45 research outputs found
Final 192-week ffficacy and safety results of the ADVANCE trial, comparing 3 first-line antiretroviral regimens
No full textBackground: ADVANCE compared 3 World Health Organization-recommended first-line regimens in participants with HIV who were antiretroviral naive.Methods: This randomized, open-label, noninferiority trial enrolled participants living with HIV with no antiretroviral exposure in the previous 6 months to 1 of the following arms: tenofovir alafenamide (TAF) / emtricitabine (FTC) + dolutegravir (DTG) (2 tablets), tenofovir disoproxil fumarate (TDF) / FTC + DTG (2 tablets), or a fixed-dose combination of TDF / FTC / efavirenz (EFV) (1 tablet). We report the final safety and efficacy data up to 192 weeks.Results: Repeat consent from the original 351 participants randomized to each arm was obtained from 230 participants (66%) in the TAF/FTC + DTG arm, 209 (60%) in the TDF/FTC + DTG arm, and 183 (52%) in the TDF/FTC/EFV arm. At 192 weeks, 213 (61%) of the original 351 participants in the TAF/FTC + DTG arm, 195 (56%) in the TDF/FTC + DTG arm, and 172 (49%) in the TDF/FTC/EFV arm had confirmed RNA <50 copies/mL, with low virologic failure in all groups and no significant integrase inhibitor mutations in any arm. Mean weight gain was 8.9 kg (SD, 7.1) in the TAF/FTC + DTG arm, 5.9 kg (SD, 7.1) in the TDF/FTC + DTG arm, and 3.2 kg (SD, 8.1) in the TDF/FTC/EFV arm at 192 weeks from baseline and was greatest among women, those taking TAF, and those with lower baseline CD4 counts. The weight trajectory slowed after week 96. There were few clinical events and minor laboratory changes and differences among arms after 96 weeks. There were no significant differences in treatment-emergent hypertension or pregnancy outcomes by arm.Conclusions: High viral suppression was seen across arms, with no resistance to DTG. Weight gain continued but slowed after 96 weeks, with few clinical events or laboratory changes
Dolutegravir plus two different prodrugs of Tenofovir to treat HIV
No full textBackground
Two drugs under consideration for inclusion in antiretroviral therapy (ART) regimens for human immunodeficiency virus (HIV) infection are dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF). There are limited data on their use in low- and middle-income countries.
Methods
We conducted a 96-week, phase 3, investigator-led, open-label, randomized trial in South Africa, in which we compared a triple-therapy combination of emtricitabine (FTC) and DTG plus either of two tenofovir prodrugs — TAF (TAF-based group) or tenofovir disoproxil fumarate (TDF) (TDF-based group) — against the local standard-of-care regimen of TDF–FTC–efavirenz (standard-care group). Inclusion criteria included an age of 12 years or older, no receipt of ART in the previous 6 months, a creatinine clearance of more than 60 ml per minute (>80 ml per minute in patients younger than 19 years of age), and an HIV type 1 (HIV-1) RNA level of 500 copies or more per milliliter. The primary end point was the percentage of patients with a 48-week HIV-1 RNA level of less than 50 copies per milliliter (as determined with the Snapshot algorithm from the Food and Drug Administration; noninferiority margin, −10 percentage points). We report the primary (48-week) efficacy and safety data.
Results
A total of 1053 patients underwent randomization from February 2017 through May 2018. More than 99% of the patients were black, and 59% were female. The mean age was 32 years, and the mean CD4 count was 337 cells per cubic millimeter. At week 48, the percentage of patients with an HIV-1 RNA level of less than 50 copies per milliliter was 84% in the TAF-based group, 85% in the TDF-based group, and 79% in the standard-care group, findings that indicate that the DTG-containing regimens were noninferior to the standard-care regimen. The number of patients who discontinued the trial regimen was higher in the standard-care group than in the other two groups. In the per-protocol population, the standard-care regimen had equivalent potency to the other two regimens. The TAF-based regimen had less effect on bone density and renal function than the other regimens. Weight increase (both lean and fat mass) was greatest in the TAF-based group and among female patients (mean increase, 6.4 kg in the TAF-based group, 3.2 kg in the TDF-based group, and 1.7 kg in the standard-care group). No resistance to integrase inhibitors was identified in patients receiving the DTG-containing regimens.
Conclusions
Treatment with DTG combined with either of two tenofovir prodrugs (TAF and TDF) showed noninferior efficacy to treatment with the standard-care regimen. There was significantly more weight gain with the DTG-containing regimens, especially in combination with TAF, than with the standard-care regimen. (ADVANCE ClinicalTrials.gov number, NCT03122262. opens in new tab.
Effect of obesity on dolutegravir exposure in Black Southern African adults living with HIV
No full textPharmacokinetics, pharmacogenetics, and toxicity of co-administered efavirenz and isoniazid
No full textBackground: CYP2B6 slow metabolisers have higher efavirenz concentrations, which are further increased by isoniazid inhibiting efavirenz’s accessory metabolic pathway.
Objectives: We investigated the association between CYP2B6 genotype and toxicity in people living with HIV (PLWH) on isoniazid and efavirenz.
Method: We enrolled participants from the efavirenz arm of the ADVANCE trial (reference no.: NCT03122262), who received isoniazid and consented to genotyping. We compared efavirenz concentrations on and off isoniazid, stratified by CYP2B6 genotype. We explored associations between the CYP2B6 genotype and efavirenz concentrations on isoniazid; and changes over 24 weeks in lipids, alanine aminotransferase (ALT), fasting plasma glucose (FPG), sleep quality, and Modified Mini Screen (MMS) scores.
Results: A total of 168 participants, median age 31 years, 57% female, had classifiable CYP2B6 genotypes. Efavirenz concentrations on isoniazid were higher (pseudo-median difference 0.49 µg/mL (95% confidence interval [CI] [0.19–0.91]) and associated with increases in total and high-density lipoprotein (HDL)-cholesterol. CYP2B6 slow metabolisers had higher efavirenz concentrations on isoniazid than extensive metabolisers (β = 1.66 [95% CI 0.98–2.34]). CYP2B6 slow metabolisers had greater increases in total (β = 0.44 mmol/L [95% CI 0.01–0.86]) and HDL-cholesterol (β = 0.39 mmol/L [95% CI 0.21–0.57]) than extensive metabolisers. There were no associations between efavirenz concentrations or CYP2B6 genotype, and change in ALT, FPG, low-density lipoprotein (LDL)-cholesterol, triglycerides, sleep quality, or MMS scores.
Conclusion: CYP2B6 slow metabolisers on isoniazid and efavirenz had greater efavirenz concentrations and increases in total and HDL-cholesterol. We found no association between CYP2B6 genotype or efavirenz concentrations and sleep or psychiatric symptoms
Implications of weight gain with newer antiretrovirals 10year predictions of cardiovascular disease and diabetes
No full textThe predicted risk of adverse pregnancy outcomes as a result of treatmentassociated obesity in a hypothetical population receiving tenofovir alafenamideemtricitabinedolutegravir tenofovir disoproxil fumarateemtricitabinedolutegravir or tenofovir diso
No full textImplications of weight gain with newer anti-retrovirals: 10-year predictions of cardiovascular disease and diabetes
No full textWeight and metabolic changes after switching from tenofovir alafenamide/emtricitabine (FTC)+dolutegravir (DTG), tenofovir disoproxil fumarate (TDF)/FTC+DTG and TDF/FTC/efavirenz (EFV) to TDF/lamivudine /DTG
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