Abstract
BackgroundAlthough being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. Beside an enhancement of resistance, L76V is also discussed to confer hypersusceptibility to the drugs Atazanavir and Saquinavir which might enable new treatment strategies by trying to take advantage of particular mutations.ResultsBased on a cohort of 47 L76V-positive patients, we examined if there might exist a clinical advantage for L76V-positive patients concerning long-term success of PI-containing regimens in patients with limited therapy options.Genotypic- and phenotypic HIV-resistance tests from 47 mostly multi-resistant, L76V-positive patients throughout Germany were accomplished retrospectively 1999-2009. Five genotype-based drug-susceptibility predictions received from online interpretation-tools for Atazanavir, Saquinavir, Amprenavir and Lopinavir, were compared to phenotype-based predictions that were determined by using a recombinant virus assay along with a Virtual Phenotype™(Virco). The clinical outcome of the L76V-adapted follow-up therapy was determined by monitoring viral load for 96 weeks.ConclusionsIn this analysis, the mostly used interpretation systems overestimated the L76V-mutation concerning Atazanavir- and SQV resistance. In fact, a clear benefit in drug susceptibility for these drugs was observed in phenotype analysis after establishment of L76V. More importantly, long-term therapy success was significantly higher in patients receiving Atazanavir and/or Saquinavir plus one L76V-selecting drug compared to patients without L76V-selecting agents (p = 0.002).In case of L76V-occurrence ATV and/or SQV may represent encouraging options for patients in deep salvage situations.
Highlights
Being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V
The reduced susceptibility to certain antiretrovirals is often accompanied with a gradual loss of viral fitness, indicating that mutations with high fitness costs are less able to persist in the absence of drug pressure [1]
M184V/I, the most prevalent NRTImutations selected under 3TC or FTC in the reverse transcriptase, do for instance revert partially the effect of thymidine-analogue mutation- (TAM) on resistance [7]
Summary
Being considered as a rarely observed HIV-1 protease mutation in clinical isolates, the L76V-prevalence increased 1998-2008 in some European countries most likely due to the approval of Lopinavir, Amprenavir and Darunavir which can select L76V. There have been recent reports about HIV strains with increased susceptibility to particular drugs when certain. M184V/I, the most prevalent NRTImutations selected under 3TC or FTC in the reverse transcriptase, do for instance revert partially the effect of thymidine-analogue mutation- (TAM) on resistance [7]. K65R and L74V are further mutations which can confer hypersusceptibility or resensitization to AZT [8] Beside these specific mutations in the reverse transcriptase, there are reports about resensitizing mutations affecting the protease gene [9,10]
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