Uncommon mutations at residue positions critical for enfuvirtide (T-20) resistance in enfuvirtide-naive patients infected with subtype B and non-B HIV-1 strains

Enfuvirtide (T-20) is the lead compound of the new class of antiretroviral drugs called fusion inhibitors. T-20 resistance-associated mutations located in the heptad repeat 1 (HR-1) domain of gp41 have been described in vitro and in clinical trials. In this study, the authors investigated the primary genotypic T-20 resistance in subtype B and non-B HIV-1 strains from patients at the beginning of their follow-up in the Luxembourg HIV Cohort as well as the emergence of primary resistance to T-20 in patients who had long-term infection with subtype B HIV-1 strains. HR-1 fragments including the gp41 amino acid 36-45, T-20-sensitive region were screened for amino acid variation. No classic T-20 resistance-associated mutations were identified in subtype B or non-B isolates. However, several uncommon mutations were found at residues 37, 39, and 42 for subtype B isolates and at residue 42 for a subtype non-B isolate. The results indicate that primary genotypic T-20 resistance seems to be rare in HIV-1, regardless of subtype or prior antiretroviral therapy (excluding fusion inhibitors). However, episodic variation within HR-1 can occur and needs further phenotypic evaluation in accurate fusion inhibitor resistance assays.     

Efficacy of antiretroviral therapy in individuals infected with HIV-1 non-B subtypes

The impact of HIV-1 subtype on clinical outcome following exposure to antiretroviral therapy is currently not well known. Natural polymorphisms are often present in HIV-1 non-B subtypes at positions known to be associated with drug resistance in clade B viruses. These changes might influence the emergence of drug-resistant viruses, modifying drug susceptibility and/or the virus replicative capacity. Moreover, different pathways may lead to drug resistance according to HIV-1 clade. Finally, the influence of subtype on the performance of phenotypic assays and in the interpretation of algorithms for genotypic resistance is currently a matter of debate. All these aspects explain why the response to antiretroviral therapy might vary in subjects infected with different HIV-1 clades.     

Tipranavir resistance associated mutations in protease inhibitor-na?ve patients with HIV-1 subtype A/E infection

BACKGROUND: Tipranavir-resistance associated mutations (TPV-RAMs) are often observed among patients with HIV-1 subtype A/E infection. Data regarding TPV resistance in subtype A/E is still limited. OBJECTIVES: To determine the prevalence of TPV-RAMs among protease inhibitor-na?ve, HIV-1 subtype A/E infected patients. STUDY DESIGN: Genotypic resistance testing was conducted among HIV-1-infected patients who were PI-na?ve. RESULTS: We studied 112 patients (mean age, 40.7 years; 58% male). Median CD4 cell count and HIV-1 RNA were 192cells/mm(3) and 4.2logcopies/mL, respectively. Ninety-three patients (83%) infected with subtype A/E; the others had subtype B. The most common TPV-RAMs were M36I (88%), H69K (61%), and I13V (48%). Median number of TPV-RAMs was 3 mutations. Patients with subtype A/E had higher prevalence of I13V (54% vs. 21%, P=0.011), M36I (96% vs. 53%, P<0.001), H69K (68% vs. 26%, P=0.001), and >2 TPV-RAMs (62% vs. 21%, P=0.002). In multivariate analysis, only subtype A/E was associated with the occurrence of >2 TPV-RAMs (OR 9.83; 95%CI, 1.95-39.57; P=0.006). CONCLUSIONS: TPV-RAMs previously described by IAS-USA are commonly observed in PI-na?ve patients with HIV-1 subtype A/E infection. Further studies to define virologic response of subtype A/E to TPV and clinical validation of TPV-RAMs in HIV-1 subtype A/E are essentially needed.