A randomized cross-over study to compare raltegravir and efavirenz (SWITCH-ER study)

Efavirenz (EFV) causes neuropsychiatric side-effects and an unfavorable blood lipid profile. We investigated the effect of replacing EFV with raltegravir (RAL) on patient preference, daytime sleepiness, sleep quality, anxiety, and lipid levels.

A randomized crossover study to compare efavirenz and etravirine treatment

Efavirenz (EFV) causes neuropsychiatric side-effects and an unfavourable blood lipid profile. We investigated the effect of replacing EFV with etravirine (ETR) on patient preference, sleep, anxiety and lipid levels.

Renal function in patients with HIV starting therapy with tenofovir and either efavirenz, lopinavir or atazanavir

Tenofovir is associated with reduced renal function, but it is not clear whether there is a greater decline in renal function when tenofovir is co-administered with a boosted protease inhibitor rather than with a nonnucleoside reverse transcriptase inhibitor (NNRTI).

The effect of efavirenz versus nevirapine-containing regimens on immunologic, virologic and clinical outcomes in a prospective observational study

OBJECTIVE: To compare regimens consisting of either efavirenz or nevirapine and two or more nucleoside reverse transcriptase inhibitors (NRTIs) among HIV-infected, antiretroviral-naive, and AIDS-free individuals with respect to clinical, immunologic, and virologic outcomes. DESIGN: Prospective studies of HIV-infected individuals in Europe and the US included in the HIV-CAUSAL Collaboration. METHODS: Antiretroviral therapy-naive and AIDS-free individuals were followed from the time they started an NRTI, efavirenz or nevirapine, classified as following one or both types of regimens at baseline, and censored when they started an ineligible drug or at 6 months if their regimen was not yet complete. We estimated the 'intention-to-treat' effect for nevirapine versus efavirenz regimens on clinical, immunologic, and virologic outcomes. Our models included baseline covariates and adjusted for potential bias introduced by censoring via inverse probability weighting. RESULTS: A total of 15 336 individuals initiated an efavirenz regimen (274 deaths, 774 AIDS-defining illnesses) and 8129 individuals initiated a nevirapine regimen (203 deaths, 441 AIDS-defining illnesses). The intention-to-treat hazard ratios [95% confidence interval (CI)] for nevirapine versus efavirenz regimens were 1.59 (1.27, 1.98) for death and 1.28 (1.09, 1.50) for AIDS-defining illness. Individuals on nevirapine regimens experienced a smaller 12-month increase in CD4 cell count by 11.49 cells/mul and were 52% more likely to have virologic failure at 12 months as those on efavirenz regimens. CONCLUSIONS: Our intention-to-treat estimates are consistent with a lower mortality, a lower incidence of AIDS-defining illness, a larger 12-month increase in CD4 cell count, and a smaller risk of virologic failure at 12 months for efavirenz compared with nevirapine.

Does tenofovir influence efavirenz pharmacokinetics?

INTRODUCTION: A recent report described a possible interaction between tenofovir (TFV) and efavirenz (EFV). Patients developed neuropsychiatric manifestations upon introduction of TFV on a stable EFV-containing regimen. We evaluated the possibility of a pharmacokinetic interaction between TFV and EFV by assessing cross-sectional and longitudinal data in 169 individuals receiving EFV. RESULTS: EFV plasma area-under-the-curve (AUC) levels were comparable among individuals receiving (n=18) or not receiving TFV (n=151); 57,962 versus 52,293 ng*h/ml. However, under conditions of limited EFV metabolism, that is, the group of 23 individuals carrying two copies of CYP2B6 loss/diminished-function alleles, plasma AUC values were highest among individuals receiving TFV (n=5, 353,031 ng*h/ml), compared with those not receiving TFV (n=18, 180,689 ng*h/ml). Statistical analysis identified both a global, sixfold effect of CYP2B6 loss/diminished function (P < 0.0001) and a significant interaction between the number of loss/diminished-function alleles and the co-medication with TFV (P = 0.009). CONCLUSION: Although there is no clear evidence for a pharmacokinetic interaction between TFV and EFV, we cannot rule out an interaction between these drugs restricted to individuals who are slow EFV metabolizers.

Predictive value of known and novel alleles of CYP2B6 for efavirenz plasma concentrations in HIV-infected individuals

To assess the association of CYP2B6 allelic diversity with efavirenz (EFV) pharmacokinetics, we performed extensive genotyping of 15 relevant single nucleotide polymorphism in 169 study participants, and full resequencing of CYP2B6 in individuals with abnormal EFV plasma levels. Seventy-seven (45.5%) individuals carried a known (CYP2B6*6, *11, *15, or *18) or new loss/diminished-function alleles. Resequencing defined two new loss-of-function alleles: allele *27 (marked by 593T>C [M198T]), that results in 85% decrease in enzyme activity and allele *28 (marked by 1132C>T), that results in protein truncation at arginine 378. Median AUC levels were 188.5 microg h/ml for individuals homozygous for a loss/diminished-function allele, 58.6 microg h/ml for carriers, and 43.7 microg h/ml for noncarriers (P<0.0001). Individuals with a poor metabolizer genotype had a likelihood ratio of 35 (95% CI, 11-110) of presenting very high EFV plasma levels. CYP2B6 poor metabolizer genotypes explain to a large extent EFV pharmacokinetics and identify individuals at risk of extremely elevated EFV plasma levels.

Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV-infected patients

BACKGROUND: Efavirenz (EFV) and nevirapine (NVP) are metabolized by cytochrome P450 2B6 (CYP2B6). Allele 516 G>T (Gln172His) is associated with diminished activity of this isoenzyme, and may lead to differences in drug exposure. METHODS: We evaluated this allele as a pharmacogenetic marker of EFV and NVP pharmacokinetics and EFV toxicity in 167 participants receiving EFV and 59 receiving NVP recruited within the genetics project of the Swiss HIV Cohort Study. Drug concentrations were measured in plasma and in peripheral blood mononuclear cells (PBMCs) from the same sample. Neuropsychological toxicity of EFV (sleep disorders, mood disorders, fatigue) was assessed using a standardized questionnaire. RESULTS AND CONCLUSIONS: CYP2B6 516TT was associated with greater plasma and intracellular exposure to EFV, and greater plasma exposure to NVP. Intracellular drug concentration, and CYP2B6 genotype were predictors of EFV neuropsychological toxicity. CYP2B6 genotyping may be useful to complement an individualization strategy based on plasma drug determinations to increase the safety and tolerability of EFV.

Virological and immunological responses to efavirenz or boosted lopinavir as first-line therapy for patients with HIV

BACKGROUND: Efavirenz and lopinavir boosted with ritonavir are both recommended as first-line therapies for patients with HIV when combined with two nucleoside reverse transcriptase inhibitors. It is uncertain which therapy is more effective for patients starting therapy with an advanced infection. METHODS: We estimated the relative effect of these two therapies on rates of virological and immunological failure within the Swiss HIV Cohort Study and considered whether estimates depended on the CD4(+) T-cell count when starting therapy. We defined virological failure as either an incomplete virological response or viral rebound after viral suppression and immunological failure as failure to achieve an expected CD4(+) T-cell increase calculated from EuroSIDA statistics. RESULTS: Patients starting efavirenz (n=660) and lopinavir (n=541) were followed for a median of 4.5 and 3.1 years, respectively. Virological failure was less likely for patients on efavirenz, with the adjusted hazard ratio (95% confidence interval) of 0.63 (0.50-0.78) then multiplied by a factor of 1.00 (0.90-1.12) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. Immunological failure was also less likely for patients on efavirenz, with the adjusted hazard ratio of 0.68 (0.51-0.91) then multiplied by a factor of 1.29 (1.14-1.46) for each 100 cells/mm(3) decrease in CD4(+) T-cell count below the mean when starting therapy. CONCLUSIONS: Virological failure is less likely with efavirenz regardless of the CD4(+) T-cell count when starting therapy. Immunological failure is also less likely with efavirenz; however, this advantage disappears if patients start therapy with a low CD4(+) T-cell count.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Virologic and immunologic responses in treatment-naive patients to ritonavir-boosted atazanavir or efavirenz with a common backbone

Background: Atazanavir boosted with ritonavir (ATV/r) and efavirenz (EFV) are both recommended as first-line therapies for HIV-infected patients. We compared the 2 therapies for virologic efficacy and immune recovery. Methods: We included all treatment-naïve patients in the Swiss HIV Cohort Study starting therapy after May 2003 with either ATV/r or EFV and a backbone of tenofovir and either emtricitabine or lamivudine. We used Cox models to assess time to virologic failure and repeated measures models to assess the change in CD4 cell counts over time. All models were fit as marginal structural models using both point of treatment and censoring weights. Intent-to-treat and various as-treated analyses were carried out: In the latter, patients were censored at their last recorded measurement if they changed therapy or if they were no longer adherent to therapy. Results: Patients starting EFV (n = 1,097) and ATV/r (n = 384) were followed for a median of 35 and 37 months, respectively. During follow-up, 51% patients on EFV and 33% patients on ATV/r remained adherent and made no change to their first-line therapy. Although intent-to-treat analyses suggest virologic failure was more likely with ATV/r, there was no evidence for this disadvantage in patients who adhered to first-line therapy. Patients starting ATV/r had a greater increase in CD4 cell count during the first year of therapy, but this advantage disappeared after one year. Conclusions: In this observational study, there was no good evidence of any intrinsic advantage for one therapy over the other, consistent with earlier clinical trials. Differences between therapies may arise in a clinical setting because of differences in adherence to therapy.

Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa. Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes. Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0). Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

Determinants of sustained viral suppression in HIV-infected patients with self-reported poor adherence to antiretroviral therapy

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.

Choice of Initial Combination Antiretroviral Therapy in Individuals With HIV Infection: Determinants and Outcomes

BACKGROUND Current guidelines give recommendations for preferred combination antiretroviral therapy (cART). We investigated factors influencing the choice of initial cART in clinical practice and its outcome. METHODS We analyzed treatment-naive adults with human immunodeficiency virus (HIV) infection participating in the Swiss HIV Cohort Study and starting cART from January 1, 2005, through December 31, 2009. The primary end point was the choice of the initial antiretroviral regimen. Secondary end points were virologic suppression, the increase in CD4 cell counts from baseline, and treatment modification within 12 months after starting treatment. RESULTS A total of 1957 patients were analyzed. Tenofovir-emtricitabine (TDF-FTC)-efavirenz was the most frequently prescribed cART (29.9%), followed by TDF-FTC-lopinavir/r (16.9%), TDF-FTC-atazanavir/r (12.9%), zidovudine-lamivudine (ZDV-3TC)-lopinavir/r (12.8%), and abacavir/lamivudine (ABC-3TC)-efavirenz (5.7%). Differences in prescription were noted among different Swiss HIV Cohort Study sites (P < .001). In multivariate analysis, compared with TDF-FTC-efavirenz, starting TDF-FTC-lopinavir/r was associated with prior AIDS (relative risk ratio, 2.78; 95% CI, 1.78-4.35), HIV-RNA greater than 100 000 copies/mL (1.53; 1.07-2.18), and CD4 greater than 350 cells/μL (1.67; 1.04-2.70); TDF-FTC-atazanavir/r with a depressive disorder (1.77; 1.04-3.01), HIV-RNA greater than 100 000 copies/mL (1.54; 1.05-2.25), and an opiate substitution program (2.76; 1.09-7.00); and ZDV-3TC-lopinavir/r with female sex (3.89; 2.39-6.31) and CD4 cell counts greater than 350 cells/μL (4.50; 2.58-7.86). At 12 months, 1715 patients (87.6%) achieved viral load less than 50 copies/mL and CD4 cell counts increased by a median (interquartile range) of 173 (89-269) cells/μL. Virologic suppression was more likely with TDF-FTC-efavirenz, and CD4 increase was higher with ZDV-3TC-lopinavir/r. No differences in outcome were observed among Swiss HIV Cohort Study sites. CONCLUSIONS Large differences in prescription but not in outcome were observed among study sites. A trend toward individualized cART was noted suggesting that initial cART is significantly influenced by physician's preference and patient characteristics. Our study highlights the need for evidence-based data for determining the best initial regimen for different HIV-infected persons.