Compact Quadruple Therapy with the Lamivudine/Zidovudine Combination Tablet Plus Abacavir and Efavirenz,Followed by the Lamivudine/Zidovudine/Abacavir Triple Nucleoside Tablet Plus Efavirenz in Treatment-Naïve HIV-Infected Adults

Abstract

Purpose: To assess efficacy, safety, and adherence with compact quadruple therapy comprising one lamivudine 150-mg/zidovudine 300-mg tablet (COM) twice daily + one abacavir (ABC) 300-mg tablet twice daily + three efavirenz (EFV) 200-mg capsules at bedtime for 24 weeks, followed by one lamivudine 150-mg/zidovudine 300-mg/ABC 300-mg triple nucleoside tablet (TZV) twice daily + three EFV 200-mg capsules at bedtime for 24 weeks. Method: A pilot 48-week, prospective, open-label trial in which 38 antiretroviral-naïve HIV-infected adults (baseline median HIV-1 RNA 5.1 log₁₀ copies/mL, CD4+ cell count 285/μL) received the above treatment and were monitored regularly with respect to plasma HIV-1 RNA levels, CD4+ cell counts, T-cell receptor excision circles (TRECs), adherence, and adverse events. Results: At Week 48, intent-to-treat, switch-included analysis showed plasma HIV-1 RNA levels <400 copies/mL in 100% (29/29) of patients and <50 copies/mL in 93% (27/29); 59% of patients who achieved <50 copies/mL had <3 copies/mL (16/27). Similar virologic suppression was observed in patients with baseline HIV-1 RNA above or below 100,000 copies/mL. HIV-1 RNA and CD4+ cell counts changed from baseline by a median of –3.4 log₁₀ copies/mL and +172 cells/μL, respectively. One virologic failure occurred at Week 16. Median TRECs/100,000 peripheral blood lymphocytes increased 6-fold between baseline and Week 48. Median adherence rates were consistently 100% by self-report and 94% by pill count. Grade 2-4 treatment-related adverse events included dreams (16%), nausea (13%), decreased white cells (8%), dizziness (8%), sleep disorders (8%), and malaise and fatigue (8%). A suspected ABC hypersensitivity reaction occurred in 8% (3/38) of patients. Conclusion: COM/ABC/EFV or TZV/EFV produced potent, durable virologic suppression and immunologic benefits, was associated with high adherence rates, and was generally well tolerated.     

Long-Term Impact of Efavirenz on Neuropsychological Performance and Symptoms in HIV-Infected Individuals (ACTG 5097s)

Abstract

Background: Efavirenz (EFV) is an antiretroviral (ARV) drug associated with neuropsychological effects. Limited data describing the long-term impact of EFV-based regimens on neuropsychological performance over more than 3 years are available. Methods: We enrolled a subset of participants from a large initially EFV placebo-controlled trial of therapies for HIV subjects naïve to ARV treatment (A5095). Clinical follow-up continued for 184 weeks of study. Subjects were assessed with brief neuropsychological testing, a symptom questionnaire of EFV-associated symptoms, the Pittsburgh Sleep Index, Center for Epidemiologic Studies-Depression Scale, and an anxiety rating interview. Results: Over 184 weeks on EFV, the median NPZ3 score in 86 evaluable patients improved from baseline by +0.5 (p < .01); all components improved, although higher EFV levels were associated with slightly lower responses. Overall symptom scores did not change, while EFV-associated CNS symptoms increased (p = .01). Median change of bad dream sleep scores and anxiety increased from the baseline while global depression score decreased. Conclusions: In participants who continued EFV-based regimens, neuropsychological performance improvement from baseline was maintained over 3 years. EFV-based treatment was generally well tolerated, but small increases from baseline in EFV-associated symptoms, bad dreams, and anxiety were detected.     

Kinetics and Mechanism of Hydrolysis of Efavirenz

Purpose. To determine the kinetics and mechanism of hydrolysis of efavirenz [(S)-6-chloro-4-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one] in aqueous solutions. Methods. The solution stability was examined at 60°C and an ionic strength of 0.3 M over the pH range of 0.6 to 12.8. The loss of efavirenz and the appearance of degradants were followed with a reverse-phase high-performance liquid chromatography assay. Characterization of the degradants was accomplished with liquid chromatography-mass spectrometry. Results. The degradation of efavirenz followed apparent first-order kinetics over the pH range of 0.6 to 12.8 at 60°C. The catalytic effect of phosphate and borate buffers was negligible while acetate and citrate demonstrated buffer catalysis. The overall rate constant indicated a pH minimum (the pH of maximum stability) of approximately 4. Mass spectra data identified a degradant with a molecular weight consistent with hydrolysis of the cyclic carbamate to the corresponding amino alcohol. The degradation route was confirmed with spiking experiments with an authentic sample of the amino alcohol indicating that the carbamate hydrolysis pathway was the predominant reaction throughout the pH range studied. Subsequent degradation of the amino alcohol proceeded at the extremes of the pH range studied via rearrangement to the quinoline. Conclusions. The pH-rate profile was consistent with a combination of a V-shaped profile in the pH range of 0-9 and a sigmoid-shaped profile in the pH range of 4-13. The plateau that began at pH 10-11 is a result of the ionization of the amine of the carbamate inhibiting the base-catalyzed hydrolysis of efavirenz, given that the ionized form of the carbamate is resonance-stabilized toward hydroxide-catalyzed degradation. Thus, increasing the pH resulted in a parallel decrease in the unionized fraction and increase in hydroxide ion concentration resulting in a constant k_obs value.     

Maternal weight and birth outcomes among women on antiretroviral treatment from conception in a birth surveillance study in Botswana

IntroductionAntiretrovirals such as dolutegravir (DTG) and tenofovir alafenamide (TAF) have been associated with excessive weight gain. The objective of this study was to understand the potential impact of ART‐associated weight gain on pregnancy outcomes among women living with HIV.MethodsUsing data from the Tsepamo birth outcomes surveillance study in Botswana, we evaluated the relationship between maternal weight (and weight gain) and severe birth outcomes (very preterm delivery <32 weeks, very small for gestational age (SGA) <3rd percentile, perinatal death), macrosomia (birthweight > 4000 g) and maternal hypertension. We estimated the relative risk of each outcome by baseline weight (first weight in pregnancy <24 weeks) and second trimester average weekly weight gain (kg/week from 12 ± 2 to 24 ± 2 weeks) using log binomial regression and evaluated effect modification by ART regimen (DTG vs. Efavirenz (EFV)).ResultsOf 22,828 women on ART at conception with singleton deliveries between August 2014 and April 2020, 16,300 (71.4%) had a weight measured <24 weeks’ gestation (baseline weight) and 4437 (19.2%) had weight measured both at 12 (±2) weeks and 24 (±2) weeks, allowing second trimester weight gain calculation. Compared to women with baseline weight 60 to 70 kg, low baseline weight (<50 kg) was associated with increased risk of very preterm delivery (aRR 1.30, 95% CI 1.03, 1.65) and very SGA (aRR1.96, 95% CI 1.69, 2.28). High baseline weight (>90 kg) was associated with increased risk of macrosomia (aRR 3.24, 95% CI 2.36, 4.44) and maternal hypertension (aRR 1.79, 95% CI 1.62, 1.97). Baseline weight was not associated with stillbirth or early neonatal death. For all outcomes, second trimester weight gain showed weaker associations than did baseline weight. Duration of pre‐pregnancy ART (years) was associated with higher baseline weight for DTG but not for EFV, and the risk of maternal hypertension by baseline weight category was higher for DTG than EFV for all strata.ConclusionsART regimens associated with weight gain may reduce the number of women at risk for certain severe adverse pregnancy outcomes associated with low weight but increase the number at risk of macrosomia and maternal hypertension. Further research could determine whether weight‐based ART treatment strategies improve maternal and child health.     

Efavirenz does not meaningfully affect the single dose pharmacokinetics of 1200 mg raltegravir

Raltegravir is a human immunodeficiency virus (HIV)‐1 integrase strand transfer inhibitor currently marketed at a dose of 400 mg twice daily (BID). Raltegravir for once daily regimen (QD) at a dose of 1200 mg (2 x 600 mg) is under development and offers a new treatment option for HIV‐1 infected treatment‐naive subjects. Since raltegravir is eliminated mainly by metabolism via an UDP‐glucuronosyltransferase (UGT) 1 A1‐mediated glucuronidation pathway, co‐administration of UGT1A1 inducers may alter plasma levels of raltegravir. Efavirenz, an UGT1A1 inducer, was used to assess the impact of altered UGT activity on a 1200 mg QD dose of raltegravir. An open label, randomized, 2‐period fixed‐sequence Phase 1 study was performed in adult healthy male and female subjects (non‐childbearing potential) ≥ 19 and ≤55 years of age, with a body mass index (BMI) ≥ 18.5 and ≤32.0 kg/m². Subjects (n = 21) received a single oral dose of 1200 mg raltegravir at bedtime on an empty stomach on Day 1 in Period 1. After a washout period of at least 7 days, subjects received oral doses of 600 mg efavirenz QD at bedtime for 14 consecutive days in Period 2. Subjects received a single oral dose of 1200 mg raltegravir co‐administered with 600 mg efavirenz on Day 12 of Period 2. Pharmacokinetic (PK) samples were collected for 72 hours following raltegravir dosing and analyzed using a validated bioanalytical method to quantify raltegravir plasma concentrations. PK parameters were estimated using non‐compartmental analysis. Administration of single 1200 mg oral doses of raltegravir alone and co‐administered with multiple oral doses of efavirenz were generally well tolerated in healthy subjects. Co‐administration with efavirenz yielded geometric mean ratios (GMRs) and their associated 90% confidence intervals (90% CIs) for raltegravir AUC_0‐∞, C_max, and C₂₄ of 0.86 (0.73, 1.01), 0.91 (0.70, 1.17), and 0.94 (0.76, 1.17), respectively. The results show that efavirenz modestly reduced the exposure of raltegravir. The reduction in raltegravir exposure is not considered clinically meaningful. Copyright © 2016 John Wiley & Sons, Ltd.     

The pharmacokinetics,pharmacodynamics, and clinical role of fixed dose combination of tenofovir disoproxil fumarate,lamivudine and reduced dose efavirenz (TLE-400) in treating HIV-1 infection

Introduction: Co-formulated fixed dose combination (FDC) of antiretroviral drugs tenofovir disoproxil fumarate, lamivudine, and reduced dose efavirenz [TDF 300 mg/3TC 300mg/EFV400 mg (TLE-400)] is a single daily tablet recently approved for the treatment of HIV-1 infection.

Areas covered: An overview of the pharmacokinetics, pharmacodynamics and role of TLE-400 in the treatment of HIV-1 infection based on the publications from Medline and Pubmed as of February, 2018.

Expert opinion: Although TLE-400 has not been formally evaluated in a clinical trial as a new formulation, previous studies have evaluated its components individually and in different doses as other FDCs have shown favorable efficacy and safety results to support continuing its approval and indication in the management of HIV-1 infection. Due to the lower dose of EFV, TLE-400 has a lower rate of toxicity and higher tolerability compared to its predecessor, the TLE-600, which contained a higher 600 mg dose of EFV. Given its low cost and ease of administration, TLE-400 is a promising alternative first line FDC in the management of HIV-1.