British HIV Association guidelines for antiretroviral treatment of HIV-2-positive individuals 2010.

British HIV Association (BHIVA), BHIVA Secretariat, Mediscript Ltd, London, UK.
HIV Medicine (Impact Factor: 3.45). 11/2010; 11(10):611-9. DOI: 10.1111/j.1468-1293.2010.00889.x
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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.
    Antimicrobial Agents and Chemotherapy 06/2013; · 4.57 Impact Factor
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    ABSTRACT: Few 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 response in adults.
    BMC Infectious Diseases 08/2014; 14(1):461. · 2.56 Impact Factor
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    ABSTRACT: BACKGROUND: HIV-2 is endemic in West Africa. There is a lack of evidence-based guidelines on the diagnosis, management and antiretroviral therapy (ART) for HIV-2 or HIV-1/HIV-2 dual infections. Because of these issues, we designed a West African collaborative cohort for HIV-2 infection within the framework of the International epidemiological Databases to Evaluate AIDS (IeDEA). METHODS: We collected data on all HIV-2 and HIV-1/HIV-2 dually seropositive patients (both ARV-naive and starting ART) and followed-up in clinical centres in the IeDEA-WA network including a total of 13 clinics in five countries: Benin, Burkina-Faso Côte d'Ivoire, Mali, and Senegal, in the West Africa region. RESULTS: Data was merged for 1,754 patients (56% female), including 1,021 HIV-2 infected patients (551 on ART) and 733 dually seropositive for both HIV-1 and HIV 2 (463 on ART). At ART initiation, the median age of HIV-2 patients was 45.3 years, IQR: (38.3-51.7) and 42.4 years, IQR (37.0-47.3) for dually seropositive patients (p = 0.048). Overall, 16.7% of HIV-2 patients on ART had an advanced clinical stage (WHO IV or CDC-C). The median CD4 count at the ART initiation is 166 cells/mm3, IQR (83-247) among HIV-2 infected patients and 146 cells/mm3, IQR (55-249) among dually seropositive patients. Overall, in ART-treated patients, the CD4 count increased 126 cells/mm3 after 24 months on ART for HIV-2 patients and 169 cells/mm3 for dually seropositive patients. Of 551 HIV-2 patients on ART, 5.8% died and 10.2% were lost to follow-up during the median time on ART of 2.4 years, IQR (0.7-4.3). CONCLUSIONS: This large multi-country study of HIV-2 and HIV-1/HIV-2 dual infection in West Africa suggests that routine clinical care is less than optimal and that management and treatment of HIV-2 could be further informed by ongoing studies and randomized clinical trials in this population.
    PLoS ONE 06/2013; 8(6):e66135. · 3.53 Impact Factor

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