Emergence of multiclass drug-resistance in HIV-2 in antiretroviral-treated individuals in Senegal: implications for HIV-2 treatment in resouce-limited West Africa

Abstract

Background: The efficacy of various antiretroviral (ARV) therapy regimens for human immunodeficiency virus type 2 (HIV-2) infection remains unclear. HIV-2 is intrinsically resistant to the nonnucleoside reverse-transcriptase inhibitors and to enfuvirtide and may also be less susceptible than HIV-1 to some protease inhibitors (PIs). However, the mutations in HIV-2 that confer ARV resistance are not well characterized.

Methods: Twenty-three patients were studied as part of an ongoing prospective longitudinal cohort study of ARV therapy for HIV-2 infection in Senegal. Patients were treated with nucleoside reverse-transcriptase inhibitor (NRTI)- and PI (indinavir)-based regimens. HIV-2 pol genes from these patients were genotyped, and the mutations predictive of resistance in HIV-2 were assessed. Correlates of ARV resistance were analyzed.

Results: Multiclass drug-resistance mutations (NRTI and PI) were detected in strains in 30% of patients; 52% had evidence of resistance to at least 1 ARV class. The reverse-transcriptase mutations M184V and K65R, which confer high-level resistance to lamivudine and emtricitabine in HIV-2, were found in strains from 43% and 9% of patients, respectively. The Q151M mutation, which confers multinucleoside resistance in HIV-2, emerged in strains from 9% of patients. HIV-1-associated thymidine analogue mutations (M41L, D67N, K70R, L210W, and T215Y/F) were not observed, with the exception of K70R, which was present together with K65R and Q151M in a strain from 1 patient. Eight patients had HIV-2 with PI mutations associated with indinavir resistance, including K7R, I54M, V62A, I82F, L90M, L99F; 4 patients had strains with multiple PI resistance-associated mutations. The duration of ARV therapy was positively associated with the development of drug resistance (P = .02). Nine (82%) of 11 patients with HIV-2 with no [corrected] detectable ARV resistance had undetectable plasma HIV-2 RNA loads (<1.4 log(10) copies/mL), compared with 3 (25%) of 12 patients with HIV-2 with detectable ARV resistance (P = .009). Patients with ARV-resistant virus had higher plasma HIV-2 RNA loads, compared with those with non-ARV-resistant virus (median, 1.7 log(10) copies/mL [range, <1.4 to 2.6 log(10) copies/mL] vs. <1.4 log(10) copies/mL [range, <1.4 to 1.6 log(10) copies/mL]; P = .003).

Conclusions: HIV-2-infected individuals treated with ARV therapy in Senegal commonly have HIV-2 mutations consistent with multiclass drug resistance. Additional clinical studies are required to improve the efficacy of primary and salvage treatment regimens for treating HIV-2 infection.

Figure 1

Plasma HIV-2 RNA loads in patients with and without antiretroviral (ARV) resistance. Viral load data were log₁₀ transformed. Raw data (circles) and box plots are shown. Nine (82%) of 11 patients with virus strains without detectable ARV resistance and 3 (25%) of 12 patients with virus strains with detectable ARV resistance had HIV-2 RNA loads that were undetectable (UD; <1.4 log₁₀ copies/mL; set to 0; P = .003, by Wilcoxon rank-sum test).

Figure 2

Neighbor-joining phylogenetic tree of amino acid sequences of the HIV-2 pol gene. Clonal sequences from virus strains from 23 patients are shown. Reverse-transcriptase (RT) and protease (PR) resistance mutations in HIV-2 are shown. Twenty-two of 23 patients were infected with HIV-2 group A strains, and 1 patient was infected with an HIV-2 group B strain. Two patients infected with closely linked viruses (patients H2A14 and H2A25 [gray]) were married. HIV-2 reference sequence HIV-2 ROD (A.SN.85.ROD accession number M15390) is shown. WT, wild type (no RT or PR mutations).