Evidence Points to Large International Network of HCV Transmission among HIV Positive Men Who Have Sex with Men

By Liz Highleyman

Since the early 2000s, clinicians in the U.K. and continental Europe have report clusters of apparently sexually transmitted acute hepatitis C virus (HCV) infection, mostly among HIV positive men who have sex with men (MSM). More recently, similar outbreaks have been reported in Australia and the U.S.

Acute hepatitis C is often asymptomatic and therefore never diagnosed. HIV positive individuals taking antiretroviral therapy typically receive regular monitoring to check for liver toxicity, and sudden unexplained increases in liver enzymes may signal acute HCV. It is unclear whether HIV positive men are actually more likely than HIV negative men to contract HCV via sex, or whether they are simply more likely to be diagnosed during the acute stage.

Numerous reports about the recent acute hepatitis C outbreaks have been presented at scientific conferences over the past several years. While specifics vary from study to study, these acute infections have been linked to unprotected anal intercourse, fisting, multiple sex partners, group sex, use of sex toys, nasal recreational drug use, and presence of other sexually transmitted diseases; the men involved typically do not report traditional HCV risk factors such as injection drug use.

Now, researchers from the U.K., Netherlands, France, Germany, and Australia have published a combined analysis of these clusters in the May 2009 issue of Gastroenterology.

The authors conducted an international phylogenetic study to investigate the existence of a common HCV transmission network among more than 200 HIV positive gay/bisexual men. The analysis included 107 men in the U.K., 58 in the Netherlands, 25 in Germany, 24 in Australia, and 12 in France who were diagnosed with acute hepatitis C between 2000 and 2006.

The men in this analysis were relatively young, with a median age of 38 years at the time of HCV diagnosis. Nearly two-thirds were on combination antiretroviral therapy and as a group they had well-preserved immune function, with a median CD4 count of 518 cells/mm3.

The researchers used real-time polymerase chain reaction (PCR) technology to amplify, sequence, and compare the NS5B region of the HCV genome. NS5B sequences were obtained from 200 (89%) of the total reported cases.

Results

Circulating HCV genotypes in the tested patients were as follows:

1a: 59%;
1b: 5%;
2b or 2c: 3%;
3a: 11%;
4d: 23% -- an otherwise uncommon type in Europe.

Phylogenetic analysis revealed 156 sequences, or 78%, that formed 11 clusters (bootstrap value > 70%).

These clusters included 86% of the European cases and 42% of the Australian cases studied.

Each cluster contained between 4 and 37 individual sequences.

Country mixing was associated with larger cluster size (average 17 sequences) relative to single-country clusters (4.5 sequences).

A "molecular clock" analysis indicated that the majority of HCV transmissions (85%) occurred after 1996.

Based on these findings, the study authors wrote, "Phylogenetic analysis revealed a large international network of HCV transmission among HIV positive MSM."

"The rapid spread of HCV among neighboring countries is supported by the large proportion (74%) of European MSM infected with an HCV strain co-circulating in multiple European countries, the low evolutionary distances among HCV isolates from different countries, and the trend toward increased country mixing with increasing cluster size," they added.

In their discussion, the researchers explained that such clustering "is typical of multiple independent, parallel chains of transmission, each seeded by a single source of infection." They added that the observed evolutionary pattern "would imply occasional introduction and transmission of HCV in the MSM population between 1975 and 1996, followed by a more rapid expansion of HCV transmission among HIV positive MSM since 1996."

"The reason for a change in HCV transmission pattern since the late 1990s remains unclear, but it probably relates to biologic and behavioral factors," they wrote. "Temporally, this epidemic coincides with the introduction of highly active antiretroviral therapy and associated increases in sexual risk behaviors."

"It is striking that permucosal transmission of HCV is almost exclusively described in HIV positive MSM," the authors continued. "HIV coinfection might facilitate HCV transmission by increasing both viral infectiousness because of higher HCV viral loads in serum and semen and viral susceptibility through impaired immunologic control of HCV," they suggested, though the men involved generally had relatively high CD4 counts.

On the other hand, they pointed out that several cases of apparently sexually transmitted HCV were recently reported among HIV negative gay/bisexual men in Brighton, UK, thus "raising the possibility of the infection bridging between HIV positive and HIV negative MSM populations." (In 2006, French researchers reported 2 similar acute HCV cases in HIV positive woman, suggesting that heterosexual transmission may also be occurring.)

The investigators recommended that "International collaborative public health efforts are needed to mitigate HCV transmission among this population."

"Annual HCV antibody screening should become part of the routine care of all HIV positive MSM and should be considered for MSM with negative or unknown HIV status who report high-risk behaviors," they elaborated. "Early detection of HCV will allow early effective treatment and identification of risk factors, which may mitigate ongoing transmission."

Health Service, Amsterdam, Netherlands; University of Oxford, Oxford, UK; University College London Centre for Hepatology, Royal Free Hospital, London, UK; Chelsea and Westminster Hospitals, London, UK; Royal Free and University College, London, UK; Medizinische Klinik und Poliklinik I, Bonn University, Bonn, Germany; Practice Dupke/Carganico/Baumgarten, Berlin, Germany; University Paris-Descartes, Paris, France; Brighton and Sussex University Hospitals Trust, Brighton, UK; Health Service, Rotterdam, Netherlands; National Centre in HIV Epidemiology and Clinical Research and School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia; Centre for Infectious Disease Control, Bilthoven, Netherlands; University of Amsterdam, Amsterdam, Netherlands; St. Vincent's Clinical School, University of New South Wales, Sydney, Australia.

6/12/09

Reference
T van de Laar, O Pybus, S Bruisten, and others. Evidence of a Large, International Network of HCV Transmission in HIV-Positive Men Who Have Sex with Men. Gastroenterology 136(5): 1609-1617. May 2009