Preformulation characterization and identification of excipients for nevirapine loaded niosomes.

Nevirapine (NVP) is used for the management of HIV/AIDS but must be dosed frequently, exhibits unpredictable bioavailability and a side effect profile that includes hepato- and dermo-toxicity. Niosomes are a colloidal drug delivery system that may be used to overcome the low bioavailability, side effect profile and frequent dosing needed when using conventional drug delivery systems. The compatibility of NVP with sorbitan esters, polysorbate, cholesterol and dihexadecyl phosphate (DCP) was investigated using Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Fourier Transform Infra-red Spectroscopy (FTIR) and X-ray Powder Diffraction (XRPD). Screening studies were undertaken to identify potential excipients that would produce niosomes with target critical quality attributes (CQA) viz, a particle size (PS) < 1000 nm, a polydispersity index (PDI) < 0.500 and an entrapment efficiency >90%. The results revealed that sorbitan esters in combination with cholesterol and 5 µmol DCP produced niosomes with the best CQA and Zeta potential (ZP) < -30 mV which suggests good stability of the niosomes on storage. Sorbitan esters produced the smallest niosomes of < 400 nm diameter with a PDI < 0.400 and an entrapment efficiency > 78% without cholesterol. The addition of cholesterol and DCP was essential to form niosomes with target CQA.

Nevirapine Pharmacokinetics in Neonates Between 25 and 32 Weeks Gestational Age for the Prevention of Mother-to-Child Transmission of HIV.

Eleven newborns from 25 to 32 weeks of gestational age, weighting from 0.66 to 1.60 kg received 2 mg/kg doses of nevirapine syrup. In 15 samples, collected 8.75-89 hours after drug intake, concentrations ranged from 0.65 to 16.68 mg/L. Three nevirapine dose of 2 mg/kg at day 0, 2 and 6 days of life achieved nevirapine concentrations above the proposed nevirapine target for HIV prophylaxis for at least 11 days.

Pharmacogenetic interactions of rifapentine plus isoniazid with efavirenz or nevirapine.

OBJECTIVES: The effect of rifapentine plus isoniazid on efavirenz pharmacokinetics was characterized in AIDS Clinical Trials Group protocol A5279 (NCT01404312). The present analyses characterize pharmacogenetic interactions between these drugs, and with nevirapine. METHODS: A subset of HIV-positive individuals receiving efavirenz- or nevirapine-containing antiretroviral therapy in A5279 underwent pharmacokinetic evaluations at baseline, and again weeks 2 and 4 after initiating daily rifapentine plus isoniazid. Associations with polymorphisms relevant to efavirenz, nevirapine, isoniazid, and rifapentine pharmacokinetics were assessed. RESULTS: Of 128 participants, 101 were evaluable for associations with rifapentine and its active 25-desacetyl metabolite, 87 with efavirenz, and 38 with nevirapine. In multivariable analyses, NAT2 slow acetylators had greater week 4 plasma concentrations of rifapentine (P = 2.6 × 10) and 25-desacetyl rifapentine (P = 7.0 × 10) among all participants, and in efavirenz and nevirapine subgroups. NAT2 slow acetylators also had greater plasma efavirenz and nevirapine concentration increases from baseline to week 4, and greater decreases from baseline in clearance. CYP2B6 poor metabolizers had greater efavirenz concentrations at all weeks and greater nevirapine concentrations at baseline. None of 47 additional polymorphisms in 11 genes were significantly associated with pharmacokinetics. CONCLUSIONS: Among HIV-positive individuals receiving efavirenz or nevirapine, and who then initiated rifapentine plus isoniazid in A5279, NAT2 slow acetylators had greater rifapentine and 25-desacetyl rifapentine concentrations, and greater increases from baseline in plasma efavirenz and nevirapine concentrations. These associations are likely mediated by greater isoniazid exposure in NAT2 slow acetylators.

Effect of nevirapine, efavirenz and lopinavir/ritonavir on the therapeutic concentration and toxicity of lumefantrine in people living with HIV at Lagos University Teaching Hospital, Nigeria.

Patients living with HIV in malarial endemic regions may experience clinically significant drug interaction between antiretroviral and antimalarial drugs. Effects of nevirapine (NVP), efavirenz (EFV) and lopinavir/ritonavir (LPVr) on lumefantrine (LM) therapeutic concentrations and toxicity were evaluated. In a four-arm parallel study design, the blood samples of 40 participants, treated with artemether/lumefantrine (AL), were analysed. Lumefantrine Cmax was increased by 32% (p = 0.012) and 325% (p < 0.0001) in the NVP and LPVr arms respectively but decreased by 62% (p < 0.0001) in the EFV-arm. AUC of LM was, respectively, increased by 50% (p = 0.27) and 328% (p < 0.0001) in the NVP and LPVr arms but decreased in the EFV-arm by 30% (p = 0.019). Median day 7 LM concentration was less than 280 ng/mL in EFV-arm (239 ng/mL) but higher in control (290 ng/mL), NVP (369 ng/mL, p = 0.004) and LPVr (1331 ng/mL, p < 0.0001) arms. There were no clinically relevant toxicities nor adverse events in both control and test arms. Artemether/lumefantrine is safe and effective for treatment of malaria in PLWHA taking NVP and LPVr based ART regimen but not EFV-based regimen.

Development of a pseudovirus assay and evaluation to screen natural products for inhibition of HIV-1 subtype C reverse transcriptase.

ETHNOPHARMACOLOGICAL RELEVANCE: Medicinal plants are used in the management of Human Immunodeficiency Virus and Acquired Immunodeficiency Syndrome (HIV/AIDS) in many developing country settings where HIV-1 subtype C drives the epidemic. Efforts to identify plant derived molecules with anti-HIV properties require reproducible assay systems for routine screening of selected plant compounds. Although a number of standardized HIV-1 pseudoviruses have been generated to assess infectivity, replicability or reproducibility, HIV-1 subtype C (HIV-1-C) pseudoviruses have not been comprehensively characterized to identify inhibitory plant substances. AIM OF THE STUDY: The current study aimed at developing an HIV-1-C pseudovirus assay, and evaluate plant substances targeting reverse transcriptase (RT) activity. MATERIALS AND METHODS: HIV-1 subtype C pseudoviruses containing a luciferase reporter gene were generated by transfection of human 293T cells. HIV-1 subtype B (HIV-1-B) wild type pseudoviruses and mutants resistant to nucleoside and non-nucleoside RT inhibitors were also generated and used as controls. Selected plant substances and the RT inhibitors Zidovudine (AZT) and Nevirapine (NVP), were used to evaluate inhibition. Pseudovirus infectivity was determined by luciferase measurement in CF2/CD4+/CCR5 cells, and cytotoxicity was determined using the MTT assay. AZT and NVP inhibited wild type pseudoviruses in a dose dependent manner, with IC50 values in the nanomolar range. RESULTS: Pseudoviruses harbouring RT drug resistance mutations were poorly suppressed by AZT and NVP. Catechin, obtained from Peltophorum africanum inhibited HIV-1-C and HIV-1-B pseudoviruses with selective indices of 6304 µM (IC50: 0.49 µM, CC50: 3089 µM) and 1343 µM (IC50: 2.3 µM, CC50: 3089 µM), respectively; while the methanol root crude extract of Elaeodendron transvaalense gave IC50 values of 11.11 µg/ml and 16.86 µg/ml, respectively. CONCLUSION: The developed HIV-1-C pseudovirus assay can be used to screen plant substances for RT inhibition, and may have utility in settings with limited access to high level biosafety facilities.

Perinatal Antiretroviral Intensification to Prevent Intrapartum HIV Transmission When Antenatal Antiretroviral Therapy Is Initiated Less Than 8 Weeks Before Delivery.

INTRODUCTION: Infants born to women living with HIV initiating combination antiretroviral therapy (cART) late in pregnancy are at high risk of intrapartum infection. Mother/infant perinatal antiretroviral intensification may substantially reduce this risk. METHODS: In this single-arm Bayesian trial, pregnant women with HIV receiving standard of care antiretroviral prophylaxis in Thailand (maternal antenatal lopinavir-based cART; nonbreastfed infants 4 weeks' postnatal zidovudine) were offered "antiretroviral intensification" (labor single-dose nevirapine plus infant zidovudine-lamivudine-nevirapine for 2 weeks followed by zidovudine-lamivudine for 2 weeks) if their antenatal cART was initiated ≤8 weeks before delivery. A negative birth HIV-DNA polymerase chain reaction (PCR) followed by a confirmed positive PCR defined intrapartum transmission. Before study initiation, we modeled intrapartum transmission probabilities using data from 3738 mother/infant pairs enrolled in our previous trials in Thailand using a logistic model, with perinatal maternal/infant antiretroviral regimen and predicted viral load at delivery as main covariates. Using the characteristics of the women enrolled who received intensification, prior intrapartum transmission probabilities (credibility intervals) with/without intensification were estimated. After including the transmission data observed in the current study, the corresponding Bayesian posterior transmission probability was derived. RESULTS: No intrapartum transmission of HIV was observed among the 88 mother/infant pairs receiving intensification. The estimated intrapartum transmission probability was 2·2% (95% credibility interval 0·5-6·1) without intensification versus 0·3% (0·0-1·6) with intensification. The probability of superiority of intensification over standard of care was 94·4%. Antiretroviral intensification appeared safe. CONCLUSION: Mother/infant antiretroviral intensification was effective in preventing intrapartum transmission of HIV in pregnant women receiving ≤8 weeks antepartum cART.

HIV-free survival among breastfed infants born to HIV-positive women in northern Uganda: a facility-based retrospective study.

INTRODUCTION: the HIV-free survival rate is the gold-standard measure of the effectiveness of interventions towards prevention of mother-to-child transmission of HIV in any setting. However, data on HIV-free survival among the HIV-exposed infants followed up in most low-resource settings are lacking. We determined the HIV-free survival among breastfed infants in two tertiary facilities in a resource-poor setting in northern Uganda. METHODS: we conducted a retrospective cohort study in May 2019 and retrospectively reviewed records of HIV-exposed infants registered in 2014 through 2016 at two tertiary facilities in northern Uganda. We analyzed data using SPSS v16 software package. The chi-square and Student t-tests were used to compare factors among infant groups. Multivariate logistic regression analysis was used to determine factors independently associated with HIV-free survival. P-value <0.05 was considered for statistical significance. RESULTS: majority of the infants were males 55.6% (203/365) and 98.6% (360/365) received nevirapine prophylaxis. A total of 345 (94.5%) infants were exclusively breastfed, only 100/345 (29.0%) of whom were exclusively breastfed for at least 6 months, while the breastfeeding status of 44/345 (12.8 %) infants could not be ascertained. The overall HIV-free survival rate was 93.7% (342/365), while 2.7% (10/365) were HIV-infected and 3.6% (13/365) died. Infants´ age at enrolment in care (aOR 5.20, p=0.008) and treatment facility (aOR 3.76, p=0.027) were the independent determinants of HIV-free survival. CONCLUSION: the HIV-free survival rate among the breastfed infants in the study setting marginally falls short of the recommended standard, thus calling for more efforts to improve survival.

Pediatric Antiretroviral Therapeutic Drug Monitoring: A Five and a Half Year Experience from a South African Tertiary Hospital.

INTRODUCTION: Antiretroviral therapeutic drug monitoring (TDM) is not routinely used in the management of human immunodeficiency virus, but may be useful in pediatric patients who are prone to altered pharmacokinetics. Data on the routine use of antiretroviral TDM in pediatrics are sparse especially data from sub-Saharan Africa. METHODS: We retrospectively reviewed the antiretroviral TDM indications at Tygerberg Children's Hospital, identified pediatric patients who had antiretroviral TDM requests from January 2012 until June 2017 and reviewed their clinical records. RESULTS: Fifty-nine patients were identified who presented with 64 clinical problems for which TDM was requested. TDM was requested for lopinavir, efavirenz and nevirapine in 83% (53/64), 14% (9/64) and 3% (2/64) of clinical problems, respectively. Lopinavir was mostly requested in patients when adherence measures did not correlate with the clinical picture, suspected non-adherence, lopinavir-rifampicin interactions and for neonatal safety monitoring. Efavirenz was requested when toxicity was suspected and nevirapine in patients receiving rifampicin. Lopinavir TDM confirmed non-adherence in 25% (4/16) of cases when adherence measures did not correlate with the clinical picture and in 43% (3/7) of cases when non-adherence was suspected by the clinician. Efavirenz TDM confirmed toxicity in 100% (6/6) of patients. CONCLUSIONS: Lopinavir TDM was mostly requested when adherence measures did not correlate with the clinical picture, when rifampicin was co-administered and for perinatal safety monitoring. Lopinavir TDM excluded pharmacokinetic reasons for failure in patients failing treatment when lopinavir dosing was supervised. Efavirenz TDM was requested for suspected toxicity with a 100% positive predictive value.

Investigating time dependent brain distribution of nevirapine via mass spectrometric imaging.

Central nervous system (CNS) HIV infection causes brain tissue inflammation and tissue deficit that contributes to neuroAIDS. This complication is escalated by the blood-brain barrier (BBB), which prevents easy access to antiretroviral drugs entering the CNS. In this study the aims were to investigate the BBB membrane penetration and brain localization patterns of Nevirapine (NVP) using Imaging Mass Spectrometry (MSI). Sprague-Dawley rats received an intraperitoneal dose of NVP (50 mg kg-1). Plasma and brain samples were harvested, and mass spectrometric methods were then applied to determine the pharmacokinetic properties and localization patterns of NVP in the brain. The pharmacokinetic parameters demonstrated a rapid bio-distribution of NVP in plasma and brain. The plasma Cmax was 6320 ng mL-1 and the brain Cmax was 1923 ng mL-1, both at a Tmax of 0.25 h. MSI of coronal brain sections showed that NVP penetrated and localized in the brain regions implicated with the development of HIV associated neurodegeneration. NVP has great potential to combat neuroAIDS.

Maternal Humoral Immune Responses Do Not Predict Postnatal HIV-1 Transmission Risk in Antiretroviral-Treated Mothers from the IMPAACT PROMISE Study.

To design immune interventions that can synergize with antiretroviral therapy (ART) to reduce the rate of HIV mother-to-child transmission (MTCT), it is essential to characterize maternal immune responses in the setting of ART during pregnancy and breastfeeding and define their effect on MTCT. Prior studies reported an association between breast milk envelope (Env)-specific antibodies and antibody-dependent cell cytotoxicity (ADCC) activity with reduced postnatal transmission. In this study, we investigated whether these immune correlates were similarly associated with protection in a matched case-control study of mother-infant pairs receiving maternal ART or infant nevirapine prophylaxis during breastfeeding in the International Maternal-Pediatric-Adolescent AIDS Clinical Trials Network Promoting Maternal-Infant Survival Everywhere (PROMISE) trial, assessing postnatal transmission risk in 19 transmitting and 57 nontransmitting mothers using conditional logistic regression models adjusted for maternal plasma viral load. The odds ratios of postnatal MTCT for a 1-unit increase in an immune correlate were 3.61 (95% confidence interval [CI], 0.56, 23.14) for breast milk Env-specific secretory IgA (sIgA), 2.32 (95% CI, 0.43, 12.56) for breast milk and 2.16 (95% CI, 0.51, 9.14) for plasma Env-specific IgA, and 4.57 (95% CI, 0.68, 30.48) for breast milk and 0.96 (95% CI, 0.25, 3.67) for plasma ADCC activity, with all CIs spanning 1.0. Interestingly, although mucosal IgA responses are poor in untreated HIV-infected women, there was a strong correlation between the magnitudes of breast milk and plasma Env-specific IgA in this cohort. In this analysis of the small number of postnatal virus transmissions in the landmark PROMISE study, no single antibody response was associated with breast milk transmission risk.IMPORTANCE Each year, >150,000 infants become newly infected with HIV-1 through MTCT despite ART, with up to 42% of infections occurring during breastfeeding. Several factors contribute to continued pediatric infections, including ART nonadherence, the emergence of drug-resistant HIV strains, acute infection during breastfeeding, and poor access to ART in resource-limited areas. A better understanding of the maternal humoral immune responses that provide protection against postnatal transmission in the setting of ART is critical to guide the design of maternal vaccine strategies to further eliminate postnatal HIV transmission. In this study, we found that in women treated with antiretrovirals during pregnancy, there was a positive correlation between plasma viral load and breast milk and plasma IgA responses; however, conclusions regarding odds of MTCT risk were limited by the small sample size. These findings will inform future studies to investigate maternal immune interventions that can synergize with ART to eliminate MTCT during breastfeeding.

Linked dual-class HIV resistance mutations are associated with treatment failure.

We hypothesized that HIV-1 with dual-class but not single-class drug resistance mutations linked on the same viral genome, present in the virus population before initiation of antiretroviral therapy (ART), would be associated with failure of ART to suppress viremia. To test this hypothesis, we utilized an ultrasensitive single-genome sequencing assay that detects rare HIV-1 variants with linked drug resistance mutations (DRMs). A case (ART failure) control (nonfailure) study was designed to assess whether linkage of DRMs in pre-ART plasma samples was associated with treatment outcome in the nevirapine/tenofovir/emtricitabine arm of the AIDS Clinical Trials Group A5208/Optimal Combined Therapy After Nevirapine Exposure (OCTANE) Trial 1 among women who had received prior single-dose nevirapine. Ultrasensitive single-genome sequencing revealed a significant association between pre-ART HIV variants with DRMs to 2 drug classes linked on the same genome (dual class) and failure of combination ART with 3 drugs to suppress viremia. In contrast, linked, single-class DRMs were not associated with ART failure. We conclude that linked dual-class DRMs present before the initiation of ART are associated with ART failure, whereas linked single-class DRMs are not.

Safety of 6-week Neonatal Triple-combination Antiretroviral Postexposure Prophylaxis in High-risk HIV-exposed Infants.

BACKGROUND: Combination antiretroviral drug regimens are increasingly preferred for neonatal postexposure prophylaxis (PEP) among HIV-exposed infants with high-risk of transmission. We evaluated the adverse events associated with the use of zidovudine (ZDV)/lamivudine (3TC)/nevirapine (NVP) for neonatal PEP during the first 6 weeks of life. METHODS: A prospective cohort of non-breast-fed HIV-exposed infants was conducted at 5 clinical sites in Thailand. Study population included 100 high-risk HIV-exposed infants (maternal HIV RNA > 50 copies/mL prior to delivery or received antiretroviral therapy less than 12 weeks) and 100 low-risk HIV-exposed neonates. High-risk infants received ZDV/3TC/NVP for 6 weeks whereas low-risk HIV-exposed neonates received a 4-week regimen of ZDV. Complete blood count, aspartate transaminase and alanine transaminase were assessed at birth, 1, 2 and 4 months of life. RESULTS: From October 2015 to November 2017, 200 infants were enrolled, of which 18.5% had low birth weight < 2500 g. The proportion of infants with anemia grade 2 or higher at 1 and 2 months of life between ZDV/3TC/NVP and ZDV prophylaxis was 48.5% vs 32.3% (P=0.02); nevertheless, severe anemia (grade 3) was not significantly different; 9.2% vs 10.2% (P=0.81), respectively. At 1 month old, infants on ZDV/3TC/NVP prophylaxis had significantly higher grade 2 anemia versus infants on ZDV alone (33.0% vs 13.4%; P=0.001); however, no difference was observed at 2 months old. No differences in neutropenia or hepatotoxicity between infant prophylactic regimens were observed. CONCLUSIONS: Triple antiretroviral neonatal PEP with ZDV/3TC/NVP for 6 weeks in high-risk HIV-exposed infants did not significantly increase the risk of short-term toxicity compared with ZDV-monotherapy prophylaxis.

A pharmacokinetic and pharmacogenetic evaluation of contraceptive implants and antiretroviral therapy among women in Kenya and Uganda.

OBJECTIVES: To evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART). DESIGN: We analyzed stored samples from women self-reporting implant use in the Partners PrEP Study. METHODS: Plasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations. RESULTS: Our analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P < 0.001] and the etonogestrel aGMR was 0.51 (0.34, 0.76; P = 0.006) compared with the control group. No difference was observed in the NVP group compared with controls [levonorgestrel 0.93 (0.74, 1.18); P = 0.64; etonogestrel 1.07 (0.77, 1.50); P = 0.73]. Possession of four allele variants were found to result in further reductions in progestin concentrations among those receiving EFV. CONCLUSION: Concomitant use of EFV significantly reduces levonorgestrel or etonogestrel concentrations by 61 and 49%, respectively, compared with no ART use. We also report allelic variants in hepatic enzymes that influenced the extent of the observed drug-interaction between progestins and EFV.

Increasing body mass index or weight does not appear to influence the association between efavirenz-based antiretroviral therapy and implant effectiveness among HIV-positive women in western Kenya.

OBJECTIVE: Our objective was to evaluate if increasing body mass index (BMI) or weight influences the association between efavirenz-based antiretroviral therapy (ART) and implant effectiveness. STUDY DESIGN: We conducted a secondary cohort analysis of HIV-positive women aged 15 to 45 years enrolled in HIV care in western Kenya using an implant from January 2011 to December 2015. Implant use, ART regimen and weight were documented at each clinic visit and height at enrollment. We categorized BMI as underweight, normal weight, overweight or obese, and weight as <70 kg or ≥70 kg. Our primary outcome was incident pregnancy diagnosed clinically. We used crude and adjusted Poisson models with robust standard errors to account for covariates and repeated observations to estimate adjusted incident rate ratios (aIRRs). RESULTS: In this analysis, 12,960 women contributed a total of 11,285 woman-years of observation time while using an implant, with a median of 6.6 months. The aIRRs comparing efavirenz- to nevirapine-based ART groups did not increase as BMI increased; the aIRRs were 2.0 (1.1-3.6) for underweight, 1.9 (1.5-2.5) for normal, 3.1 (1.6-6.0) for overweight and 2.1 (0.6-6.9) for obese women. The aIRRs comparing efavirenz- to nevirapine-based ART groups did not increase as weight increased; the aIRRs were 2.0 (1.6-2.6) for weight <70 kg and 2.1 (1.0-4.5) for weight ≥70 kg. CONCLUSION: Higher BMI or weight did not appear to modify the relationship between efavirenz use and implant effectiveness. IMPLICATIONS: Programs should not recommend differential counseling for women with higher BMI or weight who concomitantly use implants and efavirenz.

Non-nucleoside reverse transcriptase inhibitor levels among HIV-exposed uninfected infants at the time of HIV PCR testing - findings from a tertiary healthcare facility in Pretoria, South Africa.

INTRODUCTION: To date, very little programmatic data has been published regarding serial antiretroviral (ARV) levels in infants exposed to maternal treatment and/or infant prophylaxis during the first months of life. Such data provide the opportunity to describe the proportion of infants exposed to virologically suppressive levels of ARVs and to gauge adherence to the prevention of mother-to-child transmission of HIV (PMTCT) programme. METHODS: From August 2014 to January 2016, HIV-exposed infants born at Kalafong Provincial Tertiary Hospital in Pretoria, South Africa were enrolled as part of an observational cohort study. Plasma samples from HIV-exposed uninfected infants were obtained at birth, 6-weeks, 10-weeks and 14-weeks of age and quantitative efavirenz (EFV) and nevirapine (NVP) drug level testing performed using liquid chromatography-mass spectrometry, irrespective of maternal ARV regimen. Descriptive analysis of EFV and NVP levels in relation to self-reported maternal and infant ARV exposure was performed. EFV levels >500 ng/mL and NVP levels >100 ng/mL were reported based on studies suggesting that trough levels above these thresholds are associated with virological suppression and PMTCT respectively. RESULTS: Among 66 infants exposed to maternal EFVin utero, 29 (44%) had virologically suppressive plasma EFV levels at birth, with a median level of 1665 ng/mL (IQR: 1094 to 3673). Among infants who were exclusively breastfed at 6-, 10- and 14 weeks, 13/48 (27%), 5/25 (25%) and 0/21 (0%) had virologically suppressive EFV levels. Among 64 infants whose mothers reported administering daily infant NVP at time of their 6-week HIV PCR test, only 45 (70%) had NVP levels above the minimum prophylactic trough level. CONCLUSIONS: During the first 10-weeks after delivery, a quarter of breastfed infants born to women on an EFV-containing treatment regimen maintained virologically suppressive EFV plasma levels. This finding highlights the importance of both careful monitoring of ARV side effects and repeat HIV PCR after the first few months of life among HIV-exposed uninfected infants. As 30% of infants had inadequate NVP plasma levels at 6-weeks of age, adherence counselling to caregivers regarding infant prophylaxis needs to be enhanced to further reduce mother-to-child transmission of HIV.

Nevirapine in HIV maintenance therapy - can "old drugs" survive in current HIV management?

AIMS OF THE STUDY: Nevirapine has an exceptional record for long-term tolerability with few side effects in human immunodeficiency virus (HIV) combined antiretroviral therapy (cART). Owing to relatively frequent hypersensitivity reactions (HSR) (15–25%) in the first 3 months after treatment initiation (especially in patients with a high CD4 count (>250/µl in women, >400/µl in men)), it is being used less and less. However, the rate of adverse events is lower when patients are already under suppressive cART. We present the results of a single centre strategy to offer the switch to a nevirapine-containing regimen and evaluate the potential role nevirapine could play in current antiretroviral treatment. METHODS: All adult HIV-positive patients starting nevirapine at our centre since 2010 were evaluated in this retrospective analysis. We examined the proportion of patients on cART containing nevirapine, as well as the number of starts and stops every 6 months. Nevirapine discontinuation rates were analysed by sex, age, hepatitis C virus (HCV) status, time on nevirapine, ethnicity, CD4 nadir as well as CD4 count, HIV-RNA and ART backbone at nevirapine start. RESULTS: Since 2014, more than a third of our treated HIV patients have been on nevirapine-containing therapy, with a stable percentage in the following years; 277 patients starting nevirapine for the first time were analysed. Thirty-three percent (92/277) of these first nevirapine therapies were discontinued, with 16 cases (17%) resuming nevirapine later during follow-up. Of the patients who continued nevirapine for more than 90 days (n = 221), 80% maintained nevirapine until their last follow-up. The nevirapine stop rate after the first 90 days was 15-fold lower (5.4 per 100 patient years, 95% confidence interval [CI] 4.0–7.2) than in the first 90 days. Overall, nevirapine was used for a median of 2.9 years (interquartile range [IQR] 0.5–5.6). In HCV co-infected patients, the treatment stop rate was 4-fold higher than in HIV mono-infected patients, but this difference was mainly due to treatment interruptions caused by drug-drug interactions with intermittent HCV therapy. Six out of seven Asian patients experienced HSR (hepatotoxicity / skin rash). In a population with 74% 3TC/ABC backbone, 81% fully suppressed, median CD4 nadir 240/µl (IQR 120–360) and median CD4 count at nevirapine start 590/µl (IQR 400–840), both high CD4 nadir and high CD4 count at nevirapine start were associated with lower rather than higher discontinuation rates. In fully suppressed patients with high CD4 count at nevirapine start, high CD4 nadir was not a risk factor for HSR. Major reasons for the discontinuation of nevirapine were HSR (liver, skin rash) in 38 cases (41% of all discontinuations) followed by other adverse drug reactions (n = 17) and non-adherence (n = 14). In patients who stopped nevirapine after more than 90 days, the major cause was non-adherence or other adverse drug reaction (both n = 12). CONCLUSIONS: In this study, two thirds of the patients continued nevirapine with favourable long-term tolerability and efficacy. Thus, this low-cost “old drug” may still represent a valid treatment switch option for maintenance therapy in selected patients with a fully suppressed viral load. However, further evaluation is needed.  .

Antiretroviral switching and bedaquiline treatment of drug-resistant tuberculosis HIV co-infection.

Bedaquiline, a potent new therapy for drug-resistant tuberculosis, results in improved survival including in HIV patients with multidrug and extensively drug-resistant tuberculosis. In line with WHO recommendations, in South Africa and other low-income and middle-income settings, antiretroviral therapy is switched from generic fixed-dose combination efavirenz-containing regimens to twice-daily nevirapine with separate companion pills because of interactions between efavirenz and bedaquiline. Early data suggest a signal for low antiretroviral therapy adherence after this antiretroviral therapy switch. Mortality and other tuberculosis-specific benefits noted with bedaquiline treatment in multidrug and extensively drug-resistant tuberculosis HIV might be compromised by HIV viral failure, and emergent antiretroviral resistance. Programmatic responses, such as adherence support and dual pharmacovigilance, should be instituted; antiretroviral therapy initiation with fixed-dose combinations without bedaquiline drug interactions should be strongly considered.

Occurrence of CYP2B6 516G>T polymorphism in patients with ARV-associated hepatotoxicity.

BACKGROUND: Hepatic enzyme cytochrome P450 2B6 (CYP2B6) plays a role in the metabolism of efavirenz drugs. CYP2B6 516G>T variation showed an implication for HIV treatment. METHODS: CYP2B6 516G>T polymorphism was genotyped in a total 165 HIV patients that include 34 with and 131 without hepatotoxicity and 155 healthy individuals by the PCR-RFLP. RESULTS: In patients with hepatotoxicity, the prevalence of CYP2B6 516TT genotype was higher as compared to healthy individuals (35.3% vs. 30.5%, OR = 1.74). Patients with hepatotoxicity using tobacco had a higher prevalence of genotypes CYP2B6 516GT, 516TT, 516GT+TT as compared to healthy individuals (28.57% vs. 25.93%; 57.14% vs. 29.63%; 85.71% vs. 55.56%). Likewise, hepatotoxicity in patients consuming alcohol showed higher distributions of CYP2B6 516GT, 516TT, 516GT+TT genotypes (57% vs. 25.93%; 42.86% vs. 33.33%; 71.43% vs. 59.26%). Nevirapine users with hepatotoxicity overrepresented genotypes CYP2B6 TT and 516GT+TT as compared to efavirenz users (47.83% vs. 45.45%, OR = 6.88, 65.22% vs. 54.55%, OR = 1.56). Similarly, in nevirapine +alcohol users with hepatotoxicity, the frequency of CYP2B6 516GT, 516GT+TT genotypes was higher than with nevirapine +alcohol nonusers (40.0% vs. 11.11%, OR = 8.00, 80.0% vs. 27.78%, OR = 4.00). In HIV patients, nevirapine users had higher frequency of CYP2B6 516GT, 516GT+TT genotypes as compared to efavirenz users (42.02% vs. 25.00%, OR = 2.53; 72.27% vs. 58.33%, OR = 1.86). Likewise, in HIV patients, genotypes CYP2B6 516GT, 516GT+TT were predominant with nevirapine +alcohol users as compared to nevirapine +alcohol nonusers (57.89% vs. 34.57%, OR = 2.46; 78.95% vs. 69.14%, OR = 1.67). In multivariate logistic regression, taking nevirapine had a protection for severity of ARV-associated hepatotoxicity (OR = 0.23, p = 0.005). CONCLUSIONS: No significant association was detected between CYP2B6 516G>T polymorphism and susceptibility to ARV-associated hepatotoxicity.

Development, manufacture and characterization of niosomes for the delivery for nevirapine.

Nevirapine (NVP), used for the treatment of HIV/AIDS, exhibits unpredictable oral bioavailability, has a poor side effect profile and requires frequent dosing. Niosomes are novel drug delivery systems that have the potential to overcome these challenges. A thin layer hydration approach was used to produce niosomes and optimisation was undertaken using design of experiments (DoE) and response surface methodology (RSM) establish and identify parameters that may affect the manufacture of niosomes. The impact of cholesterol and surfactant content, hydration time and temperature on manufacture was investigated. Critical quality attributes (CQA) in respect of particle size (PS), entrapment efficiency (EE), polydispersity index (PDI) and the amount of NVP released at 48 hours was also assessed. The optimised niosome composition was identified and manufactured and the CQA characterised prior to placing the batch on stability for 12 weeks at 4±2 °C and 22±2 °C. The PS, PDI, EE and % NVP released at 48 h was 523.36±23.16 nm, 0.386±0.054, 96.8 % and 25.3 % for niosomes manufactured with Span® 20. Similarly, the parameters were 502.87±21.77 nm and 0.394±0.027, 98.0 % and 25.0 % for mean PS, PDI, EE and %NVP released at 48 h for Span® 80 niosomes. All characterisation was undertaken on the day of manufacture. In conclusion, a simple, cheap, rapid and precise method of manufacture of NVP niosomes was developed, validated and optimised using DoE and RSM and the product exhibited the target CQA.