Emerging Issues

Hepatitis C

HCV infection is the most common chronic bloodborne infection in the United States, with an estimated 2.7 million persons living with chronic infection (222). HCV is not efficiently transmitted through sex (170, 223). Studies of HCV transmission between heterosexual or homosexual couples have yielded mixed results, but generally have found either no or very minimally increased rates of HCV infection in partners of persons with HCV infection compared with those whose partners are not HCV-infected (223-230). However, data indicate that sexual transmission of HCV can occur, especially among persons with HIV infection. Increasing incidence of acute HCV infection among MSM with HIV infection has been reported in New York City (231,232) and Boston (175, 177), along with multiple European cities (233-235). These men usually engage in high-risk and traumatic sexual practices and might have concurrent genital ulcerative disease or STD-related proctitis (233, 235). Other common practices associated with new cases of HCV infection include group sex and use of cocaine and other nonintravenous drugs during sex. Certain studies have revealed that risk increases commensurate with increasing numbers of sex partners among heterosexual persons with HIV infection (225, 226,236-238) and MSM (239-242), especially if their partners are also coinfected with HIV (234,235, 239-243).

Persons newly infected with HCV typically are either asymptomatic or have a mild clinical illness. HCV RNA can be detected in blood within 1–3 weeks after exposure. The average time from exposure to antibody to HCV (anti-HCV) seroconversion is 8–9 weeks, and anti-HCV can be detected in >97% of persons by 6 months after exposure. Chronic HCV infection develops in 70%–85% of HCV-infected persons; 60%–70% of chronically infected persons develop evidence of active liver disease. Most infected persons remain unaware of their infection because they are not clinically ill. However, infected persons serve as a source of transmission to others and are at risk for CLD and other HCV-related chronic diseases decades after infection.

HCV is primarily transmitted parenterally, usually through shared drug-injection needles and paraphernalia. HCV also can be transmitted through exposures in health-care settings as a consequence of inadequate infection-control practices (244). Transmission following receipt of blood, tissues, and organs from donors with HCV infection has occurred only rarely since 1992, when routine screening of these donated products was mandated in the United States. Tattoos applied in regulated settings have not been associated with HCV transmission, although those obtained in unregulated settings have been linked to such transmission (224). Occupational and perinatal exposures also can result in transmission of HCV, but such transmission is uncommon.

Acute hepatitis C is a reportable condition in 49 states, and matching viral hepatitis and HIV surveillance registries can facilitate early detection of social networks of HCV transmission among MSM with HIV infection. Suspected clusters of acute HCV infection should be reported to the appropriate public health authorities.

HCV screening is recommended by CDC and USPSTF for all persons born during 1945–1965 and others based on their risk for infection or on a recognized exposure, including past or current injection drug use, receiving a blood transfusion before 1992, long-term hemodialysis, being born to a mother with HCV infection, intranasal drug use, receipt of an unregulated tattoo, and other percutaneous exposures (109, 224,245).

Diagnosis

Testing for HCV infection should include use of an FDA-cleared test for antibody to HCV (i.e., immunoassay, EIA, or enhanced chemiluminescence immunoassay and, if recommended, a supplemental antibody test) followed by NAAT to detect HCV RNA for those with a positive antibody result (178). Persons with HIV infection with low CD4-positive cell count might require further testing by NAAT because of the potential for a false-negative antibody assay.

Persons determined to be anti-HCV positive should be evaluated (by referral or consultation, if appropriate) for the presence of acute infection; presence, severity, or development of CLD; and eligibility for treatment. Nucleic acid testing, including reverse transcriptase polymerase chain reaction (RT-PCR) to detect HCV RNA, is necessary to confirm the diagnosis of current HCV infection, and testing of liver function (alanine aminotransferase level) provides biochemical evidence of CLD.

Treatment

Providers should consult with specialists knowledgeable about management of hepatitis C infection. Further, they can consult existing guidelines to learn about the latest advances in the management of hepatitis C (www.hcvguidelines.org).

Management of Sex Partners

Because incident HCV has not been demonstrated to occur in heterosexual couples followed over time (223, 227-229), condom use might not be necessary in such circumstances. Persons with HCV infection with one long-term, steady sex partner do not need to change their sexual practices. However, they should discuss the low but present risk for transmission with their partner and discuss the need for testing (170, 245). Heterosexuals and MSM with HCV infection and more than one partner, especially those with concurrent HIV infection, should protect their partners against HCV and HIV acquisition by using male latex condoms (231, 234,235). Partners of persons with HCV and HIV infection should be tested for HCV and HIV, if not known to be infected.

Other Management Considerations

All persons with HCV for whom HIV and HBV infection status is unknown should be tested for these infections. Those who have HIV or HBV should be referred for or provided with appropriate care and treatment.

Prevention

Reducing the burden of HCV infection and disease in the United States requires implementation of both primary and secondary prevention activities. Primary prevention reduces or eliminates HCV transmission, whereas secondary prevention activities are aimed at reducing CLD and other chronic diseases in persons with HCV infection by first identifying them and then providing medical management and antiviral therapy, if appropriate. No vaccine for hepatitis C is available, and prophylaxis with immune globulin is not effective in preventing HCV infection after exposure.

Persons with HCV infection should be provided information regarding how to protect their liver from further harm (i.e., hepatotoxic agents); for instance, persons with HCV infection should be advised to avoid drinking alcohol and taking any new medicines (including over-the-counter and herbal medications) without checking with their clinician. In addition, a determination for the need of hepatitis A and B vaccination should be made; persons who are not immune should be vaccinated.

To reduce the risk for transmission to others, persons with HCV infection should be advised 1) not to donate blood, body organs, other tissue, or semen; 2) not to share any personal items that might have blood on them (e.g., toothbrushes and razors); and 3) to cover cuts and sores on the skin to keep the virus from spreading by blood or secretions. Women with HCV infection do not need to avoid pregnancy or breastfeeding.

Persons who use or inject drugs should be counseled about the importance of stopping drug-use behaviors and provided with assistance to enter and complete substance-abuse treatment (including relapse prevention). Persons who continue to inject drugs despite counseling should be encouraged to take the following additional steps to reduce personal and public health risks:

• never reuse or share syringes, water, or drug preparation equipment;
• only use syringes obtained from a reliable source (e.g., pharmacies);
• use a new, sterile syringe to prepare and inject drugs;
• if possible, use sterile water to prepare drugs; otherwise, use clean water from a reliable source (e.g., fresh tap water);
• use a new or disinfected container (i.e., cooker) and a new filter (i.e., cotton) to prepare drugs;
• clean the injection site before injection with a new alcohol swab; and
• safely dispose of syringes after one use.

Postexposure Follow-Up

No postexposure prophylaxis has been demonstrated to be effective against HCV. HCV testing is recommended for health-care workers after percutaneous or permucosal exposures to HCV-positive blood. Children born to women with HCV infection also should be tested for HCV. Prompt identification of acute infection is important, because outcomes are improved when treatment is initiated early in the course of illness.

Special Considerations

Pregnancy

Routine screening for HCV infection is not recommended for all pregnant women. Pregnant women with a known risk factor for HCV infection should be offered screening. Although the rate for transmission is highly variable, up to six of every 100 infants born to HCV-infected women become infected; this infection occurs predominantly during or near delivery, and no treatment or delivery method—such as caesarian section—has been demonstrated to decrease this risk (246). However, the risk is increased by the presence of maternal HCV viremia at delivery and is two- to threefold greater if the woman is coinfected with HIV. HCV has not been shown to be transmitted through breast milk, although mothers with HCV infection should consider abstaining from breastfeeding if their nipples are cracked or bleeding. Infants born to mothers with HCV infection should be tested for HCV infection; because maternal antibody is present for the first 18 months of life and before the infant mounts an immunologic response, nucleic acid testing is recommended. (https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6218a5.htm).

HIV Infection

All persons with HIV infection should undergo serologic screening for HCV at initial evaluation (17, 247). Providers should be aware of the likelihood that MSM with HIV infection will acquire HCV after initial screening. Because of accumulating evidence of acute HCV infection acquisition in persons with HIV infection, especially MSM, and cost-effectiveness of regular screening (176,177), periodic HCV screening should be considered (170-175). For persons with HIV infection, HCV screening with HCV antibody assays can be considered at least yearly in those at high risk for infection and more frequently depending on specific circumstances (e.g., community HCV prevalence and incidence, high-risk sexual behavior, and concomitant ulcerative STDs and STD-related proctitis). Indirect testing (e.g., ALT) is not recommended for detecting incident HCV infections because such testing, especially if performed once a year, can miss many persons who have reverted after acute HCV infection to a normal ALT level at the time of testing (175, 177). Conversely, ALT can be elevated by antiretroviral and other medications, alcohol, and toxins. If ALT levels are being monitored, persons with HIV infection who experience new and unexplained increases in ALT should be tested for acute HCV infection and evaluated for possible medication toxicity or excessive alcohol use.

Continued unprotected sexual contact between partners with HIV infection can facilitate spread of HCV, as the virus can be recovered from the semen of men with HIV (248). Specific prevention practices (e.g., barrier precautions that limit contact with body fluids during sexual contact with other MSM) should be discussed.

Because a minimal percentage of persons with HIV infection fail to develop HCV antibodies, HCV RNA testing should be performed in persons with unexplained liver disease who are anti-HCV negative. The course of liver disease is more rapid in HIV/HCV coinfected persons, and the risk for cirrhosis is nearly twice that of persons with HCV infection alone. Coinfected persons receiving HIV antiviral regimens are now being treated for HCV after their CD4+ cell counts increase, optimizing their immune response.

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Mycoplasma genitalium

M. genitalium was first identified in the early 1980s (249) and has become recognized as a cause of male urethritis, responsible for approximately 15%–20% of nongonococcal urethritis (NGU) cases, 20%–25% of nonchlamydial NGU, and approximately 30% of persistent or recurrent urethritis (250). In most settings, it is more common than N. gonorrhoeae but less common than C. trachomatis. While M. genitalium is often the sole pathogen detected, coinfection with C. trachomatis is not uncommon in selected areas (251-253).

Although strong and consistent evidence has linked M. genitalium to urethritis in men, it remains unknown whether this infection can cause male infertility or other male anogenital tract disease syndromes. The organism has been detected in men with epididymitis in a limited number of cases, but this has not been extensively investigated. Similarly, M. genitalium has been found in the rectum, but detection is infrequently accompanied by rectal symptoms, and its presence does not appear to cause a syndrome of clinical proctitis.

The pathogenic role of M. genitalium is less definitive in women than it is in men. M. genitalium can be found in the vagina, cervix, and endometrium and, like chlamydial and gonococcal infections, M. genitalium infections in women are commonly asymptomatic. M. genitalium can be detected in 10%–30% of women with clinical cervicitis, and most (253-259) studies have found that this organism is more common among women with cervicitis than those without this syndrome (251,260,261).

M. genitalium is found in the cervix and/or endometrium of women with PID more often than in women without PID (262-271), and endosalpingitis develops in nonhuman primates after inoculation with M. genitalium, suggesting that this organism can cause PID. M. genitalium has been detected in 2%–22% of PID cases (median: 10%) depending on the setting, but the frequency with which M. genitalium-infected women experience PID has been under studied. Although one study in Sweden reported a substantial increase in risk for postabortal PID among women with M. genitalium (262), the proportion of M. genitalium-positive women who subsequently experienced PID in two other studies was relatively low (<5%) (272,273), and evidence from serologic studies assessing the association of PID with antibody to M. genitalium is inconsistent. Overall, evidence suggests that M. genitalium can cause PID, but that this occurs less frequently than it does with C. trachomatis (271, 273).

A few seroepidemologic studies have found that women with tubal factor infertility are more likely to have antibodies to M. genitalium than fertile women, suggesting that this organism might cause female infertility. However, more research is needed. On the basis of certain reports, M. genitalium was uncommonly identified in women who experience adverse pregnancy outcomes, but was associated with increased risk for preterm delivery in one U.S. and another Peruvian study (274,275). Data are scarce regarding M. genitalium and ectopic pregnancy.

Diagnostic Considerations

M. genitalium is a slow-growing organism. Culture can take up to 6 months, and only a few laboratories in the world are able to recover clinical isolates. Therefore, NAAT is the preferred method for M. genitalium detection. In research settings, M. genitalium is diagnosed by NAAT testing of urine, urethral, vaginal, and cervical swabs and through endometrial biopsies, typically using in-house PCR or assays intended for research use only. NAAT tests (polymerase chain reaction or transcription mediated amplification) for M. genitalium  are available in some large medical centers and commercial laboratories, but there is no diagnostic test for M. genitalium that is  cleared by the FDA for use in the United States. In the absence of validated tests, M. genitalium should be suspected in cases of persistent or recurrent urethritis and may be considered in persistent or recurrent cases of cervicitis and PID.

Treatment

M. genitalium lacks a cell wall, and thus antibiotics targeting cell-wall biosynthesis (e.g., beta-lactams including penicillins and cephalosporins) are ineffective against this organism. Given the diagnostic challenges, treatment of most M. genitalium infections will occur in the context of syndromic management for urethritis, cervicitis, and PID.

Urethritis and cervicitis

The 7-day doxycycline regimen recommended for treatment of urethritis is largely ineffective against M. genitalium with a median cure rate of approximately 31% (276-278). The 1-g single dose of azithromycin was significantly more effective against M. genitalium than doxycycline in two randomized urethritis treatment trials (276,277) and is preferred over doxycycline. However, resistance to azithromycin appears to be rapidly emerging. The median cure rate for both men and women is approximately 85%, but was only 40% in the most recent trial (278). Persons with treatment failures after the 1-g azithromycin regimen frequently have macrolide-resistant strains, suggesting that single-dose azithromycin therapy might select for resistance. A longer course of azithromycin (an initial 500-mg dose followed by 250 mg daily for 4 days) might be marginally superior to the single dose regimen (279-281). However, in some settings, approximately 50% of all M. genitalium infections are caused by organisms that are already resistant to azithromycin (282), and persons who do not respond to the 1-g azithromycin regimen generally do not benefit from retreatment with the extended dose regimen.

Moxifloxacin (400 mg daily x 7, 10 or 14 days) has been successfully used to treat M. genitalium in men and women with previous treatment failures, with cure rates of 100% in initial reports (280, 283). However, moxifloxacin has been used in only a few cases, and the drug has not been tested in clinical trials. Although generally considered effective, studies in Japan, Australia, and the United States have reported moxifloxacin treatment failures after the 7 day regimen (284-287).

PID

Recommended PID treatment regimens are based on antibiotics that are not effective against M. genitalium. Therefore, clinicians might consider M. genitalium in cases that do not respond to therapy within 7–10 days. Where validated M. genitalium testing is available, clinicians might test women with PID for M. genitalium. When M. genitalium is detected, a regimen of moxifloxacin 400 mg/day for 14 days has been effective in eradicating the organism (288). Nevertheless, no data have been published that assess the benefits of testing women with PID for M. genitalium, and the importance of directing treatment against this organism is currently unknown.

Follow-up

In settings where validated M. genitalium testing is available, persons with persistent urethritis, cervicitis, or PID accompanied by persistent detection of M. genitalium might be treated with moxifloxacin. However, routine tests-of-cure in asymptomatic persons are not recommended.

Management of Sex Partners

Sex partners should be managed according to guidelines for patients with nongonococcal urethritis (NGU), cervicitis, and PID. In settings with access to validated M. genitalium tests, partner testing and treatment of identified infections might be considered.

Special considerations

HIV infection

Persons who have an M. genitalium infection and HIV infection should receive the same treatment regimen as those who are HIV negative. Treatment of most M. genitalium infections will occur in the context of syndromic management for urethritis, cervicitis, and PID (See Mycoplasma genitalium, Treatment).

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