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

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.

Proximate and ultimate causes of reproductive suppression among female yellow baboons at Mikumi National Park, Tanzania.

Attack coalitions, whereby two or more individuals attack another animal simultaneously, were studied in 53 sexually mature female baboons from one small and two large troops at Mikumi National Park, Tanzania. For 14 months, three observers recorded coalition behavior throughout the day, using focal group sampling on a behavior-dependent basis. Coalition rates were considerably greater in the two large troops than in the small troop, and primarily involved natal females rather than males. Coalition frequencies corresponded closely to measures of reproductive synchrony, both within and between troops. Involvement in attack coalition behavior depended on the reproductive states and ranks of both attackers and recipients. The first few females to give birth in the cohort received particularly high amounts of coalition aggression just before and immediately after giving birth. Receipt of attack coalitions was significantly associated with an increased number of cycles to conception and longer interbirth intervals, as well spontaneous abortion, premature birth, and prolonged gestation. A parallel study on survivorship patterns of immature baboons at Mikumi provided evidence for ultimate cause of the observed coalition patterns. These combined results suggest that attack coalition behavior is a form of reproductive competition whereby females attempt to suppress the reproduction of others at predictably competitive times and thereby reduce the competition their own infants face from the time they are weaned.

HIV-2 integrase variation in integrase inhibitor-naïve adults in Senegal, West Africa.

BACKGROUND: Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance. METHODS: We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2-infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1. RESULTS: No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein. CONCLUSION: Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at "secondary" HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2-infected patients.

Characteristics and presenting complaints of outpatients with undiagnosed HIV infection: potential utility in selecting subjects for HIV testing.

HIV testing of individuals presenting to outpatient medical clinics has generally been based upon a selection system, with testing limited to those having signs or symptoms previously found associated with HIV-1 infection among hospitalized patients. However, little is known about the efficacy of this approach, particularly in Africa. Among patients presenting to a large outpatient infectious disease clinic in Dakar, Senegal, the utility of using specific demographic and behavioral characteristics and individual presenting complaints to identify individuals with previously undiagnosed HIV-1 or HIV-2 infection was examined. Using a simple statistical approach, a composite screening rule was estimated to identify subjects with the highest probability of testing HIV positive, ie, patients who would most benefit from HIV testing. Using the presenting complaint allows identification of 83% of HIV-infected women by testing only 35% of women presenting to the clinic. Similarly, using the presenting complaint and various demographic and behavioral characteristics, it was possible to identify 84% of HIV-infected men by screening 40% of men presenting to the clinic. This study suggests that this method might provide a cost-effective approach that permits limited screening resources to be spent in a way that maximizes individual and societal benefit.