February 6, 2001
The use of abacavir (ABC) as a part of triple-nucleoside HAART is increasing. Triple nuke therapy has the potential advantage of sparing both non-nukes and protease inhibitors for a later time. Clearly, pill counts are minimized to their current nadir of one pill twice daily. This should have positive benefits for patient adherence. Abacavir resistance seems to appear slowly in HIV and is mediated by mutations at the reverse transcriptase (RT) codons 184, 65, 74 and 115. Multiple mutations in the RT gene are needed to have high-level resistance to abacavir. In patients, resistance is typically mediated by the M184V mutation in concert with other mutations (usually three or more) in RT. An important question about the use of triple-nucleoside therapy is the kind of mutation and resistance pattern that emerges after treatment failure. A major concern is the relative ease of the development of the 184 mutation, as only a single nucleotide change in the gene could spell treatment failure, or facilitate the rapid emergence of other mutations in RT.
This study presents the 96-week analysis of viral resistance in the GlaxoSmithKlein-sponsored study CNA3005. This large placebo-controlled, double-blinded study compared the outcomes of Combivir/ABC to Combivir/indinavir (IDV) in 562 treatment-naive patients. Treatment failure occurred in 15% of the ABC-arm patients and 11% in the IDV-arm patients. The majority of patients experiencing treatment failure had genotypic analyses performed. Genotypes were performed at first viral load >400 copies/mL and at last time on study. Some patients continued on blinded treatment despite detectable viremia (see figure 1 from poster). At first genotype (median time 28 weeks), 23% of patients had wild type RT; 61% only the M184V mutation; 7% had M184V and other mutations. At time of last genotype (median time 72 weeks), 16% had wild type RT; 40% had M184 only; 35% had M184 and other mutations. Overall, at time of first genotype, M184V or wild type was present in 35/39 patients on Combivir/ABC and 28/29 (97%) on Combivir/IDV. Interestingly, even when other RT mutations were present, there were still reductions in viral loads; on average -1.5 log.
This analysis gives a glimpse into the time line for the accumulation of mutations during ABC-containing therapy (see figure 4 from poster). The percentage of patients with viral isolates with M184V and other RT mutations gradually increases with time after the first genotype. At week 0-8, only 10% of patients have M184V and other RT mutations; by week 17-24, this percentage increases to 25%. By weeks 41-48, over 50% of patients have viruses with M184V and other RT mutations.
The preliminary success of subsequent therapy is also described. Sixty-seven percent of combivir/ABC failures and 50% of combivir/IDV failures achieve viral loads <400 copies at least Four weeks after treatment switch. The most common salvage regimen after COM/ABC failure was a switch to d4T/ddI with a protease or NNRTI (6/15 patients); Four patients had IDV alone added to the regimen. Long-term durability analysis was not presented.
These data are of limited immediate relevance for the treatment community. An important aspect of the study is the confirmation that most patients failing ABC-containing triple-nuke therapy fail with mutations only in codon 184. The appearance of other RT mutations appears relatively slowly, with three-quarters of failing patients remaining wild type or M184V alone after four months on not fully suppressive therapy. In our practice, only a few patients currently receive initial therapy with Trizivir. These data give additional information as to how to manage Trizivir patients; information that helps to manage patients with initial viral load blips and the potential for subsequent treatment success.
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