Removal of antiretroviral drugs from wastewater using activated macadamia nutshells: Adsorption kinetics, adsorption isotherms, and thermodynamic studies.

Antiretroviral drugs (ARVDs) have been extensively employed in health care to improve the quality of life and lifecycle longevity. However, overuse and improper disposal of ARVDs have been recognized as an emerging concern whereby wastewater treatment major recipients. Therefore, in this work, the activated macadamia nutshells (MCNs) were explored as low-cost adsorbents for the removal of ARVDs in wastewater samples. Fourier transform infrared spectroscopy (FTIR), Scanning Electron microscopy (SEM), Brunauer-Emmet-Teller (BET), and Powder X-ray diffraction (PXRD). The highest removal efficiency (R.E) was above 86% for the selected analytes nevirapine, abacavir, and efavirenz. The maximum adsorption capacity of the functionalized MCN adsorbent was 10.79, 27.44, and 38.17 mg/g for nevirapine, abacavir, and efavirenz for HCl-modified adsorbent. In contrast, NaOH modified had adsorption capacities of 13.67, 14.25, and 20.79 mg/g. The FTIR showed distinct functional groups OH and CO, which facilitate the removal of selected ARVDs. From studying kinetics parameters, the pseudo-second-order (R2 = 0.990-0.996) was more dominant than the pseudo-first-order (R2 = 0.872-0.994). The experimental data was most fitted in the Freundlich model with (R2 close to 1). The thermodynamic parameters indicated that the adsorption process was spontaneous and exothermic. The study indicated that MCNs are an eco-friendly, low-cost, and effective adsorbent for the removal of nevirapine, abacavir, and efavirenz. PRACTITIONER POINTS: Modification macadamia nutshell with HCl and NaOH improved physio-chemical properties that yielded high removal efficiency compared with raw macadamia nutshells. Modification of macadamia by HCl showed high removal efficiency, which could be attributed to high interaction such as H-bonding that improves adsorption. The macadamia nutshell as an adsorbent showed so much robustness with regeneration studies yielding to about 69.64% of selected compounds.

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

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

Analysis of ART effects and drug resistance in adult HIV/AIDS patients in Meigu County, Liangshan Prefecture, China.

BACKGROUND OBJECTIVE: This study aimed to understand the basic situation of adults with human immunodeficiency virus (HIV) receiving antiretroviral therapy (ART) in Meigu County, Liangshan Yi Autonomous Prefecture. The information of patients who had been on ART for more than 6 months, the effect of ART, the possible reasons for ART failure, knowledge of drug resistance among patients with ART failure and the possible reasons for the emergence of drug resistance were analyzed. METHODS: A total of 2753 people living with HIV (PLWH) were collected for HIV-1 RNA virus nucleic acid testing. Plasma specimens with HIV-1 RNA ≥ 1000 copies/mL were sent to the laboratory for nucleic acid extraction, PCR, electrophoresis and sequencing, and the sequencing results were submitted to the HIV drug resistance database of Stanford University for subtyping to determine the drug resistance mutation sites and drug sensitivity levels. RESULTS: A total of 2753 patients were enrolled in this study. Antiviral therapy failed in 288 patients and was successfully amplified in 245, of which 111 had resistance genes. The resistance rate to failure of viral suppression was 45.3% (111/245). The highest rates of resistance to NNRTIs were found for efavirenz (EFV) and nevirapine (NVP) (42.9%), and the highest rates of resistance to NRTIs were found for 3TC and emtricitabine (FTC) (15.9%). The most common NNRTI resistance mutation site was K103N (20.8%), followed by V179D (9.4%) and V106M (7.8%); the most common NRTI resistance mutation site was M184V/I/MV (14.3%), followed by K65R (6.9%); three PI-associated resistance mutation sites were identified. The subtype of the resistant strain was CRF07-BC in almost all patients (98.9%). CONCLUSIONS: Compared with the previous low ART efficacy in the county, this study showed that the overall virological failure (VF) resistance rate in the county is still low, dominated by resistance to EFV, NVP, 3TC, FTC, and didanosine (DDI). Due to economic constraints, the core regimen is still 3TC + TDF, but before initiating ART, testing for HIV-1 subtypes and resistance should be conducted to avoid resistance that can lead to VF, especially for patients with high risk factors for resistance as shown by epidemiologic investigations.

The development and characterization of a CRISPR/Cas9-mediated PD-1 functional knockout rat as a tool to study idiosyncratic drug reactions.

Idiosyncratic drug reactions are rare but serious adverse drug reactions unrelated to the known therapeutic properties of the drug and manifest in only a small percentage of the treated population. Animal models play an important role in advancing mechanistic studies examining idiosyncratic drug reactions. However, to be useful, they must possess similarities to those seen clinically. Although mice currently represent the dominant mammalian genetic model, rats are advantageous in many areas of pharmacologic study where their physiology can be examined in greater detail and is more akin to that seen in humans. In the area of immunology, this includes autoimmune responses and susceptibility to diabetes, in which rats more accurately mimic disease states in humans compared with mice. For example, oral nevirapine treatment can induce an immune-mediated skin rash in humans and rats, but not in mice due to the absence of the sulfotransferase required to form reactive metabolites of nevirapine within the skin. Using CRISPR-mediated gene editing, we developed a modified line of transgenic rats in which a segment of IgG-like ectodomain containing the core PD-1 interaction motif containing the native ligand and therapeutic antibody domain in exon 2 was deleted. Removal of this region critical for mediating PD-1/PD-L1 interactions resulted in animals with an increased immune response resulting in liver injury when treated with amodiaquine.

HIV-1 reservoir size after neonatal antiretroviral therapy and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase 1/2 proof-of-concept study.

BACKGROUND: Infants born with HIV-1 require lifelong antiretroviral therapy (ART). We aimed to assess whether very early ART in neonates might restrict HIV-1 reservoirs, an important step towards ART-free remission. METHODS: IMPAACT P1115 is an ongoing, phase 1/2, proof-of-concept study in which infants were enrolled at 30 research clinics in 11 countries (Brazil, Haiti, Kenya, Malawi, South Africa, Tanzania, Thailand, Uganda, the USA, Zambia, and Zimbabwe) into two cohorts. Infants at least 34 weeks' gestational age at high risk for in-utero HIV-1 with either untreated maternal HIV-1 (cohort 1) or who were receiving pre-emptive triple antiretroviral prophylaxis outside of the study (maternal ART permissible; cohort 2) were included. All infants initiated treatment within 48 h of life. Cohort 1 initiated three-drug nevirapine-based ART, and cohort 2 initiated three-drug nevirapine-based prophylaxis then three-drug nevirapine-based ART following HIV diagnosis by age 10 days. We added twice-daily coformulated oral ritonavir 75 mg/m2 and lopinavir 300 mg/m2 from 14 days of life and 42 weeks postmenstrual age. We discontinued nevirapine 12 weeks after two consecutive plasma HIV-1 RNA levels below limit of detection. We tracked virological suppression, safety outcomes, and meeting a predetermined biomarker profile at age 2 years (undetectable RNA since week 48, HIV-1 antibody-negative, HIV-1 DNA not detected, and normal CD4 count and CD4 percentage) to assess qualification for analytical treatment interruption. This study is registered with ClinicalTrials.gov, NCT02140255. FINDINGS: Between Jan 23, 2015, and Dec 14, 2017, 440 infants were included in cohort 1 and 20 were included in cohort 2. 54 of these infants (34 from cohort 1 and 20 from cohort 2) had confirmed in-utero HIV-1 and were enrolled to receive study ART. 33 (61%) of 54 infants were female and 21 (39%) were male. The estimated probability of maintaining undetectable plasma RNA through to 2 years was 33% (95% CI 17-49) in cohort 1 and 57% (28-78) in cohort 2. Among infants maintaining protocol-defined virological control criteria through to study week 108, seven of 11 (64%, 95% CI 31-89) in cohort 1 and five of seven (71%, 29-96) in cohort 2 had no detected HIV-1 DNA. Ten of 12 (83%, 52-100) in cohort 1 and all seven (100%, 59-100) in cohort 2 tested HIV-1 antibody-negative at week 108. Among 54 infants initiated on very early ART, ten (19%; six in cohort 1 and four in cohort 2) met all criteria for possible analytical treatment interruption. Reversible grade 3 or 4 adverse events occurred in 15 (44%) of 34 infants in cohort 1 and seven (35%) of 20 infants in cohort 2. INTERPRETATION: Very early ART for in-utero HIV-1 can achieve sustained virological suppression in association with biomarkers indicating restricted HIV-1 reservoirs by age 2 years, which might enable potential ART-free remission. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Occurrence and environmental risks of contaminants of emerging concern across the River Athi Basin, Kenya, in dry and wet seasons.

Globally, the environmental occurrence of Contaminants of Emerging Concern (CECs) including pharmaceuticals (PhACs), personal care products (PCPs) and modern polar pesticides has raised ecological and human health awareness. However, as the developed world races against time to establish regulatory measures to mitigate their effects, developing nations including Kenya are lagging behind, partly due to unavailability of adequate data. In this work, a multi-residue analysis of 86 CECs was carried out on 198 surface water and 18 effluent samples collected at 24 sites across the River Athi basin area, Kenya, in both dry and rainy seasons. Overall, 57 CECs comprising 31 PhACs (0.4 ng L-1-142 µg L-1), 6 PCPs (0.7-570 ng L-1) and 20 pesticides (0.3 ng L-1-8.3 µg L-1) were detected. The maximum loads varied from 217 g day-1 (PCPs) to 46 kg day-1 (PhACs). Individually, carbamazepine, nevirapine, sulfamethoxazole and DEET were the most ubiquitous CECs, with detection frequencies (DF) higher than 80 %. The highest concentrations were observed at river sites that are heavily impacted by informal settlements, highlighting the critical role of slums in urban rivers pollution. At least 8 CECs including acetamiprid, alachlor, atrazine, diuron, nevirapine and paracetamol show potential risk to algae, Daphnia magna and fish, as exemplified by Risk Quotients (RQ) up to 174. Similarly, potential risk of antibiotic resistant bacteria development is evident (RQ up to 64), being driven by metronidazole, sulfamethoxazole and trimethoprim. Ultimately, further studies on the occurrence and distribution of antibiotic resistant bacteria within the basin and among the communities consuming untreated river water for drinking is merited.

Potential Involvement of Sulfotransferase in the Mechanism of Lamotrigine-induced Skin Rash.

The mechanism of drug-induced skin rash is not well understood. Circumstantial evidence suggests that the covalent binding of a reactive metabolite is involved in the mechanism of most idiosyncratic drug reactions. However, there is a limited quantity of drug metabolizing enzymes in the skin, except for sulfotransferases. It is possible that some drugs are metabolized to reactive sulfate metabolites that are responsible for skin rashes. For example, nevirapine-induced skin rash involves metabolism of nevirapine to 12-hydroxy-nevirapine, which is further metabolized by sulfotransferase in the skin to a reactive benzylic sulfate that covalently binds to proteins. The working hypothesis is that lamotrigine, valdecoxib, and sertraline skin rashes involve the formation of reactive sulfate in the skin. Lamotrigine-N-oxide, hydroxy-valdecoxib, and hydroxy-sertraline were tested as substrates with known human sulfotransferases. Hydroxy-valdecoxib and the benzylic alcohol metabolite of sertraline were not substrates for human sulfotransferases. Therefore, this pathway is presumably not involved in the mechanism by which they cause skin rashes. In contrast, lamotrigine-N-oxide is a substrate for several human sulfotransferases and the sulfate is chemically reactive. Furthermore, lamotrigine-N-sulfate not only alkylates proteins as we described previously but also forms the sulfate of tyrosine, suggesting another possible mechanism for protein modification. This study has further added to the understanding of the potential of the sulfotransferase pathways and protein sulfation to play a role in drug-induced skin rash.

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

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

Associations of modern initial antiretroviral therapy regimens with all-cause mortality in people living with HIV in resource-limited settings: a retrospective multicenter cohort study in China.

Despite the proven virological advantages, there remains some controversy regarding whether first-line integrase strand transfer inhibitors (INSTIs)-based antiretroviral therapy (ART) contributes to reducing mortality of people living with HIV (PLHIV) in clinical practice. Here we report a retrospective study comparing all-cause mortality among PLHIV in China who were on different initial ART regimens (nevirapine, efavirenz, dolutegravir, lopinavir, and others [including darunavir, raltegravie, elvitegravir and rilpivirine]) between 2017 and 2019. A total of 41,018 individuals were included across China, representing 21.3% of newly reported HIV/AIDS cases collectively in the country during this period. Only the differences in all-cause mortality of PLHIV between the efavirenz group and the nevirapine group, the dolutegravir group and the nevirapine group, and the lopinavir group and the nevirapine group, were observed in China. After stratifying the cause of mortality, we found that the differences in mortality between initial ART regimens were mainly observed in AIDS-related mortality.

Exploring antiviral potency of N-1 substituted pyrimidines against HIV-1 and other DNA/RNA viruses: Design, synthesis, characterization, ADMET analysis, docking, molecular dynamics and biological activity.

A novel series of pyrimidine derivatives, bearing modified benzimidazoles at N-1 position, has been designed, synthesized and screened as NNRTIs against HIV and as broad-spectrum antiviral agents. The molecules were screened against different HIV targets using molecular docking experiment. The docking results indicated that the molecules interacted well with the residues Lys101, Tyr181, Tyr188, Trp229, Phe227 and Tyr318 present in NNIBP of HIV-RT protein, formed quite stable complexes and, thus, behaved as probable NNRTIs. Among these compounds, 2b and 4b showed anti-HIV activity with IC50 values as 6.65 µg/mL (SI = 15.50) and 15.82 µg/mL (SI = 14.26), respectively. Similarly, compound 1a showed inhibitory property against coxsackie virus B4 and compound 3b against different viruses. Molecular dynamics simulation results unequivocally demonstrated the higher stability of the complex HIV-RT:2b than the HIV-RT:nevirapine complex. The MM/PBSA-based binding free energy (-) 114.92 kJ/mol of HIV-RT:2b complex in comparison to that of HIV-RT:nevirapine complex (-) 88.33 kJ/mol, further demonstrated the higher binding strength of 2b and thus, established the potential of compound 2b as a lead molecule as an HIV-RT inhibitor.

Optimizing antiretroviral therapy for children living with HIV: Experience from an observational cohort in Lesotho.

INTRODUCTION: We describe transition of HIV-positive children from efavirenz- or nevirapine-based antiretroviral therapy (ART) to optimal dolutegravir (DTG) or lopinavir/ritonavir (LPV/r) (solid formulation)-based ART in Lesotho. METHODS: We followed a cohort of children less than 15 years of age who were initiated on ART on or after January 1, 2018 from 21 selected health facilities in Lesotho. From March 2020 to May 2022, we collected data retrospectively through chart abstraction and prospectively through caregiver interviews to cover a period of 24 months following treatment initiation. We used a structured questionnaire to collect data on demographics, ART regimen, drug formulations and switches, viral suppression, retention, and drug administration challenges. Data were summarized as frequencies and percentages, using SAS ver.9.4. RESULTS: Of 310 children enrolled in the study, 169 (54.5%) were female, and median age at ART initiation was 5.9 years (IQR 1.1-11.1). During follow-up, 19 (6.1%) children died, 41 (13.2%) were lost to follow-up and 74 (23.9%) transferred to non-study sites. At baseline, 144 (46.4%) children were receiving efavirenz-based ART regimen, 133 (42.9%) LPV/r, 27 (8.7%) DTG, 5 (1.6%) nevirapine; 1 child had incomplete records. By study end, 143 (46.1%) children were receiving LPV/r-based ART regimen, 109 (35.2%) DTG, and 58 (18.7%) were on efavirenz or nevirapine-based regimen. Of 116 children with viral load results after six months or more on a consistent regimen, viral suppression was seen in 35/53 (66.0%) children on LPV/r, 36/38 (94.7%) children on DTG and 19/24 (79.2%) children on efavirenz. CONCLUSION: Following optimal ART introduction in Lesotho, most children in the cohort were transitioned and many attained or maintained viral suppression after transition; however, we recommend more robust viral load monitoring and patient tracking to reduce losses and improve outcomes after ART transition.

Uptake of selected antiretrovirals by pepper (Capsicum annum), radish (Raphanus sativus), and ryegrass (Lolium perenne) grown on two contrasting soils and fertilized with human urine-derived fertilizers.

The use of urine-derived fertilizers has several economic and environmental advantages. However, there is concern that pharmaceutical residues present in urine could enter the food chain after plant uptake and pose potential risks to human and animal health. A pot experiment was conducted to evaluate the uptake of nine target antiretroviral drugs (ARVDs) by pepper (Capsicum annum), ryegrass (Lolium perenne) and radish (Raphanus sativus) grown in two soils of contrasting texture and organic matter content and fertilized with stored urine, nitrified urine concentrate (NUC), and struvite. Nevirapine was the only ARVD detected in crops grown with NUC and struvite on both soils, but the concentrations were below the limit of quantification. Plants fertilized with stored urine absorbed lamivudine, ritonavir, stavudine, emtricitabine, nevirapine, and didanosine, while abacavir, efavirenz and zidovudine were not detected. The ARVDs detected in the soils after harvest were significantly higher in the soil with high organic matter and clay content. To assess direct human exposure the estimated daily dietary intake (DDI) of ARVDs by consumption of the pepper and radish fertilized with stored urine was compared with the Threshold of Toxicological Concern (TTC) values based on the Cramer classification tree. The calculated DDI values for all ARVDs were about 300-3000 times lower than the TTC values for class III compounds. Therefore, daily consumption of these crops fertilized with stored urine does not pose a health risk to the consumer. Future research is required to assess the impact of ARVD metabolites, which may be more harmful to human health than the parent compounds.

Bone and Renal Health in Infants With or Without Breastmilk Exposure to Tenofovir-Based Maternal Antiretroviral Treatment in the PROMISE Randomized Trial.

BACKGROUND: We assessed bone and kidney outcomes in infants randomized postdelivery as mother-infant pairs within the IMPAACT PROMISE trial to maternal tenofovir disoproxil fumarate-based antiretroviral treatment (mART) or infant nevirapine prophylaxis (iNVP) to prevent breastfeeding HIV transmission. METHODS: Infants were coenrolled in the P1084s substudy on randomization day and followed through Week 74. Lumbar spine bone mineral content (LS-BMC) was assessed at entry (6-21 age days) and Week 26 by dual-energy x-ray absorptiometry. Creatinine clearance (CrCl) was calculated at entry; Weeks 10, 26, and 74. Student t tests compared mean LS-BMC and CrCl at Week 26 and mean change from entry between arms. RESULTS: Of 400 enrolled infants, the mean (SD; n) for entry LS-BMC was 1.68 g (0.35; n = 363) and CrCl was 64.2 mL/min/1.73 m 2 (24.6; n = 357). At Week 26, 98% of infants were breastfeeding and 96% on their assigned HIV prevention strategy. The mean (SD) Week 26 LS-BMC was 2.64 g (0.48) for mART and 2.77 g (0.44) for iNVP; mean difference (95% confidence interval [CI]) -0.13 g (-0.22 to -0.04), P = 0.007, n = 375/398 (94%). Mean absolute (-0.14 g [-0.23 to -0.06]) and percent (-10.88% [-18.53 to -3.23]) increase in LS-BMC from entry was smaller for mART than iNVP. At Week 26, the mean (SD) CrCl was 130.0 mL/min/1.73 m 2 (34.9) for mART vs. 126.1 mL/min/1.73 m 2 (30.0) for iNVP; mean difference (95% CI) 3.8 (-3.0 to 10.7), P = 0.27, n = 349/398 (88%). CONCLUSION: Week 26 mean LS-BMC was lower in infants in the mART group compared with the iNVP group. However, this difference (∼0.23 g) was less than one-half SD, considered potentially clinically relevant. No infant renal safety concerns were observed.

Methods optimization and application: Solid phase extraction, ultrasonic extraction and Soxhlet extraction for the determination of antiretroviral drugs in river water, wastewater, sludge, soil and sediment.

The continuous release of antiretroviral drugs into the environmental has resulted in the interest to assess their occurrence in various environmental matrices. Their presence has led to antiretroviral drugs being considered the pollutants of concern due to their possible alterations of the ecosystem as well as the antiviral resistance that may develop upon their unintentional consumption. Therefore, in this work, solid phase extraction (SPE), ultrasonic extraction (UE), Soxhlet extration (SE) and liquid chromatography coupled to photodiode array detector (LC-PDA) methods have been optimized and validated. They were then applied for the simultaneous determination of abacavir, nevirapine and efavirenz antiretroviral drugs in wastewater, river water, sludge, soil and sediments. The percentage recoveries ranged from 71% to 112% for SPE, 88 - 108% for SE and 61 - 104% for UE. Good precision with a relative standard deviation less than 20% in all compounds for all methods was obtained. The LODs and LOQs ranged between 0.68 and 0.77 µg/L and 2.1-2.4 µg/L for SPE; 0.8-0.9 µg/kg and 2.3-2.8 µg/kg for SE and 1.6-2.8 µg/kg and 4.9 - 7.0 µg/kg for UE, respectively. The concentrations ranged from

Prevalence of pretreatment drug resistance in persons initiating and reinitiating antiretroviral therapy in Sri Lanka: results from a national representative survey.

BACKGROUND: We conducted a nationwide cross-sectional study to estimate pretreatment drug resistance (PDR) prevalence in adults initiating ART in Sri Lanka following the WHO's recommendations. METHODS: HIV drug resistance was determined on dried blood spots (DBSs) using population-based sequencing of the protease and reverse transcriptase genes and interpretation was based on Stanford HIVdb v9.0. Analyses were weighted to adjust for multistage sampling and genotypic failure rate. We used logistic regression to assess differences between groups. RESULTS: Overall, in 10% (15 of 150) of patients initiating ART, HIV drug resistance mutations were detected. The prevalence of resistance to NNRTI drugs efavirenz/nevirapine was 8.4% (95% CI 4.6-15.0) but differed among those reporting having prior antiretroviral (ARV) exposure (24.4%, 95% CI 13.8-39.5) compared with 4.6% (95% CI 1.6-12.8) for those reporting as being ARV naive (OR 4.6, 95% CI 1.3-16.6, P = 0.021). PDR to efavirenz/nevirapine was also nearly twice as high among women (14.1%, 95% CI 6.1-29.4) compared with men (7.0%, 95% CI 3.1-14.7) (P = 0.340) and three times high among heterosexuals (10.4%, 95% CI 2.4-35.4) compared with MSM (3.8%, 95% CI 1.1-12.7) (P = 0.028). NRTI PDR prevalence was 3.8% (95% CI 1.1-12.1) and no PI PDR was observed in the study. CONCLUSIONS: A high prevalence of efavirenz/nevirapine PDR was reported, especially in patients with prior ARV exposure, in women and those reporting being heterosexual. These findings highlight the need to fast-track the transition to the WHO-recommended dolutegravir-based first-line ART.

The quality of antiretroviral medicines: an uncertain problem.

OBJECTIVES: Substandard and falsified (SF) antiretrovirals (ARVs) risk poor outcomes and drug resistance, potentially affecting millions of people in need of treatment and prevention. We assessed the available evidence on SF ARV and related medical devices to discuss their potential public health impact. METHODS: Searches were conducted in Embase, PubMed, Google, Google Scholar, Web of Science and websites with interest in ARV quality in English and French up to 30 November 2021. Publications reporting on the prevalence of SF ARV were assessed in a quantitative analysis using the Medicine Quality Assessment Reporting Guidelines (MEDQUARG). RESULTS: We included 205 publications on SF ARV and 11 on SF medical devices. Nineteen prevalence surveys of SF ARV, published between 2003 and 2021, were included, with no surveys relevant to SF medical devices. The prevalence survey sample size ranged from 3 to 2630 samples (median (Q1-Q3): 16.0 (10.5-44.5); 3 (15.8%) used random outlet sampling methods. Of the 3713 samples included in the prevalence surveys, 1.4% (n=51) failed at least one test. Efavirenz, nevirapine and lamivudine-nevirapine-stavudine combination were the most surveyed ARV with failure frequencies of 3.6% (7/193), 2.6% (5/192) and 2.8% (5/177), respectively. The median (Q1%-Q3%) concordance with the MEDQUARG criteria was 42.3% (34.6%-55.8%). CONCLUSION: These results suggest that there are few data in the public domain of the quality of ARV in supply chains; the proportion of SF ARV is relatively low in comparison to other classes of essential medicines. Even a low proportion of the ARV supply chain being poor quality could make a large difference in the HIV/AIDS international landscape. The 95-95-95 target for 2026 and other international targets could be greatly hampered if even 1% of the millions of people taking ARV (for both prevention and prophylaxis) receive medicines that do not meet quality standards. More surveillance of SF ARV is needed to ensure issues are detected.

Brief Report: Long-Term Clinical, Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in Botswana: A Nonrandomized Controlled Clinical Trial.

BACKGROUND: Early antiretroviral treatment (ART) improves outcomes in children, but few studies have comprehensively evaluated the impact of ART started from the first week of life. METHODS: Children diagnosed with HIV within 96 hours of life were enrolled into the Early Infant Treatment Study in Botswana and followed on ART for 96 weeks. Nevirapine, zidovudine, and lamivudine were initiated; nevirapine was switched to lopinavir/ritonavir between weeks 2-5 in accordance with gestational age. Clinical and laboratory evaluations occurred at weeks 1, 2, 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96. FINDINGS: Forty children initiated ART at a median of 2 (IQR 2, 3) days of life; 38 (95%) completed follow-up through 96 weeks, and 2 (5%) died between 12 and 24 weeks. ART was well tolerated; 9 children (24%) experienced a grade 3 or 4 hematologic event, and 2 (5%) required treatment modification for anemia. The median 96-week CD4 count was 1625 (IQR 1179, 2493) cells/mm 3 with only 5/38 (13%) having absolute counts <1000 cells/mm 3 . Although 23 (61%) had at least one visit with HIV-1 RNA ≥40 copies/mL at or after 24 weeks, 28 (74%) had HIV-1 RNA <40 copies/mL at the 96-week visit. Median cell-associated HIV-1 DNA at 84/96-week PBMCs was 1.9 (IQR 1.0, 2.6) log 10 copies/10 6 cells. Pre-ART reservoir size at birth was predictive of the viral reservoir at 84/96 weeks. INTERPRETATION: Initiation of ART in the first week of life led to favorable clinical outcomes, preserved CD4 cell counts, and low viral reservoir through 96 weeks of life.

Antiretroviral postnatal prophylaxis to prevent HIV vertical transmission: present and future strategies.

INTRODUCTION: Maternal antiretroviral therapy (ART) with viral suppression prior to conception, during pregnancy and throughout the breastfeeding period accompanied by infant postnatal prophylaxis (PNP) forms the foundation of current approaches to preventing vertical HIV transmission. Unfortunately, infants continue to acquire HIV infections, with half of these infections occurring during breastfeeding. A consultative meeting of stakeholders was held to review the current state of PNP globally, including the implementation of WHO PNP guidelines in different settings and identifying the key factors affecting PNP uptake and impact, with an aim to optimize future innovative strategies. DISCUSSION: WHO PNP guidelines have been widely implemented with adaptations to the programme context. Some programmes with low rates of antenatal care attendance, maternal HIV testing, maternal ART coverage and viral load testing capacity have opted against risk-stratification and provide an enhanced PNP regimen for all infants exposed to HIV, while other programmes provide infant daily nevirapine antiretroviral (ARV) prophylaxis for an extended duration to cover transmission risk throughout the breastfeeding period. A simplified risk stratification approach may be more relevant for high-performing vertical transmission prevention programmes, while a simplified non-risk stratified approach may be more appropriate for sub-optimally performing programmes given implementation challenges. In settings with concentrated epidemics, where the epidemic is often driven by key populations, infants who are found to be exposed to HIV should be considered at high risk for HIV acquisition. All settings could benefit from newer technologies that promote retention during pregnancy and throughout the breastfeeding period. There are several challenges in enhanced and extended PNP implementation, including ARV stockouts, lack of appropriate formulations, lack of guidance on alternative ARV options for prophylaxis, poor adherence, poor documentation, inconsistent infant feeding practices and in inadequate retention throughout the duration of breastfeeding. CONCLUSIONS: Tailoring PNP strategies to a programmatic context may improve access, adherence, retention and HIV-free outcomes of infants exposed to HIV. Newer ARV options and technologies that enable simplification of regimens, non-toxic potent agents and convenient administration, including longer-acting formulations, should be prioritized to optimize the effect of PNP in the prevention of vertical HIV transmission.

Case study on antiretroviral drugs uptake from soil irrigated with contaminated water: Bio-accumulation and bio-translocation to roots, stem, leaves, and fruits.

This study aimed to evaluate the potential of uptake of the commonly used antiretroviral drugs (ARVDs) in South Africa (abacavir, nevirapine, and efavirenz) by vegetable plants (beetroot, spinach, and tomato) from contaminated soil culture. The study results showed that all the studied vegetables have the potential to take up abacavir, nevirapine, and efavirenz from contaminated soil, be absorbed by the root, and translocate them to the aerial part of the plants. The total percentage of ARVDs found in the individual plant was mainly attributed to abacavir which contributed 53% in beetroot and 48% in spinach, while efavirenz (42%) was the main contributor in tomato. Abacavir was found at high concentrations to a maximum of 40.21 µg/kg in the spinach root, 18.43 µg/kg in the spinach stem, and 6.77 µg/kg in the spinach soil, while efavirenz was the highest concentrations, up to 35.44 µg/kg in tomato leaves and 8.86 µg/kg in tomato fruits. Spinach roots accumulated more ARVDs than beetroot and tomato however, the concentrations were not statistically different. Hydrophobicity was the main effect on the linearity, accumulation, and translocation of ARVDs. This study advances knowledge on the fate of ARVDs in agroecosystems, particularly in plant root - ARVD interaction and the resulting potentially toxic effects on plants. These results suggest that the quality of water used for crop irrigation needs to be assessed prior to irrigation to avoid vegetable plant pollution as contaminated water results in the contaminants uptake by plants. This may lead to the transfer of pollutants to the edible crops parts of and thus be unintentionally consumed by humans. More studies need to be continuously conducted to evaluate ARVDs bioaccumulation and their mechanism of uptake by other vegetables. The use of the pot-plant system can be recommended because it closely relates to the agricultural world.