NVP-based Antiretroviral Therapy Research Articles

APOC3 Gene Polymorphism and Antiretroviral Therapy-Induced Dyslipidemia in HIV-Infected Children.

Children exposed to antiretroviral therapy (ART) are at risk of developing metabolic complications. The association between gene polymorphisms and the development of dyslipidemia in children post ART initiation was studied. Children initiating first-line ART were followed for 2 years at the National Institute for Research in Tuberculosis (Chennai, India), and St. John's Medical College Hospital (Bangalore, India). Clinical examination and fasting serum lipid profiles were measured every 6 months. Participants were genotyped for the polymorphisms in the APOC3 gene (rs2854116; rs2854117, and rs5128). Changes in lipid levels from baseline to months 6, 12, and 24, and the difference between the various genotype variants were analyzed using a modified analysis of variance test. Study enrolled 393 ART-naive HIV-infected children (mean age: 7.6 ± 3 years, mean weight: 18 ± 6) of whom 289 (75%) were started on nevirapine (NVP)-based ART and the remaining 96 (25%) were started on efavirenz-based ART. Only children carrying the GG allele of rs5128 genotype showed a decrease in CD4% and serum triglycerides pre-ART. An increasing trend of total cholesterol, high-density lipoprotein cholesterol (HDL-c), and low-density lipoprotein cholesterol were seen at 6 months in both EFZ and NVP groups, which subsequently stabilized by 12 months irrespective of genotype variants. Genotype variants of APOC3 (rs2854116 and rs2854117 polymorphism) did not show significant changes in serum lipid levels after 24 months of ART, whereas rs5128 polymorphism with "G" allele showed an association with HDL-c levels when on NVP-based ART. Our results suggest that ART plays a major role in normalizing lipid levels in HIV-infected children and APOC3 polymorphisms may not play a significant role in ART-induced dyslipidemia.

Role of pharmacogenetics and clinical parameters on nevirapine plasma concertation among HIV-1 patients receiving Antiretroviral Therapy in Kenya

Background:Patients’ clinical outcomes and pharmacogenetic factors are important predictors of nevirapine (NVP) plasma concentration. This study evaluated the association of socio-demographic factors and Cytochrome P450 2B6 (CYP2B6) polymorphisms with NVP plasma concentrations among patients receiving antiretroviral therapy (ART) treatment in western and coastal Kenya.Methods:Blood samples were collected from 377 consenting HIV adult patients receiving an NVP-based first-line ART regimen. A detailed sociodemographic questionnaire was administered. NVP plasma concentration was measured by liquid chromatography - tandem mass spectrometry (LC-MS/MS). CYP2B6 c.516 G>T rs3745274 and c.983T>C genotypes were evaluated using real-time polymerase chain reaction. HIV drug resistance mutations were detected using an in-house genotypic assay.Results:The patients’ mean age was 41.6 (SD ± 11.5) years and the majority (59.2%) were female. The mean duration of ART was 5.1 (SD ± 4.8) years. Overall NVP plasma levels ranged from 4-44207 ng/mL (median 6213 ng/mL, IQR 3097–8606.5 ng/mL). There were 105 (25.5%) participants with NVP levels of <3100 ng/mL, associated with poor viral suppression. Multivariate linear regression analysis showed CYP2B6 516 G>T polymorphism (β 0.71, 95% CI 0.4–0.98; p<0.0001), male gender (β 0.45, 95% CI 0.01–0.9; p=0.047) and presence of HIV drug-resistant virus (β 1.98, 95% CI 1.24–2.72; p<0.001) were the independent factors influencing NVP plasma concentration.Conclusions:The majority of patients receiving an NVP-based ART regimen had plasma concentrations within the therapeutic range. CYP2B6 516 G>T polymorphism, gender and presence of a HIV drug-resistant mutation significantly influences NVP plasma concentration. Routine pharmacogenetic testing and measurement of NVP plasma concentrations, considering gender and presence of HIV drug-resistant mutations are key to ensuring optimal ART treatment outcomes in Kenya.

Factors affecting high-density lipoprotein cholesterol in HIV-infected patients on nevirapine-based antiretroviral therapy.

Background & objectives:Cardiovascular disease (CVD) risk with low high-density lipoprotein cholesterol (HDL-C) and high triglycerides is common in the general population in India. As nevirapine (NVP)-based antiretroviral therapy (ART) tends to increase HDL-C, gene polymorphisms associated with HDL-C metabolism in HIV-infected adults on stable NVP-based ART were studied.Methods:A cross-sectional study was conducted between January 2013 and July 2014 among adults receiving NVP-based ART for 12-15 months. Blood lipids were estimated and gene polymorphisms in apolipoprotein C3 (APOC3), cholesteryl ester transfer protein (CETP) and lipoprotein lipase (LPL) genes were analyzed by real-time polymerase chain reaction. Framingham's 10-yr CVD risk score was estimated. Logistic regression was done to show factors related to low HDL-C levels.Results:Of the 300 patients included (mean age: 38.6±8.7 yr; mean CD4 count 449±210 cell/μl), total cholesterol (TC) >200 mg/dl was observed in 116 (39%) patients. Thirty nine per cent males and 47 per cent females had HDL-C levels below normal while 32 per cent males and 37 per cent females had TC/HDL ratio of 4.5 and 4.0, respectively. Body mass index [adjusted odds ratio (aOR)=1.70, 95% confidence interval (CI) 1.01-2.84, P=0.04] and viral load (aOR=3.39, 95% CI: 1.52-7.52, P=0.003) were negatively associated with serum HDL-C levels. The 10-yr risk score of developing CVD was 11-20 per cent in 3 per cent patients. Allelic variants of APOC3 showed a trend towards low HDL-C.Interpretation & conclusions:High-risk lipid profiles for atherosclerosis and cardiovascular disease were common among HIV-infected individuals, even after 12 months of NVP-based ART. Targeted interventions to address these factors should be recommended in the national ART programmes.

Efavirenz — but not nevirapine — based antiretroviral therapy significantly reduces etonogestrel concentrations among HIV-positive women using subdermal contraceptive implants

Objectives: The etonogestrel (ENG) implant is a popular contraceptive method because it is highly effective, increasingly accessible and well tolerated. However, there is concern for decreased contraceptive effectiveness among HIV-infected women due to drug interactions with antiretroviral therapy (ART), particularly efavirenz (EFV). We aimed to characterize the pharmacokinetics of ENG among HIV-infected Ugandan women using EFV- or nevirapine (NVP)-based ART and the ENG implant. Methods: This nonrandomized, parallel group study compared ENG pharmacokinetic parameters in three groups of women; those who were ART naïve, those receiving EFV- or NVP-based ART (N=20 per group). Following implant placement, serum ENG concentrations were assessed at weeks 1, 4, 12 and 24. ART adherence was assessed by serum EFV or NVP concentrations at each visit. Participants on EFV additionally used copper IUDs to ensure pregnancy prevention. ENG and ART concentrations were analyzed using validated LC-MS/MS and HPLC methods, respectively. Results: The groups were similar in age, weight and CD4 count. Data from 58 participants are included; one participant each was excluded from the EFV (ART nonadherence) and NVP (processing error) groups. Geometric mean (GM) ENG concentrations at week 24 were 362, 66 and 341 pg/mL in the ART-naïve, EFV and NVP groups, respectively [GM ratio (90% CI): EFV:ART-naïve,0.18 (0.17–0.20); NVP:ART-naïve, 0.94 (0.90–1.0)]. Conclusions: After 24 weeks of combined use, ENG concentrations were 82% lower among women using EFV-based ART than among ART-naïve women. In contrast, NVP did not significantly change ENG concentrations. These findings are highly concerning for reduced effectiveness of the ENG implant among HIV-infected women receiving EFV-based ART.

Assessment of the nevirapine safety signal using data from the national antiretroviral dispensing database: a retrospective study.

BackgroundClinical trials showed a higher risk of skin- and liver- related adverse reactions when NVP-based antiretroviral therapy (ART) was initiated in female and male patients with baseline CD4 cell counts ≥250 and ≥400, respectively. Some studies reported no difference in risk between the high and low CD4 count groups. Consequently, the use of NVP-based ART in all patients with a CD4 cell count <350, was recommended. In 2011, the Pharmacovigilance Centre detected an increase in reports of grade III and IV reactions. The center was required to determine if there was an increase in NVP-related reactions.MethodsAutomated dispensing records from January 2008 to November 2011 were accessed from the National Antiretroviral Dispensing Database (NDB). Records of patients who were initiated on NVP-based ART were selected, and records showing a replacement of NVP with protease inhibitor (PI) were identified. The proportions of grade III and IV reactions were calculated per quarter, and Odds Ratios (OR) were calculated, with the confidence interval set at 95 % and a p-value of <0.05.ResultsFrom 2008 to 2011 a total of 84,741 patients were started on ART. Of these 67,794 were initiated on NVP-containing ART. Of these, 211 females and 79 males were substituted from NVP to a PI. The OR for females was 2.4 (95 % confidence interval [CI] 1.8 – 3.1). For males the OR was 2.4 (OR 2.4; 95 % CI 1.4 – 3.8) which occurred nine months after the change observed in the females. The odds of a NVP-to-PI substitution in females compared to males before the launch of Namibia’s 2010 ART guidelines was the same as the odds after the publication of the guidelines (before, OR 1.6; 95 % CI 1.1 – 2.5; after, OR 1.6; 95 % CI 1.2 – 2.2).ConclusionsThere was an increase in substitutions of NVP with a PI following the increase in the CD4 threshold for initiating NVP-based HAART, meaning that there was an increase in grade III and IV reactions associated with NVP. Therefore the NVP-safety signal was confirmed to be a true signal, which contributed to the Ministry’s decision to review the use of NVP.

Single-dose nevirapine exposure does not affect response to antiretroviral therapy in HIV-infected African children aged below 3 years.

To assess the impact of exposure to single-dose nevirapine (sdNVP) on virological response in young Ugandan/Zimbabwean children (<3 years) initiating antiretroviral therapy (ART), and to investigate other predictors of response. Observational analysis within the ARROW randomized trial. sdNVP exposure was ascertained by the caregiver's self-report when the child initiated non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART. Viral load was assayed retrospectively over a median 4.1 years of follow-up. Multivariable logistic regression models were used to identify independent predictors of viral load below 80 copies/ml, 48 and 144 weeks after ART initiation (backwards elimination, exit P = 0.1). Median (IQR) age at ART initiation was 17 (10-23) months in 78 sdNVP-exposed children vs. 21 (14-27) months in 289 non-exposed children (36 vs. 20% <12 months). At week 48, 49 of 73 (67%) sdNVP-exposed and 154 of 272 (57%) non-exposed children had viral load below 80 copies/ml [adjusted odds ratio (aOR) 2.34 (1.26-4.34), P = 0.007]; 79 and 77% had viral load below 400 copies/ml. Suppression was significantly lower in males (P = 0.009), those with higher pre-ART viral load (P = 0.001), taking syrups (P = 0.05) and with lower self-reported adherence (P = 0.04). At week 144, 55 of 73 (75%) exposed and 188 of 272 (69%) non-exposed children had less than 80 copies/ml [aOR 1.75 (0.93-3.29), P = 0.08]. There was no difference between children with and without previous sdNVP exposure in intermediate/high-level resistance to NRTIs (P > 0.3) or NNRTIs (P > 0.1) (n = 88) at week 144. Given the limited global availability of lopinavir/ritonavir, its significant formulation challenges in young children, and the significant paediatric treatment gap, tablet fixed-dose-combination NVP-based ART remains a good alternative to syrup lopinavir-based ART for children, particularly those over 1 year and even if exposed to sdNVP.

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients.

We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

Nevirapine-related adverse events among children switched from efavirenz to nevirapine as compared to children who were started on nevirapine-based antiretroviral therapy directly

In this retrospective study, incidence of nevirapine (NVP) toxicity in children who were switched from efavirenz (EFV) to NVP (treatment experienced [TE] group) was compared with that of children who had started NVP-based antiretroviral therapy directly (treatment naïve [TN] group). This study also identified risk factors associated with development of NVP toxicity in children. The incidence and risk of developing NVP toxicities were significantly higher in TE when compared to TN group. Median duration of onset of NVP toxicity from the initiation was 2.14 and 3.84 weeks in TE and TN children, respectively. Mean CD4 count was found to be significantly higher in children who developed toxicity (577 ± 81 cells/µL) as compared to the children who did not develop toxicity (403 ± 29 cells/µL). Similarly, children in TE group who developed NVP toxicity had higher mean CD4 cell count than children in TN with NVP toxicity. The risk factors for the development of NVP toxicity include female gender with CD4 count >250 cells/μL and TE children especially girls with CD4% >15% and boys with CD4 count >400 cells/μL. To conclude, the higher incidence of NVP toxicity among TE group warrants a cautious approach while switching the NVP- from EFV-based therapy.

Efavirenz‐ but not nevirapine‐based antiretroviral therapy decreases exposure to the levonorgestrel released from a sub‐dermal contraceptive implant

IntroductionSub-dermal hormone implants, such as levonorgestrel (LNG), are a safe and desirable form of long-acting contraception, but their use among HIV-positive women on antiretroviral therapy (ART) may be compromised given the potential for a cytochrome P450 3A-mediated drug–drug interaction. Our study aimed to characterize the pharmacokinetics of LNG released from a sub-dermal implant over six months in HIV-positive Ugandan women on nevirapine (NVP)- or efavirenz (EFV)-based ART.Material and MethodsThis non-randomized, parallel group study compared LNG pharmacokinetics between HIV-positive Ugandan women not yet eligible for ART (control group, n=18) and those on stable NVP- (n=20) or EFV- (n=20) based ART. The two-rod (75 mg/rod) LNG sub-dermal implant was inserted at study enrolment. LNG sampling was obtained pre-implant and at weeks 1, 4, 12 and 24 post-insertion. LNG concentrations were analyzed using a validated LC-MS/MS method, with an assay calibration range of 50–1500 pg/mL. Safety monitoring, including a pregnancy test, was conducted at each study visit.ResultsAt enrolment, participants had a mean age of 31 years; CD4+ cell counts were similar between the control, NVP and EFV groups (758, 645 and 568 cells/mm3, respectively; p=0.09); all women in the NVP and EFV groups had an undetectable HIV-RNA. Women in the control group had a higher baseline body weight (73 kg) compared to those in the NVP (63 kg; p=0.03) or EFV groups (60 kg; p<0.01). By linear regression, weight was a significant predictor of LNG concentrations (1 kg increase in weight=5 pg/mL decrease in LNG, p=0.03). LNG concentrations are reported in the table.ConclusionsOver a 24-week period, LNG concentrations were 40–54% lower in women on EFV-based ART, despite their having a significantly lower body weight, compared to those not on ART. In women on NVP-based ART, LNG concentrations were 32–39% higher than those observed in the control group, a difference partially explained by body weight. These data confirm a significant drug interaction occurs between the LNG implant and EFV, adding to growing concern for reduced contraceptive efficacy with their combined use. In contrast, these data support use of the LNG implant with NVP-based ART.

Impact of adherence and anthropometric characteristics on nevirapine pharmacokinetics and exposure among HIV-infected Kenyan children.

There are insufficient data on pediatric antiretroviral therapy (ART) pharmacokinetics (PK), particularly for children in low- and middle-income countries. We conducted a prospective nevirapine (NVP) PK study among HIV-infected Kenyan children aged 3-13 years initiating an NVP-based ART regimen. NVP dose timing was measured through medication event monitors. Participants underwent 2 inpatient assessments: 1 at 4-8 weeks after ART initiation and 1 at 3-4 months after ART initiation. Allometric scaling of oral clearance (CL)/bioavailability (F) and volume of distribution (Vd)/F values were computed. Nonlinear mixed-effects modeling using the first-order conditional estimation with interaction method was performed with covariates. The impact of adherence on time below minimum effective concentration was assessed in the final PK model using medication event monitors data and model-estimated individual parameters. Among 21 children enrolled, mean age was 5.4 years and 57% were female. CL/F was 1.67 L/h and Vd/F was 3.8 L for a median child weighing 15 kg. Participants' age had a significant impact on CL/F (P < 0.05), with an estimated decrease in CL of 6.2% for each 1-year increase in age. Total body water percentage was significantly associated with Vd/F (P < 0.001). No children had >10% of time below minimum effective concentration when the PK model assumed perfect adherence compared with 10 children when adherence data were used. Age and body composition were significantly associated with children's NVP PK parameters. ART adherence significantly impacted drug exposure over time, revealing subtherapeutic windows that may lead to viral resistance.

Predictors of virologic and clinical response to nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with and without prior nevirapine exposure for the prevention of mother-to-child HIV transmission.

In a randomized trial comparing nevirapine (NVP)-based versus lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) in HIV-infected children [primary endpoint discontinuation of study treatment for any reason or virologic failure by week 24] aged 2 months to 3 years, we assessed whether clinical, virologic, immunologic and safety outcomes varied by prior single-dose NVP exposure (PrNVP) for prevention of mother-to-child HIV transmission and other covariates. Efficacy was assessed by time to ART discontinuation or virologic failure, virologic failure/death and death; safety by time to ART discontinuation because of a protocol-defined toxicity and first ≥ grade 3 adverse event; immunology and growth by changes in CD4%, weight/height World Health Organization z-scores from entry to week 48. Cox proportional hazards and linear regression models were used to test whether treatment differences depended on PrNVP exposure and other covariates. Over a median follow up of 48 (PrNVP) and 72 (no PrNVP) weeks, there was no evidence of differential treatment effects by PrNVP exposure or any other covariates. LPV/r-based ART was superior to NVP-based ART for efficacy and safety outcomes; however, those on NVP had larger improvements in CD4%, weight and height z-scores. Lower pretreatment CD4% and higher HIV-1 RNA levels were associated with reduced efficacy, lower pretreatment CD4% with shorter time to ART discontinuation because of a protocol-defined toxicity, and no PrNVP with shorter time to first grade ≥ 3 adverse event. Differences between LPV/r and NVP ART in efficacy, safety, immunologic and growth outcomes did not depend on PrNVP exposure, prior breast-feeding, sex, HIV-1 subtype, age, pretreatment CD4%, HIV-1 RNA or World Health Organization disease stage. This finding should be considered when selecting an ART regimen for young children.

Adverse events associated with nevirapine use in pregnancy

The risk of adverse drug events associated with nevirapine (NVP) is suggested to be greater in pregnant women. We conducted a systematic review and meta-analysis of severe adverse events in HIV-positive women who initiated NVP while pregnant. We searched six databases for studies reporting adverse events among HIV-positive pregnant women who had received NVP-based antiretroviral therapy for at least 7 days. Data were pooled by the fixed-effects method. Twenty studies (3582 pregnant women) from 14 countries were included in the final review. The pooled proportion of patients experiencing a severe hepatotoxic event was 3.2% [95% confidence interval (CI) 2.1-4.3%], severe rash was experienced by 3.3% of patients (95% CI 2.1-4.5%) and 6.1% (95% CI 3.9-8.3%) of patients discontinued NVP due to an adverse event. These results were comparable to frequencies observed in the general adult patient population, and to frequencies reported in non-pregnant women within the same cohort. For pregnant women with a CD4 cell count above 250 cells/μl there was a non-significant tendency towards an increased likelihood of severe cutaneous adverse events (OR 1.4, 95% CI 0.8-2.4) and severe hepatotoxic events (OR 1.5, 95%CI 0.9-2.3) and consequently an increased risk of toxicity-driven regimen substitution (OR 1.7, 95% CI 1.1-2.6). These results suggest that the frequency of adverse events associated with NVP use in pregnant women, although high, is no higher than reported for NVP in the general adult population. Pregnant women with a high CD4 cell count may be at increased risk of adverse events, but evidence supporting this association is weak.

Long‐term clinical and immunologic outcomes of HIV‐infected women with and without previous exposure to nevirapine

To determine and compare the clinical and immunologic outcomes for HIV-infected women initiated on antiretroviral therapy (ART), with and without previous exposure to single-dose nevirapine in the MTCT-Plus programme - Kampala, Uganda, from 2003 to 2011. Retrospective comparison of prospectively collected programmatic data of clinical and immunologic treatment outcomes among HIV-infected Ugandan women, with and without prior exposure to sdNVP, who received NNRTI-based ART for a median follow-up of 6years. Of the 408 women in the programme, 289 (70.8%) were started on ART, of whom 205 (70.9%) had prior exposure to sdNVP. Clinical, immunologic and combined (clinical and or immunologic) treatment failure occurred in 29 (10.0%), 132 (45.7%) and 142 (49.1%) women, respectively. There was no significant difference in the distribution of time to immunologic failure for women by exposure to sdNVP (log-rank P=0.98). In Cox proportional hazard modelling, exposure to sdNVP was not associated with immunologic failure [adjusted hazard ratio (HR)=0.89, 95% confidence interval (CI): 0.61-1.30]. CD4 count >100cells/mm(3) at initiation was associated with reduced incidence of immunologic failure in adjusted analyses (HR=0.32, 95% CI: 0.22-0.48). HIV-infected Ugandan women initiated on an NVP-based ART regimen had similar immunologic treatment outcomes irrespective of previous NVP exposure. CD4 cell count prior to initiating HAART was a key prognostic factor for successful long-term immunologic treatment outcomes. In poor settings, regular follow-up of patients on HAART with adequate counselling to promote adherence and safe disclosure may promote low clinical failure rates.

Safety of nevirapine in HIV-infected pregnant women initiating antiretroviral therapy at higher CD4 counts: A systematic review and meta-analysis

The package insert for nevirapine (NVP) cautions use in HIV-infected women (including pregnant women) with CD4 counts ≥250 cells/µl. However, recent studies showed that the CD4 count of pregnant women receiving antiretroviral therapy (ART) was not predictive of NVP toxicity. To determine whether ART-naive pregnant women initiating NVP-based ART at higher CD4 counts experience greater toxicity compared with pregnant women at lower CD4 counts. We reviewed studies comparing serious adverse NVP-related events among ART-naive pregnant women who commenced therapy at higher v. lower CD4 counts. Relevant studies were extracted from PubMed, SCOPUS and EMBASE, major journals and conference proceedings prior to December 2011. Authors were contacted for additional data. Data were independently extracted and entered into Review Manager. Fourteen studies (2 663 participants) were included for analysis. The odds ratio (OR) for overall NVP toxicity among pregnant women with CD4 <250 cells/µl was 0.61 (95% confidence interval (CI) 0.43 - 0.85). When analysis was restricted to prospective studies only (7 studies, 1 318 participants), the results were consistent for overall NVP toxicity (OR 0.43; 95% CI 0.25 - 0.73) and severe hepatotoxicity (OR 0.45; 95% CI 0.22 - 0.90), but not for severe cutaneous reaction (OR 0.53; 95% CI 0.26 - 1.10). Initiating NVP-based ART during pregnancy at CD4 ≥250 cells/µl increases toxicity risk and should be avoided, necessitating urgent revision of current guidelines supporting this practice.

Safety and effectiveness of efavirenz versus nevirapine-based regimens in resource-limited settings

639–641Keywords: efavirenz, effectiveness, modelling, nevirapine, safety,sub-Saharan AfricaCombination antiretroviral therapy (ART) with eitherefavirenz (EFV) or nevirapine (NVP), both nonnucleo-side reverse transcriptase inhibitors (NNRTIs), and twonucleoside reverse transcriptase inhibitors (NRTI) isrecommended by the WHO as first-line therapy inresource-limited countries [1]. Compared with NVP,EFV is easier to monitor, is relatively well tolerated, hasless frequent and less severe rash and hepatic toxicity thanNVP, and can be administered once daily. Whereas NVPandEFVhavegenerallycomparableclinicalandvirologicefficacy [2–5], because of lower drug–drug interactions,EFV-based ART is associated with superior virologicoutcome compared with NVP-based ART in individualswith tuberculosis (TB) receiving anti-TB therapycontaining rifampicin. Therefore, efavirenz is theNNRTI antiretroviral drug of choice of TB-coinfectedindividuals [6–9]. However, there have been concernsregarding potential for central nervous system birthdefects with first-trimester exposure to EFV based onstudiesinpregnantrhesusmacaquesandretrospectivecasereportsinhumansthathavelimitedEFVuseinwomenofchildbearing age. This is a problem in many resource-limitedsettings,wherewomenconstitute50%or moreofHIV-infected individuals and TB is endemic, but there islimited access to contraception or women may wish tobecome pregnant.In this issue, Ouattara and colleagues use a computersimulation model to evaluate the risks and benefits ofusing EFV and NVP in women of childbearing age inresource-limited countries [10]. Using the previouslyvalidated Cost-Effectiveness of Preventing AIDS Com-plications (CEPAC) International model, the authorssimulated the trade-off between potential excess birthdefects and potential long-term clinical benefits forwomen starting EFV-based versus NVP-based ART inCote d’Ivoire. In a ‘hypothetical’ cohort of 100000women starting ARTwith EFV, the authors found that adrug with lower toxicity and requiring less regimenswitching led to approximately 911 more women aliveafter 10 years compared with those starting with NVP, animprovement in survival of approximately 1%. However,over thesameperiod,therewere59morebirthdefectsinwomen initiating EFV-based ART than those startingwith NVP. The authors concluded that in Cote d’Ivoire,initiating ART with EFV instead of NVP is likely to

Approaches to effectively documenting prior single dose nevirapine exposure among women in Africa

Background: Single dose nevirapine (sdNVP) is widely used in resource-limited settings for the prevention of mother to child transmission of HIV, but can result in NVP resistance that negatively impacts the subsequent efficacy of maternal antiretroviral therapy (ART). It is important to determine prior sdNVP exposure status to help guide treatment decisions, but systematic data on approaches to documenting previous sdNVP ingestion are lacking. Aim: With the growing body of evidence of the effects of sdNVP exposure on subsequent choices of ART, we aim to highlight some of the practical challenges that exist in documenting prior sdNVP exposure or lack thereof. Materials and Methods: ACTG A5208 Optimized Combination Therapy after Nevirapine Exposure (OCTANE) is a randomized treatment trial of protease inhibitor vs. NVP-based ART that enrolled 745 HIV-infected women in 7 African countries. Documentation of previous exposure to sdNVP (or lack thereof) was collected prospectively and intensively, as were locally-available sources of such data. Results: All 243 women who were exposed to sdNVP recalled having taken sdNVP; written documentation of sdNVP exposure was found for 73% and an additional 20% identified having ingested a NVP tablet when the tablet was shown to them. Among 502 women not exposed to sdNVP, only 10 (2%) had written documentation of lack of sdNVP exposure. NVP resistance was detected in 33 (13.8%) of sdNVP-exposed and 1 of non-exposed women. Conclusion: Maternal self-report of prior sdNVP exposure was corroborated by supporting evidence in the majority of women participating in the trial.

Nevirapine-Based Antiretroviral Therapy Impacts Artesunate and Dihydroartemisinin Disposition in HIV-Infected Nigerian Adults

Background. Nevirapine- (NVP-) based antiretroviral therapy (ART) and artesunate-amodiaquine are frequently coprescribed in areas of HIV and malaria endemicity. We explored the impact of this practice on artesunate and dihydroartemisinin pharmacokinetics. Methods. We conducted a parallel-group pharmacokinetic comparison between HIV-infected patients receiving NVP-based ART (n = 10) and ART-naive controls (n = 11). Artesunate-amodiaquine 200/600 mg was given daily for three days. Measurement of drug concentrations occurred between 0 and 96 hours after the final dose. Pharmacokinetic parameters were determined using noncompartmental analysis. Results. Comparing the NVP group to controls, clearance of artesunate was reduced 50% (1950 versus 2995 L/h; P = 0.03), resulting in a 45% increase in the AUC0-96 (105 versus 69 ug∗hr/L; P = 0.02). The half-life of dihydroartemisinin was shorter in the NVP group (1.6 versuss 3.2 h; P = 0.004), but other dihydroartemisinin pharmacokinetic parameters were unchanged. A lower conversion of artesunate to dihydroartemisinin was observed in the NVP group (dihydroartemisinin: artesunate AUC0-96 = 5.6 versuss 8.5 in NVP and control groups, respectively, P = 0.008). Conclusion. Although NVP-containing ART impacted some pharmacokinetic parameters of artesunate and dihydroartemisinin, overall exposure was similar or better in the NVP group.

Virologic Suppression in Nevirapine-Exposed HIV-Infected Infants Initiating Antiretroviral Therapy in Rural Uganda

We measured virologic suppression among 34 nevirapine (NVP)-exposed HIV-infected children with median age of 8.6 months (range: 3.2-19.9) initiating NVP-based antiretroviral therapy (ART) in rural Uganda. In Kaplan-Meier analysis, the cumulative probability of virologic suppression, defined as having two consecutive HIV-1 RNA <400 copies ml(-1) by 18 months was 56%. In multivariate Cox proportional hazard modeling, the following pre-ART measurements were independently associated with an increased probability of viral suppression: increasing age [hazard ratio (HR) =1.28 per 1 month increase in age, p = 0.002], lower viral load (HR = 3.54 for HIV RNA > 7 50 000 copies ml(-1), p = 0.03) and high CD4% (HR = 6.0 for CD4% > 25, p = 0.003). These results lend additional support to the 2010 World Health Organization recommendations that protease inhibitors be used to treat NVP-exposed children, but that NVP-based ART should be initiated before the decline of CD4% to optimize outcomes in NVP-exposed children when protease inhibitors are not available.

Pregnancy Outcomes in Women Exposed to Efavirenz and Nevirapine: An Appraisal of the IeDEA West Africa and ANRS Databases, Abidjan, Côte d'Ivoire

An increasing number of HIV-infected women become pregnant while receiving efavirenz (EFV). We compared the pregnancy outcomes of women exposed to EFV and to nevirapine (NVP) during the first trimester. A retrospective study in 4 HIV care centers participating to clinical trials and international cohort collaboration. All HIV-infected pregnant women who conceived on EFV-based or NVP-based antiretroviral therapy (ART) between 2003 and 2009 were included. Pregnancy outcomes were as follows: abortion (voluntary termination), miscarriage [unwanted termination <20 weeks of amenorrhea (WA)], stillborn (death ≥ 20 WA), preterm delivery (live-birth <37 WA), and low birth weight (LBW) (<2500 grams). Overall, 344 HIV-infected pregnant women conceived on ART (213 on EFV and 131 on NVP). Median age was 29 years, and median CD4 count 217 cells per microliter at ART initiation. The overall proportion was 11.7% for abortion, 5.2% for miscarriage, 6.7% for stillborn, 10.8% for preterm delivery, and 20.2% for LBW. There was no difference between EFV and NVP exposure, except for abortion (14.3% vs 7.3%; P = 0.05). No external and visible congenital malformation was observed neither in women exposed to EFV nor in women exposed to NVP. Among women exposed to EFV, no significant increased risk of unfavorable pregnancy outcome was reported except for abortion.

Three Generic Nevirapine-Based Antiretroviral Treatments in Chinese HIV/AIDS Patients: Multicentric Observation Cohort

BackgroundThe purpose of this study was to evaluate the efficacy and safety of three nevirapine-based antiretroviral treatments for adult antiretroviral-naïve Chinese patients with HIV-1 infection.MethodologyThis was a prospective, multicenter study. 198 antiretroviral-naïve HIV-1 positive subjects with CD4 lymphocyte counts between 100/ul and 350/ul and plasma HIV-1 RNA levels more than 500 copies/ml were randomized to start three NVP-based antiretroviral treatments: group A, NVP+AZT+ddI; group B, NVP+3TC+d4T; group C, NVP+AZT+3TC. Viral responses, immunologic responses, adverse events and drug resistence were monitored at baseline and the end of week 4, 12, 24, 36, 52. Viralogical response and immunological response were also comparaed in different strata of baseline CD4 T lymphocyte counts and plasma HIV-1 RNA concentrations. At baseline, the plasma HIV-1 RNA was 4.44±0.68, 4.52±0.71 and 4.41±0.63 lg copies/ml in group A, B and C respectively (p = 0.628). At the end of the study, the plasma viral load reached 2.54±1.11, 1.89±0.46 and 1.92±0.58 lg copies/ml in group A, B and C respectively (p<0.001). At week 52, suppression of plasma HIV-1 RNA to less than 50 copies/ml was achieved in more patients in group B and C than in group A (68.2%, 69% vs. 39.7%; p<0.001). In planned subgroup analyses, the decrease of viral response rate was seen in group A when CD4 cell count >200/ul (subgroup H). But in subgroup L, viral response rate of three groups has no significant statistic difference. There were no statistically significant differences among three groups in immunological response wthin any of the CD4 or pVL strata. 3 out of 193 patients with available genotype at baseline showed primary drug resistant. Of 26 patients with virologic failure, 17 patients showed secondary drug resistant, 16 subjects in group A and 1 subject in group B. Logistic regression analysis indicated that presence of hepatotoxicity was associated with HCV-Ab positive (OR = 2.096, 95%CI: 1.106–3.973, P = 0.023) and higher CD4 baseline (CD4 count >250/ul)(OR = 2.096, 95%CI: 1.07–4.107, P = 0.031).ConclusionOur findings strongly support the use of 3TC+d4T and 3TC+AZT as the nucleoside analogue combination in NVP-based antiretroviral therapy. The regimen of AZT+ddI+NVP produced poor virological response especially in the stratum of CD4 count more than 200/ul. More patients showed secondary drug resistant in this arm too. Patients with HCV-Ab+ and CD4 count >250/ul appear to have significantly high risk of hepatoxicity.Trial RegistrationClinicalTrials.gov NCT00618176