Emergence of Multiclass Drug-Resistance in HIV-2 in Antiretroviral-Treated Individuals in Senegal: Implications for HIV-2 Treatment in Resouce-Limited West Africa

Department of Medicine, School of Medicine, University of Washington, Seattle, WA 98195, USA.
Clinical Infectious Diseases (Impact Factor: 9.42). 03/2009; 48(4):476-83. DOI: 10.1086/596504
Source: PubMed

ABSTRACT 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.
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.
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).
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.

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    ABSTRACT: g Protease inhibitor (PI)-based antiretroviral therapy (ART) can effectively suppress HIV-2 plasma load and increase CD4 counts; however, not all PIs are equally active against HIV-2, and few data exist to support second-line therapy decisions. To identify therapeutic options for HIV-2 patients failing ART, we evaluated the frequency of PI resistance-associated amino acid changes in HIV-2 sequences from a cohort of 43 Senegalese individuals receiving unboosted indinavir (n ‫؍‬ 18 subjects)-, lopinavir/ritona-vir (n ‫؍‬ 4)-, or indinavir and then lopinavir/ritonavir (n ‫؍‬ 21)-containing ART. Common protease substitutions included V10I, V47A, I54M, V71I, I82F, I84V, L90M, and L99F, and most patients harbored viruses containing multiple changes. Based on geno-typic data, we constructed a panel of 15 site-directed mutants of HIV-2 ROD9 containing single-or multiple-treatment-associated amino acid changes in the protease-encoding region of pol. We then quantified the susceptibilities of the mutants to the HIV-2 "active" PIs saquinavir, lopinavir, and darunavir using a single-cycle assay. Relative to wild-type HIV-2, the V47A mutant was resistant to lopinavir (6.3-fold increase in the mean 50% effective concentration [EC 50 ]), the I54M variant was resistant to darunavir and lopinavir (6.2-and 2.7-fold increases, respectively), and the L90M mutant was resistant to saquinavir (3.6-fold increase). In addition, the triple mutant that included I54M plus I84V plus L90M was resistant to all three PIs (31-, 10-, and 3.8-fold increases in the mean EC 50 for darunavir, saquinavir, and lopinavir, respectively). Taken together, our data demonstrate that PI-treated HIV-2 patients frequently harbor viruses that exhibit complex patterns of PI cross-resistance. These findings sug-gest that sequential PI-based regimens for HIV-2 treatment may be ineffective. H IV-2 is endemic in West Africa and affects one to two million people worldwide (1). Despite the relatively protracted course of HIV-2 infection, characterized by a lower plasma viral load, a lower rate of CD4 ϩ T cell count decline and a much longer asymptomatic stage compared to HIV-1 (2, 3), substantial num-bers of HIV-2-infected individuals eventually progress to AIDS and may benefit from antiretroviral therapy (ART) (4). Several features that distinguish HIV-2 from HIV-1 warrant special con-sideration when choosing treatment regimens. HIV-2 is intrinsi-cally resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI) and the fusion inhibitor enfuvirtide (T-20) (5), and mu-tations conferring broad resistance to nucleoside/nucleotide re-verse transcriptase inhibitors (NRTI) are frequently observed in HIV-2 sequences from patients receiving ART (6). Although an increasing body of evidence supports the utility of integrase strand transfer inhibitors (INSTI) against HIV-2 (7), these compounds are not routinely available in resource-limited settings. These lim-itations present major challenges to HIV-2 treatment, particularly in the areas in which HIV-2 is most prevalent. Although antiretroviral protease inhibitors (PIs) can be used effectively to treat HIV-2, HIV-1 and HIV-2 also exhibit impor-tant differences in their susceptibilities to these agents. Culture-based studies indicate that saquinavir (SQV), lopinavir (LPV), and darunavir (DRV) are potent inhibitors of wild-type HIV-2 replication, with 50% effective concentrations (EC 50 s) compara-ble to those seen with HIV-1 (8, 9), and that HIV-2 is resistant to amprenavir (APV) (5, 8–11) and atazanavir (ATV) (8, 11). Two small-scale observational studies support the clinical use of ritonavir-boosted lopinavir (LPV/r) for HIV-2 treatment (12, 13), whereas regimens containing ritonavir-boosted ATV or un-boosted PIs lead to high rates of immunovirologic failure and drug resistance (14–16). Based on these findings, current treatment guidelines from the United States, Great Britain, and France rec-ommend the use of LPV/r, SQV/r, or DRV/r for HIV-2-infected individuals (17–20). However, regimens containing these PIs have yet to be evaluated against HIV-2 in randomized clinical trials, and information needed to guide second-line treatment is lacking. In addition, the genetic pathways leading to PI resistance in HIV-2 remain poorly characterized.
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    ABSTRACT: BackgroundFew data are available on antiretroviral therapy (ART) response among HIV-2 infected patients. We conducted a systematic review on treatment outcomes among HIV-2 infected patients on ART, focusing on the immunological and virological responses in adults.MethodsData were extracted from articles that were selected after screening of PubMed/MEDLINE up to November 2012 and abstracts of the 1996–2012 international conferences. Observational cohorts, clinical trials and program reports were eligible as long as they reported data on ART response (clinical, immunological or virological) among HIV-2 infected patients. The determinants investigated included patients’ demographic characteristics, CD4 cell count at baseline and ART received.ResultsSeventeen reports (involving 976 HIV-2 only and 454 HIV1&2 dually reactive patients) were included in the final review, and the analysis presented in this report are related to HIV-2 infected patients only. There was no randomized controlled trial and only two cohorts had enrolled more than 100 HIV-2 only infected patients. The median CD4 count at ART initiation was 165 cells/mm3, [IQR; 137–201] and the median age at ART initiation was 44 years (IQR: 42–48 years). Ten studies included 103 patients treated with three nucleoside reverse transcriptase inhibitors (NRTI). Protease inhibitor (PI) based regimens were reported by 16 studies. Before 2009, the most frequent PIs used were Nelfinavir and Indinavir, whereas it was Lopinavir/ritonavir thereafter. The immunological response at month-12 was reported in six studies and the mean CD4 cell count increase was +118 cells/μL (min-max: 45–200 cells/μL).ConclusionOverall, clinical and immuno-virologic outcomes in HIV-2 infected individuals treated with ART are suboptimal. There is a need of randomized controlled trials to improve the management and outcomes of people living with HIV-2 infection.
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