Search

The human T-lymphotropic virus type 1 (HTLV-1) infects millions of people globally and is endemic to various resource-limited regions. Infections persist for life and are associated with increased susceptibility to opportunistic infections and severe diseases including adult T cell leukemia/lymphoma and HTLV-1-associated myelopathy-tropical spastic paraparesis. No HTLV-1-specific anti-retrovirals have been developed and it is unclear whether existing anti-retrovirals developed for treatment of human immunodeficiency virus (HIV) have efficacy against HTLV-1. To understand the structural basis for therapeutic binding, homology modelling and machine learning were used to develop a structural model of the HTLV-1 reverse transcriptase. With this, molecular docking experiments using a panel of FDA-approved inhibitors of viral reverse transcriptases to assess their capacity for binding, and in turn, inhibition. Importantly, nucleoside/nucleotide reverse transcriptase inhibitor but not non-nucleoside reverse transcriptase inhibitors were predicted to bind the HTLV-1 reverse transcriptase, with similar affinity to HIV-1 reverse transcriptase. By strengthening the rationale for clinical testing of therapies such as tenofovir alafenamide, zidovudine, lamivudine, and azvudine for treatment of HTLV-1, this study has demonstrated the power of in silico structural biology approaches in drug design and therapeutic testing. [ABSTRACT FROM AUTHOR]

Background: There is limited data on dolutegravir (DTG)-associated weight gain from settings with a dual burden of HIV and overnutrition. Methods: In Eswatini (at Matsanjeni), among 156 and 160 adult patients on DTG-based and EFV-based antiretroviral therapy (ART), respectively, we studied excessive weight gain (BMI at 24 months ART greater than baseline and ≥25 kg/m2). Results: The median BMI increase in DTG-based patients was 1.09 (IQR:-0.28,3.28) kg/m2 compared to 0.20 (IQR:-0.85,2.18) kg/m2 in EFV-based patients (p value = 0.001). DTG-based ART predicted excessive weight gain (aOR 2.61;95% CI:1.39–4.93). Conclusion: Practitioners should consider DTG-based regimens as one of the risk factors for overweight/obesity. [ABSTRACT FROM AUTHOR]

Tanzania adopted a Dolutegravir (DTG)-based regimen as first-line treatment in 2019 following the World Health Organization recommendation. Data on the DTG safety profile from sub-Saharan Africa including Tanzania are limited. We investigated the incidence of DTG-related adverse events (AEs) and associated factors among people living with HIV (PLHIV) initiated on a DTG regimen. A prospective cohort study was conducted from 25 Care and Treatment Clinics in mainland Tanzania. PLHIV aged 12 years and above who were initiated on a DTG-based regimen were actively followed up for three months. The Cox regression model was used to determine the predictors of occurrence of AEs over time. A p-value of 0.05 was considered statistically significant. From January 2020 to June 2022, a cohort of 935 participants who were both newly diagnosed and ART-experienced who transitioned to a DTG-based regimen was enrolled. Out of 935 participants, 59 (6.3%) reported a total of 62 AEs. The most frequently experienced AE was skin itching and rashes (15/62; 24.2%). DTG-associated neuropsychiatric AEs were less common and included headache (6 [9.6%]) and sleep disturbances (3 [4.8%]). The overall incidence of occurrence of the first AEs was 96.7 per 1000 person-months [95% C.I: 74.4–125.7] with the highest incidence observed among the elderly (≥ 60 years). Individuals on WHO HIV Clinical Stage 2 had a 2.7 significantly higher risk of developing AEs (adjusted hazard ratio = 2.73, 95% CI = 1.46–5.12, p = 0.017). We report a low incidence of grade I (mild) and grade II (moderate) DTG-associated AEs suggesting that the regimen is generally safe in the population. Continued monitoring of DTG safety in the population is recommended. [ABSTRACT FROM AUTHOR]

Glasdegib (DAURISMO) is a hedgehog pathway inhibitor approved for the treatment of acute myeloid leukemia (AML). Cytochrome P450 3A4 (CYP3A4) has been identified as a major metabolism and clearance pathway for glasdegib. The role of CYP3A4 in the clearance of glasdegib has been confirmed with clinical drug–drug interaction (DDI) studies following the coadministration of glasdegib with the strong CYP3A4 inhibitor ketoconazole and the strong inducer rifampin. To evaluate potential drug interactions with CYP3A4 modulators, the coadministration of glasdegib with a moderate CYP3A4 inducer, efavirenz, was evaluated using physiologically based pharmacokinetic (PBPK) modeling using the Simcyp simulator. The glasdegib compound file was developed using measured physicochemical properties, data from human intravenous and oral pharmacokinetics, absorption, distribution, metabolism, and excretion studies, and in vitro reaction phenotyping results. The modeling assumptions, model parameters, and assignments of fractional CYP3A4 metabolism were verified using results from clinical pharmacokinetics (PK) and DDI studies with ketoconazole and rifampin. The verified glasdegib and efavirenz compound files, the latter of which was available in the Simcyp simulator, were used to estimate the potential impact of efavirenz on the PK of glasdegib. PBPK modeling predicted a glasdegib area under the concentration–time curve ratio of 0.45 and maximum plasma concentration ratio of 0.75 following coadministration with efavirenz. The PBPK results, in lieu of a formal clinical study, informed the drug label, with the recommendation to double the clinical dose of glasdegib when administered in conjunction with a moderate CYP3A4 inducer, followed by a resumption of the original dose 7 days post‐discontinuation. [ABSTRACT FROM AUTHOR]

Poor aqueous solubility often results in poor dissolution behavior and, consequently, poor bioavailability for those drugs whose intestinal absorption is dissolution rate limited. It is essential for formulation scientists to identify strategies to improve the solubility and dissolution rate of candidate drugs in order to improve their bioavailability. The present study investigated electrospun polymeric nanofibers for efavirenz (an antiretroviral drug), a Class II drug in the Biopharmaceutical Classification System. In order to fabricate nanofibers, hydrophilic spinnable polymer like Soluplus was used. Statistical design of experiments was used to optimize electrospinning parameters. Scanning electron microscopy (SEM) studies confirmed the presence of nanofibrous material in the mat. The x-ray diffraction (XRD) and differential scanning calorimetry (DSC) studies advocated the amorphization of efavirenz in the nanofiber samples. The optimized nanofiber-based platform significantly improved in vitro dissolution of efavirenz (89.0 ± 3.2% in 120 minutes) compared to pure efavirenz crystals (27.3 ± 2.4%). [ABSTRACT FROM AUTHOR]

Context: Combating human immunodeficiency virus/acquired immunodeficiency syndrome epidemic has been possible due to advances in prevention strategies and Antiretroviral therapy (ART). Optimal adherence to ART is a major factor in achieving the desired immunological, virological, and patient well‑being outcomes. Several socio‑demographic, patient, treatment, and health‑care system‑related factors influence nonadherent behavior to ART. Aims: This study was planned to assess (1) ART adherence level, (2) factors and reasons associated with nonadherence, and (3) impact of suboptimal adherence on treatment outcomes. Settings and Design: This was a cross‑sectional analytical study of 300 patients in a tertiary care hospital in Puducherry, India. Methods: Random sampling was used to collect data from patient treatment cards and a predesigned structured questionnaire. The pill count method was used to calculate adherence level. Statistical Analysis Used: Nonadherence was chosen as a dependent variable and factors affecting adherence were chosen as independent variables. Test for significance was carried out by Chi‑square test and Fisher’s exact test. Results: Optimal adherence was seen in 68.3%. Factors significantly associated with nonadherence were lower education level, high prior CD4 count, irregular follow‑up, missing doses in the past, and being late for pharmacy pill refills. Adherence was positively associated with mean increase in CD4 count over 6 months. Conclusions: In our study, the adherence rate is suboptimal which can lead to failure of ART. Nonadherence was associated with a decrease in CD4 count overtime. Most of the factors significantly affecting ART adherence were patient behavior related. These factors can be used for target intervention during reinforcement adherence counseling. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non‐nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti‐HIV drugs. Zidovudine, didanosine, and stavudine are FDA‐approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA‐approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV‐1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA‐approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART). [ABSTRACT FROM AUTHOR]

Aim: To retrospectively assess the efficacy and safety of sofosbuvir/velpatasvir for hepatitis C virus (HCV) genotype 3b in HIV-infected patients receiving antiretroviral therapy (ART) treatment of lamivudine/tenofovir disoproxil fumarate/efavirenz. Methods: The primary end point of HCV treatment was estimated by sustained virologic response 12 weeks after treatment (SVR12). Results: Sixteen subjects who were followed up for 48 weeks after treatment were included. The SVR12 and SVR48 were 87.5% (95% CI: 60.4–97.8%) and 81.3% (95% CI: 53.7–95.0%), respectively. One patient experienced persistent low-level viremia of HIV after 12 weeks of treatment. Conclusion: 12 weeks of sofosbuvir/velpatasvir is safe but has limited efficacy for HCV GT3b in HIV-infected patients receiving ART regimen including efavirenz, especially among patients with baseline HCV RNA≥6.0 log10 IU/ml. [ABSTRACT FROM AUTHOR]

Antiretroviral therapy-linked metabolic abnormalities have become a growing concern among people living with HIV. There is limited data regarding the effects of dolutegravir-based treatment on blood glucose levels and serum lipid profiles in people living with HIV in Ethiopia. Thus, this study aimed to assess blood glucose levels and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based therapy. An institutional-based comparative cross-sectional study was conducted from 30 June 2021 to 30 August 2021. A total of 128 participants (64 in the dolutegravir-based group and 64 in the efavirenz-based group) were enrolled in the study. The Chi-square, independent t-test, Mann–Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 26.0 for this study. A p-value of <0.05 was considered statistically significant. The prevalence of hyperglycemia and dyslipidemia were 17.2% (11/64) and 79.7% (51/64) in the dolutegravir group, and 9.4% (6/64) and 75% (48/64) in the efavirenz group, respectively. The efavirenz group had significantly higher mean values of total cholesterol (190.73 ± 44.13 vs. 175.27 ± 37.67 mg/dl, p = 0.035) and high-density lipoprotein (47.53 ± 14.25 vs. 40.92 ± 13.17 mg/dl, p = 0.007) than the dolutegravir group. For a Kg/m2 increase in BMI and for each month's increase in the duration of HIV, the patients were 66% (AOR = 1.66, 95% CI: 1.13, 2.44), and 13% (AOR = 1.13, 95% CI: 1.03, 1.23) more likely to have hyperglycemia, respectively. In contrast, female patients were 3.04 times more likely to have dyslipidemia (AOR = 3.03, 95% CI: 1.14, 8.05) as compared to male patients, and with an increase in CD4 cell count of 1 cell/mm3, the odds of dyslipidemia increased by 0.3% (AOR = 1.003, 95% CI: 1.001, 1.006). Efavirenz-based therapy resulted in higher mean values of total cholesterol and high-density lipoprotein as compared with dolutegravir-based therapy. It is important to consider and evaluate high-density lipoprotein levels in HIV patients on dolutegravir-based therapy, and total cholesterol levels in people living with HIV on efavirenz-based therapy. The long-term use of ART is thought to be one of the potential causes of metabolic abnormalities such as dysregulation of glucose and lipid metabolism. The burden of DTG-based cART-related metabolic abnormalities in resource-limited settings has not been well characterized. This study aimed to address these gaps by assessing blood glucose levels and serum lipid profiles among people living with HIV on DTG-based versus EFV-based regimens and identifying factors associated with hyperglycemia and dyslipidemia. [ABSTRACT FROM AUTHOR]

Aims: Intramuscular cabotegravir/rilpivirine (IM CAB/RPV) are metabolized by UGT1A1/CYP3A4. Efavirenz induces both enzymes; therefore, switching from an efavirenz‐containing regimen to IM CAB/RPV could possibly result in suboptimal levels. Due to their long dosing interval, clinical studies with IM CAB/RPV are challenging. We used physiologically based pharmacokinetics (PBPK) modelling to simulate the switch from efavirenz to IM CAB/RPV. Methods: First, we developed the drug models and verified the performance of the PBPK model to predict the pharmacokinetics of IM cabotegravir, IM rilpivirine and efavirenz by comparing the simulations against observed clinical data. Second, we verified the ability of the model to predict the effect of residual induction with observed data for the switch from efavirenz to dolutegravir or rilpivirine. Finally, we generated a cohort of 100 virtual individuals (20–50 years, 50% female, 18.5–30 kg/m2) to simulate IM CAB/RPV concentrations after discontinuing efavirenz in extensive and slow metabolizers of efavirenz. Results: IM CAB concentrations were predicted to decrease by 11% (95% confidence interval 7–15%), 13% (6–21%) and 8% (0–18%) at day 1, 7 and 14 after efavirenz discontinuation. CAB concentrations were predicted to remain above the minimal efficacy threshold (i.e., 664 ng/mL) throughout the switch period both in extensive and slow metabolizers of efavirenz. Similarly, IM RPV concentrations were modestly decreased with the lowest reduction being 10% (6–14%) on day 7 post last efavirenz dose. Conclusion: Our simulations indicate that switching from an efavirenz‐containing regimen to IM CAB/RPV does not put at risk of having a time window with suboptimal drug levels. [ABSTRACT FROM AUTHOR]

Background Switching from non-nucleoside reverse transcriptase inhibitor (NNRTI)–based regimens to dolutegravir (DTG) has been associated with greater weight gain. Methods We conducted our analysis using a longitudinal cohort of people with HIV (PWH) in Western Kenya. We evaluated changes in the rate of weight gain among treatment-experienced, virally suppressed PWH who switched from NNRTI to tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD). We modeled the weights pre- and postswitch using a 2-phase model with linear trend preswitch and an inverted exponential function postswitch. We estimated an 18-month excess weight gain by comparing the projected weight with that expected using the preswitch rate. Results A total of 18 662 individuals were included in our analysis, with 55% switching from efavirenz (EFV) and 45% from nevirapine (NVP). Of the studied individuals, 51% were female, and the median age and body mass index (BMI) were 51 years and 22 kg/m2, respectively. For the overall population, the rate of weight gain increased from 0.47 kg/year preswitch to 0.77 kg/year, with higher increases for females (0.57 kg/year to 0.96 kg/year) than males (0.34 kg/year to 0.62 kg/year). The rate of weight gain for individuals switching from EFV-based regimens significantly increased from 0.57 kg/year preswitch to 1.11 kg/year postswitch but remained stable at 0.35 kg/year preswitch vs 0.32 kg/year postswitch for individuals switching from NVP-based regimens. Conclusions Switching from NNRTI-based regimens to TLD is associated with a modest increase in the rate of weight gain, with the preswitch NNRTI being the key determinant of the amount of weight gain experienced postswitch. [ABSTRACT FROM AUTHOR]

Unannounced phone-based pill counts (UPC) are an objective measure of medication adherence that may be used in resource limited settings. The current study reports the feasibility and validity of UPC for monitoring antiretroviral therapy (ART) adherence among people living with HIV in South Africa. People living with HIV (N = 434) in an economically impoverished township and receiving ART for at least 3-months completed: two UPC in a one-month period; measures of clinic and medication experiences; and provided blood samples for HIV viral load and CD4 testing. Analyses compared two methods for managing values of over-dosing (> 100%), specifically censoring values to 100% (> 100% = 100%) vs. subtracting over-dosing from two months of perfect adherence (200% - > 100% value). Findings showed that two UPC calls were successfully completed with 91% of participants in a one-month period. The average number of call attempts needed to reach participants was 2.4. Results showed that lower UPC adherence was significantly associated with male gender, alcohol use, higher HIV viral loads, lower CD4 cell counts, running out of ART, and intentionally not taking ART. Comparisons of methods for adjusting over-dosing found subtraction yielding a better representation of the data than censoring. UPC were demonstrated feasible and valid with patients receiving ART in a resource limited setting and offers a viable method for objectively measuring ART adherence in these settings. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.

Abstract Introduction In 2018, the Malawi Ministry of Health adopted the recommendation to switch first-line antiretroviral therapy (ART) from an efavirenz (EFV)-based to a dolutegravir (DTG)-based regimen. Little is known about patients’ experience during this transition. We conducted a qualitative study to explore DTG-related counselling challenges among providers of HIV care and factors influencing regimen switching or non-switching among women living with HIV in Lilongwe, Malawi. Methods Between February-July 2020, we recruited participants who took part in DTG counselling on reasons to switch, side effects, and benefits from two government health facilities providing HIV care: Area 18 health centre and Bwaila district hospital in Lilongwe, Malawi. We purposively sampled and interviewed 8 women living with HIV who remained on an EFV-based regimen after counselling, 10 women who switched to a DTG-based regimen, and 10 HIV care providers who provided counselling about ART switching. In-depth interviews were used to explore patient’s perceptions of DTG, factors affecting the decision to switch, and both patient and provider experience with counselling. Interview data was coded for themes using inductive and deductive codes. Interviews were conducted until thematic saturation was achieved. Data matrices were used for analysis and thematic extraction. Results Most women in both groups were well versed on DTG’s potential side effects and felt well counselled on the benefits of switching, such as quicker viral load suppression. Many women associated DTG with birth defects and expressed concern. However, the primary reason for not switching was concern with how the new medication would be tolerated, especially when they were satisfied with their current regimen. Almost all providers expressed difficulty providing DTG counselling. Primary reasons included feeling inadequately trained and/or not having resources to use during counselling, such as diagrams or brochures. Conclusion DTG counselling was well accepted by women; however, some felt that their concerns were not fully addressed. Providers reflected this sentiment in that they did not feel adequately trained or well-equipped to provide adequate counselling. Training on counselling for new ART regimens should be intensified and utilize patient-centered educational materials to address the concerns raised by both patients and health care providers.

ObjectivesLong-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics.Study designWe enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression.ResultsWe collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion.ConclusionsUnlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations.ImplicationsThe findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives.

A small dose of the anti-HIV drug efavirenz (EFV) was previously discovered to activate CYP46A1, a cholesterol-eliminating enzyme in the brain, and mitigate some of the manifestation of Alzheimer's disease in 5XFAD mice. Herein, we investigated the retina of these animals, which were found to have genetically determined retinal vascular lesions associated with deposits within the retinal pigment epithelium and subretinal space. We established that EFV treatment activated CYP46A1 in the retina, enhanced retinal cholesterol turnover, and diminished the lesion frequency >5-fold. In addition, the treatment mitigated fluorescein leakage from the aberrant blood vessels, deposit size, activation of retinal macrophages/microglia, and focal accumulations of amyloid β plaques, unesterified cholesterol, and Oil Red O-positive lipids. Studies of retinal transcriptomics and proteomics identified biological processes enriched with differentially expressed genes and proteins. We discuss the mechanisms of the beneficial EFV effects on the retinal phenotype of 5XFAD mice. As EFV is an FDA-approved drug, and we already tested the safety of small-dose EFV in patients with Alzheimer's disease, our data support further clinical investigation of this drug in subjects with retinal vascular lesions or neovascular age-related macular degeneration.

BackgroundPreventing unintended pregnancies is paramount for women living with HIV (WLHIV). Previous studies have suggested that efavirenz-containing antiretroviral therapy (ART) reduces contraceptive effectiveness of implants, but there are uncertainties regarding the quality of the electronic medical record (EMR) data used in these prior studies.MethodsWe conducted a retrospective, cohort study of EMR data from 2011 to 2015 among WLHIV of reproductive age accessing HIV care in public facilities in western Kenya. We validated a large subsample of records with manual chart review and telephone interviews. We estimated adjusted incidence rate ratios (aIRRs) with Poisson regression accounting for the validation sampling using inverse probability weighting and generalized raking.ResultsA total of 85,324 women contributed a total of 170,845 women-years (w-y) of observation time; a subset of 5080 women had their charts reviewed, and 1285 underwent interviews. Among implant users, the aIRR of pregnancy for efavirenz- vs. nevirapine-containing ART was 1.9 (95% CI 1.6, 2.4) using EMR data only and 3.2 (95% CI 1.8, 5.7) when additionally using both chart review and interview validated data. Among efavirenz users, the aIRR of pregnancy for depomedroxyprogesterone acetate (DMPA) vs. implant use was 1.8 (95% CI 1.5, 2.1) in EMR only and 2.4 (95% CI 1.0, 6.1) using validated data.ConclusionPregnancy rates are higher when contraceptive implants are concomitantly used with efavirenz-containing ART, though rates were similar to leading alternative contraceptive methods such as DMPA. Our data provides policymakers, program staff, and WLHIV greater confidence in guiding their decision-making around contraceptive and ART options. Our novel, 3-phase validation sampling provides an innovative tool for using routine EMR data to improve the robustness of data quality.

Background: Levonorgestrel implant is a highly effective hormonal contraceptive, but its efficacy may be compromised when used with cytochrome enzyme inducers such as efavirenz. The primary aim of this study was to evaluate methods of mitigating the drug interaction. Methods: Using a physiologically-based pharmacokinetic (PBPK) model for levonorgestrel that we developed within the Simcyp® program, we evaluated a higher dose of levonorgestrel implant, a lower dose of efavirenz, and the combination of both, as possible methods to mitigate the interaction. In addition, we investigated the impact on levonorgestrel total and unbound concentrations of other events likely to be associated with efavirenz coadministration: changes in plasma protein binding of levonorgestrel (as with displacement) and high variability of efavirenz exposure (as with genetic polymorphism of its metabolism). The range of fraction unbound tested was 0.6% to 2.6%, and the range of efavirenz exposure ranged from the equivalent of 200 mg to 4800 mg doses. Results: Levonorgestrel plasma concentrations at any given time with a standard 150 mg implant dose are predicted to be approximately 68% of those of control when given with efavirenz 600 mg and 72% of control with efavirenz 400 mg. With double-dose levonorgestrel, the predictions are 136% and 145% of control, respectively. A decrease in levonorgestrel plasma protein binding is predicted to primarily decrease total levonorgestrel plasma concentrations, whereas higher efavirenz exposure is predicted to decrease total and unbound concentrations. Conclusions: Simulations suggest that doubling the dose of levonorgestrel, particularly in combination with 400 mg daily efavirenz, may mitigate the drug interaction. Changes in levonorgestrel plasma protein binding and efavirenz genetic polymorphism may help explain differences between model predictions and clinical data but need to be studied further.

Most HIV-antiretroviral drugs have adverse effects. Efavirenz (EFV) is an example of a drug with neuropsychiatric effects, such as anxiety, depression, and suicidal thoughts, in people living with HIV (PLWH). The mechanisms by which EFV causes neuropsychiatric alterations in PLWH are complex, multifactorial, and not fully understood, although several studies in animals have reported changes in brain energy metabolism, alterations in monoamine turnover, GABA, and glutamate levels, and changes in 5-HT receptors. In this report, we studied the effects of EFV on the serotonergic system in healthy mice, specifically, whether EFV results in alterations in the levels of the tryptophan hydroxylase 2 (Tph2) gene in the brain. EFV (10 mg/kg) and distilled water (1.5 µL/kg) (control group) were orally administered to the mice for 36 days. At the end of the treatment, Tph2 expression levels in mouse brains were measured, and mood was evaluated by three trials: the forced swim test, elevated plus maze, and open field test. Our results revealed dysregulation of Tph2 expression in the brainstem, amygdala, and hypothalamus in the EFV group, and 5-HT levels increased in the amygdala in the EFV group. In the behavioral tests, mice given EFV exhibited a passive avoidance response in the forced swim test and anxiety-like behavior in the elevated plus maze, and they lost weight. Herein, for the first time, we showed that EFV triggered dysregulation of the Tph2 gene in the three serotonergic areas studied; and 5-HT levels increased in the amygdala using the ELISA method. However, further studies will be necessary to clarify the increase of 5-HT in the amygdala as well as understand the paradoxical decrease in body weight with the simultaneous increase in food consumption. It will also be necessary to measure 5-HT by other techniques different from ELISA, such as HPLC.

Physiologically based pharmacokinetic (PBPK) models were utilized to investigate potential interactions between aflatoxin B1 (AFB1) and efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor drug and inducer of several CYP enzymes, including CYP3A4. PBPK simulations were conducted in a North European Caucasian and Black South African population, considering different dosing scenarios. The simulations predicted the impact of EFV on AFB1 metabolism via CYP3A4 and CYP1A2. In vitro experiments using human liver microsomes (HLM) were performed to verify the PBPK predictions for both single- and multiple-dose exposures to EFV. Results showed no significant difference in the formation of AFB1 metabolites when combined with EFV (0.15 µM) compared to AFB1 alone. However, exposure to 5 µM of EFV, mimicking chronic exposure, resulted in increased CYP3A4 activity, affecting metabolite formation. While co-incubation with EFV reduced the formation of certain AFB1 metabolites, other outcomes varied and could not be fully attributed to CYP3A4 induction. Overall, this study provides evidence that EFV, and potentially other CYP1A2/CYP3A4 perpetrators, can impact AFB1 metabolism, leading to altered exposure to toxic metabolites. The results emphasize the importance of considering drug interactions when assessing the risks associated with mycotoxin exposure in individuals undergoing HIV therapy in a European and African context.

In an analysis of randomized trials, use of efavirenz for treatment of human immunodeficiency virus (HIV) infection was associated with increased suicidal thoughts/behaviors. However, analyses of observational data have found no evidence of increased risk. To assess whether population differences might explain this divergence, we transported the effect of efavirenz use from these trials to a specific target population. Using inverse odds weights and multiple imputation, we transported the effect of efavirenz on suicidal thoughts/behaviors in these randomized trials (participants were enrolled in 2001-2007) to a trials-eligible cohort of US adults initiating antiretroviral therapy while receiving HIV clinical care at medical centers between 1999 and 2015. Overall, 8,291 cohort participants and 3,949 trial participants were eligible. Prescription of antidepressants (19% vs. 13%) and injection drug history (16% vs. 10%) were more frequent in the cohort than in the trial participants. Compared with the effect in trials, the estimated hazard ratio for efavirenz on suicidal thoughts/behaviors was attenuated in our target population (trials: hazard ratio (HR) = 2.3 (95% confidence interval (CI): 1.2, 4.4); transported: HR = 1.8 (95% CI: 0.9, 4.4)), whereas the incidence rate difference was similar (trials: HR = 5.1 (95% CI: 1.6, 8.7); transported: HR = 5.4 (95% CI: -0.4, 11.4)). In our target population, there was greater than 20% attenuation of the hazard ratio estimate as compared with the trials-only estimate. Transporting results from trials to a target population is informative for addressing external validity.

Tongtong Wang,1,&ast; Yingchu Liu,2,&ast; Chunyu Zhu,1,&ast; Siyuan Yang,3 Di Yang,4 Jiang Xiao,4 Guiju Gao4 1Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 2School of General Practice and Continuing Education, Capital Medical University, Beijing, People’s Republic of China; 3Laboratory of Infectious Diseases Center, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China; 4Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guiju Gao, Professor of Medicine Clinical and Research Center of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, No. 8, Jingshun Dongjie, Chaoyang District, Beijing, 100015, People’s Republic of China, Email guiju.gao@163.comBackground: Rifampicin is a known inducer of the cytochrome P450 (CYP2B6) enzyme, which can lead to a decrease in the concentration of efavirenz. Therefore, we conducted a study to evaluate the effect of daily rifampicin intake on efavirenz 600mg pharmacokinetics and HIV-1 virological suppression.Methods: Patients receiving antiretroviral therapy containing efavirenz (600mg daily), and we collected efavirenz concentration at four visit points: ART day 14 (PK1), ART day 42 (PK2), ART day 140 (PK3), and ART day 336 (PK4), and performed pharmacokinetics analysis.Results: From February 2017 to November 2020, 29 HIV/TB co-infection patients were included. Ninety percent of patients had a concentration of ≥ 1000ng/mL of efavirenz during the study. All patients had efavirenz Cmax ≥ 1000ng/mL, 86% patients showed good virology response.Conclusion: Our study shows that the use of rifampicin in HIV/TB co-infection patients does not affect efavirenz drug concentrations, that virological suppression is good and that no efavirenz dose adjustment is required.Keywords: HIV/TB, rifampicin, efavirenz, pharmacokinetics

BackgroundCurrently, integrase inhibitors (INIs)-based ART regimens are the preferred initial therapy for AIDS patients. There is scarce information on the use of dolutegravir (DTG) among late-presenter people living with HIV (PLHIV).ObjectivesTo compare the effect of DTG- or efavirenz (EFV)-based regimens on the outcomes of patients with advanced AIDS.MethodsWe compared two cohorts of consecutive symptomatic AIDS patients (WHO stage 4, CD4 count 200 cells/mL compared to the EFV group at 48 weeks (45% vs. 29%, p = 0.03). Treatment changes (ITT, M = F) were significantly more frequent in the EFV group (1% vs. 17%, p

BackgroundThe newly approved third-generation oral anti-HIV-1 drug, ainuovirine (ANV), was used in combination with nucleoside reverse transcriptase inhibitors (NRTIs) in our study, and its effects on the lipid profile of antiretroviral-experienced HIV/AIDS patients are unclear.ObjectivesThis study aimed to examine the effects of antiretroviral agents on the lipid profile in patients with HIV/AIDS.MethodsWe conducted a real-world prospective study involving treatment-naive and treatment-experienced adult participants living with HIV-1 infection provided with ANV- or efavirenz (EFV)-based regimens. The primary endpoint was the proportion of participants with an HIV-1 RNA level of

This article aims to analyze the development of a rapid and sensitive HPLC–MS/MS method for quantification of efavirenz in rat plasma. The developed method included a liquid-liquid extraction process with methyl-tert-butyl ether solution, where hydrochlorothiazide was used as internal standard. The analyte was separated on an ACE Phenyl C18 column and eluted by a system consisting of mobile phase A (0.2% acetic acid) and mobile phase B (acetonitrile) at a proportion of 35:65 (v/v), pumped with a flow rate of 1.0 mL min-1 (run time < 4 min). Mass spectrometric detection was performed on a triple quadrupole instrument using multiple reaction monitoring. The electrospray ionization source was performed in negative ion mode. The precursor/product ion pairs monitored were m/z 313.644→68.800 and m/z 295.541→268.700 for efavirenz and internal standard, respectively. The limit of quantification was 10.0 ng mL-1 and calibration curves were linear over 10.0–1,500 ng mL-1. Intra-day and inter-day precision at three levels were 1.80–10.49% and 4.72–10.28%, respectively. Accuracy ranged between 93.54% and 105.73%. Finally, the described method was applied to rats administered with efavirenz, demonstrating the suitability for quantification of efavirenz in a pharmacokinetic study. Therefore, it can be used in normal, hemolyzed or lipemic samples for efavirenz quantification.

AbstractBackground Antiretroviral therapy-linked metabolic abnormalities have become a growing concern among people living with HIV. There is limited data regarding the effects of dolutegravir-based treatment on blood glucose levels and serum lipid profiles in people living with HIV in Ethiopia. Thus, this study aimed to assess blood glucose levels and serum lipid profiles among people living with HIV on dolutegravir-based versus efavirenz-based therapy.Method and materials An institutional-based comparative cross-sectional study was conducted from 30 June 2021 to 30 August 2021. A total of 128 participants (64 in the dolutegravir-based group and 64 in the efavirenz-based group) were enrolled in the study. The Chi-square, independent t-test, Mann–Whitney U-test, and logistic regression were used as appropriate statistical tests using SPSS Version 26.0 for this study. A p-value of

Introduction: To examine electroencephalogram (EEG) as a diagnostic tool for late-onset efavirenz (EFV) neurotoxicity syndrome (LENS), an uncommon but severe and potentially fatal complication of EFV therapy. Methods: We conducted a Retrospective case-control study. EEGs from confirmed cases of LENS (clinical syndrome and plasma EFV >4ug/mL) recorded from June 2016 to May 2021 were compared with control EEGs from the same time-period. Controls were adults (18–70 years) with a similar indication for EEG (eg. encephalopathy or confusion), dysrhythmia generalised grade II, and LENS excluded. EEGs were reviewed by two blinded interpreters given a description of the characteristic EEG changes, ie. persistent, diffuse, high voltage, bisynchronous, monomorphic 4–7 Hz theta frequency waveforms with transient attenuation on eye opening. Interpreters were asked to determine whether EEGs showed definite, probable or no changes. Results: Thirteen LENS cases were compared with 50 control EEGs. Interpreter 1 labelled 11/13 LENS cases as having define or probable changes, and interpreter 2 labelled 10/13. Interpreter 1 labelled probable changes in 1/50 controls and interpreter 2 in 3/50. Neither interpreter labelled any controls as having definite changes. Interrater reliability was good with 95% agreement and a Cohen's kappa of 0.83. Sensitivity of EEG under these conditions for the diagnosis of LENS was 85% and 77% for interpreters 1 and 2 respectively, and specificity was 98% and 94%. Conclusions: EEG is a useful tool in the diagnosis of LENS which can be used to aid clinical decisions while awaiting EFV levels, or in low-resource settings where EFV levels are not available. [ABSTRACT FROM AUTHOR]

A simple, rapid chemical coating and patterning method was developed and optimized for paper-based substrates for use in paper spray mass spectrometry (PS-MS). A variety of chlorosilanes were explored for coating paper substrates, and their effectiveness in forming hydrophobic surfaces was characterized via contact angle goniometry, scanning electron microscopy, and energy dispersive X-ray spectroscopy. Trichloromethylsilane was selected as the primary coating agent because of the short time required to produce a hydrophobic surface (contact angle > 130°), as well as the ease of patterning. Patterning was performed using 3D-printed masks and an oxygen/plasma cleaner. Optimal mask thickness and oxygen/plasma cleaning parameters were determined to produce channels varying from 0.5 to 2.5 mm in width. The effectiveness of the patterned substrates for PS-MS was determined via analysis of four antiretrovirals: emtricitabine, lamivudine, efavirenz, and dolutegravir. Calibration curves were made for each antiretroviral at varying channel widths, and the limits of detection and limits of quantification for each drug were determined. These results show that this patterning method results in an average 7.2-fold improvement in sensitivity and an average 190-fold improvement in limits of detection over uncoated paper substrates in a neat matrix. In a proof-of-concept experiment, calibration curves were generated for each antiretroviral in urine. A patterned paper substrate with a 2-mm channel resulted in an average 7.4-fold improvement in sensitivity and an average 18-fold improvement in limits of detection over uncoated paper substrates. [ABSTRACT FROM AUTHOR]

Efavirenz (EFV), a widely prescribed antiviral medication, has been implicated in dyslipidemia and can activate the pregnane X receptor (PXR), leading to hepatic steatosis and hypercholesterolemia in mice. Resveratrol (RES) can ameliorate hepatic steatosis and functions as a partial PXR agonist, capable of mitigating PXR expression induced by other PXR agonists. Therefore, we hypothesized that RES could attenuate EFV-induced hepatic steatosis and hypercholesterolemia by downregulating PXR expression and suppressing inflammatory cytokine production. Here, we conducted an in vivo study involving 6-week-old male mice, which were divided into 4 groups for a 7-day intervention: control (carrier solution), EFV (80 mg/kg), RES (50 mg/kg), and RES + EFV groups. Serum and hepatic tissue samples were collected to assess cholesterol and triglyceride concentrations. Hepatic lipid accumulation was evaluated through hematoxylin-eosin and oil red O staining. Polymerase chain reaction and western blot were performed to quantify hepatic inflammatory factors, lipogenic gene, and PXR expression. Our results indicated that hepatic lipid droplet accumulation was reduced in the RES + EFV group compared with the EFV group. Similarly, the expressions of hepatic inflammatory factors were attenuated in the RES + EFV group relative to the EFV group. Furthermore, RES counteracted the upregulation of hepatic lipid-metabolizing enzymes induced by EFV at both the transcriptional and protein levels. Importantly, PXR expression was downregulated in the RES + EFV group compared with the EFV group. Conclusively, our findings suggest that RES effectively mitigates EFV-induced hepatic steatosis and hypercholesterolemia by inhibiting PXR activation and decreasing inflammation. RES confers a protective effect against EFV-induced hepatic steatosis. Specifically, EFV treatment leads to the upregulation of PXR and pro-inflammatory cytokines, which modulates hepatic lipid metabolic enzymes (CD36, CPT2, SQLE, SRBI), leading to liver steatosis. Remarkably, RES counteracts these adverse effects by downregulating PXR expression and attenuating hepatic inflammation, thereby restoring the expression of key enzymes involved in lipid metabolism. These mechanistic insights suggest that RES could be an effective therapeutic intervention for alleviating EFV-induced hepatic steatosis. Abbreviations: CD36, cluster of differentiation 36; CPT2, carnitine palmitoyltransferase 2; EFV, efavirenz; PXR, pregnane X receptor; RES, resveratrol; SQLE, squalene epoxidase; SRBI, scavenger receptor class B type I. [Display omitted] [ABSTRACT FROM AUTHOR]

Aims: Clinically significant interactions with food occur for more than half of antiretroviral drugs. Different physiochemical properties deriving from the chemical structures of antiretroviral drugs may contribute to the variable food effect. Chemometric methods allow analysing a large number of interrelated variables concomitantly and visualizing correlations between them. We used a chemometric approach to determine the types of correlations among different features of antiretroviral drugs and food that may influence interactions. Methods: Thirty‐three antiretroviral drugs were analysed: ten nucleoside reverse transcriptase inhibitors, six non‐nucleoside reverse transcriptase inhibitors, five integrase strand transfer inhibitors, ten protease inhibitors, one fusion inhibitor and one HIV maturation inhibitor. Input data for the analysis were collected from already published clinical studies, chemical records and calculations. We constructed a hierarchical partial least squares (PLS) model with three response parameters: postprandial change of time to reach maximum drug concentration (ΔTmax), albumin binding (%) and logarithm of partition coefficient (logP). Predictor parameters were the first two principal components of principal component analysis (PCA) models for six groups of molecular descriptors. Results: PCA models explained 64.4% to 83.4% of the variance of the original parameters (average: 76.9%), whereas the PLS model had four significant components and explained 86.2% and 71.4% of the variance in the sets of predictor and response parameters, respectively. We observed 58 significant correlations between ΔTmax, albumin binding (%), logP and constitutional, topological, hydrogen bonding and charge‐based molecular descriptors. Conclusions: Chemometrics is a useful and valuable tool for analysing interactions between antiretroviral drugs and food. [ABSTRACT FROM AUTHOR]

Nucleoside reverse transcriptase inhibitors are the first class of drugs to be approved by the FDA for the suppression of HIV-1 and are widely used for this purpose in combination with drugs of other classes. Despite the progress in HIV-1 treatment, there is still the need to develop novel efficient antivirals. Here the efficiency of HIV-1 inhibition by a set of original 5-substituted uridine nucleosides was studied. We used the replication deficient human immunodeficiency virus (HIV-1)-based lentiviral particles and identified that among the studied compounds, 2′,3′-isopropylidene-5-iodouridine was shown to cause anti-HIV-1 activity. Importantly, no toxic action of this compound against the cells of T-cell origin was found. We determined that this compound is significantly more efficient at suppressing HIV-1 compared to Azidothymidine (AZT) when taken at the high non-toxic concentrations. We did not find any profit when using AZT in combination with 2′,3′-isopropylidene-5-iodouridine. 2′,3′-Isopropylidene-5-iodouridine acts synergistically to repress HIV-1 when combined with the CDK4/6 inhibitor Palbociclib in low non-toxic concentration. No synergistic antiviral action was detected when AZT was combined with Palbociclib. We suggest 2′,3′-isopropylidene-5-iodouridine as a novel perspective non-toxic compound that may be used for HIV-l suppression. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) reverse transcriptase (RT) works in the life cycle of HIV and is one of the key targets for anti-HIV-1 drug development. Recently, a novel series of diarylpyrimidine derivatives (DAPYs) have been reported as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs), and they exhibit potent antiviral activity. Here we explored the binding interaction patterns of a set of 2,4,5-trisubstituted pyrimidine derivatives using molecular docking, three-dimensional quantitative structure–activity relationships (3D-QSAR), and molecular dynamics (MD) simulations. Molecular docking for exploring the mechanism of action of small molecule ligands with receptor proteins. Comparative molecular field (CoMFA q2 = 0.828, r2 = 0.988, r2pred = 0.981) and comparative molecular similarity index (CoMSIA q2 = 0.859, r2 = 0.968, r2pred = 0.980) were performed to build stable and reliable 3D-QSAR models. The contour plots revealed the relationship between structural features and inhibitory activities. Based on the molecular docking analysis and contour maps, some novel compounds with higher predicted activities were designed and further MD simulations and bind free energy calculations were performed. Our models results may provide an essential reference for the design and development of effective novel HIV-1 NNRTIs. [ABSTRACT FROM AUTHOR]

Background: We aimed in this article to assess the likeliness of efavirenz to induce functional senescence in Drosophila melanogaster (fruit fly). Methods: Ten different concentrations of EFV were mixed with fly food and fed to 3-day-old flies orally for a 7 day LC50 calculation. Drug concentrations from LC50 were selected for a 28 day survival to determine the duration of treatment for behavioral and biochemical assays. A 5day feeding plan was used to investigate the effects of the drug on organismal, neuromuscular, reproductive, and metabolic senescence. An in silico study was executed to decipher a molecular interaction of Drosophila enzymes glutathione-s-transferase (GST) or acetylcholinesterase (AChE) with EFV. Results: The calculated LC50 of EFV was 118 mg/10-g fly diet. The test drug induced a significant (P < 0.05) increase in fly mortality, climbing difficulty, and procreative deficits after a 5 day oral exposure. Similarly, there were significant (P < 0.05) biochemical alterations, which suggested in vivo biochemical damage against total thiols (T-SH), SOD (superoxide dismutase), CAT (catalase), GST, AChE, and MDA (malondialdehyde) in the test flies compared to the control groups. In silico study revealed a significantly (P < 0.05) higher binding energy between EFV and the active amino acids of fly AChE and GST when compared to the substrates or standard inhibitors respectively. Conclusion: EFV exhibited ecotoxic potentials evidenced by age-related deficits in the fly's functional integrity such as sluggish movement, procreative deficiency, increased mortality, and oxidant-antioxidant inequality. Results from in silico study suggested antagonism against GST and AChE activities as a likely mechanism of EFV-induced toxicity in the fruit fly. Graphical Abstract [ABSTRACT FROM AUTHOR]

The untreated human immunodeficiency virus (HIV), a lentivirus species that attacks immune cells (CD4+ T cells), causes acquired immunodeficiency syndrome (AIDS). HIV-positive people manage HIV/AIDS by using antiretroviral therapy (ART). The ART treatment regimen contains two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor/integrase strand transfer inhibitor. Tenofovir, an NRTI approved for managing HIV infection, is associated with hepatic steatosis and lactic acidosis, which are linked to mitochondrial toxicity and oxidative stress. Due to side-effects associated with ART, people living with HIV often use medicinal plants or a combination of medicinal plants with ART to promote adherence and diminish the side-effects and cytotoxicity. The Moringa oleifera (MO) tree from the family of Moringaceae is among the medicinal trees studied in managing HIV/AIDS in sub-Saharan Africa. The MO tree extracts have been reported to have inhibitory activity primarily against HIV due to their bioactive compounds. However, there is a scarcity of knowledge about the use of the MO tree amongst HIV/AIDS patients receiving ART in South Africa and its effect on patient compliance and outcomes. Thus, this review aims to outline the impact of MO aqueous leaf extract on oxidative stress and antioxidant responses in human HepG2 liver cells after exposure to antiretrovirals such as tenofovir. The review will contribute to a comprehensive understanding of the potential protective effect of MO aqueous leaf extract on tenofovir-induced cytotoxicity. [ABSTRACT FROM AUTHOR]

Introduction: In 2018, the Malawi Ministry of Health adopted the recommendation to switch first-line antiretroviral therapy (ART) from an efavirenz (EFV)-based to a dolutegravir (DTG)-based regimen. Little is known about patients' experience during this transition. We conducted a qualitative study to explore DTG-related counselling challenges among providers of HIV care and factors influencing regimen switching or non-switching among women living with HIV in Lilongwe, Malawi. Methods: Between February-July 2020, we recruited participants who took part in DTG counselling on reasons to switch, side effects, and benefits from two government health facilities providing HIV care: Area 18 health centre and Bwaila district hospital in Lilongwe, Malawi. We purposively sampled and interviewed 8 women living with HIV who remained on an EFV-based regimen after counselling, 10 women who switched to a DTG-based regimen, and 10 HIV care providers who provided counselling about ART switching. In-depth interviews were used to explore patient's perceptions of DTG, factors affecting the decision to switch, and both patient and provider experience with counselling. Interview data was coded for themes using inductive and deductive codes. Interviews were conducted until thematic saturation was achieved. Data matrices were used for analysis and thematic extraction. Results: Most women in both groups were well versed on DTG's potential side effects and felt well counselled on the benefits of switching, such as quicker viral load suppression. Many women associated DTG with birth defects and expressed concern. However, the primary reason for not switching was concern with how the new medication would be tolerated, especially when they were satisfied with their current regimen. Almost all providers expressed difficulty providing DTG counselling. Primary reasons included feeling inadequately trained and/or not having resources to use during counselling, such as diagrams or brochures. Conclusion: DTG counselling was well accepted by women; however, some felt that their concerns were not fully addressed. Providers reflected this sentiment in that they did not feel adequately trained or well-equipped to provide adequate counselling. Training on counselling for new ART regimens should be intensified and utilize patient-centered educational materials to address the concerns raised by both patients and health care providers. [ABSTRACT FROM AUTHOR]

Bioanalytical method development for Tenofovir (TFR) as an antiretroviral drug by LCMS Technique. A developed Bioanalytical analysis method for TFR can be used routinely in a commercial laboratory. All the solvents used were of HPLC grade. 4000 QTrap along with the Shimadzu LC 20AD LC System used to develop and validate the method. The LLOQ and LOQ for Tenofovir was found were 5ng/mL and 15ng/mL. The method was accurate (within ±15% of control) and precise (coefficient of variation =15%). Analytes were stable for five freeze/thaw cycles and up to 6 days at room temperature, whereas long-term at -20°C or at -80°C. For Precision study using QCs of the drug-85%, 100% and 115% concentration of drug chosen and the levels M1QC (75ng/mL), MQC (300ng/mL) and HQC (600ng/mL) where the % CV were observed of = 15%. In a Precision and Accuracy study (inter day and intraday), the % CV obtained for Tenofovir was observed = 15%. Recovery studies for extracted samples with LQC (15ng/mL), MQC (300ng/mL) and HQC (600ng/mL) were 94.51%, 91.83% and 90.91% respectively. Stability was within 15% deviation. The results of System Suitability Test for TFR and Acyclovir (ACR) are an internal standard with observed %CV = 2.0%. The aim of the study was to develop a method that could be used as an alternative to the existing Tenofovir indirect method. The existing method observes separating the parent drug from the metabolite in LCMS/MS. This method is a good alternative to the indirect methods currently in use. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]