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 detectable ARV resistance had undetectable plasma HIV-2 RNA loads (<1.4 log10 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 log10 copies/mL [range, <1.4 to 2.6 log10 copies/mL] vs. <1.4 log10 copies/mL [range, <1.4 to 1.6 log10 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.

Cell-Associated Viral Burden Provides Evidence of Ongoing Viral Replication in Aviremic HIV-2-Infected Patients

“…A rapid emergence of mutations potentially associated with drug resistance has been reported for HIV-2 ϩ patients under ART (25,29,41). We confirmed the presence of mutations in the reverse transcriptase and protease in our ART-treated HIV-2 cohort (Table 4).…”

Mutation V111I in HIV-2 Reverse Transcriptase Increases the Fitness of the Nucleoside Analogue-Resistant K65R and Q151M Viruses

“…This could be due to differences in the assay used to determine drug susceptibility. Although there was no evidence for ABC resistance mediated by K65R in these in vitro studies, in vivo, the mutation was reported to be selected in HIV-2-infected patients experiencing virological failure while receiving an ABC-containing regimen (14,15,20). In both in vitro studies, mutation K65R was introduced in the HIV-2 ROD9 background, which suggests that variations or mutations present in the patient isolates contribute to resistance mediated by the K65R mutation.…”

“…In HIV-2 patients failing therapy, V111I was previously reported to be coselected with mutation Q151M (14,15,20). Mutation Q151M alone was suggested to confer resistance to d4T and ABC, whereas resistance to other NRTIs would involve the coselection of V111I (20).…”

“…Several studies suggest that HIV-1 and HIV-2 evolve NRTI resistance by different mutational pathways. Although relying on limited amounts of genotypic data for HIV-2, three key resistance mutations, K65R, Q151M, and M184V, were reported to be associated with drug resistance (12)(13)(14)(15). The K65R and Q151M substitutions are more common in HIV-2 than in HIV-1 and often appear together with M184V in patients who received NRTI therapy.…”

“…For instance, mutation V111I was reported to be coselected with mutation Q151M in HIV-2 patients failing therapy (14,15,20). A study using patient-derived HIV-2 isolates suggested that Q151M alone confers resistance only to stavudine (d4T) and abacavir (ABC), whereas resistance to other NRTIs involved the coselection of V111I (20).…”