Proportion of HIV exposed infants aged 0-6 months that missed nevirapine prophylaxis in Mulago National Referral Hospital, Uganda: a cross-sectional study.

BACKGROUND: Nevirapine prophylaxis has been found to lower the risk of HIV transmission in breastfed infants. While about 95% of HIV positive pregnant and lactating mothers use Antiretroviral therapy in Uganda, a smaller percentage of HIV exposed infants (HEI) receive nevirapine (NVP) prophylaxis. This study aimed to determine the proportion of HEI who missed NVP prophylaxis and associated factors. METHODS: This was a cross-sectional study done using quantitative methods, conducted at Mulago National Referral Hospital (MNRH). A total of 228 mother-infant pairs were enrolled. The proportion of HEI who missed NVP, maternal, infant and health facility factors associated were determined using a pre-tested questionnaire. Bivariate analysis and binary logistic regression model were used to determine the proportion and factors associated with missing NVP prophylaxis. RESULTS: The proportion of HEI who missed NVP prophylaxis was 50/228 (21.9%). Factors significantly associated with HEI missing NVP prophylaxis included delivery from outside government health facilities (AOR = 8.41; P = 0.001), mothers not undergoing PMTCT counselling (AOR = 12.01; P = 0.001), not on ART (AOR = 8.47; P = 0.003) and not having disclosed their HIV status to their partners (AOR = 2.80; P = 0.001). The HEI that missed nevirapine and were HIV positive were 35 (70.0%). The HEI that were HIV infected despite receiving nevirapine prophylaxis were 5 out of 40(12.5%). CONCLUSION: One in five HEI missed NVP prophylaxis and nearly three quarters of those who missed NVP prophylaxis were HIV infected. Improving uptake of nevirapine by HEI will require interventions that can aid to strengthen PMTCT counselling.

The use of PD-1 functional knockout rats to study idiosyncratic adverse reactions to nevirapine.

Idiosyncratic drug reactions (IDRs) are associated with significant patient morbidity/mortality and lead to considerable drug candidate attrition in drug development. Their idiosyncratic nature makes the study of IDRs difficult. In particular, nevirapine is associated with a relatively high risk of serious skin rash and liver injury. We previously found that nevirapine causes a similar skin rash in female Brown Norway rats, but these animals do not develop significant liver injury. Programmed cell death protein-1 (PD-1) is an immune checkpoint involved in immune tolerance, and anti-PD-1 antibodies have been used to treat cancer. However, they increase the risk of liver injury caused by co-administered drugs. We found that PD-1-/- mice are more susceptible to drug-induced liver injury, but PD-1-/- mice are not a good model for all drugs. In particular, they do not develop a skin rash when treated with nevirapine, at least in part because they lack the sulfotransferase in their skin that forms the reactive metabolite responsible for the rash. Therefore, we developed a PD-1 mutant (PD-1m/m) rat, with an excision in the ligand-binding domain of PD-1, to test whether nevirapine would cause a more serious skin rash in these animals. The PD-1m/m rat was based on a Sprague Dawley background, which has a lower incidence of skin rash than Brown Norway rats. The treated PD-1m/m rats developed more severe liver injury than PD-1-/- mice, but in contrast to expectations, they did not develop a skin rash. Functional knockouts provide a unique tool to study the mechanisms of IDRs.

Optimizing removal of antiretroviral drugs from tertiary wastewater using chlorination and AI-based prediction with response surface methodology.

Chemical and pharmaceutical chemicals found in water sources create substantial risks to human health and the environment. The presence of pharmaceutical contaminants in water can cause antibiotic resistance development, toxicity to aquatic organisms, and endocrine disruption. Hence, the elimination of chemicals and other contaminants from wastewater prior to its release is a burgeoning concern in the domains of engineering and science. The use of treatment technologies in wastewater treatment plants can remove pharmaceutical contaminants through the oxidation process. However, many traditional wastewater treatment plants lack the advanced monitoring tools required to detect low concentrations of pharmaceuticals. Without the ability to detect these compounds, it's challenging to treat them effectively. The goal of this study was to use Response Surface Methodology (RSM) and Artificial Neural Networks (ANN) algorithms to model and improve how Nevirapine and Efavirenz break down in different chlorination conditions. The RSM analysis revealed statistically significant models (F-values: Nevirapine, pH-t: 108.15, T-t: 76.55, ICC-t: 110.84), indicating a strong correlation between operational parameters (pH, temperature, and initial chlorine concentration) and degradation behavior. The ANN model accurately predicted the degradation of both Nevirapine and Efavirenz under various chlorination conditions, as confirmed by analyzing actual-predicted graphs, residual plots, and Mean Squared Error (MSE) values. The ANN model using ICC-t achieved the highest MOD value of 31.31 % for Nevirapine. The ANN model based on ICC-t yielded a maximum MOD value of 16.06 % for Efavirenz. These findings provide valuable insights into optimizing chlorination processes for better removal of these pharmaceutical contaminants from water.

Integrated study of antiretroviral drug adsorption onto calcined layered double hydroxide clay: experimental and computational analysis.

This study focused on the efficacy of a calcined layered double hydroxide (CLDH) clay in adsorbing two antiretroviral drugs (ARVDs), namely efavirenz (EFV) and nevirapine (NVP), from wastewater. The clay was synthesized using the co-precipitation method, followed by subsequent calcination in a muffle furnace at 500 °C for 4 h. The neat and calcined clay samples were subjected to various characterization techniques to elucidate their physical and chemical properties. Response surface modelling (RSM) was used to evaluate the interactions between the solution's initial pH, adsorbent loading, reaction temperature, and initial pollutant concentration. Additionally, the adsorption kinetics, thermodynamics, and reusability of the adsorbent were evaluated. The results demonstrated that NVP exhibited a faster adsorption rate than EFV, with both reaching equilibrium within 20-24 h. The pseudo-second order (PSO) model provided a good fit for the kinetics data. Thermodynamics analysis revealed that the adsorption process was spontaneous and exothermic, predominantly governed by physisorption interactions. The adsorption isotherms followed the Freundlich model, and the maximum adsorption capacities for EFV and NVP were established to be 2.73 mg/g and 2.93 mg/g, respectively. Evaluation of the adsorption mechanism through computational analysis demonstrated that both NVP and EFV formed stable complexes with CLDH, with NVP exhibiting a higher affinity. The associated adsorption energies were established to be -731.78 kcal/mol for NVP and -512.6 kcal/mol for EFV. Visualized non-covalent interaction (NCI) graphs indicated that hydrogen bonding played a significant role in ARVDs-CLDH interactions, further emphasizing physisorption as the dominant adsorption mechanism.

The role of corticosterone in nevirapine-induced idiosyncratic drug-induced liver injury.

Nevirapine, an antiretroviral used in the treatment of HIV, is associated with idiosyncratic drug-induced liver injury (IDILI), a potentially life-threatening adverse drug reaction. Its usage has decreased due to this concern, but it is still widely used in lower-resource settings. In general, the mechanisms underlying idiosyncratic drug reactions (IDRs) are poorly understood, but evidence indicates that most are immune-mediated. There is very limited understanding of the early immune response following administration of drugs associated with IDRs, which likely occurs due to reactive metabolite formation. In this work, we aimed to characterize the links between covalent binding of nevirapine, the development of an early immune response, and the subsequent liver injury using a mouse model. We describe initial attempts to characterize an early immune response to nevirapine followed by the discovery that nevirapine induced the release of corticosterone. Corticosterone release was partially associated with the degree of drug covalent binding in the liver but was also likely mediated by additional mechanisms at higher drug doses. Transcriptomic analysis confirmed metabolic activation, glucocorticoid signaling, and decreased immune activation; GDF-15 also warrants further investigation as part of the immune response to nevirapine. Finally, glucocorticoid blockade preceding the first dose of nevirapine attenuated nevirapine-induced liver injury at 3 weeks, suggesting that acute glucocorticoid signaling is harmful in the context of nevirapine-induced liver injury. This work demonstrates that nevirapine induces acute corticosterone release, which contributes to delayed-onset liver injury. It also has implications for screening drug candidates for IDILI risk and preventing nevirapine-induced IDILI.

Effects of solution chemistry on dielectric barrier atmospheric non-thermal plasma for operative degradation of antiretroviral drug nevirapine.

The global prevalence of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has been an environmental menace. Tons of drug wastes from antiretroviral therapy are released into the environment annually. We, for the first time, employed the novel dielectric barrier atmospheric non-thermal plasma (DBANP) discharge, to mitigate the inadvertent pollution arising from the antiretroviral therapy. A 40-min treatment of nevirapine achieved >94 % (0.075 min-1) removal efficiency at discharge power of 63.5 W and plasma working gas of atmospheric air. Chemical probes confirmed •OH, ONOO- and eaq- as the dominant reactive species whilst further revealing the reaction acceleration role of NaNO3 and CCl4 which are known reaction terminators. The commonly coexisting inorganic anions potentiated nevirapine removal with over 98 % efficiency, achieving the highest rate constant of 0.148 min-1 in this study. Moreover, the initial solution pH (1.5-11.1) was no limiting factor either. The insensitivity of the DBANP discharge to actual water matrices was an eminent inference of its potential applicability in practical conditions. With reference to data obtained from the liquid chromatography-mass spectrometer analysis, nevirapine degradation pathway was proposed. A nucleophilic attack by ONOO- at the cyclopropyl group and •OH attack at the carbonyl carbon of the amide group, respectively, initiated nevirapine degradation process. It is anticipated that the findings herein, will provide new insights into antiretroviral drug waste management in environmental waters using the innovative and green non-thermal plasma process.

A Phase-IV Non-interventional Study to Assess Virological Effectiveness, Safety, and Tolerability of DTG-based Antiretroviral Therapy in HIV-1 Infected Indian Persons Living with HIV.

BACKGROUND: Dolutegravir (DTG) is a novel yet preferential first- and -second-line treatment for persons living with HIV (PLH). Owing to its recent introduction, DTG-based regimens have not undergone a comprehensive, systematic evaluation regarding their real-world utilization and safety profile among a sizeable Indian population. OBJECTIVE: This study aimed to assess the 24 week immunovirological outcomes, anthropometric and metabolic changes, tolerability, and adverse events (AEs) of DTG-based antiretroviral (ART) regimens. METHODS: A single-centre phase-IV non-interventional observational study involving 322 ART naïve and treatment-experienced PLH initiating DTG-based-regimens until October 2022 were followed up for outcomes at 24 weeks. RESULTS: At 24 weeks, all PLH (n = 113) in the naïve group, all PLH (n = 67) in the first-line substitution group, 93.9% PLH (n = 46) in the first-line failure group, and 95.7% PLH (n = 89) in the second-line substitution group were virologically suppressed to plasma HIV-RNA <1000 copies/mL. Virological suppression rates to plasma HIV-RNA <200 copies/mL and <50 copies/mL were consistent among PLH who received DTG as first- or second-line ART. The mean-unadjusted weight gain observed was 3.5 kg (SE: 0.330), and it was significantly higher in PLH with poorer health at baseline (either HIV-RNA ≥ 1000 copies/ml or CD4 cell count <350 cells/µL). Overall, 27.3% PLH (n = 88) gained ≥10% of their baseline body weight, corresponding to 3.7% incidence (n = 12) of treatment-emergent clinical obesity. DTG had an overall lipid-neutral effect, with an advantageous effect being observed in PLH switching from non-nucleoside analogue reverse-transcriptase inhibitors (NNRTI) or ritonavir-boosted protease inhibitors (b/PI), especially in dyslipidemic pre-treated PLH (median change in total cholesterol: 28.5 mg/dL and triglycerides: 51 mg/dL), possibly emanating from the withdrawal of the offending ART. The incidence of DTG-specific AEs, including CNS AEs, was low. Two PLH developed proximal myopathy and one developed transaminitis, warranting DTG discontinuation. Asymptomatic serum-CPK elevation and drug-induced transaminitis were seen in 25.2% (n = 27) and 3.2% (n = 10) PLH, respectively. No apparent negative effects on renal function were detected. CONCLUSION: Our results from a large Indian cohort indicate a favourable virological and metabolic response, with good tolerance of DTG-based ART at 24 weeks.

CD4/CD8 Ratio Recovered as a Predictor of Decreased Liver Damage in Adults Infected With HIV: 16-Year Observational Cohort Study.

BACKGROUND: As the life expectancy of individuals infected with HIV continues to increase, vigilant monitoring of non-AIDS-related events becomes imperative, particularly those pertaining to liver diseases. In comparison to the general population, patients infected with HIV experience a higher frequency of liver-related deaths. The CD4/CD8 ratio is emerging as a potential biomarker for non-AIDS-related events. However, few existing studies have been specially designed to explore the relationship between the CD4/CD8 ratio and specific types of non-AIDS-related events, notably liver damage. OBJECTIVE: This study aimed to investigate the potential association between the CD4/CD8 ratio and the development of liver damage in a sizable cohort of patients infected with HIV receiving antiretroviral treatment (ART). Additionally, the study sought to assess the effectiveness of 3 antiretroviral drugs in recovering the CD4/CD8 ratio and reducing the occurrence of liver damage in this population. METHODS: We conducted an observational cohort study among adults infected with HIV receiving ART from 2004 to 2020 in Guangxi, China. Propensity score matching, multivariable Cox proportional hazard, and Fine-Gray competing risk regression models were used to determine the relationship between the CD4/CD8 ratio recovered and liver damage. RESULTS: The incidence of liver damage was 20.12% among 2440 eligible individuals during a median follow-up period of 4 person-years. Patients whose CD4/CD8 ratio did not recover to 1.0 exhibited a higher incidence of liver damage compared to patients with a CD4/CD8 ratio recovered (adjusted hazard ratio 7.90, 95% CI 4.39-14.21; P<.001; subdistribution hazard ratio 6.80, 95% CI 3.83-12.11; P<.001), findings consistent with the propensity score matching analysis (adjusted hazard ratio 6.94, 95% CI 3.41-14.12; P<.001; subdistribution hazard ratio 5.67, 95% CI 2.74-11.73; P<.001). The Efavirenz-based regimen exhibited the shortest time for CD4/CD8 ratio recovery (median 71, IQR 49-88 months) and demonstrated a lower prevalence of liver damage (4.18/100 person-years). CONCLUSIONS: Recovery of the CD4/CD8 ratio was associated with a decreased risk of liver damage in patients infected with HIV receiving ART, adding evidence for considering the CD4/CD8 ratio as a potential marker for identifying individuals at risk of non-AIDS-related diseases. An efavirenz-based regimen emerged as a recommended choice for recovering the CD4/CD8 ratio and mitigating the risk of liver damage.

Biochemical and structural comparisons of non-nucleoside reverse transcriptase inhibitors against feline and human immunodeficiency viruses.

BACKGROUND: Feline immunodeficiency virus (FIV) causes an acquired immunodeficiency-like syndrome in cats. FIV is latent. No effective treatment has been developed for treatment the infected cats. The first and second generations non-nucleoside reverse transcriptase inhibitors (NNRTIs) for HIV treatment, nevirapine (NVP) and efavirenz (EFV), and rilpivirine (RPV), were used to investigate the potential of NNRTIs for treatment of FIV infection. OBJECTIVE: This study aims to use experimental and in silico approaches to investigate the potential of NNRTIs, NVP, EFV, and RPV, for inhibition of FIV reverse transcriptase (FIV-RT). METHODS: The FIV-RT and human immunodeficiency virus reverse transcriptase (HIV-RT) were expressed and purified using chromatography approaches. The purified proteins were used to determine the IC50 values with NVP, EFV, and RPV. Surface plasmon resonance (SPR) analysis was used to calculate the binding affinities of NNRTIs to HIV-RT and FIV-RT. The molecular docking and molecular dynamic simulations were used to demonstrate the mechanism of FIV-RT and HIV-RT with first and second generation NNRTI complexes. RESULTS: The IC50 values of NNRTIs NVP, EFV, and RPV against FIV-RT were in comparable ranges to HIV-RT. The SPR analysis showed that NVP, EFV, and RPV could bind to both enzymes. Computational calculation also supports that these NNRTIs can bind with both FIV-RT and HIV-RT. CONCLUSIONS: Our results suggest the first and second generation NNRTIs (NVP, EFV, and RPV) could inhibit both FIV-RT and HIV-RT.

Breakthrough mother-to-child transmission of HIV in a low-health facility in Uganda.

Objectives: Mother-to-child transmission (MTCT) of HIV can be minimized using elimination of MTCT (eMTCT) services. This study aimed to determine the proportion of infants who tested positive for HIV despite receiving eMTCT services in a rural setting in Northern Uganda. Methods: We retrospectively reviewed the early infant diagnosis register for the year January 2019 through June 2021 to collect data on participants enrolled in eMTCT services at Lalogi Health Centre IV in Omoro district, Uganda. Breakthrough HIV infection was defined as a positive HIV RNA on a dried blood sample at 18 months in a patient who received eMTCT services as recommended by national guidelines. Results: A total of 118 infants were enrolled in the study, 64 (54.2%) of whom were female. Most of the participants (n = 111, 94.1%) were on nevirapine prophylaxis for at least 6 weeks, 115 (97.5%) were exclusively breastfed, two (1.7%) were on complementary feeding, and one (0.8%) was not breastfed. Only five (4.2%) infants were lost to follow-up, four (3.4%) had incomplete data, and three (2.5%) had breakthrough HIV infections (positive HIV RNA and HIV antibody tests). All three cases of breakthrough HIV infection (one male and two female infants) were born to mothers who were diagnosed with HIV at delivery and were on nevirapine prophylaxis for less than 6 weeks. Conclusion: Our findings indicate that while eMTCT services were largely successful in minimizing vertical transmission of HIV in the rural setting in Northern Uganda, there were still some cases of breakthrough HIV infection associated with non-adherence to nevirapine prophylaxis and delayed maternal HIV diagnosis. Therefore, adhering to the national guidelines on nevirapine prophylaxis for at least 6 weeks for children born to mothers with HIV is recommended to further reduce the risk of vertical transmission of HIV.

Proportion of HIV exposed infants aged 0-6 months that missed nevirapine prophylaxis in Mulago National Referral Hospital, Uganda: a cross-sectional study.

Background: Nevirapine prophylaxis has been found to lower the risk of HIV transmission in breast-fed infants. While about 95% of pregnant and lactating mothers use Antiretroviral therapy in Uganda, a smaller percentage of HIV exposed infants (HEI)receive nevirapine (NVP)prophylaxis. This study aimed to determine the proportion of HEI whomissed NVP prophylaxis and associated factors. Methods: This was a cross-sectional study done using quantitative methods. It was conducted at Mulago National Referral Hospital. A total of 228mother-infant pairs were enrolled.The proportion of HEI who missed NVP, maternal, infant and health facility factors associated were measured using a pre-tested questionnaire. Bivariate analysis and binary logistic regression model were used to determine the proportion and factors associated with missing NVP prophylaxis. Results: The proportion of HEI who missed NVP prophylaxis was 50/228(21.9%). Factors significantly associated with HEI missing NVP prophylaxis included; delivery from outside government health facilities [AOR=8.41 95% (CI 3.22-21.99)], mothers; not undergoing PMTCT counselling [AOR=12.01 95% (CI 4.53-31.87)], not on ART[AOR=8.47 95% (CI 2.06-34.88)] and not having disclosed their HIV status to their partners [AOR=2.80 95% (CI 1.13-6.95)].The HEI that missed nevirapine and were HIV positive were 35(70.0%). Conclusion: One in five HEI missed NVP prophylaxis and nearly three quarters of those who missed NVP prophylaxis were HIV infected. Improving uptake of nevirapine by HEI will require interventions tostrengthen PMTCT counselling, assisted partner notification, reduction of HIV stigma and support to the private sector in the provision of PMTCT services.

Me-Better Drug Design Based on Nevirapine and Mechanism of Molecular Interactions with Y188C Mutant HIV-1 Reverse Transcriptase.

In this paper, the Y188C mutant HIV-1 reverse transcriptase (Y188CM-RT) target protein was constructed by homology modeling, and new ligands based on nevirapine (NVP) skeleton were designed by means of fragment growth. The binding activity of new ligands to Y188CM-RT was evaluated by structural analysis, ADMET prediction, molecular docking, energy calculation and molecular dynamics. Results show that 10 new ligands had good absorbability, and their binding energies to Y188CM-RT were significantly higher than those of wild-type HIV-1 reverse transcriptase(wt). The binding mode explained that fragment growth contributed to larger ligands, leading to improved suitability at the docking pocket. In the way of fragment growth, the larger side chain with extensive contact at terminal is obviously better than substituted benzene ring. The enhancement of docking activity is mainly due to the new fragments such as alkyl chains and rings with amino groups at NVP terminal, resulting in a large increase in hydrophobic bonding and the new addition of hydrogen bonding or salt bonding. This study is expected to provide reference for the research on non-nucleoside reverse transcriptase inhibitors resistance and AIDS treatment.

Association of Human Leukocyte Antigen Alleles and Hypersensitivity of Efavirenz/Nevirapine in HIV-Infected Chinese Patients.

To examine the association between human leukocyte antigen (HLA) and nevirapine (NVP)- and efavirenz (EFV)-induced cutaneous adverse reactions in human immunodeficiency virus (HIV) patients, we conducted a case-control study at our center consisting of 96 patients. Patients were further assigned based on the occurrence of cutaneous adverse events and the drugs involved. All patients were subjected to next generation sequencing (NGS)-based screening with focus on HLA phenotype, including the presence of HLA-B, HLA-C, and HLA-DRB1. Our data indicated that the HLA-C*01:02:01 allele presence was observed in 47.4% (18/38) of patients in the EFV-hypersensitivity group compared with 18.9% (7/30) in the control group [odds ratio (OR) = 5.837; 95% confidence interval (CI) = 1.727-19.722, p = .005]. In contrast, the occurrence of HLA-DRB1*08:03 was found to be significantly lower in the EFV-hypersensitivity group (4/38, 10.5%) compared with the corresponding control group (12/37, 32.4%) (OR = 0.148; 95% CI = 0.035-0.625, p = .009). In addition, the HLA-DRB1*04:05:01 antigen was expressed more frequently in the NVP-hypersensitivity group (23.8%, 5/21) compared with the control group (10.8%, 4/37) (OR = 7; 95% CI = 1.265-38.793, p = .026). Our data not only revealed a significant association between HLA-C*01:02:01 and EFV-induced cutaneous adverse reactions but may also shed light on defining the treatment for Chinese HIV patients.

Pharmacotechnical Evaluation by SeDeM Expert System to Develop Orodispersible Tablets.

Sediment delivery model (SeDeM) system is innovative tool to correlate micromeritic properties of powders with compressibility. It involves computation of indices which facilitate direct compressibility of solids and enable corrective measures through particle engineering. Study had multiple objectives, viz, (i) to enhance solubility of BCS class II, nevirapine using solid dispersions; (ii) SeDeM analyses of excipients and solid dispersions to analyze direct compressibility; and (iii) prepare orodispersible tablets (ODT). Solid dispersions were prepared by solvent evaporation. Superdisintegrants and solid dispersions were analyzed for primary indices of dimension, compressibility, flowability, stability, and disgregability derived from micromeritic properties. Radar diagrams were constructed to provide visual clues to deficient properties for direct compressibility. ODTs were prepared using excipients which passed criteria for direct compressibility and evaluated for tablet properties. Solid dispersions with Eudragit S100 revealed 6 to 10 fold increase in solubility in various dissolution media including biorelevant media in comparison with plain drug. Solubility was found to be pH dependent. SeDeM analyses facilitated identification of superdisintegrants and excipients with unfavorable compressibility. Radar diagrams provided a clear pictorial evidence of lacunae in powder properties. Based on SeDeM results, tablets were formulated by direct compression using crosspovidone, croscarmellose sodium, and mannitol. All batches showed 40% release in first minute in simulated salivary fluid.

Trough plasma nevirapine levels, immunologic and virologic responses in composite CYP2B6*6/*18 HIV-infected adult Nigerian patients.

The influence of composite CYP2B6*6/*18 genotype on trough plasma nevirapine levels, HIV RNA levels (virologic response) and CD4+ T lymphocyte and absolute lymphocyte counts (immunologic response) of HIV-infected patients were evaluated. Patients with records of trough plasma nevirapine levels, CD4+ T lymphocyte, absolute lymphocyte and viral load counts at baseline and months 6 and 12 after initiation of nevirapine-based antiretroviral therapy combinations were retrospectively analysed. Participants were from a cohort of 150 patients previously genotyped and with measured plasma nevirapine levels. Relationship between genotype and nevirapine levels, absolute lymphocyte and CD4+ T lymphocyte counts and viral load were explored. Composite CYP2B6*6/*18 genotype was significantly associated with trough plasma nevirapine levels (geometric mean [standard deviation]: 4482 ng/ml [1349] of normal metabolizers vs. 4632 ng/ml [1793] of intermediate metabolizers vs. 6229 ng/ml [2549] of poor metabolizers; P < 0.001), but not the plasma HIV RNA levels, absolute lymphocyte and CD4+ T lymphocyte counts. Overall, immunologic response showed improvement with approximately 61.3% and 70.4% of patients with CD4+ T lymphocyte count >350 cells/mm3 at months 6 and 12 therapy duration respectively compared to 23.1% at baseline. Composite CYP2B6*6/*18 genotype correlated with plasma nevirapine levels but not immunologic and virologic responses.

The Clinical Characteristics, Putative Drugs, and Optimal Management of 62 Patients With Stevens-Johnson Syndrome and/or Toxic Epidermal Necrolysis: A Retrospective Observational Study.

BACKGROUND: Case reviews of severe cutaneous adverse drug reactions (ADRs) such as SJS/TEN provide useful insights for clinical characteristics, putative drugs, and management protocols. PATIENTS AND METHODS: Medical charts of 62 (m:f- 20:42) patients with SJS/TEN hospitalized between 2010 and 2019 were analyzed retrospectively for clinical attributes, putative drugs and their indications, extracutaneous complications, and therapeutic outcome. The diagnosis was clinical based on established criteria. WHO-UMC scale for reporting ADR and ALDEN algorithm score were used for causality assessment. Therapies were customized based on in-house resources and affordability. RESULTS: Cases included were SJS (41.9%), SJS/TEN overlap (33.9%), and TEN (24.2%) aged 4-85 years. Complications included transaminitis (69.4%), lymphadenopathy (15.5%), septicemia (11.3%), and wound infections (4.8%). Aromatic anticonvulsants (37.1%), disease-modifying antirheumatic drugs (25.8%), antiretroviral drugs (12.9%), non-steroidal anti-inflammatory drugs (8.1%), antimicrobials (4.8%), and trihexyphenidyl (3.2%) were major putative drugs. The mean latent period was 16.6 days. The observed 8% mortality was because of primary comorbidities or multiorgan failure. Addition of fresh blood transfusion (BT, n = 11) or IVIg (n = 7) to systemic corticosteroids showed early relief in skin tenderness, improvement in general condition, and re-epithelialization. Only 16% of patients developed sequelae. CONCLUSION: Aromatic anticonvulsants, allopurinol, nevirapine, cotrimoxazole, paracetamol, and diclofenac remain the most implicated drugs. Sulfasalazine, leflunomide, ethambutol, and trihexyphenidyl were uncommon additions. A short course of high-dose dexamethasone in the early stage was useful. Addition of BT or IVIg provided rapid relief. Preexisting HIV disease, kidney disease, and sepsis remain important for in-hospital deaths. Retrospective study design and small number of cases remain major limitations.

Studies on some neuropharmacological properties of Nevirapine in mice.

Nevirapine (NVP) is non-nucleoside reverse transcriptase inhibitor and an anti-retroviral drug (ARV) with the highest BBB penetrating ability. Its specific pharmacologic effects on central nervous system (CNS) are not well known. The objective of the study was to investigate some CNS effects of Nevirapine. Oral acute toxicity test (Lorke, 1983) was used to estimate the LD50. Exploratory or sedative effects were tested using open field test(OFT), Hole-board test (HBT), diazepam-induced sleeping time test, and ketamine-induced sleeping time test. Five groups of mice were used (5 mice /group). The negative control group received vehicle (distilled water) (10 mL /kg) while groups II, III, and IV received NVP- 15.625 mg/kg, 31.25 mg/kg, 62.5 mg/kg body weight respectively while group V received 0.25 mg/kg of diazepam intraperitoneal. Groups I to IV were treated orally. The oral LD50 was determined to be 2154. 07 mg/kg. NVP, in a dose dependent fashion, increased the number of line-crossing in the OFT. Also, NVP in a dose-dependent fashion, significantly reduced the duration of diazepam-induced sleeping time as well as delayed onset. NVP significantly potentiated ketamine-induced sleeping time duration. Nevirapine possess excitatory effects possibly through antagonism of GABA receptors. Nevirapine causes wakefulness (shortening of sleep) possibly via antagonism of GABAergic neurotransmission.

Maternal Human Immunodeficiency Virus (HIV) Drug Resistance Is Associated With Vertical Transmission and Is Prevalent in Infected Infants.

BACKGROUND: We aimed to assess if maternal human immunodeficiency virus (HIV) drug resistance is associated with an increased risk of HIV vertical transmission and to describe the dynamics of drug resistance in HIV-infected infants. METHODS: This was a case-control study of PROMISE study participants. "Cases" were mother-infant pairs with HIV vertical transmission during pregnancy or breastfeeding and "controls" were mother-infant pairs without transmission matched 1:3 by delivery date and clinical site. Genotypic HIV drug resistance analyses were performed on mothers' and their infants' plasma at or near the time of infant HIV diagnosis. Longitudinal analysis of genotypic resistance was assessed in available specimens from infants, from diagnosis and beyond, including antiretroviral therapy (ART) initiation and last study visits. RESULTS: Our analyses included 85 cases and 255 matched controls. Maternal HIV drug resistance, adjusted for plasma HIV RNA load at infant HIV diagnosis, enrollment CD4 count, and antepartum regimens, was not associated with in utero/peripartum HIV transmission. In contrast, both maternal plasma HIV RNA load and HIV drug resistance were independent risk factors associated with vertical transmission during breastfeeding. Furthermore, HIV drug resistance was selected across infected infants during infancy. CONCLUSIONS: Maternal HIV drug resistance and maternal viral load were independent risk factors for vertical transmission during breastfeeding, suggesting that nevirapine alone may be insufficient infant prophylaxis against drug-resistant variants in maternal breast milk. These findings support efforts to achieve suppression of HIV replication during pregnancy and suggest that breastfeeding infants may benefit from prophylaxis with a greater barrier to drug resistance than nevirapine alone.

Multivariate optimization of a two-way technique for extraction of pharmaceuticals in surface water using a combination of membrane assisted solvent extraction and a molecularly imprinted polymer.

This work demonstrates development and evaluation of a two-way technique based on the combination of membrane assisted solvent extraction and a molecularly imprinted polymer (MASE-MIP) for selective and efficient extraction of five selected pharmaceuticals belonging to five different therapeutic classes. The pharmaceuticals were extracted from surface water samples followed by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-qTOF/MS) determination. A central composite design was applied to optimize the influence of the sample salt content, the stirring rate, the stirring time and the amount of MIP on the extraction of an anticonvulsant (carbamazepine), a cardiac stimulant (etilefrine), a muscle relaxant (methocarbamol), an antiretroviral (nevirapine) and an antidepressant (venlafaxine) from surface water. Optimization of the analytical method was performed by spiking water with a mixture of all five pharmaceuticals at 500 ng mL-1. Optimum extraction conditions for a sample volume of 18 mL were found to be 5 g of salt content, a stirring rate of 400 rpm, an extraction time of 60 min and 50 mg of MIP. The MASE-MIP-LC-qTOF/MS method gave detection and quantification limits ranging from 0.09 to 0.20 ng mL-1 and 0.31-0.69 ng mL-1, respectively. The spiked river water samples yielded recoveries ranging from 38 to 91% for the selected model compounds belonging to the five classes of pharmaceuticals. Upon the application of the developed analytical method in water analysis, all selected pharmaceuticals were detected in South African river water with nevirapine and venlafaxine being more prominent attaining the maximum concentrations of 1.64 and 2.48 ng mL-1, respectively.

Solid State Characterization and Dissolution Enhancement of Nevirapine Cocrystals.

Purpose: Novel cocrystals of nevirapine (NP) were designed and prepared with salicylamide and 3-hydroxy benzoic acid (3-HBA). Methods: The cocrystals were prepared by solvent drop grinding method by adding few drops of acetone to enhance the solubility and dissolution. The drug and cocrystals were characterized by differential scanning calorimetry (DSC) and powder x-ray diffraction (PXRD). The solubility of NP, its wet ground form, and cocrystals were investigated at different pH. Moreover, the effect of surfactant on solubility of cocrystals was also studied. Finally, intrinsic dissolution rate (IDR) and stability of cocrystals was examined. Results: The characterization of cocrystals by DSC and PXRD revealed formation of new solid forms due to changes in thermogram and PXRD pattern. The cocrystal of NP with 3-HBA showed 4.5 folds greater solubility in pH 1.2 buffer and 5.5 folds in 1% Tween 80 as compared to original drug. IDR of cocrystals was higher than the pure drug in 0.1 N hydrochloric acid (HCl). Moreover, cocrystals were found physically stable after 3 months as evident from unchanged IDR. Conclusion: Hence, the present research indicates the new stable solid forms of NP with improved dissolution rate than pure drug.