Efavirenz Arm Research Articles

Comparison of dolutegravir and efavirenz on depression, anxiety and sleep disorders in pregnant and postpartum women living with HIV.

Both dolutegravir and efavirenz are known to be effective in pregnancy and postpartum to prevent vertical transmission of HIV and to maintain maternal health. Both drugs have also been associated with neuropsychiatric symptoms. To what extent, these symptoms occur in pregnant and postpartum women, however, is not yet known. This was a secondary analysis of the DolPHIN2 study, a multicentre randomized trial among women presenting late in pregnancy with untreated HIV - who received either a dolutegravir-containing or efavirenz-containing regimen. Longitudinal measures of depression, anxiety and sleep quality were analysed during pregnancy and up to 48 weeks postpartum. Among 268 women, median (IQR) Edinburgh Post Natal Depression Score (EPDS) scores were 8 (3-11) and highest at enrolment. In the dolutegravir and efavirenz arm, respectively, 23.7 and 25.6% had an EPDS score above 9, indicating possible or probable depression. Abnormal Hospital Anxiety Depression scores (HADS) (above 11) were seen at least once during follow-up in 42 of patients (15.7%), although no differences were seen between treatment arms. No association was found between EPDS, suicidality and HADS scores and the assigned regimen ( P = 0.93, 0.97 and 0.18 respectively). Median (IQR) Pittsburgh Sleep Quality index (PSQI) scores for dolutegravir and efavirenz were 6 (5-7) and 5 (5-6.5), respectively, P = 0.70. No statistically significant differences were observed between efavirenz-containing or dolutegravir-containing regimens. Rates of depression were high, but decreased over the course of time and confirm the need for psychological support after initial HIV diagnosis in pregnancy.

Efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients with tuberculosis: systematic review and meta-analysis

Integrase Inhibitors are a promising new class of antiretroviral. However, studies of these drugs in tuberculosis (TB) and, HIV/aids coinfection are scarce. Therefore, the aim of this review was evaluate the efficacy, effectiveness, and safety of integrase inhibitors in the treatment of HIV/AIDS in patients coinfected with tuberculosis (TB). The searches were performed in the MEDLINE, EMBASE, LILACS, COCHRANE, Web of Science, Scopus, and CINAHL databases using the terms “HIV”, “AIDS”, “tuberculosis”, “raltegravir potassium”, “dolutegravir”, “elvitegravir”, “bictegravir”, “integrase inhibitor”, and their respective synonyms. Reports from three randomised clinical trials and a historical cohort were included. Patients coinfected with TB and HIV/AIDS showed a good response to TB treatment (cure or treatment completed), which was above 85% in all arms of the evaluated studies. As a primary outcome, the HIV viral load suppression rates at week 48 were greater than 60% in all arms. The therapies evaluated in patients coinfected with TB and HIV/AIDS were also within the limits of the included studies, there were no significant drug-related adverse events. However, there was no significant difference in the efficacy outcomes viral load suppression between the efavirenz and integrase inhibitor arms, and regarding safety outcomes, there were few events compared with the total. Integrase inhibitors in patients co-infected with TB and HIV/AIDS appear to be effective, well tolerated and constitute an alternative to efavirenz in clinical protocols. However, the use of this drug twice a day compromises adherence to treatment. The role of these drugs should be better determined by further good methodological quality studies to assess their long-term efficacy, effectiveness and safety.

Concentration-response relationships of dolutegravir and efavirenz with weight change after starting antiretroviral therapy.

AimDolutegravir is associated with more weight gain than efavirenz in people starting antiretroviral therapy (ART). We investigated the concentration-response relationships of efavirenz and dolutegravir with weight gain.MethodsWe determined concentration-response relationships of dolutegravir and efavirenz (both combined with tenofovir disoproxil fumarate and emtricitabine) with changes in weight and fat distribution, derived from dual-energy x-ray absorptiometry scans, in a nested study of ART-naïve participants from a randomised controlled trial. Pharmacokinetic parameters used in analyses were efavirenz mid-dosing interval (MDI) concentrations and estimated dolutegravir area under the concentration-time curve (AUC0-24) using a population pharmacokinetic model developed in the study population. Study outcomes were percentage changes from baseline to week 48 in weight, and visceral and subcutaneous adipose tissue (VAT and SAT) mass.ResultsPharmacokinetic data were available for 158 and 233 participants in the efavirenz arm and dolutegravir arms respectively; 57.0% were women. On multivariable linear regression there were independent negative associations between efavirenz concentrations and changes in both weight (P <0.001) and SAT mass (P = 0.002). Estimated dolutegravir AUC0-24 was not associated with change in weight (P = 0.109) but was negatively associated with change in VAT mass (P = 0.025).ConclusionWe found an independent negative concentration-response relationship between efavirenz concentrations and weight change in ART-naïve participants. Dolutegravir concentrations were not independently associated with weight change. These findings suggest that weight gain differences between efavirenz and dolutegravir are driven by efavirenz toxicity impairing weight gain rather than by off-target effects of dolutegravir causing weight gain.

Efavirenz versus Protease Inhibitors in Patients with HIV: A Systematic Review and Meta-Analysis

Efavirenz- and protease inhibitor (PI)-based regimens remain viable options across the globe. We conducted a meta-analysis to compare the effectiveness of efavirenz-based regimens relative to PI-based regimens. EMBASE, PubMed, Cochrane, and clinicaltrials.gov were searched for randomized controlled trials conducted between 1987 and 2018 comparing efavirenz- with PI-based regimens. This was followed by title, abstract, and full-text screens. The quality of selected studies was assessed using the Cochrane risk of bias tool. Meta-analysis of the odds of virological suppression was conducted using the robust variance estimation approach. Fifteen studies met the inclusion criteria and totaled 6712 patients (efavirenz arm = 3339; PI arm = 3373), of which 1610 (24.0%) were females. Follow-up ranged from 24 to 144 weeks. Mean/median age ranged from 33 to 44 years. Mean/median baseline CD4 count ranged from 32 to 557 cells/mL while mean/median baseline viral load ranged from log10 4.5 to log10 5.5 copies/mL. Meta-analysis showed that patients receiving efavirenz-based regimens had 37% higher odds of virological suppression compared to PI-based regimens (odds ratio = 1.37, 95% confidence interval = 1.06-1.77, p = 0.02). The Egger test suggested the presence of publication bias (B = 0.927, t = 2.214, p = 0.033). The main threat to the quality of evidence was attrition bias. Regarding virological suppression, efavirenzbased regimens were more effective than PI-based regimens and, therefore, might be ideal for the management of treatment naïve patients with HIV in settings where NNRTIs and PIs are used.

Brief Report: Vaginal Viral Shedding With Undetectable Plasma HIV Viral Load in Pregnant Women Receiving 2 Different Antiretroviral Regimens: A Randomized Clinical Trial.

Pregnant women using antiretrovirals (ARVs) may have persistent vaginal viral shedding, which could be associated with sexual and perinatal HIV transmission. However, there are scant data on vaginal viral load (VVL) in pregnant women with undetectable plasma viral load (PVL). This study was a post hoc analysis of an open-label randomized trial to evaluate the virologic response of 2 ART regimens. The participants were ART-naive women living with HIV initiating ART regimens between 20 and 36 weeks of pregnancy recruited at 19 clinical sites in 6 countries. Participants were randomized to receive 400 mg of raltegravir 2 times a day or 600 mg of efavirenz 4 times a day in addition to 150 mg of lamivudine and 300 mg of zidovudine 2 times a day. VVL and PVL tests were performed at every study visit. The primary outcome measures were HIV-1 PVL and VVL at maternal study week 4 and rates of perinatal HIV transmission. A total of 408 were enrolled, of whom 323 had VVL samples 4 weeks after enrollment and were included in this analysis. Among women with undetectable/nonquantifiable PVL during ART, the overall rate of quantifiable VVL at week 4 was 2.54% (7/275). Of the 275 with nonquantifiable PVL, 99.1% (115/116) and 96.2% (153/159) had nonquantifiable VVL in the efavirenz and raltegravir arms, respectively. None of the 7 women with quantifiable VVL at the week 4 study visit transmitted HIV to their infants. Detectable VVL in pregnant women with undetectable/nonquantifiable PVL while receiving ART was rare and not associated with perinatal HIV transmission.

Higher plasma drug levels in elderly people living with HIV treated with darunavir.

BackgroundThe proportion of elderly people living with HIV-1 (PLHIV) is rising. In older patients, comorbidities and concomitant medications are more frequent, increasing the risk of potential drug-drug interactions (PDDIs). Data on the pharmacokinetics of ART in individuals aged ≥ 65 years of age are scarce. We compared plasma drug levels of ART, PDDIs, and side-effects in PLHIV aged ≥ 65 years of age, with controls ≤ 49 years of age.MethodsPatients ≥ 65 years of age and controls ≤ 49 years of age, all of whom were on stable treatment with atazanavir (ATV), darunavir (DRV), or efavirenz (EFV) were included cross-sectionally. Plasma drug levels of ART were analyzed, comorbidities, concomitant medication, adherence, and side-effects recorded, and PDDIs analyzed using drug interactions databases.ResultsBetween 2013 and 2015, we included 100 individuals ≥ 65 years of age (study group) and 99 controls (≤ 49 years of age). Steady-state DRV concentrations were significantly higher in the study group than in the control group (p = 0.047). In the ATV group there was a trend towards a significant difference (p = 0.056). No significant differences were found in the EFV arm. The DRV arm had a higher frequency of reported side-effects than the ATV and EFV arms in the study group (36.7% vs. 0% and 23.8% respectively (p = 0.014), with significant differences between DRV vs. ATV, and EFV vs. ATV).ConclusionsHigher steady-state plasma levels of DRV and ATV (but not EFV) were found in PLHIV aged ≥ 65 years of age, compared to controls ≤ 49 years of age.

CYP2B6 Genotype and Weight Gain Differences Between Dolutegravir and Efavirenz.

BackgroundDolutegravir is associated with more weight gain than efavirenz. Loss-of-function polymorphisms in CYP2B6 result in higher efavirenz concentrations, which we hypothesized would impair weight gain among people living with human immunodeficiency virus (HIV; PLWH) starting efavirenz-based antiretroviral therapy (ART).MethodsWe studied ART-naive participants from the ADVANCE study randomized to the efavirenz /emtricitabine/tenofovir disoproxil fumarate (TDF) and dolutegravir/emtricitabine/TDF arms. We compared changes in weight and regional fat on DXA from baseline to week 48 between CYP2B6 metabolizer genotypes in the efavirenz arm, and with the dolutegravir arm.ResultsThere were 342 participants in the dolutegravir arm and 168 in the efavirenz arm who consented to genotyping. Baseline characteristics were similar. Weight gain was greater in women than men. In the efavirenz arm CYP2B6 metaboliser genotype was associated with weight gain (P = .009), with extensive metabolizers gaining the most weight, and with changes in regional fat in women, but not in men. Weight gain was similar in CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm (P = .836). The following variables were independently associated with weight gain in all participants: baseline CD4 count, baseline human immunodeficiency virus type 1 (HIV-1) RNA, and CYP2B6 metaboliser genotype.Conclusions CYP2B6 metaboliser genotype was associated with weight gain in PLWH starting efavirenz-based ART. Weight gain was similar between CYP2B6 extensive metabolizers in the efavirenz arm and in the dolutegravir arm, suggesting that impaired weight gain among CYP2B6 slow or intermediate metabolizers could explain the increased weight gain on dolutegravir compared with efavirenz observed in ADVANCE and other studies.

Efavirenz versus Protease Inhibitors in Patients with Human Immunodeficiency Virus – A Systematic Review and Meta-Analysis

Background: Efavirenz- and protease inhibitor-based regimens remain viable options across the globe. We conducted a meta-analysis to compare the effectiveness of efavirenz-based regimens relative to protease inhibitor-based regimens (PIs). Methods: Embase, PubMed, Cochrane, and clinicaltrials.gov were searched for randomised controlled trials (RCTs) conducted between 1987 and 2018 comparing efavirenz- with PI-based regimens. This was followed by title, abstract, and full-text screens. The quality of selected studies was assessed using the Cochrane risk of bias tool. Meta-analysis of the odds of virological suppression was conducted using the robust variance estimation approach. Findings: Fifteen studies met the inclusion criteria and totaled 6,712 patients (efavirenz arm=3,339; PI arm=3,373), of which 1,610 (24.0%) were females. Follow-up ranged from 24 to 144 weeks. Mean/median age ranged from 33 to 44 years. Mean/median baseline CD4 count ranged from 32 to 557 cells/mL while mean/median baseline viral load ranged from log10 4·5 to log10 5·5 copies /mL. Meta-analysis showed that patients receiving efavirenz-based regimens had 37% higher odds of virological suppression compared to PI-based regimens (OR=1·37, 95% CI=1·06-1·77, p=0.02). The Egger test suggested the presence of publication bias (B=0·927, t=2·214, p=0·033). The main threat to the quality of evidence was attrition bias. Interpretation: Regarding virological suppression, efavirenz-based regimens were more effective than PI-based regimens and, therefore, might be ideal for the management of treatment naive patients with HIV in settings where NNRTIs and PIs are used. Funding Statement: The authors stated that there were no funding sources for the study. Declaration of Interests: The authors have no conflicts of interests to declare. Ethics Approval Statement: The study was approved by the University of Texas at Austin Institutional Review Board and determined to be non-human subjects research as it involved obtaining information from publicly available data. Hence, informed consent was not required. The study was registered with PROSPERO, an international database supported by PRISMA (ID: CRD42018100296).

2840. Long-term Efficacy, Safety, and Durability of CAB and RPV as Two Drug Oral Maintenance Therapy: LATTE Week 312 Results

BackgroundCabotegravir (CAB), an INI, is under development in both oral and long-acting (LA) injectable formulations. LATTE (NCT01641809) was designed to select a daily oral dose of CAB and evaluate a two-drug ART regimen with rilpivirine (RPV), as suppressive maintenance therapy. Results enabled the LATTE-2 (NCT02120352) study to evaluate CAB LA + RPV LA dosed once every 1 or 2 months.MethodsPhase 2b, multicentre, partially blinded dose-ranging study in ART-naïve HIV infected adults, randomized 1:1:1:1 to the induction regimen of once-daily oral CAB 10, 30, or 60 mg or efavirenz (EFV) 600 mg with TDF/FTC or ABC/3TC through W24. CAB patients with VL <50 c/mL immediately prior to W24 discontinued NRTIs and began RPV 25 mg as a two-drug oral maintenance regimen through W96. No change was made to the EFV arm. After W96, at the start of the open-label (OL) phase, all patients randomized to CAB were given the option to continue and switch to the sponsor-selected dose of oral CAB 30 mg. EFV patients completed the study at W96. The OL phase was completed at W312 (288 weeks on CAB + RPV). Successful CAB + RPV patients transitioned to the POLAR study (NCT03639311).ResultsA total of 243 patients were randomized and initiated treatment (ITT-E). Of those randomized to CAB (n = 181), 160 patients began CAB + RPV (W24) and 138 continued into OL phase (W96). One hundred and ten patients successfully completed the study (W312). Among patients who began CAB + RPV at W24, 66% maintained <50 c/mL, 9% had HIV-1 RNA ≥ 50 c/mL, and 25% were categorized as “No Virologic Data” by Snapshot at W312 (ITT-ME). There were 11 protocol-defined virologic failures (PDVF) on CAB; only 2 occurring after W144. Six patients developed treatment emergent (TE) resistance to one or both agents during the study; of which 4 patients developed TE major INI resistance mutations, 3 after W96. The median increase in CD4+ cell count from Baseline was 393 cells/mm3 (−174 to 1118). During the maintenance and OL phases, 4% of CAB patients reported drug-related AEs ≥ Grade 2; SAEs occurred in 9% of CAB patients (none drug related); 3% of CAB patients withdrew due to AEs. 43% of CAB patients who entered maintenance phase reported TE lab abnormalities ≥ Grade 3.ConclusionAs maintenance therapy in virologically suppressed patients, the 2DR CAB + RPV provided durable viral suppression through W312. Through 7 years of study, CAB + RPV continues to be generally safe and well tolerated. Disclosures All Authors: No reported Disclosures.

Switching at Low HIV-1 RNA into Fixed Dose Combinations: TDF/FTC/RPV is non-inferior to TDF/FTC/EFV in first-line suppressed patients living with HIV.

BackgroundIn low- and middle-income countries (LMICs), a substantial unmet need for affordable single-tablet regimen (STR) options remains. Rilpivirine (RPV, TMC278) is formulated in a low-cost STR with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC).ObjectivesSwitching at Low HIV-1 RNA into Fixed Dose Combinations (SALIF) compared RPV with efavirenz (EFV), both as STRs with TDF and FTC, in maintaining virologic suppression.MethodsSALIF was a phase 3b, randomised, open-label, non-inferiority study in virologically suppressed adults (HIV-1 RNA < 50 copies/mL) on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based first-line antiretroviral therapy (ART) in Cameroon, Kenya, Senegal, South Africa, Uganda and Thailand. Patients (N = 426), stratified by NNRTI use, were randomised 1:1 to receive TDF/FTC/RPV (300/200/25 mg qd) or TDF/FTC/EFV (300/200/600 mg qd). Primary endpoint was proportion of patients with virologic suppression (HIV-1 RNA < 400 copies/mL) at week 48 (intent-to-treat, modified Food and Drug Administration Snapshot, 10% non-inferiority margin).ResultsPatients received TDF/FTC/RPV (n = 213) or TDF/FTC/EFV (n = 211). At week 48, virologic suppression was maintained in 200/213 (93.9%) patients in the RPV arm and 203/211 (96.2%) in the EFV arm (difference –2.3%; 95% confidence interval: −6.4, +1.8), demonstrating non-inferiority of TDF/FTC/RPV. One patient in each arm experienced virologic failure without treatment-emergent resistance. Twenty-seven patients discontinued prematurely (8.0% RPV vs. 4.7% EFV), the most frequent reasons being adverse events (3.3% vs. 0.5%, respectively), site closure (1.9% vs. 0.5%), loss to follow-up (0.9% vs. 1.4%) and consent withdrawal (0.9% vs. 1.4%).ConclusionIn adults with suppressed viral load on first-line NNRTI-based ART in LMICs, switching to an STR of TDF/FTC/RPV was non-inferior to TDF/FTC/EFV in maintaining high rates of viral suppression with a comparable tolerability profile.

Changes in plasma lipidome following initiation of antiretroviral therapy.

IntroductionHIV and antiretroviral therapy (ART) have been associated with increased cardiovascular disease and important changes in lipid metabolism. Advances in mass-spectrometry technology allow for the detailed assessment of individual lipid species which may illuminate the mechanisms underlying increased cardiovascular risk. We describe the change in plasma lipidome with initiation of antiretroviral therapy and compare these by regimen.MethodsPlasma lipid profiling (by electrospray isonisation-tandem mass spectrometry) was performed on ARV-naive HIV positive participants randomised to one of three regimens; tenofovir/emtricitabine with efavirenz, ritonavir-boosted atazanavir (atazanavir/r) or zidovudine/abacavir. Participants (n = 115) who remained on their randomised regimen with complete samples available at baseline, week 12 and 48 were included. 306 lipid species from 22 lipid classes were analysed.ResultsInitiation of ART led to significant changes in lipidome which were partly dependent on the randomised regimen received. This led to significant differences in 72 lipid species and 7 classes (cholesterol ester, free cholesterol, phosphatidylcholine, GM3 ganglioside, trihexosylceramide, monohexosylceramide, and ceramides) by arm at week 48. Consistently higher lipid concentrations were seen with efavirenz compared with atazanavir/r or zidovudine/abacavir. Twelve of the lipid species and two lipid classes (cholesterol esters and ceramides) that were significantly increased in the efavirenz arm compared with the atazanavir/r or zidovudine/abacavir arms have previously been associated with future cardiovascular events in HIV positive patients. Change in HIV viral load was predictive of change in 3 lipid species.ConclusionsInitiation of ART lead to significant changes in the plasma lipidome that were greatest in those receiving efavirenz.

APOBEC3G/3A Expression in Human Immunodeficiency Virus Type 1-Infected Individuals Following Initiation of Antiretroviral Therapy Containing Cenicriviroc or Efavirenz.

Apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3) family members are cytidine deaminases that play crucial roles in innate responses to retrovirus infection. The mechanisms by which some of these enzymes restrict human immunodeficiency virus type 1 (HIV-1) replication have been extensively investigated in vitro. However, little is known regarding how APOBEC3 proteins affect the pathogenesis of HIV-1 infection in vivo and how antiretroviral therapy influences their expression. In this work, a longitudinal analysis was performed to evaluate APOBEC3G/3A expression in peripheral blood mononuclear cells of antiretroviral-naive HIV-1-infected individuals treated with cenicriviroc (CVC) or efavirenz (EFV) at baseline and 4, 12, 24, and 48 weeks post-treatment follow-up. While APOBEC3G expression was unaffected by therapy, APOBEC3A levels increased in CVC but not EFV arm at week 48 of treatment. APOBEC3G expression correlated directly with CD4+ cell count and CD4+/CD8+ cell ratio, whereas APOBEC3A levels inversely correlated with plasma soluble CD14. These findings suggest that higher APOBEC3G/3A levels may be associated with protective effects against HIV-1 disease progression and chronic inflammation and warrant further studies.

Estradiol Levels Are Altered in Human Immunodeficiency Virus-Infected Pregnant Women Randomized to Efavirenz-Versus Lopinavir/Ritonavir-Based Antiretroviral Therapy.

Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. NCT00993031.

Risk Factors for Incident Diabetes in a Cohort Taking First-Line Nonnucleoside Reverse Transcriptase Inhibitor-Based Antiretroviral Therapy.

Efavirenz is the preferred nonnucleoside reverse transcriptase inhibitor (NNRTI) in first-line antiretroviral therapy (ART) regimens in low- and middle-income countries, where the prevalence of diabetes is increasing. Randomized control trials have shown mild increases in plasma glucose in participants in the efavirenz arms, but no association has been reported with overt diabetes. We explored the association between efavirenz exposure and incident diabetes in a large Southern African cohort commencing NNRTI-based first-line ART. Our cohort included HIV-infected adults starting NNRTI-based ART in a private sector HIV disease management program from January 2002 to December 2011. Incident diabetes was identified by the initiation of diabetes treatment. Patients with prevalent diabetes were excluded. We included 56,298 patients with 113,297 patient-years of follow-up (PYFU) on first-line ART. The crude incidence of diabetes was 13.24 per 1000 PYFU. Treatment with efavirenz rather than nevirapine was associated with increased risk of developing diabetes (hazard ratio 1.27 (95% confidence interval (CI): 1.10-1.46)) in a multivariate analysis adjusting for age, sex, body mass index, baseline CD4 count, viral load, NRTI backbone, and exposure to other diabetogenic medicines. Zidovudine and stavudine exposure were also associated with an increased risk of developing diabetes. We found that treatment with efavirenz, as well as stavudine and zidovudine, increased the risk of incident diabetes. Interventions to detect and prevent diabetes should be implemented in ART programs, and use of antiretrovirals with lower risk of metabolic complications should be encouraged.

Efficacy and safety of lopinavir/ritonavir versus efavirenz-based antiretroviral therapy in HIV-infected pregnant Ugandan women.

Combination antiretroviral therapy (ART) is now the global standard for HIV-infected pregnant and breastfeeding women at all CD4⁺ cell counts. We compared the efficacy and safety of an efavirenz versus lopinavir/ritonavir regimen for HIV-infected pregnant women initiating ART in rural Uganda. Randomized clinical trial. We performed a planned secondary analysis comparing viral load suppression (HIV-1 RNA ≤400 copies/ml), safety, and HIV transmission to infants in a trial designed to test the hypothesis that lopinavir/ritonavir versus efavirenz-based ART would reduce placental malaria (PROMOTE, ClinicalTrials.gov, NCT00993031). HIV-infected, ART-naive pregnant women at 12-28 weeks gestation and any CD4⁺ cell count were randomized. ART was provided and participants were counseled to breastfeed for 1 year postpartum. The median age of the 389 study participants was 29 years; median CD4⁺ cell count was 370 cells/μl. At delivery, virologic suppression was 97.6% in the efavirenz arm and 86.0% in the lopinavir/ritonavir arm (P < 0.001). At 48 weeks postpartum, 91.0% of women on efavirenz and 88.4% on lopinavir/ritonavir had viral suppression (P = 0.49). Grade 1 or 2 gastrointestinal adverse events were higher among women on lopinavir/ritonavir versus efavirenz. Only two infants acquired HIV (both in the lopinavir/ritonavir arm), and HIV-free infant survival was similar between study arms: 92.9% (lopinavir/ritonavir) versus 97.2% (efavirenz) (P = 0.10). Virologic suppression at delivery was higher with an efavirenz versus lopinavir/ritonavir-based regimen. However, women in both arms achieved high levels of virologic suppression through 1 year postpartum and the risk of transmission to infants was low.

Cerebrospinal-fluid exposure of efavirenz and its major metabolites when dosed at 400 and 600 mg once daily; a randomized controlled trial.

Introduction The optimal penetration of antiretroviral agents into central nervous system (CNS) may be a balance between providing adequate drug exposure to inhibit HIV-replication whilst avoiding concentrations associated with toxicities.Methods Cerebrospinal-fluid (CSF) exposure of efavirenz and metabolites 7-hydroxy (7OH-) and 8OH-efavirenz were assessed after at least 12 weeks of antiretroviral therapy in HIV-infected subjects randomized to commence antiretroviral regimens containing efavirenz at either 400 mg or 600 mg once daily. Clinical, pharmacokinetic and pharmacogenomic factors associated with CSF efavirenz and its metabolite concentrations were assessed.Results Of 28 subjects who completed all study procedures (14/14 on efavirenz 400 mg/600 mg), CSF HIV RNA was below 20 copies/mL in all at the time of examination. Concentrations of efavirenz and 7OH-efavirenz in the CSF were slightly lower when dosed at 400 mg versus 600 mg, although this was not statistically significant. A different trend was observed regarding 8OH-efavirenz concentrations where CSF exposure was slightly increased in the 400 mg efavirenz arm (see Table 1). Efavirenz concentration in the CSF was above 0.51 ng/mL (proposed CSF IC50 for WT virus) in all subjects and 8OH-efavirenz concentration in the CSF was above 3.3 ng/mL (a proposed toxicity threshold, reference) in 11/14 and 7/14 subjects randomized to the 400 mg and 600 mg doses of efavirenz, respectively. Whilst CSF efavirenz concentration was significantly associated with plasma concentration (P<0.001) and CYP2B6 genotype (CSF efavirenz GG to GT/TT GM ratio 0.56, 90% CI 0.42–0.74), CSF 8OH-efavirenz concentration was not (P=0.242 for association with plasma concentration and CSF 8OH-efavirenz GG to GT/TT GM ratio 1.52, 90% CI 0.97–2.36). Lastly, CSF 8OH-efavirenz concentration was associated with efavirenz symptom questionnaire results at one year (Spearman's correlation 0.13, P=0.05). Conclusions With both doses of efavirenz studied, CSF concentrations were considered adequate to inhibit HIV-replication, although concentrations of 8OH-efavirenz were greater than that reportedly associated with neuronal toxicity. CSF exposure of 8OH-efavirenz was not dependent on plasma exposure and we postulate may be subject to saturable pharmacokinetic effects.

Cenicriviroc blocks HIV entry but does not lead to redistribution of HIV into extracellular space like maraviroc.

IntroductionCenicriviroc (CVC), a once-daily, dual CCR5/CCR2 co-receptor antagonist, has completed Phase 2b development. CVC demonstrated favourable safety and similar efficacy compared with efavirenz (EFV) in Study 202 (NCT01338883); an ex vivo sub-analysis evaluated treatment effects on HIV entry, measured by intracellular HIV DNA declines, in subjects with virologic success at Week 24. In addition, in vitro assays determined and compared the extent of any cell-free virion redistribution that CVC or maraviroc (MVC) may cause.MethodsEx vivo: intracellular DNA (frozen PBMCs) from 30 subjects with virologic success at Week 24 (10, 13 and 7 subjects on CVC 100 mg, CVC 200 mg and EFV, respectively). Early (strong-stop) and late (full-length) reverse transcript levels were measured by qPCR. In vitro: PM-1 cells were infected with CCR5-tropic HIV-1 BaL in the presence or absence of inhibitory concentrations of CVC (20 nM), MVC (50 nM) or controls. P24 and viral load levels were measured by ELISA and qRT-PCR after 4 hours.ResultsEx vivo analysis showed full-length HIV DNA declines were similar across all groups (CVC 100 mg, CVC 200 mg and EFV) at Week 24. Strong-stop HIV DNA declines (a marker of HIV entry) at Week 24 were pronounced for both CVC arms (CVC 100 mg, 51% decline; CVC 200 mg, 37% decline) compared to no decline for the EFV arm. In vitro experiments revealed that CVC-treated cells had lower levels of supernatant P24 at 4 hours versus baseline (0 hrs: 506 ng/mL; 4 hrs: 192 ng/mL), but P24 levels remained constant for MVC-treated cells after 4 hours (0 hrs: 506 ng/mL; 4 hrs: 520 ng/mL). Viral load levels for CVC-treated cells remained stable after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.26×1010 copies/mL). MVC-treated cells exhibited a slight increase in viral load after 4 hours (0 hrs: 1.19×1010 copies/mL; 4 hrs: 1.67×1010 copies/mL).ConclusionsEx vivo analysis confirmed that CVC treatment blocks HIV entry (strong-stop HIV DNA declines), while in vitro analysis showed that CVC-treated cells do not repel virus back into the extracellular space, as seen with MVC. Experiments are underway to determine whether or not interactions between CVC and HIV at the binding site may explain these unanticipated findings.

Risk factors for preterm birth among HIV-infected pregnant Ugandan women randomized to lopinavir/ritonavir- or efavirenz-based antiretroviral therapy.

Protease inhibitor-based antiretroviral therapy (ART) has been associated with preterm birth in some studies. We examined risk factors for preterm birth among women randomized to lopinavir/ritonavir (LPV/r)- or efavirenz (EFV)-based ART. This was a planned secondary analysis of the PROMOTE-Pregnant Women and Infants Study, an open-label, randomized controlled trial comparing the risk of placental malaria among HIV-infected, ART-naive pregnant Ugandan women assigned to initiate LPV/r- or EFV-based ART at 12-28 weeks gestation. Gestational age was determined based on last menstrual period and ultrasound biometry. All women received bednets and trimethoprim-sulfamethoxazole. Stillbirths, spontaneous abortions, and multiple gestations were excluded from the primary analysis. Potential risk factors for preterm birth (<37 weeks gestation) were evaluated by univariate and multivariate logistic regression. Three hundred fifty-six women were included in this analysis. At enrollment, median gestational age was 21 weeks and median CD4 cell count was 368 cells per cubic millimeter. 14.7% of deliveries in the EFV arm and 16.2% in the LPV/r arm were preterm. Preterm birth was associated with gestational weight gain below 0.1 kg/week versus 0.1 kg/week or more [odds ratio (OR) = 2.49; 95% confidence interval (CI): 1.38 to 4.47; P = 0.003]. Neither ART regimen of LPV/r versus EFV (OR = 1.12; 95% CI: 0.63 to 2.00; P = 0.69) nor placental malaria (OR = 0.74; 95% CI: 0.38 to 1.44; P = 0.37) was associated with preterm birth. LPV/r was not associated with an increased risk of preterm birth compared with EFV. However, interventions are needed to address modifiable risk factors for preterm birth, such as nutritional status (ClinicalTrials.gov, NCT00993031).

Differential subcutaneous adipose tissue gene expression patterns in a randomized clinical trial of efavirenz or lopinavir-ritonavir in antiretroviral-naive patients.

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.).

Population-Based Sequencing of the V3-loop Can Predict the Virological Response to Maraviroc in Treatment-Naive Patients of the MERIT Trial

MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing. HIV env V3-loop was amplified in triplicate using reverse transcriptase-polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876). Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar. The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.