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TPV/r had superior antiviral activity and increased immunologic benefits, compared with CPI/r, at week 24 among treatment-experienced patients infected with multidrug-resistant HIV-1.

SummaryBackgroundCross-resistance after first-line antiretroviral therapy (ART) failure is expected to impair activity of nucleoside reverse-transcriptase inhibitors (NRTIs) in second-line therapy for patients with HIV, but evidence for the effect of cross-resistance on virological outcomes is limited. We aimed to assess the association between the activity, predicted by resistance testing, of the NRTIs used in second-line therapy and treatment outcomes for patients infected with HIV.MethodsWe did an observational analysis of additional data from a published open-label, randomised trial of second-line ART (EARNEST) in sub-Saharan Africa. 1277 adults or adolescents infected with HIV in whom first-line ART had failed (assessed by WHO criteria with virological confirmation) were randomly assigned to a boosted protease inhibitor (standardised to ritonavir-boosted lopinavir) with two to three NRTIs (clinician-selected, without resistance testing); or with raltegravir; or alone as protease inhibitor monotherapy (discontinued after week 96). We tested genotypic resistance on stored baseline samples in patients in the protease inhibitor and NRTI group and calculated the predicted activity of prescribed second-line NRTIs. We measured viral load in stored samples for all patients obtained every 12–16 weeks. This trial is registered with Controlled-Trials.com (number ISRCTN 37737787) and ClinicalTrials.gov (number NCT00988039).FindingsBaseline genotypes were available in 391 (92%) of 426 patients in the protease inhibitor and NRTI group. 176 (89%) of 198 patients prescribed a protease inhibitor with no predicted-active NRTIs had viral suppression (viral load <400 copies per mL) at week 144, compared with 312 (81%) of 383 patients in the protease inhibitor and raltegravir group at week 144 (p=0·02) and 233 (61%) of 280 patients in the protease inhibitor monotherapy group at week 96 (p<0·0001). Compared with results with no active NRTIs, 95 (85%) of 112 patients with one predicted-active NRTI had viral suppression (p=0·3) and 20 (77%) of 26 patients with two or three active NRTIs had viral suppression (p=0·08). Over all follow-up, greater predicted NRTI activity was associated with worse viral load suppression (global p=0·0004).InterpretationGenotypic resistance testing might not accurately predict NRTI activity in protease inhibitor-based second-line ART. Our results do not support the introduction of routine resistance testing in ART programmes in low-income settings for the purpose of selecting second-line NRTIs.FundingEuropean and Developing Countries Clinical Trials Partnership, UK Medical Research Council, Institito de Salud Carlos III, Irish Aid, Swedish International Development Cooperation Agency, Instituto Superiore di Sanita, WHO, Merck.

.5.01; Virco). A control group of patients failing on other regimens was similarly tested. Sixty-one samples were analyzed, 40 of which belonged to patients failing on RAL-containing regimens. Full RAL susceptibility was found in 20/21 controls, while susceptibility to EVG was diminished in 8 subjects, with a median fold change (FC) of 2. T he introduction of highly active antiretroviral therapy (HAART) has transformed the prognosis of HIV-positive patients, with dramatic improvements in survival. However, selection for drug resistance still represents a major challenge and promotes switches in therapeutic regimens for a substantial proportion of patients (3). Virologic failure with some antiretroviral drugs is associated with cross-resistance to agents within the same family, limiting rescue therapeutic options (16). Nevirapine and efavirenz are good examples of crossresistance between members of the same drug family, almost completely sharing resistance patterns. To a lesser extent, this also occurs with failures of some protease inhibitors (12) and nucleoside analogues.Integrase inhibitors (INIs) are a new and promising drug family for the treatment of HIV infection. Raltegravir (RAL) is the first-in-class approved drug for clinical use in both treatmentnaïve (11) and treatment-experienced (19) individuals. Elvitegravir (EVG) will most likely be the second INI compound to be marketed (4). Resistance to INIs has been shown to be driven by changes located mainly in the central domain of the viral integrase. The results of clinical trials and clinical experience have highlighted that failure on RAL-containing regimens is generally driven by the selection of the mutations Y143RHC, Q148HRK, and/or N155H, often accompanied by secondary changes (G140SA, E138K, and L74M, etc.) (2). However, a relatively high proportion of patients does not show such changes upon virologic failure on RAL-containing regimens. Although unidentified resistance mutations might exist, a recent report highlighted that the absence of INI resistance mutations in these individuals is explained mainly by poor drug compliance, given that RAL plasma levels were undetectable in most of them (6).Information about resistance to EVG in vivo is scarce. In the phase II GS-US-183-105 study (13), 28 individuals failed EVG after 24 weeks of treatment. Overall, 39% of them selected the E92Q mutation, 32% selected the Q148HRK mutation, and 25% selected the N155H mutation. Accordingly, broad cross-resistance between RAL and EVG should be expected. The aim of our study was to characterize RAL phenotypic susceptibilities in samples from a group of patients experiencing RAL failure, exploring whether mutations not previously involved in RAL resistance might be recognized and the extent of phenotypic cross-resistance to EVG. MATERIALS AND METHODSStudy population. HIV-1-infected individuals treated at several clinics in Spain who experienced virological failure on a RAL-containing antiretroviral regimen were identified during 2009. Virological failure was defined...

We studied the prevalence of and risk factors for Staphylococcus aureus nasal colonization in HIV-positive outpatients in Singapore. Overall prevalence was 23% (45 of 195), with 3% (6 of 195) being MRSA. Recent antibiotic use and hospitalization were independent predictors of MRSA colonization. Isolates were genotypically identical to our hospital's inpatient circulating strain.

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SummaryBackgroundMillions of HIV-infected people worldwide receive antiretroviral therapy (ART) in programmes using WHO-recommended standardised regimens. Recent WHO guidelines recommend a boosted protease inhibitor plus raltegravir as an alternative second-line combination. We assessed whether this treatment option offers any advantage over the standard protease inhibitor plus two nucleoside reverse-transcriptase inhibitors (NRTIs) second-line combination after 144 weeks of follow-up in typical programme settings.MethodsWe analysed the 144-week outcomes at the completion of the EARNEST trial, a randomised controlled trial done in HIV-infected adults or adolescents in 14 sites in five sub-Saharan African countries (Uganda, Zimbabwe, Malawi, Kenya, Zambia). Participants were those who were no longer responding to non-NRTI-based first-line ART, as assessed with WHO criteria, confirmed by viral-load testing. Participants were randomly assigned to receive a ritonavir-boosted protease inhibitor (lopinavir 400 mg with ritonavir 100 mg, twice per day) plus two or three clinician-selected NRTIs (protease inhibitor plus NRTI group), protease inhibitor plus raltegravir (400 mg twice per day; protease inhibitor plus raltegravir group), or protease inhibitor monotherapy (plus raltegravir induction for first 12 weeks, re-intensified to combination therapy after week 96; protease inhibitor monotherapy group). Randomisation was by computer-generated randomisation sequence, with variable block size. The primary outcome was viral load of less than 400 copies per mL at week 144, for which we assessed non-inferiority with a one-sided α of 0·025, and superiority with a two-sided α of 0·025. The EARNEST trial is registered with ISRCTN, number 37737787.FindingsBetween April 12, 2010, and April 29, 2011, 1837 patients were screened for eligibility, of whom 1277 patients were randomly assigned to an intervention group. In the primary (complete-case) analysis at 144 weeks, 317 (86%) of 367 in the protease inhibitor plus NRTI group had viral loads of less than 400 copies per mL compared with 312 (81%) of 383 in the protease inhibitor plus raltegravir group (p=0·07; lower 95% confidence limit for difference 10·2% vs specified non-inferiority margin 10%). In the protease inhibitor monotherapy group, 292 (78%) of 375 had viral loads of less than 400 copies per mL; p=0·003 versus the protease inhibitor plus NRTI group at 144 weeks. There was no difference between groups in serious adverse events, grade 3 or 4 adverse events (total or ART-related), or events that resulted in treatment modification.InterpretationProtease inhibitor plus raltegravir offered no advantage over protease inhibitor plus NRTI in virological efficacy or safety. In the primary analysis, protease inhibitor plus raltegravir did not meet non-inferiority criteria. A regimen of protease inhibitor with NRTIs remains the best standardised second-line regimen for use in programmes in resource-limited settings.FundingEuropean and Developing Countries Clinical Trials Partnership (...