Evaluation of Primary Resistance to HIV Entry Inhibitors Among Brazilian Patients Failing Reverse Transcriptase/Protease Inhibitors Treatment Reveal High Prevalence of Maraviroc Resistance-Related Mutations

Abstract

Entry inhibitor is a new class of drugs that target the viral envelope protein. This region is variable; hence resistance to these drugs may be present before treatment. The aim of this study was to analyze the frequency of patients failing treatment with transcriptase reverse and protease inhibitors that would respond to the entry inhibitors Enfuvirtide, Maraviroc, and BMS-806. The study included 100 HIV-1 positive patients from one outpatient clinic in the city of Sao Paulo, for whom a genotype test was requested due to treatment failure. Proviral DNA was amplified and sequenced for regions of gp120 and gp41. A total of 80 could be sequenced and from those, 73 (91.3%), 5 (6.3%) and 2 (2.5%) were classified as subtype B, F, and recombinants (B/ F and B/C), respectively. CXCR4 co-receptor use was predicted in 30% of the strains. Primary resistance to Enfuvirtide was found in 1.3%, following the AIDS Society consensus list, and 10% would be considered resistant if a broader criterion was used. Resistance to BMS-806 was higher; 6 (7.5%), and was associated to non-B strains. Strikingly, 27.5% of samples harbored one or more mutation among A316T, I323V, and S405A, which have been related to decreased susceptibility of Maraviroc; 15% of them among viruses predictive to be R5. A more common mutation was A316T, which was associated to the Brazilian B strain harboring the GWGR motif at the tip of V3 loop and their derivative sequences. These results may be impact guidelines for genotype testing and treatment in Brazil.

Naturally occurring resistance mutations to HIV-1 entry inhibitors in subtypes B, C, and CRF31_BC

“…26 Due to the dates of sample collection viral mutations described here, in the ARV-naïve population, were unlikely selected and transmitted from patients under use of entry inhibitors antiretroviral therapy. Therefore, these Resistance to ENF is characterized by a low genetic barrier, as phenotypic resistance arises with mutations in the codons 36-45.…”

Maraviroc: a review of its use in HIV infection and beyond

“… 119 A high prevalence of the A316T mutation, which results in partial resistance to MVC, was found in Zambian mother–infant pairs infected with HIV-1 subtype-C. 120 A study of 80 HIV-infected patients in Brazil who had failed treatment showed that 27.5% harbored the the A316T, I323V, and/or S405A mutations in the gp120. 121 However, in another study of 498 individuals infected with R5-tropic, subtype-B HIV-1, mutation patterns associated with MVC resistance were less than 5%. 122 Single mutations were more commonly observed, but their significance on MVC resistance was not examined.…”

Frequency of coreceptor tropism in PBMC samples from HIV-1 recently infected blood donors by massively parallel sequencing: the REDS II study

“…Despite the fact that Maraviroc has been used in Brazil since 2007, few data are available about its efficacy during routine use. Recently, Alencar et al [ 17 ] found that 27.5 % of samples from patients failing previous antiretroviral therapy harbored one or more mutations that confer some degree of susceptibility to maraviroc. In another study, Araújo and coworkers [ 18 ] reported that most of the resistance-associated mutations in ARV-naïve patients occur in subtype C compared with subtype B strains.…”