Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis

BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.     

Therapeutic drug monitoring study on the switch from coformulated 600-mg efavirenz,tenofovir disoproxil fumarate,and emtricitabine to coformulated 400-mg efavirenz,tenofovir disoproxil fumarate,and lamivudine among HIV-positive patients with viral suppression

ObjectivesThis study evaluated the efavirenz (EFV) mid-dose plasma concentration (C12), clinical efficacy, and safety after the switch to a single-tablet regimen containing tenofovir disoproxil fumarate (TDF), lamivudine (3TC), and 400-mg EFV in virally suppressed HIV-positive Taiwanese who were receiving co-formulated TDF, emtricitabine (FTC), and 600-mg EFV.MethodsIn this single-arm, open-label study, HIV-positive adults who had undetectable plasma HIV RNA load (<50 copies/ml) for 6 months or longer while receiving co-formulated TDF, FTC, and 600-mg EFV with EFV C12 of ≥1 mg/L were enrolled. The participants were switched to co-formulated TDF, 3TC, and 400-mg EFV and followed for 24 weeks. The primary endpoint was the proportion of participants with EFV C12 ≥ 1 mg/L at Week 4. The secondary endpoints included virologic response and change of CD4 lymphocyte count up to Week 24. Specific adverse effects associated with EFV were recorded before and after the switch.ResultsFrom December 2018 to January 2019, 50 participants were enrolled. EFV C12 remained ≥1 mg/L in 48 (96.0%) participants with a median reduction of 38.9% (interquartile range 29.0–44.4) at Week 4 after switch. All participants had undetectable plasma HIV RNA by Week 12, whereas 96.0% of them remained so at Week 24. Significant increases of CD4 lymphocyte count were observed at Weeks 12 and 24. Thirty-three participants (66.0%) reported improvement of pre-existing adverse effects.ConclusionSwitch to coformulated TDF, 3TC, and 400-mg EFV in virally suppressed HIV-positive Taiwanese maintained effective EFV concentration and viral suppression while the adverse effects were reduced.     

Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients

BACKGROUND: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. METHODS: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. RESULTS: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057). CONCLUSIONS: After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.     

Systematic review of renal and bone safety of the antiretroviral regimen efavirenz,emtricitabine, and tenofovir disoproxil fumarate in patients with HIV infection

Background: Tenofovir disoproxil fumarate (TDF) is a component of many combinations of antiretroviral treatment (ART) regimens. Although potent and generally well tolerated, TDF may cause renal and bone toxicity. The magnitude of off-target side effects is proposed to be related to tenofovir plasma concentrations, which are affected by food and drug–drug interactions with concomitant antiretrovirals.

Objective: To perform a systematic literature review and qualitatively report on renal and bone safety outcomes associated with efavirenz (EFV), emtricitabine (FTC), and TDF (EFV+FTC+TDF) ART.

Methods: Embase and PubMed databases were searched for randomized clinical trials and observational cohort studies reporting on HIV treatment with EFV+FTC+TDF. Relevant articles were hand-searched for renal (Grade 3–4 serum creatinine/estimated glomerular filtration rate elevations, renal adverse events [AEs], discontinuation due to renal AEs, and urinary biomarkers) and bone outcomes (bone mineral density [BMD] reductions, bone turnover markers, and fracture), and results compiled qualitatively.

Results: Of 337 retrieved articles, 29 reporting renal and 11 reporting bone outcomes met the review criteria. EFV+FTC+TDF was associated with a low frequency of renal AEs and treatment discontinuations due to renal AEs. Renal AEs were more frequent when TDF was taken with protease inhibitor (PI)- or cobicistat-containing ART. EFV+FTC+TDF was associated with reduced BMD and increased bone turnover markers, but BMD reductions were less than with PI-containing ART. No treatment-related bone fractures were identified.

Conclusions: EFV+FTC+TDF appeared to have a more favorable renal safety profile than TDF administered with a PI or cobicistat. BMD decreased with EFV+FTC+TDF, but no treatment-related fractures were identified.     

Pharmacokinetics of emtricitabine, tenofovir, and GS-9137 following coadministration of emtricitabine/tenofovir disoproxil fumarate and ritonavir-boosted GS-9137

OBJECTIVES: To evaluate the potential for clinically relevant drug-drug interaction between emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) and the ritonavir-boosted HIV integrase inhibitor GS-9137 (GS-9137/r). METHODS: Healthy adults were administered FTC/TDF (200/300 mg once daily) for 7 days, followed by randomization to the order of receiving GS-9137/r (50/100 mg once daily) and GS-9137/r plus FTC/TDF in a crossover fashion under fed conditions for 10 days. Pharmacokinetic (PK) blood draws were performed on days 7, 17, and 27. Lack of PK alteration for FTC, tenofovir (TFV), and GS-9137 was defined as a 90% confidence interval (CI) for the estimated ratio of geometric least squares means (coadministration/alone) between 70% and 143% for the primary PK parameters: maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve over dosing interval (AUCtau), and trough concentration (Ctau). RESULTS: Twenty-four of the 26 enrolled subjects completed the study with no serious adverse events or discontinuations attributable to adverse events. FTC, TFV, and GS-9137 PKs were unaffected during coadministration, with Cmax, AUCtau, and Ctau, meeting the protocol definition of equivalence and also the stricter bioequivalence criteria (90% CI: 80% to 125%). FTC and TFV PK parameters were comparable to historical values. CONCLUSION: There is no clinically relevant drug-drug interaction between FTC/TDF and GS-9137/r on their coadministration.     

Effectiveness and safety of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate single-tablet combination among HIV-infected patients in Turkey: results from a real world setting

BackgroundEfficacy of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil (E/C/F/TDF) in treatment-naïve and experienced patients with HIV infection was demonstrated in phase 3 trials. The primary objective of this study was to evaluate effectiveness and safety of E/C/F/TDF in real world settings.MethodsRetrospective, observational data collected by the Turkish ACTHIV-IST study group between May 2015 and December 2016 were analysed.ResultsA total of 387 patients were prescribed E/C/F/TDF; 210 patients with available data at 6th month were eligible; 91.5% were male, and mean age was 35.2 (SD: 10.8) years; 54.0% of males identified themselves as MSM. Sixty-three percent (133) of the study population were treatment-naïve patients, and 37% (77) were treatment experienced. HIV RNA level was below 100 copies/mL in 78.9% of treatment-naïve patients and 89.9% of treatment experienced patients at month 6. Median increase in CD4 T lymphocyte count was 218 copies/mL in treatment-naïve patients and remained stable or increased in treatment experienced patients. Adverse events were observed in 15% of the patients, and the regimen was discontinued in only six patients.ConclusionReal world data on the effectiveness and safety of E/C/F/TDF is comparable with the phase 3 trial results Adverse events are uncommon and manageable.     

Comparison of once-daily atazanavir with efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial therapy for patients infected with HIV

BACKGROUND: Atazanavir, an azapeptide protease inhibitor (PI), has pharmacokinetics that allow once-daily dosing, and it is not associated with significant PI-associated dyslipidemia. METHODS: A randomized, double-blind, double-dummy, active-controlled, 2-arm study comparing the antiviral efficacy and safety of atazanavir 400 mg administered once daily with efavirenz 600 mg administered once daily in combination with open-label fixed-dose zidovudine plus lamivudine twice daily. The 810 treatment-naive patients were stratified by HIV RNA level. The primary efficacy end point was the proportion of treated patients with HIV RNA levels <400 copies/mL through week 48. RESULTS: At week 48, HIV RNA levels were <400 copies/mL in 70% of patients receiving atazanavir and 64% of patients receiving efavirenz (intent-to-treat, difference; 95% confidence interval: 5.2%; -1.2%, 11.7%). Median CD4 cell counts increased at comparable magnitudes and rates in the 2 treatment arms (mean change at week 48: 176 cells/mm with atazanavir, 160 cells/mm with efavirenz). Atazanavir-treated patients relative to comparator-treated patients did not demonstrate significant increases in total cholesterol, fasting low-density lipoprotein cholesterol, or fasting triglycerides over 48 weeks of therapy. Atazanavir-linked bilirubin elevations infrequently resulted in treatment discontinuation (<1%). Atazanavir treatment did not increase fasting glucose or insulin levels. CONCLUSIONS: For initial HIV treatment, a highly active antiretroviral therapy regimen of atazanavir/zidovudine/lamivudine is as efficacious and well tolerated as the combination of efavirenz/zidovudine/lamivudine.     

Assessment of drug-drug interactions between tenofovir disoproxil fumarate and the nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz in HIV-infected patients

BACKGROUND: Tenofovir disoproxil fumarate (DF) has been studied in combination with efavirenz in healthy volunteers and no interaction was found. No data are available on the possible interaction of tenofovir DF with nevirapine and efavirenz in HIV-infected patients. In this study the combination of nevirapine 200 mg twice daily with tenofovir DF 300 mg once daily and nevirapine 400 mg once daily with tenofovir DF 300 mg once daily were compared with nevirapine twice daily or once daily without tenofovir DF in HIV-infected patients. Furthermore, the combination of efavirenz 600 mg and tenofovir DF 300 mg once daily was compared with use of efavirenz 600 mg once daily only. METHODS: Data were retrospectively collected from routine therapeutic drug monitoring plasma samples. Nevirapine, efavirenz, and tenofovir plasma levels and tenofovir concentration ratios were analyzed. The concentration ratio represents the measured plasma concentration compared with the time-adjusted average concentration, as measured in a reference population. Six different groups were studied: 200 mg nevirapine twice daily, 400 mg nevirapine once daily, 600 mg efavirenz once daily, all without tenofovir DF (groups 1, 2, and 3, respectively), and the same groups with the drugs combined with tenofovir 300 mg once daily (groups 4, 5, and 6, respectively). RESULTS: Plasma samples were evaluable for 272, 18, 126, 32, 94, and 118 patients in the groups 1-6, respectively. No differences were found in plasma levels for tenofovir, nevirapine, and efavirenz for either of the combinations studied. Addition of tenofovir DF to efavirenz or nevirapine in HIV-infected patients does not influence the plasma levels of nevirapine or efavirenz. Furthermore, nevirapine and efavirenz have no effect on tenofovir plasma levels or tenofovir concentration ratios. CONCLUSION: Efavirenz or nevirapine can be coadministered with tenofovir DF in HIV-infected patients without dose modifications.     

Daily tenofovir disoproxil fumarate/emtricitabine and hydroxychloroquine for pre-exposure prophylaxis of COVID-19: a double-blind placebo-controlled randomized trial in healthcare workers

ObjectivesTo assess the effect of hydroxychloroquine (HCQ) and Tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) as pre-exposure prophylaxis on COVID-19 risk.MethodsEPICOS is a double-blind, placebo-controlled randomized trial conducted in Spain, Bolivia, and Venezuela. Healthcare workers with negative SARS-CoV-2 IgM/IgG test were randomly assigned to the following: daily TDF/FTC plus HCQ for 12 weeks, TDF/FTC plus HCQ placebo, HCQ plus TDF/FTC placebo, and TDF/FTC placebo plus HCQ placebo. Randomization was performed in groups of four. Primary outcome was laboratory-confirmed, symptomatic COVID-19. We also studied any (symptomatic or asymptomatic) COVID-19. We compared group-specific 14-week risks via differences and ratios with 95% CIs.ResultsOf 1002 individuals screened, 926 (92.4%) were eligible and there were 14 cases of symptomatic COVID-19: 220 were assigned to the TDF/FTC plus HCQ group (3 cases), 231 to the TDF/FTC placebo plus HCQ group (3 cases), 233 to the TDF/FTC plus HCQ placebo group (3 cases), and 223 to the double placebo group (5 cases). Compared with the double placebo group, 14-week risk ratios (95% CI) of symptomatic COVID-19 were 0.39 (0.00–1.98) for TDF + HCQ, 0.34 (0.00–2.06) for TDF, and 0.49 (0.00–2.29) for HCQ. Corresponding risk ratios of any COVID-19 were 0.51 (0.21–1.00) for TDF + HCQ, 0.81 (0.44–1.49) for TDF, and 0.73 (0.41–1.38) for HCQ. Adverse events were generally mild.DiscussionThe target sample size was not met. Our findings are compatible with both benefit and harm of pre-exposure prophylaxis with TDF/FTC and HCQ, alone or in combination, compared with placebo.