Does efavirenz replacement improve neurological function in treated HIV infection?
ABSTRACT: The contribution of specific antiretroviral drugs to cognitive function in HIV-infected people remains poorly understood. Efavirenz (EFV) may plausibly cause cognitive impairment. The objective of this study was therefore to determine whether chronic EFV therapy is a modifier of neurocognitive and neurometabolic function in the setting of suppressive highly active antiretroviral therapy.We performed an open-label phase IV controlled trial. Adult subjects who were stable on suppressive EFV therapy for at least 6 months were switched to ritonavir-boosted lopinavir (LPV/r) with no change in the nucleoside reverse transcriptase inhibitor (NRTI) backbone. The following parameters were assessed before and 10 weeks after therapy switch: cognitive function (by CogState® computerized battery); brain metabolites (by proton magnetic resonance spectroscopy); brain activity [by attentional processing task-based functional magnetic resonance imaging]; and sleep quantity and quality [by sleep diary, Pittsburgh Sleep Quality Index (PSQI) and Epworth Sleepiness Scale].Sixteen subjects completed the study. Despite most subjects (81%) self-reporting memory problems at baseline, cognitive function, brain metabolites, and brain activity showed no change at 10 weeks after switch. Sleep quality improved on switch off EFV [mean PSQI (standard deviation): EFV, 8.5 (6.5); LPV/r, 5.8 (5.5); mean difference -0.4; 95% confidence interval -6.0 to -0.7].This is the first study to assess the effects of chronic EFV therapy on neurological function in a controlled setting. We conclude that EFV withdrawal is unlikely to result in significant modification of neurocognitive function in otherwise stable HIV-infected people.
Project description:Background:The NEVEREST-3 (South Africa) and MONOD-ANRS-12206 (Côte d'Ivoire, Burkina Faso) randomized trials found that switching to efavirenz (EFV) in human immunodeficiency virus-infected children >3 years old who were virologically suppressed by ritonavir-boosted lopinavir (LPV/r) was noninferior to continuing o LPV/r. We evaluated the cost-effectiveness of this strategy using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric model. Methods:We examined 3 strategies in South African children aged ?3 years who were virologically suppressed by LPV/r: (1) continued LPV/r, even in case of virologic failure, without second-line regimens; continued on LPV/r with second-line option after observed virologic failure; and preemptive switch to EFV-based antiretroviral therapy (ART), with return to LPV/r after observed virologic failure. We derived data on 24-week suppression (<1000 copies/mL) after a switch to EFV (98.4%) and the subsequent risk of virologic failure (LPV/r, 0.23%/mo; EFV, 0.15%/mo) from NEVEREST-3 data; we obtained ART costs (LPV/r, $6-$20/mo; EFV, $3-$6/mo) from published sources. We projected discounted life expectancy (LE) and lifetime costs per person. A secondary analysis used data from MONOD-ANRS-12206 in Côte d'Ivoire. Results:Continued LPV/r led to the shortest LE (18.2 years) and the highest per-person lifetime cost ($19 470). LPV/r with second-line option increased LE (19.9 years) and decreased per-person lifetime costs($16 070). Switching led to the longest LE (20.4 years) and the lowest per-person lifetime cost ($15 240); this strategy was cost saving under plausible variations in key parameters. Using MONOD-ANRS-12206 data in Côte d'Ivoire, the Switch strategy remained cost saving only compared with continued LPV/r, but the LPV/r with second-line option strategy was cost-effective compared with switching. Conclusion:For children ?3 years old and virologically suppressed by LPV/r-based ART, preemptive switching to EFV can improve long-term clinical outcomes and be cost saving. Clinical Trials Registration:NCT01127204.
Project description:BACKGROUND:The 2016 World Health Organization guidelines recommend all children <3 years start antiretroviral therapy (ART) on protease inhibitor-based regimens. But lopinavir/ritonavir (LPV/r) syrup has many challenges in low-income countries, including limited availability, requires refrigeration, interactions with anti-tuberculous drugs, twice-daily dosing, poor palatability in young children, and higher cost than non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs. Successfully initiating LPV/r-based ART in HIV-infected children aged <2 years raises operational challenges that could be simplified by switching to a protease inhibitor-sparing therapy based on efavirenz (EFV), although, to date, EFV is not recommended in children <3 years. METHODS:The MONOD ANRS 12026 study is a phase 3 non-inferiority open-label randomised clinical trial conducted in Abidjan, Côte d'Ivoire, and Ouagadougou, Burkina Faso (ClinicalTrial.gov registry: NCT01127204). HIV-1-infected children who were tuberculosis-free and treated before the age of 2 years with 12-15 months of suppressive twice-daily LPV/r-based ART (HIV-1 RNA viral load (VL) <500 copies/mL, confirmed) were randomised to two arms: once-daily combination of abacavir (ABC) + lamivudine (3TC) + EFV (referred to as EFV) versus continuation of the twice-daily combination zidovudine (ZDV) or ABC + 3TC + LPV/r (referred to as LPV). The primary endpoint was the difference in the proportion of children with virological suppression by 12 months post-randomisation between arms (14% non-inferiority bound, Chi-squared test). RESULTS:Between May 2011 and January 2013, 156 children (median age 13.7 months) were initiated on ART. After 12-15 months on ART, 106 (68%) were randomised to one of the two treatment arms (54 LPV, 52 EFV); 97 (91%) were aged <3 years. At 12 months post-randomisation, 46 children (85.2%) from LPV versus 43 (82.7%) from EFV showed virological suppression (defined as a VL <500 copies/mL; difference, 2.5%; 95% confidence interval (CI), -11.5 to 16.5), whereas seven (13%) in LPV and seven (13.5%) in EFV were classed as having virological failure (secondary outcome, defined as a VL ≥1000 copies/mL; difference, 0.5%; 95% CI, -13.4 to 12.4). No significant differences in adverse events were observed, with two adverse events in LPV (3.7%) versus four (7.7%) in EFV (p = 0.43). On genotyping, 13 out of 14 children with virological failure (six out of seven EFV, seven out of seven LPV) had a drug-resistance mutation: nine (five out of six EFV, four out of seven LPV) had one or more major NNRTI-resistance mutations whereas none had an LPV/r-resistance mutation. CONCLUSIONS:At the VL threshold of 500 copies/mL, we could not conclusively demonstrate the non-inferiority of EFV on viral suppression compared to LPV because of low statistical power. However, non-inferiority was confirmed for a VL threshold of <1000 copies/mL. Resistance analyses highlighted a high frequency of NNRTI-resistance mutations. A switch to an EFV-based regimen as a simplification strategy around the age of 3 years needs to be closely monitored. TRIAL REGISTRATION:ClinicalTrial.gov registry n° NCT01127204 , 19 May 2010.
Project description:Background:We previously demonstrated the noninferiority of switching to efavirenz (EFV) versus remaining on ritonavir-boosted lopinavir (LPV/r) for virologic control in children infected with human immunodeficiency virus (HIV) and exposed to nevirapine (NVP) for prevention of mother-to-child transmission. Here we assess outcomes up to 4 years post-randomization. Methods:From 2010-2013, 298 NVP-exposed HIV-infected children ?3 years of age were randomized to switch to EFV or remain on LPV/r in Johannesburg, South Africa (Clinicaltrials.gov NCT01146873). After trial completion, participants were invited to enroll into observational follow-up. We compared HIV RNA levels, CD4 counts and percentages, lipids, and growth across groups through four years post-randomization. Results:HIV RNA levels 51-1000 copies/mL were less frequently observed in the EFV group than the LPV/r group (odds ratio [OR] 0.67, 95% confidence interval [CI]: 0.51-0.88, P = .004), as was HIV RNA >1000 copies/mL (OR 0.52 95% CI: 0.28-0.98, P = .04). The probability of confirmed HIV RNA >1000 copies/mL by 48 months was 0.07 and 0.12 in the EFV and LPV/r groups, respectively (P = .21). Children randomized to EFV had a reduced risk of elevated total cholesterol (OR 0.45 95% CI: 0.27-0.75, P = .002) and a reduced risk of abnormal triglycerides (OR 0.42, 95% CI 0.29-0.62, P < .001). Conclusions:Our results indicate that the benefits of switching virologically suppressed NVP-exposed HIV-infected children ?3 years of age from LPV/r to EFV are sustained long-term. This approach has several advantages, including improved palatability, reduced metabolic toxicity, simplified cotreatment for tuberculosis, and preservation of second line options. Clinical Trials Registration:NCT01146873.
Project description:To evaluate the pharmacokinetics and pharmacogenomics of efavirenz (EFV) and lopinavir/ritonavir (LPV/RTV) in HIV-infected persons requiring hemodialysis.Prospective, observational study of HIV-infected hemodialysis patients receiving one 600 mg tablet daily of EFV (N = 13) or three 133.3/33.3 mg capsules twice daily of LPV/RTV (N = 13).Twenty-four-hour EFV and 12-h LPV/RTV pharmacokinetics were assessed. Geometric mean ratios were calculated using historical controls with normal renal function. The effects of several candidate gene polymorphisms were also explored.The geometric mean [95% confidence interval (CI); percentage of coefficient of variation (% CV)] Cmin, Cmax, and area under the curve (AUC) for the EFV group were 1.81 microg/ml (0.93, 3.53; 103%), 5.04 microg/ml (3.48, 7.29; 72%), and 71.5 microg h/ml (43.2, 118.3; 93%), respectively. These parameters were 2.76 microg/ml (1.86, 4.11; 53%), 8.45 microg/ml (6.41, 11.15; 52%), and 69.6 microg h/ml (55.6, 87.2; 37%) for LPV and 0.08 microg/ml (0.05, 0.14; 63%), 0.58 microg/ml (0.44, 0.76; 41%), and 3.74 microg h/ml (2.91, 4.80; 37%) for RTV. The AUC geometric mean ratios (90% CI) for EFV, LPV, and RTV were 132% (89, 197), 81% (67, 97), and 92% (76, 111), respectively. LPV Cmin was lower than expected in the hemodialysis group. Higher EFV concentrations were associated with the CYP2B6 516G>T polymorphism.The pharmacokinetics of EFV and LPV/RTV in hemodialysis suggests that no dosing adjustments are necessary in treatment-naive patients. As HIV-infected hemodialysis patients are disproportionately black, the increased frequency of the CYP2B6 516G>T polymorphism may lead to higher EFV levels. The potentially lower LPV trough levels in this population suggest that LPV/RTV should be used with caution in protease-inhibitor-experienced patients.
Project description:Single nucleotide polymorphisms (SNPs) in the genes that encode the cytochrome P450 (CYP) drug metabolizing enzymes and drug transporters have been reported to influence antiretroviral drug pharmacokinetics. Although primarily metabolized by CYP2B6 and -3A, efavirenz (EFV) and lopinavir/ritonavir (LPV/r) are substrates of P-glycoprotein and the solute carrier organic (SLCO) anion transporter, respectively. We investigated the association between SNPs and efavirenz (EFV) or lopinavir/ritonavir (LPV/r) concentrations in Chinese children infected with the human immunodeficiency virus (HIV). Genotyping was performed on CYP2B6 516G?T, -1459C?T, and -983T?C, ABCB1 3435C?T, and SLCO1B1 521T?C in 229 HIV-infected Chinese pediatric patients (age range 4.0 to 17.5 yrs). Plasma concentrations of EFV and LPV/r were measured using validated high-performance liquid chromatography coupled with the mass spectrum method among 39 and 69 children who received EFV- and LPV/r-containing regimens, respectively. The frequencies of CYP2B6 516G?T in the study participants were 71%, 25%, and 4% for the G/G, G/T, and T/T genotypes, respectively. Among the children under therapeutic drug monitoring, 21% and 39% experienced EFV and LPV concentrations, respectively, above the upper threshold of the therapeutic window. CYP2B6 516G?T was significantly associated with EFV concentrations (p<0.001). Older children (older than 10 yrs) were more likely to have significantly higher EFV concentrations than the younger ones (p=0.0314). CYP2B6 genotyping and EFV concentration monitoring may help optimize antiretroviral therapy in pediatric patients who initiate an EFV-based regimen.
Project description:Gene expression studies of subcutaneous adipose tissue may help to better understand the mechanisms behind body fat changes in HIV-infected patients who initiate antiretroviral therapy (ART). Here, we evaluated early changes in adipose tissue gene expression and their relationship to fat changes in ART-naive HIV-infected patients randomly assigned to initiate therapy with emtricitabine/tenofovir plus efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r). Patients had abdominal subcutaneous adipose tissue biopsies at baseline and week 16 and dual-energy-X-ray absorptiometry at baseline and weeks 16 and 48. mRNA changes of 11 genes involved in adipogenesis, lipid and glucose metabolism, mitochondrial energy, and inflammation were assessed through reverse transcription-quantitative PCR (RT-qPCR). Additionally, correlations between gene expression changes and fat changes were evaluated. Fat increased preferentially in the trunk with EFV and in the limbs with LPV/r (P < 0.05). After 16 weeks of exposure to the drug regimen, transcripts of CEBP/A, ADIPOQ, GLUT4, LPL, and COXIV were significantly down-regulated in the EFV arm compared to the LPV/r arm (P < 0.05). Significant correlations were observed between LPL expression change and trunk fat change at week 16 in both arms and between CEBP/A or COXIV change and trunk fat change at the same time point only in the EFV arm and not in the LPV/r arm. When combined with emtricitabine/tenofovir as standard backbone therapy, EFV and LPV/r induced differential early expression of genes involved in adipogenesis and energy metabolism. Moreover, these mRNA expression changes correlated with trunk fat change in the EFV arm. (This was a substudy of a randomized clinical trial [LIPOTAR study] registered at ClinicalTrials.gov under identifier NCT00759070.).
Project description:To evaluate the effects of sex and initial antiretroviral regimen on decay of HIV-RNA and virologic outcome.We conducted a viral dynamics substudy of A5142, a trial comparing lopinavir (LPV)/ritonavir with efavirenz (LPV/EFV) versus LPV and two nucleoside reverse transcriptase inhibitor (NRTI) (LPV) versus EFV and two NRTI (EFV) in antiretroviral (ARV)-naive individuals. HIV-RNA was measured at days 2, 10, and 14 in the substudy and at weeks 1, 4, and 8 in A5142 participants. Two-phase viral decay was estimated in the substudy with biexponential mixed-effects modeling and compared using Wilcoxon tests. Week 1 HIV-RNA change was assessed as a predictor of virologic failure (HIV-RNA above 50 or 200? copies/ml) at weeks 24-96 using logistic regression.Sixty-eight individuals were enrolled in the substudy (median HIV-RNA 4.9 log(10) ?copies/ml). Median rates of phase 1 viral decay by treatment were 0.61(EFV/LPV), 0.53(LPV), and 0.63(EFV) per day. Phase 1 decay was significantly faster for EFV than LPV (P?=?0.023); other comparisons were not significant (P?>?0.11). Viral decay did not differ by sex (P?=?0.10). Week 1 HIV-RNA change, calculated in 571 participants of A5142, was greater for the EFV (median -1.47 log(10) ?copies/ml) than either the LPV/EFV or LPV groups (-1.21 and -1.16 log(10?) copies/ml, respectively; P?<?0.001). Week 1 HIV-RNA change was associated with virologic failure above 50 ?copies/?ml at weeks 24 and 48 (P?<?0.018), but not above 200? copies/ml at these time points or for any value at week 96.Phase 1 decay was faster for EFV than LPV or LPV/EFV. Week 1 HIV-RNA change predicted virologic outcome up to week 48, but not at week 96.
Project description:BACKGROUND: Good adherence to antiretroviral therapy (ART) is critical for successful HIV treatment. However, some patients remain virologically suppressed despite suboptimal adherence. We hypothesized that this could result from host genetic factors influencing drug levels. METHODS: Eligible individuals were Caucasians treated with efavirenz (EFV) and/or boosted lopinavir (LPV/r) with self-reported poor adherence, defined as missing doses of ART at least weekly for more than 6 months. Participants were genotyped for single nucleotide polymorphisms (SNPs) in candidate genes previously reported to decrease EFV (rs3745274, rs35303484, rs35979566 in CYP2B6) and LPV/r clearance (rs4149056 in SLCO1B1, rs6945984 in CYP3A, rs717620 in ABCC2). Viral suppression was defined as having HIV-1 RNA <400 copies/ml throughout the study period. RESULTS: From January 2003 until May 2009, 37 individuals on EFV (28 suppressed and 9 not suppressed) and 69 on LPV/r (38 suppressed and 31 not suppressed) were eligible. The poor adherence period was a median of 32 weeks with 18.9% of EFV and 20.3% of LPV/r patients reporting missed doses on a daily basis. The tested SNPs were not determinant for viral suppression. Reporting missing >1 dose/week was associated with a lower probability of viral suppression compared to missing 1 dose/week (EFV: odds ratio (OR) 0.11, 95% confidence interval (CI): 0.01-0.99; LPV/r: OR 0.29, 95% CI: 0.09-0.94). In both groups, the probability of remaining suppressed increased with the duration of continuous suppression prior to the poor adherence period (EFV: OR 3.40, 95% CI: 0.62-18.75; LPV/r: OR 5.65, 95% CI: 1.82-17.56). CONCLUSIONS: The investigated genetic variants did not play a significant role in the sustained viral suppression of individuals with suboptimal adherence. Risk of failure decreased with longer duration of viral suppression in this population.
Project description:<h4>Background</h4>Despite evidence shown of dolutegravir (DTG)-related neurotoxicity, which may be more common when combined with abacavir (ABC), its reversibility has not been explored in a clinical trial.<h4>Methods</h4>We conducted a randomized, multicenter, open-label, pilot trial to evaluate the reversibility of patient-reported neuropsychiatric symptoms, developed or worsened on DTG/ABC/lamivudine (DTG/ABC/3TC), in virologically suppressed patients switched to cobicistat-boosted-elvitegravir/emtricitabine/tenofovir-alafenamide (EVG/COBI/FTC/TAF). Participants were randomized to immediate switch (baseline) or to defer switch (week 4), and then all completed 24 weeks of follow up on EVG/COBI/FTC/TAF. At each visit, participants completed Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression (HAD) scales and were interviewed about 11 neuropsychiatric symptoms potentially related with DTG through a questionnaire. At baseline and at the end of follow up, they also performed neurocognitive testing. Our primary objective was to compare changes in neuropsychiatric symptoms and PSQI and HAD scales between arms at week 4. Secondary objectives were to evaluate changes in neuropsychiatric symptoms and PSQI and HAD scales at weeks 4, 12, and 24 after switching to EVG/COBI/FTC/TAF and in neurocognitive performance and magnetic resonance imaging biomarkers at end of follow up.<h4>Results</h4>Thirty-eight participants were included. Study arms were similar at baseline. At week 4, neuropsychiatric symptoms and PSQI and HAD scores remained unchanged in participants receiving DTG/ABC/3TC and improved significantly in participants receiving EVG/COBI/FTC/TAF. These significant improvements were also observed at weeks 4, 12, and 24 after all participants switched to EVG/COBI/FTC/TAF. In addition, global neurocognitive performance improved (NPZ-7) after switching to EVG/COBI/FTC/TAF.<h4>Conclusions</h4>Neuropsychiatric symptoms in patients on DTG/ABC/3TC could resolve or improve after switching to EVG/COBI/FTC/TAF.
Project description:BACKGROUND:Recent evidence indicates that disrupted sleep could contribute to the development of Alzheimer's disease by influencing the production and/or clearance of the amyloid-? protein. We set up a case-control study to investigate the association between long-term work-induced sleep disruption, cognitive function, and brain amyloid-? burden. METHODS:Nineteen male maritime pilots (aged 48-60?years) with chronic work-related sleep disruption and a sex-, age-, and education-matched control sample (n?=?16, aged 50-60?years) with normal sleep completed the study. Primary sleep disorders were ruled out with in-lab polysomnography. Additional sleep measurements were obtained at home using actigraphy, sleep-wake logs, and a single-lead EEG device. Cognitive function was assessed with a neuropsychological test battery, sensitive to early symptomatic Alzheimer's disease. Brain amyloid-? burden was assessed in maritime pilots using 18F-flutemetamol amyloid PET-CT. RESULTS:Maritime pilots reported significantly worse sleep quality (Pittsburgh Sleep Quality Index (PSQI)?=?8.8?±?2.9) during work weeks, compared to controls (PSQI?=?3.2?±?1.4; 95% CI 0.01 to 2.57; p?=?0.049). This was confirmed with actigraphy-based sleep efficiency (86% ±?3.8 vs. 89.3% ±?4.3; 95% CI 0.43 to 6.03; p?=?0.03). Home-EEG recordings showed less total sleep time (TST) and deep sleep time (DST) during work weeks compared to rest weeks (TST 318.56 (250.21-352.93) vs. TST 406.17 (340-425.98); p?=?0.001; DST 36.75 (32.30-58.58) vs. DST 51.34 (48.37-69.30); p?=?0.005)). There were no differences in any of the cognitive domains between the groups. For brain amyloid-? levels, mean global cortical standard uptake value ratios of 18F-flutemetamol were all in the normal range (1.009?±?0.059; 95% CI 0.980 to 1.037), confirmed by visual reads. CONCLUSIONS:Capitalizing on the particular work-rest schedule of maritime pilots, this study with a small sample size observed that long-term intermittent sleep disruption had no effects on global brain amyloid-? levels or cognitive function.