Clinical benefits of novel non-nucleoside reverse transcriptase inhibitors: A prospective cohort study.

INTRODUCTION: The efficacy and safety of ainuovirine+lamivudine+tenofovir (ANV+3TC+TDF) and efavirenz+lamivudine+tenofovir (EFV+3TC+TDF) have been confirmed in previous clinical trials; however, there are no related studies on patient-reported outcomes. This study aimed to evaluate the effectiveness and safety of these 2 antiretroviral therapy regimens and to understand the patient's symptom experience and subjective experience of sleep quality through patient-reported outcomes. METHODS: This is a single-center prospective cohort study with 243 patients evaluated from October 1, 2021 to June 30, 2022. Virological effectiveness and patient-reported outcomes results were analyzed. The primary endpoint was the proportion of HIV viral load <50 copies/mL (virological suppression rate) at 48 weeks and the changes in the HIV symptom index and Pittsburgh sleep quality index. RESULTS: The virological suppression rates in the ANV+3TC+TDF and EFV+3TC+TDF groups were 83.6% (102/122) and 87.6% (106/121), respectively, at 48 weeks. In the ANV+3TC+TDF group, the scores of HIV symptom index and pittsburgh sleep quality index in the 48th week were lower than the baseline level (p < 0.05). Logistic regression results showed that the baseline regimen EFV+3TC+TDF was a risk factor for dizziness/lightheadedness (odds ratio = 3.153, 95% confidence interval: 1.473-6.748, p = 0.003), sadness/depression odds ratio = 2.404, 95% confidence interval:1.188-4.871, p = 0.015), and difficulty sleeping (odds ratio = 2.802, 95% confidence interval: 1.437-5.463, p = 0.002) at 48 weeks. CONCLUSIONS: Both regimens showed good virological effectiveness; however, compared with ANV+3TC+TDF, the EFV+3TC+TDF regimen reduced the prevalence of HIV-related symptoms.

Islatravir: evaluation of clinical development for HIV and HBV.

INTRODUCTION: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3'OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability. AREAS COVERED: The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed. EXPERT OPINION: Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.

Initial antiretroviral therapy regimen and risk of heart failure.

OBJECTIVES: Heart failure risk is elevated in people with HIV (PWH). We investigated whether initial antiretroviral therapy (ART) regimens influenced heart failure risk. DESIGN: Cohort study. METHODS: PWH who initiated an ART regimen between 2000 and 2016 were identified from three integrated healthcare systems. We evaluated heart failure risk by protease inhibitor, nonnucleoside reverse transcriptase inhibitors (NNRTI), and integrase strand transfer inhibitor (INSTI)-based ART, and comparing two common nucleotide reverse transcriptase inhibitors: tenofovir disoproxil fumarate (tenofovir) and abacavir. Follow-up for each pairwise comparison varied (i.e. 7 years for protease inhibitor vs. NNRTI; 5 years for tenofovir vs. abacavir; 2 years for INSTIs vs. PIs or NNRTIs). Hazard ratios were from working logistic marginal structural models, fitted with inverse probability weighting to adjust for demographics, and traditional cardiovascular risk factors. RESULTS: Thirteen thousand six hundred and thirty-four PWH were included (88% men, median 40 years of age; 34% non-Hispanic white, 24% non-Hispanic black, and 24% Hispanic). The hazard ratio (95% CI) were: 2.5 (1.5-4.3) for protease inhibitor vs. NNRTI-based ART (reference); 0.5 (0.2-1.8) for protease inhibitor vs. INSTI-based ART (reference); 0.1 (0.1-0.8) for NNRTI vs. INSTI-based ART (reference); and 1.7 (0.5-5.7) for tenofovir vs. abacavir (reference). In more complex models of cumulative incidence that accounted for possible nonproportional hazards over time, the only remaining finding was evidence of a higher risk of heart failure for protease inhibitor compared with NNRTI-based regimens (1.8 vs. 0.8%; P  = 0.002). CONCLUSION: PWH initiating protease inhibitors may be at higher risk of heart failure compared with those initiating NNRTIs. Future studies with longer follow-up with INSTI-based and other specific ART are warranted.

[Current antiretroviral therapy: A review].

The article presents an overview of clinical recommendations for currant antiretroviral therapy. Currently, the current preferred first-line antiretroviral therapy regimens are combinations of 2 or 3 antiretroviral drugs (ARVs) in one tablet with a frequency of administration 1 time per day and, as a rule, include drugs of the 2nd generation (integrase inhibitors or non-nucleoside reverse transcriptase inhibitors). These schemes have high efficiency and a good genetic barrier in the development of HIV resistance mutations. HIV protease inhibitors are used as alternative regimens. Schemes with the least number and spectrum of side effects, no effect on metabolic processes and minimal drug interactions have advantages. Switching patients to injectable therapy regimens with a frequency of administration of drugs once every 2 months can significantly improve the quality of life of patients and, accordingly, adherence to their treatment. The development and introduction of new classes of ARVs into clinical practice ensures the suppression of HIV replication in most patients with HIV strains resistant to drugs of the main groups of ARVs (nucleoside/nucleotide reverse transcriptase.

Repurposing nucleoside reverse transcriptase inhibitors (NRTIs) to slow aging.

Repurposing drugs already approved in the clinic to be used off-label as geroprotectors, compounds that combat mechanisms of aging, are a promising way to rapidly reduce age-related disease incidence in society. Several recent studies have found that a class of drugs-nucleoside reverse transcriptase inhibitors (NRTIs)-originally developed as treatments for cancers and human immunodeficiency virus (HIV) infection, could be repurposed to slow the aging process. Interestingly, these studies propose complementary mechanisms that target multiple hallmarks of aging. At the molecular level, NRTIs repress LINE-1 elements, reducing DNA damage, benefiting the hallmark of aging of 'Genomic Instability'. At the organellar level, NRTIs inhibit mitochondrial translation, activate ATF-4, suppress cytosolic translation, and extend lifespan in worms in a manner related to the 'Loss of Proteostasis' hallmark of aging. Meanwhile, at the cellular level, NRTIs inhibit the P2X7-mediated activation of the inflammasome, reducing inflammation and improving the hallmark of aging of 'Altered Intercellular Communication'. Future development of NRTIs for human aging health will need to balance out toxic side effects with the beneficial effects, which may occur in part through hormesis.

Adherence, safety, and choice of the monthly dapivirine vaginal ring or oral emtricitabine plus tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis among African adolescent girls and young women: a randomised, open-label, crossover trial.

BACKGROUND: Half of new HIV acquisitions in Africa occur in adolescent girls and young women. Pre-exposure prophylaxis (PrEP) with oral tenofovir disoproxil fumarate plus emtricitabine or the monthly dapivirine vaginal ring is efficacious but has lower adherence and effectiveness among adolescent girls and young women. We aimed to assess product adherence, safety, and choice of oral PrEP compared with the dapivirine ring among African adolescent girls and young women. METHODS: MTN-034/REACH was a randomised, open-label, phase 2a crossover trial among HIV-seronegative, non-pregnant adolescent girls and young women aged 16-21 years at four clinical research sites in South Africa, Uganda, and Zimbabwe. Participants were randomly assigned (1:1) to either the dapivirine ring or daily oral PrEP (200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) for 6 months, then switched to the other product option for 6 months, followed by a third 6-month period in which participants were given a choice of oral PrEP, the dapivirine ring, or neither. Fixed block randomisation was used, stratified by site. The primary adherence endpoint was use of each product during the randomised periods, with high use defined as tenofovir-diphosphate concentrations greater than or equal to 700 fmol/punch (associated with taking an average of four or more tablets per week in the previous month) and greater than or equal to 4 mg dapivirine released from the returned ring (continuous use for 28 days in the previous month) based on residual drug concentrations. The primary safety endpoint was grade 2 or higher adverse events during each randomised period of 24 weeks of ring and oral PrEP. This trial is registered at ClinicalTrials.gov, NCT03593655. FINDINGS: From Feb 6, 2019 to Sept 9, 2021, 396 adolescent girls and young women were screened, 247 of whom were enrolled and randomly assigned (6 months of the ring followed by 6 months of oral PrEP n=124; 6 months of oral PrEP followed by 6 months of the ring n=123). Median age was 18 years (IQR 17-19). 54 grade 2 or higher product-related adverse events were reported during oral PrEP and five during dapivirine ring use, with no product-related serious adverse events. High adherence was observed in 753 (57%) of the 1316 oral PrEP visits and 806 (57%) of the 1407 dapivirine ring visits. Four women acquired HIV during follow-up. INTERPRETATION: Adherence was moderately high and similar between oral PrEP and the dapivirine ring with favourable safety and tolerability. Oral PrEP and the dapivirine ring are effective, safe, and well tolerated HIV prevention options for adolescent girls and young women who would benefit from a choice of PrEP formulations to meet their needs and preferences. FUNDING: National Institutes of Health.

Efficacy and tolerability of dolutegravir/lamivudine versus dolutegravir/rilpivirine in switching from a three-drug regimen based on nonnucleoside reverse transcriptase inhibitors: A retrospective cohort study.

Real-life comparisons of dolutegravir/rilpivirine (DTG/RPV) and DTG/lamivudine (3TC) regimens in people living with human immunodeficiency virus (PLWHIV) who switched from a standard three-drug regimen based on nonnucleoside reverse transcriptase inhibitors (NNRTIs) are missing. This study aimed to compare DTG/3TC and DTG/RPV in virologically suppressed patients (HIV-RNA < 50 copies/mL) coming from any NNRTI-based regimen in terms of discontinuation due to virologic failure (VF) discontinuation rates due to all causes, and adverse events. As a secondary outcome, we evaluated the difference in creatinine, total cholesterol, CD4, and triglycerides from baseline to weeks 48 after the switch. Of the 415 PLWHs included in the study, 278 (66.9%) switched to DTG/3TC, and 137 (33.1%) switched to DTG/RPV. Overall, 48 PLWHs (11.6%) discontinued the treatment:38 with DTG/3TC and 10 with DTG/RPV with similar discontinuation rates: 5.01 × 100 py (95% confidence interval [CI] 3.64-6.94) and 4.66 × 100 py (95% CI 2.51-8.67), respectively. The most common reason for discontinuation was toxicity (26 patients, 22/278 [7.9%] in the DTG/3TC group and 4/137 [2.9%] in the DTG/RPV group), mainly neurologic toxicity (never above grade 2). We found no differences in discontinuation rates due to treatment adverse events. Two study participants experienced virological failure in the DTG/3TC arm. We observed no significant difference in CD4 cell counts, lipid parameters, or renal function between the two groups at 48 weeks. This study demonstrated that, in clinical practice, a two-drug regimen with DTG/3TC or DTG/RPV is characterized by a low discontinuation rate and VF in virologically suppressed PLWHs switched from an NNRTI-based three antiretroviral drugs regimen.

Treatment success of rescue regimens after dual therapy failure in people living with HIV in a real-life setting.

OBJECTIVES: Few data on management of two-drug regimen (2DR) failure in people living with HIV (PLWH) are available. METHODS: Retrospective study of treatment-experienced PLWH on a 2DR who experienced virological failure (VF) [two consecutive viral loads (VLs) ≥50 copies/mL, single VL ≥1000 copies/mL, or antiretroviral therapy (ART) switch after single VL ≥50 copies/mL with previous blips] or discontinuation for toxicity (baseline). Integrase strand transfer inhibitor (INSTI)-based [one INSTI plus one nucleoside reverse transcriptase inhibitor (NRTI) (n = 78) or one non-NRTI (n = 20)] or boosted protease inhibitor (PI/b)-based [one PI/b plus one NRTI (n = 116) or one INSTI (n = 12)] 2DRs were included. Probabilities of treatment success (TS), VF and discontinuation for any other cause of rescue regimens were estimated by Kaplan-Meier curves. A stepwise Cox model was performed to assess predictors of TS. RESULTS: Overall, 226 PLWH were evaluated: at baseline, 144 individuals discontinued 2DR for toxicity and 82 had VF [median viraemia 81 (63-212) copies/mL]; 171 switched therapy (49.7% to triple regimen, 40.9% to different 2DR), while 55 (exclusively with VF) maintained failing regimens. Probabilities of 12- and 24-month TS were 75.6% and 64.7%, respectively. Higher TS probabilities were observed in individuals who switched ART at 2DR failure (P = 0.003) and PLWH who discontinued 2DR for toxicity (P = 0.008). Therapy switch was the only predictor of TS (P = 0.002). CONCLUSIONS: Overall probability of rescue regimens' TS introduced after 2DR failure is good. Prompt ART switch after 2DR failure is advisable.

Safety and Efficacy of Triple Therapy With Dolutegravir Plus 2 Nucleoside Reverse Transcriptase Inhibitors in Treatment-Naive Human Immunodeficiency Virus Type 2 Patients: Results From a 48-Week Phase 2 Study.

BACKGROUND: Integrase strand transfer inhibitor-based regimens are recommended for first-line therapy in human immunodeficiency virus type 2 (HIV-2). Nonetheless, dolutegravir (DTG) clinical trial data are lacking. METHODS: We conducted a phase 2, single-arm, open-label trial to evaluate the safety and efficacy of a triple therapy regimen that included DTG in persons with HIV-2 (PWHIV-2) in Portugal. Treatment-naive adults receive DTG in combination with 2 nucleoside reverse transcriptase inhibitors (NRTIs). Treatment efficacy was evaluated by the proportion of patients who achieved a plasma viral load (pVL) <40 copies/mL and/or by the change from baseline in CD4+ T-cell count and in CD4/CD8 ratio at week 48. RESULTS: A total of 30 patients were enrolled (22 women; median age, 55 years). At baseline, 17 (56.7%) individuals were viremic (median, pVL 190 copies/mL; interquartile range [IQR], 99-445). The median CD4 count was 438 cells/µL (IQR, 335-605), and the CD4/CD8 ratio was 0.8. Three patients discontinued the study. At week 48, all participants (27) had pVL <40 copies/mL. No virological failures were observed. Mean changes in CD4 count and CD4/CD8 ratio at week 48 were 95.59 cells/µL (95% confidence interval [CI], 28-163) and 0.32 (95% CI, .19 to .46). The most common drug-related adverse events were headache and nausea. One participant discontinued due to central nervous system symptoms. No serious adverse events were reported. CONCLUSIONS: DTG plus 2 NRTIs is safe and effective as first-line treatment for PWHIV-2 with a tolerability profile previously known. No virological failures were observed that suggest a high potency of DTG in HIV-2 as occurs in HIV-1. CLINICAL TRIALS REGISTRATION: M NCT03224338.

The effects of ART on the dynamics of lipid profiles in Chinese Han HIV-infected patients: comparison between NRTI/NNRTI and NRTI/INSTI.

Introduction: This article aimed to compare the prevalence of dyslipidemia and determine risk factors associated with lipid levels in a cohort of HIV-infected patients receiving two different antiretroviral therapy (ART) regimens, nucleoside reverse transcriptase inhibitor/non-nucleoside reverse transcriptase inhibitor (NRTI/NNRTI) and nucleoside reverse transcriptase inhibitor/integrase strand transfer inhibitor (NRTI/INSTI). Methods: This longitudinal study analyzed 633 HIV-infected patients with complete blood lipid profile records for at least 1 year at the ART clinic of Zhongnan Hospital of Wuhan University, China, from June 2018 to March 2021. Demographic and clinical data, including age, gender, body weight, height, current/former/non-smoker, current drinker, diabetes mellitus, hypertension, were extracted from electronic medical records. Laboratory tests included hematology, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Lipoprotein(a) and CD4 cell count. The observation duration of this study was a maximum of 33 months. Data comparisons were performed using the Chi-square test, Student's t-test and Mann-Whitney U test. Generalized linear mixed-effects model (GLMM) and value of p < 0.05 were used to determine factors associated with serum lipid profiles. Results: In this study, the effect of the NNRTIs group on the lipid profile over time was mainly an increase in TC and HDL-C, while a decrease in TC/HDL-C and LDL/HDL-C. However, the INSTIs group had higher mean TC and lower HDL-C compared to the NNRTIs group, with significantly increased levels of TC, TG, HDL-C, and LDL-C. In the analysis of dyslipidemia rates, there were significant differences in the prevalence of abnormal TG and TC/HDL-C in HIV-infected patients receiving two different ART regimen groups during different follow-up periods. Dyslipidemia, defined as hypercholesterolemia, hypertriglyceridemia, and low HDL-C, was more prevalent in the INSTIs group, with a higher risk of developing hypertriglyceridemia and a higher TC/HDL-C ratio compared to the NNRTIs group. GLMM analysis suggested significantly higher TG values in the INSTIs group (estimated 0.36[0.10, 0.63], SE 0.14, p = 0.008) compared to the NNRTIs group, even after adjusting for other covariates. In addition, GLMM analysis also showed that age, gender, BMI, CD4 count, and ART duration were associated with dyslipidemia. Conclusion: In conclusion, treatment with both commonly-used ART regimens can increase the mean values of lipid profiles and the risk of dyslipidemia. The findings indicated that TG values were significantly higher in the INSTIs group than in HIV-infected patients receiving the NNRTIs regimens. Longitudinal TG values are independently associated with the clinical types of ART regimens.Clinical Trial Number: ChiCTR2200059861.

Association between integrase strand transfer inhibitor use with insulin resistance and incident diabetes mellitus in persons living with HIV: a systematic review and meta-analysis.

Whether integrase strand transfer inhibitors (INSTIs) are associated with a higher risk of incident type 2 diabetes mellitus (DM) than other antiretroviral therapies (ART) needs to be established.MEDLINE, Embase, Web of Science, and ClinicalTrials.gov registries were searched for studies published between 1 January 2000 and 15 June 2022. Eligible studies reported incident DM or mean changes in insulin resistance measured by Homeostatic Model for Insulin Resistance (HOMA-IR) in patients on INSTIs compared with other ARTs. We performed random-effects meta-analyses to obtain pooled relative risks (RRs) with 95% CIs.A total of 16 studies were pooled: 13 studies meta-analyzed for incident diabetes with a patient population of 72 404 and 3 for changes in HOMA-IR. INSTI therapy was associated with a lower risk of incident diabetes in 13 studies (RR 0.80, 95% CI 0.67 to 0.96, I2=29%), of which 8 randomized controlled trials demonstrated a 22% reduced risk (RR 0.88, 95% CI 0.81 to 0.96, I2=0%). INSTIs had a lower risk compared with non-nucleoside reverse transcriptase inhibitors (RR 0.75, 95% CI 0.63 to 0.89, I2=0%) but similar to protease inhibitor-based therapy (RR 0.78, 95% CI 0.61 to 1.01, I2=27%). The risk was lower in studies with longer follow-up (RR 0.70, 95% CI 0.53 to 0.94, I2=24%) and among ART-naïve patients (RR 0.78, 95% CI 0.65 to 0.94, I2=3%) but increased in African populations (RR 2.99, 95% CI 2.53 to 3.54, I2=0%).In conclusion, exposure to INSTIs was not associated with increased risk of DM, except in the African population. Stratified analyses suggested reduced risk among ART-naïve patients and studies with longer follow-up.International Prospective Register of Systematic Reviews (PROSPERO) registration number: CRD42021273040.

Predictors of virologic outcome among people living with HIV who continue a protease inhibitor-based antiretroviral regimen following virologic failure with no or limited resistance.

BACKGROUND: Treatment management after repeated failure of antiretroviral therapy (ART) is difficult due to resistance and adherence challenges. For people who have failed non-nucleoside reverse transcriptase inhibitor-(NNRTI-) and protease inhibitor-(PI-) based regimens with no or limited resistance, remaining on PI-based ART is an option. Using data from an ART strategy trial (A5288) in low/middle-income countries which included this option, we explored whether predictors can be identified distinguishing those who experienced further virologic failure from those who achieved and maintained virologic suppression. METHODS: A5288 enrolled people with confirmed HIV-1 RNA ≥ 1000 copies/mL after ≥ 24 weeks of PI-based ART and prior failure on NNRTI-based ART. This analysis focused on the 278 participants with no resistance to the PI being taken and no or limited nucleoside reverse transcriptase inhibitor (NRTI) resistance, who continued their PI with flexibility to change NRTIs. Proportional hazards models were used to evaluate predictors of virologic failure during follow-up (VF: confirmed HIV-1 RNA ≥ 1000 copies/mL at ≥ 24 weeks of follow-up). RESULTS: 56% of participants were female. At study entry, median age was 40 years, time on ART 7.8 years, CD4 count 169 cells/mm3, HIV-1 RNA 20,444 copies/mL; and 37% had NRTI resistance. The estimated proportion experiencing VF increased from 39% at week 24 to 60% at week 96. In multivariable analysis, significant predictors at study entry of VF were higher HIV-1 RNA (adjusted hazard ratio: 2.20 for ≥ 10,000 versus < 10,000 copies/mL), lower age (1.96 for < 30 versus ≥ 30 years), NRTI resistance (1.74 for present versus absent), lower CD4 count (1.73 for < 200 versus ≥ 200 cells/mm3), and shorter ART duration (1.62 for < 10 versus ≥ 10 years). There was a strong trend in proportion with VF at week 96 with the number of these five risk factors that a participant had, varying from 8% for zero, to 31%, 40%, 73%, and 100% for one, two, three, and four/five. Only 13% of participants developed new NRTI or PI resistance mutations. CONCLUSION: A simple count of five predictors might have value for identifying risk of continued VF. Novel antiretroviral and adherence support interventions are needed to improve virologic outcomes for higher risk individuals.

Adverse perinatal outcomes associated with prenatal exposure to protease-inhibitor-based versus non-nucleoside reverse transcriptase inhibitor-based antiretroviral combinations in pregnant women with HIV infection: a systematic review and meta-analysis.

BACKGROUND: About 1.3 million pregnant women lived with HIV and were eligible to receive antiretroviral therapy (ART) worldwide in 2021. The World Health Organization recommends protease inhibitors (PI)-based regimen as second or third-line during pregnancy. With remaining pregnant women exposed to PIs, there is still an interest to assess whether this treatment affects perinatal outcomes. Adverse perinatal outcomes after prenatal exposure to PI-based ART remain conflicting: some studies report an increased risk of preterm birth (PTB) and low-birth-weight (LBW), while others do not find these results. We assessed adverse perinatal outcomes associated with prenatal exposure to PI-based compared with non-nucleoside reverse transcriptase (NNRTI)-based ART. METHODS: We performed a systematic review searching PubMed, Reprotox, Clinical Trial Registry (clinicaltrials.gov) and abstracts of HIV conferences between 01/01/2002 and 29/10/2021. We used Oxford and Newcastle-Ottawa scales to assess the methodological quality. Studied perinatal outcomes were spontaneous abortion, stillbirth, congenital abnormalities, PTB (< 37 weeks of gestation), very preterm birth (VPTB, < 32 weeks of gestation), LBW (< 2500 grs), very low-birth-weight (VLBW, < 1500 g), small for gestational age (SGA) and very small for gestational age (VSGA). The association between prenatal exposure to PI-based compared to NNRTI-based ART was measured for each adverse perinatal outcome using random-effect meta-analysis to estimate pooled relative risks (RR) and their corresponding 95% confidence intervals (CI). Pre-specified analyses were stratified according to country income and study quality assessment, and summarized when homogeneous. RESULTS: Out of the 49,171 citations identified, our systematic review included 32 published studies, assessing 45,427 pregnant women. There was no significant association between prenatal exposure to PIs compared to NNRTIs for VPTB, LBW, SGA, stillbirth, and congenital abnormalities. However, it was inconclusive for PTB, and PI-based ART is significantly associated with an increased risk of VSGA (sRR 1.41 [1.08-1.84]; I2 = 0%) compared to NNRTIs. CONCLUSIONS: We did not report any significant association between prenatal exposure to PIs vs NNRTIs-based regimens for most of the adverse perinatal outcomes, except for VSGA significantly increased (+ 41%). The evaluation of antiretroviral exposure on pregnancy outcomes remains crucial to fully assess the benefice-risk balance, when prescribing ART in women of reproductive potential with HIV. PROSPERO NUMBER: CRD42022306896.

Safety and Pharmacokinetics of Islatravir in Individuals with Severe Renal Insufficiency.

Islatravir (MK-8591) is a high-potency reverse transcriptase translocation inhibitor in development for the treatment of HIV-1 infection. Data from preclinical and clinical studies suggest that ~30% to 60% of islatravir is excreted renally and that islatravir is not a substrate of renal transporters. To assess the impact of renal impairment on the pharmacokinetics of islatravir, an open-label phase 1 trial was conducted with individuals with severe renal insufficiency (RI). A single dose of islatravir 60 mg was administered orally to individuals with severe RI (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and to healthy individuals without renal impairment (matched control group; eGFR ≥90 mL/min/1.73 m2). Safety and tolerability were assessed, and blood samples were collected to measure the pharmacokinetics of islatravir and its major metabolite 4'-ethynyl-2-fluoro-2'deoxyinosine (M4) in plasma, as well as active islatravir-triphosphate (TP) in peripheral blood mononuclear cells (PBMCs). Plasma islatravir and M4 area under the concentration-time curve from zero to infinity (AUC0-∞) were ~2-fold and ~5-fold higher, respectively, in participants with severe RI relative to controls, whereas islatravir-TP AUC0-∞ was ~1.5-fold higher in the RI group than in the control group. The half-lives of islatravir in plasma and islatravir-TP in PBMCs were longer in participants with severe RI than in controls. These findings are consistent with renal excretion playing a major role in islatravir elimination. A single oral dose of islatravir 60 mg was generally well tolerated. These data provide guidance regarding administration of islatravir in individuals with impaired renal function. (This study has been registered at ClinicalTrials.gov under registration no. NCT04303156.).

EDP-514 in healthy subjects and nucleos(t)ide reverse transcriptase inhibitor-suppressed patients with chronic hepatitis B.

BACKGROUND: Chronic hepatitis B (CHB) remains a major cause of morbidity and mortality. EDP-514 is a potent core inhibitor of hepatitis B virus (HBV) that reduces viral load reduction in HBV-infected chimeric mice. This first-in-human study evaluated the safety, tolerability, and pharmacokinetics (PK) of EDP-514 in healthy subjects and antiviral activity in patients with CHB. METHODS: In Part 1, 82 subjects received placebo or EDP-514 in fed or fasted state as single ascending doses of 50-800 mg and multiple ascending doses of 200-800 mg for 14 days. In Part 2, 24 HBV DNA-suppressed, nucleos(t)ide (NUC)-treated (i.e., NUC-suppressed) CHB patients received EDP-514 200-800 mg or placebo for 28 days. RESULTS: EDP-514 was well tolerated in healthy subjects and CHB patients with most adverse events of mild intensity. In Part 1, EDP-514 exposure increased in an approximately dose proportional manner up to 600 mg after single doses and up to 400 mg after 14-day dosing. In Part 2, EDP-514 exposure increased linearly with dose on Day 1 and Day 28, with some accumulation for Day 28 and median trough concentrations (Ctrough) approximately 20-fold above the protein-adjusted 50% effective concentration (EC50) for the dose range. Mean change in HBV RNA from baseline to Day 28 was -2.03, -1.67, -1.87, and -0.58 log U/mL in the 200 mg, 400 mg, 800 mg, and placebo CHB groups, respectively. CONCLUSIONS: EDP-514 was well tolerated, had a PK profile supporting once daily dosing, and reduced HBV RNA levels in NUC-suppressed CHB patients.

Safety and efficacy of abacavir for treating infants, children, and adolescents living with HIV: a systematic review and meta-analysis.

BACKGROUND: Abacavir is a nucleoside reverse transcriptase inhibitor recommended in paediatric HIV care. We assessed the safety and efficacy profile of abacavir used in first, second, or subsequent lines of treatment for infants, children, and adolescents living with HIV to inform 2021 WHO paediatric ART recommendations. METHODS: In this systematic review and meta-analysis, we included observational and experimental studies conducted in infants aged 0-1 year, children aged 1-10 years, and adolescents aged 10-19 years living with HIV; with data on safety or efficacy, or both, of abacavir-based antiretroviral therapy (ART); published in English or French between Jan 1, 2009, and Oct 1, 2020, plus an updated search to incorporate studies published between Oct 1, 2020, and May 15, 2022. Studies could be non-randomised or non-comparative and include patients who are treatment-naive or those who previously received abacavir (only if abacavir was combined with other ART). Case studies, studies in adults aged 18 years or older, and those assessing the effect of maternal ART exposure were excluded. We extracted data related to study identifier, study design, study period, setting, population characteristics, ART treatment, and safety (any hypersensitivity reaction, death, grade 3 or 4 adverse events, treatment discontinuation, any other morbidities, and serious adverse events), and efficacy outcomes (HIV viral load and CD4 counts reported at 6 and 12 months after ART initiation). Using random-effect models, we estimated weighted pooled incidence and relative risk (RR) of outcomes. The protocol is published in PROSPERO (CRD42022309230). FINDINGS: Of 1777 records identified, 1475 (83%) were screened after removing duplicates and a further 1421 (96%) were excluded. Of 54 full-text articles assessed for eligibility, 33 (61%) were excluded. Four records were identified from grey literature plus one duplicate from database searching, resulting in 24 studies included (two randomised controlled trials, one single-arm trial, 12 prospective cohorts, seven retrospective cohorts, and two cross-sectional studies). 19 studies described safety data and 15 described efficacy data. 18 (75%) studies were conducted in ART-naive participants. The risk of bias was considered moderate to high for most studies, and all outcomes had significant between-study heterogeneity. Data from 24 265 participants were included, of whom 7236 (30%) received abacavir. Abacavir hypersensitivity reaction was reported in nine (38%) studies, with an incidence ranging from 0·00% to 8·26% (I2=85%; p<0·0001). The incidence of death (reported in seven studies) following abacavir treatment varied from 0·00% to 5·49% (I2=58%; p=0·026). Viral suppression (<400 copies per mL) varied from 50% to 70% at 6 months (I2=92%, p<0·0001) and from 57% to 78% at 12 months (I2=88%, p<0·0001). INTERPRETATION: Toxic effects due to abacavir use remain rare and manageable. Despite scarce data on efficacy, this meta-analysis supports the use of abacavir as a preferred first-line regimen for infants and children living with HIV. FUNDING: WHO.

Brief Report: Efficacy and Safety of Oral Islatravir Once Daily in Combination With Doravirine Through 96 Weeks for Treatment-Naive Adults With HIV-1 Infection Receiving Initial Treatment With Islatravir, Doravirine, and Lamivudine.

BACKGROUND: Islatravir (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor in development for treatment and prevention of HIV-1. We present efficacy and safety data for islatravir and doravirine (DOR) through 96 weeks of the phase 2b trial (NCT03272347). METHODS: In this randomized, double-blind, dose-ranging trial, participants initially received islatravir (0.25, 0.75, or 2.25 mg) with doravirine (100 mg) and lamivudine (3TC, 300 mg) or a fixed-dose combination of doravirine, 3TC, and tenofovir disoproxil fumarate (DOR/3TC/TDF) daily. Beginning at week 24, participants receiving islatravir stopped 3TC if HIV-1 RNA from the prior visit was <50 copies per milliliter and continued taking the assigned islatravir dose (still blinded) with doravirine. All islatravir groups transitioned to open-label use of 0.75 mg between weeks 60 and 84. Efficacy end points at week 96 included the proportion of participants maintaining HIV-1 RNA of <50 copies per milliliter (FDA Snapshot). Safety was assessed by adverse event (AE) reporting. RESULTS: One hundred twenty-one treatment-naive participants received the study drugs and were included in the analyses. Through week 96, HIV-1 RNA<50 copies per milliliter was maintained in 86.2% (25/29), 90.0% (27/30), and 67.7% (21/31) of participants in the 0.25-, 0.75-, and 2.25-mg islatravir groups, respectively, 81.1% (73/90) of the combined islatravir group, and 80.6% (25/31) of the DOR/3TC/TDF group. One participant in the 2.25-mg islatravir group had Protocol-Defined Virologic Failure after week 48. Drug-related AE rates were higher for DOR/3TC/TDF participants (22.6%) compared with islatravir (combined 7.8%). Two participants (2.2%) receiving islatravir with doravirine and one (3.2%) receiving DOR/3TC/TDF discontinued because of an AE. CONCLUSIONS: Treatment regimens containing islatravir and doravirine maintained viral suppression through week 96 and were well tolerated regardless of dose.

Dyslipidemia Secondary to the Use of HAART in Adults: A Systematic Review.

BACKGROUND: HIV infection affects millions of people globally. Currently, although several drugs have brought an improvement in the quality and life expectancy of these individuals, they are accompanied by several adverse effects. OBJECTIVE: To conduct a systematic review of studies examining the relationship between antiretroviral therapy (ART) uses and secondary dyslipidemia. METHODS: The review followed the criteria defined by PRISMA. Only articles that completely evaluated the lipid profile were included, which consisted of total cholesterol (TC), triglycerides (TG), and LDL cholesterol (LDL-c), HDL cholesterol (HDL-c). RESULTS: It was observed that the use of nucleoside and non-nucleoside reverse transcriptase inhibitor (NNRTI and NNRTI respectively) drugs and protease inhibitors are the most used in ART and are associated with changes in lipid profiles. The main changes observed were increases in TC, TG, and LDL-c in addition to a decrease in HDL-c. These patients had a higher risk of developing cardiovascular disease not only due to the use of therapy, but also due to the presence of other comorbidities evaluated in these studies, such as obesity, diabetes, and hypertension. The increase in age, the difference between genders, CD4 T-cell count, and viral load, were observed as risk factors for worsening dyslipidemia. CONCLUSION: According to the findings of this study, anti-HIV therapy is linked to dyslipidemia, which may or may not be the primary cause, and is frequently connected with a number of metabolic problems that can exacerbate the illness.

Cumulative effects of hypertriglyceridemia in HIV-infected patients switching from NNRTIs to PI-based antiretroviral therapy.

INTRODUCTION: The objective of this study was to investigate changes in serum lipids among HIV-infected patients switching from non-nucleoside-reverse transcriptase inhibitors (NNRTI) to protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), and to determine if changes of lipid profiles impacted the monocyte subsets recovery. METHODOLOGY: Fifty-seven subjects who switched from NNRTIs to PI-based HAART (NNRTIs to PI group) and fifty-five subjects who initially started with PI-based HAART (initial PI group) were recruited. According to their baseline triglyceride (TG) levels, the NNRTIs to PI and initial PI groups were further divided into non-hypertriglyceridemia and hypertriglyceridemia subgroups, respectively. The effects of PI-based HAART on lipid profiles and monocyte subsets were analyzed. RESULTS: At 48 weeks, the TG changes in the NNRTIs to PI group was higher than that of the initial PI group. The increases of serum TG levels in the initial PI non-hypertriglyceridemia group was greater than that of the NNRTIs to PI non-hypertriglyceridemia group. For the hypertriglyceridemia group at baseline, significant increment in TG levels were observed in the NNRTIs to PI hypertriglyceridemia group. The percentages of circulating CD14highCD16+ and CD14lowCD16+ subsets were elevated in the two groups. At 48 weeks, the proportion of CD14highCD16+ monocytes declined gradually, and the proportion of CD14lowCD16+ monocytes decreased independently of the TG level. CONCLUSIONS: For non-hypertriglyceridemia individuals at baseline, PI-based regimens increased the TG level in the initial PI group. For the NNRTIs to PI hypertriglyceridemia group, PI-based regimens reinforced HAART-related hypertriglyceridemia.

Incidence of hypertension in people with HIV who are treated with integrase inhibitors versus other antiretroviral regimens in the RESPOND cohort consortium.

OBJECTIVE: To compare the incidence of hypertension in people living with HIV receiving integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) versus non-nucleoside reverse transcriptase inhibitors (NNRTIs) or boosted protease inhibitors (PIs) in the RESPOND consortium of HIV cohorts. METHODS: Eligible people with HIV were aged ≥18 years who initiated a new three-drug ART regimen for the first time (baseline), did not have hypertension, and had at least two follow-up blood pressure (BP) measurements. Hypertension was defined as two consecutive systolic BP measurements ≥140 mmHg and/or diastolic BP ≥90 mmHg or initiation of antihypertensives. Multivariable Poisson regression was used to determine adjusted incidence rate ratios (aIRRs) of hypertension, overall and in those who were ART naïve or experienced at baseline. RESULTS: Overall, 4606 people living with HIV were eligible (INSTIs 3164, NNRTIs 807, PIs 635). The median baseline systolic BP, diastolic BP, and age were 120 (interquartile range [IQR] 113-130) mmHg, 78 (70-82) mmHg, and 43 (34-50) years, respectively. Over 8380.4 person-years (median follow-up 1.5 [IQR 1.0-2.7] years), 1058 (23.0%) participants developed hypertension (incidence rate 126.2/1000 person-years, 95% confidence interval [CI] 118.9-134.1). Participants receiving INSTIs had a higher incidence of hypertension than those receiving NNRTIs (aIRR 1.76; 95% CI 1.47-2.11), whereas the incidence was no different in those receiving PIs (aIRR 1.07; 95% CI 0.89-1.29). The results were similar when the analysis was stratified by ART status at baseline. CONCLUSION: Although unmeasured confounding and channelling bias cannot be excluded, INSTIs were associated with a higher incidence of hypertension than were NNRTIs, but rates were similar to those of PIs overall, in ART-naïve and ART-experienced participants within RESPOND.