Boosted protease inhibitor regimens with 3TC work despite M184V resistance

People with HIV who have developed resistance to 3TC (lamivudine) can still achieve viral load suppression using boosted protease inhibitor regimens that include 3TC as part of the nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) "backbone", researchers reported this week at the 49^th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.

Resistance to 3TC is commonly seen amongst people who experience virological failure on a first-line antiretroviral regimen, typically due to emergence of the M184V mutation in the HIV reverse transcriptase enzyme. This mutation also confers cross-resistance to the related drug FTC (emtricitabine, Emtriva).

Drug resistance generally increases the risk of treatment failure and disease progression, but the presence of the M184V mutation appears to decrease viral fitness by reducing its ability to replicate and increasing susceptibility to other NRTIs. This is demonstrated by the fact that viral load may increase by a small amount when people with this mutation stop taking 3TC, indicating that the drug had an antiviral effect despite resistance.

Treatment guidelines for resource-limited settings recommend that second-line treatment should consist of a boosted protease inhibitor, coupled with either abacavir and ddI or tenofovir and 3TC. However, there is little evidence to date on the effectiveness of regimens containing 3TC in second-line treatment.

Mark Hull and colleagues with the British Columbia Centre for Excellence in HIV/AIDS in Vancouver, Canada, looked at treatment outcomes after developing the M184V mutation.

This retrospective study included 184 patients enrolled in the British Columbia HIV Drug Treatment Program who had M184V mutations detected between January 2000 and July 2006. Of these, 117 (64%) were resistant to 3TC, with or without non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, whilst 67 (36%) had resistance to other NRTIs, NNRTIs and/or protease inhibitors along with the M184V mutation.

Most participants (about 85%) were men and the median age was 38 years. Approximately 45% were coinfected with hepatitis C. Overall, they had fairly advanced immune deficiency, with a median CD4 cell count of 100-165 cells/mm³. Three-quarters were either new to antiretroviral therapy or on their second regimen. The median amount of time on a regimen when resistance was detected was just under one year.

Participants were classified according to what type of regimen they used after M184V detection (they were not randomly assigned to these regimens): 3TC or FTC plus another NRTI plus a boosted protease inhibitor (41%); the same combination plus one or more additional active drugs (21%); or two NRTIs not including 3TC or FTC, plus a boosted protease inhibitor with or without additional active drugs (38%).

Overall, 74% of participants achieved viral load suppression below 50 copies/ml, but the rate varied according to several characteristics including history of injection drug use and hepatitis C coinfection. In a multivariate analysis that adjusted for confounding factors, participants taking 3TC or FTC plus another NRTI plus a boosted protease inhibitor were as likely to achieve undetectable viral load as those taking the other two types of regimen.

The researchers concluded that amongst individuals with documented M184V mutations, with or without additional NNRTI resistance, standard three-drug boosted protease inhibitor-based regimens containing 3TC "appeared equally effective" at achieving virological suppression compared with more intensive multi-drug combinations or 3TC-sparing regimens.

They suggested that early detection of virological failure before extensive NRTI resistance develops may enable subsequent virological suppression by adding a boosted protease inhibitor to the 3TC backbone, rather than having to switch to a more complex second-line regimen.