The hepatitis B drug entecavir (Baraclude) demonstrates activity against HIV and selects for mutations that confer resistance to certain antiretroviral medications, according to a study presented Wednesday at the Fourteenth Conference on Retroviruses and Opportunistic Infections in Los Angeles.
Two agents currently approved for the treatment of hepatitis B virus (HBV) infection – lamivudine (3TC; Epivir-HBV) and adefovir (Hepsera) also demonstrate activity against HIV. Further, two approved anti-HIV drugs -- emtricitabine (Emtriva) and tenofovir (Viread) – are also active against HBV, and are in clinical trials for this indication.
This leaves few antiviral drugs that are believed to be active only against HBV, namely entecavir and telbivudine (Sebivo); Tyzeka), which was just approved by the European Medicines Agency last week. (Interferon works in a different way, by stimulating the body’s immune response rather than acting directly against HBV.)
Such agents are important because some HIV/HBV co-infected individuals do not yet require HIV treatment. Using a single dually-active agent such as lamivudine for HBV treatment is likely to select for drug-resistant HIV strains, as it would be equivalent to using antiretroviral monotherapy.
The study presented this week, however, suggests that entecavir is in fact active against HIV and encourages the development of an HIV mutation known as M184V, which confers resistance not only to entecavir, but also to lamivudine and emtricitabine. Both drugs are commonly used as “backbone” nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral therapy regimens; lamivudine is a component of the Combivir, Trizivir and Epzicom fixed-dose combination pills, whilst emtricitabine is included in the Truvada and Atripla pills.
Presenter Dr Chloe Thio from Johns Hopkins University reported on three cases in which HIV/HBV co-infected patients not receiving antiretroviral therapy experienced at least a 1-log decline in HIV viral load after starting entecavir for hepatitis B treatment. HIV RNA levels later rebounded in two of these individuals.
To explore this effect, Dr Thio and colleagues performed a laboratory analysis in which HIV-infected CD4 cells were exposed to increasing concentrations of antiviral drugs. To assess the emergence of resistance mutations, they obtained and cloned HIV isolates from the patient described in the first case report at several time points while on entecavir monotherapy. In addition, they used PCR testing to determine whether HIV replication was affected by exposure to entecavir.
They found that entecavir potently inhibited HIV replication with a 50% inhibitory concentration (IC50) between 0.1 and 1 nM, which is below the plasma concentration typically achieved with a normal dose of entecavir for hepatitis B treatment. PCR tests showed that entecavir inhibited the activity of the HIV reverse transcriptase enzyme, thereby slowing viral replication.
The analysis of the HIV samples from the co-infected patient showed that the M184V mutation accumulated over time. At baseline, none of the HIV clones harboured the mutation, compared with 61% at four months and 96% at six months after starting entecavir.
The researchers concluded that entecavir is a potent -- but partial -- inhibitor of HIV replication in vivo and in vitro, and that it can select for the M184V mutation, which confers high-level resistance to entecavir.
During discussion of the presentation, a representative from entecavir manufacturer Bristol-Myers Squibb said that the company had extensively tested the drug over ten years, and did not see activity against HIV. Dr Thio replied that her study used a more precise assay that was not yet available when entecavir was in development.