Explore the vast range of titles available.

In this randomized, controlled trial involving women in South Africa and Uganda, twice-yearly subcutaneous lenacapavir was superior to daily oral emtricitabine–tenofovir disoproxil fumarate in preventing HIV infection.

Twice-yearly subcutaneous lenacapavir has been shown to be efficacious for prevention of human immunodeficiency virus (HIV) infection in cisgender women. The efficacy of lenacapavir for preexposure prophylaxis (PrEP) in cisgender men, transgender women, transgender men, and gender-nonbinary persons is unclear. In this phase 3, double-blind, randomized, active-controlled trial, we randomly assigned participants in a 2:1 ratio to receive subcutaneous lenacapavir every 26 weeks or daily oral emtricitabine-tenofovir disoproxil fumarate (F/TDF). The primary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with the background HIV incidence in the screened population. The secondary efficacy analysis compared the incidence of HIV infection in the lenacapavir group with that in the F/TDF group. Among 3265 participants who were included in the modified intention-to-treat analysis, HIV infections occurred in 2 participants in the lenacapavir group (0.10 per 100 person-years; 95% confidence interval [CI], 0.01 to 0.37) and in 9 participants in the F/TDF group (0.93 per 100 person-years; 95% CI, 0.43 to 1.77). The background HIV incidence in the screened population (4634 participants) was 2.37 per 100 person-years (95% CI, 1.65 to 3.42). The incidence of HIV infection in the lenacapavir group was significantly lower than both the background incidence (incidence rate ratio, 0.04; 95% CI, 0.01 to 0.18; P<0.001) and the incidence in the F/TDF group (incidence rate ratio, 0.11; 95% CI, 0.02 to 0.51; P = 0.002). No safety concerns were identified. A total of 26 of 2183 participants (1.2%) in the lenacapavir group and 3 of 1088 (0.3%) in the F/TDF group discontinued the trial regimen because of injection-site reactions. The HIV incidence with twice-yearly lenacapavir was significantly lower than the background incidence and the incidence with F/TDF. (Funded by Gilead Sciences; PURPOSE 2 ClinicalTrials.gov number, NCT04925752.).

Antiretroviral therapy (ART) during pregnancy is important for both maternal health and prevention of perinatal HIV-1 transmission; however adequate data on the safety and efficacy of different ART regimens that are likely to be used by pregnant women are scarce. In this trial we compared the safety and efficacy of three antiretroviral regimens started in pregnancy: dolutegravir, emtricitabine, and tenofovir alafenamide fumarate; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; and efavirenz, emtricitabine, and tenofovir disoproxil fumarate. This multicentre, open-label, randomised controlled, phase 3 trial was done at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Pregnant women (aged ≥18 years) with confirmed HIV-1 infection and at 14–28 weeks' gestation were eligible. Women who had previously taken antiretrovirals in the past were excluded (up to 14 days of ART during the current pregnancy was permitted), as were women known to be pregnant with multiple fetuses, or those with known fetal anomaly or a history of psychiatric illness. Participants were randomly assigned (1:1:1) using a central computerised randomisation system. Randomisation was done using permuted blocks (size six) stratified by gestational age (14–18, 19–23, and 24–28 weeks' gestation) and country. Participants were randomly assigned to receive either once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir alafenamide fumarate 25 mg; once-daily oral dolutegravir 50 mg, and once-daily oral fixed-dose combination emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg; or once-daily oral fixed-dose combination of efavirenz 600 mg, emtricitabine 200 mg, and tenofovir disoproxil fumarate 300 mg. The primary efficacy outcome was the proportion of participants with viral suppression, defined as an HIV-1 RNA concentration of less than 200 copies per mL, at or within 14 days of delivery, assessed in all participants with an HIV-1 RNA result available from the delivery visit, with a prespecified non-inferiority margin of −10% in the combined dolutegravir-containing groups versus the efavirenz-containing group (superiority was tested in a pre-planned secondary analysis). Primary safety outcomes, compared pairwise among treatment groups, were the occurrence of a composite adverse pregnancy outcome (ie, either preterm delivery, the infant being born small for gestational age, stillbirth, or spontaneous abortion) in all participants with a pregnancy outcome, and the occurrence of grade 3 or higher maternal and infant adverse events in all randomised participants. This trial was registered with ClinicalTrials.gov, NCT03048422. Between Jan 19, 2018, and Feb 8, 2019, we enrolled and randomly assigned 643 pregnant women: 217 to the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group, 215 to the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group, and 211 to the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group. At enrolment, median gestational age was 21·9 weeks (IQR 18·3–25·3), the median HIV-1 RNA concentration among participants was 902·5 copies per mL (152·0–5182·5; 181 [28%] of 643 participants had HIV-1 RNA concentrations of <200 copies per mL), and the median CD4 count was 466 cells per μL (308–624). HIV-1 RNA concentrations at delivery were available for 605 (94%) participants. Of these, 395 (98%) of 405 participants in the combined dolutegravir-containing groups had viral suppression at delivery compared with 182 (91%) of 200 participants in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (estimated difference 6·5% [95% CI 2·0 to 10·7], p=0·0052; excluding the non-inferiority margin of −10%). Significantly fewer participants in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (52 [24%] of 216) had a composite adverse pregnancy outcome than those in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (70 [33%] of 213; estimated difference −8·8% [95% CI −17·3 to −0·3], p=0·043) or the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (69 [33%] of 211; −8·6% [–17·1 to −0·1], p=0·047). The proportion of participants or infants with grade 3 or higher adverse events did not differ among the three groups. The proportion of participants who had a preterm delivery was significantly lower in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (12 [6%] of 208) than in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (25 [12%] of 207; −6·3% [–11·8 to −0·9], p=0·023). Neonatal mortality was significantly higher in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (ten [5%] of 207 infants) than in the dolutegravir, emtricitabine, and tenofovir alafenamide fumarate group (two [1%] of 208; p=0·019) or the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (three [2%] of 202; p=0·050). When started in pregnancy, dolutegravir-containing regimens had superior virological efficacy at delivery compared with the efavirenz, emtricitabine, and tenofovir disoproxil fumarate regimen. The dolutegravir, emtricitabine, and tenofovir alafenamide fumarate regimen had the lowest frequency of composite adverse pregnancy outcomes and of neonatal deaths. National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Lifelong HIV antiretroviral therapy (ART) has prompted an interest in two-drug regimens to minimise cumulative drug exposure and toxicities. The safety, tolerability, and efficacy of dolutegravir and rilpivirine suggest potential compatibility and effectiveness as a two-drug regimen. We aimed to investigate this two-drug regimen in a phase 3 study. We identically designed SWORD-1 and SWORD-2, which were open-label, parallel-group, multicentre, phase 3, randomised, non-inferiority studies in 12 countries evaluating efficacy and safety of once-daily dolutegravir 50 mg plus rilpivirine 25 mg versus current ART regimen (CAR). We included participants aged 18 years or older who were on first or second ART with stable plasma HIV-1 RNA (viral load <50 copies per mL) for 6 months or longer at screening. We randomly assigned participants (1:1) with stratification by third-agent class, age, and planned participation in a bone mineral density substudy. The primary endpoint was proportion of participants with viral load lower than 50 copies per mL at week 48 among those individuals who received one or more doses of study medication. Investigators monitored adverse events to assess safety. These trials are registered with ClinicalTrials.gov, numbers NCT02429791 (SWORD-1) and NCT02422797 (SWORD-2). We screened for participants from April 14, 2015, to Oct 15, 2015, for SWORD-1 and from April 21, 2015, to Sept 25, 2015, for SWORD-2. We randomly assigned 516 participants to dolutegravir-rilpivirine and 512 to continue with CAR. At week 48 (last patient visit was Nov 22, 2016), in the pooled analysis of the intention-to-treat population, 95% of participants had viral loads lower than 50 copies per mL in each group (486 of 513 in the dolutegravir-rilpivirine group vs 485 of 511 in the CAR group), with an adjusted treatment difference of −0·2% (95% CI −3·0 to 2·5) and showed non-inferiority with a predefined margin of −8%. 395 (77%) of 513 participants in the dolutegravir-rilpivirine group and 364 (71%) of 511 participants in the CAR group reported adverse events. The most common adverse events were nasopharyngitis (49 [10%] for dolutegravir-rilpivirine vs 50 [10%] for CAR) and headache (41 [8%] vs 23 [5%]). More participants taking dolutegravir-rilpivirine (17 [3%]) reported adverse events leading to withdrawal than did participants taking CAR (three [<1%]). Dolutegravir-rilpivirine was non-inferior to CAR over 48 weeks in participants with HIV suppression and showed a safety profile consistent with its components. Results support the use of this two-drug regimen to maintain HIV suppression. ViiV Healthcare and Janssen Pharmaceutica NV.

Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.

Oral emtricitabine/tenofovir disoproxil fumarate (F/TDF) preexposure prophylaxis (PrEP) effectiveness against HIV acquisition highly depends on adherence. For men who have sex with men, a dosing study in the United States (US) population defined clinically meaningful tenofovir diphosphate (TFV-DP) thresholds in dried blood spots (DBS) based on the rounded 25th percentile for 2, 4, and 7 doses/week as 350, 700, and 1,250 fmol/punch. However, divergent efficacy results in the first generation randomized clinical trials of F/TDF PrEP among African women led to several hypotheses to question whether the pharmacology and adherence requirement for oral F/TDF PrEP may be different in cisgender women compared to what is already established for men. We conducted an open-label, parallel, randomized directly observed dosing (DOD) study of oral F/TDF PrEP among women without HIV who were not pregnant or breastfeeding in Kenya. Participants were randomly assigned to 2, 4, or 7 DOD F/TDF doses/week for 8 weeks. Blood was collected weekly, and TFV-DP and emtricitabine triphosphate (FTC-TP) concentrations in DBS and peripheral blood mononuclear cells (PBMCs) were quantified using validated liquid chromatography-tandem mass spectrometry. For DBS, concentrations were quantified from a 3-mm punch using the 70% methanol/30% water (70:30) extraction method as the primary process-the same method used for the original TFV-DP benchmarks derived in US adults, and additionally with 50% methanol/50% water (50:50) extraction using punches from the same DBS spot to compare the extraction performance of 70:30 versus 50:50 methods. The primary outcome was the steady-state fitted concentrations of TFV-DP and dose proportionality in DBS and the observed PBMC TFV-DP levels by study dosing groups. Secondary outcomes included the quantitative concentrations of FTC-TP in DBS, TFV-DP half-life in DBS, and the relative TFV-DP recovery from DBS using the 70:30 versus 50:50 extraction method. One-compartment population pharmacokinetic models were fit to estimate steady-state DBS concentrations. Descriptive statistics were summarized as range, means, and medians with interquartile range (IQR) for continuous outcomes and proportions for categorical variables. Fifty-four women were enrolled and randomized. Median age was 22 (IQR, 20-25) years. The observed median (IQR) week 8 TFV-DP concentrations in DBS were 359 (266-464), 749 (596-923), and 1,389 (1,151-1,551) fmol/punch after 2, 4, and 7 doses/week, respectively. At week 8, FTC-TP was quantifiable in 71%, 19%, and 0% DBS samples for 7, 4, and 2 doses/week groups, respectively. Fitted median (IQR) steady-state DBS TFV-DP concentrations were 416 (316, 516), 832 (631, 1,033), and 1,457 (1,106, 1,808) fmol/punch for 2, 4, and 7 doses/week, respectively, similar to previous estimates in US adults. TFV-DP exhibited a mean half-life of 17.5 days (95%CI: 16.7, 18.4) in DBS and steady-state TFV-DP concentrations varied in direct proportion to the dosing frequency [slope: 1.02 90% confidence interval 0.84, 1.20]. The 50:50 DBS extraction method yielded 1.27 (95% CI 1.25, 1.28) higher TFV-DP concentrations compared to the 70:30 method. When the 1.27 conversion factor was applied to the original 70:30 method-derived TFV-DP thresholds, the updated TFV-DP adherence interpretation benchmarks based on the 50:50 extraction were: <450 for <2 dose/week, 450-899 for 2-3 doses/week, 900-1,599 for 4-6 doses/week, and ≥1,600 fmol/punch for 7 doses/week. The observed mean (standard deviation) steady-state PBMC TFV-DP concentrations was 11.99 ± 8.47, 31.81 ± 15.66, and 63.1 ± 28.97 fmol/106 cells after 2, 4, and 7 doses/week, respectively. Overall, oral F/TDF PrEP was well tolerated. No grade 3 or higher adverse events were observed during the dosing phase. The primary study limitation was dosing for 8 weeks, but population pharmacokinetic modeling enabled steady-state estimates. Steady-state DBS TFV-DP concentrations from directly observed F/TDF PrEP dosing in African cisgender women participants are similar to previous estimates defined from US-based participants. These data demonstrate that cisgender women achieve similar DBS and PBMC TFV-DP concentrations as men for the same adherence level and validate the original TFV-DP benchmarks to interpret F/TDF adherence in HIV prevention studies and PrEP programs among cisgender women. Clinicaltrials.gov: NCT05057858.

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.

INTRODUCTION:The course of maternal antiviral prophylaxis to prevent mother-to-child transmission of hepatitis B virus (HBV-MTCT) varies greatly, and it has not been demonstrated in a randomized controlled study.METHODS:In this multicenter, open-label, randomized controlled trial, eligible pregnant women with HBV DNA of 5.3–9.0 log10 IU/mL who received tenofovir alafenamide fumarate (TAF) from the first day of 33 gestational weeks to delivery (expected 8 week) or to 4 weeks postpartum (expected 12 week) were randomly enrolled at a 1:1 ratio and followed until 6 months postpartum. All infants received standard immunoprophylaxis (hepatitis B immunoglobulin and vaccine). The primary end point was the safety of mothers and infants. The secondary end point was the HBV-MTCT rate of infants at the age of 7 months.RESULTS:Among 119 and 120 intention-to-treat pregnant women, 115 and 116 women were followed until delivery, and 110 and 112 per-protocol mother-infant dyads in 2 groups completed the study. Overall, TAF was well tolerated, no one discontinued the therapy due to adverse events (0/239, 0%, 95% confidence interval [CI] 0%–1.6%), and no infant had congenital defects or malformations at delivery (0/231, 0%, 95% CI 0%–1.6%). The infants' physical development at birth (n = 231) and at 7 months (n = 222) was normal. Furthermore, 97.0% (224/231, 95% CI 93.9%–98.5%) of women achieved HBV DNA <5.3 log10 IU/mL at delivery. The intention-to-treat and per-protocol infants' HBV-MTCT rates were 7.1% (17/239, 95% CI 4.5%–11.1%) and 0% (0/222, 95% CI 0%–1.7%) at the age of 7 months. Comparatively, 15.1% (18/119, 95% CI 9.8%–22.7%) vs 18.3% (22/120, 95% CI 12.4%–26.2%) of women in the 2 groups had mildly elevated alanine aminotransferase levels at 3 months and 6 months postpartum, respectively (P = 0.507); notably, no one experienced alanine aminotransferase flare (0% [0/119, 95% CI 0%–3.1%] vs 0% [0/120, 0%–3.1%]).DISCUSSION:Maternal TAF prophylaxis to prevent HBV-MTCT is generally safe and effective, and expected 8-week prenatal duration is feasible. ClinicalTrials.gov, NCT04850950.

Our objective was to assess the therapeutic noninferiority of dual therapy with darunavir/ritonavir and lamivudine compared to triple therapy with darunavir/ritonavir plus 2 nucleos(t)ides for maintenance of human immunodeficiency virus type 1 (HIV-1) suppression. This was a multicenter, open-label, noninferiority trial (margin 12%). Patients with HIV-1 RNA <50 copies/mL for 6 months or longer on triple therapy with darunavir/ritonavir and 2 nucleos(t)ides (tenofovir disoproxil fumarate and emtricitabine or abacavir and lamivudine) and with no resistance were randomized to continue therapy (n = 128) or switch to darunavir/ritonavir and lamivudine (n = 129). The primary endpoint was the proportion of participants with HIV-RNA <50 copies/mL after 48 weeks of follow-up according to the snapshot algorithm. A total of 249 participants received study drugs (intention-to-treat exposed). The proportion of participants with HIV-RNA <50 copies/mL in the dual- and triple-therapy arms was 88.9% (112/126) and 92.7% (114/123; difference, -3.8%; 95% confidence interval, -11.0 to 3.4), respectively. Four participants in the dual-therapy arm and 2 in the triple-therapy arm developed protocol-defined virological failure. Switching to dual therapy was associated with a significant increase in total, low-density lipoprotein, and high-density lipoprotein (HDL) cholesterol, but not in the total-to-HDL cholesterol ratio. Serious adverse events and study drug discontinuations due to adverse events occurred in 4.8% vs 4.9%P = .97) and in 0.8% (1/126) vs 1.6% P = .55) in dual therapy vs triple therapy, respectively. Dual therapy with darunavir/ritonavir and lamivudine demonstrated noninferior therapeutic efficacy and similar tolerability compared to triple therapy. NCT02159599.

In this clinical trial of second-line antiretroviral therapy in children with HIV in Africa, regimens including tenofovir alafenamide fumarate as the backbone and dolutegravir as the anchor drug were most effective.