Zidovudine, a brief history before the first antirretroviral in Mexico.

In the 1980s in Mexico, that of the «moral renewal¼, there was the opening to the market and the manifestation of human immunodeficiency virus (HIV) and AIDS. In this writing, the historical and therapeutic conditions are related to alleviate the syndrome until the arrival of the first antiretroviral. It is a reconstruction of the events, of which the medical-social, main clinical manifestations and of course the pharmacological therapy, until de the development zidovudina or azidotimidina of AZT, the first antiretroviral to be approved. Nevertheless, in the Mexican context, this event wasn't decisive to significantly change the morbility and the mortality.

En el México de la década de 1980, el de la «renovación moral¼, se vivió la apertura al mercado y la manifestación del virus de la inmunodeficiencia humana (VIH) y el sida. En este escrito se relatan las condiciones históricas y terapéuticas del síndrome en los pacientes mexicanos, hasta la llegada del primer antirretroviral. Se trata de una reconstrucción de los hechos, de los cuales se ha profundizado en aspectos médico-sociales, principales manifestaciones clínicas y terapéutica farmacológica, hasta que interviene en la patogenia del VIH/sida el desarrollo de la zidovudina o azidotimidina (AZT), primer antirretroviral en ser aprobado. No obstante, en el contexto mexicano este suceso no fue determinante para cambiar de manera significativa la morbimortalidad de los infectados.

Effects of individual drug and combination antiretroviral therapy on trophoblast proliferation.

BACKGROUND: Combination antiretroviral therapy (cART) has been reported to reduce perinatal transmission of human immunodeficiency virus (HIV) and improve maternal survival outcomes. Recent studies have associated in-utero exposure to cART drugs with adverse outcomes such as pre-eclampsia, preterm delivery, low birth weight and small-for-gestational-age births. However, the exact molecular mechanisms underlying cART-induced adverse pregnancy outcomes remain poorly defined. OBJECTIVES: To investigate the effects of cART drugs on trophoblast proliferation in the HTR-8/SVneo cell line. STUDY DESIGN: HTR-8/SVneo cells were exposed to tenofovir (0.983-9.83 µM), emtricitabine (0.809-8.09 µM) and efavirenz (0.19-1.09 µM), the individual drugs of the first-line single tablet cART regimen termed 'Atripla', and zidovudine (1.12-1.12 µM), lamivudine (0.65-6.5 µM), lopinavir (0.32-3.2 µM) and ritonavir (0.69-6.9 µM), the individual drugs of the second-line single tablet cART regimen termed 'Aluvia'. The cells were treated for 24, 48, 72 and 96 h, and trophoblast proliferation was assessed using a colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltretrazolium bromide assay. RESULTS: Two-way analysis of variance showed a significant dose-dependent decrease (p < 0.05) in trophoblast proliferation in response to individual and combined drug components of first- and second-line antiretroviral therapy. CONCLUSIONS: First- and second-line cART drugs inhibit trophoblast proliferation, and may contribute to placenta-mediated adverse pregnancy outcomes in patients with HIV.

Endoplasmic reticulum transporter OAT2 regulates drug metabolism and interaction.

Xenobiotic metabolic reactions in the hepatocyte endoplasmic reticulum (ER) including UDP-glucuronosyltransferase and carboxylesterase play central roles in the detoxification of medical agents with small- and medium-sized molecules. Although the catalytic sites of these enzymes exist inside of ER, the molecular mechanism for membrane permeation in the ER remains enigmatic. Here, we investigated that organic anion transporter 2 (OAT2) regulates the detoxification reactions of xenobiotic agents including anti-cancer capecitabine and antiviral zidovudine, via the permeation process across the ER membrane in the liver. Pharmacokinetic studies in patients with colorectal cancer revealed that the half-lives of capecitabine in rs2270860 (1324C > T) variants was 1.4 times higher than that in the C/C variants. Moreover, the hydrolysis of capecitabine to 5'-deoxy-5-fluorocytidine in primary cultured human hepatocytes was reduced by OAT2 inhibitor ketoprofen, whereas capecitabine hydrolysis directly assessed in human liver microsomes were not affected. The immunostaining of OAT2 was merged with ER marker calnexin in human liver periportal zone. These results suggested that OAT2 is involved in distribution of capecitabine into ER. Furthermore, we clarified that OAT2 plays an essential role in drug-drug interactions between zidovudine and valproic acid, leading to the alteration in zidovudine exposure to the body. Our findings contribute to mechanistically understanding medical agent detoxification, shedding light on the ER membrane permeation process as xenobiotic metabolic machinery to improve chemical changes in hydrophilic compounds.

Efficacy and safety of three antiretroviral therapy regimens for treatment-naive African adults living with HIV-2 (FIT-2): a pilot, phase 2, non-comparative, open-label, randomised controlled trial.

BACKGROUND: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches. METHODS: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per µL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants. FINDINGS: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group. INTERPRETATION: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen. FUNDING: ANRS MIE.

The use of suboptimal antiretroviral therapy when applying for migration to Australia: a case series.

Background Australia imposes restrictions for people living with HIV (PLHIV) applying for permanent residency (PR), including spending less than AUD51,000 on medical costs over 10years. Some PLHIV opted for suboptimal and cheaper antiretroviral therapy (ART) regimens to increase their chances of receiving PR. We collated a case series to examine PLHIV on suboptimal ART because of visa issues. Methods We identified all patients applying for a PR in Australia who obtained nevirapine, efavirenz or zidovudine between July 2022 and July 2023 from the Melbourne Sexual Health Centre. Pathology results and records detailing psychological issues relating to the patients' wishes to remain on suboptimal ART were extracted from clinical records by two researchers. Results We identified six patients with a mean age of 39years migrating from Asian and European countries. Three patients used efavirenz, and three used nevirapine. All desired to remain on cheaper, suboptimal ART to stay below visa cost thresholds, which they considered to aid favourably with their application. Four displayed stress and anxiety arising from visa rejections, appeal deadlines and the lengthy visa application process. Conclusions Despite access to more effective and safer ART, we identified patients who chose to remain on cheaper ART to improve chances of obtaining an Australian visa, potentially putting their health at risk. We found significant evidence of stress and anxiety among patients. There is a need to review and revise current migration policies and laws in Australia that discriminate against PLHIV and jeopardise public health.

A Novel Validated GC-MS/MS Method for the Estimation of N-Nitroso Dimethyl Amine and N-Nitroso Diethyl Amine in Zidovudine.

A novel method has been developed for the estimation of N-Nitroso dimethyl amine impurities (NDMA) and N-Nitroso diethyl amine (NDEA) in Zidovudine by using Gas chromatograph Triple Quadrupole Mass with Liquid autosampler (GC-MS/MS) and the method is validated as per International Conference on Harmonization recommendations. Sample analysis was executed for Zidovudine by developed method. Both NDMA and NDEA were detected in below quantitation limit for the Zidovudine batches. Efficient chromatographic separation was achieved on a DB-WAX 30 m length × 0.25 mm internal diameter, 0.5-µm film thickness, Triple quad-8040 GC-MS/MS. Quantification was carried out at Triple quad electron ionization source was at a column flow of 1.5 mL/min at a column oven temperature 50°C. The precision was in the range of 0.9-2.5% for NDMA and 0.8-2.3% for NDEA, and regression analysis shows as r value (correlation coefficient) of is >0.99. This method is capable to detect the NDMA and NDEA impurities in Zidovudine at a level of 0.006 ppm for limit of detection and 0.018 ppm for limit of quantitation with respect to test concentration of 66.66 mg/mL.

Clinical Trials That Have Changed Clinical Practice and Care of Pregnant People With HIV.

Over the last 4 decades, significant advances in the care of HIV during pregnancy have successfully reduced, and nearly eliminated, the risk of perinatal HIV transmission. The baseline risk of transmission without intervention (25% to 30%) is now <1% to 2% in the United States with contemporary antepartum, intrapartum, and postnatal interventions. In this review, we discuss 3 landmark clinical trials that substantially altered obstetric practice for pregnant individuals with HIV and contributed to this extraordinary achievement: 1) the Pediatric AIDS Clinical Trials Group 076 Trial determined that antepartum and intrapartum administration of antiretroviral drug zidovudine to the pregnant individual, and postnatally to the newborn, could reduce the risk of perinatal transmission by approximately two-thirds; 2) the European Mode of Delivery Collaboration Trial demonstrated performance of a prelabor cesarean birth before rupture of membranes among pregnant people with viremia reduced the risk of perinatal transmission compared with vaginal birth; and 3) the International Maternal Pediatric Adolescent AIDS Clinical Trials Network 2010 Trial identified that dolutegravir-containing, compared with efavirenz-containing, antiretroviral regimens during pregnancy achieved a significantly higher rate of viral suppression at delivery with shorter time to viral suppression, with fewer adverse pregnancy outcomes. Collectively, these trials not only advanced obstetric practice but also advanced scientific understanding of the timing, mechanisms, and determinants of perinatal HIV transmission. For each trial, we will describe key aspects of the study protocol and outcomes, insights gleaned about the dynamics of perinatal transmission, how each study changed clinical practice, and relevant updates to current practice since the trial's publication.

Identification of dihydroquinolizinone derivatives with nitrogen heterocycle moieties as new anti-HBV agents.

The sustained loss of HBsAg is considered a pivotal indicator for achieving functional cure of HBV. Dihydroquinolizinone derivatives (DHQs) have demonstrated remarkable inhibitory activity against HBsAg both in vitro and in vivo. However, the reported neurotoxicity associated with RG7834 has raised concerns regarding the development of DHQs. In this study, we designed and synthesized a series of DHQs incorporating nitrogen heterocycle moieties. Almost all of these compounds exhibited potent inhibition activity against HBsAg, with IC50 values at the nanomolar level. Impressively, the compound (S)-2a (10 µM) demonstrated a comparatively reduced impact on the neurite outgrowth of HT22 cells and isolated mouse DRG neurons in comparison to RG7834, thereby indicating a decrease in neurotoxicity. Furthermore, (S)-2a exhibited higher drug exposures than RG7834. The potent anti-HBV activity, reduced neurotoxicity, and favorable pharmacokinetic profiles underscore its promising potential as a lead compound for future anti-HBV drug discovery.

Prevented perinatal HIV infections in the era of antiretroviral prophylaxis and treatment, United States, 1994-2020.

OBJECTIVE: The primary aim of this serial cross-sectional analysis is to estimate the total number of prevented perinatal HIV transmissions from the time of the initial recommendation for perinatal zidovudine (ZDV) prophylaxis in 1994 through 2020 in the US. METHODS: The estimated number of prevented transmissions was calculated as annual differences between expected and observed numbers of perinatal HIV transmissions. Annual expected number of transmissions was estimated by multiplying the annual number of births to women with HIV by 0.2255 (22.55%), i.e., the transmission rate of the control group in the ACTG Protocol 076 trial. We used published point estimates or, if only ranges were given, the midpoints of those ranges as the best estimates of the annual numbers of births to women with HIV and infants with perinatal HIV. When data were not available, we linearly interpolated or extrapolated the available data to obtain estimated numbers for each year. RESULTS: Between 1978 and 2020, the approximate number of live births to women with HIV was 191 267 (95% confidence interval [CI] 190 392-192 110) and for infants with diagnosed perinatal HIV, it was 21 379 (95% CI 21 088-21 695). Since 1994, the annual number of infants born with HIV decreased from 1263 (95% CI 1194-1333) to 33 in 2019 (95% CI 22-45) and 36 in 2020 (95% CI 25-48), corresponding to a 97% reduction. Cumulatively, an estimated total of 22 732 (95% CI 21 340-24 462) perinatal HIV infections were prevented from 1994 through to 2020. CONCLUSION: The elimination of perinatal HIV transmission-accompanied by the cumulative number of prevented cases exceeding that of perinatal HIV infections-is a major public health achievement in the US.

Systemic inflammation in pregnant women with HIV: relationship with HIV treatment regimen and preterm delivery.

OBJECTIVE: HIV treatment regimen during pregnancy was associated with preterm delivery (PTD) in the PROMISE 1077 BF trial. Systemic inflammation among pregnant women with HIV could help explain differences in PTD by treatment regimen. We assessed associations between inflammation, treatment regimen, and PTD. DESIGN/METHODS: A nested 1 : 1 case-control study ( N  = 362) was conducted within a multicountry randomized trial comparing three HIV regimens in pregnant women: zidovudine alone, or combination antiretroviral therapy (ART) with lopinavir/ritonavir and either zidovudine or tenofovir. Cases were women with PTD (<37 weeks of gestational age). The following inflammatory biomarkers were measured in plasma samples using immunoassays: soluble CD14 (sCD14) and sCD163, intestinal fatty acid-binding protein, interleukin (IL)-6, interferon γ, and tumor necrosis factor α. We fit regression models to assess associations between second trimester biomarkers (measured before ART initiation at 13-23 weeks of gestational age and 4 weeks later), treatment regimen, and PTD. We also assessed whether inflammation was a mediator in the relationship between ART regimen and PTD. RESULTS: Persistently high interleukin-6 was associated with increased PTD. Compared with zidovudine alone, the difference in biomarker concentration between week 0 and week 4 was significantly higher ( P  < 0.05) for both protease inhibitor-based regimens. However, the estimated proportion of the ART effect on increased PTD mediated by persistently high biomarker levels was 5% or less for all biomarkers. CONCLUSION: Persistently high IL-6 during pregnancy was associated with PTD. Although protease inhibitor-based ART was associated with increases in inflammation, factors other than inflammation likely explain the increased PTD in ART-based regimens compared with zidovudine alone.

A ProTide of AZT Shows Activity Against Human Papillomaviruses.

Infection by human papillomaviruses (HPV) can cause warts and tumors. So far, no small molecule antiviral has been approved for the treatment of infections with this DNA virus, although preclinical studies show activity for nucleosidic compounds, such as 9-(2-phosphonylmethoxy)ethylguanine (PMEG) or cidofovir. This prompted us to test new prodrug versions of the nucleoside analog 3'-azido-2',3'-dideoxythymidine (AZT), known to be active against reverse transcriptases and approved for the treatment of HIV. Here we report the synthesis of an ethylbutyl alaninyl ester phosphosphoramidate prodrug of AZT, dubbed AZAEB, and its activity against HPV, a target not known to be sensitive to AZT. A methyl ester derivative was found to be inactive against this and three other DNA viruses, while the phosphoramidate prodrug AZAEB showed a modest inhibitory effect against HPV types 6, 11, 18 and 31. Our results open up new avenues of study for the treatment of diseases caused by members of the papillomaviridae family.

A Central Auditory Test reveals differences between drug treatment regimens in adults living with HIV.

OBJECTIVE: This exploratory study examined whether central auditory tests show differences between people living with HIV (PLWH) treated with two predominant antiretroviral drug therapy (ART) regimens. DESIGN: Cross-sectional. STUDY SAMPLE: 253 PLWH (mean age 39.8 years) from the Shanghai Public Health Clinical Centre, China. METHODS: The Hearing in Noise Test speech reception threshold (SRT) assessed central auditory function and the Montreal Cognitive Assessment (MoCA) assessed cognition. The relationship between ART regimen and SRT was evaluated with multivariable linear regression incorporating age, HIV duration, and peripheral hearing ability. Multivariable logistic regression was used to ascertain if SRT and ART regimen predicted MoCA impairment. RESULTS: The two predominant ART regimens differed by one drug (zidovudine or tenofovir). Participants taking the zidovudine-containing regimen had poorer SRT performance (p=.012) independent of age and hearing thresholds. MoCA scores did not differ between drug regimens, but a negative relationship was found between SRT and MoCA impairment (p=.048). CONCLUSIONS: ART regimens differed in their association with central auditory test performance likely reflecting neurocognitive changes in PLWH taking the zidovudine-containing regimen. Central auditory test performance also marginally predicted cognitive impairment, supporting further assessment of central auditory tests to detect neurocognitive deficits in PLWH.

Mitochondrial DNA mutations in HIV-exposed uninfected infants following the cessation of triple antiretroviral drugs.

OBJECTIVES: Mitochondrial mutations in HIV-exposed uninfected (HEU) infants after cessation of ART are rarely studied. We analysed a group of HEU newborns born to mothers with late HIV diagnosis who received three doses of ART immediately after birth. We observed mitochondrial DNA (mtDNA) mutations at different times of withdrawal. METHODS: The study was based on a clinical trial conducted from 2015 to 2020. Newborns of the intervention group who met the criteria for this study received triple antiretroviral drugs, zidovudine + lamivudine + nevirapine, within 2 h after the birth, as post-partum prophylaxis, and at 14 days were switched to zidovudine + lamivudine + lopinavir/ritonavir, which was continued until 6 weeks of age. From August to November 2019, blood samples from HEU infants were also collected after ceasing 12 months of ART, and analysed for mtDNA. RESULTS: Our study found that mtDNA mutations remained prevalent in HEU infants a few years after three ARTs were stopped immediately after birth. Among them, D-loop, ND1 and CYTB are the first three mutated regions during different withdrawal periods. This pattern of mutations is similar to, but not exactly consistent with, HIV-infected children receiving standard ART. CONCLUSIONS: Further studies are needed to determine the effects of these mutations on the development of HEU infants and whether stopping ART leads to the restoration of mitochondrial function.

In utero/peripartum antiretroviral therapy exposure and mental health outcomes at 8-18 years old: A longitudinal comparative study of children with perinatally acquired HIV, children perinatally HIV exposed but uninfected, and children unexposed uninfected from Uganda.

In utero/peripartum antiretroviral therapy (IPA) exposure type was examined in relationship to mental health symptoms among 577 children with perinatally acquired HIV (CPHIV), children perinatally HIV exposed but uninfected (CHEU), and children HIV unexposed uninfected (CHUU). IPA exposure was categorized for CPHIV and CHEU as none, single-dose nevirapine with or without zidovudine (sdNVP±AZT), sdNVP+AZT+lamivudine (3TC), or combination antiretroviral therapy (cART). Anxiety and depressive symptoms were reported at baseline, 6-, and 12-month follow-up per behavioral assessment system for children. Multivariable linear mixed models were used to estimate differences (b) with 95% confidence intervals (95% CI) for IPA exposure types versus CHEU without IPA exposure. Depressive and anxiety symptoms were lower in CHUU relative to CHEU and CPHIV but did not differ between CPHIV and CHEU. CHEU with sdNVP±AZT exposure had greater anxiety (b = 0.51, 95% CI: [0.06, 0.96]) and depressive symptoms (b = 0.48, 95% CI: [0.07, 0.89]) than CHEU without IPA exposure. CHEU with sdNVP+AZT+3TC exposure had higher anxiety (b = 0.0.45, 95% CI: [0.03, 0.86]) and depressive symptoms (b = 0.72, 95% CI: [0.27, 1.17]) versus CHEU without IPA exposure. Depressive and anxiety symptoms were not different for CHEU and CPHIV exposed to cART (b = 0.12-0.60, 95% CI: [-0.41, 1.30]) and CHEU and CHUU (b = -0.04 to 0.08, 95% CI: [-0.24, 0.29]) without IPA exposure. Among CHEU, peripartum sdNVP±AZT and sdNVP+AZT+3TC but not cART compared to no IPA exposure was associated with clinically important elevations in anxiety and depressive symptoms. Monitoring of mental health trajectory of HIV-affected children considering IPA is needed to inform mental health interventions. Patient Contribution: Caregivers and their dependents provided consent for participation and collaborated with study team to identify mutually convenient times for protocol implementation.

Bioequivalence and Pharmacokinetics Study of Two Zidovudine/Lamivudine Tablets in Chinese Healthy Volunteers.

Zidovudine/lamivudine tablets are nucleoside reverse transcriptase inhibitors that are used to treat human immunodeficiency virus. The objective of this study was to investigate the bioequivalence and pharmacokinetics (PKs) of test and reference preparations of zidovudine/lamivudine tablets in healthy Chinese subjects. We designed a randomized, open, single-center, single-dose, 2-crossover experiment with a 7-day washout period involving 20 healthy subjects. The subjects were given a single dose of the test or reference preparation after fasting overnight for 10 hours. Blood samples were subsequently collected at scheduled time points from 0 hour (preadministration) up to 24 hours postadministration. The plasma concentrations of zidovudine and lamivudine were determined by a validated ultra-performance liquid chromatography-tandem mass spectrometry method. Analysis of variance (ANOVA) was used to compare differences in the mean values of key PK parameters between the 2 preparations. Bioequivalence was evaluated by 2 one-sided t-tests and 90% confidence intervals (CIs) of the geometric mean ratio (GMR). In total, 19 of the 20 subjects completed the trial. Based on the analysis of PK parameters, the relative bioavailability of zidovudine and lamivudine was 101.1% ± 2.0% and 100.3% ± 1.5%, respectively. ANOVA found no significant difference in primary PK parameters when compared between the 2 formulations, and the 90% CIs of the GMR of the 2 formulations were within the bioequivalence margins of 80%-125%. No serious adverse events occurred. Thus, we confirmed that the 2 preparations were bioequivalent in healthy Chinese volunteers. Our analysis demonstrated that both products showed good tolerance in all subjects.

Incidence and Predictors of Major Adverse Drug Reactions Among Human Immunodeficiency Virus-infected Children on Antiretroviral Treatment in West Amhara Comprehensive Specialized Hospitals, Northwest Ethiopia: A Multicenter Retrospective Follow-up Study.

PURPOSE: Major adverse drug reactions (ADRs) are the leading causes of poor adherence, switching of drugs, morbidity, and mortality. A limited studies was conducted to investigate major ADR in developing countries including Ethiopia, and the purpose of this study was to assess the incidence and predictors of major ADRs among HIV-infected children receiving antiretroviral therapy (ART) in West Amhara Comprehensive Specialized Hospitals, Northwest Ethiopia. METHODS: An institutional-based retrospective follow-up study was conducted among 460 children receiving ART from January 1, 2014 to December 31, 2021. A simple random sampling technique was employed, and data were collected using Kobo Toolbox software and then deployed to STATA 14 for analysis. The Kaplan-Meier survival curve and the log-rank test were used to estimate and compare survival times. Both bivariable and multivariable Weibull regression models were fitted to identify predictors. Finally, an adjusted hazards ratio (AHR) with a 95% CI was computed, and variables with P < 0.05 were considered statistically significant predictors of major ADR. FINDINGS: The overall incidence rate of major ADRs was 5.8 (95% CI, 4.6-7.3) per 1000 child months. Being female (AHR, 2.71; 95% CI, 1.52-4.84), tuberculosis (TB)-HIV co-infection (AHR, 2.49; 95% CI, 1.32-4.68), World Health Organization stage (III and IV) (AHR, 2.52; 95% CI, 1.39-4.56), zidovudine-based (AHR, 2.84; 95% CI, 1.11-7.31), and stavudine-based (AHR, 5.96; 95% CI, 1.63-21.84) regimens were found to be significant predictors of major ADRs. IMPLICATIONS: The major ADR incidence rate was high. Health professionals should employ early screening and close follow-up for children with advanced World Health Organization clinical staging, females, those with TB-HIV co-infection, and those receiving stavudine- and zidovudine-based initial regimens to reduce the incidence of major ADRs.

Applications of some advanced sequencing, analytical, and computational approaches in medicinal plant research: a review.

The potential active chemicals found in medicinal plants, which have long been employed as natural medicines, are abundant. Exploring the genes responsible for producing these compounds has given new insights into medicinal plant research. Previously, the authentication of medicinal plants was done via DNA marker sequencing. With the advancement of sequencing technology, several new techniques like next-generation sequencing, single molecule sequencing, and fourth-generation sequencing have emerged. These techniques enshrined the role of molecular approaches for medicinal plants because all the genes involved in the biosynthesis of medicinal compound(s) could be identified through RNA-seq analysis. In several research insights, transcriptome data have also been used for the identification of biosynthesis pathways. miRNAs in several medicinal plants and their role in the biosynthesis pathway as well as regulation of the disease-causing genes were also identified. In several research articles, an in silico study was also found to be effective in identifying the inhibitory effect of medicinal plant-based compounds against virus' gene(s). The use of advanced analytical methods like spectroscopy and chromatography in metabolite proofing of secondary metabolites has also been reported in several recent research findings. Furthermore, advancement in molecular and analytic methods will give new insight into studying the traditionally important medicinal plants that are still unexplored.

Lower academic performance among children with perinatal HIV exposure in Botswana.

INTRODUCTION: Studies have reported a higher risk of suboptimal neurodevelopment among children who are HIV-exposed uninfected (HEU) compared to children HIV-unexposed uninfected (HUU). Actual academic performance among school-aged children by HIV exposure status has not been studied. METHODS: Academic performance in Mathematics, Science, English, Setswana and overall among children enrolled in the Botswana-based FLOURISH study who were attending public primary school and ranging in age from 7.1 to 14.6 years were compared by HIV exposure status using a Cochran-Mantel-Haenszel test. Lower academic performance was defined as a grade of "C" or lower (≤60%). Unadjusted and adjusted logistic regression models were fit to assess for an association between HIV exposure and lower academic performance. RESULTS: Between April 2021 and December 2022, 398 children attending public primary school enrolled in the FLOURSH study, 307 (77%) were HEU. Median age was 9.4 years (IQR 8.9-10.2). Only 17.9% of children HEU were breastfeed versus 100% of children HUU. Among children HEU, 80.3% had foetal exposure to three-drug antiretroviral treatment, 18.7% to zidovudine only and 1.0% had no antiretroviral exposure. Caregivers of children HEU were older compared to caregivers of children HUU (median 42 vs. 36 years) and more likely to have no or primary education only (15.0% vs. 1.1%). In unadjusted analyses, children HEU were more likely to have lower overall academic performance compared to their children HUU (odds ratio [OR]: 1.96 [95% confidence interval (CI): 1.16, 3.30]), and lower performance in Mathematics, Science and English. The association was attenuated after adjustment for maternal education, caregiver income, breastfeeding, low birth weight and child sex (aOR: 1.86 [95% CI: 0.78, 4.43]). CONCLUSIONS: In this Botswana-based cohort, primary school academic performance was lower among children HEU compared to children HUU. Biological and socio-demographic factors, including child sex, appear to contribute to this difference. Further research is needed to identify modifiable contributors, develop screening tools to identify the risk of poor academic performance and design interventions to mitigate risk.

Strategies in the Design and Development of Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs).

AIDS (acquired immunodeficiency syndrome) is a potentially life-threatening infectious disease caused by human immunodeficiency virus (HIV). To date, thousands of people have lost their lives annually due to HIV infection, and it continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), to date, 30 drugs have been approved by the FDA, primarily targeting reverse transcriptase, integrase, and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) includes more than one antiretroviral agent targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, bioisosterism, high-throughput screening, covalent-binding, targeting highly hydrophobic channel, targeting dual site, and multi-target-directed ligand to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapies and long-acting regimens of NNRTIs to improve pharmacokinetic profiles and provide sustained therapeutic effects.

Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.