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HCV Sexual Transmission: HIV Negative May Be at Risk, More Awareness and Testing Needed

Hepatitis C virus (HCV) is known to be sexually transmitted among HIV positive men who have sex with men, but HIV negative men may be at risk as well, according to recent reports. Other recent studies have looked at awareness of HCV sexual transmission and screening practices, suggesting that improvement is needed in both areas.

Starting in the early 2000s, researchers in the U.K. and elsewhere in Europe began reporting clusters of apparently sexually transmitted acute HCV infection among HIV positive gay and bisexual men in major cities; similar outbreaks followed in Australia and the U.S. A number of risk factors have been implicated -- including condomless anal sex, fisting, group sex, other sexually transmitted infections (STIs), and non-injection recreational drug use -- but these have not been consistent across studies.

The U.S. Centers for Disease Control and Prevention (CDC) has long held that sexual transmission of HCV is rare -- at least among HIV negative heterosexuals. It is unclear why sexual transmission appears more common among HIV positive men, since it can occur in people who still have well-preserved immune function with high CD4 T-cell counts.

HIV positive people on antiretroviral therapy (ART) are regularly monitored for liver toxicity, and unexplained alanine aminotransferase (ALT) liver enzyme elevations can lead to testing that reveals HCV infection. Some have suggested that sexually transmitted acute HCV is seldom found in HIV negative men who have sex with men (MSM) because they are not usually tested for it, but previous studies have found very low rates when such testing has been done.

London Study

As described in a presentation at the 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last month in Washington, DC, Katie McFaul from Chelsea and Westminster Hospital and colleagues did a retrospective study of acute hepatitis C in a population of HIV negative gay/bisexual men in London. 

The researchers looked at data from all HIV negative MSM seen at 3 sexual health clinics between January 2010 and May 2014. McFaul estimated that more than 623,000 total sexual health check-ups were done during this period, including approximately 261,036 for HIV negative MSM.

They identified all cases of HCV antibody positive men using European AIDS Network (NEAT) criteria to determine acute infection, as indicated by a positive HCV antibody or HCV RNA test following a documented negative test. Other criteria included substantial ALT elevation following a normal level or clinical symptoms such as fever, fatigue, nausea, jaundice, dark urine, or right upper abdominal pain.

Results

• A total of 44 HIV negative men were found to have acute HCV infection.
• 15 had a positive HCV antibody test but undetectable HCV RNA, and were classified as having spontaneous or natural HCV clearance.
• 11 were diagnosed based on ALT elevation and 18 had a clinical diagnosis of acute hepatitis C.
• The median age at the time of hepatitis C diagnosis was 37 years (range 24-75 years).
• The men reported a median of 2 sexual partners during the previous 3 months (range 0 to 100).
• HCV genotype was available for 22 men, of whom 19 had genotype 1, 1 had genotype 3, and 2 had genotype 4.
• 8 men had received HIV post-exposure prophylaxis (PEP) in the 6 months prior to acute hepatitis C diagnosis and 2 were in an HIV pre-exposure prophylaxis (PrEP) study.
• Among 30 men asked about their partners' serostatus, 2 had a known HCV positive partner, 13 had HIV positive partners, 6 had HIV/HCV coinfected partners, and 9 did not know.
• Men with acute HCV reported the following risk factors:

o   Unprotected anal sex: 93% (2% insertive only, 9% receptive only, and 82% both receptive and insertive);

o   Group sex: approximately 30%;

o   Fisting: approximately 30%;

o   Other STIs: 33% (including 7 men with gonorrhea, 3 with chlamydia, 2 with both gonorrhea and chlamydia, and 3 with syphilis).

o   Recreational drug use: 36% nasal use and 20% injection drug use (including cocaine, GHB, mephedrone, crystal methamphetamine, and ketamine.

o   Sex while using recreational drugs ("chem sex"): 31%.

With regard to outcomes, one-third experienced spontaneous HCV clearance, one-quarter received treatment for hepatitis C, 30% remained under observation, and 11% were lost to follow-up. 10 patients were successfully treated and cured -- prior to the advent of highly effective next-generation HCV direct-acting antivirals.

Looking at testing practices in a typical month, 3811 HIV negative MSM sought sexual health services during November 2013. Of these, only 15% received an HCV antibody or HCV RNA test. Extrapolating back over the study period, McFaul estimated that 34,657 HIV negative MSM had been screened for HCV, while nearly 200,000 were not screened.

Though the rate of acute HCV diagnosis was low in this population -- just 44 cases out of more than 34,000 HIV negative men tested, or less than 1% -- the researchers consider it an important concern.

"We know HIV negative MSM are at risk of HCV infection as they engage in the same risk behaviors as HIV positive MSM," McFaul concluded. "A minority of our cohort report injection and nasal drug use, supporting the hypothesis for sexual transmission of hepatitis C in HIV negative MSM."

Noting the low rates of HCV screening in this study, and the potential for onward transmission when men are not diagnosed, they recommend that hepatitis C testing "should form a routine part of sexual health screening" for all individuals with sex- or drug-related risk factors, especially in areas of high hepatitis C prevalence.

Swiss Study

A related study presented at ICAAC showed that awareness about hepatitis C and how it is transmitted and treated remains low among at-risk gay/bisexual men in southern Switzerland.

In this study, researchers from Lausanne University Hospital and Geneva University Hospital surveyed men attending STI screening clinics for MSM and at sex venues such as saunas and sex clubs. Participant completed anonymous surveys about their knowledge of hepatitis C and received rapid HCV antibody testing. People who already had a known hepatitis C diagnosis were excluded.

A total of 654 participants enrolled in the study, out of more than 900 invited. The median age was 33 years and more than half were Swiss. About 80% identified as gay and about 20% as bisexual.

Results

• During the preceding year, 55% reported condomless anal sex, one-quarter had anal sex with an anonymous partner, and 28% reported what the researchers called "traumatic sex."
• Just half had been screened for STIs, and 11% reported having an STI during the past year.
• Only 3% reported being HIV positive, 66% said they were HIV negative, 21% had unknown HIV status, and 10% declined to disclose.
• One-third said they used recreational drugs during the past year, but only 4 reported drug injection.
• Half the participants (54%) were unaware of hepatitis C.
• One-quarter said they had been screened for HCV, but a majority were not sure; among participants aware of HCV, half had previously been screened and 10% were unsure.
• Among the 302 HCV-aware participants, about one-third did not know if they had sex partners with HCV.
• Most (83%) knew HCV was transmitted via blood and 84% said it was transmitted by anal sex, but one-third did not know if it could be transmitted via sex toys or oral sex.
• 28% did not now whether HCV infection is symptomatic and 8% did not know whether it could lead to serious complications.
• With regard to treatment, 29% thought hepatitis C could not be treated and 25% were unsure.
• Among the full population of 654 participants, only 1 person (0.15%) was found to be HCV positive on rapid testing; he did not report injection drug use and his only apparent risk factor was condomless anal sex with 2 stable partners.

Although HCV prevalence was low in this population -- no doubt lower than overall prevalence, since people known to have hepatitis C were excluded -- the researchers advised that "the high percentage and frequency of unprotected anal intercourse suggest that [HCV] screening should be offered in this uninformed population."

Other HIV Negative HCV Reports

Several studies presented at the British HIV Association BHIVA meeting in April focused on HCV sexual transmission, according to a report by Simon Collins in a recent HIV i-Base HIV Treatment Bulletin.

McFaul and colleagues reported earlier findings from their retrospective review of acute HCV among HIV negative men at Chelsea and Westminster sexual health clinics. Between January 2010 and December 2013, there were 36 cases of acute HCV infection. The 8 additional cases identified through May 2014, as reported at ICAAC, suggest that incidence has been stable over the past few years.

Juan Tiraboschi reported on acute HCV infection among HIV negative men in PROUD study of daily tenofovir/emtricitabine PrEP. While HCV screening was not routinely incorporated -- because the risk for HIV negative men is thought to be low -- 160 (41%) of the participants enrolled through December 2013 were tested for HCV at least once during follow-up.

Among these 160 men, 5 were found to have acute hepatitis C -- an incidence rate of 1.3% overall or 3.1% of the tested group. 3 of these men were randomized to receive PrEP while 2 were in a deferred PrEP control arm. Only 1 man was symptomatic, with jaundice, while the rest were tested due to recent risk behavior or having an HCV positive partner. All 5 men reported condomless anal sex, 1 had chlamydia and gonorrhea, and 1 reported injection drug use.

These findings led the researchers to conclude that HCV testing should be considered in PrEP studies, according to Collins' report.

Finally, Jonathan Volk from Kaiser Permanente in San Francisco recently gave a report on PrEP use among health plan participants at a September 16 Community Engagement forum sponsored by the San Francisco Department of Public Health.

Volk reported that from early 2012 through July 2014, there were a total of 525 referrals for PrEP, 419 intake visits, and 307 participants were prescribed PrEP. This makes Kaiser the largest PrEP program to date, according to iPrEx principal investigator Robert Grant.

There have been no new HIV infections among Kaiser San Francisco participants prescribed PrEP. However, there have been a "large number" of other STIs, most commonly chlamydia, according to Volk. These include 4 cases of hepatitis C infection -- including 2 new cases -- among HIV negative individuals. Based on these findings, Volk said, Kaiser is now doing regular ALT testing, with follow-up if elevated, as well as annual HCV antibody screening for PrEP recipients.

HCV in Semen

Sexual transmission of HCV is still not fully understood, and conflicting risk factors have been seen in different studies of HIV positive men with acute hepatitis C. Whether HCV is transmitted via semen remains unclear.

In another presentation at the BHIVA meeting, Daniel Bradshaw from the University of New South Wales reported on HCV RNA levels in semen. They measured HCV RNA in semen from 66 men, of whom 40 were HIV positive, according to Collins' overview. Among the HIV positive men, 18 had acute HCV and 22 had chronic infection, while all 26 HIV negative men had chronic hepatitis C.

At baseline, 29 men (44%) had detectable HCV RNA in their semen. Among 35 men with follow-up semen samples, 74% had detectable HCV in at least 1 sample, while 34% had detectable HCV in 2 samples.

The median semen HCV viral load was 2.1 log IU/mL -- approximately 4 logs lower than the median blood viral load. Having detectable HCV in semen was not associated with HIV status or having acute vs chronic hepatitis C. However, among people with acute HCV infection, those with detectable semen HCV RNA had higher blood HCV levels than those with no detectable HCV in their semen (approximately 6.1 vs 4.2 log IU/mL, respectively).

Testing for Acute HCV

Two recently published studies shed further light on testing for acute hepatitis C.

As described in the September 3 advance edition of Clinical Infectious Diseases, Joost Vanhommerig from the Netherlands Public Health Service of Amsterdamand colleagues looked at changes in HCV antibody levels among HIV positive men following acute HCV infection and reinfection.

HCV antibody titers may decline after viral clearance, ultimately resulting in "seroreversion." Some people spontaneously clear HCV without treatment, while those who are treated may achieve sustained virological response, considered to be a cure. But prior HCV infection does not confer future immunity and reinfection is possible -- and, in fact, is quite common in some groups.

This analysis included 63 HIV positive MSM with acute HCV infection. Time of infection was determined using stored blood samples. The age range was 35-47 years and most were on effective antiretroviral therapy. The most common HCV genotypes were 1a and 4d (which is otherwise uncommon in Europe outside sexual transmission clusters).

HCV antibody screening was done every 6-12 months, with a median follow-up period of 4 years. 43 men elected to undergo hepatitis C treatment, which at the time of the study involved pegylated interferon, with or without ribavirin.

Results

• All study participants experienced HCV seroconversion, or production of enough antibodies to show up on a test.
• The median time from HCV infection to seroconversion was 74 days -- comparable to the window period for HIV negative people.
• 41% of participants did not produce detectable HCV antibodies until 3 months after infection, and 27% did not do so until 4 months post-infection.
• Time to seroconversion was not affected by current or nadir (lowest-ever) CD4 T-cell count.
• 36 participants experienced sustained plasma HCV RNA clearance, and they showed a significant decrease in HCV antibody levels.
• Among 5 men with spontaneous HCV clearance without treatment, HCV antibody levels fell but full seroreversion did not occur.
• Among 31 men with sustained virological response to treatment, 8 became HCV antibody negative during follow-up.
• The cumulative likelihood of HCV antibody seroreversion within 3 years after seroconversion was 37%.
• 18 participants became reinfected with HCV during follow-up, coinciding with a subsequent increase in HCV antibody levels.
• 1 man was reinfected twice and 1 was reinfected 3 times, for a total of 21 reinfections.
• Peak HCV antibody levels were significantly lower during initial infection compared with reinfection.
• 72% of participants had elevated ALT during initial HCV infection, but this became less likely, with only 44% having elevated ALT during reinfection.

"A decline of anti-HCV [antibody] reactivity was associated with HCV RNA clearance," the study authors concluded. "Seroreversion was very common following SVR."

"Upon reinfection, anti-HCV levels increased again," they continued. "Monitoring anti-HCV levels might therefore be an effective alternative for diagnosis of HCV reinfection."

According to a second reportin the same issue, repeat HCV screening is uncommon among HIV positive men in the U.S. National guidelines recommend HCV screening for everyone at the time of HIV diagnosis and annually for those at ongoing high risk -- which is important for detecting acute infection -- but the best schedule for regular screening and what counts as "risk" is not well-defined.

J Morgan Freiman from Boston Medical Center and colleagues looked at trends in screening for incident (new) HCV infection among HIV positive individuals in HIV primary care clinics, using data from the CFAR Network of Integrated Clinical Systems (CNICS).

Among 17,090 patients registered at CNICS clinics between 2000 and 2011, 85% received HCV antibody screening within 3 months of enrolling in care. Among 9077 participants who were initially HCV negative and remained in care for at least a year, 57% ever received subsequent HCV screening. Among people with substantial ALT elevation (>100 IU/L), only 27% were tested for HCV antibodies or HCV RNA within 12 months. Out of 5042 people who underwent repeat HCV testing, 267 (5%) were found to have seroconverted.

HCV retesting practices varied widely across clinics, with rates ranging from 35% to 79%. Follow-up HCV screening was found to increase over time -- perhaps due to better awareness of HCV sexual transmission or availability of new and better treatment for hepatitis C -- but again, not uniformly across all sites. People who reported injection drug use, methamphetamine use, condomless anal sex, having an AIDS diagnosis, or a history of other types of liver disease were more likely to receive repeat HCV testing.

"Though most HIV-infected patients were screened for prevalent HCV infection at enrollment in care, only half who were HCV-uninfected were screened again," the researchers concluded. "Guidelines are needed to help HIV providers know who to screen, how frequently to screen, and which screening test to use."

Given the relatively long window period before development of HCV antibodies in many people, HCV RNA testing -- which detects viral genetic material -- might be a better approach than antibody testing to screen for acute HCV infection, Thomas Reiberger from the University of Vienna suggested in an accompanying editorial.

Detecting HCV sooner could enable more effective treatment -- though with new direct-acting antivirals, cure rates are high even during chronic infection -- as well as reducing the risk of onward transmission.

"These novel data on anti-HCV dynamics in HIV positive MSM are highly relevant, since they support a broader use of a sensitive quantitative PCR-based HCV RNA testing in this high-risk population to prevent potential transmission during the early phase of acute hepatitis C (as the patient is otherwise unaware of the HCV coinfection) and to allow early administration of antiviral therapy (that is likely associated with improved response rates)," Reiberger wrote.

10/10/14

References

KM McFaul, A Maghlaoui, M Nzuruba, et al. Acute Hepatitis C Infection in HIV-negative Men Who Have Sex With Men. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract V-676.

O Clerc, K Darling, V Jobin, M Cavassini, et al. Knowledge and Seroprevalence of Hepatitis C Virus Infection among Men who have Sex with Men in the Swiss Lemanic Area. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract V-675.

S Collins. Sexually transmitted HCV in HIV positive and negative gay men.HIV Treatment Bulletin. HIV i-Base. May 27, 2014.

J Tiraboschi et al. Acute hepatitis C in the PROUD pilot study. 3rd Joint BHIVA/BASHH Conference. Liverpool, April 3-6, 2014. Abstract O45.

D Bradshaw et al. Seminal HCV RNA level may mirror dynamics of plasma HCV RNA in HIV-infected men with acute HCV. 3rd Joint BHIVA/BASHH Conference, Liverpool, April 3-6, 2014. Abstract O23.

J Volk. PrEP Community Engagement Meeting. San Francisco Department of Public Health. September 16, 2014.

JW Vanhommerig, XV Thomas, JT van der Meer, et al. Hepatitis C Virus (HCV) Antibody Dynamics following Acute HCV Infection and Reinfection among HIV-infected Men who have Sex with Men. Clinical Infectious Diseases. September 3, 2014 (Epub ahead of print).

JM Freiman, W Huang, L White, et al. Current Practices of Screening for Incident Hepatitis C Virus Infection among HIV-infected HCV-uninfected Individuals in Primary Care. Clinical Infectious Diseases. September 3, 2014 (Epub ahead of print).

T Reiberger. Acute Hepatitis C Virus Infection in HIV+ MSM: Should We Change Our Screening Practice? Clinical Infectious Diseases. September 3, 2014 (Epub ahead of print).