Durable Efficacy and Safety of Raltegravir Versus Efavirenz When Combined With Tenofovir/Emtricitabine in Treatment-Naive HIV-1–Infected Patients : Final 5-Year Results From STARTMRK

Q1Q1Artículo original77-85Background: STARTMRK, a phase III noninferiority trial of raltegravir-based versus efavirenz-based therapy in treatment-naive patients, remained blinded until its conclusion at 5 years. We now report the final study results. Methods: Previously untreated patients without baseline resistance to efavirenz, tenofovir, or emtricitabine were eligible for a randomized study of tenofovir/emtricitabine plus either raltegravir or efavirenz. Yearly analyses were planned, with primary and secondary end points stipulated at weeks 48 and 96, respectively. The primary efficacy outcome was the percentage of patients with viral RNA (vRNA) levels <50 copies per milliliter counting noncompleters as failures (NC=F). Changes from baseline CD4 count were computed using an observed-failure approach to missing data. No formal hypotheses were formulated for testing at week 240. Results: Overall, 71 of 281 raltegravir recipients (25%) and 98 of 282 efavirenz recipients (35%) discontinued the study; discontinuations due to adverse events occurred in 14 (5%) and 28 (10%) patients in the respective groups. In the primary NC=F efficacy analysis at week 240, 198 of 279 (71.0%) raltegravir recipients and 171 of 279 (61.3%) efavirenz recipients had vRNA levels <50 copies per milliliter, yielding a treatment difference {[INCREMENT] [95% confidence interval (CI)] = 9.5 (1.7 to 17.3)}. Generally comparable between-treatment differences were seen in both the protocol-stipulated sensitivity analyses and the prespecified subgroup analyses. The mean (95% CI) increments in baseline CD4 counts at week 240 were 374 and 312 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [[INCREMENT] (95% CI) = 62 (22 to 102)]. Overall, significantly fewer raltegravir than efavirenz recipients experienced neuropsychiatric side effects (39.1% vs 64.2%, P < 0.001) or drug-related clinical adverse events (52.0% vs 80.1%, P < 0.001). Conclusions: In this exploratory analysis of combination therapy with tenofovir/emtricitabine in treatment-naive patients at week 240, vRNA suppression rates and increases in baseline CD4 counts were significantly higher in raltegravir than efavirenz recipients. Over the entire study, fewer patients experienced neuropsychiatric and drug-related adverse events in the raltegravir group than in the efavirenz group. Based on better virologic and immunologic outcomes after 240 weeks, raltegravir/tenofovir/emtricitabine seemed to have superior efficacy compared with efavirenz/tenofovir/emtricitabine

Culturally-adapted and audio-technology assisted HIV/AIDS awareness and education program in rural Nigeria: a cohort study

Background: HIV-awareness programs tailored toward the needs of rural communities are needed. We sought to quantify change in HIV knowledge in three rural Nigerian villages following an integrated culturally adapted and technology assisted educational intervention. Methods: A prospective 14-week cohort study was designed to compare short-term changes in HIV knowledge between seminar-based education program and a novel program, which capitalized on the rural culture of small-group oral learning and was delivered by portable digital-audio technology. Results: Participants were mostly Moslem (99%), male (53.5%), with no formal education (55%). Baseline HIV knowledge was low (\u3c 80% correct answers for 9 of the 10 questions). Knowledge gain was higher (p \u3c 0.0001 for 8 of 10 questions) in the integrated culturally adapted and technology-facilitated (n = 511) compared with the seminar-based (n = 474) program. Conclusions: Baseline HIV-awareness was low. Culturally adapted, technology-assisted HIV education program is a feasible cost-effective method of raising HIV awareness among low-literacy rural communities

Screening for UGT1A1 Genotype in Study A5257 Would Have Markedly Reduced Premature Discontinuation of Atazanavir for Hyperbilirubinemia

Background. Some patients are not prescribed atazanavir because of concern about possible jaundice. Atazanavir-associated hyperbilirubinemia correlates with UGT1A1 rs887829 genotype. We examined bilirubin-related discontinuation of atazanavir in participants from AIDS Clinical Trials Group Study A5257. Methods. Discriminatory properties of UGT1A1 T/T genotype for predicting bilirubin-related atazanavir discontinuation through 96 weeks after antiretroviral initiation were estimated. Results. Genetic analyses involved 1450 participants, including 481 who initiated randomized atazanavir/ritonavir. Positive predictive values of rs887829 T/T for bilirubin-related discontinuation of atazanavir (with 95% confidence intervals [CIs]) were 20% (CI, 9%–36%) in Black, 60% (CI, 32%–84%) in White, and 29% (CI, 8%–58%) in Hispanic participants; negative predictive values were 97% (CI, 93%–99%), 95% (CI, 90%–98%), and 97% (CI, 90%–100%), respectively. Conclusions. Bilirubin-related discontinuation of atazanavir was rare in participants not homozygous for rs887829 T/T, regardless of race or ethnicity. We hypothesize that the higher rate of discontinuation among White participants homozygous for rs887829 T/T may reflect differences in physical manifestations of jaundice by race and ethnicity. Selective avoidance of atazanavir initiation among individuals with T/T genotypes would markedly reduce the likelihood of bilirubin-related discontinuation of atazanavir while allowing atazanavir to be prescribed to the majority of individuals. This genetic association will also affect atazanavir/cobicistat

Efficacy and safety of raltegravir for treatment of HIV for 5 years in the BENCHMRK studies: Final results of two randomised, placebo-controlled trials

BACKGROUND: Two randomised, placebo-controlled trials-BENCHMRK-1 and BENCHMRK-2-investigated the efficacy and safety of raltegravir, an HIV-1 integrase strand-transfer inhibitor. We report final results of BENCHMRK-1 and BENCHMRK-2 combined at 3 years (the end of the double-blind phase) and 5 years (the end of the study). METHODS: Integrase-inhibitor-naive patients with HIV resistant to three classes of drug and who were failing antiretroviral therapy were enrolled. Patients were randomly assigned (2:1) to raltegravir 400 mg twice daily or placebo, both with optimised background treatment. Patients and investigators were masked to treatment allocation until week 156, after which all patients were offered open-label raltegravir until week 240. The primary endpoint was previously assessed at 16 weeks. We assessed long-term efficacy with endpoints of the proportion of patients with an HIV viral load of less than 50 copies per mL and less than 400 copies per mL, and mean change in CD4 cell count, at weeks 156 and 240. FINDINGS: 1012 patients were screened for inclusion. 462 were treated with raltegravir and 237 with placebo. At week 156, 51% in the raltegravir group versus 22% in the placebo group (non-completer classed as failure) had viral loads of less than 50 copies per mL, and 54% versus 23% had viral loads of less than 400 copies per mL. Mean CD4 cell count increase (analysed by an observed failure approach) was 164 cells per μL versus 63 cells per μL. After week 156, 251 patients (54%) from the raltegravir group and 47 (20%) from the placebo group entered the open-label raltergravir phase; 221 (47%) versus 44 (19%) completed the entire study. At week 240, viral load was less than 50 copies per mL in 193 (42%) of all patients initially assigned to raltegravir and less than 400 copies per mL in 210 (45%); mean CD4 cell count increased by 183 cells per μL. Virological failure occurred in 166 raltegravir recipients (36%) during the double-blind phase and in 17 of all patients (6%) during the open-label phase. The most common drug-related adverse events at 5 years in both groups were nausea, headache, and diarrhoea, and occurred in similar proportions in each group. Laboratory test results were similar in both treatment groups and showed little change after year 2. INTERPRETATION: Raltegravir has a favourable long-term efficacy and safety profile in integrase-inhibitor-naive patients with triple-class resistant HIV in whom antiretroviral therapy is failing. Raltegravir is an alternative for treatment-experienced patients, particularly those with few treatment options

The Team Keck Treasury Redshift Survey of the GOODS-North Field

We report the results of an extensive imaging and spectroscopic survey in the GOODS-North field completed using DEIMOS on the Keck II telescope. Observations of 2018 targets in a magnitude-limited sample of 2911 objects to R=24.4 yield secure redshifts for a sample of 1440 galaxies and AGN plus 96 stars. In addition to redshifts and associated quality assessments, our catalog also includes photometric and astrometric measurements for all targets detected in our R-band imaging survey of the GOODS-North region. We investigate various sources of incompleteness and find the redshift catalog to be 53% complete at its limiting magnitude. The median redshift of z=0.65 is lower than in similar deep surveys because we did not select against low-redshift targets. Comparison with other redshift surveys in the same field, including a complementary Hawaii-led DEIMOS survey, establishes that our velocity uncertainties are as low as 40 km/s for red galaxies and that our redshift confidence assessments are accurate. The distributions of rest-frame magnitudes and colors among the sample agree well with model predictions out to and beyond z=1. We will release all survey data, including extracted 1-D and sky-subtracted 2-D spectra, thus providing a sizable and homogeneous database for the GOODS-North field which will enable studies of large scale structure, spectral indices, internal galaxy kinematics, and the predictive capabilities of photometric redshifts.Comment: 17 pages, 18 figures, submitted to AJ; v2 minor changes; see survey database at http://www2.keck.hawaii.edu/realpublic/science/tksurvey

Antiretroviral Therapy Initiated During Acute HIV Infection Fails to Prevent Persistent T-Cell Activation

Initiation of ART during acute HIV-1 infection may prevent persistent immune activation. We analyzed longitudinal CD38+HLA-DR+ CD8+ T cell percentages in 31 acutely infected individuals who started early (median 43 days since infection) and successful ART, and maintained viral suppression through 96 weeks. Pre-therapy a median of 72.6% CD8+ T cells were CD38+HLA-DR+, and while this decreased to 15.6% by 96 weeks, it remained substantially higher than seronegative controls (median 8.9%, p=0.008). Shorter time to suppression predicted lower activation at 96 weeks. These results support the hypothesis that very early events in HIV-1 pathogenesis may result in prolonged immune dysfunction

Drought-Induced, Punctuated Loss of Freshwater Mussels Alters Ecosystem Function Across Temporal Scales

Punctuated, mass mortality events are increasing for many animal taxa and are often related to climatic extremes such as drought. Freshwater mussels are experiencing increased mass mortality events linked to hydrologic drought. Because mussels play important functional roles in rivers it is important to understand the ecosystem effects of these die-offs. Here, we address how mass mortality events of mussels caused by drought may impact stream ecosystem function. We first present a conceptual model, based on the literature, of how mussel mass mortality should affect different ecosystem functions across various ecological time scales, from hours to decades. Next, we highlight two case studies of drought-linked, mussel-mass mortality events from rivers in the southern U.S. We then present the results of an experiment we performed quantifying the ecosystem effects of a punctuated mussel die-off. Finally, we combine our experimental results with field data from a recent mussel die-off to predict how mussel losses will influence ecosystem function. Based on the presented case studies, our mesocosm experiment, and our extrapolated nutrient pulse due to a mussel die-off, we conclude that stream ecosystems are extensively altered following mussel mass mortality events. Mussel loss is governed by drought severity, location within the river network, and species-specific drought tolerances. In the short term, decomposing carrion from mussel die-offs releases a large pulse of nutrients into the water which stimulates food web productivity. In the long term, the overall loss of mussel biomass, and the loss of functional traits as more sensitive species decline, leads to decreases in ecosystem function which may take decades to recover. Drought and human demand for water will make mussel die-offs more likely in the future and it is unlikely that drought sensitive species will recover without changes in water management and restoration of populations through mussel propagation. Our research provides an example of how the loss of an abundant, long-lived organism has cascading and long-term impacts on ecosystems.Open Access fees paid for in whole or in part by the University of Oklahoma LibrariesYe

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial

In a double-blind trial, Rajesh Gandhi and colleagues detect no significant reduction in viral load after people with low-level HIV viremia added an integrase inhibitor to their treatment regimen

Comparison of the Metabolic Effects of Ritonavir-Boosted Darunavir or Atazanavir Versus Raltegravir, and the Impact of Ritonavir Plasma Exposure: ACTG 5257

Background. Metabolic effects following combination antiretroviral therapy (cART) vary by regimen type. Changes in metabolic effects were assessed following cART in the AIDS Clinical Trials Group (ACTG) A5257 study, and correlated with plasma ritonavir trough concentrations (C24)