Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-week analysis

BACKGROUND: As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important. METHODS: A regimen of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior virologic, immunologic and morphologic effects compared with a regimen of fixed-dose zidovudine/lamivudine (ZDV/3TC) and EFV through 96 weeks in a randomized open-label trial. After 96 weeks, patients on TDF + FTC transitioned to fixed-dose combination TDF/FTC. RESULTS: Through 144 weeks, significantly more patients in the TDF/FTC arm reached and maintained an HIV RNA level <400 copies/mL (71% receiving TDF/FTC and EFV vs. 58% receiving ZDV/3TC and EFV; P = 0.004), with a trend toward greater CD4 cell increase in the TDF/FTC arm (312 vs. 271 cells/mm; P = 0.09). Over 144 weeks of follow-up, more patients in the ZDV/3TC arm discontinued therapy because of adverse events (11% vs. 5%; P = 0.01) and no patients discontinued because of renal events. Patients in the ZDV/3TC arm had significantly less limb fat than patients in the TDF/FTC arm (5.4 vs. 7.9 kg; P < 0.001) at 144 weeks. CONCLUSIONS: Cumulative results from 3 years of follow-up suggest that a regimen of TDF/FTC and EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV.     

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.     

Short-term cost and efficiency analysis of raltegravir versus atazanavir/ritonavir or darunavir/ritonavir for treatment-naive adults with HIV-1 infection in Spain

Introduction: The AIDS Clinical Trial Group (ACTG) 5257 clinical trial showed that raltegravir (RAL) was superior to atazanavir/ritonavir (ATV/r) and darunavir/ritonavir (DRV/r), when used in combination with emtricitabine/tenofovir DF (FTC/TDF), in a 96-week composite endpoint combining virologic efficacy and tolerability for treatment-naive adults with HIV-1 infection. This study aimed to estimate the efficiency associated with these three regimens in Spain.

Methods: An economic model was developed to estimate costs for antiretroviral drugs, adverse event management, and HIV care for individuals initiating first-line therapy. Antiretroviral drug costs were based on hospital costs with mandatory discounts applied. Adverse event management costs and HIV care costs were obtained from published sources and inflated to 2015 euros. Head-to-head efficacy and safety data (discontinuation rates, mean CD4 cell-count changes, adverse event incidence) up to 96 weeks for each regimen were obtained from the clinical trial. The efficiency of each regimen, as measured by the cost per successfully treated patient (i.e. on first-line therapy for 96 weeks), was estimated and examined in sensitivity analyses. All cost outcomes were discounted at 3.0% annually.

Results: Total costs per successfully treated patient were €22,377 for RAL, €26,629 for ATV/r, and €23,928 for DRV/r. These results were found to be robust in sensitivity analyses.

Discussion: RAL has the lowest cost per successfully treated patient when compared with DRV/r and ATV/r, each used in combination with FTC/TDF, for treatment-naive adults with HIV-1 infection in Spain. This economic evidence complements the clinical benefits of RAL reported in the ACTG 5257 clinical trial.     

Switching From Twice-Daily Raltegravir Plus Tenofovir Disoproxil Fumarate/Emtricitabine to Once-Daily Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate in Virologically Suppressed,HIV-1–Infected Subjects: 48 Weeks Data

Background: Pill burden, dosing frequency, and concerns about safety and toler-ability are important obstacles to maintaining adequate medication adherence. Ralte-gravir (RAL) is indicated for twice-daily dosing and when taken with emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF), it becomes a twice-daily multiple-tablet regimen. Elvitegravir (EVG)/cobicistat (COBI)/FTC/TDF, STB, is the first approved once-a-day integrase strand transfer inhibitor (INSTI) containing single-tablet regimen that combines EVG, an INSTI, and COBI, a novel pharmacoenhancer, with the preferred nucleos(t)ide backbone of FTC/TDF. Methods: This was a 48-week prospective, single-arm open-label study of the switch to STB in virologically sup-pressed HIV-1–infected adult patients on FTC/TDF and twice-daily RAL for at least 6 months. Objectives were to evaluate the tolerability and safety of a regimen simpli-fication to once-a-day STB, while maintaining viral suppression through 48 weeks. Results: Forty-eight individuals in the United States were enrolled. The median age was 44 years, 96% were male, and 83% were White. The median time on RAL + FTC/TDF treatment prior to enrollment was 34 months. Ninety-six percent of participants cited regimen simplification as the reason to enroll in the switch study. At base-line, the median CD4 count was 714 cell/µL and estimated glomerular filtration rate (eGFR) was 105 mL/min. At week 48, all assessed study participants remained viro-logically suppressed to the lower limit of quantification (HIV-1 RNA<50 copies/mL) and maintained high CD4 cell count (median, 751 cells/mL) and stable eGFR (median, 100.5 mL/min). STB was well tolerated with no discontinuations, no study drug–related serious adverse events, and no study drug–related grade 3/4 adverse events. Conclusions: All participants switching to 1 tablet once-a-day STB from a twice-daily RAL + FTC/TDF regimen remained virologically suppressed. STB was well tolerated. Switching to STB may be a viable option for virologically suppressed patients wanting to simplify from a twice-daily RAL-containing regimen.     

Steady-State Amprenavir,Tenofovir, and Emtricitabine Pharmacokinetics Before and After Reducing Ritonavir Boosting of a Fosamprenavir/Tenofovir/Emtricitabine Regimen from 200 mg to 100 mg Once Daily (TELEX II)

Abstract

Purpose: Evaluate how reducing ritonavir (RTV) boosting from 200 mg to 100 mg once daily (QD) affects steady-state pharmacokinetics of components of a fosamprenavir (FPV)-based regimen. Methods: Prospective, open-label, pharmacokinetic study in 12 HIV-infected patients stabilized on FPV/RTV 1400 mg/200 mg + tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) 300 mg/200 mg QD (TELEX II). Pharmacokinetics were assessed by noncompartmental analysis at baseline and 4 weeks after RTV reduction to 100 mg QD. Results: Baseline median minimum plasma concentration (C_min) and area under the plasma concentration-time curve over 24 hours post dose (AUC_24h) were as follows: APV: 1,708 ng/mL, 84,260 h ? ng/mL; tenofovir: 53 ng/mL, 2,420 h ? ng/mL; FTC: 58 ng/mL, 9,190 h ? ng/mL; RTV: 80 ng/mL, 10,230 h ? ng/mL. Four weeks after reducing RTV, changes in C_min and AUC_24h were: APV: +26%, +0.6%; tenofovir: +77%, +30%; FTC: +188%, +13%; RTV –64%, –79%. Component plasma concentration ranges were consistent with historical values. Median APV C_min was 14.7-fold above the protein-binding-adjusted 50% inhibitory concentration of wild-type HIV. Four weeks after RTV reduction, HIV-1 RNA levels remained <50 copies/mL in all patients, median CD4+ count increased from 465 to 495 cells/mm³, and favorable lipid changes and no adverse events were observed. Conclusion: Reducing RTV boosting from 200 to 100 mg QD of FPV/TDF/FTC QD conferred no detrimental effect on APV, tenofovir, FTC, or RTV pharmacokinetics and maintained virologic suppression.     

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.     

Long-term immunologic and virologic responses on raltegravir-containing regimens among ART-experienced participants in the HIV Outpatient Study

Objectives:

Raltegravir (RAL)-containing antiretroviral therapy (ART) produced better immunologic and virologic responses than optimized background ART in clinical trials of heavily ART-experienced patients, but few data exist on long-term outcomes in routine HIV care.

Methods:

We studied ART-experienced HIV outpatient study (HOPS) participants seen at 10 US HIV-specialty clinics during 2007–2011.We identified patients who started (baseline date) either continuous ≥?30?days of RAL-containing or RAL-sparing ART, and used propensity score (PS) matching methods to account for baseline clinical and demographic differences. We used Kaplan–Meier methods and log-rank tests for the matched subsets to evaluate probability of death, achieving HIV RNA ??3 during follow-up.

Results:

Among 784 RAL-exposed and 1062 RAL-unexposed patients, 472 from each group were matched by PS. At baseline, the 472 RAL-exposed patients (mean nadir CD4, 205?cells?mm^??3; mean baseline CD4, 460?cells?mm^??3; HIV RNA ??1 in 61%; mean years on prescribed ART, 7.5) were similar to RAL unexposed. During a mean follow-up of over 3?years, mortality rates and immunologic and virologic trajectories did not differ between the two groups. Among patients with detectable baseline HIV RNA levels, 76% of RAL-exposed and 63% of RAL-unexposed achieved HIV RNA ??1 (P?=?0.51); 69 and 58%, respectively, achieved a CD4 increase ≥?50?cells?mm^??3 (P?=?0.70).

Discussion:

In our large cohort of US ART-experienced patients with a wide spectrum of clinical history, similar outcomes were observed when prescribed RAL containing versus other contemporary ART.     

Sleep and neuropsychological performance in HIV+ subjects on efavirenz-based therapy and response to switch in therapy

The antiretroviral drug efavirenz (EFV) has been linked to disordered sleep and cognitive abnormalities. We examined sleep and cognitive function and subsequent changes following switch to an alternative integrase inhibitor-based regimen. Thirty-two HIV-infected individuals on EFV, emtricitabine, and tenofovir (EFV/FTC/TDF) without traditional risk factors for obstructive sleep apnea (OSA) were randomized 2:1 to switch to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/COBI/FTC/TDF) or to continue EFV/FTC/TDF therapy for 12 weeks. Overnight polysomnography and standardized sleep and neuropsychological assessments were performed at baseline and at 12 weeks. No significant differences in change over 12 weeks were noted between the two arms in any sleep or neuropsychological test parameter. At entry, however, the rate of sleep disordered breathing (SDB) was substantially higher in study subjects compared to published age-matched norms and resulted in a high assessed OSA rate of 59.4%. Respiratory Disturbance Index (RDI), a measure of SDB, correlated with age- and education-adjusted global neuropsychological Z-score (NPZ) (r?=??0.35, p?=?0.05). Sleep Maintenance Efficiency, Wake after Sleep Onset, REM Sleep and RDI correlated with domain-specific NPZ for learning and memory (all p-values ≤ 0.05). Among HIV-infected individuals on EFV-based therapy and without traditional risk factors for OSA, sleep and neuropsychological abnormalities do not readily reverse after discontinuation of EFV. High baseline rates of SDB and abnormalities in sleep architecture exist in this population correlating with neuropsychological impairment. The role of HIV immuno-virologic or lifestyle factors as contributing etiologies should be explored. OSA may be an under-recognized etiology for cognitive dysfunction during chronic HIV.     

Impact of Switching Virologically Suppressed,HIV-1-Infected Patients from Twice-Daily Fixed-Dose Zidovudine/Lamivudine to Once-Daily Fixed-Dose Tenofovir Disoproxil Fumarate/Emtricitabine

Abstract

Objective: Evaluate the impact of switching from twice-daily zidovudine/lamivudine (AZT/3TC) to once-daily tenofovir DF plus emtricitabine (TDF/FTC) with efavirenz (EFV). Design: Prospective, multicenter, single-arm 24-week trial. Methods: Patients on EFV + AZT/3TC for =8 weeks with HIV-1 RNA <400 copies/mL were switched to EFV + TDF/FTC and assessed for safety/tolerability, virologic and immunologic responses, adherence, and quality of life at 4, 12, and 24 weeks. Results: Of 402 patients, 2% discontinued for an adverse event (AE) and 1 patient for virologic failure. At 24 weeks, 87% had HIV RNA <400 copies/mL, and 74% versus 71% at baseline had undetectable (HIV RNA <50 copies/mL) viral load (ITT; M=F). Treatment-emergent AEs were infrequent (≤5%) with gastrointestinal complaints being the most common. At 24 weeks compared to baseline, hemoglobin (Hb) increased by a median of 0.6 g/dL (p < .001), and a decrease in creatinine clearance of 7.6 mL/min (p < .001) was observed. Fasting lipids decreased slightly (p < .02) in a subset of patients studied (n = 160). A higher percentage of patients reported being “very satisfied” with treatment and the absence of regimen side effects at 24 weeks versus baseline (p < .001). At 24 weeks, 86% of patients took ≥95% of doses versus 78% at baseline (p = .002). Conclusion: Patients switched to EFV + TDF/FTC maintained virologic suppression and the regimen was well tolerated. Patients reported increased satisfaction with treatment and fewer were bothered by side effects.     

Addition of single-dose tenofovir and emtricitabine to intrapartum nevirapine to reduce perinatal HIV transmission

OBJECTIVE: To determine the impact of adjuvant single-dose peripartum tenofovir/emtricitabine (TDF/FTC) on intrapartum/early postpartum HIV transmission. METHODS: In the setting of routine short-course zidovudine (ZDV) and peripartum nevirapine (NVP) for perinatal HIV prevention, participants were randomized to single-dose TDF (300 mg)/FTC (200 mg) or to no intervention in labor. Six-week infant HIV infection was compared according to actual-use drug regimens. RESULTS: Of 397 women randomized, 355 (89%) had infants who were alive and active at 6 weeks postpartum. Of these, 18 (5.1%) were infected in utero and 6 (1.8%) were infected intrapartum/early postpartum. Among the 243 who used ZDV and NVP, intrapartum/early postpartum transmission was not reduced among infants whose mothers received TDF/FTC compared with those who did not (2 of 123 [1.6%] vs. 3 of 109 [2.8%]; P = 0.67). Among the 49 infants whose mothers did not receive antenatal ZDV but who had confirmed NVP ingestion, transmission similarly did not differ (0 of 19 [0%] vs. 1 of 26 [3.4%]). TDF/FTC was not significantly associated with reduced overall transmission (odds ratio [OR] = 0.7, 95% confidence interval [CI]: 0.3 to 1.6), even when other antiretroviral drugs were considered (adjusted OR = 0.8, 95% CI: 0.3 to 1.8). CONCLUSIONS: Adjuvant peripartum single-dose TDF/FTC did not reduce perinatal transmission. Whether a higher dose might be effective remains unknown but should be studied in settings in which NVP is used without antenatal ZDV.     

The pharmacokinetic profile of raltegravir-containing antiretroviral therapy in HIV-infected individuals over 60 years of age

Background:

Antiretroviral safety and efficacy and may differ in older versus younger HIV-infected patients. The objective of this study was to assess the pharmacokinetic (PK) profile in older HIV-infected subjects (>60?years) switching combination antiretroviral therapy (cART) to a raltegravir (RAL) containing regimen.

Methods:

Nineteen HIV-infected patients over 60?years of age on effective cART (HIV-RNA Results:

In HIV-infected subjects over the age of 60 (mean?±?SD age: 66?±?3.4?years, n?=?19) switching to a RAL containing regimen, we observed no safety concerns, no plasma virological rebounds, and no differences in RAL apparent oral clearance when compared to younger HIV-infected populations (mean?±?SD age: 41?±?9.2?years, n?=?38) based on population pharmacokinetic analysis. After 24?weeks of study therapy a decline in cognitive function was observed [change in (SD) global score of (0.91 (1.3), P?=?0.018].

Conclusions:

No significant changes in RAL exposure associated with age were observed.