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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. . . .

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.

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 . . .

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.

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.

Nucleoside reverse transcriptase translocation inhibitors (NRTTIs) are potent antiretroviral agents that block HIV replication. A comprehensive lead optimization campaign was undertaken to develop a novel long-acting NRTTI with the potential for extended-duration dosing for HIV prophylaxis. Broad exploration of nucleoside structure–activity relationship (SAR), leveraging ribose core, periphery, and nucleobase modifications, along with systematic progression of compounds of interest through key in vitro and in vivo studies led to the discovery of MK-8527. MK-8527 is a novel deoxyadenosine analog that is phosphorylated intracellularly to its active triphosphate (TP) form, which inhibits reverse transcription. Iron footprinting and primer extension assays demonstrated that MK-8527-TP inhibits translocation of reverse transcriptase on the primer and template, and this inhibition allows for both immediate and delayed chain termination of reverse transcription. MK-8527 inhibits viral replication in human peripheral blood mononuclear cells (PBMCs), with a half maximal inhibitory concentration (IC 50 ) of 0.21 nM. The pharmacokinetic (PK) profile of MK-8527 in rats and rhesus monkeys was characterized by low-to-moderate clearance and volume of distribution, with good oral absorption (57% and 100% in rats and monkeys, respectively). Following oral administration of MK-8527 to monkeys, MK-8527-TP exhibited an intracellular half-life of approximately 48 h in PBMCs, significantly longer than the apparent plasma half-life of the parent compound (approximately 7 h). MK-8527 and MK-8527-TP demonstrated favorable in vitro off-target profiles, with IC 50 values of ≥95 µM against human DNA polymerases tested, and no off-target activities at 10 μM against a panel of 114 enzyme and receptor binding assays. Collectively, the potent antiretroviral activity and favorable preclinical PK and off-target profiles make MK-8527 an attractive clinical candidate, and it is currently in clinical trials for once-monthly oral HIV-1 pre-exposure prophylaxis.

In Human Immunodeficiency Virus-1 treatment-naive adults, a fixed combination of doravirine/lamivudine/tenofovir disoproxil fumarate demonstrated non-inferior antiretroviral efficacy to efavirenz/emtricitabine/tenofovir disoproxil fumarate at week 48, with similar immunologic effects, low viral drug resistance rates, and significantly fewer neuropsychiatric adverse events. Abstract Background Doravirine (DOR), a novel non-nucleoside reverse-transcriptase inhibitor (NNRTI), is active against wild-type Human Immunodeficiency Virus (HIV)-1 and the most common NNRTI-resistant variants, and has a favorable and unique in vitro resistance profile. Methods DRIVE-AHEAD is a phase 3, double-blind, non-inferiority trial. Antiretroviral treatment-naive adults with ≥1000 HIV-1 RNA copies/mL were randomized (1:1) to once-daily, fixed-dose DOR at 100 mg, lamivudine at 300 mg, and tenofovir disoproxil fumarate (TDF) at 300 mg (DOR/3TC/TDF) or to efavirenz at 600 mg, emtricitabine at 200 mg, and TDF at 300 mg (EFV/FTC/TDF) for 96 weeks. The primary efficacy endpoint was the proportion of participants with <50 HIV-1 RNA copies/mL at week 48 (Food and Drug Administration snapshot approach; non-inferiority margin 10%). Results Of the 734 participants randomized, 728 were treated (364 per group) and included in the analyses. At week 48, 84.3% (307/364) of DOR/3TC/TDF recipients and 80.8% (294/364) of EFV/FTC/TDF recipients achieved <50 HIV-1 RNA copies/mL (difference 3.5%, 95% CI, -2.0, 9.0). DOR/3TC/TDF recipients had significantly lower rates of dizziness (8.8% vs 37.1%), sleep disorders/disturbances (12.1% vs 25.2%), and altered sensorium (4.4% vs 8.2%) than EFV/FTC/TDF recipients. Mean changes in fasting low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) were significantly different between DOR/3TC/TDF and EFV/FTC/TDF (−1.6 vs +8.7 mg/dL and −3.8 vs +13.3 mg/dL, respectively). Conclusions In HIV-1 treatment-naive adults, DOR/3TC/TDF demonstrated non-inferior efficacy to EFV/FTC/TDF at week 48 and was well tolerated, with significantly fewer neuropsychiatric events and minimal changes in LDL-C and non-HDL-C compared with EFV/FTC/TDF. Clinical Trials Registration NCT02403674

Whether long-term suppression of replication of hepatitis B virus (HBV) has any beneficial effect on regression of advanced liver fibrosis associated with chronic HBV infection remains unclear. We aimed to assess the effects on fibrosis and cirrhosis of at least 5 years' treatment with tenofovir disoproxil fumarate (DF) in chronic HBV infection. After 48 weeks of randomised double-blind comparison (trials NCT00117676 and NCT00116805) of tenofovir DF with adefovir dipivoxil, participants (positive or negative for HBeAg) were eligible to enter a 7-year study of open-label tenofovir DF treatment, with a pre-specified repeat liver biopsy at week 240. We assessed histological improvement (≥2 point reduction in Knodell necroinflammatory score with no worsening of fibrosis) and regression of fibrosis (≥1 unit decrease by Ishak scoring system). Of 641 patients who received randomised treatment, 585 (91%) entered the open-label phase, and 489 (76%) completed 240 weeks. 348 patients (54%) had biopsy results at both baseline and week 240. 304 (87%) of the 348 had histological improvement, and 176 (51%) had regression of fibrosis at week 240 (p<0·0001). Of the 96 (28%) patients with cirrhosis (Ishak score 5 or 6) at baseline, 71 (74%) no longer had cirrhosis (≥1 unit decrease in score), whereas three of 252 patients without cirrhosis at baseline progressed to cirrhosis at year 5 (p<0·0001). Virological breakthrough occurred infrequently and was not due to resistance to tenofovir DF. The safety profile was favourable: 91 (16%) patients had adverse events but only nine patients had serious events related to the study drug. In patients with chronic HBV infection, up to 5 years of treatment with tenofovir DF was safe and effective. Long-term suppression of HBV can lead to regression of fibrosis and cirrhosis. Gilead Sciences.

Doravirine is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) that has demonstrated good efficacy, tolerability, and safety for the treatment of patients with human immunodeficiency virus (HIV)-1 infection in phase III clinical trials. Doravirine achieved non-inferiority when compared with efavirenz- and darunavir/ritonavir-based regimens. Fewer adverse effects, including neuropsychiatric effects were observed with doravirine compared with efavirenz. Key pharmacodynamic and pharmacokinetic characteristics as well as drug-drug interactions and the resistance profile were assessed in this clinical review. Doravirine is a pyridinone NNRTI with potent antiviral activity against wild-type HIV-1 virus and common NNRTI variants. Studies in healthy volunteers and HIV-infected individuals have shown that doravirine has a favorable pharmacokinetic profile for once-daily dosing, with an elimination half-life of around 15 h, median time to maximum plasma concentrations of 1-4 h, and time to steady-state concentration of 7 days. The pharmacokinetics of doravirine are not greatly influenced by sex, age, race, or hepatic impairment. Although no dose adjustment is required for doravirine in renal impairment when given as a single tablet, the fixed-dose combination tablet of doravirine/lamivudine/tenofovir disoproxil fumarate is not recommended in patients with a creatinine clearance of < 50 mL/min. Doravirine has a low potential for drug-drug interactions and does not impact on the pharmacokinetics of other drugs. However, it is metabolized via cytochrome P450 (CYP) 3A enzymes and is thus susceptible to interactions with CYP3A inhibitors and inducers. Strong CYP3A inhibitors can significantly increase doravirine exposure; however, this is not considered to be clinically relevant. Conversely, strong CYP3A inducers, such as rifampin, are contraindicated with doravirine owing to a significant reduction in exposure with potential for impaired virological efficacy. Moderate CYP3A inducers, such as rifabutin, may be co-administered if the doravirine dose is increased to 100 mg twice daily. Doravirine has a unique resistance profile and has demonstrated in vitro activity against some of the most common, clinically relevant NNRTI-resistant mutations. Prevalence of baseline NNRTI resistance to doravirine appears to be low in treatment-naïve cohorts. Further data on the efficacy of doravirine in patients with previous treatment experience and/or transmitted NNRTI resistance are required to further inform its place in the current armamentarium of drugs for the treatment of HIV infection.

Gilead Sciences has developed a single tablet anti-HIV-1 medication (Biktarvy ® ) combining the novel integrase strand transfer inhibitor (INSTI) bictegravir with the nucleos(t)ide reverse transcriptase inhibitors (NRTIs) emtricitabine and tenofovir alafenamide. This fixed dose combination has demonstrated efficacy as treatment for both anti-retroviral naïve and virologically suppressed HIV-1 infection in patients switching therapy, and was recently approved in the USA. This article summarizes the milestones in the development of bictegravir leading to this first approval of bictegravir/emtricitabine/tenofovir alafenamide as treatment for HIV-1 infection.