ICAAC: Cross-resistance to 3TC and FTC develops slowly with entecavir monotherapy

Resistance to FTC and 3TC emerges slowly and does not occur in all HIV-positive patients if they are exposed to the hepatitis B drug entecavir (Baraclude) when not taking anti-HIV therapy, researchers reported this week at the 47^th Interscience Conference on Antimicrobial Agents and Chemotherapy in Chicago.

Entecavir is a nucleoside analogue drug (a guanosine analogue) used as an antiviral treatment for hepatitis B. As entecavir was originally thought to have selective activity against hepatitis B virus (HBV) polymerase only, it has been the recommended therapy for HBV treatment in people with HIV-HBV coinfection.

However, a research team from the Johns Hopkins University School of Medicine recently reported that entecavir is also an inhibitor of HIV reverse transcriptase (RT), after observing HIV viral load drops in coinfected patients who began entecavir treatment.

In some such patients, entecavir use has selected for the M184V mutation in HIV, conferring cross-resistance to 3TC (lamivudine) and FTC (emtricitabine). The manufacturer Bristol-Myers Squibb has issued a press release and added a black box warning to the package insert regarding this danger.

In their presentation this week, the same group of Johns Hopkins researchers further investigated the evolution of drug resistant HIV in HBV-HIV co-infected patients who took entecavir monotherapy. HIV variants were obtained and sequenced for phylogenetic analysis using RT-PCR and cloning. The phylogenetic analysis documented the emergence of the M184V mutation associated with 3TC and FTC resistance in the HIV reverse transcriptase (RT) gene in these patients.

Dose response showed that, above a certain point, increasing plasma concentrations of entecavir do not result in increased anti-HIV effect. The significance is that entecavir is, at best, a partial inhibitor of HIV, creating selective pressure and a favourable environment for HIV resistance to develop, even at high entecavir concentrations.

In the in vitro studies, significant minority viral populations with the M184V mutation emerged after 92 days of culture and grew to half the viral population by 180 days.

In vitro studies suggested that, compared to wild-type HIV, virus with the M184V mutation has only a modest advantage in replicative fitness at entecavir concentrations that would be encountered in clinical use (C_max, 30 nM).

The researchers suggest that "this may not only explain why the M184V mutation arises slowly in vitro but also why some patients, after several months of entecavir monotherapy, do not have the M184V mutation." They also suggest that different cellular factors affect the viral response to entecavir.

The study team concluded that "these data provide an explanation for the variable rate at which M184V variants emerge in patients on entecavir monotherapy[,] highlight the clinical significance of the anti-HIV activity by entecavir and provide a basis for understanding the evolution of drug resistant HIV in patients taking entecavir."