Use Of Efavirenz Research Articles

Incidence of neuropsychiatric side effects of efavirenz in HIV-positive treatment-naïve patients in public-sector clinics in the Eastern Cape.

BackgroundIt is acknowledged that almost half of patients initiated on efavirenz will experience at least one neuropsychiatric side effect.ObjectivesThe aim was to determine the incidence and severity of neuropsychiatric side effects associated with efavirenz use in five public-sector primary healthcare clinics in the Eastern Cape.MethodThe study was a prospective drug utilisation study. A total of 126 medical records were reviewed to obtain the required information. After baseline assessment, follow-up reviews were conducted at 4 weeks, 12 weeks and 24 weeks from 2014 to 2015.ResultsThe participant group was 74.60% female (n = 94), and the average age was 37.57±10.60 years. There were no neuropsychiatric side effects recorded for any patient. After the full follow-up period, there were a total of 49 non-adherent patients and one patient had demised. A non-adherent patient was defined as a patient who did not return to the clinic for follow-up assessment and medication refills 30 days or more after the appointed date. Some patients (n = 11) had sent a third party to the clinic to collect their antiretroviral therapy (ART). The clinic pharmacy would at times dispense a two-month supply of medication resulting in the patient presenting only every two months.ConclusionFurther pharmacovigilance studies need to be conducted to determine the true incidence of these side effects. Healthcare staff must be encouraged to keep complete records to ensure meaningful patient assessments. Patients being initiated on ART need to personally attend the clinic monthly for at least the first 6 months of treatment. Clinic staff should receive regular training concerning ART, including changes made to guidelines as well as reminders of side effects experienced.

Efavirenz and ritonavir-boosted lopinavir use exhibited elevated markers of atherosclerosis across age groups in people living with HIV in Ethiopia

BackgroundHIV patients on highly-active antiretroviral therapy (HAART) have shown elevated incidence of dyslipidemia, lipodystrophy, and markers of cardiovascular disease. Evidence is beginning to emerge that implicates efavirenz (EFV) as a potential mediator of early on-set cardiovascular disease. MethodsPediatric and adult HIV-infected HAART-naïve, EFV-treated, nevirapine (NVP)-treated, and ritonavir-boosted lopinavir (LPV/r)-treated subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Pulse wave velocity (PWV), carotid intima-media thickness (cIMT), carotid arterial stiffness, brachial artery flow-mediated dilation (FMD), body mass index, waist-to-hip circumference ratio, and skinfold thickness were measured. CD4+ cell count, fasting glucose, lipoprotein profiles and triglycerides were also determined. Results were segmented into pediatric (6–17 years of age), young adults (25–39 years old) and older adults (40–60 years old). ResultsPWV was generally elevated in EFV- and LPV/r-treated subjects compared to NVP-treated subjects across age groups. cIMT was elevated in EFV- and LPV/r-treated compared to NVP-treated older adults and in EFV-treated compared to HAART-naïve older adults. FMD was impaired in EFV- and LPV/r-treated compared to HAART-naïve younger adults, in EFV-treated compared to NVP-treated young and older adults, and in LPV/r-treated compared to NVP-treated older adults. Differences in lipoprotein profiles and skinfold thickness with HAART regimen were observed in pediatric and young adults, but less so in older adults. ConclusionsWhereas LPV/r and other protease inhibitors have long been recognized as mediators of HIV/HAART-associated atherosclerosis, this report supports the emerging evidence that EFV may also mediate cardiovascular disease in people living with HIV on HAART.

A Population Pharmacokinetic/Pharmacodynamic Model Predicts Favorable HDL Cholesterol Changes Over the First 5 Years in Children Treated With Current Efavirenz-Based Regimens.

Efavirenz use is associated with changes in cholesterol concentrations, but it is unclear whether this effect is related to drug concentrations. Using efavirenz and cholesterol plasma concentrations measured in 87 antiretroviral-naive children in Thailand, we assessed indirect response models to describe the evolution of high- and low-density lipoprotein (HDL, LDL) cholesterol concentrations in relation to efavirenz plasma concentrations over time where efavirenz was assumed to either stimulate cholesterol production or inhibit its elimination. Simulations of cholesterol evolution for children with different average efavirenz concentrations (Cav ) according to their assumed status of "fast" or "slow" metabolizers of efavirenz were performed. At treatment initiation, children's median (interquartile range, IQR) age was 8 years (5 to 10), body mass index z-score 0.01 (-1.05 to 1.44), HDL 31 mg/dL (24 to 44), and LDL 83 mg/dL (69 to 100). Median (IQR) efavirenz Cav was 1.7 mg/L (1.3 to 2.1) during the period of observation. The best model describing the evolution of HDL and LDL cholesterol concentrations over time assumed that efavirenz inhibited their elimination. HDL concentrations increase over 5 years, whereas LDL concentrations increased only during the first 4 months and then returned to baseline levels afterward. Simulations predicted that, after 3 years, HDL would increase to 63 mg/dL in "fast" metabolizers and 97 mg/dL in "slow" metabolizers of efavirenz. The population pharmacokinetic-pharmacodynamic (PK-PD) model shows that favorable HDL cholesterol changes can be expected in children with current efavirenz dosing guidelines over 5 years of treatment.

Inhibition of CYP2B6 by Medicinal Plant Extracts: Implication for Use of Efavirenz and Nevirapine-Based Highly Active Anti-Retroviral Therapy (HAART) in Resource-Limited Settings.

Highly active antiretroviral therapy (HAART) has greatly improved health parameters of HIV infected individuals. However, there are several challenges associated with the chronic nature of HAART administration. For populations in health transition, dual use of medicinal plant extracts and conventional medicine poses a significant challenge. There is need to evaluate interactions between commonly used medicinal plant extracts and antiretroviral drugs used against HIV/AIDS. Efavirenz (EFV) and nevirapine (NVP) are the major components of HAART both metabolized by CYP2B6, an enzyme that can potentially be inhibited or induced by compounds found in medicinal plant extracts. The purpose of this study was to evaluate the effects of extracts of selected commonly used medicinal plants on CYP2B6 enzyme activity. Recombinant human CYP2B6 was used to evaluate inhibition, allowing the assessment of herb-drug interactions (HDI) of medicinal plants Hyptis suaveolens, Myrothamnus flabellifolius, Launaea taraxacifolia, Boerhavia diffusa and Newbouldia laevis. The potential of these medicinal extracts to cause HDI was ranked accordingly for reversible inhibition and also classified as potential time-dependent inhibitor (TDI) candidates. The most potent inhibitor for CYP2B6 was Hyptis suaveolens extract (IC50 = 19.09 ± 1.16 µg/mL), followed by Myrothamnus flabellifolius extract (IC50 = 23.66 ± 4.86 µg/mL), Launaea taraxacifolia extract (IC50 = 33.87 ± 1.54 µg/mL), and Boerhavia diffusa extract (IC50 = 34.93 ± 1.06 µg/mL). Newbouldia laevis extract, however, exhibited weak inhibitory effects (IC50 = 100 ± 8.71 µg/mL) on CYP2B6. Launaea taraxacifolia exhibited a TDI (3.17) effect on CYP2B6 and showed a high concentration of known CYP450 inhibitory phenolic compounds, chlorogenic acid and caffeic acid. The implication for these observations is that drugs that are metabolized by CYP2B6 when co-administered with these herbal medicines and when adequate amounts of the extracts reach the liver, there is a high likelihood of standard doses affecting drug plasma concentrations which could lead to toxicity.

Long term adverse drug reaction to Efavirenz in a HIV infected adolescent

Efavirenz is one of the medications used in combined antiretroviral therapy (ART) for the management of HIV infection in adolescents. Various central nervous system adverse reactions have been reported in patients commencing antiretroviral therapy with a regimen containing Efavirenz. These reactions tend to be acute, commonly occurring in the first six months of therapy. Adverse reactions following long term use of Efavirenz for ART is rare among adults and rarer still among children and adolescents. There is only one published case of serious adverse reaction to Efavirenz in an adolescent after long-term use. The case of a male HIV Positive Nigerian patient aged 13 years. He presented with five-day history of Difficulty sleeping, abnormal dreams, inability to concentrate, restlessness, irrational behavior and long-term memory loss. There was no previous history of psychiatric illness and no suggestive social or family history. Patient was on Efavirenz containing regimen about 6.5 years till presentation with adverse reaction mainly affecting behavior, thought processes and memory. After discontinuing Efavirenz and replacing with Nevirapine in his combined ART regimen, all neuropsychiatric manifestations ceased .He regained his memory, no longer had bad dreams or demonstrated any irrational behavior or attitude. Physicians who are involved in the care of HIV infected patients need to be aware of the possibility of adverse Drug reactions occurring in patients who have been on antiretroviral drugs for years. This possibility should not be excluded from possible differential diagnosis. KEY WORDS: Adolescent; Efavirenz; HIV Infection; Reactions; Adverse drug; Psychomotor Agitation; Long term

Incidence and risk factors for neuropsychiatric events among Ghanaian HIV patients on long-term non-nucleoside reverse transcriptase inhibitor-based therapy.

BackgroundNon-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART) is associated with neuropsychiatric toxicity. Little is known about the risk of short- and long-term neuropsychiatric toxicity in sub-Saharan Africa, where NNRTIs are widely used in first-line combination ART. This observational study assessed the risk of neuropsychiatric toxicity in Ghanaian patients starting first-line ART between 2004 and 2010 at a single centre.MethodsIn this retrospective observational study, frequencies of documented neuropsychiatric toxicity events were assessed and time to events calculated using a Kaplan–Meier analysis. Associations of neuropsychiatric toxicity with specific NNRTIs and other explanatory variables were examined using Cox proportional hazards modelling.ResultsOf 3999 patients initiating NNRTI-based ART, who were followed for a median of 30 (0.25–90) months (11,237 person years), 218 (5.5%) reported symptoms of neuropsychiatric toxicity at a rate of 21.4 events per 1000 person-years (95% CI, 18.8–24.2/1000 py). Events were more common with efavirenz than nevirapine (7.6% versus 2.4%), were usually reported within the first 2 months of ART initiation and persisted up to 84 months in a few patients. The most commonly reported neuropsychiatric adverse drug reactions were insomnia (50%), headaches (8%), dizziness (7%) and abnormal dreams (6%). The factors independently associated with neuropsychiatric toxicity were BMI < 16 kg/m2 (aHR of 1.44 [95% CI, 1.02–2.03]) and use of efavirenz (aHR 3.29 [95% CI, 2.32–4.69]). Substitution of NNRTI on account of toxicity was reported in up to 17% of patients experiencing neuropsychiatric events.ConclusionsNNRTI-related neuropsychiatric toxicity, mainly due to efavirenz, was infrequently documented in this Ghanaian cohort under routine clinical care settings. Regimens with more favourable tolerability will be needed as first-line agents in sub-Saharan Africa in the coming years.

No Evidence of an Association Between Efavirenz Exposure and Suicidality Among HIV Patients Initiating Antiretroviral Therapy in a Retrospective Cohort Study of Real World Data.

Recently, published studies have reported conflicting results regarding the association between efavirenz exposure and the risk of suicidality among patients with human immunodeficiency virus. The objective of this analysis was to compare the rate of suicidality among patients initiating efavirenz-containing versus efavirenz-free antiretroviral (ARV) regimens.This retrospective cohort study used US administrative claims data for commercially and Medicaid-insured individuals for the years 2006 to 2013. ARV-naive patients aged ≥12 years initiating an efavirenz-containing or efavirenz-free ARV regimen with ≥6 months of continuous insurance enrollment prior to ARV initiation were selected. The primary outcome was suicidality, defined as the occurrence of any medical claim with a diagnosis code for suicidal ideation or an inpatient or emergency department medical claim for suicide attempt. Unadjusted incidence rates were calculated and propensity score-adjusted hazard ratios were estimated to account for differences in patient characteristics.There were 19,983 patients (efavirenz-containing, n = 11,187; efavirenz-free, n = 8796) in the commercial database and 5154 patients (efavirenz-containing, n = 2224; efavirenz-free, n = 2930) in the Medicaid database. Unadjusted incidence rates (95% confidence interval [CI]) of suicidality per 1000 person-years were: commercial, efavirenz-containing (3.3 [2.4-4.4]), efavirenz-free (4.0 [2.7-5.8]); Medicaid, efavirenz-containing (25.7 [18.8-34.4]), efavirenz-free (40.6 [31.9-50.9]). In propensity score-adjusted analyses, efavirenz use was not associated with suicidality: adjusted hazard ratio (95% CI) of suicidality compared with efavirenz-free regimen, commercial, 1.029 (0.636-1.665); Medicaid, 0.902 (0.617-1.319).This analysis found no conclusive evidence of an increased risk of suicidality among patients initiating an efavirenz-containing ARV regimen. However, channeling bias may exist even after adjusting for measured patient characteristics.

Antiretroviral Therapy, Especially Efavirenz, Is Associated with Low Bone Mineral Density in HIV-Infected South Africans

PurposeWe determined the prevalence and correlates of low bone mineral density (BMD) in HIV-infected South Africans as there is a paucity of such data from Africa.MethodsBMD and serum 25-hydroxyvitamin D were measured in HIV-positive participants on antiretroviral therapy (ART) and in those not yet on ART (ART-naïve).ResultsWe enrolled 444 participants [median age 35(IQR: 30, 40) years; 77% women]. BMD was low (z score <-2SD) in 17% and 5% of participants at the lumbar spine and total hip, respectively. Total hip [0.909 (SD 0.123) vs 0.956 (SD 0.124) g/cm2, p = 0.0001] and neck of femur BMD [0.796 (SD 0.130) vs 0.844 (SD 0.120) g/cm2, p = 0.0001] were lower in the ART, compared to the ART-naïve group. Vitamin D deficiency was present in 15% of participants and was associated with efavirenz use [adjusted OR 2.04 (95% CI 1.01 to 4.13)]. In a multivariate linear regression, exposure to efavirenz or lopinavir-based ART was associated with lower total hip BMD, whereas higher weight, being male and higher vitamin D concentration were associated with higher total hip BMD (adjusted R2 = 0.28). Age, weight, sex, and the use of efavirenz-based ART were independently associated with lumbar spine BMD (adjusted R2 = 0.13).ConclusionsVitamin D status, use of efavirenz or lopinavir/ritonavir, weight, age and sex are significantly associated with lower BMD in this young cohort of HIV-infected South Africans.

The Association of Gender, Age, Efavirenz Use, and Hypovitaminosis D Among HIV-Infected Adults Living in the Tropics.

Vitamin D, which is important for calcium homeostasis and bone metabolism, has several noncalcemic actions. Low vitamin D levels have been observed in HIV-infected patients from high latitudes, with consequently reduced bone mineral density (BMD), but data from the tropics are scarce. We aimed to determine the prevalence of and risk factors for hypovitaminosis D among HIV-infected patients in the tropics. This was a cross-sectional study to determine serum 25-hydroxyvitamin D [25(OH)D] levels in HIV-infected patients who attended our HIV clinic in Bangkok, Thailand from July 2010 to June 2011. Hypovitaminosis D was defined as vitamin D insufficiency and deficiency [25(OH)D 20-30 ng/ml and <20 ng/ml, respectively]. Hypovitaminosis D prevalence was calculated and risk factors were determined using multivariate logistic regression. A total of 673 HIV-infected adults were included. The median age was 41 years and 47% were females. The median body mass index (BMI) was 21.9 kg/m(2) and 93% were using antiretroviral therapy (ART), with a median (IQR) duration of 8.9 (5.0-10.4) years. Thirty-one percent were using efavirenz (EFV). The prevalence of vitamin D insufficiency and deficiency was 40.6% and 29.9%, respectively. In multivariate analysis, female gender [odds ratio: OR (95% confidence interval: 95% CI) 1.7 (1.2-2.3), p = 0.005], age >37 years [OR (95% CI) 1.6 (1.1-2.4), p = 0.01], and EFV use [OR (95% CI) 2.0 (1.3-3.2), p = 0.004] were independent predictors of hypovitaminosis D. Even in tropical areas where the sun is abundant, hypovitaminosis D is highly prevalent. Thus, treatment of low vitamin D in HIV-infected patients at high risk should not be ignored to prevent reductions in BMD and other hypovitaminosis D-related comorbidities.

Long-term efavirenz use is associated with worse neurocognitive functioning in HIV-infected patients.

Neurocognitive (NC) complications continue to afflict a substantial proportion of HIV-infected people taking effective antiretroviral therapy (ART). One contributing mechanism for this is antiretroviral neurotoxicity. Efavirenz (EFV) is associated with short-term central nervous system (CNS) toxicity, but less is known about its long-term effects. Our objective was to compare NC functioning with long-term use of EFV to that of a comparator, lopinavir-ritonavir (LPV/r), in a cohort of well-characterized adults. Four hundred forty-five patients were selected from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort based on their use of either EFV (n = 272, mean duration 17.9 months) or LPV/r (n = 173, mean duration 16.4 months) and the lack of severe NC comorbidities. All patients had undergone standardized comprehensive NC testing. Univariable and multivariable analyses to predict NC outcomes were performed. Compared with LPV/r users, EFV users were more likely to be taking their first ART regimen (p < 0.001), were less likely to have AIDS (p < 0.001) or hepatitis C virus (HCV) coinfection (p < 0.05), had higher CD4+ T cell nadirs (p < 0.001), had lower peak (p < 0.001) and current (p < 0.001) plasma HIV RNA levels, and were less likely to have detectable HIV RNA in cerebrospinal fluid (CSF) (p < 0.001). Overall, EFV users had worse speed of information processing (p = 0.04), verbal fluency (p = 0.03), and working memory (p = 0.03). An interaction with HCV serostatus was present: Overall among HCV seronegatives (n = 329), EFV users performed poorly, whereas among HCV seropositives (n = 116), LPV/r users had overall worse performance. In the subgroup with undetectable plasma HIV RNA (n = 269), EFV users had worse speed of information processing (p = 0.02) and executive functioning (p = 0.03). Substantial differences exist between EFV and LPV/r users in this observational cohort, possibly because of channeling by clinicians who may have prescribed LPV/r to more severely ill patients or as second-line therapy. Despite these differences, EFV users had worse functioning in several cognitive abilities. A potentially important interaction was identified that could indicate that the NC consequences of specific antiretroviral drugs may differ based on HCV coinfection. The complexity of these data is substantial, and findings would best be confirmed in a randomized clinical trial.

P17.33 Efavirenz-associated serious adverse reactions: an analysis of the thai adverse events reporting system

Introduction Voluntary spontaneous reporting system has been used as a major method to report ADRs in Thailand. Efavirenz is in the NNRTI class, combined use with other antiretroviral (ARV) to treat the infection. Efavirenz is metabolised by liver and various adverse drug reactions (ADRs) can be found when used it for long term or with other drugs. Explore the distribution and determinant of ADR associated with ARV in Thai population is not well established but crucial for improve patient care and generate risk minimization in both population and individual level. Objective The Thai adverse event reports from 2010 to 2014 were reviewed to assess serious adverse events induced by efavirenz. Methods Thai adverse event reports data were assessed by elimination of duplicated records as well as adjustments to standardise drug names, reports involving efavirenz were analysed. Exposure variables are efavirenz used. Outcome variables are serious ADRs which happened within the study period. Other important variable such as sex, co morbidity, multiple drugs used are evaluated. Hepatitis, exfoliative dermatitis, and Stevens Johnson syndrome were focused on as serious adverse events. Signals in the data were detected by quantitative data mining algorithms, the reporting odds ratio. Results A total of 1,763 reports related to efavirenz were analysed. The average age were 46.42 years. Two cases were fatal outcome. Significant signals of the adverse events were detected with hepatitis, exfoliative dermatitis and Stevens Johnson syndrome. Drug eruption was also detected. Conclusions Serious reactions from efavirenz were hepatitis, exfoliative dermatitis and Stevens Johnson syndrome. They made fatal and life threatening outcome. The recommendation is further specific monitoring to reduce serious risk in efavirenz use. Disclosure of interest statement Serious reactions from efavirenz were hepatitis, exfoliative dermatitis and Stevens Johnson syndrome. They made fatal and life threatening outcome. The recommendation is further specific monitoring to reduce serious risk in efavirenz use.

Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C.

Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C. Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model. The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23. The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes.

Comparative Safety and Neuropsychiatric Adverse Events Associated With Efavirenz Use in First-Line Antiretroviral Therapy: A Systematic Review and Meta-Analysis of Randomized Trials.

Efavirenz (EFV) is widely used for the treatment of antiretroviral-naive HIV-positive individuals, but there are concerns about the risk of adverse neuropsychiatric events. We systematically reviewed the safety of EFV in first-line therapy. Four databases were searched until October 2014 for randomized trials comparing EFV against non-EFV-based regimens for the treatment of antiretroviral-naive HIV-positive adults and children. The primary outcome was drug discontinuation as a result of any adverse event. Relative risks and proportions were pooled using random-effects meta-analysis. Forty-two trials were included for review. A lower relative and absolute risk of discontinuations due to adverse drug reactions was seen with EFV compared to nevirapine. The relative and absolute risk of discontinuation was greater for EFV compared with low-dose EFV, rilpivirine, tenofovir, atazanavir, and maraviroc. The relative risk of discontinuation was greater for EFV compared with dolutegravir and raltegravir, but absolute risks were not significantly different. There was no difference in the risk of any severe clinical adverse events for any comparison. With the exception of dizziness, fewer than 10% of patients exposed to EFV experienced any other specific type of neuropsychiatric event. No suicides were reported. This review found that over 90% of patients remained on an EFV-based first-line regimen after an average follow-up time of 78 weeks. The relative risk of discontinuations due to adverse events was higher for EFV compared with most other first-line options, but absolute differences were less than 5% for all comparisons.

A Global Health Diagnostic for Personalized Medicine in Resource-Constrained World Settings: A Simple PCR-RFLP Method for Genotyping CYP2B6 g.15582C>T and Science and Policy Relevance for Optimal Use of Antiretroviral Drug Efavirenz.

The use of pharmacogenomics (PGx) knowledge in treatment of individual patients is becoming a common phenomenon in the developed world. However, poorly resourced countries have thus far been constrained for three main reasons. First, the cost of whole genome sequencing is still considerably high in comparison to other (non-genomics) diagnostics in the developing world where both science and social dynamics create a dynamic and fragile healthcare ecosystem. Second, studies correlating genomic differences with drug pharmacokinetics and pharmacodynamics have not been consistent, and more importantly, often not indexed to impact on societal end-points, beyond clinical practice. Third, ethics regulatory frames over PGx testing require improvements based on nested accountability systems and in ways that address the user community needs. Thus, CYP2B6 is a crucial enzyme in the metabolism of antiretroviral drugs, efavirenz and nevirapine. More than 40 genetic variants have been reported, but only a few contribute to differences in plasma EFV and NVP concentrations. The most widely reported CYP2B6 variants affecting plasma drug levels include c.516G>T, c.983T>C, and to a lesser extent, g.15582C>T, which should be considered in future PGx tests. While the first two variants are easily characterized, the g.15582C>T detection has been performed primarily by sequencing, which is costly, labor intensive, and requires access to barely available expertise in the developing world. We report here on a simple, practical PCR-RFLP method with vast potentials for use in resource-constrained world regions to detect the g.15582C>T variation among South African and Cameroonian persons. The effects of CYP2B6 g.15582C>T on plasma EFV concentration were further evaluated among HIV/AIDS patients. We report no differences in the frequency of the g.15582T variant between the South African (0.08) and Cameroonian (0.06) groups, which are significantly lower than reported in Asians (0.39) and Caucasians (0.31). The g.15582C/T and T/T genotypes were associated with significantly reduced EFV levels (p=0.006). This article additionally presents the policy relevance of the PGX global health diagnostics and therefore, collectively makes an original interdisciplinary contribution to the field of integrative biology and personalized medicine in developing world. Such studies are, in fact, broadly important because resource-constrained regions exist not only in developing world but also in major geographical parts of the G20 nations and the developed countries.

Short Communication: Increase of HIV-1 K103N Transmitted Drug Resistance and Its Association with Efavirenz Use in South Korea.

Previous studies reported a relatively low prevalence of transmitted drug resistance (TDR) in South Korea (<5%). A genotypic resistance test was performed on 131 treatment-naive HIV-1-infected individuals from February 2013 to February 2014. Eleven individuals (8.4%) presented TDR, of whom eight had K103N, revealing a significant increase in K103N TDR compared to previous studies (p<0.001). Using phylogenetic analysis, we identified three distinct clustering pairs with genetic relativeness and a total of five independent strains among the eight K103N cases. Our findings suggest that multiple sources of K103N occurred, most likely as a consequence of increased efavirenz use in South Korea.

Current Efavirenz (EFV) or ritonavir-boosted lopinavir (LPV/r) use correlates with elevate markers of atherosclerosis in HIV-infected subjects in Addis Ababa, Ethiopia.

BackgroundHIV patients on antiretroviral therapy have shown elevated incidence of dyslipidemia, lipodystrophy, and cardiovascular disease (CVD). Most studies, however, focus on cohorts from developed countries, with less data available for these co-morbidities in Ethiopia and sub-Saharan Africa.MethodsAdult HIV-negative (n = 36), treatment naïve (n = 51), efavirenz (EFV)-treated (n = 91), nevirapine (NVP)-treated (n = 95), or ritonavir-boosted lopinavir (LPV/r)-treated (n=44) subjects were recruited from Black Lion Hospital in Addis Ababa, Ethiopia. Aortic pressure, augmentation pressure, and pulse wave velocity (PWV) were measured via applanation tonometry and carotid intima-media thickness (cIMT) and carotid arterial stiffness, and brachial artery flow-mediated dilation (FMD) were measured via non-invasive ultrasound. Body mass index, waist-to-hip circumference ratio (WHR), skinfold thickness, and self-reported fat redistribution were used to quantify lipodystrophy. CD4+ cell count, plasma HIV RNA levels, fasting glucose, total-, HDL-, and LDL-cholesterol, triglycerides, hsCRP, sVCAM-1, sICAM-1, leptin and complete blood count were measured.ResultsPWV and normalized cIMT were elevate and FMD impaired in EFV- and LPV/r-treated subjects compared to NVP-treated subjects; normalized cIMT was also elevated and FMD impaired in the EFV- and LPV/r-treated subjects compared to treatment-naïve subjects. cIMT was not statistically different across groups. Treated subjects exhibited elevated markers of dyslipidemia, inflammation, and lipodystrophy. PWV was associated with age, current EFV and LPV/r used, heart rate, blood pressure, triglycerides, LDL, and hsCRP, FMD with age, HIV duration, WHR, and glucose, and cIMT with age, current EFV use, skinfold thickness, and blood pressure.ConclusionsCurrent EFV- or LPV/r-treatment, but not NVP-treatment, correlated with elevated markers of atherosclerosis, which may involve mechanisms distinct from traditional risk factors.

Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study

The week 48 primary analysis of the ENCORE1 trial established the virological non-inferiority and safety of efavirenz 400 mg compared with the standard 600 mg dose, combined with tenofovir and emtricitabine, as first-line HIV therapy. This 96-week follow-up of the trial assesses the durability of efficacy and safety of this treatment over 96 weeks. ENCORE1 was a double-blind, placebo-controlled, non-inferiority trial done at 38 clinical sites in 13 countries. HIV-infected adult patients (≥16 years of age) with no previous antiretroviral therapy, a CD4 cell count of 50-500 cells per μL, and plasma HIV-1 viral load of at least 1000 copies per mL were randomly assigned (1:1) by an electronic case report form to receive fixed-dose daily tenofovir 300 mg and emtricitabine 200 mg plus efavirenz either 400 mg daily or 600 mg daily. Participants, physicians, and all other trial staff were masked to treatment assignment. Randomisation was stratified by HIV-1 viral load at baseline (≤ or >100 000 copies per mL). The primary endpoint was the difference in the proportions of patients in the two treatment groups with a plasma HIV-1 viral load below 200 copies per mL at week 96. Treatment groups were deemed to be non-inferior if the lower limit of the 95% CI for the difference in viral load was above -10% by modified intention-to-treat analysis. Non-inferiority was assessed in the modified intention-to-treat, per-protocol, and non-completer=failure (NC=F) populations. Adverse events and serious adverse events were summarised by treatment group. This study is registered with ClinicalTrials.gov, number NCT01011413. Between Aug 24, 2011, and March 19, 2012, 636 eligible participants were enrolled and randomly assigned to the two treatment groups (324 to efavirenz 400 mg and 312 to efavirenz 600 mg). The intention-to-treat population who received at least one dose of study drug comprised 630 patients: 321 in the efavirenz 400 mg group and 309 in the efavirenz 600 mg group. 585 patients (93%; 299 in the efavirenz 400 mg group and 286 in the 600 mg group) completed 96 weeks of follow-up. At 96 weeks, 289 (90·0%) of 321 patients in the efavirenz 400 mg group and 280 (90·6%) of 309 in the efavirenz 600 mg group had a plasma HIV-1 viral load less than 200 copies per mL (difference -0·6, 95% CI -5·2 to 4·0; p=0·72), which suggests continued non-inferiority of the lower efavirenz dose. Non-inferiority was recorded for thresholds of less than 50 and less than 400 copies per mL, irrespective of baseline plasma viral load. Adverse events were reported by 291 (91%) of 321 patients in the efavirenz 400 mg group and by 285 (92%) of 309 in the 600 mg group (p=0·48). The proportions of patients reporting an adverse event that was definitely or probably related to efavirenz were 126 (39%) for efavirenz 400 mg and 148 (48%) for efavirenz 600 mg (p=0·03). The number of patients who reported serious adverse events did not differ between the groups (p=0·20). Our findings confirm that efavirenz 400 mg is non-inferior to the standard dose of 600 mg in combination with tenofovir and emtricitabine as initial HIV therapy over 96 weeks. Fewer efavirenz-related adverse events were reported with the 400 mg efavirenz dose than with the 600 mg dose. These findings support the routine use of efavirenz 400 mg. The coadministration of rifampicin and efavirenz 400 mg needs further investigation. Bill & Melinda Gates Foundation, and UNSW Australia.

Risk of first-line antiretroviral therapy failure in HIV-infected Thai children and adolescents.

Adolescence may affect adherence and response to highly active antiretroviral therapy (HAART). Limited data are available regarding the long-term treatment outcomes of perinatal HIV-infected adolescents. Data from perinatally acquired HIV-infected Thai children who started first-line nonnucleoside analog-based HAART before 18 years of age and treated for ≥24 weeks were analyzed. Children were categorized by age at HAART initiation; age<3 years, 3-9 years, early adolescence (10-13 years) and middle adolescence (14-16 years). CD4 and HIV-RNA were monitored every 6-12 months. Virologic failure (VF) was defined as HIV-RNA≥1000 copies/mL after ≥24 weeks of HAART. Of 840 children, 68% were in pre-adolescence. Median baseline CD4% was 7.9%. Use of nevirapine versus efavirenz was 77:23%. Median duration of nonnucleoside reverse transcriptase inhibitor-based HAART was 5.6 years. No differences between groups were observed for rate of HIV-RNA<50 copies/mL (68%, P=0.18) and rate of VF (28%, P=0.82), median time to VF (22 months, P=0.13). Incidence of VF per 100 child-year in children age<3 years, 3-9 years, early adolescence and middle adolescence were 7.9, 4.7, 7.4 and 10.8, respectively (P=0.012). Median adherence by pill count was 97.3% (P=0.23). By multivariate analysis, predictors for VF were age at HAART initiation of <3 years (HR: 1.73, 95% CI: 1.18-2.55), age 10-16 years (HR: 1.47, 95% CI: 1.09-1.97), and nevirapine use (HR: 1.63, 95% CI: 1.14-2.32). VF rates were observed in one-third of long-term treated Thai children on first-line HAART. Age 3-9 years at HAART initiation was associated with less VF compared with those younger or older, whereas children who used nevirapine had higher VF.

Predicted residual activity of rilpivirine in HIV-1 infected patients failing therapy including NNRTIs efavirenz or nevirapine

Rilpivirine is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI) currently indicated for first-line therapy, but its clinical benefit for HIV-1 infected patients failing first-generation NNRTIs is largely undefined. This study quantified the extent of genotypic rilpivirine resistance in viral isolates from 1212 patients upon failure of efavirenz- or nevirapine-containing antiretroviral treatment, of whom more than respectively 80% and 90% showed high-level genotypic resistance to the failing NNRTI. Of all study patients, 47% showed a rilpivirine resistance-associated mutation (RPV-RAM), whereas preserved residual rilpivirine activity was predicted in half of the patients by three genotypic drug resistance interpretation algorithms. An NNRTI-dependent impact on rilpivirine resistance was detected. Compared with the use of nevirapine, the use of efavirenz was associated with a 32% lower risk of having a RPV-RAM and a 50% lower risk of predicted reduced rilpivirine susceptibility. Most prevalent RPV-RAMs after nevirapine experience were Y181C and H221Y, whereas L100I+K103N, Y188L and K101E occurred most in efavirenz-experienced patients. Predicted rilpivirine activity was not affected by HIV-1 subtype, although frequency of individual mutations differed across subtypes. In conclusion, this genotypic resistance analysis strongly suggests that the latest NNRTI, rilpivirine, may retain activity in a large proportion of HIV-1 patients in whom resistance failed while they were on an efavirenz- or nevirapine-containing regimen, and may present an attractive option for second-line treatment given its good safety profile and dosing convenience. However, prospective clinical studies assessing the effectiveness of rilpivirine for NNRTI-experienced patients are warranted to validate knowledge derived from genotypic and phenotypic drug resistance studies.

Efavirenz Causes Oxidative Stress, Endoplasmic Reticulum Stress, and Autophagy in Endothelial Cells.

The non-nucleoside reverse transcriptase inhibitor efavirenz is a widely prescribed antiretroviral drug used in combined antiretroviral therapy. Despite being an essential and life-saving medication, the required lifelong use of HIV drugs has been associated with a variety of adverse effects, including disturbances in lipid metabolism and increased cardiovascular risk. Efavirenz belongs to those HIV drugs for which cardiovascular and endothelial dysfunctions have been reported. It is here shown that elevated concentrations of efavirenz can inhibit endothelial meshwork formation on extracellular matrix gels by normal and immortalized human umbilical vein cells. This inhibition was associated with an increase in oxidative stress markers, endoplasmic reticulum (ER) stress markers, and autophagy. Induction of ER stress occurred at pharmacologically relevant concentrations of efavirenz and resulted in reduced proliferation and cell viability of endothelial cells, which worsened in the presence of elevated efavirenz concentrations. In combination with the HIV protease inhibitor nelfinavir, both oxidative stress and ER stress became elevated in endothelial cells. These data indicate that pharmacologically relevant concentrations of efavirenz can impair cell viability of endothelial cells and that these effects may be aggravated by either elevated concentrations of efavirenz or by a combined use of efavirenz with other oxidative stress-inducing medications.