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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.

Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1. Rilpivirine, a new non-nucleoside reverse transcriptase inhibitor, has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors. We aimed to assess the efficacy, safety, and tolerability of rilpivirine versus efavirenz, each combined with tenofovir-disoproxil-fumarate and emtricitabine. We did a phase 3, randomised, double-blind, double-dummy, active-controlled trial, in patients infected with HIV-1 who were treatment-naive. The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater, and viral sensitivity to all study drugs. Our trial was done at 112 sites across 21 countries. Patients were randomly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz, each with tenofovir-disoproxil-fumarate and emtricitabine. Our primary objective was to show non-inferiority (12% margin) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response (viral load <50 copies per mL intention-to-treat time-to-loss-of-virological-response [ITT-TLOVR] algorithm) at week 48. Our primary analysis was by intention-to-treat. We also used logistic regression to adjust for baseline viral load. This trial is registered with ClinicalTrials.gov, number NCT00540449. 346 patients were randomly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug, with 287 (83%) and 285 (83%) in the respective groups having a confirmed response at week 48. The point estimate from a logistic regression model for the percentage difference in response was −0·4 (95% CI −5·9 to 5·2), confirming non-inferiority with a 12% margin (primary endpoint). The incidence of virological failures was 13% (rilpivirine) versus 6% (efavirenz; 11% vs 4% by ITT-TLOVR). Grade 2–4 adverse events (55 [16%] on rilpivirine vs 108 [31%] on efavirenz, p<0·0001), discontinuations due to adverse events (eight [2%] on rilpivirine vs 27 [8%] on efavirenz), rash, dizziness, and abnormal dreams or nightmares were more common with efavirenz. Increases in plasma lipids were significantly lower with rilpivirine. Rilpivirine showed non-inferior efficacy compared with efavirenz, with a higher virological-failure rate, but a more favourable safety and tolerability profile. Tibotec.

The non-nucleoside reverse transcriptase inhibitor (NNRTI), rilpivirine (TMC278; Tibotec Pharmaceuticals, County Cork, Ireland), had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1, but fewer adverse events. We aimed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors (N[t]RTIs). We undertook a 96-week, phase 3, randomised, double-blind, double-dummy, non-inferiority trial in 98 hospitals or medical centres in 21 countries. We enrolled adults (≥18 years) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs. We randomly allocated patients (1:1) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily; all patients received an investigator-selected regimen of background N(t)RTIs (tenofovir-disoproxil-fumarate plus emtricitabine, zidovudine plus lamivudine, or abacavir plus lamivudine). The primary outcome was non-inferiority (12% margin on logistic regression analysis) at 48 weeks in terms of confirmed response (viral load <50 copies per mL, defined by the intent-to-treat time to loss of virologic response [TLOVR] algorithm) in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00543725. From May 22, 2008, we screened 947 patients and enrolled 340 to each group. 86% of patients (291 of 340) who received at least one dose of rilpivirine responded, compared with 82% of patients (276 of 338) who received at least one dose of efavirenz (difference 3·5% [95% CI −1·7 to 8·8]; p non-inferiority<0·0001). Increases in CD4 cell counts were much the same between groups. 7% of patients (24 of 340) receiving rilpivirine had a virological failure compared with 5% of patients (18 of 338) receiving efavirenz. 4% of patients (15) in the rilpivirine group and 7% (25) in the efavirenz group discontinued treatment due to adverse events. Grade 2–4 treatment-related adverse events were less common with rilpivirine (16% [54 patients]) than they were with efavirenz (31% [104]; p<0·0001), as were rash and dizziness (p<0·0001 for both) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz (p<0·0001). Despite a slightly increased incidence of virological failures, a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1. Tibotec.

Background. Pooled ECHO/THRIVE lipid and body fat data are presented from the ECHO (Efficacy Comparison in Treatment-Naïve, HIV-Infected Subjects of TMC278 and Efavirenz) and THRIVE (TMC278 Against HIV, in a Once-Daily Regimen Versus Efavirenz) trials. Methods. We assessed the 96-week effects on lipids, adverse events (AEs), and body fat distribution (dual-energy x-ray absorptiometry) of rilpivirine (RPV) and EFV plus 2 nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs) in treatment-naive adults infected with human immunodeficiency virus type 1 (HIV-1). Results. Rilpivirine produced minimal changes in total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. Compared with RPV, EFV significantly (P < .001) increased lipid levels. Decreases in the TC/HDL-C ratio were similar with RPV and EFV. Background N[t] RTI affected RPV-induced lipid changes; all levels increased with zidovudine/lamivudine (3TC) and abacavir/3TC (except triglycerides, which were unchanged). With emtricitabine/tenofovir, levels of HDL-C were increased, TC and LDL-C were unchanged, and triglycerides were decreased. With EFV, lipid levels increased in each N[t]RTI subgroup (except triglycerides were unchanged with abacavir/3TC). Fewer (P < .001) RPV-treated patients than EFV-treated patients had TC, LDL-C, and triglyceride levels above National Cholesterol Education Program cutoffs. More RPV-than EFV-treated patients had HDL-C values below these cutoffs (P = .02). Dyslipidemia AEs were less common with RPV than with EFV. Similar proportions of patients had a ≥10% decrease in limb fat (16% with RPV and 17% with EFV). Limb fat was significantly (P < .001) increased to a similar extent (by 12% with RPV and 11% with EFV). At week 96, patients receiving zidovudine/3TC had lost limb fat, and those receiving emtricitabine/tenofovir had gained it. Conclusions. Over the course of 96 weeks, RPV-based therapy was associated with lower increases in lipid parameters and fewer dyslipidemia AEs than EFV-based treatment. Body fat distribution changes were similar between treatments. The N[t]RTI regimen affected lipid and body fat distribution changes.

Tenofovir disoproxil fumarate (tenofovir DF) is a bioavailable prodrug of tenofovir, a potent nucleotide analogue reverse-transcriptase inhibitor with activity against human immunodeficiency virus (HIV) and hepatitis B virus. It is administered as a single 300-mg tablet once daily. It was approved for the treatment of HIV infection on the basis of data from clinical trials demonstrating activity in treatment-experienced patients, and it was subsequently shown to be effective when used as a component of initial therapy. Tenofovir DF is active against some nucleoside-resistant strains of HIV. However, cross-resistance is associated with multiple thymidine analogue mutations that include 41L or 210W. The signature mutation is the K65R mutation, which causes variable loss in susceptibility to tenofovir DF, didanosine, and abacavir. Tenofovir DF has been well tolerated in clinical trials with durations of follow-up up to 96 weeks. It is associated with more-favorable lipid profiles than stavudine and has not been associated with the mitochondrial toxicity attributed to other nucleoside analogues.

Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate—adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes. We reviewed all GenBank submissions of HIV-1 reverse transcriptase sequences with or without protease and identified 287 studies published between March 1, 2000, and December 31, 2013, with more than 25 recently or chronically infected ARV-naïve individuals. These studies comprised 50,870 individuals from 111 countries. Each set of study sequences was analyzed for phylogenetic clustering and the presence of 93 surveillance drug-resistance mutations (SDRMs). The median overall TDR prevalence in sub-Saharan Africa (SSA), south/southeast Asia (SSEA), upper-income Asian countries, Latin America/Caribbean, Europe, and North America was 2.8%, 2.9%, 5.6%, 7.6%, 9.4%, and 11.5%, respectively. In SSA, there was a yearly 1.09-fold (95% CI: 1.05-1.14) increase in odds of TDR since national ARV scale-up attributable to an increase in non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance. The odds of NNRTI-associated TDR also increased in Latin America/Caribbean (odds ratio [OR] = 1.16; 95% CI: 1.06-1.25), North America (OR = 1.19; 95% CI: 1.12-1.26), Europe (OR = 1.07; 95% CI: 1.01-1.13), and upper-income Asian countries (OR = 1.33; 95% CI: 1.12-1.55). In SSEA, there was no significant change in the odds of TDR since national ARV scale-up (OR = 0.97; 95% CI: 0.92-1.02). An analysis limited to sequences with mixtures at less than 0.5% of their nucleotide positions—a proxy for recent infection—yielded trends comparable to those obtained using the complete dataset. Four NNRTI SDRMs—K101E, K103N, Y181C, and G190A—accounted for >80% of NNRTI-associated TDR in all regions and subtypes. Sixteen nucleoside reverse transcriptase inhibitor (NRTI) SDRMs accounted for >69% of NRTI-associated TDR in all regions and subtypes. In SSA and SSEA, 89% of NNRTI SDRMs were associated with high-level resistance to nevirapine or efavirenz, whereas only 27% of NRTI SDRMs were associated with high-level resistance to zidovudine, lamivudine, tenofovir, or abacavir. Of 763 viruses with TDR in SSA and SSEA, 725 (95%) were genetically dissimilar; 38 (5%) formed 19 sequence pairs. Inherent limitations of this study are that some cohorts may not represent the broader regional population and that studies were heterogeneous with respect to duration of infection prior to sampling. Most TDR strains in SSA and SSEA arose independently, suggesting that ARV regimens with a high genetic barrier to resistance combined with improved patient adherence may mitigate TDR increases by reducing the generation of new ARV-resistant strains. A small number of NNRTI-resistance mutations were responsible for most cases of high-level resistance, suggesting that inexpensive point-mutation assays to detect these mutations may be useful for pre-therapy screening in regions with high levels of TDR. In the context of a public health approach to ARV therapy, a reliable point-of-care genotypic resistance test could identify which patients should receive standard first-line therapy and which should receive a protease-inhibitor-containing regimen.

The human immunodeficiency virus type 1 (HIV-1) is a type of retrovirus responsible for immunodeficiency syndrome, a sickness that significantly compromises the immune system’s ability to function. The latest data on the global HIV epidemic reveals that 39,9 million people are living with HIV, 1,3 million have newly acquired the virus, and 630,000 have died from HIV-related illnesses. Given the high costs and complexities of experimental screenings, this study proposes an ensemble approach that combines machine learning and molecular docking to rank potential HIV-1 drug candidates for repurposing. This integrative approach targeting multiple key HIV-1 enzymes (protease, integrase, and reverse transcriptase) contributes to ongoing efforts to identify and repurpose potential inhibitors, completing existing studies focused on one or two molecular targets. The meta-learning based integrative strategy demonstrated robust predictive performance across all three HIV-1 targets. For HIV-1 integrase, the meta-learning model mllh-18-hp achieved a Matthews correlation coefficient (MCC) of 99.14% and a precision-recall area under the curve (PR-AUC) of 99.68%, while the mllh-18 model reached 98.28% MCC and 99.36% PR-AUC. For HIV-1 protease, the mllh-18 and mllh-18-hp models yielded MCC values of 97.20% and 95.29%, with PR-AUCs of 99.96% and 99.97%, respectively. In the case of HIV-1 reverse transcriptase, the mllh-18-hp model recorded 97.49% MCC and 99.61% PR-AUC, whereas the mllh-18 model showed 96.07% MCC and 99.32% PR-AUC. These models were subsequently used to screen the DrugCentral database, and compounds classified as active were docked and integrated into a pipeline to prioritize the most promising candidates for repurposing. The results indicate that three drugs (enoxacin, larotrectinib, and pipamazine), originally developed for other diseases, have potential as candidates for HIV-1 management, but experimental tests are advised. Beyond the explored potential for repurposing HIV-1 drugs, this research highlights an meta-learning based approach that could improve the prediction of potential candidates and provide useful insights for future drug development efforts.

There is a strong demand for new and efficient antiviral compounds. A series of 2-hydroxy-1,4-naphthoquinone Mannich bases were screened for their HIV-1-RNase H inhibitory activity. An HIV-1-RNase H assay was used to study the RNase H inhibition by the test compounds. Docking of active derivatives into the active site of the enzyme was carried out. Compounds 1e and 2k showed distinctly higher HIV-1-RNase H inhibitory activity (IC50 = 2.8–3.1 µM) than the known inhibitors RDS1759 and compound 13. The binding mode and possible interactions of 1e and 2k with the HIV-1-RNase H active site were determined using molecular docking, which led to the identification of salient and concealed pharmacophoric features of these molecules. The docking analysis revealed that there are significant differences in the binding mode of these compounds within the active site of the target enzyme. A selection of HIV-1-RNase H-inhibitory Mannich bases was tested for antiviral activity against HIV-1, and compound 2k showed the highest activity at low toxicity to host cells. The lawsone Mannich bases 1e and 2k also underwent a preliminary screening for activity against SARS-CoV-2, and compound 1e was found to inhibit SARS-CoV-2 replication (IC50 = 11.2 µM).

Development of resistance remains a major challenge for drugs to treat HIV-1 infections, including those targeting the essential viral polymerase, HIV-1 reverse transcriptase (RT). Resistance associated with the Tyr181Cys mutation in HIV-1 RT has been a key roadblock in the discovery of nonnucleoside RT inhibitors (NNRTIs). It is the principal point mutation that arises from treatment of HIV-infected patients with nevirapine, the first-in-class drug still widely used, especially in developing countries. We report covalent inhibitors of Tyr181Cys RT (CRTIs) that can completely knock out activity of the resistant mutant and of the particularly challenging Lys103Asn/Tyr181Cys variant. Conclusive evidence for the covalent modification of Cys181 is provided from enzyme inhibition kinetics, mass spectrometry, protein crystallography, and antiviral activity in infected human T-cell assays. The CRTIs are also shown to be selective for Cys181 and have lower cytotoxicity than the approved NNRTI drugs efavirenz and rilpivirine.