December 17, 2005
Antiretroviral treatment is often compromised by the emergence of resistance mutations that decrease the susceptibility of HIV to particular drugs included in a given regimen. Understanding the type of mutations and the time at which such mutations emerge during the course of treatment can help clinicians better design effective therapeutic regimens for their patients.
In the ESS30009 clinical trial, patients received combination treatment with tenofovir (TDF, Viread) + abacavir (ABC, Ziagen) + lamivudine (3TC, Epivir). This trial was terminated prematurely, because a high proportion of individuals experienced virologic failure concomitant with the appearance of both the M184V and K65R mutations.
The current study presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy follows up on these observations to assess whether additional mutations might also have been selected during patient exposure to the combination of tenofovir + abacavir + lamivudine. In particular, the investigators decided to assess for the presence of substitutions in the HIV-1 reverse transcriptase (RT) at codon S68, as such mutations have been observed after virologic failure on regimens containing tenofovir + abacavir + either didanosine (ddI, Videx) or stavudine (d4T, Zerit). Mutations at position S68 have also occasionally been associated with the selection of the RT K65R substitution.
The study group, led by Lisa Ross, includes scientists based at GlaxoSmithKline (Glaxo) in Research Triangle Park, North Carolina, as well as leading clinicians who had participated in the ESS30009 clinical trial. Glaxo was the pharmaceutical sponsor of the ESS30009 study.
Genotypes from ESS30009 individuals who had failed tenofovir + abacavir + lamivudine therapy were compared with samples available at baseline and at pre-therapy switch time points. In particular, mutations at position S68 were evaluated using a sensitive detection procedure established for this purpose by Monogram Biosciences, Inc. In addition, HIV clonal analysis was performed at the Glaxo laboratories in Research Triangle Park.
A total of 81 individuals were analyzed. Most of the viral samples from these individuals contained the M184I/V mutation (78/81, 96%), the K65R mutation (43/81, 53%) and the Y115F substitution (9/81, 11%). Six individuals also harbored substitutions at codon S68 (i.e., S68G/N or D), and all of these patients additionally possessed the K65R and M184V substitutions. In almost all cases, emergence of the S68 mutation appeared to follow the initial selection of the M184V and K65R mutations and occurred between 10 to 21 weeks after the initiation of therapy.
It is conceivable that the S68 mutation, selected in 14% of patients already harboring the K65R mutation, may represent an attempt by the virus to compensate for impaired RT fitness. The additional presence of the Y115F substitution together with the K65R and S68G/N mutations, which was observed in two patients, resulted in increased levels of resistance to all drugs evaluated -- tenofovir, lamivudine and abacavir.
These findings are consistent with results reported by other investigators who have also observed S68 substitutions in concert with the K65R mutation in individuals who had experienced virologic failure.
In some cases, mutations at position S68 were observed in individuals who had selected the Q151M substitution as well, which is associated with multiple nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) drug resistance. These findings are interesting and highlight the need to better understand how mutational interactions in the HIV-1 RT may compensate for reduced viral fitness and contribute to the observed phenotype.
To that end, Ross et al will hopefully perform biochemical experiments to more fully determine the impact of the S68 substitutions together with the K65R and/or M184V mutations on RT function.
The clinical significance of the observations reported here are unclear at this time. Further analysis may be unlikely given that the co-administration of abacavir + lamivudine + tenofovir is not likely to be attempted in future clinical trials.
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