Entecavir, a guanosine analogue, is approved by the U.S. Food and Drug Administration (FDA) for treatment of hepatitis B virus (HBV) infection. In previous studies, entecavir was found to have no significant activity against HIV, and has been recommended as a treatment for hepatitis B in HIV/HBV coinfected patients for whom HIV treatment is not given simultaneously.(1)

A presentation at the recent 14th Conference on Retroviruses and Opportunistic Infections and a "Dear Health Care Provider" letter from the manufacturer of entecavir, Bristol-Myers Squibb, provide evidence that entecavir has anti-HIV activity and may select for resistance to antiretroviral drugs.(2,3) Researchers identified 3 HIV/HBV coinfected patients who were not receiving antiretroviral therapy (ART) and had a decline in HIV RNA of ≥1 log₁₀ copies/mL after starting entecavir monotherapy. In 1 patient, the M184V resistance mutation, which confers resistance to both lamivudine and emtricitabine, emerged during entecavir monotherapy. The number of HIV clones with M184V mutations increased with duration of exposure to entecavir; M184V was associated with resistance to both lamivudine and entecavir. In vitro studies using laboratory strains of HIV also demonstrated inhibition of HIV replication with entecavir monotherapy.

Entecavir has not been studied in HIV/HBV coinfected patients who were not receiving effective ART. Pending further investigations, the development of antiretroviral resistance from entecavir monotherapy cannot be ruled out, and entecavir should be used cautiously in HIV/HBV coinfected patients who are not on fully suppressive ART regimens.

1. U.S. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. October 10, 2006.

2. McMahon M, Jilek B, Brennan T, et al. The Anti-Hepatitis B Drug Entecavir Inhibits HIV-1 Replication and Selects HIV-1 Variants Resistant to Antiretroviral Drugs. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 136LB.

3. Bristol-Myers Squibb. Re: Important Information Regarding Baraclude (entecavir) in Patients Co-Infected with HIV and HBV. Dear Health Care Provider. [PDF] February 2007.

Many protease inhibitors alter hepatic metabolism of HMG Co-A reductase inhibitors (statins), often resulting in significantly increased serum statin levels. Rosuvastatin is not metabolized by cytochrome 450 3A4 and, for this reason, was believed to have no significant interactions with protease inhibitors. However, a study presented at the recent 14th Conference on Retroviruses and Opportunistic Infections suggests that lopinavir/ritonavir (LPV/r) increases serum rosuvastatin concentration.(1)

This prospective drug interaction study showed a 2.1-fold increase in the rosuvastatin area under the concentration time curve (AUC) and a 4.7-fold increase in rosuvastatin maximum concentration (C_max) in 15 HIV-uninfected subjects when LPV/r was added to a stable rosuvastatin regimen. One subject developed a creatine phosphokinase (CPK) increase of >10 times the upper limit of normal after 7 days of combined treatment, and 3 others had less substantial CPK elevations. Surprisingly, the effects of rosuvastatin on total and low-density lipoprotein (LDL) cholesterol appeared to be blunted when LPV/r was coadministered, despite the increase in serum rosuvastatin levels. Lopinavir and ritonavir levels were not affected by rosuvastatin.

The mechanism for this interaction is unknown. Until further data are available, caution must be used if rosuvastatin is to be combined with any protease inhibitor.

1. Hoody D, Kiser JJ, Predhomme J, et al. Drug-drug Interaction between Lopinavir/Ritonavir and Rosuvastatin. In: Program and abstracts of the 14th Conference on Retroviruses and Opportunistic Infections; February 25-28, 2007; Los Angeles. Abstract 564.