Treatment with 3TC in the presence of viral rebound is likely to promote NNRTI resistance in people receiving non-nucleoside reverse transcriptase inhibitors at the same time, and treatment with 3TC after NNRTI treatment ceases is also likely to preserve NNRTI resistance mutations, according to findings presented at the Sixth International Congress on Drug Therapy in HIV Infection last week in Glasgow.
The study was carried out by Dr Alan Winston and colleagues at the Chelsea and Westminster Hospital, London.
Forty four individuals with two resistance tests and evidence of NNRTI resistance on the first test were assessed to see what happened to NNRTI resistance by the time of the second test.
Half of the group continued NNRTI treatment to the time of the second test.
In patients who were receiving 3TC treatment at the time of the second resistance test, 15% showed reduced evidence of genotypic resistance to NNRTIs, compared to 27% of the cohort as a whole. This difference was non-significant. However, patients receiving 3TC treatment at the time of the second resistance test were significantly more likely to show signs of increased genotypic resistance to NNRTIs (35% vs 18% of the total cohort, and 13% of patients who continued NNRTI treatment, p=0.02). Patients currently receiving 3TC were also significantly more likely to have the M184V mutation associated with 3TC treatment (70% vs 37%, p=0.031). This pattern was not observed with any other nucleoside analogue.
The authors of the study say that “The presence of M184V may push viral evolution to select further development of NNRTI mutations”.
In contrast, a number of recent studies have suggested that nucleoside analogue resistance (including 3TC resistance) in the absence of NNRTI resistance mutations may lead to a state of NNRTI hypersusceptibility in a substantial minority of patients. See
Resistance to NNRTIs elsewhere on this website for further information on this topic.
If these findings are replicated in larger cohort analyses, they are likely to further discourage the practice of maintaining 3TC treatment in patients who have failed their first 3TC-containing regimen. A randomised study presented at the XI International HIV Drug Resistance Workshop this summer showed that individuals who maintained 3TC treatment had a twofold higher risk of virological failure (defined as rebound above 2,000 copies/ml) when compared with individuals who replaced 3TC with ddI (Winter).
A study called COLATE is currently testing whether it is better to continue with 3TC in second-line treatment or drop 3TC treatment. This study is testing 3TC in combination with a protease inhibitor rather than an NNRTI.
Winston A et al. The effects of continuing therapy on NNRTI-associated mutations over time. Sixth International Congress on Drug Therapy in HIV Infection, Glasgow, abstract P210, 2002.
Winter MA et al. Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside-experienced patients. Antiviral Therapy 7: S101, 2002.