gs-7340 and efavirenz

Integrase inhibitors, including dolutegravir (DTG), are associated with weight gain and obesity, especially when combined with tenofovir alafenamide (TAF). Obesity increases the risk of adverse pregnancy outcomes (APOs). This study aimed to predict the risk of APOs caused by treatment-associated obesity, using a hypothetical sample based on the ADVANCE trial.. Risk prediction.. Firstly, a meta-analysis was performed to determine the relative risk (RR) for APOs in women with obese (≥30) versus normal prepregnancy BMIs (18.5-24.9). For the hypothetical sample, 3000 nonpregnant women with normal BMIs at Week 0 of treatment were evenly allocated across the following treatment arms: TAF/FTC+DTG, TDF/FTC+DTG, TDF/FTC/EFV. The treatment-associated obesity rates from ADVANCE were used to calculate the number of women with obese and normal BMIs expected at Week 96 in our sample. This was combined with the APO RRs to predict the number of women at risk of APOs, in each treatment arm, assuming they conceived at Week 96.. At Week 96, the percentage of women predicted to be obese was 14.1% with TAF/FTC+DTG, 7.9% with TDF/FTC+DTG and 1.5% with TDF/FTC/EFV. The RR in women with obese versus normal BMIs was significantly higher for most APOs. Therefore, the number of women at risk of APOs was higher with TAF/FTC+DTG than TDF/FTC+DTG and TDF/FTC/EFV. For example, 11/1000 additional gestational hypertension cases were predicted with TAF/FTC+DTG, 6/1000 with TDF/FTC+DTG and 1/1000 with TDF/FTC/EFV.. Treatment-associated obesity increased the APO risk in women. This risk is likely to increase, as preliminary data from ADVANCE demonstrates ongoing weight gain beyond Week 96.

Topics: Alanine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Obesity; Oxazines; Piperazines; Pregnancy; Pregnancy Outcome; Pyridones; Tenofovir

Reduced dose efavirenz, dolutegravir, and/or tenofovir alafenamide (TAF) are likely to be used in the next generation of first-line antiretroviral therapy in resource limited settings, where HIV-associated tuberculosis is common. Rifampicin, which is a key component of first-line antituberculosis therapy, is a potent inducer of many drug transporters and metabolising enzymes. We reviewed the literature for potential or actual drug--drug interactions between these antiretrovirals and rifampicin.. Dose adjustments of standard dose efavirenz are not necessary with rifampicin, because auto-induction of CYP2B6 by efavirenz counteracts the induction of rifampicin. However, patients with extensive metabolizer CYP2B6 genotypes have lower efavirenz concentrations and may have less auto-induction of CYP2B6; the additive inducing effects of rifampicin on CYP2B6 could result in clinically significant reductions of efavirenz concentrations. Doubling the dose of dolutegravir overcomes induction by rifampicin. TAF is more prone to be the victim in drug--drug interactions than tenofovir disoproxil fumarate. Interactions between TAF and rifampicin have not been studied, but there is likely to be significant interaction.. Further research on drug--drug interactions between rifampicin and the next generation of first-line antiretrovirals will be needed before they can be recommended in patients with HIV-associated tuberculosis.

Topics: Adenine; Alanine; Alkynes; Anti-Retroviral Agents; Antitubercular Agents; Benzoxazines; Cyclopropanes; Cytochrome P-450 CYP2B6; Drug Interactions; Heterocyclic Compounds, 3-Ring; HIV Infections; Humans; Oxazines; Piperazines; Pyridones; Rifampin; Tenofovir

ADVANCE compared the efficacy and safety of two antiretroviral first-line combinations (dolutegravir combined with emtricitabine and either tenofovir disoproxil fumarate or tenofovir alafenamide), with a third regimen (efavirenz combined with emtricitabine and tenofovir disoproxil fumarate) previously recommended by WHO. Here, we report the 96-week data for the study.. This randomised, open-label, non-inferiority phase 3 trial, was done at two research sites in Johannesburg, South Africa, after participant recruitment from 11 public health clinics also in Johannesburg. Eligible participants were aged 12 years or older with HIV-1 infection, who weighed at least 40 kg, had no antiretroviral exposure in the previous 6 months, with a creatinine clearance of more than 60 mL/min (>80 mL per min in individuals aged <19 years), and a plasma HIV-1 RNA concentration of 500 copies per mL or higher. Individuals who were pregnant or had tuberculosis were excluded. Participants were randomly assigned (1:1:1) by study staff using a computerised randomisation system. Randomisation was stratified by age (12 and <19 years and ≥19 years). Participants were randomly assigned to once-daily oral fixed-dose combination tenofovir alafenamide 25 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; once-daily oral fixed-dose combination tenofovir disoproxil fumarate 300 mg and emtricitabine 200 mg, and once-daily oral dolutegravir 50 mg; or once-daily oral fixed-dose combination of tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and efavirenz 600 mg. The primary efficacy endpoint was the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at week 48, which has been reported previously. Here, we report the key secondary efficacy endpoint of the proportion of participants who had a plasma HIV-1 RNA concentration of less than 50 copies per mL at the week 96 visit, assessed in all participants who received at least one dose of any study drug, with a prespecified non-inferiority margin of -10%. Safety data, including clinical, dual-energy X-ray absorptiometry and laboratory data, are also reported. This study was registered with ClinicalTrials.gov, NCT03122262.. Between Jan 17, 2017, and May 14, 2018, we screened 1453 individuals, of whom 1053 were enrolled: 351 participants were randomly assigned to the tenofovir alafenamide, emtricitabine, and dolutegravir group, 351 to the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 351 to the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group. All participants received at least one dose of study medication and were included in the primary analysis. At week 96, 276 (79%) of 351 participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group, 275 (78%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 258 (74%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group had achieved a plasma HIV-1 RNA concentration of less than 50 copies per mL. Non-inferiority was established in all three comparisons. The proportion of patients with protocol-defined virological failure at week 96 was low in all treatment groups. Participants in the tenofovir alafenamide, emtricitabine, and dolutegravir group had fewer changes in bone density than the two other treatment groups. Mean weight gain was substantial (7·1 kg [SD 7·4] in the tenofovir alafenamide, emtricitabine, and dolutegravir group; 4·3 kg [6·7] in the tenofovir disoproxil fumarate, emtricitabine, and dolutegravir group, and 2·3 kg [7·0] in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group), and was greater among women than men. Ten (3%) of 351 participants in the tenofovir disoproxil fumarate, emtricitabine, and efavirenz group discontinued due to treatment-related adverse events, of which liver dysfunction (n=4) and rash (n=4) were most common.. Medium-term and long-term metabolic and clinical consequences of the considerable increase in bodyweight observed in participants given these antiretroviral regimens and the trajectory of this weight gain over time, especially among women, require further study.. USAID, Unitaid, South African Medical Research Council, ViiV Healthcare.

Topics: Adenine; Adolescent; Adult; Alanine; Alkynes; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Benzoxazines; Body Composition; Body Weight; Cyclopropanes; Duration of Therapy; Emtricitabine; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV-1; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Treatment Outcome; Viral Load; Young Adult

Tenofovir alafenamide is a prodrug that reduces tenofovir plasma concentrations by 90% compared with tenofovir disoproxil fumarate, thereby decreasing bone and renal risks. The coformulation of rilpivirine, emtricitabine, and tenofovir alafenamide has recently been approved, and we aimed to investigate the efficacy, safety, and tolerability of switching to this regimen compared with remaining on coformulated efavirenz, emtricitabine, and tenofovir disoproxil fumarate.. In this randomised, double-blind, placebo-controlled, non-inferiority trial, HIV-1-infected adults were enrolled at 120 hospitals and outpatient clinics in eight countries in North America and Europe. Participants were virally suppressed (HIV-1 RNA <50 copies per mL) on efavirenz, emtricitabine, and tenofovir disoproxil fumarate for at least 6 months before enrolment and had creatinine clearance of at least 50 mL/min. Participants were randomly assigned (1:1) to receive a single-tablet regimen of rilpivirine (25 mg), emtricitabine (200 mg), and tenofovir alafenamide (25 mg) or to continue a single-tablet regimen of efavirenz (600 mg), emtricitabine (200 mg), and tenofovir disoproxil fumarate (300 mg), with matching placebo. Investigators, participants, study staff, and those assessing outcomes were masked to treatment group. The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 (assessed by the US Food and Drug Administration snapshot algorithm), with a prespecified non-inferiority margin of 8%. This study was registered with ClinicalTrials.gov, number NCT02345226.. Between Jan 26, 2015, and Aug 27, 2015, 875 participants were randomly assigned and treated (438 with rilpivirine, emtricitabine, and tenofovir alafenamide and 437 with efavirenz, emtricitabine, tenofovir disoproxil fumarate). Viral suppression at week 48 was maintained in 394 (90%) of 438 participants assigned to the tenofovir alafenamide regimen and 402 (92%) of 437 assigned to the tenofovir disoproxil fumarate regimen (difference -2·0%, 95·001% CI -5·9 to 1·8), demonstrating non-inferiority. 56 (13%) of 438 in participants in the rilpivirine, emtricitabine, and tenofovir alafenamide group experienced treatment-related adverse events compared with 45 (10%) of 437 in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group.. Switching to rilpivirine, emtricitabine, and tenofovir alafenamide from efavirenz, emtricitabine, and tenofovir disoproxil fumarate was non-inferior in maintaining viral suppression and was well tolerated at 48 weeks. These findings support guidelines recommending tenofovir alafenamide-based regimens, including coformulation with rilpivirine and emtricitabine, as initial and ongoing treatment for HIV-1 infection.. Gilead Sciences.

Topics: Adenine; Adult; Alanine; Alkynes; Anti-HIV Agents; Benzoxazines; Cyclopropanes; Drug Therapy, Combination; Emtricitabine; Female; HIV Infections; HIV-1; Humans; Middle Aged; Rilpivirine; Tenofovir

Though bictegravir/emtricitabine/tenofovir (BIC/FTC/TAF) have been regulatory approved and included in the National Reimbursement Drug List in China, due to the affordability concern, generic version of efavirenz + lamivudine + tenofovir (EFV + 3TC + TDF) is still recommended as the first-line therapy in the clinical guideline and widely used in clinical practice. The aim of the study is to assess the persistence with first-line BIC/TAF/TAF and EFV + 3TC + TDF in newly treated HIV-1 patients in the real-world setting in Hunan Province in China.. A retrospective analysis of the medical records of HIV patients initiating first-line antiretroviral therapy in the First Hospital of Changsha in January 1st, 2021-July 31st, 2022 was conducted. Persistence was assessed as the number of days on the therapy from the index until treatment discontinuation or end of data availability. Kaplan-Meier Curves and Cox Proportional Hazard models were used to evaluate the discontinuation rates. Subgroup analysis was performed excluding BIC/FTC/TAF patients with treatment discontinuation due to economic reason, and EFV + 3TC + TDF patients with a viral load > 500,000 copies/mL.. A total of 310 eligible patients were included in the study, with 244 and 66 patients in the BIC/FTC/TAF group and EFV + 3TC + TDF group, respectively. Compared with EFV + 3TC + TDF patients, BIC/FTC/TAF patients were older, more living in the capital city currently, and had significantly higher total cholesterol and low-density level (all p < 0.05). No significant difference was shown in the time to discontinuation between BIC/FTC/TAF patients and EFV + 3TC + TDF patients. After excluding BIC/FTC/TAF patients with treatment discontinuation due to economic reason, EFV + 3TC + TDF group were shown to have a significantly higher risk of discontinuation than BIC/FTC/TAF group (hazard ratio [HR] = 11.1, 95% confidence interval [CI] = 1.3-93.2). After further removing the EFV + 3TC + TDF patients with a viral load > 500,000 copies/mL, the analysis showed similar results (HR = 10.1, 95% CI = 1.2-84.1). 79.4% of the EFV + 3TC + TDF patients discontinued treatment due to clinical reasons, while 83.3% of the BIC/FTC/TAF patients discontinued treatment due to economic reasons.. Compared with BIC/FTC/TAF, EFV + TDF + 3TC patients were significantly more likely to discontinue the first-line treatment in Hunan Province in China.

Topics: China; Drug Combinations; Heterocyclic Compounds, 4 or More Rings; HIV Infections; HIV-1; Humans; Lamivudine; Retrospective Studies; Tenofovir

Topics: Anti-HIV Agents; Emtricitabine; HIV Infections; Humans; Tenofovir

We aimed to examine the evolution of blood lipids and compare the risk of dyslipidemia between antiretroviral-naive people living with HIV who received tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and efavirenz (EFV) (TDF + 3TC + EFV) and those who received coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide (E/C/F/TAF).. We retrospectively reviewed the medical records of 2343 antiretroviral-naive people living with HIV who initiated TDF + 3TC + EFV or E/C/F/TAF. A propensity score matching method was used to compare longitudinal changes of blood lipids between the 2 groups.. By using 1:3 matching ratio, we included 253 and 91 matched patients in TDF + 3TC + EFV group and E/C/F/TAF group, respectively. The levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol were higher in E/C/F/TAF group than those in TDF + 3TC + EFV group at 3, 6, 9, and 12 months (Wilcoxon test, all Ps < 0.05), except for high-density lipoprotein cholesterol at 9 and 12 months. The cumulative rates of hypercholesterolemia, hypertriglyceridemia, and high LDL-C in PLWH with normal lipid levels in E/C/F/TAF group were higher than those in TDF + 3TC + EFV group (hypercholesterolemia, 59.7% vs 21.5%, P < 0.001; hypertriglyceridemia, 69.5% vs 46.3%, P < 00.001; and high LDL-C, 41.5% vs 14.2%, P < 0.001). Multivariate analysis showed treatment with E/C/F/TAF was associated with a significantly higher risk of hypercholesterolemia [adjusted hazard ratio (HR), 4.12; 95% confidence interval (CI): 2.65 to 6.41], hypertriglyceridemia (adjusted HR, 1.69; 95% CI: 1.18 to 2.43), and high LDL-C (adjusted HR, 4.60; 95% CI: 2.66 to 7.97).. We concluded that treatment with E/C/F/TAF resulted in higher risks of dyslipidemia compared with TDF + 3TC + EFV.

Topics: Adenine; Alanine; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Cholesterol, LDL; Cobicistat; Cyclopropanes; Emtricitabine; HIV Infections; HIV-1; Humans; Hypercholesterolemia; Hypertriglyceridemia; Lamivudine; Lipoproteins, HDL; Quinolones; Retrospective Studies; Tenofovir

Central nervous system (CNS) symptoms after efavirenz (EFV) treatment in people living with human immunodeficiency virus (HIV) could persist and impact their quality of life. We assessed the impact of EFV-based regimen replacement with elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF), which is considered an alternative option for subjects who do not tolerate EFV. Most specifically, we assessed the safety and the efficacy of E/C/F/TAF and its effects on the participants' neuropsychiatric toxicity symptoms in a real-life setting.. A prospective cohort study was conducted among virologic suppressed HIV-positive participants receiving EFV-based regimens with ongoing CNS toxicity ≥ grade 2. The participants were switched to single-pill combination regimens E/C/F/TAF and followed up for 48 weeks. The neuropsychiatric toxicity symptoms were measured using a CNS side effects questionnaire, as well as the Hospital Anxiety and Depression Scale and the Pittsburgh Sleep Quality Index. The primary outcome measure was the proportion of participants experiencing grade 2 or higher CNS toxicity after EFV switch off at weeks 12, 24, and 48. Secondary endpoints included virologic and immunological responses and the effect on fasting lipids at week 48 after switch.. One hundred ninety-six participants (96.9% men, median age: 37.5 years, median: 3.7 years on prior EFV-containing regimens) were included in the study. Significant improvements in anxiety and sleep disturbance symptoms were observed at 12, 24, and 48 weeks after switching to E/C/F/TAF (P < 0.05). No significant change in depression symptom scores was observed. At 48 weeks after switch, HIV viral load <50 copies/mL was maintained in all of the participants, median fasting lipid levels were moderately increased (total cholesterol [TC]: 8.2 mg/dL, low-density lipoprotein cholesterol [LDL-C]: 8.5 mg/dL, high-density lipoprotein cholesterol [HDL-C]: 2.9 mg/dL, and triglyceride (TG): 1.6 mg/dL, and the TC:HDL-C ratio remained stable.. The single-pill combination regimens E/C/F/TAF is safe and well tolerated. This study reveals that switching from EFV to E/C/F/TAF significantly reduces neuropsychiatric toxicity symptoms in people living with HIV with grade 2 or higher CNS complaints.

Topics: Adenine; Adult; Alanine; Alkynes; Anti-HIV Agents; Benzoxazines; Central Nervous System; Cobicistat; Cyclopropanes; Drug Combinations; Emtricitabine; Female; HIV Infections; Humans; Male; Prospective Studies; Quality of Life; Quinolones; Sleep Quality; Tenofovir

Evaluate differences in weight change by regimen among people living with HIV (PLWH) initiating antiretroviral therapy (ART) in the current era.. Between 2012 and 2019, 3232 ART-naïve PLWH initiated ≥3-drug ART regimens in 8 Centers for AIDS Research Network of Integrated Clinical Systems sites. We estimated weight change by regimen for 11 regimens in the immediate (first 6 months) and extended (all follow-up on initial regimen) periods using linear mixed models adjusted for time on regimen, interaction between time and regimen, age, sex, race/ethnicity, hepatitis B/C coinfection, nadir CD4, smoking, diabetes, antipsychotic medication, and site. We included more recently approved regimens [eg, with tenofovir alafenamide fumarate (TAF)] only in the immediate period analyses to ensure comparable follow-up time.. Mean follow-up was 1.9 years on initial ART regimen. In comparison to efavirenz/tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC), initiating bictegravir/TAF/FTC {3.9 kg [95% confidence interval (CI): 2.2 to 5.5]} and dolutegravir/TAF/FTC [4.4 kg (95% CI: 2.1 to 6.6)] were associated with the greatest weight gain in the immediate period, followed by darunavir/TDF/FTC [3.7 kg (95% CI: 2.1 to 5.2)] and dolutegravir/TDF/FTC [2.6 kg (95% CI: 1.3 to 3.9)]. In the extended period, compared with efavirenz/TDF/FTC, initiating darunavir/TDF/FTC was associated with a 1.0 kg (95% CI: 0.5 to 1.5) per 6-months greater weight gain, whereas dolutegravir/abacavir/FTC was associated with a 0.6-kg (95% CI: 0.3 to 0.9) and dolutegravir/TDF/FTC was associated with a 0.6-kg (95% CI: 0.1 to 1.1) per 6-months greater gain. Weight gain on dolutegravir/abacavir/FTC and darunavir/TDF/FTC was significantly greater than that for several integrase inhibitor-based regimens.. There is heterogeneity between regimens in weight gain following ART initiation among previously ART-naïve PLWH; we observed greater gain among PLWH taking newer integrase strand transfer inhibitors (DTG, BIC) and DRV-based regimens.

Topics: Adult; Alanine; Alkynes; Anti-HIV Agents; Anti-Retroviral Agents; Benzoxazines; Cyclopropanes; Dideoxynucleosides; Female; Heterocyclic Compounds, 3-Ring; HIV Infections; HIV Integrase Inhibitors; Humans; Male; Middle Aged; Oxazines; Piperazines; Pyridones; Tenofovir; Weight Gain