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Hep C sofosbuvir/daclatasvir combo promising for COVID-19
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
research from an open-label Iranian study shows.
And the good news is that the treatment combination “already has a well-established safety profile in the treatment of hepatitis C,” said investigator Andrew Hill, PhD, from the University of Liverpool, United Kingdom.
But although the results look promising, they are preliminary, he cautioned. The combination could follow the path of ritonavir plus lopinavir (Kaletra, AbbVie Pharmaceuticals) or hydroxychloroquine (Plaquenil, Sanofi Pharmaceuticals), which showed promise early but did not perform as hoped in large randomized controlled trials.
“We need to remember that conducting research amidst a pandemic with overwhelmed hospitals is a clear challenge, and we cannot be sure of success,” he added.
Three Trials, 176 Patients
Data collected during a four-site trial of the combination treatment in Tehran during an early spike in cases in Iran were presented at the Virtual COVID-19 Conference 2020 by Hannah Wentzel, a masters student in public health at Imperial College London and a member of Hill’s team.
All 66 study participants were diagnosed with moderate to severe COVID-19 and were treated with standard care, which consisted of hydroxychloroquine 200 mg twice daily with or without the combination of lopinavir plus ritonavir 250 mg twice daily.
The 33 patients randomized to the treatment group also received the combination of sofosbuvir plus daclatasvir 460 mg once daily. These patients were slightly younger and more likely to be men than were those in the standard-care group, but the differences were not significant.
All participants were treated for 14 days, and then the researchers assessed fever, respiration rate, and blood oxygen saturation.
More patients in the treatment group than in the standard-care group had recovered at 14 days (88% vs 67%), but the difference was not significant.
However, median time to clinical recovery, which took into account death as a competing risk, was significantly faster in the treatment group than in the standard-care group (6 vs 11 days; P = .041).
The researchers then pooled their Tehran data with those from two other trials of the sofosbuvir plus daclatasvir combination conducted in Iran: one in the city of Sari with 48 patients and one in the city of Abadan with 62 patients.
A meta-analysis showed that clinical recovery in 14 days was 14% better in the treatment group than in the control group in the Sari study, 32% better in the Tehran study, and 82% better in the Abadan study. However, in a sensitivity analysis, because “the trial in Abadan was not properly randomized,” only the improvements in the Sari and Tehran studies were significant, Wentzel reported.
The meta-analysis also showed that patients in the treatment groups were 70% more likely than those in the standard-care groups to survive.
However, the treatment regimens in the standard-care groups of the three studies were all different, reflecting evolving national treatment guidelines in Iran at the time. And SARS-CoV-2 viral loads were not measured in any of the trials, so the effects of the different drugs on the virus itself could not be assessed.
Still, overall, “sofosbuvir and daclatasvir is associated with faster discharge from hospital and improved survival,” Wentzel said.
These findings are hopeful, “provocative, and encouraging,” said Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, and he echoed Hill’s call to “get these kinds of studies into randomized controlled trials.”
But he cautioned that more data are needed before the sofosbuvir and daclatasvir combination can be added to the National Institutes of Health COVID-19 Treatment Guidelines, which clinicians who might be under-resourced and overwhelmed with spikes in COVID-19 cases rely on.
Results from three double-blind randomized controlled trials – one each in Iran, Egypt, and South Africa – with an estimated cumulative enrollment of about 2,000 patients, are expected in October, Hill reported.
“Having gone through feeling so desperate to help people and try new things, it’s really important to do these trials,” said Kristen Marks, MD, from Weill Cornell Medicine in New York City.
“You get tempted to just kind of throw anything at people. And I think we really have to have science to guide us,” she told Medscape Medical News.
This article first appeared on Medscape.com.
Hyperglycemia predicts COVID-19 death even without diabetes
new research indicates.
The findings, from a retrospective analysis of 605 patients with COVID-19 seen at two hospitals in Wuhan, China, were published online July 10 in Diabetologia by Sufei Wang, of the department of respiratory and critical care medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and colleagues.
Several previous studies have demonstrated a link between hyperglycemia and worse outcomes in COVID-19, and at least one diabetes diagnosis, but this is the first to focus specifically on that group of patients.
Wang and colleagues found that a fasting blood glucose of 7.0 mmol/L (126 mg/dL) or greater on admission – present in 45.6% of those without a prior diabetes diagnosis – was an independent predictor of 28-day mortality.
Although A1c data weren’t analyzed, the population is believed to include both individuals with preexisting but undiagnosed diabetes and those without diabetes who have acute stress hyperglycemia.
“Glycemic testing and control should be recommended for all COVID-19 patients even if they do not have preexisting diabetes, as most COVID-19 patients are prone to glucose metabolic disorders,” they emphasized.
“Addressing elevated fasting blood glucose at an early stage can help clinicians better manage the condition and lower the mortality risk of COVID-19 patients,” Wang and colleagues noted.
Hyperglycemia predicts COVID-19 death, complications
The study involved consecutive patients with COVID-19 and definitive 28-day outcome and fasting blood glucose measurement on admission to two Wuhan-area hospitals between Jan. 24 to Feb. 10, 2020. A total of 605 patients did not have a previous diabetes diagnosis. They were a median age of 59 years and 53.2% were men.
Just over half, 54.4%, had a fasting blood glucose below 6.1 mmol/L (110.0 mg/dL). The rest had dysglycemia: 16.5% had a fasting blood glucose of 6.1-6.9 mmol/L (110-125 mg/dL), considered the prediabetes range, and 29.1% had a fasting blood glucose of 7 mmol/L (126 mg/dL) or above, the cutoff for diabetes.
“These results indicate that our study included both undiagnosed diabetic patients and nondiabetic patients with hyperglycemia caused by an acute blood glucose disorder,” the authors noted.
Over 28 days of hospitalization, 18.8% (114) of the patients died and 39.2% developed one or more in-hospital complications.
The authors used the CRB-65 score, which assigns 1 point for each of four indicators – confusion, respiratory rate >30 breaths/min, systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤60 mm Hg, and age ≥65 years – to assess pneumonia severity.
Just over half, 55.2%, had a CRB-65 score of 0, 43.1% had a score of 1-2, and 1.7% had a score of 3-4.
In multivariable analysis, significant independent predictors of 28-day mortality were age (hazard ratio, 1.02), male sex (HR, 1.75), CRB-65 score 1-2 (HR, 2.68), CRB-65 score 3-4 (HR, 5.25), and fasting blood glucose ≥7.0 mmol/L (HR, 2.30).
Compared with patients with normal glucose (<6.1 mmol/L), 28-day mortality was twice as high (HR, 2.06) for those with a fasting blood glucose of 6.1-6.9 mmol/L and more than threefold higher for ≥7.0 mmol/L (HR, 3.54).
Pneumonia severity also predicted 28-day mortality, with hazard ratios of 4.35 and 13.80 for patients with CRB-65 scores of 1-2 and 3-4, respectively, compared with 0.
Inhospital complications, including acute respiratory distress syndrome or acute cardiac, kidney, or liver injury or cerebrovascular accident, occurred in 14.2%, 7.9%, and 17.0% of those in the lowest to highest fasting blood glucose groups.
Complications were more than twice as common in patients with a fasting blood glucose of 6.1-6.9 mmol/L (HR, 2.61) and four times more common (HR, 3.99) among those with a fasting blood glucose ≥7.0 mmol/L, compared with those with normoglycemia.
The study was supported by the National Natural Science Foundation of China and Major Projects of the National Science and Technology. The authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
new research indicates.
The findings, from a retrospective analysis of 605 patients with COVID-19 seen at two hospitals in Wuhan, China, were published online July 10 in Diabetologia by Sufei Wang, of the department of respiratory and critical care medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and colleagues.
Several previous studies have demonstrated a link between hyperglycemia and worse outcomes in COVID-19, and at least one diabetes diagnosis, but this is the first to focus specifically on that group of patients.
Wang and colleagues found that a fasting blood glucose of 7.0 mmol/L (126 mg/dL) or greater on admission – present in 45.6% of those without a prior diabetes diagnosis – was an independent predictor of 28-day mortality.
Although A1c data weren’t analyzed, the population is believed to include both individuals with preexisting but undiagnosed diabetes and those without diabetes who have acute stress hyperglycemia.
“Glycemic testing and control should be recommended for all COVID-19 patients even if they do not have preexisting diabetes, as most COVID-19 patients are prone to glucose metabolic disorders,” they emphasized.
“Addressing elevated fasting blood glucose at an early stage can help clinicians better manage the condition and lower the mortality risk of COVID-19 patients,” Wang and colleagues noted.
Hyperglycemia predicts COVID-19 death, complications
The study involved consecutive patients with COVID-19 and definitive 28-day outcome and fasting blood glucose measurement on admission to two Wuhan-area hospitals between Jan. 24 to Feb. 10, 2020. A total of 605 patients did not have a previous diabetes diagnosis. They were a median age of 59 years and 53.2% were men.
Just over half, 54.4%, had a fasting blood glucose below 6.1 mmol/L (110.0 mg/dL). The rest had dysglycemia: 16.5% had a fasting blood glucose of 6.1-6.9 mmol/L (110-125 mg/dL), considered the prediabetes range, and 29.1% had a fasting blood glucose of 7 mmol/L (126 mg/dL) or above, the cutoff for diabetes.
“These results indicate that our study included both undiagnosed diabetic patients and nondiabetic patients with hyperglycemia caused by an acute blood glucose disorder,” the authors noted.
Over 28 days of hospitalization, 18.8% (114) of the patients died and 39.2% developed one or more in-hospital complications.
The authors used the CRB-65 score, which assigns 1 point for each of four indicators – confusion, respiratory rate >30 breaths/min, systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤60 mm Hg, and age ≥65 years – to assess pneumonia severity.
Just over half, 55.2%, had a CRB-65 score of 0, 43.1% had a score of 1-2, and 1.7% had a score of 3-4.
In multivariable analysis, significant independent predictors of 28-day mortality were age (hazard ratio, 1.02), male sex (HR, 1.75), CRB-65 score 1-2 (HR, 2.68), CRB-65 score 3-4 (HR, 5.25), and fasting blood glucose ≥7.0 mmol/L (HR, 2.30).
Compared with patients with normal glucose (<6.1 mmol/L), 28-day mortality was twice as high (HR, 2.06) for those with a fasting blood glucose of 6.1-6.9 mmol/L and more than threefold higher for ≥7.0 mmol/L (HR, 3.54).
Pneumonia severity also predicted 28-day mortality, with hazard ratios of 4.35 and 13.80 for patients with CRB-65 scores of 1-2 and 3-4, respectively, compared with 0.
Inhospital complications, including acute respiratory distress syndrome or acute cardiac, kidney, or liver injury or cerebrovascular accident, occurred in 14.2%, 7.9%, and 17.0% of those in the lowest to highest fasting blood glucose groups.
Complications were more than twice as common in patients with a fasting blood glucose of 6.1-6.9 mmol/L (HR, 2.61) and four times more common (HR, 3.99) among those with a fasting blood glucose ≥7.0 mmol/L, compared with those with normoglycemia.
The study was supported by the National Natural Science Foundation of China and Major Projects of the National Science and Technology. The authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
new research indicates.
The findings, from a retrospective analysis of 605 patients with COVID-19 seen at two hospitals in Wuhan, China, were published online July 10 in Diabetologia by Sufei Wang, of the department of respiratory and critical care medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, and colleagues.
Several previous studies have demonstrated a link between hyperglycemia and worse outcomes in COVID-19, and at least one diabetes diagnosis, but this is the first to focus specifically on that group of patients.
Wang and colleagues found that a fasting blood glucose of 7.0 mmol/L (126 mg/dL) or greater on admission – present in 45.6% of those without a prior diabetes diagnosis – was an independent predictor of 28-day mortality.
Although A1c data weren’t analyzed, the population is believed to include both individuals with preexisting but undiagnosed diabetes and those without diabetes who have acute stress hyperglycemia.
“Glycemic testing and control should be recommended for all COVID-19 patients even if they do not have preexisting diabetes, as most COVID-19 patients are prone to glucose metabolic disorders,” they emphasized.
“Addressing elevated fasting blood glucose at an early stage can help clinicians better manage the condition and lower the mortality risk of COVID-19 patients,” Wang and colleagues noted.
Hyperglycemia predicts COVID-19 death, complications
The study involved consecutive patients with COVID-19 and definitive 28-day outcome and fasting blood glucose measurement on admission to two Wuhan-area hospitals between Jan. 24 to Feb. 10, 2020. A total of 605 patients did not have a previous diabetes diagnosis. They were a median age of 59 years and 53.2% were men.
Just over half, 54.4%, had a fasting blood glucose below 6.1 mmol/L (110.0 mg/dL). The rest had dysglycemia: 16.5% had a fasting blood glucose of 6.1-6.9 mmol/L (110-125 mg/dL), considered the prediabetes range, and 29.1% had a fasting blood glucose of 7 mmol/L (126 mg/dL) or above, the cutoff for diabetes.
“These results indicate that our study included both undiagnosed diabetic patients and nondiabetic patients with hyperglycemia caused by an acute blood glucose disorder,” the authors noted.
Over 28 days of hospitalization, 18.8% (114) of the patients died and 39.2% developed one or more in-hospital complications.
The authors used the CRB-65 score, which assigns 1 point for each of four indicators – confusion, respiratory rate >30 breaths/min, systolic blood pressure ≤90 mm Hg or diastolic blood pressure ≤60 mm Hg, and age ≥65 years – to assess pneumonia severity.
Just over half, 55.2%, had a CRB-65 score of 0, 43.1% had a score of 1-2, and 1.7% had a score of 3-4.
In multivariable analysis, significant independent predictors of 28-day mortality were age (hazard ratio, 1.02), male sex (HR, 1.75), CRB-65 score 1-2 (HR, 2.68), CRB-65 score 3-4 (HR, 5.25), and fasting blood glucose ≥7.0 mmol/L (HR, 2.30).
Compared with patients with normal glucose (<6.1 mmol/L), 28-day mortality was twice as high (HR, 2.06) for those with a fasting blood glucose of 6.1-6.9 mmol/L and more than threefold higher for ≥7.0 mmol/L (HR, 3.54).
Pneumonia severity also predicted 28-day mortality, with hazard ratios of 4.35 and 13.80 for patients with CRB-65 scores of 1-2 and 3-4, respectively, compared with 0.
Inhospital complications, including acute respiratory distress syndrome or acute cardiac, kidney, or liver injury or cerebrovascular accident, occurred in 14.2%, 7.9%, and 17.0% of those in the lowest to highest fasting blood glucose groups.
Complications were more than twice as common in patients with a fasting blood glucose of 6.1-6.9 mmol/L (HR, 2.61) and four times more common (HR, 3.99) among those with a fasting blood glucose ≥7.0 mmol/L, compared with those with normoglycemia.
The study was supported by the National Natural Science Foundation of China and Major Projects of the National Science and Technology. The authors have reported no relevant financial relationships.
This article first appeared on Medscape.com.
Infants around the world with bronchiolitis received excess tests despite guidelines
While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.
For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.
In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.
Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.
Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.
The most common nonrecommended tests performed in the study were:
- Nasopharyngeal viral testing without admission to hospital (n = 591).
- Chest x-ray without ICU admission (n = 507).
- Complete blood counts (n = 222).
- Blood cultures (n = 129).
- Urinalysis in the absence of fever (n = 86).
- Febrile infants 3 months of age or less had blood cultures (n = 49).
In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.
“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.
“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”
The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.
In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).
He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.
The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.
Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.
SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.
While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.
For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.
In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.
Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.
Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.
The most common nonrecommended tests performed in the study were:
- Nasopharyngeal viral testing without admission to hospital (n = 591).
- Chest x-ray without ICU admission (n = 507).
- Complete blood counts (n = 222).
- Blood cultures (n = 129).
- Urinalysis in the absence of fever (n = 86).
- Febrile infants 3 months of age or less had blood cultures (n = 49).
In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.
“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.
“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”
The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.
In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).
He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.
The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.
Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.
SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.
While guidelines for bronchiolitis aim to reduce gratuitous tests and treatments, one-third of infants presenting at EDs with bronchiolitis receive an unnecessary intervention, according to a new global study.
For infants with symptoms of bronchiolitis, viral testing, blood tests, and chest x-rays are discouraged in most cases. Antibiotics are not recommended as treatment.
In a study published in Pediatrics, Amy Zipursky, MD, of the Hospital for Sick Children and the University of Toronto, and colleagues, reviewed records for 2,359 infants aged 2-11 months diagnosed with bronchiolitis during the year 2013. The data came from a network of 38 EDs in the Australia, Canada, Ireland, New Zealand, Portugal, Spain, the United Kingdom, and the United States.
Dr. Zipursky and colleagues found that, while 8% of infants in the cohort had been treated with antibiotics, 33% had received at least one nonrecommended test, with rates ranging widely across regions. In the United Kingdom and Ireland, for example, only 15% received such a test, compared with 50% in Spain and Portugal.
Of the children given antibiotics, two-thirds had suspected bacterial infections, the researchers found. Antibiotic use was highest in the United States, at 11% of infants seen for bronchiolitis, and lowest in the United Kingdom and Ireland at 4%. Administration of chest x-rays – which occurred in nearly a quarter of the cohort – increased the likelihood of antibiotics being administered (odds ratio, 2.29; 95% confidence interval, 1.62-3.24) independent of fever or severe symptoms.
The most common nonrecommended tests performed in the study were:
- Nasopharyngeal viral testing without admission to hospital (n = 591).
- Chest x-ray without ICU admission (n = 507).
- Complete blood counts (n = 222).
- Blood cultures (n = 129).
- Urinalysis in the absence of fever (n = 86).
- Febrile infants 3 months of age or less had blood cultures (n = 49).
In some treatment centers the rate of nonrecommended tests performed was 6%, while others saw rates of 74%.
“Despite the evidence that laboratory testing rarely impacts bronchiolitis management and that bacterial infections in bronchiolitis are uncommon, our study reveals that these tests continue to be performed frequently in many parts of the world,” Dr. Zipursky and colleagues wrote in their analysis.
“Plausible reasons may include ‘automatic’ blood draws with intravenous placement, uncertainty about institutional policies, perceived need for reassurance about the diagnosis, perception of ‘doing something,’ and parental desire for a viral label,” the authors surmised. “Because parental pressure to provide interventions may be a driver of care in infants with bronchiolitis in some countries, ED clinicians need to have higher confidence in the evidence-based bronchiolitis care and convey this trust to families.”
The researchers listed among the weaknesses of their study its retrospective design, and that results from x-rays and lab tests performed were not available.
In an editorial comment accompanying the study, Joseph J. Zorc, MD, of Children’s Hospital of Philadelphia and the University of Pennsylvania in Philadelphia, noted that some of the regional differences seen in the study may be attributable to different clinical criteria used to diagnose bronchiolitis. In the United Kingdom, for example, national guidelines include the presence of crackles, while in North America guidelines focus on wheeze. “Perhaps clinicians in the United Kingdom accept the presence of crackles as an expected finding in infant with bronchiolitis and are less likely to order imaging,” Dr. Zorc said (Pediatrics. 2020 Jul 13;146[2]:e20193684).
He also pointed out that the coronavirus pandemic caused by SARS-CoV-2 (COVID- 19) could have an impact on global testing and treatment practices for bronchiolitis, as coronaviruses are a known cause of bronchiolitis. The Pediatric Emergency Research Network, comprising the 38 EDs from which Dr. Zipursky and colleagues drew their data, is conducting a prospective study looking at pediatric disease caused by SARS-CoV-2.
The “collaboration of international networks of pediatric emergency providers is an encouraging sign of potential opportunities to come ... [providing] an opportunity to evaluate variation that can lead to innovation,” Dr. Zorc concluded.
Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures. Dr. Zorc reported no relevant conflicts of interest.
SOURCE: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.
FROM PEDIATRICS
Key clinical point:
Major finding: In a global cohort, 33% of infants received at least one nonrecommended test, most commonly viral tests, chest x-rays, and blood cultures.
Study details: A retrospective cohort of 2,359 infants aged 2-11 months seen in 38 EDs in developed countries.
Disclosures: Dr. Zipursky and colleagues reported no external funding or relevant financial disclosures.
Source: Zipursky A et al. Pediatrics. 2020 Jul 13;146(2):e2020002311.
Influenza vaccine efficacy called undiminished in MS
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
, Jackie Nguyen reported at the virtual annual meeting of the Consortium of Multiple Sclerosis Centers (CMSC). She presented a systematic review and meta-analysis of nine published cohort studies including 417 MS patients and more than 500 healthy controls, all of whom received inactivated seasonal influenza vaccine.
The impetus for this project was a recognition that the great majority of the research on the impact of influenza vaccine in patients with MS has focused on safety and MS relapse rates. In contrast, the nine studies included in the meta-analysis contained data on influenza vaccine efficacy as reflected in the ability to mount an adequate immune response. This was defined in standard fashion either by seroconversion, which required at least a fourfold increase in antibody titers following vaccination, or seroprotection, with a postvaccination antihemagglutination immunoglobulin G titer of at least 40. The analysis included patients with MS irrespective of disease duration or severity or treatment regimen, noted Ms. Nguyen, a third-year medical student at Nova Southeastern University College of Allopathic Medicine in Davie, Fla.
The researchers found that there was no significant difference between patients with MS and healthy controls in the rates of an adequate immune response for influenza H1N1, H3N2, or influenza B virus. “The vaccine should thus continue to be recommended for MS patients, as the data shows it to be efficacious,” she said.
Her conclusion is consistent with guidance provided in the American Academy of Neurology’s 2019 practice guideline update on immunization in MS, highlighted elsewhere at CMSC 2020 in a presentation by Marijean Buhse, PhD, of Stony Brook University in New York.
The guideline, updated for the first time in 17 years, states that all MS patients should be advised to receive influenza vaccine annually: “With known risks of exacerbation and other morbidity with influenza infection and no identified risks of exacerbation with influenza vaccines, benefits of influenza vaccination outweigh the risks in most scenarios. The exception involves the relatively few MS patients having a specific contraindication to the influenza vaccine, such as a previous severe reaction, noted Dr. Buhse, who wasn’t involved in developing the evidence-based guidelines.
The available evidence indicates that some but not all disease-modifying therapies for MS reduce the effectiveness of vaccination against influenza.
According to the guideline, “it is possible” that persons with MS being treated with glatiramer acetate have a reduced likelihood of seroprotection from influenza vaccine, a conclusion the guidelines committee drew with “low confidence in the evidence.” Further, the guideline states that “it is probable” MS patients on fingolimod have a lower likelihood of obtaining seroprotection from influenza vaccine than patients not on the drug, with moderate confidence in the evidence. Also, it is deemed probable that patients with MS who are taking mitoxantrone have a reduced likelihood of response to influenza vaccination, compared with healthy controls. But it is probable that patients with MS who are receiving interferon-beta have no diminution in the likelihood of seroprotection. According to the guideline, there is insufficient evidence to say whether patients with MS who are on natalizumab, teriflunomide, or methotrexate have a diminished response to influenza vaccination.
Dr. Buhse noted that rituximab is off-label therapy for MS, so there are no data available regarding the likelihood of seroprotection in response to influenza vaccination in that setting. However, rituximab profoundly decreases the immunogenicity of influenza and pneumococcal vaccines in rheumatoid arthritis patients. It is therefore recommended that inactivated influenza vaccine be given to patients with MS at least 2 weeks prior to starting rituximab or 6 months after the last dose in order to optimize the humoral results. Ms. Nguyen reported having no financial conflicts regarding her presentation. Dr. Buhse reported having received honoraria from Genzyme and Biogen.
REPORTING FROM CMSC 2020
Diagnosing molluscum contagiosum can be tricky
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
The way James R. Treat, MD, sees it, if there ever were a truism in the field of dermatology, it’s that everyone hates molluscum contagiosum.
“It tortures all of us,” Dr. Treat, a pediatric dermatologist at Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “It’s very distressing to parents, but often more distressing to parents than to kids.”
A viral disorder of the skin and mucous membranes characterized by discrete single or multiple, flesh-colored papules, “When you look at inflamed molluscum it can be very difficult to recognize because it looks like a more complicated infection,” said Dr. Treat, who is also associate professor of clinical pediatrics and dermatology, at the University of Pennsylvania, Philadelphia.
An epidemiologic review of 302 MC cases found that 80% of patients were aged younger than 8 years, 63% had more than 15 lesions, and 24% had concomitant atopic dermatitis (J Am Acad Dermatol. 2006; 2006;54[1]:47-54). “Children with atopic dermatitis often have their molluscum last longer,” he said. “The average time course for molluscum is 18 months, but it can certainly be longer than that. So if you say, ‘it’s probably going to go away in a few months,’ that’s probably not going to happen.”
The telltale MC lesion is glossy and contains a white core in the center that can be revealed by shining an otoscope sideways on the lesion. “Umbilication doesn’t always occur, but if the center part looks white, that will help with diagnosis,” Dr. Treat said. “If they’re inflamed and they’re red and you’re worried that there’s a bacterial infection, do a culture, pop the lesion open, and get some of the pus out. If you’re concerned, start them on antibiotics. It’s always worse to miss an infection than to overtreat molluscum. But once you’ve done it a few times and you realize that the cultures are coming back negative, then you’ll probably have your threshold a little higher.”
The most useful clinical sign of MC is the so-called “BOTE” (beginning of the end) sign, which is characterized by erythema and swelling of MC skin lesions. “When the parents come to us in pediatric dermatology, often it’s because their kids have had molluscum for a while,” he said. “It spreads and becomes inflamed and the parents ask, ‘Is it infected?’ The answer is, yes, it’s an infection, but it’s not infected with what you think it is [which is Staphylococcus or Streptococcus], it’s the virus being recognized by the body. When the virus is recognized by the body, it creates a huge inflammatory reaction. That’s usually the time at which the body has had enough of the virus, and it eradicates the rest of it. It means the inflammatory response is finding the molluscum and it’s going to take care of it.”
MC brings its own eczematous response, which can complicate efforts to confirm the diagnosis. Dr. Treat spoke of a young patient he recently saw who had an eczematous reaction on the inner parts of the arms and the upper flank – with no such clinical history. “It kind of came out of the blue,” he said. “You think about contact allergies and other types of dermatitis, but molluscum brings its own eczema. Often what the parents recognize is the eczematous eruption and not the little dots of molluscum. So if you see someone with a new eruption in typical molluscum areas – the flank and your thighs and the back of the legs – and they’ve never had eczema in the past, or they’ve only had mild eczema, think about eczema as a response to molluscum.”
MC can also result in a Gianotti-Crosti syndrome-like reactions (Arch Dermatol. 2012;148[11]:1257-64). “These are angry, inflamed red papules on the knees and on the elbows and on the buttocks and on the cheeks,” Dr. Treat said. “It typically spares the trunk, and they look like molluscum.”
He went on to note that MC can present as cysts, and that MC in the gluteal cleft is a mimicker of condyloma. MC can also cause conjunctivitis, which is increased in HIV patients and in those with atopic dermatitis. “These are patients who should probably see an ophthalmologist” to make no damage has occurred, Dr. Treat said.
He closed his remarks by noting that rarely, MC can be the presenting sign of an immunodeficiency. “The immune system dysregulation that shows up this way is called a DOCK8 mutation, which have eczema and widespread viral disease including warts and molluscum,” Dr. Treat said.
He reported having no financial disclosures.
FROM PEDIATRIC DERMATOLOGY 2020
Injection beats pill for long-lasting HIV prevention
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Injections of cabotegravir (ViiV Healthcare) given every other month are more effective in blocking HIV transmission than is the once-a-day combination of tenofovir disoproxil fumarate and emtricitabine (Truvada, Gilead Science), new data from the HPTN 083 trial show.
The findings “could transform the HIV prevention landscape for so many people,” said Megan Coleman, DNP, from Whitman-Walker Health in Washington, DC, who regularly prescribes Truvada as pre-exposure prophylaxis (PrEP).
At Whitman-Walker alone, about 3000 people were taking the pill in early 2020, but “for some people, taking a pill every day just isn’t a viable option,” said Coleman. “To have something that can support a patient’s choice and a patient’s ability to reduce their own risk of HIV is amazing.”
Final results from the trial — which looked at the drug in cisgender men and transgender women who have sex with men — were presented at the International AIDS Conference 2020.
Early Study Termination
Half of the 4566 study participants — from 43 sites in Africa, Asia, Latin America, and the United States — were younger than 30 years, 12.4% were transgender women, 29.7% were black, and 46.1% were Hispanic.
By design, ViiV Healthcare, the study sponsor, required that 50% of American participants be black to reflect the population at risk for HIV in the United States, said Raphael Landovitz, MD, from the UCLA David Geffen School of Medicine in Los Angeles, who is protocol chair for HPTN 083. In fact, 49.7% of the American cohort was black and 17.8% was Hispanic.
Patients randomized to the cabotegravir group received daily oral cabotegravir plus daily oral placebo for 5 weeks, to assess safety, followed by a cabotegravir injection at weeks 5 and 9 and every 2 months thereafter out to week 153 plus daily oral placebo. Patients randomized to the Truvada group received daily oral Truvada plus daily oral placebo for 5 weeks, followed by daily oral Truvada plus placebo injection, on the same schedule, out to week 153.
After the final injection, all participants continued on daily oral Truvada for 48 weeks.
The researchers expected to wait until 172 participants acquired HIV; they decided at the outset that this number would be sufficient to power a decision on whether or not cabotegravir injections are better than daily oral Truvada. But by May 2020, when 52 of the study participants had acquired HIV, the results were so lopsided in favor of cabotegravir that the trial was stopped. At that point, all participants were offered cabotegravir injections every 2 months.
Thirty-nine of the 52 (75%) new HIV infections occurred in the Truvada group. In fact, (hazard ratio, 0.34).
“This definitively establishes the superiority of cabotegravir,” said Landovitz.
He and his colleagues had been legitimately concerned that HIV acquisition would be so low in the trial that they wouldn’t be able to show how effective the injectable was. The success of Truvada PrEP has made it difficult to design prevention trials.
“We know that Truvada works extremely well, so the fact that we were able to show that cabotegravir in this population works better” is a powerful observation, said Landovitz. This is especially true because the rates of sexually transmitted infections — which are thought to increase risk for HIV transmission — were so high. Overall, 16.5% of the participants tested positive for syphilis during the trial, 13.3% tested positive for gonorrhea, and 21.1% tested positive for Chlamydia.
Five Surprising Seroconversions
Eleven of the 15 HIV infections in the cabotegravir group occurred in people who had received at least one injection. Three of these infections actually occurred during the first 5 weeks of the study when participants were taking oral cabotegravir, two occurred when participants chose to discontinue the injection and return to daily oral Truvada, and one occurred after a participant missed the injection for a prolonged period of time.
But five of the transmissions occurred in participants who appeared to be perfectly adherent.
Landovitz offered a number of possible reasons for this surprising finding.
“Number one could be that there’s something about these five particular individuals such that they grind up and eliminate the cabotegravir faster than other people, so an 8-week interval is too long for them,” he explained. “Another possibility, although pretty rare, is that there is a rare circulating virus that is intrinsically resistant to cabotegravir.”
Breakthrough HIV transmissions have been rare in people taking oral PrEP.
Disruptions caused by the COVID-19 pandemic have meant that the researchers don’t yet have the data on drug-resistant mutations or drug levels for these five participants, but they will.
“I suspect the truth is that there will never be a 100% failsafe HIV prevention mechanism,” said Landovitz.
“Impressive” Findings
The findings were greeted with excitement, although questions remain.
They are “impressive,” especially the data on black and Hispanic participants, said Paul Sax, MD, medical director of the Division of Infectious Diseases at Brigham and Women’s Hospital in Boston.
However, he said he is interested in the data showing that although participants in both groups gained weight during the study, there was early weight loss in the Truvada group, meaning that those in the cabotegravir group weighed more at the end of the study than those in the Truvada group.
“I’ve been watching the data on weight with integrase inhibitors,” he explained, including weight data specific to Truvada and to the combination of emtricitabine and tenofovir alafenamide (Descovy, Gilead). It looks like Truvada “has some sort of weight-suppressive effects. That’s going to be a thing we’re going to have to watch.”
Coleman said she is already thinking about patients at Whitman-Walker who might do well on cabotegravir and those who can start PrEP for the first time with this option.
“Not only would people probably switch to this option, but maybe people would be interested in starting a biomedical prevention approach that isn’t a pill every day,” she said. “It’s just exciting to have another option. Hopefully, in a few years, we’ll have implantable devices and rings; I can’t even imagine what all those brilliant minds are coming up with.”
But that’s still a ways off. First, cabotegravir has yet to be approved for HIV prevention, and ideally, eventually, there will be a way to determine if cabotegravir is safe for each patient that doesn’t involve a month of daily pills.
“We need to solve that problem because it’s so complicated to do an oral lead-in for a month or so,” said Carl Dieffenbach, PhD, director of the Division of AIDS at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. “Otherwise it’s not going to be feasible.”
We need to make sure this gets licensed for men and women and transgender individuals.
Even with these positive data, Dieffenbach and other officials are not keen to have ViiV apply for licensing right away. Last October, Descovy was the second oral PrEP pill approved for HIV prevention, but only for use by gay men and transgender women — it hadn’t been well studied in cisgender women — causing an outcry. Now, officials are suggesting that ViiV not make the same mistake.
They are urging the company to hold off until data from the sister study of the medication in women — HPTN 084 — is completed in 2022.
“We need to make sure this gets licensed for men and women and transgender individuals,” Dieffenbach told Medscape Medical News. “We just need to give this a little more time and then build a plan with contingencies, so that if something happens, we still have collected all the safety data in women so we can say it’s safe.”
ViiV seems to be making such a plan.
“Our goal is to seek approval across all genders and we will work with the FDA and other regulatory agencies to map out a plan to achieve this goal,” said Kimberly Smith, MD, head of research and development at ViiV Healthcare.
The World Health Organization (WHO), meanwhile, doesn’t expect to change its guidelines on HIV prevention medications until data from HPTN 084 are reported.
“What’s important when we look at guidelines is that we also look across populations,” said Meg Doherty, coordinator of treatment and care in the Department of HIV/AIDS at WHO. “We’re waiting to know more about how cabotegravir works in women, because we certainly want to have prevention drugs that can be used in men and women at different age ranges and, ideally, during pregnancy.”
International AIDS Conference 2020: Abstracts OAXLB01. Presented July 8, 2020.
This article first appeared on Medscape.com.
Children rarely transmit SARS-CoV-2 within households
“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.
In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.
In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said
In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.
The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.
Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).
The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.
In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.
the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”
“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.
The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.
SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.
“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.
In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.
In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said
In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.
The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.
Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).
The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.
In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.
the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”
“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.
The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.
SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.
“Unlike with other viral respiratory infections, children do not seem to be a major vector of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, with most pediatric cases described inside familial clusters and no documentation of child-to-child or child-to-adult transmission,” said Klara M. Posfay-Barbe, MD, of the University of Geneva, Switzerland, and colleagues.
In a study published in Pediatrics, the researchers analyzed data from all COVID-19 patients younger than 16 years who were identified between March 10, 2020, and April 10, 2020, through a hospital surveillance network. Parents and household contacts were called for contact tracing.
In 31 of 39 (79%) households, at least one adult family member had a suspected or confirmed SARS-CoV-2 infection before onset of symptoms in the child. These findings support data from previous studies suggesting that children mainly become infected from adult family members rather than transmitting the virus to them, the researchers said
In only 3 of 39 (8%) households was the study child the first to develop symptoms. “Surprisingly, in 33% of households, symptomatic HHCs [household contacts] tested negative despite belonging to a familial cluster with confirmed SARS-CoV-2 cases, suggesting an underreporting of cases,” Dr. Posfay-Barbe and associates noted.
The findings were limited by several factors including potential underreporting of cases because those with mild or atypical presentations may not have sought medical care, and the inability to confirm child-to-adult transmission. The results were strengthened by the extensive contact tracing and very few individuals lost to follow-up, they said; however, more diagnostic screening and contact tracing are needed to improve understanding of household transmission of SARS-CoV-2, they concluded.
Resolving the issue of how much children contribute to transmission of SARS-CoV-2 is essential to making informed decisions about public health, including how to structure schools and child-care facility reopening, Benjamin Lee, MD, and William V. Raszka Jr., MD, both of the University of Vermont, Burlington, said in an accompanying editorial (Pediatrics. 2020 Jul 10. doi: 10.1542/peds/2020-004879).
The data in the current study support other studies of transmission among household contacts in China suggesting that, in most cases of childhood infections, “the child was not the source of infection and that children most frequently acquire COVID-19 from adults, rather than transmitting it to them,” they wrote.
In addition, the limited data on transmission of SARS-CoV-2 by children outside of the household show few cases of secondary infection from children identified with SARS-CoV-2 in school settings in studies from France and Australia, Dr. Lee and Dr. Raszka noted.
the editorialists wrote. “This would be another manner by which SARS-CoV2 differs drastically from influenza, for which school-based transmission is well recognized as a significant driver of epidemic disease and forms the basis for most evidence regarding school closures as public health strategy.”
“Therefore, serious consideration should be paid toward strategies that allow schools to remain open, even during periods of COVID-19 spread,” the editorialists concluded. “In doing so, we could minimize the potentially profound adverse social, developmental, and health costs that our children will continue to suffer until an effective treatment or vaccine can be developed and distributed or, failing that, until we reach herd immunity,” Dr. Lee and Dr. Raszka emphasized.
The study received no outside funding. The researchers and editorialists had no financial conflicts to disclose.
SOURCE: Posfay-Barbe KM et al. Pediatrics. 2020 Jul 10. doi: 10.1542/peds.2020-1576.
FROM PEDIATRICS
Risky business: Longer-course prophylactic perioperative antimicrobials
Background: National guidelines recommend that surgical prophylactic antimicrobials be initiated within 1 hour prior to incision and discontinued 24 hours postoperatively. However, the risks and benefits of longer duration of antimicrobials are uncertain.
Study design: Retrospective cohort study.
Setting: Veterans Affairs hospitals.
Synopsis: After stratification by type of surgery and adjustment for covariates, antibiotic prophylaxis greater than 24 hours was not associated with lower SSI risk.
However, the odds of postoperative AKI increased with each additional day of prophylaxis (adjusted odds ratios, 1.82; 95% confidence interval,1.54-2.16 and aOR, 1.79; 95% CI, 1.27-2.53) with longer than 72 hours prophylaxis for cardiac and noncardiac surgery, respectively). Similarly, C. difficile infections increased with each additional day beyond 24 hours (aOR, 3.65; 95% CI, 2.40-5.55 with more than 72 hours of use).
Bottom line: Each day of perioperative antimicrobial prophylaxis beyond 24 hours increases the risk for postoperative AKI or C. difficile infection without reducing the risk of surgical site infection.
Citation: Branch-Elliman W et al. Association of duration and type of surgical prophylaxis with antimicrobial-associated adverse events. JAMA Surg. 2019 Apr 24. doi: 10.1001/jamasurg.2019.0569.
Dr. Miller is a hospitalist at the University of Colorado at Denver, Aurora.
Background: National guidelines recommend that surgical prophylactic antimicrobials be initiated within 1 hour prior to incision and discontinued 24 hours postoperatively. However, the risks and benefits of longer duration of antimicrobials are uncertain.
Study design: Retrospective cohort study.
Setting: Veterans Affairs hospitals.
Synopsis: After stratification by type of surgery and adjustment for covariates, antibiotic prophylaxis greater than 24 hours was not associated with lower SSI risk.
However, the odds of postoperative AKI increased with each additional day of prophylaxis (adjusted odds ratios, 1.82; 95% confidence interval,1.54-2.16 and aOR, 1.79; 95% CI, 1.27-2.53) with longer than 72 hours prophylaxis for cardiac and noncardiac surgery, respectively). Similarly, C. difficile infections increased with each additional day beyond 24 hours (aOR, 3.65; 95% CI, 2.40-5.55 with more than 72 hours of use).
Bottom line: Each day of perioperative antimicrobial prophylaxis beyond 24 hours increases the risk for postoperative AKI or C. difficile infection without reducing the risk of surgical site infection.
Citation: Branch-Elliman W et al. Association of duration and type of surgical prophylaxis with antimicrobial-associated adverse events. JAMA Surg. 2019 Apr 24. doi: 10.1001/jamasurg.2019.0569.
Dr. Miller is a hospitalist at the University of Colorado at Denver, Aurora.
Background: National guidelines recommend that surgical prophylactic antimicrobials be initiated within 1 hour prior to incision and discontinued 24 hours postoperatively. However, the risks and benefits of longer duration of antimicrobials are uncertain.
Study design: Retrospective cohort study.
Setting: Veterans Affairs hospitals.
Synopsis: After stratification by type of surgery and adjustment for covariates, antibiotic prophylaxis greater than 24 hours was not associated with lower SSI risk.
However, the odds of postoperative AKI increased with each additional day of prophylaxis (adjusted odds ratios, 1.82; 95% confidence interval,1.54-2.16 and aOR, 1.79; 95% CI, 1.27-2.53) with longer than 72 hours prophylaxis for cardiac and noncardiac surgery, respectively). Similarly, C. difficile infections increased with each additional day beyond 24 hours (aOR, 3.65; 95% CI, 2.40-5.55 with more than 72 hours of use).
Bottom line: Each day of perioperative antimicrobial prophylaxis beyond 24 hours increases the risk for postoperative AKI or C. difficile infection without reducing the risk of surgical site infection.
Citation: Branch-Elliman W et al. Association of duration and type of surgical prophylaxis with antimicrobial-associated adverse events. JAMA Surg. 2019 Apr 24. doi: 10.1001/jamasurg.2019.0569.
Dr. Miller is a hospitalist at the University of Colorado at Denver, Aurora.
Even a few days of steroids may be risky, new study suggests
Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.
Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.
In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.
With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.
Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.
“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.
The findings were published online July 6 in Annals of Internal Medicine.
Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.
Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.
“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.
The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.
Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).
The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.
“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.
Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.
“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.
Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.
In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”
She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”
She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.
But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.
“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.
Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.
Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.
According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.
The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
A version of this article originally appeared on Medscape.com.
Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.
Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.
In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.
With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.
Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.
“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.
The findings were published online July 6 in Annals of Internal Medicine.
Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.
Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.
“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.
The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.
Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).
The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.
“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.
Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.
“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.
Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.
In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”
She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”
She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.
But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.
“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.
Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.
Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.
According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.
The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
A version of this article originally appeared on Medscape.com.
Extended use of corticosteroids for chronic inflammatory conditions puts patients at risk for serious adverse events (AEs), including cardiovascular disease, osteoporosis, cataracts, and diabetes. Now, a growing body of evidence suggests that even short bursts of these drugs are associated with serious risks.
Most recently, a population-based study of more than 2.6 million people found that taking corticosteroids for 14 days or less was associated with a substantially greater risk for gastrointestinal (GI) bleeding, sepsis, and heart failure, particularly within the first 30 days after therapy.
In the study, Tsung-Chieh Yao, MD, PhD, a professor in the division of allergy, asthma, and rheumatology in the department of pediatrics at Chang Gung Memorial Hospital in Taoyuan, Taiwan, and colleagues used a self-controlled case series to analyze data from Taiwan’s National Health Insurance Research Database of medical claims. They compared patients’ conditions in the period from 5 to 90 days before treatment to conditions from the periods from 5 to 30 days and from 31 to 90 days after therapy.
With a median duration of 3 days of treatment, the incidence rate ratios (IRRs) were 1.80 (95% confidence interval, 1.75-1.84) for GI bleeding, 1.99 (95% CI, 1.70-2.32) for sepsis, and 2.37 (95% CI, 2.13-2.63) for heart failure.
Given the findings, physicians should weigh the benefits against the risks of rare but potentially serious consequences of these anti-inflammatory drugs, according to the authors.
“After initiating patients on oral steroid bursts, physicians should be on the lookout for these severe adverse events, particularly within the first month after initiation of steroid therapy,” Dr. Yao said in an interview.
The findings were published online July 6 in Annals of Internal Medicine.
Of the 15,859,129 adult Asians in the Taiwanese database, the study included 2,623,327 adults aged 20-64 years who received single steroid bursts (14 days or less) between Jan. 1, 2013, and Dec. 31, 2015.
Almost 60% of the indications were for skin disorders, such as eczema and urticaria, and for respiratory tract infections, such as sinusitis and acute pharyngitis. Among specialties, dermatology, otolaryngology, family practice, internal medicine, and pediatrics accounted for 88% of prescriptions.
“Our findings are important for physicians and guideline developers because short-term use of oral corticosteroids is common and the real-world safety of this approach remains unclear,” the authors wrote. They acknowledged that the database did not provide information on such potential confounders as disease severity and lifestyle factors, nor did it include children and vulnerable individuals, which may limit the generalizability of the results.
The findings echo those of a 2017 cohort study conducted by researchers at the University of Michigan in Ann Arbor. That study, by Akbar K. Waljee, MD, assistant professor of gastroenterology, University of Michigan, Ann Arbor, and colleagues, included data on more than 1.5 million privately insured U.S. adults. The researchers included somewhat longer steroid bursts of up to 30 days’ duration and found that use of the drugs was associated with a greater than fivefold increased risk for sepsis, a more than threefold increased risk for venous thromboembolism, and a nearly twofold increased risk for fracture within 30 days of starting treatment.
Furthermore, the elevated risk persisted at prednisone-equivalent doses of less than 20 mg/d (IRR, 4.02 for sepsis, 3.61 for venous thromboembolism, and 1.83 for fracture; all P < .001).
The U.S. study also found that during the 3-year period from 2012 to 2014, more than 20% of patients were prescribed short-term oral corticosteroids.
“Both studies indicate that these short-term regimens are more common in the real world than was previously thought and are not risk free,” Dr. Yao said.
Recognition that corticosteroids are associated with adverse events has been building for decades, according to the authors of an editorial that accompanies the new study.
“However, we commonly use short corticosteroid ‘bursts’ for minor ailments despite a lack of evidence for meaningful benefit. We are now learning that bursts as short as 3 days may increase risk for serious AEs, even in young and healthy people,” wrote editorialists Beth I. Wallace, MD, of the Center for Clinical Management Research at the VA Ann Arbor Healthcare System and the Institute for Healthcare Policy and Innovation at Michigan Medicine, Ann Arbor, and Dr. Waljee, who led the 2017 study.
Dr. Wallace and Dr. Waljee drew parallels between corticosteroid bursts and other short-term regimens, such as of antibiotics and opiates, in which prescriber preference and sometimes patient pressure play a role. “All of these treatments have well-defined indications but can cause net harm when used. We can thus conceive of a corticosteroid stewardship model of targeted interventions that aims to reduce inappropriate prescribing,” they wrote.
In an interview, Dr. Wallace, a rheumatologist who prescribes oral steroids fairly frequently, noted that the Taiwan study is the first to investigate steroid bursts. “Up till now, these very short courses have flown under the radar. Clinicians very commonly prescribe short courses to help relieve symptoms of self-limited conditions like bronchitis, and we assume that because the exposure duration is short, the risks are low, especially for patients who are otherwise healthy.”
She warned that the data in the current study indicate that these short bursts – even at the lower end of the 1- to 2-week courses American physicians prescribe most often – carry small but real increases in risk for serious AEs. “And these increases were seen in young, healthy people, not just in people with preexisting conditions,” she said. “So, we might need to start thinking harder about how we are prescribing even these very short courses of steroids and try to use steroids only when their meaningful benefits really outweigh the risk.”
She noted that a patient with a chronic inflammatory condition such as rheumatoid arthritis may benefit substantially from short-term steroids to treat a disease flare. In that specific case, the benefits of short-term steroids may outweigh the risks, Dr. Wallace said.
But not everyone thinks a new strategy is needed. For Whitney A. High, MD, associate professor of dermatology and pathology at the University of Colorado at Denver, Aurora, the overprescribing of short-term corticosteroids is not a problem, and dermatologists are already exercising caution.
“I only prescribe these drugs short term to, at a guess, about 1 in 40 patients and only when a patient is miserable and quality of life is being seriously affected,” he said in an interview. “And that’s something that can’t be measured in a database study like the one from Taiwan but only in a risk-benefit analysis,” he said.
Furthermore, dermatologists have other drugs and technologies in their armamentarium, including topical steroids with occlusion or with wet wraps, phototherapy, phosphodiesterase inhibitors, calcipotriene, methotrexate and other immunosuppressive agents, and biologics. “In fact, many of these agents are specifically referred to as steroid-sparing,” Dr. High said.
Nor does he experience much pressure from patients to prescribe these drugs. “While occasionally I may encounter a patient who places pressure on me for oral steroids, it’s probably not nearly as frequently as providers in other fields are pressured to prescribe antibiotics or narcotics,” he said.
According to the Taiwanese researchers, the next step is to conduct more studies, including clinical trials, to determine optimal use of corticosteroids by monitoring adverse events. In the meantime, for practitioners such as Dr. Wallace and Dr. High, there is ample evidence from several recent studies of the harms of short-term corticosteroids, whereas the benefits for patients with self-limiting conditions remain uncertain. “This and other studies like it quite appropriately remind providers to avoid oral steroids when they’re not necessary and to seek alternatives where possible,” Dr. High said.
The study was supported by the National Health Research Institutes of Taiwan, the Ministry of Science and Technology of Taiwan, the Chang Gung Medical Foundation, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH). Dr. Yao has disclosed no relevant financial relationships. Dr. Wu has received grants from GlaxoSmithKline outside the submitted work. The editorialists and Dr. High have disclosed no relevant financial relationships. Dr. Wallace received an NIH grant during the writing of the editorial.
A version of this article originally appeared on Medscape.com.
Retreatment of Hepatitis C Infection With Direct-Acting Antivirals
An estimated 3.5 million people in the US have chronic hepatitis C virus (HCV) infection, and between 10% and 20% of those developed cirrhosis over 20 to 30 years.1 There are at least 6 genotypes (GTs) of HCV, with GT1 being the most common in the US and previously one of the most difficult to treat.2,3 The goal of treatment is to achieve viral cure, called sustained virologic response (SVR) when HCV viral load remains undetectable several weeks after therapy completion. In the 2000s, pegylated interferon (pegIFN) and ribavirin (RBV) were the standard of care.2 For patients with GT1 infections, an SVR of 40 to 50% was commonly seen after 48 weeks of pegIFN/RBV regimens compared with 70 to 80% SVR for GT2 or GT3 after 24 weeks of pegIFN/RBV therapy.2 However, treatment has evolved rapidly (Table 1).2-17
In 2011, the US Food and Drug Administration (FDA) approved the protease inhibitors (PIs) boceprevir and telaprevir, which added a new class of agents with increased SVR for patients with GT1 infection; however, pegIFN and RBV were still needed for treatment.4 In addition, both PIs required multiple doses per day and strict adherence to an 8-hour schedule.4 Boceprevir required treatment with RBV and pegIFN for 48 weeks unless futility rule was met at 24 weeks of treatment (ie, viral load still detectable).4 The SVR in patients with GT1 infection improved to > 65% for patients in clinical trials.2 FDA approval of the direct-acting antivirals (DAAs) sofosbuvir and simeprevir in late 2013 decreased the usual duration of therapy to only 12 weeks with improved SVR rates 12 weeks posttherapy (SVR12) to 90% or higher.2,6,10
FDA approval of ledipasvir (LDV)/sofosbuvir (SOF) in October 2014 resulted in the first interferon-free all-oral regimen indicated for HCV GT1 infection.11 In December 2014, FDA approved a combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD).12 In 2015 GT-specific approvals were issued for daclastavir to be used with SOV for GT1 and GT3 and a combination similar to PrOD without dasabuvir (PrO) for GT4.13 In 2016, a combination of elbasvir (ERB) and grazoprevir (GZP) was approved for GT1 and GT4.14
In 2016, a pangenotypic DAA of SOF and velpatasvir (VEL) was approved.15 Most recently, combinations of SOF, VEL, and voxilaprevir (VOX), and glecaprevir (GLE) and pibrentasvir (PIB) were approved for patients with previous DAA treatment failures.7, 8,16,17 These oral regimens avoided the significant adverse events (AEs) associated with pegIFN and RBV (eg, thrombocytopenia, depression), were expected to improve treatment adherence and shorten duration of therapy.
The West Palm Beach Veterans Affairs has had a nurse practitioner (NP)-based HCV treatment clinic since the late 1990s. When PIs became available, a CPS started reviewing patient electronic health records (EHRs) and monitored response to therapy along with the NP to ensure discontinuation of therapy if futility criteria were met.7 Our unpublished experience showed SVR > 60% with both boceprevir and SOF regimens and > 90% with oral DAA regimens.
This review will provide the SVR rates for patients that needed retreatment for HCV infection since 2015 until December 2019. We treated all willing patients, beginning with the patients who had experienced failures with previous regimens. Patients first received education on HCV infection and treatment options in a group class then they were seen by the NP individually for specific education on treatment. The CPS reviewed the patient’s medical record to assess for appropriate therapy, possible drug-drug interactions and contraindications to therapy. In addition, patient outcomes (eg, viral load, AEs) were documented by the CPS in collaboration with the NP throughout treatment until viral load for SVR evaluation was obtained.
Methods
A retrospective EHR review of patients retreated from January 2015 to December 2019 was conducted. Data collected included age, sex, HCV GT, previous therapy, new medications prescribed, creatinine clearance, and achievement of SVR12. This retrospective review was approved by the facility’s scientific advisory committee as part of performance improvement efforts. Descriptive statistics are provided.
Results
Boceprevir
We treated 31 patients with boceprevir of which 3 met futility rule and 28 completed therapy. Eighteen of 28 responded (64%) to the treatment. The 10 patients who failed treatment were retreated with LDV/SOF, and all achieved SVR.
Sofosbuvir
A total of 53 patients were treated with SOF, RBV, and pegIFN for 12 weeks. Forty-one achieved SVR (77%). Of the 12 who failed therapy, all have been retreated and achieved SVR (Table 2).
Interferon-Free DAA Oral Regimens
More than 900 patients have been treated with interferon-free regimens since 2015 and outcomes were documented for > 800 patients. The SVR rates by GT were as follows: GT1 639 of 676 (95%); GT2 76 of 79 (96%); GT3 40 of 48 (83%); and GT4 6 of 6 (100%). Eighty-four percent of patients had GT1 infection. The median age of patient was 62 years, 72% were treatment naïve, and 35% having cirrhosis (based on liver biopsy or FIB4 score).18
Of 48 treatment failures, 30 patients were retreated; the rest of the patients were lost to follow-up (n = 9) or unable to receive retreatment (n = 9) mainly due to decompensated cirrhosis or liver cancer and short life expectancy. The median age of patient in this retreatment group was 62 years, 62% had cirrhosis, and most were infected with GT1. The average creatinine clearance was 73 mL/min. Twenty-two patients who failed therapy with ledipasvir/SOF were retreated (Table 3). A total of 13 patients out of the 19 tested eventually achieved SVR (68%). Four of the patients who had treatment failure again had GT1 infection and the other 2 GT3. All had cirrhosis.
Thirty-five patients were treated with PrOD, and 32 achieved SVR (91%). All 3 patients were retreated. One patient each achieved SVR with ERB/GZP, SOF/VEL and SOF/VEL/VOX. Fifty patients were treated with ERB/GZP and 45 achieved SVR (90%). All 5 treatment failures were retreated. Four achieved SVR and 1 was lost to follow-up (Table 4). Overall, of 30 patients who were retreated after failure with an all-oral DAA regimen, 27 patients had SVR values available and 21 achieved it (78%).
Discussion
Overall SVR was very high for patients who received oral treatment for HCV infection. A low number of patients failed therapy and were retreated. Patients who failed therapy again were similar in age but were more likely to have cirrhosis when compared with the overall interferon-free treated group. Thus, prompt treatment after HCV detection and before disease progression may improve treatment outcomes. Achieving SVR has been shown to improve fibrosis, portal hypertension, splenomegaly and cirrhosis, and reduce the risk of hepatocellular carcinoma by 70% and liver-related mortality by 90%.19-21/
Patients who failed therapy primarily had GT1—the most prevalent GT treated. A higher prevalence of GT1 is expected since it is the most common GT in the US.6 However, disease progression occurs more rapidly in those with GT3 and is more difficult to treat.22 The overall response rate was lower with this GT (83%) in this report, with only 1 of 3 patients retreated achieving an SVR.
Similar results are documented in retreatment trials.23 In the POLARIS-1 trial, treatment with SOF/VEL/VOX resulted in an overall response rate of 96% but only 91% for patients with GT3, compared with 95 to 100% for GTs 1, 2, or 4.23 In the current report, only 1 patient (GT1) failed retreatment with SOF/VEL/VOX. At this time, there are no clear treatment options for this patient. However, patients who fail GLE/PIB (none so far in the current report) may be able to receive SOF/VEL/VOX.24 In a small study, 29 of 31 patients achieved SVR with SOF/VEL/VOX after GLE/PIB failure (12 of 13 GT1 and 17 of 18 GT3).24
Limitations
This review was an observational, nonrandomized design, and only 1 medical center was involved. These results may not be applicable to other patient populations without a clinic set up with routine follow-ups to encourage adherence and completion of therapy.
Conclusions
Treatment of HCV infection has improved significantly over the past 10 years. Use of DAAs results in SVR for > 90% of patients, especially if the disease had not progressed to cirrhosis. Failure after retreatment for HCV infection was rare as well. Given that cirrhosis seems to increase the chance of treatment failure, it is imperative to identify candidates for treatment before the infection has progressed to cirrhosis. Patients infected with GT3 in particular should be more aggressively identified and treated.
Acknowledgments
The authors thank Nick P. Becky, PharmD, for his contributions to the identification of patients needing treatment for their HCV infection and review of initial manuscript information.
1. Centers for Disease Control and Prevention. Viral hepatitis: hepatitis C information. https://www.cdc.gov/hepatitis/hcv/index.htm. Reviewed April 14, 2020. Accessed June 16, 2020.
2. American Association for the Study of Liver Disease, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org. Accessed June 16, 2020.
3. Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin N Am. 2015;44(4):717-734. doi:10.1016/j.gtc.2015.07.003
4. Foote BS, Spooner LM, Belliveau PP. Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. Ann Pharmacother. 2011;45(9):1085-1093. doi:10.1345/aph.1P744
5. Kayali Z, Schmidt WN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med. 2014:7:387-398. doi:10.2147/PGPM.S52629
6. Falade-Nwulis O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166(9):637-648. doi:10.7326/M16-2575
7. Carrion AF, Martin P. Glecaprevir + pibrentasvir for treatment of hepatitis C. Expert Opinion Pharmacother. 2018;19(4):413-419. doi:10.1080/14656566.2018.1444030
8. Chahine EB, Kelley D, Childs-Kean LM. Sofosbuvir/velpatasvir/voxilaprevir: a pan-genotypic direct-acting antiviral combination for hepatitis C. Ann Pharmacother. 2018;52(4):352-363. doi:10.1177/1060028017741508
9. Lagasca AM, Kan VL. Hepatitis C treatment at a Veteran Affairs medical center after the availability of direct-acting agents: things are looking up. Clin Infect Dis. 2015:61(8):1347-1349. doi:10.1093/cid/civ573
10. Sovaldi (sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
11. Harvoni (ledipasvir and sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
12. Viekira Pak (ombitasvir, paritaprevir and ritonavir; dasabuvir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
13. Technivie (ombitasvir, paritaprevir and ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
14. Zepatier (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2018.
15. Epclusa (sofosbuvir and velpatasvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
16. Mavyret (glecaprevir and pibrentasvir) [package insert]. North Chicago, IL: AbbVie Inc; 2019.
17. Vosevi (sofosbuvir, velpatasvir and voxilaprevir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
18. Vallet-Pichard A, Mallet V, Nalpas V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology. 2017;46(1):32-36. doi:10.1002/hep.21669
19. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5, pt 1):329-337. doi:10.7326/0003-4819-158-5-201303050-00005
20. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
21. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-684. doi:10.7326/0003-4819-147-10-200711200-00003
22. Chen A, Patel K, Naggie S. Genotype 3 infection: the last stand of hepatitis C virus. Drugs. 2017;77(2):131-144. doi:10.1007/s40265-016-0685-x
23. Bourlière M, Gordon SC, Flamm SL, et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, velpatasvir and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2136-2146. doi:10.1056/NEJMoa1613512
24. Pearlman B, Perrys M, Hinds A. Sofosbuvir/velpatasvir/voxilaprevir for previous treatment failures with glecaprevir/pibrentasvir in chronic hepatitis C infection. Am J Gastroenterol. 2019;114(9):1550-1552. doi:10.14309/ajg.0000000000000248
An estimated 3.5 million people in the US have chronic hepatitis C virus (HCV) infection, and between 10% and 20% of those developed cirrhosis over 20 to 30 years.1 There are at least 6 genotypes (GTs) of HCV, with GT1 being the most common in the US and previously one of the most difficult to treat.2,3 The goal of treatment is to achieve viral cure, called sustained virologic response (SVR) when HCV viral load remains undetectable several weeks after therapy completion. In the 2000s, pegylated interferon (pegIFN) and ribavirin (RBV) were the standard of care.2 For patients with GT1 infections, an SVR of 40 to 50% was commonly seen after 48 weeks of pegIFN/RBV regimens compared with 70 to 80% SVR for GT2 or GT3 after 24 weeks of pegIFN/RBV therapy.2 However, treatment has evolved rapidly (Table 1).2-17
In 2011, the US Food and Drug Administration (FDA) approved the protease inhibitors (PIs) boceprevir and telaprevir, which added a new class of agents with increased SVR for patients with GT1 infection; however, pegIFN and RBV were still needed for treatment.4 In addition, both PIs required multiple doses per day and strict adherence to an 8-hour schedule.4 Boceprevir required treatment with RBV and pegIFN for 48 weeks unless futility rule was met at 24 weeks of treatment (ie, viral load still detectable).4 The SVR in patients with GT1 infection improved to > 65% for patients in clinical trials.2 FDA approval of the direct-acting antivirals (DAAs) sofosbuvir and simeprevir in late 2013 decreased the usual duration of therapy to only 12 weeks with improved SVR rates 12 weeks posttherapy (SVR12) to 90% or higher.2,6,10
FDA approval of ledipasvir (LDV)/sofosbuvir (SOF) in October 2014 resulted in the first interferon-free all-oral regimen indicated for HCV GT1 infection.11 In December 2014, FDA approved a combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD).12 In 2015 GT-specific approvals were issued for daclastavir to be used with SOV for GT1 and GT3 and a combination similar to PrOD without dasabuvir (PrO) for GT4.13 In 2016, a combination of elbasvir (ERB) and grazoprevir (GZP) was approved for GT1 and GT4.14
In 2016, a pangenotypic DAA of SOF and velpatasvir (VEL) was approved.15 Most recently, combinations of SOF, VEL, and voxilaprevir (VOX), and glecaprevir (GLE) and pibrentasvir (PIB) were approved for patients with previous DAA treatment failures.7, 8,16,17 These oral regimens avoided the significant adverse events (AEs) associated with pegIFN and RBV (eg, thrombocytopenia, depression), were expected to improve treatment adherence and shorten duration of therapy.
The West Palm Beach Veterans Affairs has had a nurse practitioner (NP)-based HCV treatment clinic since the late 1990s. When PIs became available, a CPS started reviewing patient electronic health records (EHRs) and monitored response to therapy along with the NP to ensure discontinuation of therapy if futility criteria were met.7 Our unpublished experience showed SVR > 60% with both boceprevir and SOF regimens and > 90% with oral DAA regimens.
This review will provide the SVR rates for patients that needed retreatment for HCV infection since 2015 until December 2019. We treated all willing patients, beginning with the patients who had experienced failures with previous regimens. Patients first received education on HCV infection and treatment options in a group class then they were seen by the NP individually for specific education on treatment. The CPS reviewed the patient’s medical record to assess for appropriate therapy, possible drug-drug interactions and contraindications to therapy. In addition, patient outcomes (eg, viral load, AEs) were documented by the CPS in collaboration with the NP throughout treatment until viral load for SVR evaluation was obtained.
Methods
A retrospective EHR review of patients retreated from January 2015 to December 2019 was conducted. Data collected included age, sex, HCV GT, previous therapy, new medications prescribed, creatinine clearance, and achievement of SVR12. This retrospective review was approved by the facility’s scientific advisory committee as part of performance improvement efforts. Descriptive statistics are provided.
Results
Boceprevir
We treated 31 patients with boceprevir of which 3 met futility rule and 28 completed therapy. Eighteen of 28 responded (64%) to the treatment. The 10 patients who failed treatment were retreated with LDV/SOF, and all achieved SVR.
Sofosbuvir
A total of 53 patients were treated with SOF, RBV, and pegIFN for 12 weeks. Forty-one achieved SVR (77%). Of the 12 who failed therapy, all have been retreated and achieved SVR (Table 2).
Interferon-Free DAA Oral Regimens
More than 900 patients have been treated with interferon-free regimens since 2015 and outcomes were documented for > 800 patients. The SVR rates by GT were as follows: GT1 639 of 676 (95%); GT2 76 of 79 (96%); GT3 40 of 48 (83%); and GT4 6 of 6 (100%). Eighty-four percent of patients had GT1 infection. The median age of patient was 62 years, 72% were treatment naïve, and 35% having cirrhosis (based on liver biopsy or FIB4 score).18
Of 48 treatment failures, 30 patients were retreated; the rest of the patients were lost to follow-up (n = 9) or unable to receive retreatment (n = 9) mainly due to decompensated cirrhosis or liver cancer and short life expectancy. The median age of patient in this retreatment group was 62 years, 62% had cirrhosis, and most were infected with GT1. The average creatinine clearance was 73 mL/min. Twenty-two patients who failed therapy with ledipasvir/SOF were retreated (Table 3). A total of 13 patients out of the 19 tested eventually achieved SVR (68%). Four of the patients who had treatment failure again had GT1 infection and the other 2 GT3. All had cirrhosis.
Thirty-five patients were treated with PrOD, and 32 achieved SVR (91%). All 3 patients were retreated. One patient each achieved SVR with ERB/GZP, SOF/VEL and SOF/VEL/VOX. Fifty patients were treated with ERB/GZP and 45 achieved SVR (90%). All 5 treatment failures were retreated. Four achieved SVR and 1 was lost to follow-up (Table 4). Overall, of 30 patients who were retreated after failure with an all-oral DAA regimen, 27 patients had SVR values available and 21 achieved it (78%).
Discussion
Overall SVR was very high for patients who received oral treatment for HCV infection. A low number of patients failed therapy and were retreated. Patients who failed therapy again were similar in age but were more likely to have cirrhosis when compared with the overall interferon-free treated group. Thus, prompt treatment after HCV detection and before disease progression may improve treatment outcomes. Achieving SVR has been shown to improve fibrosis, portal hypertension, splenomegaly and cirrhosis, and reduce the risk of hepatocellular carcinoma by 70% and liver-related mortality by 90%.19-21/
Patients who failed therapy primarily had GT1—the most prevalent GT treated. A higher prevalence of GT1 is expected since it is the most common GT in the US.6 However, disease progression occurs more rapidly in those with GT3 and is more difficult to treat.22 The overall response rate was lower with this GT (83%) in this report, with only 1 of 3 patients retreated achieving an SVR.
Similar results are documented in retreatment trials.23 In the POLARIS-1 trial, treatment with SOF/VEL/VOX resulted in an overall response rate of 96% but only 91% for patients with GT3, compared with 95 to 100% for GTs 1, 2, or 4.23 In the current report, only 1 patient (GT1) failed retreatment with SOF/VEL/VOX. At this time, there are no clear treatment options for this patient. However, patients who fail GLE/PIB (none so far in the current report) may be able to receive SOF/VEL/VOX.24 In a small study, 29 of 31 patients achieved SVR with SOF/VEL/VOX after GLE/PIB failure (12 of 13 GT1 and 17 of 18 GT3).24
Limitations
This review was an observational, nonrandomized design, and only 1 medical center was involved. These results may not be applicable to other patient populations without a clinic set up with routine follow-ups to encourage adherence and completion of therapy.
Conclusions
Treatment of HCV infection has improved significantly over the past 10 years. Use of DAAs results in SVR for > 90% of patients, especially if the disease had not progressed to cirrhosis. Failure after retreatment for HCV infection was rare as well. Given that cirrhosis seems to increase the chance of treatment failure, it is imperative to identify candidates for treatment before the infection has progressed to cirrhosis. Patients infected with GT3 in particular should be more aggressively identified and treated.
Acknowledgments
The authors thank Nick P. Becky, PharmD, for his contributions to the identification of patients needing treatment for their HCV infection and review of initial manuscript information.
An estimated 3.5 million people in the US have chronic hepatitis C virus (HCV) infection, and between 10% and 20% of those developed cirrhosis over 20 to 30 years.1 There are at least 6 genotypes (GTs) of HCV, with GT1 being the most common in the US and previously one of the most difficult to treat.2,3 The goal of treatment is to achieve viral cure, called sustained virologic response (SVR) when HCV viral load remains undetectable several weeks after therapy completion. In the 2000s, pegylated interferon (pegIFN) and ribavirin (RBV) were the standard of care.2 For patients with GT1 infections, an SVR of 40 to 50% was commonly seen after 48 weeks of pegIFN/RBV regimens compared with 70 to 80% SVR for GT2 or GT3 after 24 weeks of pegIFN/RBV therapy.2 However, treatment has evolved rapidly (Table 1).2-17
In 2011, the US Food and Drug Administration (FDA) approved the protease inhibitors (PIs) boceprevir and telaprevir, which added a new class of agents with increased SVR for patients with GT1 infection; however, pegIFN and RBV were still needed for treatment.4 In addition, both PIs required multiple doses per day and strict adherence to an 8-hour schedule.4 Boceprevir required treatment with RBV and pegIFN for 48 weeks unless futility rule was met at 24 weeks of treatment (ie, viral load still detectable).4 The SVR in patients with GT1 infection improved to > 65% for patients in clinical trials.2 FDA approval of the direct-acting antivirals (DAAs) sofosbuvir and simeprevir in late 2013 decreased the usual duration of therapy to only 12 weeks with improved SVR rates 12 weeks posttherapy (SVR12) to 90% or higher.2,6,10
FDA approval of ledipasvir (LDV)/sofosbuvir (SOF) in October 2014 resulted in the first interferon-free all-oral regimen indicated for HCV GT1 infection.11 In December 2014, FDA approved a combination of paritaprevir, ritonavir, ombitasvir, and dasabuvir (PrOD).12 In 2015 GT-specific approvals were issued for daclastavir to be used with SOV for GT1 and GT3 and a combination similar to PrOD without dasabuvir (PrO) for GT4.13 In 2016, a combination of elbasvir (ERB) and grazoprevir (GZP) was approved for GT1 and GT4.14
In 2016, a pangenotypic DAA of SOF and velpatasvir (VEL) was approved.15 Most recently, combinations of SOF, VEL, and voxilaprevir (VOX), and glecaprevir (GLE) and pibrentasvir (PIB) were approved for patients with previous DAA treatment failures.7, 8,16,17 These oral regimens avoided the significant adverse events (AEs) associated with pegIFN and RBV (eg, thrombocytopenia, depression), were expected to improve treatment adherence and shorten duration of therapy.
The West Palm Beach Veterans Affairs has had a nurse practitioner (NP)-based HCV treatment clinic since the late 1990s. When PIs became available, a CPS started reviewing patient electronic health records (EHRs) and monitored response to therapy along with the NP to ensure discontinuation of therapy if futility criteria were met.7 Our unpublished experience showed SVR > 60% with both boceprevir and SOF regimens and > 90% with oral DAA regimens.
This review will provide the SVR rates for patients that needed retreatment for HCV infection since 2015 until December 2019. We treated all willing patients, beginning with the patients who had experienced failures with previous regimens. Patients first received education on HCV infection and treatment options in a group class then they were seen by the NP individually for specific education on treatment. The CPS reviewed the patient’s medical record to assess for appropriate therapy, possible drug-drug interactions and contraindications to therapy. In addition, patient outcomes (eg, viral load, AEs) were documented by the CPS in collaboration with the NP throughout treatment until viral load for SVR evaluation was obtained.
Methods
A retrospective EHR review of patients retreated from January 2015 to December 2019 was conducted. Data collected included age, sex, HCV GT, previous therapy, new medications prescribed, creatinine clearance, and achievement of SVR12. This retrospective review was approved by the facility’s scientific advisory committee as part of performance improvement efforts. Descriptive statistics are provided.
Results
Boceprevir
We treated 31 patients with boceprevir of which 3 met futility rule and 28 completed therapy. Eighteen of 28 responded (64%) to the treatment. The 10 patients who failed treatment were retreated with LDV/SOF, and all achieved SVR.
Sofosbuvir
A total of 53 patients were treated with SOF, RBV, and pegIFN for 12 weeks. Forty-one achieved SVR (77%). Of the 12 who failed therapy, all have been retreated and achieved SVR (Table 2).
Interferon-Free DAA Oral Regimens
More than 900 patients have been treated with interferon-free regimens since 2015 and outcomes were documented for > 800 patients. The SVR rates by GT were as follows: GT1 639 of 676 (95%); GT2 76 of 79 (96%); GT3 40 of 48 (83%); and GT4 6 of 6 (100%). Eighty-four percent of patients had GT1 infection. The median age of patient was 62 years, 72% were treatment naïve, and 35% having cirrhosis (based on liver biopsy or FIB4 score).18
Of 48 treatment failures, 30 patients were retreated; the rest of the patients were lost to follow-up (n = 9) or unable to receive retreatment (n = 9) mainly due to decompensated cirrhosis or liver cancer and short life expectancy. The median age of patient in this retreatment group was 62 years, 62% had cirrhosis, and most were infected with GT1. The average creatinine clearance was 73 mL/min. Twenty-two patients who failed therapy with ledipasvir/SOF were retreated (Table 3). A total of 13 patients out of the 19 tested eventually achieved SVR (68%). Four of the patients who had treatment failure again had GT1 infection and the other 2 GT3. All had cirrhosis.
Thirty-five patients were treated with PrOD, and 32 achieved SVR (91%). All 3 patients were retreated. One patient each achieved SVR with ERB/GZP, SOF/VEL and SOF/VEL/VOX. Fifty patients were treated with ERB/GZP and 45 achieved SVR (90%). All 5 treatment failures were retreated. Four achieved SVR and 1 was lost to follow-up (Table 4). Overall, of 30 patients who were retreated after failure with an all-oral DAA regimen, 27 patients had SVR values available and 21 achieved it (78%).
Discussion
Overall SVR was very high for patients who received oral treatment for HCV infection. A low number of patients failed therapy and were retreated. Patients who failed therapy again were similar in age but were more likely to have cirrhosis when compared with the overall interferon-free treated group. Thus, prompt treatment after HCV detection and before disease progression may improve treatment outcomes. Achieving SVR has been shown to improve fibrosis, portal hypertension, splenomegaly and cirrhosis, and reduce the risk of hepatocellular carcinoma by 70% and liver-related mortality by 90%.19-21/
Patients who failed therapy primarily had GT1—the most prevalent GT treated. A higher prevalence of GT1 is expected since it is the most common GT in the US.6 However, disease progression occurs more rapidly in those with GT3 and is more difficult to treat.22 The overall response rate was lower with this GT (83%) in this report, with only 1 of 3 patients retreated achieving an SVR.
Similar results are documented in retreatment trials.23 In the POLARIS-1 trial, treatment with SOF/VEL/VOX resulted in an overall response rate of 96% but only 91% for patients with GT3, compared with 95 to 100% for GTs 1, 2, or 4.23 In the current report, only 1 patient (GT1) failed retreatment with SOF/VEL/VOX. At this time, there are no clear treatment options for this patient. However, patients who fail GLE/PIB (none so far in the current report) may be able to receive SOF/VEL/VOX.24 In a small study, 29 of 31 patients achieved SVR with SOF/VEL/VOX after GLE/PIB failure (12 of 13 GT1 and 17 of 18 GT3).24
Limitations
This review was an observational, nonrandomized design, and only 1 medical center was involved. These results may not be applicable to other patient populations without a clinic set up with routine follow-ups to encourage adherence and completion of therapy.
Conclusions
Treatment of HCV infection has improved significantly over the past 10 years. Use of DAAs results in SVR for > 90% of patients, especially if the disease had not progressed to cirrhosis. Failure after retreatment for HCV infection was rare as well. Given that cirrhosis seems to increase the chance of treatment failure, it is imperative to identify candidates for treatment before the infection has progressed to cirrhosis. Patients infected with GT3 in particular should be more aggressively identified and treated.
Acknowledgments
The authors thank Nick P. Becky, PharmD, for his contributions to the identification of patients needing treatment for their HCV infection and review of initial manuscript information.
1. Centers for Disease Control and Prevention. Viral hepatitis: hepatitis C information. https://www.cdc.gov/hepatitis/hcv/index.htm. Reviewed April 14, 2020. Accessed June 16, 2020.
2. American Association for the Study of Liver Disease, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org. Accessed June 16, 2020.
3. Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin N Am. 2015;44(4):717-734. doi:10.1016/j.gtc.2015.07.003
4. Foote BS, Spooner LM, Belliveau PP. Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. Ann Pharmacother. 2011;45(9):1085-1093. doi:10.1345/aph.1P744
5. Kayali Z, Schmidt WN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med. 2014:7:387-398. doi:10.2147/PGPM.S52629
6. Falade-Nwulis O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166(9):637-648. doi:10.7326/M16-2575
7. Carrion AF, Martin P. Glecaprevir + pibrentasvir for treatment of hepatitis C. Expert Opinion Pharmacother. 2018;19(4):413-419. doi:10.1080/14656566.2018.1444030
8. Chahine EB, Kelley D, Childs-Kean LM. Sofosbuvir/velpatasvir/voxilaprevir: a pan-genotypic direct-acting antiviral combination for hepatitis C. Ann Pharmacother. 2018;52(4):352-363. doi:10.1177/1060028017741508
9. Lagasca AM, Kan VL. Hepatitis C treatment at a Veteran Affairs medical center after the availability of direct-acting agents: things are looking up. Clin Infect Dis. 2015:61(8):1347-1349. doi:10.1093/cid/civ573
10. Sovaldi (sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
11. Harvoni (ledipasvir and sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
12. Viekira Pak (ombitasvir, paritaprevir and ritonavir; dasabuvir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
13. Technivie (ombitasvir, paritaprevir and ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
14. Zepatier (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2018.
15. Epclusa (sofosbuvir and velpatasvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
16. Mavyret (glecaprevir and pibrentasvir) [package insert]. North Chicago, IL: AbbVie Inc; 2019.
17. Vosevi (sofosbuvir, velpatasvir and voxilaprevir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
18. Vallet-Pichard A, Mallet V, Nalpas V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology. 2017;46(1):32-36. doi:10.1002/hep.21669
19. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5, pt 1):329-337. doi:10.7326/0003-4819-158-5-201303050-00005
20. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
21. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-684. doi:10.7326/0003-4819-147-10-200711200-00003
22. Chen A, Patel K, Naggie S. Genotype 3 infection: the last stand of hepatitis C virus. Drugs. 2017;77(2):131-144. doi:10.1007/s40265-016-0685-x
23. Bourlière M, Gordon SC, Flamm SL, et al; POLARIS-1 and POLARIS-4 Investigators. Sofosbuvir, velpatasvir and voxilaprevir for previously treated HCV infection. N Engl J Med. 2017;376(22):2136-2146. doi:10.1056/NEJMoa1613512
24. Pearlman B, Perrys M, Hinds A. Sofosbuvir/velpatasvir/voxilaprevir for previous treatment failures with glecaprevir/pibrentasvir in chronic hepatitis C infection. Am J Gastroenterol. 2019;114(9):1550-1552. doi:10.14309/ajg.0000000000000248
1. Centers for Disease Control and Prevention. Viral hepatitis: hepatitis C information. https://www.cdc.gov/hepatitis/hcv/index.htm. Reviewed April 14, 2020. Accessed June 16, 2020.
2. American Association for the Study of Liver Disease, Infectious Diseases Society of America. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. https://www.hcvguidelines.org. Accessed June 16, 2020.
3. Lingala S, Ghany MG. Natural history of hepatitis C. Gastroenterol Clin N Am. 2015;44(4):717-734. doi:10.1016/j.gtc.2015.07.003
4. Foote BS, Spooner LM, Belliveau PP. Boceprevir: a protease inhibitor for the treatment of chronic hepatitis C. Ann Pharmacother. 2011;45(9):1085-1093. doi:10.1345/aph.1P744
5. Kayali Z, Schmidt WN. Finally sofosbuvir: an oral anti-HCV drug with wide performance capability. Pharmgenomics Pers Med. 2014:7:387-398. doi:10.2147/PGPM.S52629
6. Falade-Nwulis O, Suarez-Cuervo C, Nelson DR, Fried MW, Segal JB, Sulkowski MS. Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review. Ann Intern Med. 2017;166(9):637-648. doi:10.7326/M16-2575
7. Carrion AF, Martin P. Glecaprevir + pibrentasvir for treatment of hepatitis C. Expert Opinion Pharmacother. 2018;19(4):413-419. doi:10.1080/14656566.2018.1444030
8. Chahine EB, Kelley D, Childs-Kean LM. Sofosbuvir/velpatasvir/voxilaprevir: a pan-genotypic direct-acting antiviral combination for hepatitis C. Ann Pharmacother. 2018;52(4):352-363. doi:10.1177/1060028017741508
9. Lagasca AM, Kan VL. Hepatitis C treatment at a Veteran Affairs medical center after the availability of direct-acting agents: things are looking up. Clin Infect Dis. 2015:61(8):1347-1349. doi:10.1093/cid/civ573
10. Sovaldi (sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
11. Harvoni (ledipasvir and sofosbuvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
12. Viekira Pak (ombitasvir, paritaprevir and ritonavir; dasabuvir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
13. Technivie (ombitasvir, paritaprevir and ritonavir) [package insert]. North Chicago, IL: AbbVie Inc; 2018.
14. Zepatier (elbasvir and grazoprevir) [package insert]. Whitehouse Station, NJ: Merck & Co Inc; 2018.
15. Epclusa (sofosbuvir and velpatasvir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
16. Mavyret (glecaprevir and pibrentasvir) [package insert]. North Chicago, IL: AbbVie Inc; 2019.
17. Vosevi (sofosbuvir, velpatasvir and voxilaprevir) [package insert]. Foster City, CA: Gilead Sciences Inc; 2017.
18. Vallet-Pichard A, Mallet V, Nalpas V, et al. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. Comparison with liver biopsy and FibroTest. Hepatology. 2017;46(1):32-36. doi:10.1002/hep.21669
19. Morgan RL, Baack B, Smith BD, Yartel A, Pitasi M, Falck-Ytter Y. Eradication of hepatitis C virus infection and the development of hepatocellular carcinoma: a meta-analysis of observational studies. Ann Intern Med. 2013;158(5, pt 1):329-337. doi:10.7326/0003-4819-158-5-201303050-00005
20. van der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584-2593. doi:10.1001/jama.2012.144878
21. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147(10):677-684. doi:10.7326/0003-4819-147-10-200711200-00003
22. Chen A, Patel K, Naggie S. Genotype 3 infection: the last stand of hepatitis C virus. Drugs. 2017;77(2):131-144. doi:10.1007/s40265-016-0685-x
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