvic pathology, and 42% had a normal pelvis. Of the 58% with pathology, the overwhelming majority—about 51 of 70 women—had endometriosis alone, and another 7 had endometriosis with adhesions. A normal ultrasound, based on the absence of hard markers, was found in 96 of 120 women. Thus, 24 of the 120 women had an abnormal scan based on the presence of these hard markers. At laparoscopy, all 24 women had abnormal laparoscopies. Of those 96 women who would have had a normal ultrasound, based on the anatomic absence of some pathology, 53% had an abnormal scan based on the presence of these soft markers while the remaining women had no soft- or hard-markers suggesting any pelvic pathology. At laparoscopy, 73% of the patients with soft markers had pelvic pathology and 27% had a normal laparoscopy. Of 45 patients who had a normal, transvaginal ultrasound, 9 were found to have small evidence of endometriosis without discrete endometriomas at laparoscopy.

To summarize the study data, 100% of patients with hard markers and chronic pelvic pain had abnormal anatomy at laparoscopy, but 73% of patients who had soft markers but otherwise would have been interpreted as normal anatomic findings had evidence of pelvic pathology. Such an approach, if used, could lead to a reduction in the number of unnecessary laparoscopies.

What it really boils down to is, if you have 100 women with chronic pelvic pain, are you willing to treat 100 patients without laparoscopy, knowing that 73 are going to have a positive laparoscopy and will require treatment anyway? You would treat 27% with a pharmaceutical agent that may provide relief of their pain, or may not, depending on what the true etiology was. I would be willing to do so, as a positive predictive value of 73% makes doing that worthwhile, and I believe a majority of clinicians would agree.

Do you have any other tips or ways to improve the reader’s understanding of transvaginal ultrasound?

Dr. Goldstein: Pelvic organs have mobility. If a premenopausal woman is examined in lithotomy position, if the ovaries are freely mobile, by gravity, they are going to go lateral to the uterus and are seen immediately adjacent to the iliac vessels. But remember, iliac vessels are retroperitoneal as they are outside the peritoneal cavity. If you were to turn that patient onto all fours, so that the ovaries are freely mobile, they are going to move somewhat toward the anterior abdominal wall. When an ovary is seen in a nonanatomic position, it could be normal or it could be held up by a loop of bowel, but it may indicate adhesions. This is where this sliding organ sign and liberal use of the other hand on the lower abdomen can be extremely important. The reader should also understand that our ability to localize ovaries on ultrasound depends on the amount of folliculogenesis. Follicles are black circles that are sonolucent, because they contain fluid, so they make it easy to localize ovaries, but also their anatomic position relative to the iliac vessels. However, there is a caveat—which is, sometimes an ovary might look like it is behind the uterus and not in its normal anatomic location. When dynamic imaging is used, you are able to cajole that ovary to move lateral and sit on top of the iliac vessels, which can enable you make the proper diagnosis.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

What is the incidence of endometriosis in women, and does the condition affect certain patient populations more often than others?

Dr. Taylor: Endometriosis occurs in about 5% to 10% of reproductive-aged women, and it is underdiagnosed. Many women have subtle endometriosis or asymptomatic endometriosis that may be missed or may take a long time to diagnose, and the incidence may be somewhat higher. It is much more common in women with pelvic pain, as these women have a greater than 50% incidence of endometriosis, and those with infertility similarly have roughly a 50% incidence of endometriosis. Endometriosis is a very common disease, most common in the reproductive age range, particularly more common in the most fertile years. The typical course of the disease is that it begins in teenagers or in the early 20s, progresses through the 20s and 30s, but starts to wane in the 40s, and goes away at the time of menopause in the early 50s. Those particularly susceptible to the disease are those with early menarche or frequent or heavy periods. Recurrent periods lead to more retrograde menstruation, which is menstrual flow through the fallopian tubes. It then starts to implant in the abdomen, specifically in the peritoneal cavity.

What are some of the reasons for missed or delayed diagnosis?

Dr. Taylor: There are many reasons why diagnosis may be missed or delayed. One of the most common reasons for delayed diagnosis is that the patient does not know that painful periods are not normal and may not report them to her clinician. Dysmenorrhea, or menstrual pain, is the only pain that we consider normal. It is the only experience we go through that is expected to hurt. It is also a very subjective issue. How do you know if your menstrual cramps are worse than someone else’s? Often, the first thing that happens when someone complains about severe dysmenorrhea is that their friends or family members will say to them, “We all get menstrual cramps. Just toughen up and bear with it.” But, of course, sometimes these menstrual cramps, or dysmenorrhea, get so bad that they become disabling. When people miss school or work, or they cannot participate in normal social or athletic activities, that is when they first get attention. Often, the disease has been bothering someone for a long time before it is diagnosed.

Another reason that diagnosis may be delayed is because of the social stigma surrounding discussing these types of issues. It is difficult sometimes, especially for a teenager, to talk about issues such as painful periods, pain with bowel movements or urination, or pain with intercourse. A generation ago, people did not talk about such topics so openly and publicly. Thankfully, it is becoming easier, and I think this generation is more open to talking about these issues, but it is still difficult for some who are hesitant to discuss it. Parents can also have a difficult time discussing these issues with their children, and they may dismiss it. Even physicians who are not familiar with this issue may not be comfortable discussing these matters.

Other times, it is truly asymptomatic. Someone can have significant endometriosis that does not show up until it is found on ultrasonography or until someone tries to get pregnant but experiences infertility, and then it is recognized. Typically, people with endometriosis do present with painful menses. If we are more attuned to listening for those symptoms and open to talking about these symptoms, I think we can catch this disease much earlier.

Another barrier to diagnosis is that for too long the gold standard has been surgery, a laparoscopy, to look for endometriosis. If that is a clinician’s method of determining if somebody has endometriosis, it creates quite a barrier to diagnosis. In the near future, I believe we will have noninvasive tests that will help us determine if somebody has endometriosis without surgery. Even now a clinical history can be very helpful in deciding who has endometriosis. I am also of the opinion that people are becoming much more confident about making a clinical diagnosis of endometriosis.

Diagnosing endometriosis relies on identifying flags in the patient’s history and through physical exams. How can clinicians better their chances for having the flags converge for successful diagnosis?

Dr. Taylor: I think it is important to keep the focus on some of the main symptoms of endometriosis. Most women with endometriosis start by having dysmenorrhea, which progresses over time. Some women with painful periods from menarche may not have endometriosis. Their primary dysmenorrhea may be due to other etiologies. If someone has relatively normal menses initially and then goes on to have progressively increasing dysmenorrhea, most often that is endometriosis. Eventually, the pain can spread to other times in the cycle, beyond just dysmenorrhea. Pain can start in the pelvis, but, as endometriosis causes side effects outside of the reproductive organs, it can start to affect other organs and start to cause pain outside of the pelvis. Endometriosis can also inflame the pelvis and affect the bowel, the bladder, and many other surrounding organs. If somebody has bowel symptoms or bladder symptoms that are cyclic and accompanied by dysmenorrhea or cyclic pelvic pain, endometriosis should be thought of first, rather than a primary bowel or bladder problem. Too often medical professionals can be misled by these other false clues. I have seen many patients who come to me after a very thorough workup for a gastrointestinal issue, including a colonoscopy, or a bladder issue, including a cystoscopy, when the underlying problem really was endometriosis. It is important not to be misled by these “red herrings,” and to focus on progressive cyclic pelvic pain.  Endometriosis is always at least initially cyclic in character.

We also know that endometriosis can have effects far beyond the pelvis. Conditions such as anxiety and depression are more common in patients with endometriosis. Women with endometriosis tend to be thinner. There are many other manifestations of this disease. Although it is complex, and can affect almost any organ system, we need to focus on the primary problem, which is cyclic pelvic pain that is progressive in nature. A woman who has dysmenorrhea that may progress to cyclic pain that gets worse over time, more than likely has endometriosis. We can rule out other etiologies, such as masses, fibroids, and cysts, with a simple physical exam and/or an ultrasound. In general, from a good history focusing on the cyclic progressive pelvic pain and a good physical exam to rule out other etiologies for that pain, we can rapidly narrow in on the diagnosis of endometriosis. We can make the diagnosis very straightforward. Cyclic progressive pelvic pain is essentially synonymous with endometriosis.

With a current medical lens focused on addressing racial disparities and inequities in medicine, do you feel that there are gaps in endometriosis study enrollment, diagnosis, and management that need to be addressed?

Dr. Taylor: Traditionally, there have been disparities in diagnosing endometriosis. There was a time when it was presumed that White women had endometriosis and Black women were more likely to have an infectious etiology for their pelvic pain—which is not true. The incidence is slightly higher in Asian and White women compared with Black women, but this is very likely because of bias and access to care. When examining women who have been diagnosed and are being evaluated and treated for infertility, those racial differences disappear. When access to care is available, when patients are seen by a physician, when they are under medical care for another reason, the racial disparities are not seen in endometriosis; it occurs equally. I think there clearly are disparities in access and bias in how we diagnose endometriosis; we should be cognizant of that and realize that endometriosis is very similar in its frequency in all ethnic groups.

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

A version of this article first appeared on Medscape.com.

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

A version of this article first appeared on Medscape.com.

Restoring movement following a stroke can be challenging, but recent proof-of-concept research may offer an effective way to do just that. Researchers behind the ongoing Cortimo trial successfully performed a procedure on a patient 2 years removed from a stroke, in which microelectrode arrays were implanted into his brain to decode signals driving motor function. These signals then allowed him to operate a powered brace worn on his paralyzed arm.

This news organization spoke with the trial’s principal investigator, Mijail D. Serruya, MD, PhD, an assistant professor of neurology at Thomas Jefferson University Hospital, Philadelphia, about the trial’s initial findings, what this technology may ultimately look like, and the implications for stroke patients in knowing that restorative interventions may be on the horizon.
 

How did you first get involved with implanting electrodes to help stroke patients with recovery?

I was involved in the first human application of a microelectrode array in a young man who had quadriplegia because of a spinal cord injury. We showed that we could record signal directly from his motor cortex and use it to move a cursor on the screen, and open and close a prosthetic hand and arm.

I was naive and thought that this would soon be a widely available clinical medical device. Now it’s nearly 15 years later, and while it certainly has been safely used in multiple labs to record signals from people with spinal cord injury, amyotrophic lateral sclerosis (ALS), or locked-in syndrome from a brain stem stroke, it still requires a team of technicians and a percutaneous connector. It really has not gotten out of the university.

A few years ago I spoke with Robert Rosenwasser, MD, chairman of the department of neurosurgery at Thomas Jefferson, who runs a very busy stroke center and performed the surgery in this trial. We put our heads together and said: “Maybe the time is now to see whether we can move this technology to this much more prevalent condition of a hemispheric stroke.” And that’s what we did.
 

How did the idea of using computer brain electrode interfaces begin?

Around 20 years ago, if you had someone who had severe paralysis and you wanted to restore movement, the question was, where can you get a good control signal from? Obviously, if someone can talk, they can use a voice-actuated system with speech recognition and maybe you can track their eye gaze. But if they’re trying to move their limbs, you want a motor control signal.

In someone who has end-stage ALS or a brain stem stroke, you can’t even record residual muscle activity; you have almost nothing to work with. The only thing left is to try to record directly from the brain itself.

It’s important to clarify that brain-computer interfaces are not necessarily stimulating the brain to inject the signal. They’re just recording the endogenous activity that the brain makes. In comparison, a deep brain stimulator is usually not recording anything; it’s just delivering energy to the brain and hoping for the best.

But what we’re doing is asking, if the person is trying to move the paralyzed limb but can’t, can we get to the source of the signal and then do something with it?
 

What’s the process for measuring that in, for example, someone who has a localized lesion in the motor cortex?

The first step is a scan. People have been doing functional MRI on patients who have had a stroke as long as we’ve had fMRI. We know that people can actually activate on MRI areas of their brain around the stroke, but obviously not in the stroke because it’s been lesioned. However, we do know that the circuit adjacent to it and other regions do appear able to be modulated.

So by having a person either imagine trying to do what they want to do or doing what they can do, if they have some tiny residual movement, you can then identify a kind of hot spot on the fMRI where the brain gobbles up all the oxygen because it’s so active. Then that gives you an anatomical target for the surgeon to place the electrode arrays.
 

The Cortimo trial’s enticing findings

What are the most striking results that you’ve seen so far with the device?

The first thing is that we were able to get such recordings at all. We knew from fMRIs that there were fluctuations in oxygen changing when the person was trying to do something they couldn’t do. But nobody knew that you would see this whole population of individual neurons chattering away when you place these electrode arrays in the motor cortex right next to the stroke, and make sense of what we’re recording.

Obviously, that’s very encouraging and gives us hope that many months or years after a stroke, people’s brains are able to maintain this representation of all these different movements and plans. It’s almost like it’s trapped on the other side of the stroke and some of the signals can’t get out.

The other discovery we’re pleased with is that we can actually decode signals in real time and the person can use it to do something, such as trigger the brain to open and close the hand. That’s very different from all the prior research with brain array interfaces.

Furthermore, the gentleman who participated actually had strokes in other parts of his brain affecting his vision; he had homonymous hemianopia. That raised the question of what happens if you affect parts of the brain that have to do with attention and visual processing. Could a system like this work? And again, the answer appears to be yes.
 

What are the next steps for this technology before it can potentially become available in the clinic?

For this to work, the system clearly has to be fully implantable. What we used was percutaneous. The risk-benefit may be acceptable for someone who has quadriplegia because of, for example, spinal cord injury or end-stage ALS who may already have a tracheostomy and a percutaneous endoscopic gastrostomy. But for someone who is hemiparetic and ambulatory, that may not be acceptable. And a fully implantable system would also have much better patient compliance.

Also, when you’re recording from lots and lots of individual brain cells at many, many samples a second on many, many channels, it’s certainly an engineering challenge. It’s not just a single channel that you occasionally query; it’s hundreds of thousands of channels of this complicated data stream.

But these are solvable challenges. People have been making a lot of progress. It’s really a matter of funding and the engineering expertise, rather than some sort of fundamental scientific breakthrough.

With that said, I think it could be within the next 5-10 years that we could actually have a product that expands the toolbox of what can be done for patients who’ve had a stroke, if they’re motivated and there’s no real contraindication.
 

Creating a novel device

On that point, are you partnering with engineering and technology companies?

The hope is that we and other groups working on this can do for the interface sort of what Celera Genomics did for the Human Genome Project. By having enough interest and investment, you may be able to propel the field forward to widespread use rather than just a purely academic, lab-science type of project.

We are in discussion with different companies to see how we can move ahead with this, and we would be pleased to work with whomever is interested. It may be that different companies have different pieces of the puzzle – a better sensor or a better wireless transmitter.

The plan is to move as quickly as we can to a fully implantable system. And then the benchmark for any kind of clinical advancement is to do a prospective trial. With devices, if you can get a big enough effect size, then you sometimes don’t need quite as many patients to prove it. If paralysis is striking enough and you can reverse that, then you can convince the Food and Drug Administration of its safety and efficacy, and the various insurance companies, that it’s actually reasonable and necessary.
 

How long will an implantable device last?

That’s a key question and concern. If you have someone like our participant, who’s in his early 40s, will it keep working 10, 20, 30, 40 years? For the rest of his life? Deep brain stimulators and cochlear implants do function for those long durations, but their designs are quite different. There’s a macroelectrode that’s just delivering current, which is very different from listening in on this microscopic scale. There are different technical considerations.

One possible solution is to make the device out of living tissue, which is something I just wrote about with my colleague D. Kacy Cullen. Living electrodes and amplifiers may seem a bit like science fiction, but on the other hand, we have over a century of plastic surgeons, neurosurgeons, and orthopedic surgeons doing all kinds of complicated modifications of the body, moving nerves and vessels around. It makes you realize that, in a sense, they’ve already done living electrodes by doing a nerve transfer. So the question becomes whether we can refine that living electrode technology, which could then open up more possibilities.
 

Are there any final messages you’d like to share with clinician audience of this news organization?

Regardless of our specialty, we’re always telling our patients about the benefits of things like eating healthy, exercise, and sleep. Now we can point to the fact that, 2 years after stroke, all of these brain areas are still active, and devices that can potentially reverse and unparalyze your limbs may be available in the coming 5- or 10-plus years. That gives clinicians more justification to tell their patients to really stay on top of those things so that they can be in as optimal brain-mind health as possible to someday benefit from them.

Patients and their families need to be part of the conversation of where this is all going. That’s one thing that’s totally different for brain devices versus other devices, where a person’s psychological state doesn’t necessarily matter. But with a brain device, your mental state, psychosocial situation, exercise, sleep – the way you think about and approach it – actually changes to the structure of the brain pretty dramatically.

I don’t want to cause unreasonable hope that we’re going to snap our fingers and it’s going to be cured. But I do think it’s fair to raise a possibility as a way to say that keeping oneself really healthy is justified.

A version of this article first appeared on Medscape.com.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

Has the introduction of direct-acting antiviral (DAA) medications had a significant benefit in special populations of patients with hepatitis C virus (HCV)?

Dr. Rosen:  Absolutely. The gaps and challenges for particular special populations have been largely overcome with the development of new HCV agents.

For example, we now know that HIV-HCV coinfection—which was a particularly vexing situation because of the significant side effects of interferon-based therapies and the much lower efficacy—has no impact on HCV treatment outcome if we use DAAs. Remarkably, the management, indication of treatment, and follow up of HCV infection are now the same for both patient populations. It is particularly relevant because we know that HIV coinfection leads to a more accelerated development of advanced fibrosis, and we know that fibrosis is the single most important predictor of outcome.

Having said that, HIV-HCV coinfected patients require careful evaluation of any potential drug-drug interactions between the HCV drugs and HIV antiretroviral therapy, and it also requires attention to medication for substance abuse and other co-medications for other comorbidities. If we look at the issue of drug-drug interactions, the good news is that the main culprit in terms of interaction with antiretroviral therapy, was ritonavir. That was approved in combination with other antivirals in 2014, but it is not part of a commonly utilized regimen of DAAs. Simeprevir is also prone to drug interactions with cytochrome P450. This was contraindicated when used with several HIV antiretrovirals, but neither one of those drugs are really used to treat HCV now. Very few clinically significant interactions are expected with sofosbuvir or ledipasvir, so we do not expect to see drug-drug interactions as we did in the first generation of DAAs.

Let us now look at people who inject drugs or use drugs (PWIDs.) I think it clearly is the biggest challenge globally to provide treatment access to these patients. If you consider that 1 person who injects drugs can theoretically infect 20 other subjects, it is imperative to treat this population.

Historically, there has been stigmatization of these patients because of the use of drugs. PWIDs are increasingly being considered to be eligible for treatment, but it is important to underscore that eligibility does not necessarily translate to or equate to access. Adherence to and response to DAA therapy among this patient population represents some additional challenges. Many of these patients are receiving opioid substitution therapy and that has actually been shown to increase the likelihood of success with DAAs, but there is a concern in this patient population of ongoing drug use and HCV reinfection.

When we treat this patient population, we have to be cognizant of these issues and develop strategies that maximize their likelihood of staying on treatment. On average, about 12% of patients who are PWIDs drop out or are lost to follow up, which is problematic. A smaller percentage of those who continue injecting drugs develop reinfection, for example, with a different genotype. We know that DAA-mediated cure does not confer immunity to different strains or even the same strain of virus, and so we need to develop processes to maximize prevention of reinfection. That may include opioid substitution therapy, or needle exchange programs. There are also a lot of data emerging around the world about the benefit of the adjunctive role of behavioral therapy. Again, it all starts with access to DAA treatment in this patient population, and then retreatment if they get reinfected.

The next population is patients with end stage renal disease. It has been a remarkable transformation. These patients in the past would not tolerate interferon-based therapy and would develop severe anemia with ribavirin. Now with DAAs, those complications do not arise. We know that successful HCV therapy improves clinical outcomes in patients who have end stage renal disease. This has been associated with a very significant survival benefit in patients on dialysis. Among diabetic patients who have end stage renal disease, if one achieves sustained virologic response, it reduces the risk of developing extrahepatic manifestations of the disease and that happens regardless of cirrhosis.

Drugs that have been very effective in patients who have chronic renal failure include elbasvir and grazoprevir, as well as glecaprevir and pibrentasvir. We know that the concentration of sofosbuvir is a concern; there are higher concentrations of the primary sofosbuvir metabolite in persons who develop renal impairment, but many studies have demonstrated the safety and efficacy of sofosbuvir-based regimens even in those patients who have an estimated GFR less than 30 mL per minute.

Are there any other unmet needs that still exist in treating any of these special patient populations?

Dr. Rosen: Addressing medical, psychological, social, and addiction-related barriers are all important for PWIDs. As we touched on earlier, there needs to be a deliberate and nuanced approach for these subjects, a multidisciplinary model of care in order to help decrease the high dropout rate. The data that are coming out certainly justifies providing access to these patients, with real-world efficacy at more than 90%. We know that these patients can be treated and that they can achieve a high cure rate.

Appropriately treating patients who have renal failure does remain a challenge. The question is, when do you treat someone who has end stage renal disease and HCV? The answer pivots on the accessibility to organs. We can use HCV positive organs in patients who have either been cured of HCV and now are negative for virus, or in people who have never been exposed to HCV.

You might wonder, what is the rationale for that? The average wait list time for an HCV negative kidney is about 6.6 years. If you are willing to take an HCV positive kidney, it is closer to 4 years. I recently saw a patient who got a kidney transplant, developed kidney allograft failure, and is now being considered for retransplantation. In this situation, if I cure his HCV—which we know we can do with the current therapies very safely—it is potentially going to extend his time waiting for his next kidney.

In this situation, my plan would be to do a fibroscan, which tells me how much scar tissue he has in his liver. If he has fibrosis 0 or 1, I will probably not treat him and put him into the pool that he receives an HCV positive kidney. If, on the other hand, he has fibrosis 3 or 4, I probably will cure his hepatitis C because he is immunosuppressed and he has a significant chance of further developing advanced liver disease and even decompensation.

I think we should treat everybody who has HCV because we know it improves quality of life, it improves liver-related mortality, and it improves all-cause mortality. In the case of patients who have end organ damage and are waiting for transplant, it may prolong their wait time unless the patient is willing to accept that HCV positive organ. Considering the remarkable success in treating HCV post-organ transplant, the use of HCV-positive organs into HCV-negative continues to expand. 

What new challenges, if any, has COVID-19 presented in treating these high risk or special populations?

Dr. Rosen: The good news is we have multiple, highly effective pangenotypic DAA regimens.

We know that all patients with HCV should be treated, especially those who have advanced fibrosis. Recent data show that patients who have advanced fibrosis, whether measured by a noninvasive blood test, like FIB-4 or a noninvasive fibroscan have a higher risk of death if they develop COVID-19.

COVID-19 is associated with liver function abnormalities in 20% or more of all patients who contract it, and those patients who develop elevated liver function tests have a higher mortality. It is particularly high in patients who have cirrhosis.

We do not think that patients who have HCV are more prone to develop COVID-19—there are no data to support that. However, if there is evidence that in patients with advanced fibrosis or evidence of hepatic involvement as manifested by elevated liver function tests, those patients have at least a twofold higher chance of mortality.

The other challenge, of course, is what COVID-19 has done to our ability to deliver care. It has made it inconvenient to treat patients. Patients who have advanced fibrosis or cirrhosis who get cured with DAAs also still need surveillance for development of hepatocellular carcinoma. Their risk of developing hepatocellular carcinoma is lower than patients who have not been cured, but there is still a residual risk which often requires imaging COVID-19-related changes have negatively impacted our ability to do that.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.

What are the largest factors creating barriers to hepatitis C virus (HCV) elimination?
 

Dr. Lim: In 2020 there remain important barriers to access to treatment because of the high cost of drugs used to eradicate HCV. There are still opportunities for us to interact with major payors to ensure adequate access, both with private commercial payers, as well as with Medicaid. We know very well that there are existing barriers that impact a significant proportion of patients, but if you look at data from the private sector, it turns out that we are doing pretty well; At least 80% of payers are covering direct-acting antiviral (DAA) medications with minimal restriction.

However, with Medicaid it is quite the reverse story; In about two-thirds of states, there are at least one or more restrictions based on the stage of their fibrosis, sobriety requirements for alcohol and drug use, and specialty providers to prescribe the medication, among others. Based on data from the National Viral Hepatitis Roundtable, it is clear that there are still many states where if you have mild disease, or recently used drugs or alcohol, or are in a rural area where you do not have access to a gastroenterologist or infectious disease specialist, you cannot get treatment. That is still a major concern for access to care.

When we think about elimination, eradication, and extinction of human diseases, HCV represents one of the few for which we actually have the tools to cure the condition permanently with a simple regimen of 1 to 3 pills per day for 2 or 3 months, with a cure rate exceeding 95%. This is truly remarkable and provides us with a historic opportunity to eradicate HCV in the United States and worldwide.

When we can diagnose HCV and offer treatment, we have a very good success rate—but therein lies the challenge. The key rate limiting steps to achieving elimination are found in ongoing deficits in the HCV care cascade, including screening, diagnosis, linkage to care, and treatment. We believe that right now only about 50% of affected persons have been diagnosed, and therefore much work remains to be done in the screening/diagnosis step of the care cascade if we are to achieve meaningful progress towards HCV elimination.

In that spirit, there have been important advances in terms of policy and legislation to support broader population-based screening. The CDC and US Preventive Services Task Force initially recommended that all baby boomers (those born between 1945 and 1965) should be screened for HCV, in addition to those with established risk factors. These include individuals who have used drugs, either through a nose or through the vein, had a blood transfusion before 1992, tattoos or body piercings, accidental needlestick exposures, or high risk sexual contacts, However, data show that risk factor-based screening simply does not work. It is difficult for clinicians to routinely ask sensitive questions about historical risk factors.

Despite the remarkable success in development of curative therapies for HCV, the rate of new incident HCV infections has not been going down—It has actually been doubling to tripling over the last 5 years. We now have what we call a bi-modal distribution of HCV, which includes baby boomers and a second younger group, between age 18 and 34. The primary route of transmission in this younger cohort is injection drug use, which is largely tied to the opiate epidemic.

It is in this context that within the last year, 4 different organizations—the CDC, the United States Preventive Services Task Force (USPSTF), the American Association for the Study of Liver Diseases (AASLD), and the Infectious Diseases Society of America (IDSA)—have expanded their guidance documents to now recommend one-time HCV screening in all adults age 18 or older plus all pregnant women regardless of age. This guidance replaces the old guidelines focused on baby boomers and individuals with risk factors. This represents a fundamental and consequential shift in US strategy to improve population-based screening.

There is also a sense that a treatment as prevention strategy can be particularly impactful in reducing spread among high-risk populations, especially in persons who inject drugs (PWID). The concept is that if you can effectively remove HCV in high-risk populations by treating active users, this may prevent spread of HCV to others who would otherwise be exposed. Although HCV treatment in patients with active drug use has historically been viewed with skepticism, and in fact remains an exclusion factor by some payors, DAA therapy in PWID is strongly recommended by the AASLD/IDSA guidelines and is increasingly embraced in both specialty and non-specialty (eg, methadone clinics, community health centers, prison clinics) settings.

Could you please elaborate more on the updated CDC guidelines and the impact that those are having in practice?

Dr. Lim: Although the revised screening guidelines by CDC and other organizations represent a critical step to promote awareness by clinicians regarding the compelling evidence to support universal HCV screening of all American adults, the reality is that just because there is a recommendation for it, does not mean that it will always be followed. Clinicians in primary care and specialty practices alike are already burdened by guideline fatigue, and an ever-growing list of mandates of standard clinical practice such as colon cancer screening, mammography, cholesterol checks, etc., and now all of this in the context of COVID-19. This further complicates the task of implementing HCV screening recommendations in real-world clinical practice.

New data published this year show that the screening rates among baby boomers have increased from approximately 10% to 20% since the original recommendations in 2014. Although this represents an important step in the right direction, it is clear there is significant room for improvement. It remains to be seen what impact this transition from birth cohort screening to universal screening of all Americans age 18 and older will have on our ability to identify previously unidentified infected persons.

In 2016 the World Health Organization (WHO) Global Health Sector Strategy called for the elimination of HCV as a major health threat by 2030. At the current rate of transmission, and considering all the barriers you mentioned that still exist, do you think that this is still a realistic timeframe? Is there any other action that physicians specifically maintain to help reach the goal?

Dr. Lim: WHO's vision was to eliminate hepatitis C by 2030 as defined as the following: 1) diagnose 90% of infected persons, 2) offer treatment to 80% of infected persons, and 3) reduce HCV-associated mortality by 65%.

Unfortunately, the United States is highly unlikely to meet this goal by 2030. Based on recently published models, only 3 of 50 states may have a chance at meeting the elimination target by that deadline. But as a country, we already know that is just simply not going to happen—unless there are dramatic changes in governmental and multi-stakeholder commitment.

Globally, there are an estimated 12 countries that are projected to achieve elimination by 2030. Some of the most prominent examples include Egypt, The Republic of Georgia, Australia, Italy, and Japan. The United States is not in this grouping, and in fact our current models suggest that we may not even achieve this goal by 2050.

There is much work that needs to be done to address some of the systemic and institutional infrastructure issues that will support effective implementation of screening, diagnosis, and linkage of care. Drug access—although that remains an important issue—is actually not the driving factor in terms of our inability to meet our targets. Within the United States, the Department of Health and Human Services has taken the lead on developing a US-based strategy. Although there has been strong language to articulate what is required and the intentionality to work on HCV elimination, this has not yet been associated with adequate funding at the federal level. Without this funding, we are destined to make only modest progress towards elimination targets within the short and intermediate timeframe.  Despite these challenges, organizations such as the AASLD, CDC, National Viral Hepatitis Roundtable, World Hepatitis Alliance, and the Coalition for Global Hepatitis Elimination remain vocal advocates to secure necessary resources and will continue to lead US efforts to implement effective strategies on the road to viral hepatitis elimination. These organizations cannot fulfill this mission alone—each of us as clinicians play a vital role in carrying out CDC and USPSTF recommendations in our individual clinical settings to ensure broad-based screening and diagnosis, timely linkage to care, and antiviral treatment.