Coinfection

Antiretroviral Treatment for HIV Appears to Protect Gay Men Against Hepatitis B

HIV-positive gay and bisexual men who use effective combination antiretroviral therapy (ART) were 80% less likely to become infected with hepatitis B virus (HBV) in a large observational study reported in the October 13 Annals of Internal Medicine. The authors emphasize, however, that ART is not a substitute for hepatitis B vaccination.

Although the viruses are not related, HIV and HBV are transmitted by the same routes -- mainly through sex and sharing drug injection equipment -- and are susceptible to some of the same nucleoside/nucleotide analog medications. Unlike HIV, however, HBV can be prevented with an effective vaccine that is now routinely given to infants in many countries.

Oluwaseun Falade-Nwulia and Chloe Thio from Johns Hopkins University and colleagues looked at predictors of incident (new) HBV infection among gay and bisexual men before and after the advent of highly active ART in the mid-1990s.

The analysis included 2375 men who have sex with men in the Multicenter AIDS Cohort Study who initially did not have hepatitis B. MACS has followed participants who are either HIV-positive or at risk for HIV since the beginning of the epidemic. About two-thirds of the men were white and the median age was 32 years. At the start of the study 41% of HIV-positive men and 28% of HIV-negative men had received at least 1 dose of the HBV vaccine, rising to 67% and 58%, respectively, by 2013 (the standard vaccine series is 3 injections over 6 months).

Results

• 244 new HBV infections occurred during a total 25,322 person-years of follow-up, with a median follow-up period of about 9.5 years per participant.
• The unadjusted HBV incidence rate was higher for HIV-positive gay men compared to HIV-negative men (incidence rate ratio [IRR] 1.9, or nearly 2-fold higher).
• HBV incidence was significantly lower during the ART era than during the pre-ART era among both HIV-positive and HIV-negative men (IRR 0.2 and 0.3, respectively).
• In a multivariate analysis, age under 40 years (IRR 2.3), having 2 or more recent sex partners (IRR 3.1), and having HIV (IRR 2.4) were all independently associated with higher HBV incidence.
• HBV vaccination, in contrast, was protective (IRR 0.3, or 70% risk reduction).
• Among people on highly active ART, treatment that reduced HIV viral load to less than 400 copies/mL was associated with HBV protection (IRR 0.2, or 80% risk reduction), while non-suppressive ART was not.
• HIV-positive men on suppressive ART had about the same likelihood of HBV infection as HIV-negative gay men.

Based on these findings, the researchers concluded, "Effective [highly active] ART is associated with lower incidence of HBV infection; however, even in the [highly active] ART era, incidence of HBV infection remains high among MSM."

This study has some limitations. As an observational analysis, it can only show a link between the availability of highly active ART and a reduction in HBV incidence among gay men -- it cannot show that ART caused the decrease.

If effective ART did in fact lead to lower HBV incidence, it is still not clear why.

Two drugs are used to treat both HIV and hepatitis B. Lamivudine (3TC or Epivir) was FDA-approved in 1995 and was used with zidovudine (AZT or Retrovir) even before the advent of multi-class combination ART. Tenofovir disoproxil fumarate(Viread, also in Truvada, Atripla, Complera, and Stribild) was approved in 2001 and has since become the most widely used NRTI, typically combined with emtricitabine (Emtriva or FTC), a drug similar to lamivudine that is also active against HBV but not approved for this purpose.

Study participants received an HBV-active drug as part of their ART regimen for 92% of follow-up time, so there was not enough time spent without such drugs to allow for a meaningful comparison. In an attempt to tease out their contributions, the authors stratified the analysis into pre- and post-tenofovir periods (1996-2001 and 2002-2013), finding that the effect on HBV incidence among HIV-positive men on suppressive ART was the same during both periods.

In their discussion the authors suggested that dually active drugs themselves may not be responsible for the reduction in hepatitis B incidence. While some prior studies have found that HBV-active drugs in an ART regimen reduced the risk of HBV infection by 50% to 90%, others did not find that using these specific drugs provided more protection than ART in general.

This may be due to the different lifecycles of HIV and HBV, they explained. HIV first copies its RNA genetic material in the cytoplasm or main body of T-cells, which then gets inserted into the cell's chromosomes; nucleoside/nucleotide analogs like lamivudine and tenofovir block this copying. HBV, in contrast, first inserts its DNA genetic material into the liver cell nucleus, which is then used to produce new virus. Therefore, lamivudine and tenofovir may not prevent new HBV infections, even though they can control viral replication and prevent it from spreading to new cells in the liver.

While this study did not look at HIV pre-exposure prophylaxis (PrEP) using tenofovir/emtricitabine (Truvada), this explanation suggests that taking these drugs to prevent HIV infection may not necessarily prevent HBV infection.

The authors noted that HIV-positive men were twice as likely as HIV-negative men to acquire HBV even after adjusting for risk behavior. They suggested that impaired immunity among people with active HIV may facilitate HBV infection, and therefore ART that controls HIV and improves immune function could reduce susceptibility to HBV. HIV-positive people with impaired immunity also do not get as much protection from the HBV vaccine.

"What this means to us is that effective HIV therapy appears to restore an impairment in the immune response that protects someone with HIV from acquiring hepatitis B infection," Thio said in a Johns Hopkins press release.

These findings, the researchers stressed, should not be taken to mean that HBV vaccination is not necessary if people are on effective ART. The vaccine is recommended for all people with HIV, men who have sex with men, people who have multiple sex partners, and others at risk.

"We found a 70 percent reduction in new HBV infections in the men who reported receiving at least 1 dose of HBV vaccine," Falade-Nwulia said. "[V]accination rates, even in high-risk individuals, such as men who have sex with men, remain low, and we need to do a better job of encouraging vaccination."

10/19/15

Reference

O Falade-Nwulia, EC Seaberg, AE Snider, C Thio, et al.Incident Hepatitis B Virus Infection in HIV-Infected and HIV-Uninfected Men Who Have Sex With Men From Pre-HAART to HAART Periods: A Cohort Study. Annals of Internal Medicine. October 13, 2015 (online ahead of print).

Other Source

Johns Hopkins School of Medicine. HIV Drugs Provide Added Benefit of Protecting Against Hepatitis B Virus. Press release. October 12, 2015.