4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

PRESSURE TO MAINTAIN THE M184V MUTATION IN TISSUE CULTURE CAN MORE EFFICIENTLY BE EXERTED BY LAMIVUDINE AND ABACAVIR THAN BY DIDANOSINE

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):18 (Abstract 21

MA Wainberg, M Götte and M Oliveira
McGill University AIDS Centre, Jewish General Hospital, Montreal, Quebec, Canada

OBJECTIVE: To analyse the stability of the M184V mutation in the presence of various inhibitors of HIV-1 reverse transcriptase (RT).

METHODS: There is growing clinical evidence that maintenance of the M184V mutation in HIV RT should be considered even in the face of treatment failure. This could conceivably be accomplished through continued use of lamivudine, against which M184V confers high-level resistance, or alternatively, through use of either abacavir or didanosine, against which M184V confers low-level diminished sensitivity. To answer this question, we have prepared mixtures of each of wild-type HxB2D virus and HxB2D containing M184V at ratios of 9:1, 1:1 and 1:9, and have grown these mixtures in peripheral blood mononuclear cells in either the absence of drug pressure, or in the presence of double the IC₅₀ concentrations of each of several drugs over a 3-month period. The drugs used and their concentrations were abacavir (1 μM), lamivudine (0.8 μM), didanosine (8 μM), zidovudine (0.002 μM) and (–)dOTC (0.5 μM). After various time periods, viral RNA was extracted from the tissue culture samples and analysed for the presence of resistance- conferring mutations in RT by LiPA technology, in order to determine the percentages of viruses that contained relevant mutations or that were wild-type in each case.

RESULTS: The results showed that wild-type virus quickly became predominant in the absence of drug pressure and that 98% of the viral outgrowth from a mixture that had started as 90% 184V and 10% wild-type contained M184 after 2 months. In contrast, close to 100% of all viral outgrowths contained the 184V mutation after this period in the case of viruses grown in the presence of lamivudine, (–)dOTC or abacavir, even when the initial mixture was 90% wild-type and 10% 184V. In contrast, ddI did not seem able to exert adequate pressure to maintain 184V in these studies; mixtures that began as 90% wild-type contained a near 100% representation of M184 after 2 months, while viruses that began as either 50% or 90% 184V contained 184V at only 50% and 70% of total outgrowth, respectively, when grown in didanosine for 2 months. In the presence of zidovudine, wild-type virus became predominant even faster than in the absence of drug pressure.

CONCLUSION: These data suggest that didanosine may not be able to exert selective pressure to maintain the 184V substitution as adequately as other drugs that can also select for this mutation. The M184V mutation may disappear even faster in the presence of other drugs, such as zidovudine, that are able to impair replication of mutated viruses more efficiently than of wild-type viruses.

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2000-06-12
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