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Islatravir (MK-8591) is a highly potent type 1 human immunodeficiency virus (HIV-1) nucleoside reverse transcriptase translocation inhibitor with a long intracellular half-life that is in development for the prevention and treatment of HIV-1. We conducted a randomized, double-blind, placebo-controlled, phase 1 trial in adults without HIV-1 infection. Participants received islatravir or placebo subdermal implants for 12 weeks and were monitored throughout this period and after implant removal. The co-primary end points were safety and tolerability of the islatravir implant and pharmacokinetics, including concentration at day 85, of islatravir triphosphate in peripheral blood mononuclear cells (PBMCs). Secondary end points included additional pharmacokinetic parameters for islatravir triphosphate in PBMCs and the plasma pharmacokinetic profile of islatravir. Based on preclinical data, two doses were assessed: 54 mg ( n  = 8, two placebo) and 62 mg ( n  = 8, two placebo). The most frequently reported adverse events were mild-to-moderate implant-site reactions (induration, hematoma, pain). Throughout the 12-week trial, geometric mean islatravir triphosphate concentrations were above a pharmacokinetic threshold of 0.05 pmol per 10 6 PBMCs, which was estimated to provide therapeutic reverse transcriptase inhibition (concentration at day 85 (percentage of geometric coefficient of variation): 54 mg, 0.135 pmol per 10 6 cells (27.3); 62 mg, 0.272 pmol per 10 6 cells (45.2)). Islatravir implants at both doses were safe and resulted in mean concentrations above the pharmacokinetic threshold through 12 weeks, warranting further investigation of islatravir implants as a potential HIV prevention strategy. A subdermal implant of the HIV-1 antiretroviral islatravir delivers sustained drug release over 12 weeks in humans.

Development of HIV-1 prevention methods is a global priority. In this randomized, controlled trial in sub-Saharan Africa, a vaginal ring containing the antiretroviral dapivirine was 27% effective in protecting against HIV-1 acquisition. More than half of the 35 million persons currently living with human immunodeficiency virus type 1 (HIV-1) infection are women. A majority of these women reside in sub-Saharan Africa, 1 a region that has some of the highest incidences of HIV-1 infection in any population worldwide. 2 – 4 The use of antiretroviral medications as pre-exposure prophylaxis is a promising approach to the prevention of HIV-1 acquisition. 5 Several clinical trials of the antiretroviral tenofovir showed such protection against HIV-1. 2 , 6 – 8 However, in three trials involving African women, adherence to tenofovir-containing pills and vaginal gels was low, and HIV-1 protection was not shown. . . .

The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3). In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum. Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy. clinicaltrials.gov NCT02245022.

Preventing HIV-1 infection, especially with female-controlled approaches, is a high priority. In this trial in South Africa and Uganda, a dapivirine vaginal ring was associated with a rate of acquisition of HIV-1 infection that was approximately 30% lower than that with placebo. In 2014, approximately 36.9 million people worldwide were living with human immunodeficiency virus (HIV) infection. 1 Rates of new HIV infection among adolescent girls and young women remain high in Eastern and Southern Africa, 2 which underscores the need for the development of safe and effective tools against HIV infection that women initiate themselves. 3 – 5 Self-inserted vaginal rings, which provide a sustained release of antiretroviral drugs over time, have the potential to offer women a prevention option that does not require daily or pericoital use. 6 The International Partnership for Microbicides (IPM) developed a monthly self-administered vaginal ring that contains the nonnucleoside reverse-transcriptase . . .

In this open-label, randomized trial conducted in seven sub-Saharan African countries, patients for whom an initial HIV-1 treatment regimen had failed were switched to a second-line regimen of either dolutegravir or darunavir plus either tenofovir or zidovudine. Dolutegravir was noninferior to darunavir and tenofovir was noninferior to zidovudine in their effects on viral suppression at 48 weeks.

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a “backbone” of two nucleoside reverse transcriptase inhibitors (NRTI) and a “base” of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

Appropriate second-line antiretroviral therapy for HIV infection is needed in resource-limited settings. In a comparison of three protease-inhibitor–based regimens in sub-Saharan Africa, the one that included nucleoside reverse-transcriptase inhibitors performed favorably. The public health approach of the World Health Organization (WHO), 1 together with large-scale donor funding, has enabled millions of adults and children in sub-Saharan Africa who are infected with the human immunodeficiency virus (HIV) to have access to lifesaving antiretroviral therapy. 2 The key principle is the use of simplified, standardized approaches that are feasible on a large scale in resource-limited settings, 1 , 3 including a first-line regimen of two nucleoside reverse-transcriptase inhibitors (NRTIs) plus one non-NRTI (NNRTI). In most settings, treatment is monitored clinically and with the use of CD4+ counts, with typically late detection of treatment failure, accompanied by substantial . . .

Background. Specific antiretroviral therapy (ART) medications and the severity of human immunodeficiency virus (HIV) disease before treatment contribute to bone mineral density (BMD) loss after ART initiation. Methods. We compared the percentage change in BMD over 96 weeks in 328 HIV-infected, treatment-naive individuals randomized equally to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) plus atazanavir/ritonavir (ATV/r), darunavir/ritonavir (DRV/r), or raltegravir (RAL). We also determined whether baseline levels of inflammation markers and immune activation were independently associated with BMD loss. Results. At week 96, the mean percentage changes from baseline in spine and hip BMDs were similar in the protease inhibitor (PI) arms (spine: -4.0% in the ATV/r group vs -3.6% in the DRV/r [P = .42]; hip: -3.9% in the ATV/r group vs -3.4% in the DRV/r group [P= .36]) but were greater in the combined PI arms than in the RAL arm (spine: -3.8% vs -1.8% [P < .001]; hip: -3.7% vs -2.4% [P = .005]). In multivariable analyses, higher baseline concentrations of high-sensitivity C-reactive protein, interleukin 6, and soluble CD14 were associated with greater total hip BMD loss, whereas markers of CD4 + T-cell senescence and exhaustion (CD4⁺ CD28⁻CD57⁺ PD1⁺) and CD4⁺ T-cell activation (CD4⁺ CD38⁺ HLA-DR⁺) were associated with lumbar spine BMD loss. Conclusions. BMD losses 96 weeks after ART initiation were similar in magnitude among patients receiving Pis, ATV/r, or DRV/r but lowest among those receiving RAL. Inflammation and immune activation/senescence before ART initiation independently predicted subsequent BMD loss.

Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir–ritonavir and lamivudine to triple treatment with lopinavir–ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir–ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference −1·2% [95% CI −9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223). Dual treatment with lopinavir–ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. AbbVie and Red Temática Cooperativa de Investigación en Sida.

Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this global, multicenter, prospective, randomized study, 1956 patients with HIV-1 infection who had not previously received abacavir were randomly assigned to undergo HLA-B*5701 screening or to receive the standard of care. Screening eliminated immunologically confirmed hypersensitivity reaction to abacavir in this predominantly white population. In this case, a pharmacogenetic test can prevent the toxic effects of this drug. Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this study of patients with HIV-1 infection, HLA-B*5701 screening eliminated immunologically confirmed hypersensitivity reaction to abacavir. Pharmacogenetic testing is not widely used in routine clinical practice to optimize drug choice or clinical management. 1 This gap between scientific knowledge and clinical application may be explained by the fact that the successful incorporation of a pharmacogenetic test into routine practice requires a combination of high-level evidence that can be generalized to diverse clinical settings, widespread availability of cost-effective and reliable laboratory tests, and effective strategies to incorporate testing into routine clinical practice. Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against the human immunodeficiency virus (HIV), available for once-daily use in combination with other antiretroviral agents, that has . . .