The L76V mutation in HIV-1 protease is potentially associated with hypersusceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage?

BACKGROUND: Although 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. RESULTS: Based 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. CONCLUSIONS: In 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.

Safety and Efficacy in HIV-1-Infected Patients Treated with Ritonavir-Boosted Saquinavir Mesylate.

OBJECTIVE: To evaluate the safety, tolerability, and efficacy of ritonavir-boosted saquinavir 1000/100 mg twice daily administered as a 500 mg film-coated tablet in HIV-1-infected patients. METHODS: In this open-label, observational, 24-week survey conducted in 8 European countries, eligible HIV-infected participants had been prescribed saquinavir/ritonavir in combination with other nonprotease inhibitor (PI) antiretroviral agents as part of their HIV treatment regimen. The safety (grade 3 or 4 adverse events [AEs]), tolerability (by an investigator-reported subjective rating system), and efficacy (the percentage of participants with <50 and <400 copies/mL HIV RNA and change from baseline in mean CD4+ cell count) were analyzed for the overall study population and 7 subpopulations. RESULTS: The enrolled population included 2122 participants with 1908 completing the study; 44 (2.1%) withdrew prematurely because of AEs, including 7 nontreatment-related deaths. There were 33 grade 3 or 4 AEs in 29 (1.4%) participants; 7 AEs in 7 (0.3%) participants were considered treatment-related. Tolerability was reported to be "very good" or "good" in 42% and 25% of participants, respectively. From baseline to week 24, the proportion of participants with HIV RNA <50 copies/mL increased from 31.2% to 47.6% and the proportion with <400 copies/mL increased from 42.5% to 61.4%; the mean CD4+ cell count increased by 75 cells/microL. In the subpopulation analysis, the greatest efficacy benefits occurred in participants who were treatment-naïve and in those not having received prior PI therapy. CONCLUSIONS: Treatment with the saquinavir 500 mg film-coated tablet resulted in few grade 3 or 4 AEs and was well tolerated and effective in a broad population of patients.