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.

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.

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.

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.

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.

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.

Virologic status and pattern of drug resistance mutation among ART-experienced HIV-infected patients in Butuo County, China.

OBJECTIVES: To assess the virological outcomes, prevalence of HIV drug resistance mutation (DRM), and correlates in Butuo County. METHODS: We conducted a cross-sectional study. Virological failure (VF) was defined as HIV-1 RNA ≥1000 copies/mL and on antiretroviral therapy (ART) for ≥6 months. Genotypic drug resistance was performed among VF cases. Correlates of DRM were identified using multivariate logistic regression. RESULTS: The overall virological suppression rate was 85.3%; DRM was detected in 42.6% (517/1215) VF cases and 6.2% of the sample patients. A total of 90.9% of patients were infected with HIV-1 CRF07_BC subtype. The prevalence of DRM to nucleoside reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) were 46.0% and 96.9%, respectively. The most prevalent mutation for NRTI was M184V (84.5%). Lamivudine (3TC), emtricitabine (FTC), and abacavir (ABC) had the highest resistance rates. For NNRTI, K103N (60.7%), nevirapine (NVP), and efavirenz (EFV) had the highest resistance rates and cross resistance to rilpivirine (RPV), doravirine (DOR), and etravirine (ETR). Ritonavir boosted lopinavir (LPV/r) resistance rate was extremely low. The occurrence of DRM was associated with age at ART ≤18 years, baseline CD4 count ≤200 cells/mL, NVP-based regimen, and ART duration >3 years. CONCLUSION: A relatively high proportion of VF and broad DRM for NRTI and NNRTI were observed, causing high-level resistance to first-line NRTI, NNRTI, and next generation NNRTI. Our findings necessitate the implementation of scaling up virological monitoring, adherence support, and timely switching to an LPV/r-containing regimen when patients with VF to reduce the occurrence of DRM.

Impact of Drug Exposure on Resistance Selection Following Artemether-Lumefantrine Treatment for Malaria in Children With and Without HIV in Uganda.

Artemisinin-based combination therapies (ACTs) are the primary treatment for malaria. It is essential to characterize the pharmacokinetics (PKs) and pharmacodynamics (PDs) of ACTs in vulnerable populations at risk of suboptimal dosing. We developed a population PK/PD model using data from our previous study of artemether-lumefantrine in HIV-uninfected and HIV-infected children living in a high-transmission region of Uganda. HIV-infected children were on efavirenz-, nevirapine-, or lopinavir-ritonavir-based antiretroviral regimens, with daily trimethoprim-sulfamethoxazole prophylaxis. We assessed selection for resistance in two key parasite transporters, pfcrt and pfmdr1, over 42-day follow-up and incorporated genotyping into a time-to-event model to ascertain how resistance genotype in relation to drug exposure impacts recurrence risk. Two hundred seventy-seven children contributed 364 episodes to the model (186 HIV-uninfected and 178 HIV-infected), with recurrent microscopy-detectable parasitemia detected in 176 episodes by day 42. The final model was a two-compartment model with first-order absorption and an estimated age effect on bioavailability. Systemic lumefantrine exposure was highest with lopinavir-ritonavir, lowest with efavirenz, and equivalent with nevirapine and HIV-uninfected children. HIV status and lumefantrine concentration were significant factors associated with recurrence risk. Significant selection was demonstrated for pfmdr1 N86 and pfcrt K76 in recurrent infections, with no evidence of selection for pfmdr1 Y184F. Less sensitive parasites were able to tolerate lumefantrine concentrations ~ 3.5-fold higher than more sensitive parasites. This is the first population PK model of lumefantrine in HIV-infected children and demonstrates selection for reduced lumefantrine susceptibility, a concern as we confront the threat to ACTs posed by emerging artemisinin resistance in Africa.

Risk factors and prognostic significance of platelet count abnormalities in children with HIV infection on antiretroviral therapy.

OBJECTIVES: To establish the incidence, risk factors and correlation with survival of thrombocytopenia and thrombocytosis (T/T) among children with HIV infection (CWH). DESIGN: A retrospective nested case control study of patients 0-18 years in five Baylor International Pediatric AIDS Initiative (BIPAI) centers in sub-Sahara Africa, 2004-2014. METHODS: Clinical and laboratory variables including complete blood counts (CBC) were extracted from the BIPAI electronic medical record system. Incident cases of T/T were identified and frequency-matched on follow-up time with controls with normal platelets. We calculated the prevalence and incidence density of T/T and used conditional logistic regression to evaluate their association with selected clinical variables. We constructed Kaplan-Meier curves and a Cox proportional hazards model to evaluate the impact of T/T on survival. RESULTS: Two thousand, one hundred and nine children were sampled. The incidence density of thrombocytopenia was 1 per 57.9 (95% confidence interval [CI] 50.3-66.8) CWH-years. Thrombocytopenia was higher in children with WHO Stage III/IV, lower in children on zidovudine, and had no association with use of lamivudine or nevirapine, CD4 + suppression, age, and nutrition status. Thrombocytopenia was independently associated with 2.2-fold higher mortality (95% CI 1.62-3.08). The incidence density of thrombocytosis was 1 per 11.4 (95% CI 10.7-12.1) CWH-years. Thrombocytosis was associated with higher CD4 + cell count, younger age, and use of lamivudine or nevirapine, and did not impact survival. CONCLUSIONS: Platelet count is a clinically valuable biomarker of HIV clinical progression and mortality. Laboratory studies are necessary to elucidate the mechanisms of T/T.

Nevirapine plasma concentration is associated with virologic failure and the emergence of drug-resistant mutations among HIV patients in Kenya: A cross sectional study.

This study aimed to determine the association between the plasma concentration of nevirapine (NVP) and clinical outcomes. In this cross-sectional study, sociodemographic and clinical data were collected from 233 HIV patients receiving NVP-based first-line antiretroviral therapy (ART) regimens in Nairobi, Kenya. The mean age was 41.2 (SD ±â€…11.9) years. Fifty-four (23.2%) patients had virological failure (>1000 copies/mL), whereas 23 (9.9%) were infected with drug-resistant HIV strains. Eleven patients had nucleoside reverse transcriptase inhibitor resistance mutations, including M184V and T215Y, whereas 22 had non-nucleoside reverse transcriptase inhibitor resistance mutations, including G190A, K103N, V106A, Y181C, A98G, and Y188L. The median NVP plasma concentration was 6180 ng/mL (IQR 4444-8843 ng/mL), with 38 (16.3%) patients having suboptimal NVP plasma levels of <3400 ng/mL. The majority 23 of the 38 (60.5%) patients with NVP Cmin < 3400 ng/mL were significantly infected with drug-resistant HIV virus (P = .001). In the multivariate analysis, the time taken to arrive at the ART clinic (ß -11.1, 95% CI -21.2 to -1.1; P = .031), higher HIV viral load (ß -2008, 95% CI -3370.7 to -645.3; P = .004), and the presence of HIV drug resistance mutation (ß 3559, 95% CI 2580.8-4537.2; P = .0001) were associated with NVP plasma concentration. A significant proportion of patients receiving the NVP-based regimen had supra- and sub-therapeutic plasma concentrations. Higher HIV viral load and the presence of HIV drug-resistant mutations are important factors associated with NVP plasma concentrations.

Findings from a pilot study of buprenorphine population pharmacokinetics: A potential effect of HIV on buprenorphine bioavailability.

BACKGROUND: Buprenorphine is widely used in the treatment of opioid use disorder (OUD). There are few pharmacokinetic models of buprenorphine across diverse populations. Population pharmacokinetics (POPPK) allows for covariates to be included in pharmacokinetic studies, thereby opening the potential to evaluate the effect of comorbidities, medications, and other factors on buprenorphine pharmacokinetics. This pilot study used POPPK to explore buprenorphine pharmacokinetics in patients with and without HIV receiving buprenorphine for OUD. METHODS: Plasma buprenorphine levels were measured in 54 patients receiving buprenorphine for OUD just prior to and 2-5 h following regular buprenorphine dosing. A linear one-compartment POPPK model with first-order estimation was used to evaluate buprenorphine clearance (CL/F) and volume of distribution (V/F). Covariates included weight and HIV status. RESULTS: All HIV+ patients reported complete past-month adherence to taking antiretroviral therapy that included either efavirenz or nevirapine. Buprenorphine CL/F was 76% higher in HIV+ patients (n = 17) than HIV- patients (n = 37). Buprenorphine V/F was 41% higher in the HIV+ patients. CONCLUSIONS: POPPK can be used to model buprenorphine pharmacokinetics in a real-world clinical population. While interactions between ART and buprenorphine alter buprenorphine CL/F, we also found alteration in V/F. Proportionate changes in CL/F and V/F might indicate a primary effect on bioavailability (F) rather than two separate effects. These findings indicate reduced buprenorphine bioavailability in patients with HIV.

Lower Insulin Sensitivity in Newborns With In Utero HIV and Antiretroviral Exposure Who Are Uninfected in Botswana.

BACKGROUND: Few data exist on early-life metabolic perturbations in newborns with perinatal HIV and antiretroviral (ARV) exposure but uninfected (HEU) compared to those perinatally HIV unexposed and uninfected (HUU). METHODS: We enrolled pregnant persons with HIV (PWH) receiving tenofovir (TDF)/emtricitabine or lamivudine (XTC) plus dolutegravir (DTG) or efavirenz (EFV), and pregnant individuals without HIV, as well as their liveborn infants. Newborns were randomized to receive either zidovudine (AZT) or nevirapine (NVP) postnatal prophylaxis. Preprandial homeostasis model assessment for insulin resistance (HOMA-IR) was assessed at birth and 1 month. Linear mixed models were fit to assess the association between in utero HIV/ARV exposure and average HOMA-IR from birth to 1 month, adjusting for confounders. RESULTS: Of 450 newborns, 306 were HEU. HOMA-IR was higher in newborns HEU versus HUU after adjusting for confounders (mean difference of 0.068 in log HOMA-IR, P = .037). Among newborns HEU, HOMA-IR was not significantly different between TDF/XTC/DTG versus TDF/XTC/EFV in utero ARV exposure and between AZT versus NVP newborn postnatal prophylaxis arms. CONCLUSIONS: Newborns HEU versus HUU had lower insulin sensitivity at birth and at 1 month of life, raising potential concern for obesity and other metabolic perturbations later in life for newborns HEU. CLINICAL TRIALS REGISTRATION: NCT03088410.

Rate of virological failure and HIV-1 drug resistance among HIV-infected adolescents in routine follow-up on health facilities in Cameroon.

The objective of this study was to determine the rates of virological failure (VF) and HIV drug resistance (HIVDR) amongst adolescents on antiretroviral Therapy (ART). A retrospectively designed study was conducted in 10 healthcare centers for adolescents living with HIV (ALHIV) in the two main cities of Cameroon (Yaoundé and Douala), from November 2018 to May 2019. Sociodemographic, clinical, therapeutic and laboratory parameters were collected from medical records. All enrolled ALHIV had viral load (VL) measurements following the national guidelines. All patients with a VL ≥ 1000 copies/ml were called to perform genotyping tests. The chi-square test was used to determine the factors associated with VF. Out of the 1316 medical records of ALHIV, we included 1083 ALHIV having a VL result. Among them, 276 (25.5%) were experiencing VF, and VF was significantly higher in ALHIV with suboptimal adherence (p<0.001), older adolescents (p<0.05), those who lived outside the city where they were receiving ART (p<0.006), severely immunocompromised (p<0.01) and started ART at infancy (p<0.02). Among the 45/276 (16.3%) participants with an available genotyping resistance testing (GRT) result, the overall rate of HIVDR was 93.3% (42/45). The most common mutations were K103N (n = 21/42, 52.3%) resulting in high-level resistance to Efavirenz and Nevirapine, followed by M184V (n = 20/42, 47.6%) and thymidine analog mutations (n = 15/42, 35.7%) associated with high-level resistance to Lamivudine and Zidovudine respectively. The high rate of VF and HIVDR among ALHIV regularly followed in health facilities in Cameroon highlights the need to develop interventions adapted to an adolescent-centered approach to preserve future ART options.

Antiretroviral therapy resistance mutations among HIV infected people in Kazakhstan.

In Kazakhstan, the number of people living with HIV (PLHIV) has increased steadily by 39% since 2010. Development of antiretroviral therapy (ART) resistance mutations (ARTRM) is a major hurdle in achieving effective treatment and prevention against HIV. Using HIV pol sequences from 602 PLHIV from Kazakhstan, we analyzed ARTRMs for their association with factors that may promote development of ARTRMs. 56% PLHIV were infected with HIV subtype A6 and 42% with CRF02_AG. The ARTRM Q174K was associated with increased viral load and decreased CD4+ cell count, while infection with CRF02_AG was associated with a lower likelihood of Q174K. Interestingly, CRF02_AG was positively associated with the ARTRM L10V that, in turn, was observed frequently with darunavir administration. Infection with CRF02_AG was positively associated with the ARTRM S162A that, in turn, was frequently observed with the administration of nevirapine, also associated with lower CD4 counts. Zidovudine or Nevirapine receipt was associated with the development of the ARTRM E138A, that, in turn, was associated with lower CD4 counts. Determination of a patient's HIV variant can help guide ART choice in Kazakhstan. For example, PLHIV infected with CRF02_AG will benefit less from darunavir and nevirapine, and emtricitabine should replace zidovudine.

Contraceptive implant use duration is not associated with breakthrough pregnancy among women living with HIV and using efavirenz: a retrospective, longitudinal analysis.

INTRODUCTION: Contraceptive implants containing etonogestrel and levonorgestrel have emerged as popular contraceptive options among women in areas of high HIV burden in sub-Saharan Africa. However, recent pharmacokinetic data have shown drug-drug interactions between implants and efavirenz-containing antiretroviral therapy (ART), reducing the effectiveness of the implants. Here, we evaluated pregnancy incidence in 6-month intervals following implant initiation among women using efavirenz and contraceptive implants to assess whether the risk of breakthrough pregnancy is higher after specific periods of implant use. METHODS: We used data from a retrospective longitudinal analysis of women living with HIV ages 18-45 years in western Kenya who attended HIV-care facilities between 2011 and 2015. We used Cox proportional hazard models to compute hazard ratios (HRs) for breakthrough pregnancy by implant type and ART regimen. Depending on the model, we adjusted for socio-demographic and clinical factors, programme, site and interaction between calendar time and ART regimen. We utilized inverse probability weights (IPWs) to account for three sampling phases (electronic medical record [EMR], chart review and phone interview) and calculated overall parameter estimates. RESULTS: Women contributed 14,768 woman-years from the largest sampling phase (EMR). The median age was 31 years. Women used etonogestrel implants for 26-69% of the time and levonorgestrel implants for 7-31% of the time, depending on the sampling phase. Women used efavirenz, nevirapine or no ART for 27-33%, 40-46% and 15-26% of follow-ups, respectively. When combining sampling phases, there was little evidence to suggest that the relative hazard of pregnancy among efavirenz-containing ART users relative to nevirapine-containing ART changed with length of time on implants: IPW-adjusted HR of 3.1 (CI: [1.5; 6.4]) at 12 months, 3.4 (CI: [1.8; 6.3]) at 24 months, 3.8 (CI: [1.9; 7.7]) at 36 months and 4.2 (CI: [1.6; 11.1]) at 48 months (interaction p-value = 0.88). Similarly, no significant change in HRs over time was found when comparing women not using ART to nevirapine-containing ART users (interaction p-value = 0.49). CONCLUSIONS: We did not find evidence to suggest implants being more fallible from drug-drug interactions with efavirenz at later time intervals of implant use. Thus, we would not recommend shortening the duration of implant use or replacing implants sooner when concomitantly used with efavirenz.