Use Of Efavirenz Research Articles

Risk of clinically significant depression in HIV‐infected patients: effect of antiretroviral drugs

We aimed to characterize depression in newly diagnosed HIV-infected patients, to determine the effect of antiretroviral therapy (ART) on its incidence, and to investigate whether efavirenz use was associated with a higher risk, compared with non-efavirenz-containing regimens, in the Spanish CoRIS cohort. CoRIS is a contemporary, multicentre cohort of HIV-infected patients, antiretroviral-naïve at entry, launched in 2004. Poisson regression models were used to investigate demographic, clinical and treatment-related factors associated with a higher incidence of clinically significant depression to October 2010. In total, 5185 patients (13 089 person-years) participated in the study, of whom 3379 (65.2%) started ART during follow-up. The incidence rates of depression before and after starting ART were 11.68 [95% confidence interval (CI) 9.01-15.15] and 7.06 (95% CI 5.45-9.13) cases per 1000 person-years, respectively. After adjustment, there was an inverse association between the occurrence of depression and the initiation of ART [incidence rate ratio (IRR) 0.53; 95% CI 0.28-0.99], while the likelihood of depression increased in patients of age > 50 years (IRR 1.94; 95% CI 1.21-3.12). Longer exposure to ART was associated with a decreased IRR of depression in unadjusted and adjusted analyses. The IRR for patients receiving < 2, 2-4 and > 4 years of ART was 0.72 (95% CI 0.36-1.44), 0.10 (95% CI 0.04-0.25) and 0.05 (95% CI 0.01-0.17), respectively, compared with ART-naïve patients. This protective effect was also observed when durations of exposure to nonnucleoside reverse transcriptase inhibitor-based regimens and efavirenz-containing regimens were analysed separately. The incidence of clinically significant depression was lower among HIV-infected patients on ART. The protective effect of ART was also observed with efavirenz-containing regimens.

Effect of Concomitant Use of Montelukast and Efavirenz on Neuropsychiatric Adverse Events

To report the case of an HIV patient who developed neuropsychiatric disturbances when montelukast was added to her therapy containing efavirenz. A 41-year-old woman with HIV infection had been on treatment with efavirenz, emtricitabine, and tenofovir disoproxil fumarate since 2007 with good tolerance. In November 2011, montelukast was started for asthma and shortly thereafter neuropsychiatric symptoms appeared, consisting of disturbed sleep, vivid dreams, irritability, confusion, and concentration difficulties. In January 2012, 2 months after the introduction of montelukast, she continued to report unbearable symptoms without any improvement; so, montelukast was withdrawn and the psychiatric symptoms completely disappeared. The combination of efavirenz and montelukast has not previously been associated with any pharmacokinetic interactions or worsening of neuropsychiatric symptoms. This case report indicates the possibility of adverse effects developing when the 2 drugs are used together. These symptoms might either be related to a drug-drug interaction or increased by the similar side effect profiles of the 2 drugs. The higher score on the Karch-Lasagna scale suggests that an adverse effect is the more likely explanation. We cannot, however, rule out a drug interaction, given that efavirenz inhibits the CYP 2C9, 2C19, and 3A4 isoenzymes and CYP 3A4, 2C9, and 2C8 are involved in the metabolism of montelukast. Considering that efavirenz is frequently used in antiretroviral therapy and that neuropsychiatric symptoms can limit its use, clinicians should consider the possibility of worsening of these symptoms, such as mood disorders and abnormal dreams, when montelukast is introduced.

Prevalence of Vitamin D Deficiency Among Perinatally HIV-infected Thai Adolescents Receiving Antiretroviral Therapy

We assessed the prevalence of vitamin D deficiency among 101 perinatally HIV-infected Thai adolescents receiving antiretroviral therapy. Median age was 14.3 (interquartile range 13.0-15.7) years, and 90% had a HIV RNA<50 copies/mL. The median (interquartile range) 25-hydroxyvitamin D (25-OHD) level was 24.8 (6.9-46.9) ng/mL; 25 (24.7%) had vitamin D deficiency (25-OHD<20 ng/mL) and 47 (46.5%) had insufficiency (25-OHD 20-30 ng/mL). Adolescents with vitamin D deficiency had significantly higher parathyroid hormone levels (54.9 vs. 40.2 pg/mL, P<0.007). No associations between vitamin D deficiency and body mass index, bone mineral density, efavirenz use, HIV RNA, CD4 or self-reported sunlight exposure were observed.

Efavirenz-induced gynecomastia in a prepubertal girl with human immunodeficiency virus infection: a case report

BackgroundPrepubertal gynecomastia is a rare condition and most frequently classified as idiopathic. In HIV-infected adults gynecomastia is a recognised but infrequent side-effect of antiretroviral treatment (ART) and mostly attributed to efavirenz use. Gynecomastia should be distinguished from pseudogynecomastia as part of the lipodystrophy syndrome caused by Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to avoid incorrect substitution of drugs. In the medical literature only five cases of prepubertal gynecomastia in children taking ART are described and underlying pathogenesis was unknown. The occurrence of adverse effects of ART may interfere with therapy adherence and long-term prognosis and for that reason requires attention. We report the first case of prepubertal gynecomastia in a young girl attributed to efavirenz use.Case presentationA seven-year-old African girl presented with true gynecomastia four months after initiation on ART (abacavir, lamivudine, efavirenz). History, physical examination and laboratory tests excluded known causes of gynecomastia and efavirenz was considered as the most likely cause. Six weeks after withdrawal of efavirenz the breast enlargement had completely resolved.ConclusionsEfavirenz-induced gynecomastia may occur in children as well as in adults. With the increasing access to ART, the possibility of efavirenz-exposure and the potential occurrence of its associated side-effects may be high. In resource-poor settings, empirical change from efavirenz to nevirapine may be considered, providing no other known or alarming cause is identified, as efavirenz-induced gynecomastia can resolve quickly after withdrawal of the drug. Timely recognition of gynecomastia as a side-effect of efavirenz is important in order to intervene while the condition may still be reversible, to sustain adherence to ART and to maintain the sociopsychological health of the child.

Would a CYP2B6 Test Help HIV Patients Being Treated With Efavirenz?

Efavirenz is a potent and effective nonnucleoside reverse transcriptase inhibitor that is a preferred component of first-line antiretroviral therapy (ART) for HIV-1-infected individuals in both wealthy and resource-limited countries [1,2]. The use of efavirenz in clinical practice has further increased in recent years, especially in developing countries. It is usually prescribed at a fixed dosage of 600 mg once daily. Some patients who receive efavirenz have experienced adverse effects such as neuropsychiatric manifestations, skin rash, hepatitis and dyslipidemia [1,3]. In clinical practice, concern over neuro psychiatric adverse effects often plays a role in the decision of whether or not to include efavirenz as part of ART. Prediction of therapeutic efficacy and the likelihood of developing psychiatric disorders have been associated with plasma efavirenz concentrations [4]. The preferable mid-dosing plasma level of efavirenz is 1000–4000 ng/ml to allow for optimized antiretroviral potency and to minimize the risk of neuropsychiatric toxicity. HIV-1-infected patients who receive standarddose efavirenz and have plasma efavirenz concentration of 4000 ng/ml may experience adverse CNS effects more frequently [4]. Many studies have highlighted the potential for serious psychiatric complications with efavirenz, including depression, psychosis, amnesia, extreme excitability, aggressive behavior, post-traumatic stress disorder symptoms and induced suicidal effect [3,4]. However, increased neuropsychiatric adverse effects were typically reported only during the first month after starting this medication [4–6]. Clinical trials have reported CNS side effects in >50% of

ER stress in human hepatic cells treated with Efavirenz: Mitochondria again

ER stress is associated with a growing number of liver diseases, including drug-induced hepatotoxicity. The non-nucleoside analogue reverse transcriptase inhibitor Efavirenz, a cornerstone of the multidrug strategy employed to treat HIV1 infection, has been related to the development of various adverse events, including metabolic disturbances and hepatic toxicity, the mechanisms of which remain elusive. Recent evidence has pinpointed a specific mitochondrial effect of Efavirenz in human hepatic cells. This study assesses the induction of ER stress by Efavirenz in the same model and the implication of mitochondria in this process. Primary human hepatocytes and Hep3B were treated with clinically relevant concentrations of Efavirenz and parameters of ER stress were studied using standard cell biology techniques. ER stress markers, including CHOP and GRP78 expression (both protein and mRNA), phosphorylation of eIF2α, and presence of the spliced form of XBP1 were upregulated. Efavirenz also enhanced cytosolic Ca(2+) content and induced morphological changes in the ER suggestive of ER stress. This response was greatly attenuated in cells with altered mitochondrial function (Rho°). The effects of Efavirenz on the ER, and particularly in regard to the mitochondrial involvement, differed from those elicited by a standard pharmacological ER stressor. This newly discovered mechanism of cellular insult involving ER stress and UPR response may help comprehend the hepatic toxicity that has been associated with the widespread and life-long use of Efavirenz. In addition, the specificity of the actions of Efavirenz observed expands our knowledge of the mechanisms that trigger ER stress and shed some light on the mitochondria/ER interplay in drug-induced hepatic challenge.

Evolution of the K65R, K103N and M184V/I reverse transcriptase mutations in HIV-1-infected patients experiencing virological failure between 2005 and 2010

To assess the prevalence of the K65R, K103N and M184V/I resistance mutations in the reverse transcriptase (RT) region in HIV-1-infected patients failing antiretroviral-based regimens between the years 2005 and 2010. HIV-1-infected patients experiencing virological failure between 2005 and 2010 with RT genotypic resistance tests available at the time of virological failure were analysed. K65R, K103N and M184V/I mutation frequencies were determined each year. Statistical analyses were performed using Fisher's exact test. Among 9586 patients failing their antiretroviral-based regimens from 2005 to 2010, the prevalence of K65R tended to decrease (P = 0.054), while K103N and M184V/I mutation frequencies decreased significantly over time (P < 0.001). The increased use of a tenofovir/emtricitabine/efavirenz single-tablet regimen was associated with decreased selection of these mutations. The global prevalence of resistance-associated mutations to tenofovir, lamivudine/emtricitabine and efavirenz decreased over time between 2005 and 2010. Despite a stable rate of efavirenz and protease inhibitor use, this phenomenon can be explained by an increased use of single-tablet regimens, which simplify drug intake and maximize adherence.

Safe Treatment of Seizures in the Setting of HIV/AIDS

HIV(+) patients are at increased risk for developing seizures due to the vulnerability of the central nervous system to HIV-associated diseases, immune dysfunction, and metabolic disturbances. In patients with acute seizures, standard protocols still apply with urgent seizure cessation being the priority. Management of the person with established epilepsy who contracts HIV is challenging, but the decision to initiate chronic antiepileptic drug (AED) therapy in an HIV(+) patient is also difficult. Chronic treatment guidelines emphasize the interactions between AEDs and antiretroviral (ARV) medications, but provide no explicit advice regarding when to initiate an AED, what medication to select, and/or the duration of treatment. Epidemiologic data regarding seizure recurrence risk in HIV(+) individuals is not available. The risk of further seizures likely depends upon the underlying etiology for the seizure(s) and patients' immune status and may be increased by the use of efavirenz (an ARV). The issues for consideration include AED-ARV interactions, organ dysfunction, seizure type, and drug side effects, which may worsen or be confused with symptoms of HIV and/or epilepsy. Co-administration of enzyme inducing (EI)-AEDs and ARVs can result in virological failure, breakthrough seizure activity, AED toxicity, and/or ARV toxicity. Where available, the AED of choice in HIV(+) patients is levetiracetam due to its broad spectrum activity, ease of use, minimal drug interactions, and favorable side effect profile. Lacosamide, gabapentin, and pregabalin are also favored choices in patients with partial onset seizures and/or those failing levetiracetam. Where newer AEDs are not available, valproic acid may be the treatment of choice in terms of an AED, which will not cause enzyme induction-associated ARV failure, but its side effect profile causes other obvious problems. In resource-limited settings (RLS) where only EI-AEDs are available, there are no good treatment options and further pressure needs to be placed upon policymakers to address this care gap and public health threat.

Association between efavirenz-based compared with nevirapine-based antiretroviral regimens and virological failure in HIV-infected children.

Worldwide, the nonnucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine are commonly used in first-line antiretroviral regimens in both adults and children with human immunodeficiency virus (HIV) infection. Data on the comparative effectiveness of these medications in children are limited. To investigate whether virological failure is more likely among children who initiated 1 or the other NNRTI-based HIV treatment. Retrospective cohort study of children (aged 3-16 years) who initiated efavirenz-based (n = 421) or nevirapine-based (n = 383) treatment between April 2002 and January 2011 at a large pediatric HIV care setting in Botswana. The primary outcome was time from initiation of therapy to virological failure. Virological failure was defined as lack of plasma HIV RNA suppression to less than 400 copies/mL by 6 months or confirmed HIV RNA of 400 copies/mL or greater after suppression. Cox proportional hazards regression analysis compared time to virological failure by regimen. Multivariable Cox regression controlled for age, sex, baseline immunologic category, baseline clinical category, baseline viral load, nutritional status, NRTIs used, receipt of single-dose nevirapine, and treatment for tuberculosis. With a median follow-up time of 69 months (range, 6-112 months; interquartile range, 23-87 months), 57 children (13.5%; 95% CI, 10.4%-17.2%) initiating treatment with efavirenz and 101 children (26.4%; 95% CI, 22.0%-31.1%) initiating treatment with nevirapine had virological failure. There were 11 children (2.6%; 95% CI, 1.3%-4.6%) receiving efavirenz and 20 children (5.2%; 95% CI, 3.2%-7.9%) receiving nevirapine who never achieved virological suppression. The Cox proportional hazard ratio for the combined virological failure end point was 2.0 (95% CI, 1.4-2.7; log rank P < .001, favoring efavirenz). None of the measured covariates affected the estimated hazard ratio in the multivariable analyses. Among children aged 3 to 16 years infected with HIV and treated at a clinic in Botswana, the use of efavirenz compared with nevirapine as initial antiretroviral treatment was associated with less virological failure. These findings may warrant additional research evaluating the use of efavirenz and nevirapine for pediatric patients.

Risk of Tuberculosis after Antiretroviral Treatment Initiation: A Comparison between Efavirenz and Nevirapine Using Inverse Probability Weighting

There is a high incidence of tuberculosis (TB) early after antiretroviral therapy (ART) initiation. This historical cohort study evaluated the association of efavirenz (EFV) compared to nevirapine (NVP) with post-ART TB among patients initiated on first-line ART from 2005 to 2009 in a large, urban HIV clinic in Uganda. Hazard ratios (HR) for developing TB were computed using multivariable Cox proportional hazards models with inverse weighting of the probability of being prescribed NVP or EFV (calculated by a multivariable logistic regression model), stratifying by baseline CD4+ T-cell count. Adjustment for time-updated CD4+ T-cell count, restriction of the analysis to patients remaining in follow-up and a TB-free survival analysis were performed as sensitivity analyses. ART was initiated in 5,797 patients; 66% were women with a mean age of 37 years (SD 9) and a median baseline CD4+ T-cell count of 117 cells/mm3 (IQR 43-182). Overall, 60% (n = 3,484) were initiated on NVP and 40% (n = 2,313) on EFV. In the first 2 years of ART, 377 patients developed TB. The use of EFV compared to NVP was independently associated with higher TB incidence in patients with a baseline CD4+ T-cell count < 100 cells/mm3 (HR 2.05 [95% CI 1.29, 3.27]; P = 0.003), but not at higher CD4+ T-cell counts (HR 0.71 [95% CI 0.39, 1.31]; P = 0.428). These estimates were robust to all sensitivity analyses. There was a higher incidence of TB in patients with baseline CD4+ T-cell counts < 100 cells/mm3 initiated on EFV compared to those initiated on NVP. Further research in a trial setting or a larger multisite observational cohort is needed to confirm these findings.

Su1719 Effectiveness and Safety of Baclofen Treatment in Alcohol-Dependent Patients With or Without Liver Cirrhosis: Results of an Open Study in True Life

Background and Aims: The endoplasmic reticulum (ER) is a multifunctional organelle involved in synthesis, processing and folding of proteins, lipid biosynthesis, and regulation of calcium and redox homeostasis. Altered ER-function due to accumulation of misfolded/unfolded proteins, oxidative stress or depletion of ER calcium, lead to a condition called “ER-stress”, particularly important in cells with a high burden of protein synthesis as hepatocytes. Efavirenz, a non-nucleoside analog reverse transcriptase inhibitor, is a cornerstone in the combined therapy of HIV1 infection. Despite being considered generally safe, it has been related to development of adverse events such as hepatic toxicity. Here we report the presence of specific ER-stress in human hepatic cells. Methods: Hep3B cells and primary human hepatocytes were exposed to short-term treatment (24h) with clinically relevant concentrations of Efavirenz. General cell biology methods were employed (RNA interference, RT-PCR, Western blot and fluorescence microscopy). Results: ER-stress markers indicative of several ER-stress pathways were up-regulated concentration-dependently by Efavirenz, including the expression of CHOP and GRP78, at protein and mRNA level, and the phosphorylated form of eIF-2a. Furthermore, we also detected an increase in the transcription of ATF4 and XBP-1, and presence of the spliced form s-XBP-1. Efavirenz also induced morphological changes in ER with enhanced ER-content and dilatation of its cisternae, and led to an increase in the cytosolic calcium level. All these changes were similar to those produced by the standard pharmacological ER-stressor, Thapsigargin. On the contrary, while Thapsigargin induced an increment in the mitochondrial calcium level, Efavirenz provoked a decrease. A differential effect was also observed with transient silencing of CHOP. The stimulating effect of Thapsigargin on the generation of reactive oxygen species and the increment in the ER-content was more pronounced in CHOP-depleted cells, but this exacerbated action was not observed when cells were treated with Efavirenz. Conclusions: Clinical concentrations of Efavirenz induce ER-stress in hepatic cells in a compound-specific manner. Given the lifelong and widespread use of Efavirenz in the multidrug therapy of HIV, this novel mechanism of cellular response to drug-induced stress could help to understand the frequent hepatic toxicities that accompany the treatment of HIV1 infection.

Factors associated with vitamin D deficiency in a population of 2044 HIV-infected patients

The high prevalence of vitamin D deficiency in HIV-infected patients has been demonstrated but there are still controversies regarding to the role of antiretroviral therapy (ART) in this setting. The aims of this study was to validate factors associated with vitamin D deficiency in a large cohort of HIV-infected patients. A retrospective analysis of 2044 consecutive patients from December 2005 to March 2011 was conducted. Factors independently associated with vitamin D deficiency (<30 ng/ml and <10 ng/ml) were analyzed. Vitamin D levels were compared according to CD4 count, viral load and ART modalities. vitamin D was <30 ng/ml in 89.2% and <10 ng/ml in 32.4%. The median value was 13.8 ng/ml (4-102). Winter season, female sex, heterosexual acquisition of HIV, the need of second lines (complex and sequential treatment modalities) and a longer duration of ART were independently associated with vitamin D deficiency (<30 ng/ml). CD4 count <200/μl, advanced stages of disease and the current efavirenz use were independently associated with severe vitamin D deficiency (<10 ng/ml). Median vitamin D levels was 14.1 ng/dl when CD4 ≥200/μl, 11.5 ng/dl when CD4<200 (p = 0.0003). The ART modalities had a significant influence on vitamin D concentrations, the highest vitamin D level was observed in the absence of treatment. In HIV-infected patients, vitamin D deficiency is associated with ART modalities and duration. The most severe vitamin D deficiencies are associated with low CD4 count, the use of efavirenz and advanced stages of disease severity.

HIV and pregnancy

In resource rich settings transmission of HIV from mother to child during pregnancy and post partum has been significantly reduced by access to interventions such as maternal and neonatal antiretroviral therapy, avoidance of breast feeding and consideration to caesarean section. Accumulating observational and randomised controlled studies provide the evidence for development of guidelines for the clinical management of these women. However, despite referencing the same studies, differences exist between recommendations originating from the United States versus the United Kingdom. The particular areas of controversy include use of efavirenz, dose adjustment of antiretrovirals during pregnancy, mode of delivery according to maternal viral load, duration of neonatal zidovudine, use of PJP prophylaxis and number of antiretrovirals to prescribe in a neonate considered high risk of acquiring HIV infection. This article summarises these differences and suggests ways of approaching and adapting these conflicting recommendations to the local setting.

Effectiveness of efavirenz-based regimens in young HIV-infected children treated for tuberculosis: a treatment option for resource-limited settings.

BackgroundAntiretroviral treatment (ART) options for young children co-infected with HIV and tuberculosis are limited in resource-poor settings due to limited data on the use of efavirenz (EFV). Using available pharmacokinetic data, an EFV dosing schedule was developed for young co-infected children and implemented as the standard of care at Macha Hospital in Southern Province, Zambia. Treatment outcomes inchildren younger than 3 years of age or weighing less than 10 kg receiving either EFV-based ART plus anti-tuberculous treatment or nevirapine-based (NVP) ART were compared.MethodsTreatment outcomes were measured in a cohort of HIV-infected children seeking care at Macha Hospital in rural Zambia from 2007 to 2010. Informationon the diagnosis and treatment of tuberculosis was abstracted from medical records.ResultsForty-five children treated for tuberculosis initiated an EFV-based regimen and 69 children initiated a NVP-based regimen, 7 of whom also were treated for tuberculosis. Children receiving both regimens were comparable in age, but children receiving EFV started ART with a lower CD4+ T-cell percentage and weight-for-age z-score. Children receiving EFV experienced increases in both CD4+ T-cell percentage and weight-for-age z-score during follow-up, such that levels were comparable to children receiving NVP after two years of ART. Cumulative survival after 12 months of ART did not differ between groups (NVP:87%;EFV:80%;p = 0.25). Eleven children experienced virologic failure during follow-up.The adjusted hazard ratio of virologic failure comparing EFV to NVP was 0.25 (95% CI:0.05,1.24) and 0.13 (95% CI:0.03,0.62) using thresholds of 5000 and 400 copies/mL, respectively.Five children receiving EFV were reported to have had convulsions after ART initiation compared to only one child receiving NVP (p = 0.04).ConclusionsDespite poorer health at ART initiation, children treated for tuberculosis and receiving EFV-based regimens showed significant improvements comparable to children receiving NVP-based regimens. EFV-based regimens should be considered for young HIV-infected children co-infected with tuberculosis in resource-limited settings.

Comparative durability of nevirapine versus efavirenz in first-line regimens during the first year of initiating antiretroviral therapy among Swaziland HIV-infected adults

Nevirapine (NVP) and Efavirenz (EFV) have generally comparable clinical and virologic efficacy. However, data comparing NVP durability to EFV are imprecise. We analyzed cohort data to compare durability of NVP to EFV among patients initiating ART in Mbabane, Swaziland. The primary outcome was poor regimen durability defined as any modification of NVP or EFV to the ART regimen. Multivariate Cox proportional hazards models were employed to estimate the risk of poor regimen durability (all-cause) for the two regimens and also separately to estimate risk of drug-related toxicity. We analyzed records for 769 patients initiating ART in Mbabane, Swaziland from March 2006 to December 2007. 30 patients (3.9%) changed their NVP or EFV-based regimen during follow up. Cumulative incidence for poor regimen durability was 5.3% and 2.7% for NVP and EFV, respectively. Cumulative incidence for drug-related toxicity was 1.9% and 2.7% for NVP and EFV, respectively. Burden of TB was high and 14 (46.7%) modifications were due to patients substituting NVP due to beginning TB treatment. Though the estimates were imprecise, use of NVP - based regimens seemed to be associated with higher risk of modifications compared to use of EFV - based regimens (HR 2.03 95%CI 0.58 - 7.05) and NVP - based regimens had a small advantage over EFV - based regimens with regard to toxicity - related modifications (HR 0.87 95%CI 0.26 - 2.90). Due to the high burden of TB and a significant proportion of patients changing their ART regimen after starting TB treatment, use of EFV as the preferred NNRTI over NVP in high TB endemic settings may result in improved first-line regimen tolerance. Further studies comparing the cost-effectiveness of delivering these two NNRTIs in light of their different limitations are required.

High prevalence of HIV-associated neurocognitive disorder in HIV-infected patients with a baseline CD4 count ≤ 350 cells/μL in Shanghai, China

This study sought to determine the prevalence and risk factors of HIV-associated neurocognitive disorder (HAND) in HIV-infected patients with a baseline CD4 count ≤ 350 cells/μL in Shanghai, China. Subjects were 309 HIV-infected patients with a baseline CD4 count ≤ 350 cells/μL. General demographic and clinical information were collected by patient interview. Patients' cognitive function was assessed using the Montreal Cognitive Assessment (MoCA), combined with a questionnaire on cognitive complaints. The median age of patients was 34 years (IQR: 28-43.5). In terms of sex, 272 (88.0%) of the patients were male. Of the patients, 236 (76.4%) had been on antiretroviral treatment (ART) (for a median duration of 14 months, IQR: 1-29 months) before the study. Of the patients, 183 (59.2%) mentioned having a cognitive disorder. MoCA screening revealed that the prevalence of HAND was 48.2% and that HAND was more prevalent in patients with cognitive complaints (53.0%) than in patients with no such complaints (41.3%) (p = 0.042). Multivariate analysis indicated that HAND was associated with being female (p = 0.006), being older (p < 0.001), having a lower level of education (p < 0.001), and longer use of efavirenz in an ART regimen (p = 0.040). This study found that HAND frequently developed in HIV-infected patients with a baseline CD4 count ≤ 350 cells/μL in Shanghai, China. Being older, being female, having a low level of education, and receiving efavirenz treatment for a longer period may be associated with a greater risk of developing HAND. This study suggests that HAND should be routinely screened for in all newly diagnosed HIV-positive patients, and especially in those with the aforementioned risk factors for developing HAND.

Genetic associations with 25-hydroxyvitamin D deficiency in HIV-1-infected youth: fine-mapping for the GC/DBP gene that encodes the vitamin D-binding protein

Serum 25-hydroxyvitamin D [25(OH)D] is often deficient (<12 ng/ml) or insufficient (<20 ng/ml) in youth living with human immunodeficiency virus type 1 infection (YLH). Based on evidence from multiple genome-wide association studies, we hypothesized that genetic factors associated with 25(OH)D deficiency should be readily detectable in YLH even when controlling for other known factors, including use of the antiretroviral drug efavirenz (EFV). Genotyping by bi-directional sequencing targeted 15 single nucleotide polymorphisms (SNPs) at the GC/DBP locus, with a focus on coding and regulatory variants, as well as those repeatedly reported in the literature. Three intronic SNPs (rs222016, rs222020, and rs222029) in a conserved haplotype block had unequivocal association signals (false discovery rate ≤ 0.006). In particular, the minor allele G for rs222020 was highly unfavorable among 192 YLH (99 African–Americans and 93 others), as gauged by relatively low likelihood for 25(OH)D sufficiency at enrollment (odds ratio = 0.31, p = 9.0 × 10-4). In a reduced multivariable model, race, season, latitude, body mass index, exposure to EFV, and rs222020-G were independent factors that collectively accounted for 38% of variance in the log10-transformed 25(OH)D concentration (p < 0.0001). Interaction terms were evident for rs222020-G × season (p < 0.001), latitude × season (especially fall and winter; p < 0.01), and race × EFV use (p = 0.024). Overall, variance in serum 25(OH)D is substantially attributable to multiple factors, but the exact contribution of genetic and non-genetic factors can be obscured by partial overlaps and frequent interactions.

The case for Option B and Optional B+: Ensuring that South Africa’s commitment to eliminating mother-to-child transmission of HIV becomes a reality

In a previous issue of the Southern African Journal of HIV Medicine, Pillay and Black summarised the trade-offs of the safety of efavirenz use in pregnancy (Pillay P, Black V. Safety, strength and simplicity of efavirenz in pregnancy. Southern African Journal of HIV Medicine 2012;13(1):28-33.). Highlighting the benefits of the World Health Organization’s proposed options for the prevention of mother-to-child transmission (PMTCT) of HIV, the authors argued that the South African government should adopt Option B as national PMTCT policy and pilot projects implementing Option B+ as a means of assessing the individual- and population-level effect of the intervention. We echo this call and further propose that the option to remain on lifelong antiretroviral therapy, effectively adopting PMTCT Option B+, be offered to pregnant women following the cessation of breastfeeding, for their own health, following the provision of counselling on associated benefits and risks. Here we highlight the benefits of Options B and B+.

Use of efavirenz during the first trimester and resulting pregnancy outcome: experience of the Ambulatory Treatment Center of Brazzaville

BackgroundThe aim of this study is to report the experience of the Ambulatory Treatment Center of Brazzaville regarding the use of efavirenz (EFV) during pregnancy.MethodsA retrospective cohort study of HIV‐positive women was conducted at the Ambulatory Treatment Center of Brazzaville. The study examined the use of an anti‐retroviral treatment containing EFV in women who reported being pregnant during follow‐up between January 2009 and September 2011. Demographic, clinical and biological data, and adverse effects associated with exposure to EFV during pregnancy were assessed after each pregnancy from the register of pregnant women in terms of preterm delivery (birth occurring before 37 weeks of age) and spontaneous miscarriage (spontaneous expulsion of the fetus before 15 weeks of age).ResultsOf 220 patients on an anti‐retroviral treatment who reported being pregnant during follow‐up, 34 patients were administered combinations containing two nucleoside reverse transcriptase inhibitors (AZT/3TC=27; d4T/3T=4; TDF/FTC=3) and EFV, with a median age of 31.95 years (IQR: 27.71–36.37) and median durations of exposure to EFV of 11.81 months (IQR: 5.46–21.22) and 35.14 weeks (IQR: 11–39.86) before and during pregnancy, respectively. In 13 patients who reported to be in their first trimester of pregnancy, a change from EFV to nevirapine was made in nine of these patients. The median CD4 count was 271.5 cells/mm3 (IQR: 233.5−414.5) and 305 cells/mm3 (IQR: 205–408) in early pregnancy and at delivery, respectively; the viral load was undetectable in 90% and 85.7% of the patients, respectively. Twenty‐three deliveries took place after 37 weeks gestation; additionally, five preterm deliveries, four spontaneous miscarriages, one terminated pregnancy, and one death in utero occurred.ConclusionsEFV used during the first trimester of pregnancy offers security, but the number of fetal deaths is also important.

Moderator effect of CYP2B6 genotype in HIV‐1 patients with tuberculosis treated with rifampicin and efavirenz

Efavirenz (EFV) is the preferred non‐nucleoside reverse transcriptase inhibitor component of the ARV regimen in HIV‐TB patients. Concomitant use of EFV with rifampicin (RIF), an important component of first‐line tuberculosis treatment, induces various hepatic cytochrome P450 enzymes and is known to decrease EFV plasma concentrations in healthy volunteers and HIV‐1 patients and EFV plasma concentrations below 1,000 µg/mL have been associated with an increased risk of virological failure [1]. Moreover, previous studies have shown that inter‐individual variability in EFV plasma concentrations are associated with the presence of allelic variants in CYP2B6 gene. Carriers of the T allele of polymorphism 516 G&gt;T are reported to be associated with slower EFV oral clearance. The aim of our study was to determine the influence of CYP2B6 genotype in EFV levels in HIV patients with TB treated with RIF. Four HIV patients who started ARV treatment concomitantly with TB treatment were analyzed. These patients started a regimen based on EFV at doses higher than standard due to RIF interaction. Viral load, CD4+ cell count and plasma levels of EFV in plasma were measured at each visit, and genotyping for CYP2B6 (516G&gt;T) polymorphism were performed. The self‐reported rates of adherence to HAART were very high. One patient, who had TT genotype, required progressive dose reduction by toxic levels (Cmin: 20 µg/mL) and effects on the central nervous system. Dose was adjusted to 600 mg qd despite treatment with RIF, and he required even lower doses after completion of TB treatment, 400 mg qd. Two other patients with non‐mutated genotype (GG) required dose escalation up to 1000 mg qd to achieve minimum recommended EFV concentrations between 1 and 4 µg/mL. All of them achieved virological suppression at six months. The fourth patient, who had non‐mutated genotype, required dose increases for several months until dose adjustment. He needed 1600 mg qd during treatment with RIF. He presented virological failure, likely to maintain infratherapeutic levels of EFV for several months. Our study shows that the variability in EFV pharmacokinetic behaviour justifies the use of therapeutic drug monitoring (TDM) in situations in which there are potential interactions with other drug. Also, it is recommended to know CYP2B6 genotype in patients receiving HIV‐TB to predict their metabolizing behaviour. TDM in clinical practise continues to be the best tool for optimizing the dosing of EFV.