Prevalence of neurotoxicity symptoms among postpartum women on isoniazid preventive therapy and efavirenz-based treatment for HIV: an exploratory objective of the IMPAACT P1078 randomized trial.

BACKGROUND: This exploratory analysis investigates the prevalence and risk factors of neurocognitive toxicity in postpartum women on HIV treatment in response to a concern of an Isoniazid Preventive Therapy (IPT)/Efavirenz interaction. TRIAL DESIGN: Pregnant women on HIV treatment from countries with high TB prevalence were randomized in IMPAACT P1078 to 28 weeks of IPT started either during pregnancy or at 12 weeks postpartum. Partway through study implementation, the Patient Health Questionnaire 9, the cognitive complaint questionnaire, and the Pittsburg Sleep Quality Index were added to evaluate depression, cognitive function, and sleep quality at postpartum weeks. Screening for peripheral neuropathy was conducted throughout the study. METHODS: We summarized percentages of women with depression symptoms, cognitive dysfunction, poor sleep quality and peripheral neuropathy and assessed the association of 11 baseline risk factors of neurotoxicity using logistic regression, adjusted for gestational age stratum. RESULTS: Of 956 women enrolled, 749 (78%) had at least one neurocognitive evaluation. During the postpartum period, the percentage of women reporting at least mild depression symptoms, cognitive complaint and poor sleep quality peaked at 13%, 8% and 10%, respectively, at 12 weeks, and the percentage of women reporting peripheral neuropathy peaked at 13% at 24 weeks. There was no evidence of study arm differences in odds of all four neurotoxic symptoms. CONCLUSIONS: Timing of IPT initiation and EFV use were not associated with symptoms of neurotoxicity. Further study is advised to formally assess risk factors of neurotoxicity.

Geographical Differences in the Self-Reported Functional Impairment of People With Human Immunodeficiency Virus (HIV) and Associations With Cardiometabolic Risk.

BACKGROUND: We sought to explore multinational differences in functional status by global burden of disease (GBD) regions in the REPRIEVE cohort. METHODS: REPRIEVE is a prospective, double-blind, randomized, placebo-controlled, multicenter, phase III primary cardiovascular prevention study of pitavastatin calcium vs placebo among people with human immunodeficiency virus (HIV, PWH) ages 40-75 on antiretroviral therapy (ART). GBD super regions were defined using World Health Organization classifications. Participants were categorized by impairment on the Duke Activity Status Instrument (DASI: none, some, moderate, severe). Logistic regression models examined risk factors and GBD regions associated with functional impairment. The association between functional impairment and cardiometabolic risk was also explored. RESULTS: Of 7736 participants, the majority were from high-income countries (n = 4065), were male (65%), and had received ART for ≥ 10 years. The median DASI score was 58.2 (interquartile range [IQR] 50.2, 58.2); 36% reported at least some impairment. In adjusted analyses, functional impairment was significantly more frequent among participants from Southeast/East Asia. Other factors associated with greater impairment included female sex, Black race, older age, current/former smoking, higher body mass index, use of ART for ≥ 10 years, and select ART regimens; differences were seen in risks across GBD regions. Functional impairment was associated with increased cardiometabolic risk. CONCLUSIONS: Over 1/3 of middle-aged and older PWH in a global cohort across diverse GBD regions demonstrate functional impairments. The associations between DASI and cardiometabolic risk suggest that a measure of functional status may improve risk prediction; these longitudinal associations will be further investigated over REPRIEVE trial follow-up.

Poor sleep quality is linked to increased frailty in middle-aged people living with HIV in Botswana.

This work aims to evaluate associations between self-reported sleep health and frailty in Botswana, a sub-Saharan Africa setting. Fifty persons living with HIV (PLWH) on suppressive antiretroviral therapy (ART) and fifty HIV seronegative control participants are enrolled in Botswana. Sleep quality is scored subjectively as "good" or "poor" based on self-report. A frailty index (FI) is constructed based on thirty-three health deficits related to body mass index, waist circumference, physical activity, emotional status, and fatigue, and scored ranging between 0 (no deficit present) and 1 (all deficits present). Sleep quality between PLWH and controls is compared using logistic regression; linear regression is performed to compare the FI between them. Linear regressions are performed to examine the association between the FI and sleep quality stratified by HIV serostatus. Age, sex, and comorbidities are adjusted; when relevant, CD4 cell and ART duration are controlled. PLWH display 2.88 (95% CI: 1.22-6.79, p = 0.02) higher odds of having poor sleep than controls. Having poor sleep is associated with increased FI in PLWH but not in controls. Specifically, compared with PLWH who have good sleep, PLWH who report poor sleep have a > 1 standard deviation (p < 0.0001) increase in their FI score.

High prevalence of albuminuria among adult males living with HIV in Botswana.

Chronic HIV disease is associated with a fivefold increase in albuminuria outside of sub-Saharan Africa. However, very little is known about albuminuria risk among people living with HIV (PLWH) in sub-Saharan Africa. Therefore, we conducted a cross-sectional observational HIV clinic-based study of albuminuria among 1533 adults aged 21 years or older between January 2020 and January 2021 in Gaborone, Botswana. Clinical albuminuria was defined using a sex-based albumin‒creatinine ratio (ACR) of 25-355 mg/g for females and 17-250 mg/g for males. The study population mean age was 48.5 (SD 10.3) years, and 764/1533 (49.7%) were female. The overall prevalence of albuminuria was 20.7% (95% CI 18.7%, 22.8%). A higher proportion of males were more likely to be categorized as having albuminuria than females, 25% (95% CI 22.0, 28.2) versus 16.4% (95% CI 13.8,19.2), P value < 0.001. In the final multivariate models, predictors of albuminuria differed by sex group. Larger longitudinal studies are required to evaluate the impact of albuminuria among PLWH with particular emphasis on the effect of sex on the risk of albuminuria.

A mixed methods approach identifying facilitators and barriers to guide adaptations to InterCARE strategies: an integrated HIV and hypertension care model in Botswana.

BACKGROUND: Botswana serves as a model of success for HIV with 95% of people living with HIV (PLWH) virally suppressed. Yet, only 19% of PLWH and hypertension have controlled blood pressure. To address this gap, InterCARE, a care model that integrates HIV and hypertension care through a) provider training; b) adapted electronic health record; and c) treatment partners (peer support), was designed. This study presents results from our baseline assessment of the determinants and factors used to guide adaptations to InterCARE implementation strategies prior to a hybrid type 2 effectiveness-implementation study. METHODS: This study employed a convergent mixed methods design across two clinics (one rural, one urban) to collect quantitative and qualitative data through facility assessments, 100 stakeholder surveys (20 each PLWH and hypertension, existing HIV treatment partners, clinical healthcare providers (HCPs), and 40 community leaders) and ten stakeholder key informative interviews (KIIs). Data were analyzed using descriptive statistics and deductive qualitative analysis organized by the Consolidated Framework for Implementation Research (CFIR) and compared to identify areas of convergence and divergence. RESULTS: Although 90.3% of 290 PLWH and hypertension at the clinics were taking antihypertensive medications, 52.8% had uncontrolled blood pressure. Results from facility assessments, surveys, and KIIs identified key determinants in the CFIR innovation and inner setting domains. Most stakeholders (> 85%) agreed that InterCARE was adaptable, compatible and would be successful at improving blood pressure control in PLWH and hypertension. HCPs agreed that there were insufficient resources (40%), consistent with facility assessments and KIIs which identified limited staffing, inconsistent electricity, and a lack of supplies as key barriers. Adaptations to InterCARE included a task-sharing strategy and expanded treatment partner training and support. CONCLUSIONS: Integrating hypertension services into HIV clinics was perceived as more advantageous for PLWH than the current model of hypertension care delivered outside of HIV clinics. Identified barriers were used to adapt InterCARE implementation strategies for more effective intervention delivery. TRIAL REGISTRATION: ClinicalTrials.gov, ClinicalTrials.gov Identifier: NCT05414526 . Registered 18 May 2022 - Retrospectively registered.

Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation study.

BACKGROUND: Child-friendly fixed-dose combination (FDC) antiretroviral therapy (ART) options are limited. We evaluated the pharmacokinetics, safety, and tolerability of dispersible and immediate-release FDC abacavir, dolutegravir, and lamivudine taken once per day in children younger than 12 years with HIV. METHODS: IMPAACT 2019 was an international, phase 1-2, multisite, open-label, non-comparative dose-confirmation study of abacavir, dolutegravir, and lamivudine in children younger than 12 years. Participants were enrolled across five weight bands: those weighing 6 kg to less than 25 kg received abacavir (60 mg), dolutegravir (5 mg), and lamivudine (30 mg) dispersible tablets (three to six tablets depending on body weight), and those weighing 25 kg to less than 40 kg received abacavir (600 mg), dolutegravir (50 mg), and lamivudine (300 mg) in an immediate-release tablet. At entry, participants were ART naive or ART experienced and virologically suppressed on stable ART for 6 months or more. Dose confirmation was based on pharmacokinetic and safety criteria in the first five to seven participants in each weight band to week 4; all participants were followed up to week 48. We present the results for the primary objectives to assess pharmacokinetics, confirm dosing, and evaluate safety through 24 weeks across all weight bands. The trial is registered with ClinicalTrials.gov (NCT03760458). FINDINGS: 57 children were enrolled and initiated study drug (26 [46%] female and 31 [54%] male; 37 [65%] Black, 18 [32%] Asian, and 1 [2%] had race reported as unknown). Within each weight band, 6 kg to less than 10 kg, 10 kg to less than 14 kg, 14 kg to less than 20 kg, 20 kg to less than 25 kg, and 25 kg or higher: the geometric mean dolutegravir area under the concentration time curve over the 24 h dosing interval (AUC0-24 h) was 75·9 h·µg/mL (33·7%), 91·0 h·µg/mL (36·5%), 71·4 h·µg/mL (23·5%), 84·4 h·µg/mL (26·3%), and 71·8 h·µg/mL (13·9%); dolutegravir concentrations 24 h after dosage (C24 h) were 0·91 µg/mL (67·6%), 1·22 µg/mL (77·5%), 0·79 µg/mL (44·2%), 1·35 µg/mL (95·5%), and 0·98 µg/mL (27·9%); abacavir AUC0-24 h was 17·7 h·µg/mL (38·8%), 19·8 h·µg/mL (50·6%), 15·1 h·µg/mL (40·3%), 17·4 h·µg/mL (19·4%), and 25·7 h·µg/mL (14·6%); lamivudine AUC0-24 h was 10·7 h·µg/mL (46·0%), 14·2 h·µg/mL (23·9%), 13·0 h·µg/mL (15·6%), 14·5 h·µg/mL (16·6%), and 21·7 h·µg/mL (26·2%), respectively. Pharmacokinetic targets and safety criteria were met within each weight band, and thus dosing of abacavir, dolutegravir, and lamivudine was confirmed at the originally selected doses. 54 (95%) of participants were treatment experienced and all who continued taking the study drug remained virologically suppressed (<200 copies per mL) through week 24. Virological suppression was achieved in two of three participants who were ART naive by week 24. There were no grade 3 or higher adverse events related to abacavir, dolutegravir, and lamivudine and no discontinuations because of toxicity to week 24. Both formulations were well tolerated. INTERPRETATION: Dosing of abacavir, dolutegravir, and lamivudine was confirmed in children weighing 6 kg to less than 40 kg, and both FDC formulations were safe, well tolerated, and efficacious through 24 weeks of treatment. These findings support global efforts to expand the availability of FDC abacavir, dolutegravir, and lamivudine to children with HIV. FUNDING: National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Mental Health, ViiV Healthcare, and GlaxoSmithKline.

Current co-morbidities burden in patients living with HIV in low- and middle-income countries.

PURPOSE OF REVIEW: The present review aims to decipher common co-morbidities faced by people living with HIV in low- to middle-income countries, and in particular the sub-Saharan region, which hosts the majority of the HIV burden worldwide. RECENT FINDINGS: Well-controlled chronic HIV disease is strongly associated with an increased risk of developing cardiovascular disease. This is partly due to the natural aging process, however recent studies show that using antiretroviral therapy as well as the HIV disease itself may be predisposing factors to the development of cardiovascular diseases, creating a new burden for healthcare facilities in the region. Furthermore, newly completed studies assessing inflammation marker albuminuria and age-related syndrome frailty have been found in a higher prevalence than in non-HIV people, with increased morbidity and mortality. SUMMARY: As antiretroviral medication continues to be well supplied in the region and well tolerated by patients living with HIV, this group is now reckoning with cardiovascular ailments faced by all ageing population therefore there is a need for cardiovascular care systems to be better integrated within the existing, well-performing HIV care cascade to address this burden.

Cost-effectiveness of cryptococcal antigen screening at CD4 counts of 101-200 cells/µL in Botswana.

Background: Cryptococcal antigen (CrAg) screening in individuals with advanced HIV reduces cryptococcal meningitis (CM) cases and deaths. The World Health Organization recently recommended increasing screening thresholds from CD4 ≤100 cells/µL to ≤200 cells/µL. CrAg screening at CD4 ≤100 cells/µL is cost-effective; however, the cost-effectiveness of screening patients with CD4 101-200 cells/µL requires evaluation. Methods: Using a decision analytic model with Botswana-specific cost and clinical estimates, we evaluated CrAg screening and treatment among individuals with CD4 counts of 101-200 cells/µL. We estimated the number of CM cases and deaths nationally and treatment costs without screening. For screening we modeled the number of CrAg tests performed, number of CrAg-positive patients identified, proportion started on pre-emptive fluconazole, CM cases and deaths. Screening and treatment costs were estimated and cost per death averted or disability-adjusted life year (DALY) saved compared with no screening. Results: Without screening, we estimated 142 CM cases and 85 deaths annually among individuals with CD4 101-200 cells/µL, with treatment costs of $368,982. With CrAg screening, an estimated 33,036 CrAg tests are performed, and 48 deaths avoided (1,017 DALYs saved).  While CrAg screening costs an additional $155,601, overall treatment costs fall by $39,600 (preemptive and hospital-based CM treatment), yielding a net increase of $116,001. Compared to no screening, high coverage of CrAg screening and pre-emptive treatment for CrAg-positive individuals in this population avoids one death for $2440 and $114 per DALY saved. In sensitivity analyses assuming a higher proportion of antiretroviral therapy (ART)-naïve patients (75% versus 15%), cost per death averted was $1472; $69 per DALY saved. Conclusions: CrAg screening for individuals with CD4 101-200 cells/µL was estimated to have a modest impact, involve additional costs, and be less cost-effective than screening populations with CD4 counts ≤100 cells/µL. Additional CrAg screening costs must be considered against other health system priorities.

Cost-effectiveness of reflex laboratory-based cryptococcal antigen screening for the prevention and treatment of cryptococcal meningitis in Botswana.

Background: Cryptococcal antigen (CrAg) screening for antiretroviral therapy (ART)-naïve adults with advanced HIV/AIDS can reduce the incidence of cryptococcal meningitis (CM) and all-cause mortality. We modeled the cost-effectiveness of laboratory-based "reflex" CrAg screening for ART-naïve CrAg-positive patients with CD4<100 cells/µL (those currently targeted in guidelines) and ART-experienced CrAg-positive patients with CD4<100 cells/µL (who make up an increasingly large proportion of individuals with advanced HIV/AIDS). Methods: A decision analytic model was developed to evaluate CrAg screening and treatment based on local CD4 count and CrAg prevalence data, and realistic assumptions regarding programmatic implementation of the CrAg screening intervention. We modeled the number of CrAg tests performed, the number of CrAg positives stratified by prior ART experience, the proportion of patients started on pre-emptive antifungal treatment, and the number of incident CM cases and CM-related deaths. Screening and treatment costs were evaluated, and cost per death or disability-adjusted life year (DALY) averted estimated. Results: We estimated that of 650,000 samples undergoing CD4 testing annually in Botswana, 16,364 would have a CD4<100 cells/µL and receive a CrAg test, with 70% of patients ART-experienced at the time of screening. Under base model assumptions, CrAg screening and pre-emptive treatment restricted to ART-naïve patients with a CD4<100 cells/µL prevented 20% (39/196) of CM-related deaths in patients undergoing CD4 testing at a cost of US$2 per DALY averted. Expansion of preemptive treatment to include ART-experienced patients with a CD4<100 cells/µL resulted in 55 additional deaths averted (a total of 48% [94/196]) and was cost-saving compared to no screening. Findings were robust across a range of model assumptions. Conclusions: Reflex laboratory-based CrAg screening for patients with CD4<100 cells/µL is a cost-effective strategy in Botswana, even in the context of a relatively low proportion of advanced HIV/AIDS in the overall HIV-infected population, the majority of whom are ART-experienced.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study.

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results.