Men's Health

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

Sexually transmitted infections (STIs) such as gonorrhea, chlamydia, and syphilis are still increasing in incidence and probably will continue to do so in the near future. Moreover, drug-resistant strains of Neisseria gonorrhoeae are emerging, as are less-known organisms such as Mycoplasma genitalium.

Now the good news: new tests for STIs are available or are coming! Based on nucleic acid amplification, these tests can be performed at the point of care, so that patients can leave the clinic with an accurate diagnosis and proper treatment for themselves and their sexual partners. Also, the tests can be run on samples collected by the patients themselves, either swabs or urine collections, eliminating the need for invasive sampling and making doctor-shy patients more likely to come in to be treated.¹ We hope that by using these sensitive and accurate tests we can begin to bend the upward curve of STIs and be better antimicrobial stewards.²

This article reviews current issues surrounding STI control, and provides detailed guidance on recognizing, testing for, and treating gonorrhea, chlamydia, trichomoniasis, and M genitalium infection.

STI RATES ARE HIGH AND RISING

STIs are among the most common acute infectious diseases worldwide, with an estimated 1 million new curable cases every day.³ Further, STIs have major impacts on sexual, reproductive, and psychological health.

In the United States, rates of reportable STIs (chlamydia, gonorrhea, and syphilis) are rising.⁴ In addition, more-sensitive tests for trichomoniasis, which is not a reportable infection in any state, have revealed it to be more prevalent than previously thought.⁵

BARRIERS AND CHALLENGES TO DIAGNOSIS

The medical system does not fully meet the needs of some populations, including young people and men who have sex with men, regarding their sexual and reproductive health. 

Ongoing barriers among young people include reluctance to use available health services, limited access to STI testing, worries about confidentiality, and the shame and stigma associated with STIs.⁶

Men who have sex with men have a higher incidence of STIs than other groups. Since STIs are associated with a higher risk of human immunodeficiency virus (HIV) infection, it is important to detect, diagnose, and manage STIs in this group—and in all high-risk groups. Rectal STIs are an independent risk factor for incident HIV infection.⁷ In addition, many men who have sex with men face challenges navigating the emotional, physical, and cognitive aspects of adolescence, a voyage further complicated by mental health issues, unprotected sexual encounters, and substance abuse in many, especially among minority youth.⁸ These same factors also impair their ability to access resources for preventing and treating HIV and other STIs.

STI diagnosis is often missed

Most people who have STIs feel no symptoms, which increases the importance of risk-based screening to detect these infections.^9,10 In many other cases, STIs manifest with nonspecific genitourinary symptoms that are mistaken for urinary tract infection. Tomas et al¹¹ found that of 264 women who presented to an emergency department with genitourinary symptoms or were being treated for urinary tract infection, 175 were given a diagnosis of a urinary tract infection. Of these, 100 (57%) were treated without performing a urine culture; 60 (23%) of the 264 women had 1 or more positive STI tests, 22 (37%) of whom did not receive treatment for an STI.

Poor follow-up of patients and partners

Patients with STIs need to be retested 3 months after treatment to make sure the treatment was effective. Another reason for follow-up is that these patients are at higher risk of another infection within a year.¹²

Although treating patients’ partners has been shown to reduce reinfection rates, fewer than one-third of STIs (including HIV infections) were recognized through partner notification between 2010 and 2012 in a Dutch study, in men who have sex with men and in women.¹³ Challenges included partners who could not be identified among men who have sex with men, failure of heterosexual men to notify their partners, and lower rates of partner notification for HIV.  

In the United States, “expedited partner therapy” allows healthcare providers to provide a prescription or medications to partners of patients diagnosed with chlamydia or gonorrhea without examining the partner.¹⁴ While this approach is legal in most states, implementation can be challenging.¹⁵

STI EVALUATION

History and physical examination

A complete sexual history helps in estimating the patient’s risk of an STI and applying appropriate risk-based screening. Factors such as sexual practices, use of barrier protection, and history of STIs should be discussed.

Physical examination is also important. Although some patients may experience discomfort during a genital or pelvic examination, omitting this step may lead to missed diagnoses in women with STIs.¹⁶

Laboratory testing

Laboratory testing for STIs helps ensure accurate diagnosis and treatment. Empiric treatment without testing could give a patient a false sense of health by missing an infection that is not currently causing symptoms but that could later worsen or have lasting complications. Failure to test patients also misses the opportunity for partner notification, linkage to services, and follow-up testing.

Many of the most common STIs, including gonorrhea, chlamydia, and trichomoniasis, can be detected using vaginal, cervical, or urethral swabs or first-catch urine (from the initial urine stream). In studies that compared various sampling methods,¹⁷ self-collected urine samples for gonorrhea in men were nearly as good as clinician-collected swabs of the urethra. In women, self-collected vaginal swabs for gonorrhea and chlamydia were nearly as good as clinician-collected vaginal swabs. While urine specimens are acceptable for chlamydia testing in women, their sensitivity may be slightly lower than with vaginal and endocervical swab specimens.^18,19

A major advantage of urine specimens for STI testing is that collection is noninvasive and is therefore more likely to be acceptable to patients. Urine testing can also be conducted in a variety of nonclinical settings such as health fairs, pharmacy-based screening programs, and express STI testing sites, thus increasing availability.

To prevent further transmission and morbidity and to aid in public health efforts, it is critical to recognize the cause of infectious cervicitis and urethritis and to screen for STIs according to guidelines.¹² Table 1 summarizes current screening and laboratory testing recommendations.

Gonorrhea and chlamydia are the 2 most frequently reported STIs in the United States, with more than 550,000 cases of gonorrhea and 1.7 million cases of chlamydia reported in 2017.⁴

Both infections present similarly: cervicitis or urethritis characterized by discharge (mucopurulent discharge with gonorrhea) and dysuria. Untreated, they can lead to pelvic inflammatory disease, inflammation, and infertility.

Extragenital infections can be asymptomatic or cause exudative pharyngitis or proctitis. Most people in whom chlamydia is detected from pharyngeal specimens are asymptomatic. When pharyngeal symptoms exist secondary to gonorrheal infection, they typically include sore throat and pharyngeal exudates. However, Komaroff et al,²⁰ in a study of 192 men and women who presented with sore throat, found that only 2 (1%) tested positive for N gonorrhoeae.

Screening for gonorrhea and chlamydia

Best practices include screening for gonorrhea and chlamydia as follows^21–23:

• Every year in sexually active women through age 25 (including during pregnancy) and in older women who have risk factors for infection¹²
• At least every year in men who have sex with men, at all sites of sexual contact (urethra, pharynx, rectum), along with testing for HIV and syphilis
• Every 3 to 6 months in men who have sex with men who have multiple or anonymous partners, who are sexually active and use illicit drugs, or who have partners who use illicit drugs
• Possibly every year in young men who live in high-prevalence areas or who are seen in certain clinical settings, such as STI and adolescent clinics.

Specimens. A vaginal swab is preferred for screening in women. Several studies have shown that self-collected swabs have clinical sensitivity and specificity comparable to that of provider-collected samples.^17,24 First-catch urine or endocervical swabs have similar performance characteristics and are also acceptable. In men, urethral swabs or first-catch urine samples are appropriate for screening for urogenital infections.

Testing methods. Testing for both pathogens should be done simultaneously with a nucleic acid amplification test (NAAT). Commercially available NAATs are more sensitive than culture and antigen testing for detecting gonorrhea and chlamydia.^25–27

Most assays are approved by the US Food and Drug Administration (FDA) for testing vaginal, urethral, cervical, and urine specimens. Until recently, no commercial assay was cleared for testing extragenital sites, but recommendations for screening extragenital sites prompted many clinical laboratories to validate throat and rectal swabs for use with NAATs, which are more sensitive than culture at these sites.^25,28 The recent FDA approval of extragenital specimen types for 2 commercially available assays may increase the availability of testing for these sites.

Data on the utility of NAATs for detecting chlamydia and gonorrhea in children are limited, and many clinical laboratories have not validated molecular methods for testing in children. Current guidelines specific to this population should be followed regarding test methods and preferred specimen types.^12,29,30

Although gonococcal infection is usually diagnosed with culture-independent molecular methods, antimicrobial resistance is emerging. Thus, failure of the combination of ceftriaxone and azithromycin should prompt culture-based follow-up testing to determine antimicrobial susceptibility.

Strategies for treatment and control

Historically, people treated for gonorrhea have been treated for chlamydia at the same time, as these diseases tend to go together. This can be with a single intramuscular dose of ceftriaxone for the gonorrhea plus a single oral dose of azithromycin for the chlamydia.¹² For patients who have only gonorrhea, this double regimen may help prevent the development of resistant gonorrhea strains.

All the patient’s sexual partners in the previous 60 days should be tested and treated, and expedited partner therapy should be offered if possible. Patients should be advised to have no sexual contact until they complete the treatment, or 7 days after single-dose treatment. Testing should be repeated 3 months after treatment.

A member of the Mycoplasmataceae family, M genitalium was originally identified as a pathogen in the early 1980s but has only recently emerged as an important cause of STI. Studies indicate that it is responsible for 10% to 20% of cases of nongonococcal urethritis and 10% to 30% of cases of cervicitis.^31–33 Additionally, 2% to 22% of cases of pelvic inflammatory disease have evidence of M genitalium.^34,35

However, data on M genitalium prevalence are suspect because the organism is hard to identify—lacking a cell wall, it is undetectable by Gram stain.³⁶ Although it has been isolated in respiratory and synovial fluids, it has so far been recognized to be clinically important only in the urogenital tract. It can persist for years in infected patients by exploiting specialized cell-surface structures to invade cells.³⁶ Once inside a cell, it triggers secretion of mycoplasmal toxins and destructive metabolites such as hydrogen peroxide, evading the host immune system as it does so.³⁷

Testing guidelines for M genitalium

Current guidelines do not recommend routine screening for M genitalium, and no commercial test was available until recently.¹² Although evidence suggests that M genitalium is independently associated with preterm birth and miscarriages,³⁸ routine screening of pregnant women is not recommended.¹²

Testing for M genitalium should be considered in cases of persistent or recurrent nongonococcal urethritis in patients who test negative for gonorrhea and chlamydia or for whom treatment has failed.¹² Many isolates exhibit genotypic resistance to macrolide antibiotics, which are often the first-line therapy for nongonococcal urethritis.³⁹

Further study is needed to evaluate the potential impact of routine screening for M genitalium on the reproductive and sexual health of at-risk populations.

Diagnostic tests for M genitalium

Awareness of M genitalium as a cause of nongonococcal urethritis has been hampered by a dearth of diagnostic tests.⁴⁰ The organism’s fastidious requirements and extremely slow growth preclude culture as a practical method of diagnosis.⁴¹ Serologic assays are dogged by cross-reactivity and poor sensitivity.^42,43 Thus, molecular assays for detecting M genitalium and associated resistance markers are preferred for diagnosis.¹²

Several molecular tests are approved, available, and in use in Europe for diagnosing M genitalium infection,⁴⁰ and in January 2019 the FDA approved a molecular test that can detect M genitalium in urine specimens and vaginal, endocervical, urethral, and penile meatal swabs. Although vaginal swabs are preferred for this assay because they have higher sensitivity (92% for provider-collected and 99% for patient-collected swabs), urine specimens are acceptable, with a sensitivity of 78%.⁴⁴

At least 1 company is seeking FDA clearance for another molecular diagnostic assay for detecting M genitalium and markers of macrolide resistance in urine and genital swab specimens. Such assays may facilitate appropriate treatment.

Clinicians should stay abreast of diagnostic testing options, which are likely to become more readily available soon.

A high rate of macrolide resistance

Because M genitalium lacks a cell wall, antibiotics such as beta-lactams that target cell wall synthesis are ineffective.

Regimens for treating M genitalium are outlined in Table 2.¹² Azithromycin is more effective than doxycycline. However, as many as 50% of strains were macrolide-resistant in a cohort of US female patients.⁴⁵ Given the high incidence of treatment failure with azithromycin 1 g, it is thought that this regimen might select for resistance. For cases in which symptoms persist, a 1- to 2-week course of moxifloxacin is recommended.¹² However, this has not been validated by clinical trials, and failures of the 7-day regimen have been reported.⁴⁶

Partners of patients who test positive for M genitalium should also be tested and undergo clinically applicable screening for nongonococcal urethritis, cervicitis, and pelvic inflammatory disease.¹²

TRICHOMONIASIS

Trichomoniasis, caused by the parasite Trichomonas vaginalis, is the most prevalent nonviral STI in the United States. It disproportionately affects black women, in whom the prevalence is 13%, compared with 1% in non-Hispanic white women.⁴⁷ It is also present in 26% of women with symptoms who are seen in STI clinics and is highly prevalent in incarcerated populations. It is uncommon in men who have sex with men.⁴⁸

In men, trichomoniasis manifests as urethritis, epididymitis, or prostatitis. While most infected women have no symptoms, they may experience vaginitis with discharge that is diffuse, frothy, pruritic, malodorous, or yellow-green. Vaginal and cervical erythema (“strawberry cervix”) can also occur.

Screening for trichomoniasis

Current guidelines of the US Centers for Disease Control and Prevention (CDC) recommend testing for T vaginalis in women who have symptoms and routinely screening in women who are HIV-positive, regardless of symptoms. There is no evidence to support routine screening of pregnant women without symptoms, and pregnant women who do have symptoms should be evaluated according to the same guidelines as for nonpregnant women.¹² Testing can be considered in patients who have no symptoms but who engage in high-risk behaviors and in areas of high prevalence.

A lack of studies using sensitive methods for T vaginalis detection has hampered a true estimation of disease burden and at-risk populations. Screening recommendations may evolve in upcoming clinical guidelines as the field advances.

As infection can recur, women should be retested 3 months after initial diagnosis.¹²

NAAT is the preferred test for trichomoniasis

Commercially available diagnostic tests for trichomoniasis include culture, antigen testing, and NAAT.⁴⁹ While many clinicians do their own wet-mount microscopy for a rapid result, this method has low sensitivity.⁵⁰ Similarly, antigen testing and culture perform poorly compared with NAATs, which are the gold standard for detection.^51,52 A major advantage of NAATs for T vaginalis detection is that they combine high sensitivity and fast results, facilitating diagnosis and appropriate treatment of patients and their partners.

In spite of these benefits, adoption of molecular diagnostic testing for T vaginalis has lagged behind that for chlamydia and gonorrhea.⁵³ FDA-cleared NAATs are available for testing vaginal, cervical, or urine specimens from women, but until recently, there were no approved assays for testing in men. The Cepheid Xpert TV assay, which is valid for male urine specimens to diagnose other sexually transmitted diseases, has demonstrated excellent diagnostic sensitivity for T vaginalis in men and women.⁵⁴ Interestingly, a large proportion of male patients in this study had no symptoms, suggesting that screening of men in high-risk groups may be warranted.

7-day metronidazole treatment beats single-dose treatment

The first-line treatment for trichomoniasis has been a single dose of metronidazole 2 g by mouth, but in a recent randomized controlled trial,⁵⁵ a course of 500 mg by mouth twice a day for 7 days was 45% more effective at 4 weeks than a single dose, and it should now be the preferred regimen.

In clinical trials,⁵⁶ a single dose of tinidazole 2 g orally was equivalent or superior to metronidazole 2 g and had fewer gastrointestinal side effects, but it is more expensive.

A 43-year-old man presented with a 3-week history of halitosis. He was also concerned about the irregular appearance of his tongue, which he had noticed over the past 3 years. He had no history of wearing dentures or of any skin disorder.

A BROAD DIFFERENTIAL DIAGNOSIS

Fissured tongue (scrotal tongue, plicated tongue, lingua plicata) is a common normal variant of the tongue surface with a male preponderance and a reported prevalence of 10% to 20% in the general population, and the incidence increases strikingly with age.¹

The cause is not known, but familial clustering is seen, and a polygenic or autosomal dominant hereditary component is presumed.¹

The condition may be associated with removable dentures, geographic tongue, pernicious anemia, Sjögren syndrome, psoriasis, acromegaly, macroglossia, oral-facial-digital syndrome type I, Pierre Robin syndrome, Down syndrome, and Melkersson Rosenthal syndrome.² It is usually asymptomatic, but if the fissures are deep, food may become lodged in them, resulting in tongue inflammation, burning sensation, and halitosis.¹

Typically, fissures of varying depth extending to the margin are apparent on the dorsal surface of the tongue. The condition is confined to the anterior two-thirds of the tongue, which is of ectodermal origin. Histologically, the epithelium, lamina propria, and musculature are all involved in the formation of the fissures.³ The deeper fissures may lack filliform papillae due to bacterial inflammation.³ The diagnosis is clinical, and treatment includes reassurance, advice on good oral hygiene, and tongue cleansing.¹

A 43-year-old man presented with a 3-week history of halitosis. He was also concerned about the irregular appearance of his tongue, which he had noticed over the past 3 years. He had no history of wearing dentures or of any skin disorder.

A BROAD DIFFERENTIAL DIAGNOSIS

Fissured tongue (scrotal tongue, plicated tongue, lingua plicata) is a common normal variant of the tongue surface with a male preponderance and a reported prevalence of 10% to 20% in the general population, and the incidence increases strikingly with age.¹

The cause is not known, but familial clustering is seen, and a polygenic or autosomal dominant hereditary component is presumed.¹

The condition may be associated with removable dentures, geographic tongue, pernicious anemia, Sjögren syndrome, psoriasis, acromegaly, macroglossia, oral-facial-digital syndrome type I, Pierre Robin syndrome, Down syndrome, and Melkersson Rosenthal syndrome.² It is usually asymptomatic, but if the fissures are deep, food may become lodged in them, resulting in tongue inflammation, burning sensation, and halitosis.¹

Typically, fissures of varying depth extending to the margin are apparent on the dorsal surface of the tongue. The condition is confined to the anterior two-thirds of the tongue, which is of ectodermal origin. Histologically, the epithelium, lamina propria, and musculature are all involved in the formation of the fissures.³ The deeper fissures may lack filliform papillae due to bacterial inflammation.³ The diagnosis is clinical, and treatment includes reassurance, advice on good oral hygiene, and tongue cleansing.¹

A 43-year-old man presented with a 3-week history of halitosis. He was also concerned about the irregular appearance of his tongue, which he had noticed over the past 3 years. He had no history of wearing dentures or of any skin disorder.

A BROAD DIFFERENTIAL DIAGNOSIS

Fissured tongue (scrotal tongue, plicated tongue, lingua plicata) is a common normal variant of the tongue surface with a male preponderance and a reported prevalence of 10% to 20% in the general population, and the incidence increases strikingly with age.¹

The cause is not known, but familial clustering is seen, and a polygenic or autosomal dominant hereditary component is presumed.¹

The condition may be associated with removable dentures, geographic tongue, pernicious anemia, Sjögren syndrome, psoriasis, acromegaly, macroglossia, oral-facial-digital syndrome type I, Pierre Robin syndrome, Down syndrome, and Melkersson Rosenthal syndrome.² It is usually asymptomatic, but if the fissures are deep, food may become lodged in them, resulting in tongue inflammation, burning sensation, and halitosis.¹

Typically, fissures of varying depth extending to the margin are apparent on the dorsal surface of the tongue. The condition is confined to the anterior two-thirds of the tongue, which is of ectodermal origin. Histologically, the epithelium, lamina propria, and musculature are all involved in the formation of the fissures.³ The deeper fissures may lack filliform papillae due to bacterial inflammation.³ The diagnosis is clinical, and treatment includes reassurance, advice on good oral hygiene, and tongue cleansing.¹

New research presents a complex picture of self-reported suicidal behavior in U.S. teenagers over the last few decades. Rates of suicidal ideation and plans dipped overall from 1991 to 2017, but the rate of suicide attempts grew slightly in black adolescents.

White young people “have historically had higher rates of suicide attempts...compared with their black counterparts; however, this study provides some evidence to the contrary,” wrote the authors of the report, which appears in the November issue of Pediatrics.

The investigators, led by Michael A. Lindsey, PhD, executive director of the McSilver Institute for Poverty Policy and Research at New York University, New York, note that suicide is the second leading cause of death in the United States in those aged 12-17. (Accidents rank first.) According to recent research, black children younger than 12 are at higher risk for death by suicide, compared with whites.

For the new study, researchers analyzed data from the Youth Risk Behavior Survey, which is conducted every 2 years among high school students in all 50 states and the District of Columbia. They examined data from 198,540 teens (mean age=16, 51% male; 49% female).

During the study period, the weighted overall prevalences rates of suicidal ideation, planning, attempt, and injury due to attempt were 19%, 15%, 8%, and 3%, respectively. “Our findings reveal that over that span of time, almost 1 in 5 adolescents are thinking about suicide... and > 1 in 10 has a suicide plan,” the researchers wrote.

Rates of suicidal ideation and planning fell overall, and among females, the rate of suicide attempts fell significantly (odds ratio [OR]=0.98). But self-reported suicide attempts grew significantly among black teens (OR=1.02), and injuries due to suicide attempts grew among black males (OR=1.04).

The findings are “troubling because attempts are the most prominent risk factor associated with suicide death,” the study authors wrote. “Findings regarding the rising rates of suicide attempts in black youth may be related to the documented disparities in mental health treatment and common social etiologic factors disproportionately experienced by black youth.”

In an accompanying commentary, psychiatrist Benjamin N. Shain, MD, PhD, of the University of Chicago, noted a seemingly “counterintuitive” fact: Black teens still have lower rates of suicide than whites teens “despite the greater, long-standing difficulties encountered by black adolescents, including disparities in mental health treatment and disproportionately higher stressors, racial discrimination, and childhood abuse and neglect, as well as other adverse experiences, such as poverty.”

It’s not clear why the reported suicide rate is lower in black adolescents than their white counterparts, Dr. Shain wrote, but misclassification and “undercount as a result of violence with suicidal intent, for example, ‘suicide by cop’” may play a role. Additionally, protective factors may have kept suicide rates down. “External attributional orientation (eg, blaming others or ‘the system’ for difficulties) among blacks may have buffered this group from internalizing blame related to psychological stressors,” he wrote.

Among black adolescents, the growing rate of suicidal behavior is concerning and may be due to a weakening of the hypothesized protective mechanism. Perhaps, Dr. Shain wrote, they now are blaming themselves more for difficulties encountered, “thus leading to an increase in suicide risk factors, particularly depression.” He stressed that, regardless of the reasons for the increase in suicide and suicide attempts, prevention and intervention efforts remain critical.

No study funding is reported, and authors report no relevant disclosures. Dr. Shain reports no relevant disclosures.


SOURCE: Lindsey MA et al, Pediatrics. 2019;144(5): e20191187, DOI:10.1542/peds.2019-1187.

New research presents a complex picture of self-reported suicidal behavior in U.S. teenagers over the last few decades. Rates of suicidal ideation and plans dipped overall from 1991 to 2017, but the rate of suicide attempts grew slightly in black adolescents.

White young people “have historically had higher rates of suicide attempts...compared with their black counterparts; however, this study provides some evidence to the contrary,” wrote the authors of the report, which appears in the November issue of Pediatrics.

The investigators, led by Michael A. Lindsey, PhD, executive director of the McSilver Institute for Poverty Policy and Research at New York University, New York, note that suicide is the second leading cause of death in the United States in those aged 12-17. (Accidents rank first.) According to recent research, black children younger than 12 are at higher risk for death by suicide, compared with whites.

For the new study, researchers analyzed data from the Youth Risk Behavior Survey, which is conducted every 2 years among high school students in all 50 states and the District of Columbia. They examined data from 198,540 teens (mean age=16, 51% male; 49% female).

During the study period, the weighted overall prevalences rates of suicidal ideation, planning, attempt, and injury due to attempt were 19%, 15%, 8%, and 3%, respectively. “Our findings reveal that over that span of time, almost 1 in 5 adolescents are thinking about suicide... and > 1 in 10 has a suicide plan,” the researchers wrote.

Rates of suicidal ideation and planning fell overall, and among females, the rate of suicide attempts fell significantly (odds ratio [OR]=0.98). But self-reported suicide attempts grew significantly among black teens (OR=1.02), and injuries due to suicide attempts grew among black males (OR=1.04).

The findings are “troubling because attempts are the most prominent risk factor associated with suicide death,” the study authors wrote. “Findings regarding the rising rates of suicide attempts in black youth may be related to the documented disparities in mental health treatment and common social etiologic factors disproportionately experienced by black youth.”

In an accompanying commentary, psychiatrist Benjamin N. Shain, MD, PhD, of the University of Chicago, noted a seemingly “counterintuitive” fact: Black teens still have lower rates of suicide than whites teens “despite the greater, long-standing difficulties encountered by black adolescents, including disparities in mental health treatment and disproportionately higher stressors, racial discrimination, and childhood abuse and neglect, as well as other adverse experiences, such as poverty.”

It’s not clear why the reported suicide rate is lower in black adolescents than their white counterparts, Dr. Shain wrote, but misclassification and “undercount as a result of violence with suicidal intent, for example, ‘suicide by cop’” may play a role. Additionally, protective factors may have kept suicide rates down. “External attributional orientation (eg, blaming others or ‘the system’ for difficulties) among blacks may have buffered this group from internalizing blame related to psychological stressors,” he wrote.

Among black adolescents, the growing rate of suicidal behavior is concerning and may be due to a weakening of the hypothesized protective mechanism. Perhaps, Dr. Shain wrote, they now are blaming themselves more for difficulties encountered, “thus leading to an increase in suicide risk factors, particularly depression.” He stressed that, regardless of the reasons for the increase in suicide and suicide attempts, prevention and intervention efforts remain critical.

No study funding is reported, and authors report no relevant disclosures. Dr. Shain reports no relevant disclosures.


SOURCE: Lindsey MA et al, Pediatrics. 2019;144(5): e20191187, DOI:10.1542/peds.2019-1187.

New research presents a complex picture of self-reported suicidal behavior in U.S. teenagers over the last few decades. Rates of suicidal ideation and plans dipped overall from 1991 to 2017, but the rate of suicide attempts grew slightly in black adolescents.

White young people “have historically had higher rates of suicide attempts...compared with their black counterparts; however, this study provides some evidence to the contrary,” wrote the authors of the report, which appears in the November issue of Pediatrics.

The investigators, led by Michael A. Lindsey, PhD, executive director of the McSilver Institute for Poverty Policy and Research at New York University, New York, note that suicide is the second leading cause of death in the United States in those aged 12-17. (Accidents rank first.) According to recent research, black children younger than 12 are at higher risk for death by suicide, compared with whites.

For the new study, researchers analyzed data from the Youth Risk Behavior Survey, which is conducted every 2 years among high school students in all 50 states and the District of Columbia. They examined data from 198,540 teens (mean age=16, 51% male; 49% female).

During the study period, the weighted overall prevalences rates of suicidal ideation, planning, attempt, and injury due to attempt were 19%, 15%, 8%, and 3%, respectively. “Our findings reveal that over that span of time, almost 1 in 5 adolescents are thinking about suicide... and > 1 in 10 has a suicide plan,” the researchers wrote.

Rates of suicidal ideation and planning fell overall, and among females, the rate of suicide attempts fell significantly (odds ratio [OR]=0.98). But self-reported suicide attempts grew significantly among black teens (OR=1.02), and injuries due to suicide attempts grew among black males (OR=1.04).

The findings are “troubling because attempts are the most prominent risk factor associated with suicide death,” the study authors wrote. “Findings regarding the rising rates of suicide attempts in black youth may be related to the documented disparities in mental health treatment and common social etiologic factors disproportionately experienced by black youth.”

In an accompanying commentary, psychiatrist Benjamin N. Shain, MD, PhD, of the University of Chicago, noted a seemingly “counterintuitive” fact: Black teens still have lower rates of suicide than whites teens “despite the greater, long-standing difficulties encountered by black adolescents, including disparities in mental health treatment and disproportionately higher stressors, racial discrimination, and childhood abuse and neglect, as well as other adverse experiences, such as poverty.”

It’s not clear why the reported suicide rate is lower in black adolescents than their white counterparts, Dr. Shain wrote, but misclassification and “undercount as a result of violence with suicidal intent, for example, ‘suicide by cop’” may play a role. Additionally, protective factors may have kept suicide rates down. “External attributional orientation (eg, blaming others or ‘the system’ for difficulties) among blacks may have buffered this group from internalizing blame related to psychological stressors,” he wrote.

Among black adolescents, the growing rate of suicidal behavior is concerning and may be due to a weakening of the hypothesized protective mechanism. Perhaps, Dr. Shain wrote, they now are blaming themselves more for difficulties encountered, “thus leading to an increase in suicide risk factors, particularly depression.” He stressed that, regardless of the reasons for the increase in suicide and suicide attempts, prevention and intervention efforts remain critical.

No study funding is reported, and authors report no relevant disclosures. Dr. Shain reports no relevant disclosures.


SOURCE: Lindsey MA et al, Pediatrics. 2019;144(5): e20191187, DOI:10.1542/peds.2019-1187.

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

Pregnant women should be screened for asymptomatic bacteriuria using urine culture because the benefit of reducing pyelonephritis during pregnancy slightly but significantly outweighs the risks of maternal and fetal antibiotic exposure, according to new recommendations set forth by the United States Preventive Services Task Force (USPSTF).

toeytoey2530/Thinkstock

However, the investigating committee reported, there is evidence against screening nonpregnant women and adult men. In fact, the committee found “adequate” evidence of potential harm associated with treating asymptomatic bacteriuria in adults of both sexes, including adverse effects of antibiotics and on the microbiome.

The new document downgrades from A to B the group’s prior recommendation that urine culture screening for asymptomatic bacteriuria should be performed among pregnant women at 12-16 weeks’ gestation or at their first prenatal visit. The USPSTF recommendation to not screen nonpregnant adults retained its D rating, Jerome A. Leis, MD and Christine Soong, MD said in an accompanying editorial.

“Not screening or treating asymptomatic bacteriuria in this population has long been an ironclad recommendation endorsed by the Infectious Diseases Society of America, as well as numerous professional societies as part of the Choosing Wisely campaign,” wrote Dr. Leis of Sunnybrook Health Sciences Centre, Toronto, and Dr. Soong of the University of Toronto. “Restating this steadfast and pervasive recommendation may seem unremarkable and almost pedantic, yet it remains stubbornly disregarded by clinicians across multiple settings.”

The new recommendations were based on a review of 19 studies involving almost 8,500 pregnant and nonpregnant women, as well as a small number of adult men. Most were carried out in the 1960s or 1970s. The most recent ones were published in 2002 and 2015. The dearth of more recent data may have limited some conclusions and certainly highlighted the need for more research, said Jillian T. Henderson, PhD, chair of the committee assigned to investigate the evidence.

“Few studies of asymptomatic bacteriuria screening or treatment in pregnant populations have been conducted in the past 40 years,” wrote Dr. Henderson of Kaiser Permanente Northwest, Portland, and associates. “Historical evidence established asymptomatic bacteriuria screening and treatment as standard obstetric practice in the United States.” But these trials typically were less rigorous than modern studies, and the results are out of touch with modern clinical settings and treatment protocols, the team noted.

Additionally, Dr. Henderson and coauthors said, rates of pyelonephritis were about 10 times higher then than they are now. In the more recent studies, pyelonephritis rates in control groups were 2.2% and 2.5%; in most of the older studies, control group rates ranged from 33% to 36%.

In commissioning the investigation, the task force looked at the following four questions:

Does screening improve health outcomes?

Neither of two studies involving 5,289 women, one from Spain and one from Turkey, addressed this question in nonpregnant women; however, studies that looked at pregnant women generally found that screening did reduce the risk of pyelonephritis by about 70%. The investigators cautioned that these studies were out of date and perhaps methodologically flawed.

The only study that looked at newborn outcomes found no difference in birth weights or premature births between the screened and unscreened cohorts.

No study examined this question in nonpregnant women or men.
 

What are the harms of such screening?

A single study of 372 pregnant women described potential prenatal and perinatal harms associated with screening and treatment. It found a slight increase in congenital abnormalities in the screened cohort (1.6%), compared with those who were not screened (1.1%). However, those who were not screened were presumably not prescribed antibiotics.

Does treatment of screening-detected asymptomatic bacteriuria improve health outcomes?

Twelve trials of pregnant women (2,377) addressed this issue. All but two were conducted in the 1960s and 1970s. Treatment varied widely; sulfonamides were the most common, including the now discarded sulfamethazine and sulfadimethoxine. Dosages and duration of treatment also were considerably higher and longer than current practice.

In all but one study, there were higher rates of pyelonephritis in the control group. A pooled risk analysis indicated that treatment reduced the risk of pyelonephritis by nearly 80% (relative risk, 0.24).

Seven studies found higher rates of low birth weight in infants born to mothers who were treated, but two studies reported a significant reduction in the risk of low birth weight.

Among the six trials that examined perinatal mortality, none found significant associations with treatment.

Five studies examined treatment in nonpregnant women with screening-detected asymptomatic bacteriuria, and one included men as well. Of the four that reported the rate of symptomatic infection or pyelonephritis, none found a significant difference between treatment and control groups. The single study that included men also found no significant difference between treatment and control groups.

Among the three studies that focused on older adults, there also were no significant between-group differences in outcomes.

What harms are associated with treatment of screening-detected asymptomatic bacteriuria?

Seven studies comprised pregnant women. Five reported congenital malformations in the intervention and control groups. Overall, there were very few cases of malformations, with more – although not significantly more – in the control groups.

Evidence related to other infant and maternal harms was “sparsely and inconsistently reported,” Dr. Henderson and coauthors noted, “and there was a lack of evidence on long-term neonatal outcomes after antibiotic treatment of asymptomatic bacteriuria in pregnancy.”

Two studies listed maternal adverse events associated with different treatments including vaginitis and diarrhea with ampicillin and rashes and nausea with nalidixic acid.

In terms of nonpregnant women and men, four studies reported adverse events. None occurred with nitrofurantoin or trimethoprim treatment; however, one study that included daily treatment with ofloxacin noted that 6% withdrew because of adverse events – vertigo and gastrointestinal symptoms.

Treatments didn’t affect hematocrit, bilirubin, serum urea, or nitrogen, although some studies found a slight reduction in serum creatinine.

Although there’s a need for additional research into this question, the new recommendations provide a good reason to further reduce unnecessary antibiotic exposure, Lindsey E. Nicolle, MD, wrote in a second commentary.

These updated recommendations “contribute to the evolution of management of asymptomatic bacteriuria in healthy women,” wrote Dr. Nicolle of the University of Manitoba, Winnipeg. “However, questions remain about the risks and benefits of universal screening for and treatment of asymptomatic bacteriuria in pregnant women in the context of current clinical practice. The effects of changes in fetal-maternal care, of low- compared with high-risk pregnancies, and of health care access need to be understood. In the short term, application of current diagnostic recommendations for identification of persistent symptomatic bacteriuria with a second urine culture may provide an immediate opportunity to limit unnecessary antimicrobial use for some pregnant women.”

No conflicts of interest were reported by the USPSTF authors, nor by Dr. Leis, Dr. Soong, or Dr. Nicolle. The USPSTF report was funded by the Agency for Healthcare Research and Quality.
 

SOURCES: U.S. Preventive Services Task Force. JAMA. 2019;322(12):1188-94; Henderson JT et al. JAMA. 2019;322(12):1195-205; Leis JA and Soong C. JAMA. 2019. doi: 10.1001/jamainternmed.2019.4515; Nicolle LE. JAMA. 2019;322(12):1152-4.

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

References

1. Markowitz L. Overview and background (HPV). CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-2-Markowitz-508.pdf. Presented February 27, 2019. Accessed August 1, 2019.
2. Brisson M, Laprise J-F. Cost-effectiveness of extending HPV vaccination above age 26 years in the U.S. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-3-Brisson-508.pdf. Presented February 2019. Accessed August 1, 2019.
3. Markowitz L. Recommendations for mid-adult HPV vaccination work group considerations. CDC Web site. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2019-02/HPV-7-Markowitz-508.pdf, Presented February 27, 2019. Accessed August 1, 2019.
4. Meites E, Szilagyi PG, Chesson HW, et al. Human papillomavirus vaccination for adults: updated recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2019;68:698-702.

SAN DIEGO – A physician assistant urged colleagues to cast a skeptical eye on male patients who try to jump on board the testosterone therapy train.

“I see many patients getting onto testosterone without having had an adequate evaluation. And I see many patients who might not need testosterone replacement,” Ji Hyun “CJ” Chun, PA-C, MPAS, BC-ADM, said at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

Mr. Chun, who is based at OptumCare Medical Group, Laguna Niguel, Calif., and has served as president of the American Society of Endocrine PAs, offered this advice on evaluating male patients for testosterone therapy:

• Pinpoint the type of hypogonadism. After hypogonadism has been confirmed with lab tests, additional testing should be done to distinguish primary from secondary hypogonadism. Primary hypogonadism refers to the failure of the testes to properly produce testosterone and sperm and is indicated by elevated levels of LH and FSH. Secondary hypogonadism is caused by failures of the hypothalamus, the pituitary, or both, to stimulate the testes to produce testosterone and sperm. It is indicated by low or low-normal levels of LH and FSH.
• Determine the cause of hypogonadism. Cases of hypogonadism are either organic or functional. Diagnostic guidelines provided by the Endocrine Society are helpful in determining the proper category, Mr. Chun said (J Clin Endocrinol Metab. 2018;103[5]:1715-44). Functional hypogonadism is caused by some medications; opioids; abuse of steroids, alcohol, or marijuana; and obesity, which also greatly increases the risk of secondary hypogonadism. These factors – and functional hypogonadism itself – can conceivably be stopped and/or reversed. This form of hypogonadism tends to be mild, compared with organic or “classic” hypogonadism, which is permanent and caused by factors such as advanced age, some types of chemotherapy, and testicle removal. “Organic male hypogonadism mimics female menopause,” Mr. Chun said, in areas such as rate of hormonal decline, which is typically rapid, and hormone deficiency, which is profound. When it comes to treatment, “the benefits far outweigh the risks in organic hypogonadism. But if [a patient has] late-onset [functional] hypogonadism, it gets more complicated.”
• Late-onset hypogonadism treatment. What should be done for patients who have late-onset, organic hypogonadism? According to Mr. Chun, the data regarding testosterone therapy in this population are mixed. The Food and Drug Administration has approved testosterone therapy only for men with organic hypogonadism, he said, noting that “none of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition.” However, the Endocrine Society guidelines are less restrictive. In its 2018 guidelines, the society frowned on testosterone therapy for men younger than 65 years with age-related hypogonadism. As for older men, it said that for those “who have symptoms or conditions suggestive of testosterone deficiency (such as low libido or unexplained anemia) and consistently and unequivocally low morning testosterone concentrations, we suggest that clinicians offer testosterone therapy on an individualized basis after explicit discussion of the potential risks and benefits.”
• Don’t push for high testosterone levels. When treating patients, “you want to restore the testosterone to an adequate level,” Mr. Chun said. “What’s an adequate level? We don’t know.” He urged colleagues to not overdo it and to consider aiming for a testosterone level ranging between 350 ng/dL and 700 ng/dL. “I get [the levels] to the lowest level at which the patient is symptomatically fine.”

Global Academy and this news organization are owned by the same parent company. Mr. Chun disclosed that he is on the AstraZeneca speakers bureau and the Sanofi advisory board.

SAN DIEGO – A physician assistant urged colleagues to cast a skeptical eye on male patients who try to jump on board the testosterone therapy train.

“I see many patients getting onto testosterone without having had an adequate evaluation. And I see many patients who might not need testosterone replacement,” Ji Hyun “CJ” Chun, PA-C, MPAS, BC-ADM, said at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

Mr. Chun, who is based at OptumCare Medical Group, Laguna Niguel, Calif., and has served as president of the American Society of Endocrine PAs, offered this advice on evaluating male patients for testosterone therapy:

• Pinpoint the type of hypogonadism. After hypogonadism has been confirmed with lab tests, additional testing should be done to distinguish primary from secondary hypogonadism. Primary hypogonadism refers to the failure of the testes to properly produce testosterone and sperm and is indicated by elevated levels of LH and FSH. Secondary hypogonadism is caused by failures of the hypothalamus, the pituitary, or both, to stimulate the testes to produce testosterone and sperm. It is indicated by low or low-normal levels of LH and FSH.
• Determine the cause of hypogonadism. Cases of hypogonadism are either organic or functional. Diagnostic guidelines provided by the Endocrine Society are helpful in determining the proper category, Mr. Chun said (J Clin Endocrinol Metab. 2018;103[5]:1715-44). Functional hypogonadism is caused by some medications; opioids; abuse of steroids, alcohol, or marijuana; and obesity, which also greatly increases the risk of secondary hypogonadism. These factors – and functional hypogonadism itself – can conceivably be stopped and/or reversed. This form of hypogonadism tends to be mild, compared with organic or “classic” hypogonadism, which is permanent and caused by factors such as advanced age, some types of chemotherapy, and testicle removal. “Organic male hypogonadism mimics female menopause,” Mr. Chun said, in areas such as rate of hormonal decline, which is typically rapid, and hormone deficiency, which is profound. When it comes to treatment, “the benefits far outweigh the risks in organic hypogonadism. But if [a patient has] late-onset [functional] hypogonadism, it gets more complicated.”
• Late-onset hypogonadism treatment. What should be done for patients who have late-onset, organic hypogonadism? According to Mr. Chun, the data regarding testosterone therapy in this population are mixed. The Food and Drug Administration has approved testosterone therapy only for men with organic hypogonadism, he said, noting that “none of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition.” However, the Endocrine Society guidelines are less restrictive. In its 2018 guidelines, the society frowned on testosterone therapy for men younger than 65 years with age-related hypogonadism. As for older men, it said that for those “who have symptoms or conditions suggestive of testosterone deficiency (such as low libido or unexplained anemia) and consistently and unequivocally low morning testosterone concentrations, we suggest that clinicians offer testosterone therapy on an individualized basis after explicit discussion of the potential risks and benefits.”
• Don’t push for high testosterone levels. When treating patients, “you want to restore the testosterone to an adequate level,” Mr. Chun said. “What’s an adequate level? We don’t know.” He urged colleagues to not overdo it and to consider aiming for a testosterone level ranging between 350 ng/dL and 700 ng/dL. “I get [the levels] to the lowest level at which the patient is symptomatically fine.”

Global Academy and this news organization are owned by the same parent company. Mr. Chun disclosed that he is on the AstraZeneca speakers bureau and the Sanofi advisory board.

SAN DIEGO – A physician assistant urged colleagues to cast a skeptical eye on male patients who try to jump on board the testosterone therapy train.

“I see many patients getting onto testosterone without having had an adequate evaluation. And I see many patients who might not need testosterone replacement,” Ji Hyun “CJ” Chun, PA-C, MPAS, BC-ADM, said at the Metabolic & Endocrine Disease Summit by Global Academy for Medical Education.

Mr. Chun, who is based at OptumCare Medical Group, Laguna Niguel, Calif., and has served as president of the American Society of Endocrine PAs, offered this advice on evaluating male patients for testosterone therapy:

• Pinpoint the type of hypogonadism. After hypogonadism has been confirmed with lab tests, additional testing should be done to distinguish primary from secondary hypogonadism. Primary hypogonadism refers to the failure of the testes to properly produce testosterone and sperm and is indicated by elevated levels of LH and FSH. Secondary hypogonadism is caused by failures of the hypothalamus, the pituitary, or both, to stimulate the testes to produce testosterone and sperm. It is indicated by low or low-normal levels of LH and FSH.
• Determine the cause of hypogonadism. Cases of hypogonadism are either organic or functional. Diagnostic guidelines provided by the Endocrine Society are helpful in determining the proper category, Mr. Chun said (J Clin Endocrinol Metab. 2018;103[5]:1715-44). Functional hypogonadism is caused by some medications; opioids; abuse of steroids, alcohol, or marijuana; and obesity, which also greatly increases the risk of secondary hypogonadism. These factors – and functional hypogonadism itself – can conceivably be stopped and/or reversed. This form of hypogonadism tends to be mild, compared with organic or “classic” hypogonadism, which is permanent and caused by factors such as advanced age, some types of chemotherapy, and testicle removal. “Organic male hypogonadism mimics female menopause,” Mr. Chun said, in areas such as rate of hormonal decline, which is typically rapid, and hormone deficiency, which is profound. When it comes to treatment, “the benefits far outweigh the risks in organic hypogonadism. But if [a patient has] late-onset [functional] hypogonadism, it gets more complicated.”
• Late-onset hypogonadism treatment. What should be done for patients who have late-onset, organic hypogonadism? According to Mr. Chun, the data regarding testosterone therapy in this population are mixed. The Food and Drug Administration has approved testosterone therapy only for men with organic hypogonadism, he said, noting that “none of the FDA-approved testosterone products are approved for use in men with low testosterone levels who lack an associated medical condition.” However, the Endocrine Society guidelines are less restrictive. In its 2018 guidelines, the society frowned on testosterone therapy for men younger than 65 years with age-related hypogonadism. As for older men, it said that for those “who have symptoms or conditions suggestive of testosterone deficiency (such as low libido or unexplained anemia) and consistently and unequivocally low morning testosterone concentrations, we suggest that clinicians offer testosterone therapy on an individualized basis after explicit discussion of the potential risks and benefits.”
• Don’t push for high testosterone levels. When treating patients, “you want to restore the testosterone to an adequate level,” Mr. Chun said. “What’s an adequate level? We don’t know.” He urged colleagues to not overdo it and to consider aiming for a testosterone level ranging between 350 ng/dL and 700 ng/dL. “I get [the levels] to the lowest level at which the patient is symptomatically fine.”

Global Academy and this news organization are owned by the same parent company. Mr. Chun disclosed that he is on the AstraZeneca speakers bureau and the Sanofi advisory board.

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

[email protected]

This article was updated 8/8/19.

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

[email protected]

This article was updated 8/8/19.

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

[email protected]

This article was updated 8/8/19.

Study Overview

Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.

Design. Multinational, open-label, randomized phase 3 trial.

Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.

Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m² every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.

Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.

Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.

Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.

Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.

Commentary

The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.^1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.^5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.^1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.³

The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.³ However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.

Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.

Applications for Clinical Practice

The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.

Design. Multinational, open-label, randomized phase 3 trial.

Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.

Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m² every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.

Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.

Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.

Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.

Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.

Commentary

The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.^1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.^5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.^1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.³

The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.³ However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.

Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.

Applications for Clinical Practice

The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.

—Daniel Isaac, DO, MS

Study Overview

Objective. To evaluate the efficacy of enzalutamide compared with standard first-line testosterone suppression in men with newly diagnosed metastatic, castrate-sensitive prostate cancer.

Design. Multinational, open-label, randomized phase 3 trial.

Setting and participants. 1125 men were randomly assigned to receive enzalutamide (563 patients) or standard care (562 patients) from March 2014 through March 2017. Eligible patients had a histologic diagnosis of prostate adenocarcinoma with metastases documented by conventional imaging with computed tomography (CT) and/or technetium-99 bone scan. Prior use of adjuvant testosterone suppression was allowed for up to 2 years, provided this had been completed at least 12 months prior to enrollment.

Intervention. Patients were randomized in a 1:1 fashion to receive enzalutamide 160 mg daily or nonsteroidal antiandrogen therapy with bicalutamide, nilutamide, or flutamide. All patients received testosterone suppression with goserelin, leuprolide, or degarelix. Therapy was continued until disease progression or intolerable adverse effects occurred. In November 2014 the protocol was amended to allow for early administration of docetaxel 75 mg/m² every 3 weeks for 6 cycles and androgen suppression. Patients were stratified according to having received docetaxel prior to randomization. This amendment was based on evidence of improved survival noted with this combination, and the decision to add docetaxel was up to the treating physician. The randomization was further stratified by disease volume, the use of bone-modifying agents, and comorbidity scores. High-volume disease was defined as the presence of visceral metastases or at least 4 bone lesions, with at least 1 being in the appendicular skeleton.

Main outcome measures. The primary endpoint was overall survival (OS). The secondary endpoints were prostate-specific antigen (PSA) progression-free survival (PFS), clinical PFS, death from any cause, or the last known follow-up PSA. PSA progression was defined as an increase in PSA level from the nadir value by ≥ 25% and by ≥ 2 ng/mL.

Main results. The baseline characteristics were well balanced between the treatment arms. High-volume disease was present in 52% of patients. Early docetaxel was planned in 45% of patients; however, 22 patients in whom docetaxel treatment was planned did not receive it. All 6 cycles of docetaxel were given to 159 patients in the enzalutamide group and 181 patients in the standard-care group. After a median follow-up of 34 months, there were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group, with a hazard ratio (HR) for death of 0.67 (95% confidence interval [CI], 0.52-0.86; P = 0.002). Early docetaxel treatment, volume of disease, and use of bone-modifying agents did not affect this outcome. At 3 years, the OS was 80% in the enzalutamide group and 72% in the standard-care group. The rate of PSA-determined PFS was higher in the enzalutamide group compared with the standard group (3-year event-free survival, 67% and 37%, respectively), with a HR of 0.39 (95% CI, 0.33-0.47; P < 0.001). There were fewer clinical PFS events in the enzalutamide group (167 events vs 320 events), with a HR of 0.40 (95% CI, 0.33-0.49; P < 0.001). Analysis of the stratified subgroups showed the effect on OS was diminished in those with use of bone-modifying agents, those with high-volume disease, and those who received early docetaxel. The clinical PFS benefit was maintained across all subgroups, albeit with a smaller effect in those with high-volume disease and in those with early docetaxel treatment.

Treatment discontinuation for reasons other than progressive disease occurred in 12% of those in the enzalutamide group and 19% of those in the standard-care group. Overall, the adverse events were consistent with the known safety profiles of the treatment regimen. Seizures occurred in 7 patients on enzalutamide and no patients in the standard-care group. Fatigue was more common with enzalutamide.

Conclusion. Enzalutamide treatment was associated with significantly longer PFS and OS compared with standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression.

Commentary

The current study shows that the addition of enzalutamide to standard androgen deprivation therapy (ADT) improves OS and PFS in men with newly diagnosed metastatic, hormone-sensitive prostate cancer. Until recently, antiandrogen therapy had been the standard of care for these men; however, with the advent of novel antiandrogen agents, outcomes in men with metastatic prostate cancer in both the androgen-sensitive and castrate-resistant settings have steadily improved.^1-5 In the castrate-resistant setting, enzalutamide has previously been shown to improve survival in chemotherapy-naïve patients and those previously exposed to docetaxel chemotherapy.^5-7 Similarly, in the hormone-sensitive setting the combination of ADT with either abiraterone or chemotherapy has been shown to improve outcomes. In the phase 3 LATITUDE and STAMPEDE trials, the combination of abiraterone plus prednisone and ADT resulted in a 30% and 37% improvement in OS, respectively.^1,2 Six cycles of docetaxel in combination with ADT also resulted in a 37% increase in OS in those with high-volume metastatic disease.³

The current study adds to the growing body of literature suggesting that combination therapy in the upfront, hormone-sensitive setting improves outcomes. In the CHAARTED trial, the combination of docetaxel and ADT improved survival in men with high-volume disease, but it did not seem to benefit those with lower-volume disease.³ However, the current data suggests a survival advantage with enzalutamide with low-volume disease as well. The use of docetaxel was similar between the 2 groups, and this suggests that the benefits of enzalutamide cannot be attributed to early integration of docetaxel. It is important to note that the subgroup analysis of those who received early docetaxel showed that these patients did not experience the same survival benefit as those who did not receive docetaxel. However, this trial was not powered for this analysis, and thus it should be interpreted with caution. PFS benefit was maintained across those who received and did not receive early docetaxel. Also worth noting is the increased docetaxel-related toxicity in the combination docetaxel and enzalutamide arm of this study. The neurological toxicity of enzalutamide was again noted, with 7 seizure events documented in this study.

Because this report on the ENZAMET study is an interim analysis, it will be important to follow these outcomes as the data set matures to ensure these effects are maintained over time. Additionally, it will be important to see what implications the addition of enzalutamide have on quality of life measures, as these data have not yet been published.

Applications for Clinical Practice

The ENZAMET study provides evidence that in men with metastatic, hormone-sensitive prostate cancer receiving ADT, the addition of enzalutamide improves PFS and OS. In men who received early docetaxel, enzalutamide was associated with increased toxicity. Additionally, while PFS was improved in men who received enzalutamide and docetaxel, OS was not improved. The neurologic toxicities of enzalutamide should be considered, particularly in those with a prior history of seizure disorders. Based on these data, enzalutamide in combination with ADT represents a reasonable treatment option in men with metastatic, hormone-sensitive prostate cancer.

—Daniel Isaac, DO, MS

Autism spectrum disorder (ASD) has increased significantly over the past 40 years. Even in the past 2 decades, the prevalence increased from 6.7 per 1,000 in 2000¹ to 14.6 per 1,000 in 2012—1 in 59 people.² Of those with ASD, 46% have an intelligence quotient (IQ) greater than 85, meaning they are of average or above-average intelligence.¹

See related editorial

As more children with autism become adults, understanding this condition across the life span grows paramount. While many studies have focused on understanding how diagnosis and treatment can help young children, few have focused on adults with autism and how primary care teams can better assist these individuals. However, this is changing, with studies of the benefits of employment programs and pharmacologic treatment, and reproductive health needs of adults with ASD. Here we provide an updated review of ASD in adult patients.

NO MORE ASPERGER SYNDROME— IT’S ON THE SPECTRUM NOW

As the scientific understanding of autism has expanded, revisions in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),³ published in 2013, have paralleled these advances. For many adult patients with autism who were evaluated as children, these revisions have led to changes in diagnosis and available services.

In the previous edition (DSM-IV-TR, published in 2000),⁴ autistic disorder and Asperger syndrome were separate (Table 1). However, DSM-5 lumped autistic disorder and Asperger disorder together under the diagnosis of ASD; this leaves it to the clinician to specify whether the patient with ASD has accompanying intellectual or language impairment and to assign a level of severity based on communication deficits and restrictive behaviors.

The shift in diagnosis was worrisome for some, particularly for clinicians treating patients with DSM-IV Asperger syndrome, who lost this diagnostic label. Concerns that patients with Asperger syndrome may not meet the DSM-5 criteria for ASD were validated by a systematic review showing that only 50% to 75% of patients with DSM-IV autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) met the DSM-5 criteria for ASD.⁵ Most of those who no longer met the criteria for ASD carried a DSM-IV diagnosis of Asperger syndrome or PDD-NOS or had an IQ over 70.⁵ Nevertheless, these individuals may struggle with impairing symptoms related to repetitive behaviors or communication or may be affected by learning or social-emotional disabilities. Additionally, even if they meet the criteria for ASD, some may identify with the Asperger syndrome label and fear they will be stigmatized should they be classified as having the more general ASD.^6,7

Although future revisions to the DSM may include further changes in classification, grouping adults with ASD according to their functional and cognitive ability may allow for pragmatic characterization of their needs. At least 3 informal groupings of autistic adults have been described that integrate cognitive ability and independence⁸:

• Those with low cognitive and social abilities, who need lifelong support
• Those with midrange cognitive and social limitations but who can complete their work in special education classes; they often find employment in supervised workshops or other work with repetitive tasks
• Those who have greater cognitive ability and some social skills; they may proceed to college and employment and live independently.

UNCERTAIN PROGNOSIS

Prognostication for people with ASD remains an area of research. Some adults experience a reduction in symptoms as they age, with significant improvements in speech and, sometimes, modest improvements in restrictive and repetitive behaviors.^9,10

Nevertheless, autism remains a lifelong disorder for many. Adults may still require significant support and may experience impairment, particularly in social interaction.¹⁰ In longitudinal studies, only 15% to 27% of patients with ASD are characterized as having a positive outcome (often defined as variables related to independent function, near-normal relationships, employment, or a quantified reduction in core symptoms), and many experience significant dependency into adulthood.^10–13

IQ has been cited as a possible prognostic factor,^10,13 with an IQ below 70 associated with poorer outcome, although an IQ above 70 does not necessarily confer a positive outcome. Less-severe impairment in speech at baseline in early childhood also suggests better outcomes in adulthood.¹⁰

As we see more adults with autism, studies that include both children and adults, such as the Longitudinal European Autism Cohort, will be important to characterize the natural history, comorbidities, and genetics of ASD and may help provide more specific predictors of disease course into adulthood.¹⁴

While many patients are recognized as having autism in early to mid-childhood, some adults may not receive a formal diagnosis until much later in life. Those with fluent language and normal-range IQ are likely to be overlooked.¹⁵ People with ASD may have had mild symptoms during childhood that did not impair their functioning until demands of daily life exceeded their capacities in adulthood. Alternatively, parents of a child with newly diagnosed ASD may realize that they themselves or another adult family member also show signs of it.

The UK National Institute of Health and Care Excellence suggests that assessment should be considered if the patient meets psychiatric diagnostic criteria and one of the following:

• Difficulty obtaining or sustaining employment or education
• Difficulty initiating or sustaining social relationships
• Past or current contact with mental health or learning disability services
• History of a neurodevelopmental or mental health disorder.^15,16

Currently, diagnosis typically involves a multidisciplinary approach, with psychiatric assessment, neuropsychological testing, and speech and language evaluation.¹⁷ Providers may need to refer patients for these services, sometimes at the patient’s request, if previous mental health misdiagnoses are suspected, if patients report symptoms or impairment consistent with ASD, or if benefits, services, or accommodations, such as a coach in the workplace, are needed.

Diagnosing ASD in adults can be difficult, given that the gold-standard diagnostic tests such as the Autism Diagnostic Observation Schedule-2 (ADOS-2)¹⁸ and the Autism Diagnostic Interview-Revised (ADI-R)¹⁹ are typically used to diagnose autism in children. However, Module 4 in the ADOS-2 was developed for adolescents and older patients with fluent language and has shown at least moderate power to distinguish adults with ASD from those without ASD.^18,20

An initial psychiatric assessment should include a thorough history taken from the patient and, if applicable, the patient’s caregiver, as well as a psychiatric interview of the patient. Neuropsychological testing should include evaluation of cognitive function, social functioning (using the ADOS-2 for adults without intellectual disability, the ADI-R, or both), and adaptive functioning (using the Vineland Adaptive Behavior Scales, second edition²¹).

Evaluation of speech and language is particularly important in patients with limited language ability and should include both expressive and receptive language abilities. Serial testing every few years, as is often recommended in childhood, may help establish the pattern of impairment over time.

Comorbid psychiatric disorders are common

Many people with ASD also have other psychiatric disorders,^17,22 which clinicians should keep in mind when seeing an adult seeking evaluation for ASD.

Attention-deficit/hyperactivity disorder is present at higher rates in patients of average intellectual function with ASD than in the general population.²³

Anxiety disorders, including obsessive-compulsive disorder, were found to often coexist with autism in a sample of adults with autism without intellectual disability,^24,25 and approximately 40% of youths with ASD have at least 1 comorbid anxiety disorder.²⁶

Mood disorders are also prevalent in adults with ASD, with a small study showing that 70% of adults with DSM-IV Asperger syndrome had at least 1 depressive episode in their lifetime.²⁷

BEHAVIORAL AND PHARMACOLOGIC THERAPIES FOR THE ADULT PATIENT

Services and medications for adults with ASD are discussed below. These will vary by individual, and services available may vary by region.

Historically, vocational and social outcomes have been poor for adults with ASD. It is estimated that most larger universities may be home to 100 to 300 students with ASD. To combat isolation, the University of California, Los Angeles, the University of Alabama, and others provide special support services, including group social activities such as board games and individual coaching.⁸ Nevertheless, half of the students with autism who attend institutions of higher learning leave without completing their intended degree.²⁹ Many still struggle to establish meaningful friendships or romantic relationships.²⁹

Planning for a transition of care

Healthcare transition planning is important  but is strikingly underused.³⁰ Individual providers, including adult psychiatrists, vary in their level of training and comfort in diagnosing, treating, and monitoring adults with autism. Youths with ASD are half as likely to receive healthcare transition services as other youths with special healthcare needs.³¹

Pediatric providers, including pediatric psychiatrists, developmental behavioral specialists, and pediatric neurologists, may be best equipped to treat young adult patients or to refer patients to appropriate generalists and specialists comfortable with autism-specific transition of care. The question of eligibility for services is important to patients and families during the transition period, with many parents and professionals unaware of services available to them.³² Receiving adequate transition services is enabled by having a medical home during childhood—that is, a comprehensive, centralized medical record, culturally competent care, interaction with schools, and patient access to clear, unbiased information.³¹

Ideally, in our experience, transitioning should be discussed well before the child ages out of the pediatric provider’s practice. If necessary, healthcare transition services should include 4 components:

• Discussing the switch to a new physician who treats adults
• Discussing changing healthcare needs as an adult
• Planning insurance coverage as an adult
• Encouragement by the physician for the child to take age-appropriate responsibility for his or her healthcare.^31,33

Tools such as the Got Transition checklist from the National Health Care Transition Center can provide support during this process.³⁴

Other services

Other services provided as an extension or adjunct to the medical home in early adulthood may include customized vocational or employment training, specialized mentorship or support in a college setting, housing support, and psychological services.³⁵

Community-based programs that emphasize leisure have been shown to improve participants’ independence and quality of life.³⁶ Similarly, participants in programs that emphasized supported employment, with a job coach, on-the-job support, collaboration with the participant’s larger social support network, and selection of tasks to match an individual’s abilities and strengths, demonstrated improved cognitive performance, particularly executive functioning,³⁷ and employment.^38,39 These programs work best for patients who have mild to moderate symptoms.^37,39

Patients with symptoms that are more severe may do better in a residential program. Many of these programs maintain an emphasis on vocational and social skills development. One such long-standing program is Bittersweet Farms, a rural farming community in Ohio for adults with ASD, where individuals with moderate to low function live in a group setting, with emphasis on scheduled, meaningful work including horticulture, animal care, carpentry; and activities of daily living.⁴⁰

Studies of patients across the autism spectrum have generally found better outcomes when vocational support is given, but larger and randomized studies are needed to characterize how to best support these individuals after they leave high school.⁴¹

Psychological services such as applied behavioral therapy, social cognition training, cognitive behavioral therapy, and mindfulness training may be particularly useful in adults.^42–44

Some versions of applied behavioral therapy, such as the Early Start Denver Model,⁴⁵ have been found to be cost-effective and offset some expenses in the care of children with autism, using play-based and relationship-based interventions to promote development across domains while reducing symptoms.

In randomized controlled trials, modified cognitive behavioral therapy⁴³ and mindfulness⁴⁴ were shown to reduce symptoms of anxiety, obsessive-compulsive disorder, and depression.

Dialectical behavior therapy, used to find a balance between accepting oneself and desiring to change, may help in some circumstances to regulate emotions and reduce reactivity and lability, although large randomized clinical trials have not been conducted in the ASD population.⁴⁶

Drug therapy

Medications may be appropriate to manage symptoms or comorbid conditions in adults with ASD. Over 75% adults with ASD have been found to use psychotropic medications.⁴⁷ However, although these drugs have been approved for treating behaviors commonly associated with ASD, none of them provide definitive treatment for this disorder, and they have not been rigorously tested or approved for use in adults with ASD.⁴⁸

Irritability and aggression associated with ASD can be treated with risperidone (approved for children over age 5), aripiprazole (approved for children ages 6–17), clozapine, or haloperidol.⁴⁹

Aberrant social behavior can be treated with risperidone.⁵⁰ Treatments under investigation include oxytocin and secretin.⁴⁹

While no approved drug has been shown to improve social communication,⁵¹ balovaptan, a vasopressin V1a agonist, has shown potential and has been granted breakthrough status by the US Food and Drug Administration for treating challenging behaviors in adults, with additional studies ongoing in children.^52,53

Repetitive behaviors, if the patient finds them impairing, can be managed with selective serotonin reuptake inhibitors.⁴⁹

Much more study of drug therapy in adults with ASD is needed to fully understand the best approaches to psychotropic medication use, including appropriate classes and effective dosage, in this population.

SEX: UNEXPLORED TERRITORY

The reproductive health needs of people with autism remain largely underexplored.⁵⁴ Historically, individuals with ASD were thought to have little interest in sexual activity or parenthood, owing to the nature of the core symptoms of the disorder. This has been shown to be untrue, particularly as studies on this topic began to engage in direct interviews with people with ASD, rather than solely gathering information from caregivers or parents. The findings reinforce the importance of broaching this component of health in this population, for the following reasons:

Adults with ASD are at increased risk of sexual victimization, with nearly 4 out of 5 reporting unwanted sexual advances, coercion, or rape.⁵⁵

They have a smaller pool of knowledge with respect to sexual health. They report⁵⁶ that they learned about sex from television and from “making mistakes.” They use fewer sources. They are less likely to speak to peers and figures of authority to gain knowledge about sexually transmitted infections, sexual behaviors, and contraception. And they are more likely to use forms of nonsocial media, such as television, for information.⁵⁵

They report more concerns about the future with respect to sexual behavior, suggesting the need for targeted sexual education programs.⁵⁶

College-age young adults with ASD who misread communication may be particularly affected by Title IX, which requires schools to promptly investigate reports of sexual harassment and sexual assault, should they struggle to comport themselves appropriately.⁵⁷ Early and frank conversations about issues of consent and appropriate displays of interest and affection may better equip youth to navigate new social scenarios as they plan to leave a supervised home environment for college or the workforce.

Gender identification: Male, female, other

In one study, 77.8% of birth-sex males with ASD said they identified as men, and 67.1% of birth-sex females identified as women,  compared with 93.1% of birth-sex males and 87.3% of birth-sex females without ASD. Many of the remaining individuals with ASD reported a transgender, genderqueer, or other gender identity.⁵⁸ Some studies have found females with ASD report a gay or bisexual orientation more often than males with ASD.^59–61

Adolescents and young adults may be exploring their changing bodies, sexual preferences, and gender roles, and as for all people at this age, these roles emerge against a backdrop of familial and societal expectations that may or may not be concordant with their own projected path regarding sexuality and reproductive health.⁶²

Having the conversation

As with non-ASD patients, a thorough sexual history should be collected via open-ended questions when possible to determine types of sexual activity and partners.

Education of the patient, alongside caregivers and parents, about healthy and safe sexual practices, screening for sexual violence, and hormonal and nonhormonal contraception options are important components of care for this population.

CAREGIVER STRESS MAY PERSIST INTO PATIENT’S ADULTHOOD

Caregiver burden is a monumental concern for parents or others who may have lifelong primary responsibility for these neurodiverse adults.⁶³ Family members may feel isolated and may feel they have encountered many barriers to services.⁶⁴ Remaining sensitive, knowledgeable, and inquisitive about the types of support that are needed may help forge a trusting relationship between the provider and the family.

Parents of children with ASD have been reported to experience worse physical and emotional health than parents whose children do not have developmental disabilities.^63,65 These disparities have been found to persist  as their children enter adolescence and young adulthood.^66,67 Parents of children with ASD report more anxiety, depression, and distress compared with parents of children without ASD,⁶³ and parents themselves may be affected by ASD symptoms, which has been linked to increased parenting stress.⁶⁸ Some studies have found blunted cortisol responses,^63,69,70 and some,⁷¹ but not all,⁶³ have found elevated blood pressure in caregivers of children with developmental disabilities. Headache, backache, muscle soreness, and fatigue may also be commonly reported.⁶⁷

In our experience, caregivers are tremendously appreciative when provided connections to adult ASD services and support systems as their child ages. The school system and other formal support systems often assist until the time of transition into adulthood. This transition can be stressful for the adolescent and family alike, and informal support systems such as friends and family may become increasingly crucial, particularly if the adolescent still lives at home.^72,73

The affected young adult’s unmet needs, as perceived by the caregiver, have been found to be significantly associated with caregiver burden, whereas the severity of the adult patient’s ASD symptoms has not.⁶⁶ Therefore, it may be helpful to ask caregivers whether they perceive any unmet needs, regardless of the clinician’s perception of the severity of the patient’s ASD symptoms. Providing support to address these needs, particularly those relating to the child’s mood disorders, communication, social needs, safety, and daytime activities, may be the domains of support that most effectively reduce the caregiver burden in this population.⁶⁶

Caregiver positivity, lower stress levels, and increased social support, particularly in the form of friends and family members providing no-cost assistance to caregivers whose children do not live independently,⁷⁴ have been linked to better outcomes for caregivers.^70,74,75 Rigorous studies that examine caregiver burden as individuals with ASD enter mid- and late-adulthood are limited.

THE ROLE OF THE INTERNIST IN CARING FOR ADULTS WITH AUTISM

A major challenge for many adults with ASD is the transition from services provided during childhood to those provided in adulthood. While children with autism have subspecialty providers who diagnose and manage their condition, including developmental-behavioral pediatricians, pediatric neurologists, and child psychiatrists, adults with autism may have fewer options.

Autism centers are becoming more available across the nation, and many provide care across the life span. However, depending on a patient’s needs, the primary care provider may need to manage residual symptoms as the patient transitions from pediatric to adult care, ultimately deciding when and where to refer the patient.

The patient’s family should pay close attention to function and mood around the time the patient leaves the structure of high school, and they should build rapport with a primary care provider they can turn to if problems persist or arise. Referrals for behavioral therapy and for social work, job training, and vocational support can greatly benefit patients as they transition to young adulthood. Referrals and suggestions for social support can also help caregivers.

Medical care

Deciding when and how to medicate the patient for symptoms of autism and related behaviors necessitates consideration of the patient’s impairment, side effects of the medication, and the impact medications may have on the patient’s other conditions. Disordered eating, mood problems, anxiety, and attention-deficit/hyperactivity disorder should be considered, and, as in all patients, regular screenings of mental health status should be conducted.^76,77

Comorbid medical conditions may cause worsening of a patient’s known behavioral symptoms or may precipitate new behaviors or aggression as a result of pain or discomfort, particularly in patients with limited speech. A change in stereotypes or increased irritability warrants a thoughtful investigation for a cause other than ASD before adding or increasing behavioral medications. Common comorbid conditions include gastrointestinal distress, most commonly constipation and diarrhea in an idiopathic ASD population, with increasing ASD symptom severity correlating with increased odds of a gastrointestinal problem.⁷⁸ Allergies, sleep disorders, seizures, and other psychiatric conditions are also frequent.⁷⁹

Preventive care, including vaccinations, should be given as scheduled. Caregivers and patients can be reminded if needed that vaccines do not cause or worsen autism, and vaccination is intended to improve the safety of the patient and those around them, protecting against potentially life-threatening disease. Regular dental care visits, particularly for patients who are using medications that may affect tooth or gingival health,⁸⁰ and regular visits to an optometrist or ophthalmologist for screening of vision are also advised.

Adverse effects. Weight gain and metabolic syndrome are common adverse effects of medications used for behavioral management, and the primary care physician may uncover diabetes, cardiac disorders, and hyperlipidemia. Patients with ASD may be particularly sensitive to the effects of medications and therefore may require a lower dose or a slower titration than other patients. Working with a behavioral team, careful weaning of psychiatric medications to the minimum needed is strongly recommended whenever possible.⁸¹

TAKE-HOME POINTS

As more adults with autism enter society, they may require varying levels of support from the healthcare community to ensure that therapeutic gains from childhood persist, allowing them to achieve maximal functional potential.

Adults with ASD may have a high, normal, or low IQ and intellectual capability. Knowledge of this and of the patient’s symptom severity and presence of comorbid psychiatric and other health conditions can help the clinician guide the patient to appropriate social services and pharmacologic treatments.

Individualized support in the workplace, as well as education regarding sexual health, can help improve outcomes for affected individuals.

Caregiver burden for individuals with autism can be high, but it can be mitigated by social support.

Further research regarding appropriate diagnostic instruments in adulthood and appropriate treatments for impairing autism-related symptoms across the life span may be particularly helpful in supporting this patient population.

Autism spectrum disorder (ASD) has increased significantly over the past 40 years. Even in the past 2 decades, the prevalence increased from 6.7 per 1,000 in 2000¹ to 14.6 per 1,000 in 2012—1 in 59 people.² Of those with ASD, 46% have an intelligence quotient (IQ) greater than 85, meaning they are of average or above-average intelligence.¹

See related editorial

As more children with autism become adults, understanding this condition across the life span grows paramount. While many studies have focused on understanding how diagnosis and treatment can help young children, few have focused on adults with autism and how primary care teams can better assist these individuals. However, this is changing, with studies of the benefits of employment programs and pharmacologic treatment, and reproductive health needs of adults with ASD. Here we provide an updated review of ASD in adult patients.

NO MORE ASPERGER SYNDROME— IT’S ON THE SPECTRUM NOW

As the scientific understanding of autism has expanded, revisions in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),³ published in 2013, have paralleled these advances. For many adult patients with autism who were evaluated as children, these revisions have led to changes in diagnosis and available services.

In the previous edition (DSM-IV-TR, published in 2000),⁴ autistic disorder and Asperger syndrome were separate (Table 1). However, DSM-5 lumped autistic disorder and Asperger disorder together under the diagnosis of ASD; this leaves it to the clinician to specify whether the patient with ASD has accompanying intellectual or language impairment and to assign a level of severity based on communication deficits and restrictive behaviors.

The shift in diagnosis was worrisome for some, particularly for clinicians treating patients with DSM-IV Asperger syndrome, who lost this diagnostic label. Concerns that patients with Asperger syndrome may not meet the DSM-5 criteria for ASD were validated by a systematic review showing that only 50% to 75% of patients with DSM-IV autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) met the DSM-5 criteria for ASD.⁵ Most of those who no longer met the criteria for ASD carried a DSM-IV diagnosis of Asperger syndrome or PDD-NOS or had an IQ over 70.⁵ Nevertheless, these individuals may struggle with impairing symptoms related to repetitive behaviors or communication or may be affected by learning or social-emotional disabilities. Additionally, even if they meet the criteria for ASD, some may identify with the Asperger syndrome label and fear they will be stigmatized should they be classified as having the more general ASD.^6,7

Although future revisions to the DSM may include further changes in classification, grouping adults with ASD according to their functional and cognitive ability may allow for pragmatic characterization of their needs. At least 3 informal groupings of autistic adults have been described that integrate cognitive ability and independence⁸:

• Those with low cognitive and social abilities, who need lifelong support
• Those with midrange cognitive and social limitations but who can complete their work in special education classes; they often find employment in supervised workshops or other work with repetitive tasks
• Those who have greater cognitive ability and some social skills; they may proceed to college and employment and live independently.

UNCERTAIN PROGNOSIS

Prognostication for people with ASD remains an area of research. Some adults experience a reduction in symptoms as they age, with significant improvements in speech and, sometimes, modest improvements in restrictive and repetitive behaviors.^9,10

Nevertheless, autism remains a lifelong disorder for many. Adults may still require significant support and may experience impairment, particularly in social interaction.¹⁰ In longitudinal studies, only 15% to 27% of patients with ASD are characterized as having a positive outcome (often defined as variables related to independent function, near-normal relationships, employment, or a quantified reduction in core symptoms), and many experience significant dependency into adulthood.^10–13

IQ has been cited as a possible prognostic factor,^10,13 with an IQ below 70 associated with poorer outcome, although an IQ above 70 does not necessarily confer a positive outcome. Less-severe impairment in speech at baseline in early childhood also suggests better outcomes in adulthood.¹⁰

As we see more adults with autism, studies that include both children and adults, such as the Longitudinal European Autism Cohort, will be important to characterize the natural history, comorbidities, and genetics of ASD and may help provide more specific predictors of disease course into adulthood.¹⁴

While many patients are recognized as having autism in early to mid-childhood, some adults may not receive a formal diagnosis until much later in life. Those with fluent language and normal-range IQ are likely to be overlooked.¹⁵ People with ASD may have had mild symptoms during childhood that did not impair their functioning until demands of daily life exceeded their capacities in adulthood. Alternatively, parents of a child with newly diagnosed ASD may realize that they themselves or another adult family member also show signs of it.

The UK National Institute of Health and Care Excellence suggests that assessment should be considered if the patient meets psychiatric diagnostic criteria and one of the following:

• Difficulty obtaining or sustaining employment or education
• Difficulty initiating or sustaining social relationships
• Past or current contact with mental health or learning disability services
• History of a neurodevelopmental or mental health disorder.^15,16

Currently, diagnosis typically involves a multidisciplinary approach, with psychiatric assessment, neuropsychological testing, and speech and language evaluation.¹⁷ Providers may need to refer patients for these services, sometimes at the patient’s request, if previous mental health misdiagnoses are suspected, if patients report symptoms or impairment consistent with ASD, or if benefits, services, or accommodations, such as a coach in the workplace, are needed.

Diagnosing ASD in adults can be difficult, given that the gold-standard diagnostic tests such as the Autism Diagnostic Observation Schedule-2 (ADOS-2)¹⁸ and the Autism Diagnostic Interview-Revised (ADI-R)¹⁹ are typically used to diagnose autism in children. However, Module 4 in the ADOS-2 was developed for adolescents and older patients with fluent language and has shown at least moderate power to distinguish adults with ASD from those without ASD.^18,20

An initial psychiatric assessment should include a thorough history taken from the patient and, if applicable, the patient’s caregiver, as well as a psychiatric interview of the patient. Neuropsychological testing should include evaluation of cognitive function, social functioning (using the ADOS-2 for adults without intellectual disability, the ADI-R, or both), and adaptive functioning (using the Vineland Adaptive Behavior Scales, second edition²¹).

Evaluation of speech and language is particularly important in patients with limited language ability and should include both expressive and receptive language abilities. Serial testing every few years, as is often recommended in childhood, may help establish the pattern of impairment over time.

Comorbid psychiatric disorders are common

Many people with ASD also have other psychiatric disorders,^17,22 which clinicians should keep in mind when seeing an adult seeking evaluation for ASD.

Attention-deficit/hyperactivity disorder is present at higher rates in patients of average intellectual function with ASD than in the general population.²³

Anxiety disorders, including obsessive-compulsive disorder, were found to often coexist with autism in a sample of adults with autism without intellectual disability,^24,25 and approximately 40% of youths with ASD have at least 1 comorbid anxiety disorder.²⁶

Mood disorders are also prevalent in adults with ASD, with a small study showing that 70% of adults with DSM-IV Asperger syndrome had at least 1 depressive episode in their lifetime.²⁷

BEHAVIORAL AND PHARMACOLOGIC THERAPIES FOR THE ADULT PATIENT

Services and medications for adults with ASD are discussed below. These will vary by individual, and services available may vary by region.

Historically, vocational and social outcomes have been poor for adults with ASD. It is estimated that most larger universities may be home to 100 to 300 students with ASD. To combat isolation, the University of California, Los Angeles, the University of Alabama, and others provide special support services, including group social activities such as board games and individual coaching.⁸ Nevertheless, half of the students with autism who attend institutions of higher learning leave without completing their intended degree.²⁹ Many still struggle to establish meaningful friendships or romantic relationships.²⁹

Planning for a transition of care

Healthcare transition planning is important  but is strikingly underused.³⁰ Individual providers, including adult psychiatrists, vary in their level of training and comfort in diagnosing, treating, and monitoring adults with autism. Youths with ASD are half as likely to receive healthcare transition services as other youths with special healthcare needs.³¹

Pediatric providers, including pediatric psychiatrists, developmental behavioral specialists, and pediatric neurologists, may be best equipped to treat young adult patients or to refer patients to appropriate generalists and specialists comfortable with autism-specific transition of care. The question of eligibility for services is important to patients and families during the transition period, with many parents and professionals unaware of services available to them.³² Receiving adequate transition services is enabled by having a medical home during childhood—that is, a comprehensive, centralized medical record, culturally competent care, interaction with schools, and patient access to clear, unbiased information.³¹

Ideally, in our experience, transitioning should be discussed well before the child ages out of the pediatric provider’s practice. If necessary, healthcare transition services should include 4 components:

• Discussing the switch to a new physician who treats adults
• Discussing changing healthcare needs as an adult
• Planning insurance coverage as an adult
• Encouragement by the physician for the child to take age-appropriate responsibility for his or her healthcare.^31,33

Tools such as the Got Transition checklist from the National Health Care Transition Center can provide support during this process.³⁴

Other services

Other services provided as an extension or adjunct to the medical home in early adulthood may include customized vocational or employment training, specialized mentorship or support in a college setting, housing support, and psychological services.³⁵

Community-based programs that emphasize leisure have been shown to improve participants’ independence and quality of life.³⁶ Similarly, participants in programs that emphasized supported employment, with a job coach, on-the-job support, collaboration with the participant’s larger social support network, and selection of tasks to match an individual’s abilities and strengths, demonstrated improved cognitive performance, particularly executive functioning,³⁷ and employment.^38,39 These programs work best for patients who have mild to moderate symptoms.^37,39

Patients with symptoms that are more severe may do better in a residential program. Many of these programs maintain an emphasis on vocational and social skills development. One such long-standing program is Bittersweet Farms, a rural farming community in Ohio for adults with ASD, where individuals with moderate to low function live in a group setting, with emphasis on scheduled, meaningful work including horticulture, animal care, carpentry; and activities of daily living.⁴⁰

Studies of patients across the autism spectrum have generally found better outcomes when vocational support is given, but larger and randomized studies are needed to characterize how to best support these individuals after they leave high school.⁴¹

Psychological services such as applied behavioral therapy, social cognition training, cognitive behavioral therapy, and mindfulness training may be particularly useful in adults.^42–44

Some versions of applied behavioral therapy, such as the Early Start Denver Model,⁴⁵ have been found to be cost-effective and offset some expenses in the care of children with autism, using play-based and relationship-based interventions to promote development across domains while reducing symptoms.

In randomized controlled trials, modified cognitive behavioral therapy⁴³ and mindfulness⁴⁴ were shown to reduce symptoms of anxiety, obsessive-compulsive disorder, and depression.

Dialectical behavior therapy, used to find a balance between accepting oneself and desiring to change, may help in some circumstances to regulate emotions and reduce reactivity and lability, although large randomized clinical trials have not been conducted in the ASD population.⁴⁶

Drug therapy

Medications may be appropriate to manage symptoms or comorbid conditions in adults with ASD. Over 75% adults with ASD have been found to use psychotropic medications.⁴⁷ However, although these drugs have been approved for treating behaviors commonly associated with ASD, none of them provide definitive treatment for this disorder, and they have not been rigorously tested or approved for use in adults with ASD.⁴⁸

Irritability and aggression associated with ASD can be treated with risperidone (approved for children over age 5), aripiprazole (approved for children ages 6–17), clozapine, or haloperidol.⁴⁹

Aberrant social behavior can be treated with risperidone.⁵⁰ Treatments under investigation include oxytocin and secretin.⁴⁹

While no approved drug has been shown to improve social communication,⁵¹ balovaptan, a vasopressin V1a agonist, has shown potential and has been granted breakthrough status by the US Food and Drug Administration for treating challenging behaviors in adults, with additional studies ongoing in children.^52,53

Repetitive behaviors, if the patient finds them impairing, can be managed with selective serotonin reuptake inhibitors.⁴⁹

Much more study of drug therapy in adults with ASD is needed to fully understand the best approaches to psychotropic medication use, including appropriate classes and effective dosage, in this population.

SEX: UNEXPLORED TERRITORY

The reproductive health needs of people with autism remain largely underexplored.⁵⁴ Historically, individuals with ASD were thought to have little interest in sexual activity or parenthood, owing to the nature of the core symptoms of the disorder. This has been shown to be untrue, particularly as studies on this topic began to engage in direct interviews with people with ASD, rather than solely gathering information from caregivers or parents. The findings reinforce the importance of broaching this component of health in this population, for the following reasons:

Adults with ASD are at increased risk of sexual victimization, with nearly 4 out of 5 reporting unwanted sexual advances, coercion, or rape.⁵⁵

They have a smaller pool of knowledge with respect to sexual health. They report⁵⁶ that they learned about sex from television and from “making mistakes.” They use fewer sources. They are less likely to speak to peers and figures of authority to gain knowledge about sexually transmitted infections, sexual behaviors, and contraception. And they are more likely to use forms of nonsocial media, such as television, for information.⁵⁵

They report more concerns about the future with respect to sexual behavior, suggesting the need for targeted sexual education programs.⁵⁶

College-age young adults with ASD who misread communication may be particularly affected by Title IX, which requires schools to promptly investigate reports of sexual harassment and sexual assault, should they struggle to comport themselves appropriately.⁵⁷ Early and frank conversations about issues of consent and appropriate displays of interest and affection may better equip youth to navigate new social scenarios as they plan to leave a supervised home environment for college or the workforce.

Gender identification: Male, female, other

In one study, 77.8% of birth-sex males with ASD said they identified as men, and 67.1% of birth-sex females identified as women,  compared with 93.1% of birth-sex males and 87.3% of birth-sex females without ASD. Many of the remaining individuals with ASD reported a transgender, genderqueer, or other gender identity.⁵⁸ Some studies have found females with ASD report a gay or bisexual orientation more often than males with ASD.^59–61

Adolescents and young adults may be exploring their changing bodies, sexual preferences, and gender roles, and as for all people at this age, these roles emerge against a backdrop of familial and societal expectations that may or may not be concordant with their own projected path regarding sexuality and reproductive health.⁶²

Having the conversation

As with non-ASD patients, a thorough sexual history should be collected via open-ended questions when possible to determine types of sexual activity and partners.

Education of the patient, alongside caregivers and parents, about healthy and safe sexual practices, screening for sexual violence, and hormonal and nonhormonal contraception options are important components of care for this population.

CAREGIVER STRESS MAY PERSIST INTO PATIENT’S ADULTHOOD

Caregiver burden is a monumental concern for parents or others who may have lifelong primary responsibility for these neurodiverse adults.⁶³ Family members may feel isolated and may feel they have encountered many barriers to services.⁶⁴ Remaining sensitive, knowledgeable, and inquisitive about the types of support that are needed may help forge a trusting relationship between the provider and the family.

Parents of children with ASD have been reported to experience worse physical and emotional health than parents whose children do not have developmental disabilities.^63,65 These disparities have been found to persist  as their children enter adolescence and young adulthood.^66,67 Parents of children with ASD report more anxiety, depression, and distress compared with parents of children without ASD,⁶³ and parents themselves may be affected by ASD symptoms, which has been linked to increased parenting stress.⁶⁸ Some studies have found blunted cortisol responses,^63,69,70 and some,⁷¹ but not all,⁶³ have found elevated blood pressure in caregivers of children with developmental disabilities. Headache, backache, muscle soreness, and fatigue may also be commonly reported.⁶⁷

In our experience, caregivers are tremendously appreciative when provided connections to adult ASD services and support systems as their child ages. The school system and other formal support systems often assist until the time of transition into adulthood. This transition can be stressful for the adolescent and family alike, and informal support systems such as friends and family may become increasingly crucial, particularly if the adolescent still lives at home.^72,73

The affected young adult’s unmet needs, as perceived by the caregiver, have been found to be significantly associated with caregiver burden, whereas the severity of the adult patient’s ASD symptoms has not.⁶⁶ Therefore, it may be helpful to ask caregivers whether they perceive any unmet needs, regardless of the clinician’s perception of the severity of the patient’s ASD symptoms. Providing support to address these needs, particularly those relating to the child’s mood disorders, communication, social needs, safety, and daytime activities, may be the domains of support that most effectively reduce the caregiver burden in this population.⁶⁶

Caregiver positivity, lower stress levels, and increased social support, particularly in the form of friends and family members providing no-cost assistance to caregivers whose children do not live independently,⁷⁴ have been linked to better outcomes for caregivers.^70,74,75 Rigorous studies that examine caregiver burden as individuals with ASD enter mid- and late-adulthood are limited.

THE ROLE OF THE INTERNIST IN CARING FOR ADULTS WITH AUTISM

A major challenge for many adults with ASD is the transition from services provided during childhood to those provided in adulthood. While children with autism have subspecialty providers who diagnose and manage their condition, including developmental-behavioral pediatricians, pediatric neurologists, and child psychiatrists, adults with autism may have fewer options.

Autism centers are becoming more available across the nation, and many provide care across the life span. However, depending on a patient’s needs, the primary care provider may need to manage residual symptoms as the patient transitions from pediatric to adult care, ultimately deciding when and where to refer the patient.

The patient’s family should pay close attention to function and mood around the time the patient leaves the structure of high school, and they should build rapport with a primary care provider they can turn to if problems persist or arise. Referrals for behavioral therapy and for social work, job training, and vocational support can greatly benefit patients as they transition to young adulthood. Referrals and suggestions for social support can also help caregivers.

Medical care

Deciding when and how to medicate the patient for symptoms of autism and related behaviors necessitates consideration of the patient’s impairment, side effects of the medication, and the impact medications may have on the patient’s other conditions. Disordered eating, mood problems, anxiety, and attention-deficit/hyperactivity disorder should be considered, and, as in all patients, regular screenings of mental health status should be conducted.^76,77

Comorbid medical conditions may cause worsening of a patient’s known behavioral symptoms or may precipitate new behaviors or aggression as a result of pain or discomfort, particularly in patients with limited speech. A change in stereotypes or increased irritability warrants a thoughtful investigation for a cause other than ASD before adding or increasing behavioral medications. Common comorbid conditions include gastrointestinal distress, most commonly constipation and diarrhea in an idiopathic ASD population, with increasing ASD symptom severity correlating with increased odds of a gastrointestinal problem.⁷⁸ Allergies, sleep disorders, seizures, and other psychiatric conditions are also frequent.⁷⁹

Preventive care, including vaccinations, should be given as scheduled. Caregivers and patients can be reminded if needed that vaccines do not cause or worsen autism, and vaccination is intended to improve the safety of the patient and those around them, protecting against potentially life-threatening disease. Regular dental care visits, particularly for patients who are using medications that may affect tooth or gingival health,⁸⁰ and regular visits to an optometrist or ophthalmologist for screening of vision are also advised.

Adverse effects. Weight gain and metabolic syndrome are common adverse effects of medications used for behavioral management, and the primary care physician may uncover diabetes, cardiac disorders, and hyperlipidemia. Patients with ASD may be particularly sensitive to the effects of medications and therefore may require a lower dose or a slower titration than other patients. Working with a behavioral team, careful weaning of psychiatric medications to the minimum needed is strongly recommended whenever possible.⁸¹

TAKE-HOME POINTS

As more adults with autism enter society, they may require varying levels of support from the healthcare community to ensure that therapeutic gains from childhood persist, allowing them to achieve maximal functional potential.

Adults with ASD may have a high, normal, or low IQ and intellectual capability. Knowledge of this and of the patient’s symptom severity and presence of comorbid psychiatric and other health conditions can help the clinician guide the patient to appropriate social services and pharmacologic treatments.

Individualized support in the workplace, as well as education regarding sexual health, can help improve outcomes for affected individuals.

Caregiver burden for individuals with autism can be high, but it can be mitigated by social support.

Further research regarding appropriate diagnostic instruments in adulthood and appropriate treatments for impairing autism-related symptoms across the life span may be particularly helpful in supporting this patient population.

Autism spectrum disorder (ASD) has increased significantly over the past 40 years. Even in the past 2 decades, the prevalence increased from 6.7 per 1,000 in 2000¹ to 14.6 per 1,000 in 2012—1 in 59 people.² Of those with ASD, 46% have an intelligence quotient (IQ) greater than 85, meaning they are of average or above-average intelligence.¹

See related editorial

As more children with autism become adults, understanding this condition across the life span grows paramount. While many studies have focused on understanding how diagnosis and treatment can help young children, few have focused on adults with autism and how primary care teams can better assist these individuals. However, this is changing, with studies of the benefits of employment programs and pharmacologic treatment, and reproductive health needs of adults with ASD. Here we provide an updated review of ASD in adult patients.

NO MORE ASPERGER SYNDROME— IT’S ON THE SPECTRUM NOW

As the scientific understanding of autism has expanded, revisions in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5),³ published in 2013, have paralleled these advances. For many adult patients with autism who were evaluated as children, these revisions have led to changes in diagnosis and available services.

In the previous edition (DSM-IV-TR, published in 2000),⁴ autistic disorder and Asperger syndrome were separate (Table 1). However, DSM-5 lumped autistic disorder and Asperger disorder together under the diagnosis of ASD; this leaves it to the clinician to specify whether the patient with ASD has accompanying intellectual or language impairment and to assign a level of severity based on communication deficits and restrictive behaviors.

The shift in diagnosis was worrisome for some, particularly for clinicians treating patients with DSM-IV Asperger syndrome, who lost this diagnostic label. Concerns that patients with Asperger syndrome may not meet the DSM-5 criteria for ASD were validated by a systematic review showing that only 50% to 75% of patients with DSM-IV autistic disorder, Asperger syndrome, or pervasive developmental disorder not otherwise specified (PDD-NOS) met the DSM-5 criteria for ASD.⁵ Most of those who no longer met the criteria for ASD carried a DSM-IV diagnosis of Asperger syndrome or PDD-NOS or had an IQ over 70.⁵ Nevertheless, these individuals may struggle with impairing symptoms related to repetitive behaviors or communication or may be affected by learning or social-emotional disabilities. Additionally, even if they meet the criteria for ASD, some may identify with the Asperger syndrome label and fear they will be stigmatized should they be classified as having the more general ASD.^6,7

Although future revisions to the DSM may include further changes in classification, grouping adults with ASD according to their functional and cognitive ability may allow for pragmatic characterization of their needs. At least 3 informal groupings of autistic adults have been described that integrate cognitive ability and independence⁸:

• Those with low cognitive and social abilities, who need lifelong support
• Those with midrange cognitive and social limitations but who can complete their work in special education classes; they often find employment in supervised workshops or other work with repetitive tasks
• Those who have greater cognitive ability and some social skills; they may proceed to college and employment and live independently.

UNCERTAIN PROGNOSIS

Prognostication for people with ASD remains an area of research. Some adults experience a reduction in symptoms as they age, with significant improvements in speech and, sometimes, modest improvements in restrictive and repetitive behaviors.^9,10

Nevertheless, autism remains a lifelong disorder for many. Adults may still require significant support and may experience impairment, particularly in social interaction.¹⁰ In longitudinal studies, only 15% to 27% of patients with ASD are characterized as having a positive outcome (often defined as variables related to independent function, near-normal relationships, employment, or a quantified reduction in core symptoms), and many experience significant dependency into adulthood.^10–13

IQ has been cited as a possible prognostic factor,^10,13 with an IQ below 70 associated with poorer outcome, although an IQ above 70 does not necessarily confer a positive outcome. Less-severe impairment in speech at baseline in early childhood also suggests better outcomes in adulthood.¹⁰

As we see more adults with autism, studies that include both children and adults, such as the Longitudinal European Autism Cohort, will be important to characterize the natural history, comorbidities, and genetics of ASD and may help provide more specific predictors of disease course into adulthood.¹⁴

While many patients are recognized as having autism in early to mid-childhood, some adults may not receive a formal diagnosis until much later in life. Those with fluent language and normal-range IQ are likely to be overlooked.¹⁵ People with ASD may have had mild symptoms during childhood that did not impair their functioning until demands of daily life exceeded their capacities in adulthood. Alternatively, parents of a child with newly diagnosed ASD may realize that they themselves or another adult family member also show signs of it.

The UK National Institute of Health and Care Excellence suggests that assessment should be considered if the patient meets psychiatric diagnostic criteria and one of the following:

• Difficulty obtaining or sustaining employment or education
• Difficulty initiating or sustaining social relationships
• Past or current contact with mental health or learning disability services
• History of a neurodevelopmental or mental health disorder.^15,16

Currently, diagnosis typically involves a multidisciplinary approach, with psychiatric assessment, neuropsychological testing, and speech and language evaluation.¹⁷ Providers may need to refer patients for these services, sometimes at the patient’s request, if previous mental health misdiagnoses are suspected, if patients report symptoms or impairment consistent with ASD, or if benefits, services, or accommodations, such as a coach in the workplace, are needed.

Diagnosing ASD in adults can be difficult, given that the gold-standard diagnostic tests such as the Autism Diagnostic Observation Schedule-2 (ADOS-2)¹⁸ and the Autism Diagnostic Interview-Revised (ADI-R)¹⁹ are typically used to diagnose autism in children. However, Module 4 in the ADOS-2 was developed for adolescents and older patients with fluent language and has shown at least moderate power to distinguish adults with ASD from those without ASD.^18,20

An initial psychiatric assessment should include a thorough history taken from the patient and, if applicable, the patient’s caregiver, as well as a psychiatric interview of the patient. Neuropsychological testing should include evaluation of cognitive function, social functioning (using the ADOS-2 for adults without intellectual disability, the ADI-R, or both), and adaptive functioning (using the Vineland Adaptive Behavior Scales, second edition²¹).

Evaluation of speech and language is particularly important in patients with limited language ability and should include both expressive and receptive language abilities. Serial testing every few years, as is often recommended in childhood, may help establish the pattern of impairment over time.

Comorbid psychiatric disorders are common

Many people with ASD also have other psychiatric disorders,^17,22 which clinicians should keep in mind when seeing an adult seeking evaluation for ASD.

Attention-deficit/hyperactivity disorder is present at higher rates in patients of average intellectual function with ASD than in the general population.²³

Anxiety disorders, including obsessive-compulsive disorder, were found to often coexist with autism in a sample of adults with autism without intellectual disability,^24,25 and approximately 40% of youths with ASD have at least 1 comorbid anxiety disorder.²⁶

Mood disorders are also prevalent in adults with ASD, with a small study showing that 70% of adults with DSM-IV Asperger syndrome had at least 1 depressive episode in their lifetime.²⁷

BEHAVIORAL AND PHARMACOLOGIC THERAPIES FOR THE ADULT PATIENT

Services and medications for adults with ASD are discussed below. These will vary by individual, and services available may vary by region.

Historically, vocational and social outcomes have been poor for adults with ASD. It is estimated that most larger universities may be home to 100 to 300 students with ASD. To combat isolation, the University of California, Los Angeles, the University of Alabama, and others provide special support services, including group social activities such as board games and individual coaching.⁸ Nevertheless, half of the students with autism who attend institutions of higher learning leave without completing their intended degree.²⁹ Many still struggle to establish meaningful friendships or romantic relationships.²⁹

Planning for a transition of care

Healthcare transition planning is important  but is strikingly underused.³⁰ Individual providers, including adult psychiatrists, vary in their level of training and comfort in diagnosing, treating, and monitoring adults with autism. Youths with ASD are half as likely to receive healthcare transition services as other youths with special healthcare needs.³¹

Pediatric providers, including pediatric psychiatrists, developmental behavioral specialists, and pediatric neurologists, may be best equipped to treat young adult patients or to refer patients to appropriate generalists and specialists comfortable with autism-specific transition of care. The question of eligibility for services is important to patients and families during the transition period, with many parents and professionals unaware of services available to them.³² Receiving adequate transition services is enabled by having a medical home during childhood—that is, a comprehensive, centralized medical record, culturally competent care, interaction with schools, and patient access to clear, unbiased information.³¹

Ideally, in our experience, transitioning should be discussed well before the child ages out of the pediatric provider’s practice. If necessary, healthcare transition services should include 4 components:

• Discussing the switch to a new physician who treats adults
• Discussing changing healthcare needs as an adult
• Planning insurance coverage as an adult
• Encouragement by the physician for the child to take age-appropriate responsibility for his or her healthcare.^31,33

Tools such as the Got Transition checklist from the National Health Care Transition Center can provide support during this process.³⁴

Other services

Other services provided as an extension or adjunct to the medical home in early adulthood may include customized vocational or employment training, specialized mentorship or support in a college setting, housing support, and psychological services.³⁵

Community-based programs that emphasize leisure have been shown to improve participants’ independence and quality of life.³⁶ Similarly, participants in programs that emphasized supported employment, with a job coach, on-the-job support, collaboration with the participant’s larger social support network, and selection of tasks to match an individual’s abilities and strengths, demonstrated improved cognitive performance, particularly executive functioning,³⁷ and employment.^38,39 These programs work best for patients who have mild to moderate symptoms.^37,39

Patients with symptoms that are more severe may do better in a residential program. Many of these programs maintain an emphasis on vocational and social skills development. One such long-standing program is Bittersweet Farms, a rural farming community in Ohio for adults with ASD, where individuals with moderate to low function live in a group setting, with emphasis on scheduled, meaningful work including horticulture, animal care, carpentry; and activities of daily living.⁴⁰

Studies of patients across the autism spectrum have generally found better outcomes when vocational support is given, but larger and randomized studies are needed to characterize how to best support these individuals after they leave high school.⁴¹

Psychological services such as applied behavioral therapy, social cognition training, cognitive behavioral therapy, and mindfulness training may be particularly useful in adults.^42–44

Some versions of applied behavioral therapy, such as the Early Start Denver Model,⁴⁵ have been found to be cost-effective and offset some expenses in the care of children with autism, using play-based and relationship-based interventions to promote development across domains while reducing symptoms.

In randomized controlled trials, modified cognitive behavioral therapy⁴³ and mindfulness⁴⁴ were shown to reduce symptoms of anxiety, obsessive-compulsive disorder, and depression.

Dialectical behavior therapy, used to find a balance between accepting oneself and desiring to change, may help in some circumstances to regulate emotions and reduce reactivity and lability, although large randomized clinical trials have not been conducted in the ASD population.⁴⁶

Drug therapy

Medications may be appropriate to manage symptoms or comorbid conditions in adults with ASD. Over 75% adults with ASD have been found to use psychotropic medications.⁴⁷ However, although these drugs have been approved for treating behaviors commonly associated with ASD, none of them provide definitive treatment for this disorder, and they have not been rigorously tested or approved for use in adults with ASD.⁴⁸

Irritability and aggression associated with ASD can be treated with risperidone (approved for children over age 5), aripiprazole (approved for children ages 6–17), clozapine, or haloperidol.⁴⁹

Aberrant social behavior can be treated with risperidone.⁵⁰ Treatments under investigation include oxytocin and secretin.⁴⁹

While no approved drug has been shown to improve social communication,⁵¹ balovaptan, a vasopressin V1a agonist, has shown potential and has been granted breakthrough status by the US Food and Drug Administration for treating challenging behaviors in adults, with additional studies ongoing in children.^52,53

Repetitive behaviors, if the patient finds them impairing, can be managed with selective serotonin reuptake inhibitors.⁴⁹

Much more study of drug therapy in adults with ASD is needed to fully understand the best approaches to psychotropic medication use, including appropriate classes and effective dosage, in this population.

SEX: UNEXPLORED TERRITORY

The reproductive health needs of people with autism remain largely underexplored.⁵⁴ Historically, individuals with ASD were thought to have little interest in sexual activity or parenthood, owing to the nature of the core symptoms of the disorder. This has been shown to be untrue, particularly as studies on this topic began to engage in direct interviews with people with ASD, rather than solely gathering information from caregivers or parents. The findings reinforce the importance of broaching this component of health in this population, for the following reasons:

Adults with ASD are at increased risk of sexual victimization, with nearly 4 out of 5 reporting unwanted sexual advances, coercion, or rape.⁵⁵

They have a smaller pool of knowledge with respect to sexual health. They report⁵⁶ that they learned about sex from television and from “making mistakes.” They use fewer sources. They are less likely to speak to peers and figures of authority to gain knowledge about sexually transmitted infections, sexual behaviors, and contraception. And they are more likely to use forms of nonsocial media, such as television, for information.⁵⁵

They report more concerns about the future with respect to sexual behavior, suggesting the need for targeted sexual education programs.⁵⁶

College-age young adults with ASD who misread communication may be particularly affected by Title IX, which requires schools to promptly investigate reports of sexual harassment and sexual assault, should they struggle to comport themselves appropriately.⁵⁷ Early and frank conversations about issues of consent and appropriate displays of interest and affection may better equip youth to navigate new social scenarios as they plan to leave a supervised home environment for college or the workforce.

Gender identification: Male, female, other

In one study, 77.8% of birth-sex males with ASD said they identified as men, and 67.1% of birth-sex females identified as women,  compared with 93.1% of birth-sex males and 87.3% of birth-sex females without ASD. Many of the remaining individuals with ASD reported a transgender, genderqueer, or other gender identity.⁵⁸ Some studies have found females with ASD report a gay or bisexual orientation more often than males with ASD.^59–61

Adolescents and young adults may be exploring their changing bodies, sexual preferences, and gender roles, and as for all people at this age, these roles emerge against a backdrop of familial and societal expectations that may or may not be concordant with their own projected path regarding sexuality and reproductive health.⁶²

Having the conversation

As with non-ASD patients, a thorough sexual history should be collected via open-ended questions when possible to determine types of sexual activity and partners.

Education of the patient, alongside caregivers and parents, about healthy and safe sexual practices, screening for sexual violence, and hormonal and nonhormonal contraception options are important components of care for this population.

CAREGIVER STRESS MAY PERSIST INTO PATIENT’S ADULTHOOD

Caregiver burden is a monumental concern for parents or others who may have lifelong primary responsibility for these neurodiverse adults.⁶³ Family members may feel isolated and may feel they have encountered many barriers to services.⁶⁴ Remaining sensitive, knowledgeable, and inquisitive about the types of support that are needed may help forge a trusting relationship between the provider and the family.

Parents of children with ASD have been reported to experience worse physical and emotional health than parents whose children do not have developmental disabilities.^63,65 These disparities have been found to persist  as their children enter adolescence and young adulthood.^66,67 Parents of children with ASD report more anxiety, depression, and distress compared with parents of children without ASD,⁶³ and parents themselves may be affected by ASD symptoms, which has been linked to increased parenting stress.⁶⁸ Some studies have found blunted cortisol responses,^63,69,70 and some,⁷¹ but not all,⁶³ have found elevated blood pressure in caregivers of children with developmental disabilities. Headache, backache, muscle soreness, and fatigue may also be commonly reported.⁶⁷

In our experience, caregivers are tremendously appreciative when provided connections to adult ASD services and support systems as their child ages. The school system and other formal support systems often assist until the time of transition into adulthood. This transition can be stressful for the adolescent and family alike, and informal support systems such as friends and family may become increasingly crucial, particularly if the adolescent still lives at home.^72,73

The affected young adult’s unmet needs, as perceived by the caregiver, have been found to be significantly associated with caregiver burden, whereas the severity of the adult patient’s ASD symptoms has not.⁶⁶ Therefore, it may be helpful to ask caregivers whether they perceive any unmet needs, regardless of the clinician’s perception of the severity of the patient’s ASD symptoms. Providing support to address these needs, particularly those relating to the child’s mood disorders, communication, social needs, safety, and daytime activities, may be the domains of support that most effectively reduce the caregiver burden in this population.⁶⁶

Caregiver positivity, lower stress levels, and increased social support, particularly in the form of friends and family members providing no-cost assistance to caregivers whose children do not live independently,⁷⁴ have been linked to better outcomes for caregivers.^70,74,75 Rigorous studies that examine caregiver burden as individuals with ASD enter mid- and late-adulthood are limited.

THE ROLE OF THE INTERNIST IN CARING FOR ADULTS WITH AUTISM

A major challenge for many adults with ASD is the transition from services provided during childhood to those provided in adulthood. While children with autism have subspecialty providers who diagnose and manage their condition, including developmental-behavioral pediatricians, pediatric neurologists, and child psychiatrists, adults with autism may have fewer options.

Autism centers are becoming more available across the nation, and many provide care across the life span. However, depending on a patient’s needs, the primary care provider may need to manage residual symptoms as the patient transitions from pediatric to adult care, ultimately deciding when and where to refer the patient.

The patient’s family should pay close attention to function and mood around the time the patient leaves the structure of high school, and they should build rapport with a primary care provider they can turn to if problems persist or arise. Referrals for behavioral therapy and for social work, job training, and vocational support can greatly benefit patients as they transition to young adulthood. Referrals and suggestions for social support can also help caregivers.

Medical care

Deciding when and how to medicate the patient for symptoms of autism and related behaviors necessitates consideration of the patient’s impairment, side effects of the medication, and the impact medications may have on the patient’s other conditions. Disordered eating, mood problems, anxiety, and attention-deficit/hyperactivity disorder should be considered, and, as in all patients, regular screenings of mental health status should be conducted.^76,77

Comorbid medical conditions may cause worsening of a patient’s known behavioral symptoms or may precipitate new behaviors or aggression as a result of pain or discomfort, particularly in patients with limited speech. A change in stereotypes or increased irritability warrants a thoughtful investigation for a cause other than ASD before adding or increasing behavioral medications. Common comorbid conditions include gastrointestinal distress, most commonly constipation and diarrhea in an idiopathic ASD population, with increasing ASD symptom severity correlating with increased odds of a gastrointestinal problem.⁷⁸ Allergies, sleep disorders, seizures, and other psychiatric conditions are also frequent.⁷⁹

Preventive care, including vaccinations, should be given as scheduled. Caregivers and patients can be reminded if needed that vaccines do not cause or worsen autism, and vaccination is intended to improve the safety of the patient and those around them, protecting against potentially life-threatening disease. Regular dental care visits, particularly for patients who are using medications that may affect tooth or gingival health,⁸⁰ and regular visits to an optometrist or ophthalmologist for screening of vision are also advised.

Adverse effects. Weight gain and metabolic syndrome are common adverse effects of medications used for behavioral management, and the primary care physician may uncover diabetes, cardiac disorders, and hyperlipidemia. Patients with ASD may be particularly sensitive to the effects of medications and therefore may require a lower dose or a slower titration than other patients. Working with a behavioral team, careful weaning of psychiatric medications to the minimum needed is strongly recommended whenever possible.⁸¹

TAKE-HOME POINTS

As more adults with autism enter society, they may require varying levels of support from the healthcare community to ensure that therapeutic gains from childhood persist, allowing them to achieve maximal functional potential.

Adults with ASD may have a high, normal, or low IQ and intellectual capability. Knowledge of this and of the patient’s symptom severity and presence of comorbid psychiatric and other health conditions can help the clinician guide the patient to appropriate social services and pharmacologic treatments.

Individualized support in the workplace, as well as education regarding sexual health, can help improve outcomes for affected individuals.

Caregiver burden for individuals with autism can be high, but it can be mitigated by social support.

Further research regarding appropriate diagnostic instruments in adulthood and appropriate treatments for impairing autism-related symptoms across the life span may be particularly helpful in supporting this patient population.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.

Testosterone replacement therapy is associated with an increased risk of cardiovascular and cerebrovascular events in older men, particularly during the first 2 years of use, a study in the American Journal of Medicine has found.

Simone Y. Loo of the Lady Davis Institute for Medical Research at the Jewish General Hospital in Montreal and colleagues looked at a cohort of 15,401 men aged 45 years or older with low testosterone levels, of whom 4,485 (29.1%) were prescribed testosterone replacement therapy on at least one occasion during a mean follow-up of 4.7 years. They saw that individuals who were currently using testosterone replacement therapy had a 21% increase in the risk of the composite outcome of ischemic stroke, transient ischemic attack, or myocardial infarction, compared with those who had not had hormone therapy.

In the first 6 months to 2 years after initiation of continuous treatment, the risk was even higher – at 35% – and was particularly high in individuals aged 45-59 years (at 44%).

However, the study also noted a significant 36% reduction in the risk of all-cause mortality in individuals currently using testosterone replacement therapy and a significant 28% higher risk of all-cause mortality in past users, compared with nonusers.

Concerns about the safety of testosterone replacement therapy had previously been kindled by the outcomes of the Testosterone in Older Men trial, which was stopped early because of the higher number of cardiovascular events in the treatment group. However, other randomized controlled trials have not seen that effect, the authors said.

They noted that the protective effect of current hormone replacement use on mortality was surprising, but suggested it could be the result of reverse causality, “in which physicians may discontinue TRT based on perceived deterioration of health or imminent death, because TRT is not a vital medication.”

“Moreover, TRT may be less frequently initiated among men with a higher baseline risk of mortality, particularly in the elderly, and those who received TRT may have been healthier overall, compared with their untreated counterparts,” the authors wrote.

Despite this, they suggested that larger observational studies were still needed to investigate the potential harms of testosterone replacement therapy. In the meantime, they advised that potential harms should be weighed against perceived benefits and caution be applied to prescribing.

The study was supported by the Canadian Institutes of Health Research. No conflicts of interest were reported.

SOURCE: Loo S et al. Am J Med 2019 Apr 3. doi: 10.1016/j.amjmed.2019.03.022.