BackgroundHypersensitivity reaction to abacavir is strongly associated with the presence of the HLA-B*5701 allele. This study was designed to establish the effectiveness of prospective HLA-B*5701 screening to prevent the hypersensitivity reaction to abacavir. MethodsThis double-blind, prospective, randomized study involved 1956 patients from 19 countries, who were infected with human immunodeficiency virus type 1 and who had not previously received abacavir. We randomly assigned patients to undergo prospective HLA-B*5701 screening, with exclusion of HLA-B*5701-positive patients from abacavir treatment (prospective-screening group), or to undergo a standard-of-care approach of abacavir use without prospective HLA-B*5701 screening (control group). All patients who started abacavir were observed for 6 weeks. To immunologically confirm, and enhance the specificity of, the clinical diagnosis of hypersensitivity reaction to abacavir, we performed epicutaneous patch testing with the use of abacavir. ResultsThe prevalence of HLA-B*5701 was 5.6% (109 of 1956 patients). Of the patients receiving abacavir, 72% were men, 84% were white, and 18% had not previously received antiretroviral therapy. Screening eliminated immunologically confirmed hypersensitivity reaction (0% in the prospective-screening group vs. 2.7% in the control group, P<0.001), with a negative predictive value of 100% and a positive predictive value of 47.9%. Hypersensitivity reaction was clinically diagnosed in 93 patients, with a significantly lower incidence in the prospective-screening group (3.4%) than in the control group (7.8%) (P<0.001). ConclusionsHLA-B*5701 screening reduced the risk of hypersensitivity reaction to abacavir. In predominantly white populations, similar to the one in this study, 94% of patients do not carry the HLA-B*5701 allele and are at low risk for hypersensitivity reaction to abacavir. Our results show that a pharmacogenetic test can be used to prevent a specific toxic effect of a drug. (ClinicalTrials.gov number, NCT00340080.) Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against the human immunodeficiency virus (HIV), available for oncedaily use in combination with other antiretroviral agents, that has shown efficacy, few drug interactions, and a favorable long-term toxicity profile. The most important adverse effect of abacavir that limits its use in therapy and mandates a high degree of clinical vigilance is an immunologically mediated hypersensitivity reaction affecting 5 to 8% of patients during the first 6 weeks of treatment. 2,3 Symptoms of a hypersensitivity reaction to abacavir include combinations of fever, rash, constitutional symptoms, gastrointestinal tract symptoms, and respiratory symptoms that become more severe with continued dosing. Immediate and permanent discontinuation of abacavir is mandated, resulting in a rapid reversal of symptoms. Subsequent rechallenge with abacavir is contraindicated, since it can result in a more severe, rapid, and potentially life-threatening reaction. 2 ...

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In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

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IntroductionDoravirine (DOR) is an investigational NNRTI (aka MK-1439) that retains activity against common NNRTI-resistant mutants. We have previously reported the Part 1 results from a two-part, randomized, double-blind, Phase IIb study in ART-naïve HIV-1-positive patients [1]. At doses of 25, 50, 100 and 200 mg qd, DOR plus open-label tenofovir/emtricitabine (TDF/FTC) demonstrated potent antiretroviral activity comparable to EFV 600 mg qhs plus TDF/FTC and was generally well tolerated at week 24. DOR 100 mg was selected for use in patients continuing in Part 1 and those newly enrolled in Part 2.MethodsPatients receiving DOR 25, 50 or 200 mg in Part 1 were switched to 100 mg after dose selection. In Part 2, 132 additional patients were randomized 1:1 to DOR 100 mg qd or EFV 600 mg qhs (each with TDF/FTC). We present week 48 efficacy and safety results for all patients in Part 1, and early (week 8) CNS tolerability only for patients randomized to DOR 100 mg or to EFV in Parts 1 and 2 combined. The primary safety endpoint is the % of patients with pre-specified CNS events (all causality) by week 8 for DOR 100 mg qd vs EFV (Parts 1 + 2 combined).ResultsPart 1 week 48 efficacy and safety results are shown below.The most common DR clinical AEs in the DOR and EFV groups, respectively, were abnormal dreams (10.2%; 9.5%), nausea (7.8%; 2.4%), fatigue (7.2%; 4.8%), diarrhoea (4.8%; 9.5%) and dizziness (3.0%; 23.8%), and were generally mild to moderate. Part 1 + 2 Week 8 CNS Event Analysis: One hundred thirty-two patients were randomized in Part 2, 66 to DOR 100 mg and 66 to EFV. Combining Part 1 and 2, a total of 108 patients received DOR 100 mg and 108 received EFV. By week 8, at least one CNS AE was reported in 22.2% of the DOR group and 43.5% of the EFV group (p<0.001). The most common CNS AEs were dizziness (DOR 9.3%; EFV 27.8%), insomnia (6.5%; 2.8%), abnormal dreams (5.6%; 16.7%) and nightmares (5.6%; 8.3%).ConclusionsIn ART-naïve, HIV-1-positive patients also receiving TDF/FTC, DOR 100 mg qd demonstrated potent antiretroviral activity and immunological effect at week 48 and was generally safe and well tolerated. Patients who received DOR 100 mg qd had significantly fewer treatment-emergent CNS AEs by week 8 than those who received EFV.

Highly active antiretroviral therapy can be administered safely and effectively to children and adolescents in resource-limited settings. Lopinavir/ritonavir-containing highly active antiretroviral therapy is a safe, effective, and durable treatment option for antiretroviral drug-experienced older children and adolescents with advanced HIV disease.

Background: The safety and efficacy of doravirine were compared with that of efavirenz as initial treatment of adults living with HIV-1 infection (NCT01632345). Methods: A Phase IIb double-blind trial with participants stratified by screening HIV-1 RNA (≤ or >100,000 copies/ml) and randomized 1:1:1:1:1 to receive oncedaily doravirine (25, 50, 100 or 200 mg) or efavirenz 600 mg (Part I) for up to 96 weeks, with open-label tenofovir disoproxil fumarate 300 mg/emtricitabine 200 mg (TDF/FTC). After dose selection at week 24, doravirine 100 mg was provided to participants receiving the other doses of doravirine and additional participants were randomized 1:1 to receive once-daily doravirine 100 mg or efavirenz 600 mg for 96 weeks with TDF/FTC (Part II). Primary outcomes were the proportion of participants with HIV-1 RNA <40 copies/ml at week 24, and central nervous system (CNS) adverse events (AEs) by weeks 8 and 24 (Parts I+II combined). Results: 210 and 132 participants were randomized in Parts I and II, respectively, and 216 (108 on doravirine 100 mg, 108 on efavirenz) were evaluable for Parts I+II combined. At week 24, the proportion of participants with HIV-1 RNA <40 copies/ml was 72.9% for doravirine 100 mg and 73.1% for efavirenz (difference -0.5 [95% CI -12.3, 11.2]). In addition, CNS AEs were reported by 26.9% and 47.2% of doravirine and efavirenz recipients, respectively (difference -20.4 [95% CI -32.6, -7.5]; P=0.002). Conclusions: Doravirine 100 mg with TDF/FTC demonstrated similar antiretroviral activity and superior CNS safety compared with efavirenz 600 mg with TDF/FTC.