Six months survival and risk factors for attrition for patients detected with cryptococcal antigenemia through screening in Malawi.

MAIN OBJECTIVE: A cohort of adult Malawian people living with HIV (PLHIV) testing positive for cryptococcal antigenemia was observed and followed to determine the outcomes and risk factors for attrition. METHODS CONCEPT: Eligible PLHIV were enrolled at 5 health facilities in Malawi, representing different levels of health care. ART naïve patients, ART defaulters returning to care, and patients with suspected or confirmed ART treatment failure with CD4 <200 cells/µL or clinical stage 3 or 4 were enrolled and received CrAg tests on whole blood specimens from August 2018 to August 2019. Hospitalized PLHIV were enrolled and tested for CrAg from January 2019 to August 2019, regardless of CD4 or clinical stage. Patients with cryptococcal antigenemia were managed per Malawian clinical guidelines and were followed up for six months. Survival and risk factors for attrition at six months were assessed. RESULTS: A total of 2146 patients were screened and 112 (5.2%) had cryptococcal antigenemia. Prevalence ranged from 3.8% (Mzuzu Central Hospital) to 25.8% (Jenda Rural Hospital). Of the 112 patients with antigenemia, 33 (29.5%) were diagnosed with concurrent CM at the time of enrollment. Six-month crude survival of all patients with antigenemia (regardless of CM status) ranged from 52.3% (assuming lost-to-follow-up (LTFU) patients died) to 64.9% (if LTFU survived). Patients who were diagnosed with concurrent CM by CSF test had poor survival (27.3-39.4%). Patients with antigenemia who were not diagnosed with concurrent CM had 71.4% (if LTFU died)- 89.8% (if LTFU survived) survival at six months. In adjusted analyses, patients with cryptococcal antigenemia detected after admission to inpatient care (aHR: 2.56, 1.07-6.15) and patients with concurrent CM at the time of positive antigenemia result (aHR: 2.48, 1.04-5.92) had significantly higher hazard of attrition at six months. CONCLUSIONS: Overall, our findings indicate a need for routine access to CrAg screening and pre-emptive fluconazole treatment as a way to detect cryptococcal antigenemia and prevent CM in outpatient and inpatient settings. Rapid access to diagnosis and treatment for cryptococcal meningitis (CM) with gold-standard antifungals is needed to improve survival of patients with advanced HIV in Malawi.

Cost-effectiveness of voluntary medical male circumcision for HIV prevention across sub-Saharan Africa: results from five independent models.

BACKGROUND: Voluntary medical male circumcision (VMMC) has been a recommended HIV prevention strategy in sub-Saharan Africa since 2007, particularly in countries with high HIV prevalence. However, given the scale-up of antiretroviral therapy programmes, it is not clear whether VMMC still represents a cost-effective use of scarce HIV programme resources. METHODS: Using five existing well described HIV mathematical models, we compared continuation of VMMC for 5 years in men aged 15 years and older to no further VMMC in South Africa, Malawi, and Zimbabwe and across a range of setting scenarios in sub-Saharan Africa. Outputs were based on a 50-year time horizon, VMMC cost was assumed to be US$90, and a cost-effectiveness threshold of US$500 was used. FINDINGS: In South Africa and Malawi, the continuation of VMMC for 5 years resulted in cost savings and health benefits (infections and disability-adjusted life-years averted) according to all models. Of the two models modelling Zimbabwe, the continuation of VMMC for 5 years resulted in cost savings and health benefits by one model but was not as cost-effective according to the other model. Continuation of VMMC was cost-effective in 68% of setting scenarios across sub-Saharan Africa. VMMC was more likely to be cost-effective in modelled settings with higher HIV incidence; VMMC was cost-effective in 62% of settings with HIV incidence of less than 0·1 per 100 person-years in men aged 15-49 years, increasing to 95% with HIV incidence greater than 1·0 per 100 person-years. INTERPRETATION: VMMC remains a cost-effective, often cost-saving, prevention intervention in sub-Saharan Africa for at least the next 5 years. FUNDING: Bill & Melinda Gates Foundation for the HIV Modelling Consortium.

Combination adherence strategy to support HIV antiretroviral therapy and pre-exposure prophylaxis adherence during pregnancy and breastfeeding: protocol for a pair of pilot randomised trials.

INTRODUCTION: To realise the expected gains from prevention of mother-to-child HIV transmission initiatives, adherence to preventative and therapeutic antiretroviral regimens is critical and interventions deployable in busy programmatic settings with a high HIV burden are needed. Based on formative research, we developed an approach that integrates patient-centred counselling and engagement of an adherence supporter for pregnant and breastfeeding women initiating HIV treatment (ie, antiretroviral therapy (ART)) or biomedical HIV prevention (ie, pre-exposure prophylaxis (PrEP)). METHODS: Tonse Pamodzi 2 is a pilot study designed to provide acceptability, fidelity and clinical outcomes data on a set of behavioural interventions for adherence support. The study comprises two parallel randomised trials, enrolling HIV-positive pregnant women initiating ART (Trial 1, n=100) and HIV-negative pregnant women with risk of HIV acquisition and willing to initiate PrEP (Trial 2, n=200). Within each trial, participants are randomised 1:1 to either the intervention or control group. The Tonse Pamodzi adherence intervention comprises patient-centred counselling (adapted Integrated Next Step Counseling(iNSC)) and external adherence support tailored to the clinical context (ie, for ART or PrEP). Participants randomly assigned to the control group receive standard counselling based on local HIV guidelines. Participants are followed for 6 months. To assess intervention acceptability, we will employ a mixed method approach to describe participant engagement, satisfaction, and discussion content. We will audit and score recorded counselling sessions to evaluate the implementation fidelity of iNSC sessions. We will also assess clinical outcomes at 3 and 6 months for both Trial 1 (retention in care and viral suppression of HIV) and Trial 2 (retention in care, and plasma and intracellular tenofovir drug concentrations). ETHICS AND DISSEMINATION: The study protocol was approved by the Malawi National Health Science Research Committee (19/05/2334) and the University of North Carolina at Chapel Hill Institutional Review Board (19-1060). TRIAL REGISTRATION NUMBER: NCT04330989.

Improving Sampling Efficiency for Determining Pediatric HIV Prevalence in National Surveys: Evidence From 8 Sub-Saharan African Countries.

BACKGROUND: Measurement of mother-to-child HIV transmission through population-based surveys requires large sample sizes because of low HIV prevalence among children. We estimate potential improvements in sampling efficiency resulting from a targeted sample design. SETTING: Eight countries in sub-Saharan Africa with completed Population-based HIV Impact Assessment (PHIA) surveys as of 2017. METHODS: The PHIA surveys used a geographically stratified 2-stage sample design with households sampled from randomly selected census enumeration areas. Children (0-14 years of age) were eligible for HIV testing within a random subsample of households (usually 50%). Estimates of child HIV prevalence in each country were calculated using jackknife replicate weights. We compared sample sizes and precision achieved using this design with a 2-phase disproportionate sample design applied to strata defined by maternal HIV status and mortality. RESULTS: HIV prevalence among children ranged from 0.4% (95% confidence interval: 0.2 to 0.6) in Tanzania to 2.8% (95% confidence interval: 2.2 to 3.4) in Eswatini with achieved relative standard errors between 11% and 21%. The expected precision improved in the targeted design in all countries included in the analysis, with proportionate reductions in mean squared error ranging from 27% in Eswatini to 61% in Tanzania, assuming an equal sample size. CONCLUSIONS: Population-based surveys of adult HIV prevalence that also measure child HIV prevalence should consider targeted sampling of children to reduce required sample size, increase precision, and increase the number of positive children tested. The findings from the PHIA surveys can be used as baseline data for informing future sample designs.

Investigating the implementation of differentiated HIV services and implications for pregnant and postpartum women: A mixed methods multi-country study.

Universal antiretroviral therapy (ART) for pregnant and postpartum women in sub-Saharan Africa has required adaptations to service delivery. We compared national policies on differentiated HIV service delivery with facility-level implementation, and explored provider and user experiences in rural Malawi, Tanzania and South Africa. Four national policies and two World Health Organization guidelines on HIV treatment for pregnant and postpartum women published between 2013 and 2017 were reviewed and summarised. Results were compared with implementation data from surveys undertaken in 34 health facilities. Eighty-seven in-depth interviews were conducted with pregnant and post-partum women living with HIV, their partners and providers. In 2018, differentiated service policies varied across countries. None specifically accounted for pregnant or postpartum women. Malawian policies endorsed facility-based multi-month scripting for clinically-stable adult ART patients, excluding pregnant or breastfeeding women. In Tanzania and South Africa, national policies proposed community-based and facility-based approaches, for which pregnant women were not eligible. Interview data suggested some implementation of differentiated services for pregnant and postpartum women beyond stipulated policies in all settings. Although these adaptations were appreciated by pregnant and postpartum women, they could lead to frustrations among other users when criteria for fast-track services or multi-month prescriptions were not clear.

Exploring the evolution of policies for universal antiretroviral therapy and their implementation across three sub-Saharan African countries: Findings from the SHAPE study.

Universal antiretroviral therapy (ART) strategies have dramatically changed HIV programming across sub-Saharan Africa. We explored factors that influenced the development, adoption and implementation of universal ART policies in Tanzania, South Africa and Malawi. We conducted 26 key informant interviews and applied Kingdon's 'streams' model to explore how problems, policies and politics converged to provide a window of opportunity for universal ART roll-out. Weak health systems and sub-optimal care retention were raised as problems during Option B+ implementation, which preceded universal ART , and persisted after its implementation. The adoption and implementation of Option B+ policy facilitated the uptake of universal ART. Politics played out through pressures from different stakeholders to accelerate or slow down implementation, from governments, civil society groups, researchers and donors. Policy processes leading to universal ART were open to pressures and influence. The extraordinary financial support which enabled the widespread and rapid implementation of universal ART skewed the power balance and sometimes left little space for locally-derived solutions to respond to specific health system abilities and epidemiological contexts. Donors may be more effective if they ensure a greater focus on strengthening the whole health system as well as accounting for local contextual factors and recent policy development histories when funding policy implementation.

Eligibility for differentiated models of HIV treatment service delivery: an estimate from Malawi and Zambia.

BACKGROUND: Little is known about the proportion of HIV-positive clients on antiretroviral therapy (ART) who meet stability criteria for differentiated service delivery (DSD) models. We report the proportion of ART clients meeting stability criteria as part of screening for a randomized trial of multimonth dispensing in Malawi and Zambia. METHODS: For a DSD trial now underway, we screened HIV-positive clients aged at least 18 years presenting for HIV treatment in 30 adult ART clinics in Malawi and Zambia to determine eligibility for DSD. Stability was defined as on first-line ART (efavirenz/tenofovir/lamivudine) for at least 6 months, no ART side effects, no toxicity or infectious complications, no noncommunicable diseases being treated in ART clinic, no lapses in ART adherence in the prior 6 months (>30 days without taking ART), and if female, not pregnant or breastfeeding. RESULTS: In total, 3465 adult ART clients were approached between 10 May 2017 and 30 April 2018 (Malawi: 1680; Zambia: 1785). Of the 2938 who answered screening questions (Malawi: 1527; Zambia: 1411), 2173 (73.5%) met criteria for DSD eligibility (Malawi: 72.8%; Zambia: 74.3%). The most common reasons for ineligibility were being on ART less than 6 months (9.6%) and a regimen other than standard first-line (7.9%). CONCLUSION: Approximately three-quarters of all adult clients presenting at ART clinics in Malawi and Zambia were eligible for DSD using a typical definition of stability. High uptake of DSD models by eligible clients would have a major impact on the infrastructure and the allocation of HIV treatment resources.

Implementing prevention policies for mother-to-child transmission of HIV in rural Malawi, South Africa and United Republic of Tanzania, 2013-2016.

OBJECTIVE: To assess adoption of World Health Organization (WHO) guidance into national policies for prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) and to monitor implementation of guidelines at facility level in rural Malawi, South Africa and the United Republic of Tanzania. METHODS: We summarized national PMTCT policies and WHO guidance for 15 indicators across the cascades of maternal and infant care over 2013-2016. Two survey rounds were conducted (2013-2015 and 2015-2016) in 46 health facilities serving five health and demographic surveillance system populations. We administered structured questionnaires to facility managers to describe service delivery. We report the proportions of facilities implementing each indicator and the frequency and durations of stock-outs of supplies, by site and survey round. FINDINGS: In all countries, national policies influencing the maternal and infant PMTCT cascade of care aligned with WHO guidelines by 2016; most inter-country policy variations concerned linkage to routine HIV care. The proportion of facilities delivering post-test counselling, same-day antiretroviral therapy (ART) initiation, antenatal care and ART provision in the same building, and Option B+ increased or remained at 100% in all sites. Progress in implementing policies on infant diagnosis and treatment varied across sites. Stock-outs of HIV test kits or antiretroviral drugs in the past year declined overall, but were reported by at least one facility per site in both rounds. CONCLUSION: Progress has been made in implementing PMTCT policy in these settings. However, persistent gaps across the infant cascade of care and supply-chain challenges, risk undermining infant HIV elimination goals.

Optimizing HIV testing services in sub-Saharan Africa: cost and performance of verification testing with HIV self-tests and tests for triage.

INTRODUCTION: Strategies employing a single rapid diagnostic test (RDT) such as HIV self-testing (HIVST) or "test for triage" (T4T) are proposed to increase HIV testing programme impact. Current guidelines recommend serial testing with two or three RDTs for HIV diagnosis, followed by retesting with the same algorithm to verify HIV-positive status before anti-retroviral therapy (ART) initiation. We investigated whether clients presenting to HIV testing services (HTS) following a single reactive RDT must undergo the diagnostic algorithm twice to diagnose and verify HIV-positive status, or whether a diagnosis with the setting-specific algorithm is adequate for ART initiation. METHODS: We calculated (1) expected number of false-positive (FP) misclassifications per 10,000 HIV negative persons tested, (2) positive predictive value (PPV) of the overall HIV testing strategy compared to the WHO recommended PPV ≥99%, and (3) expected cost per FP misclassified person identified by additional verification testing in a typical low-/middle-income setting, compared to the expected lifetime ART cost of $3000. Scenarios considered were as follows: 10% prevalence using two serial RDTs for diagnosis, 1% prevalence using three serial RDTs, and calibration using programmatic data from Malawi in 2017 where the proportion of people testing HIV positive in facilities was 4%. RESULTS: In the 10% HIV prevalence setting with a triage test, the expected number of FP misclassifications was 0.86 per 10,000 tested without verification testing and the PPV was 99.9%. In the 1% prevalence setting, expected FP misclassifications were 0.19 with 99.8% PPV, and in the Malawi 2017 calibrated setting the expected misclassifications were 0.08 with 99.98% PPV. The cost per FP identified by verification testing was $5879, $3770, and $24,259 respectively. Results were sensitive to assumptions about accuracy of self-reported reactive results and whether reactive triage test results influenced biased interpretation of subsequent RDT results by the HTS provider. CONCLUSIONS: Diagnosis with the full algorithm following presentation with a reactive triage test is expected to achieve PPV above the 99% threshold. Continuing verification testing prior to ART initiation remains recommended, but HIV testing strategies involving HIVST and T4T may provide opportunities to maintain quality while increasing efficiency as part of broader restructuring of HIV testing service delivery.

Implementing prevention policies for mother-to-child transmission of HIV in rural Malawi, South Africa and United Republic of Tanzania, 2013­2016

Objective To assess adoption of World Health Organization (WHO) guidance into national policies for prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) and to monitor implementation of guidelines at facility level in rural Malawi, South Africa and the United Republic of Tanzania. Methods : We summarized national PMTCT policies and WHO guidance for 15 indicators across the cascades of maternal and infant care over 2013­2016. Two survey rounds were conducted (2013­2015 and 2015­2016) in 46 health facilities serving five health and demographic surveillance system populations. We administered structured questionnaires to facility managers to describe service delivery. We report the proportions of facilities implementing each indicator and the frequency and durations of stock-outs of supplies, by site and survey round.Findings In all countries, national policies influencing the maternal and infant PMTCT cascade of care aligned with WHO guidelines by 2016; most inter-country policy variations concerned linkage to routine HIV care. The proportion of facilities delivering post-test counselling, same-day antiretroviral therapy (ART) initiation, antenatal care and ART provision in the same building, and Option B+ increased or remained at 100% in all sites. Progress in implementing policies on infant diagnosis and treatment varied across sites. Stock-outs of HIV test kits or antiretroviral drugs in the past year declined overall, but were reported by at least one facility per site in both rounds. Conclusion Progress has been made in implementing PMTCT policy in these settings. However, persistent gaps across the infant cascade of care and supply-chain challenges, risk undermining infant HIV elimination goals

Varying intervals of antiretroviral medication dispensing to improve outcomes for HIV patients (The INTERVAL Study): study protocol for a randomized controlled trial.

BACKGROUND: Requirements for frequent dispensing of antiretroviral therapy (ART) place demands on health systems and can lead to suboptimal adherence and disengagement in care for patients due to the time and cost of frequent clinic visits. Rigorous data are needed to define optimal ART dispensing strategies and to evaluate the impact of a longer medication supply on retention and virologic suppression and determine whether this strategy lowers costs for both the patient and the health system. To date, no randomized studies have tested the benefits of 6-month dispensing of ART compared to 3-month and standard of care approaches. METHODS: This study will be an unblinded cluster-randomized, matched controlled trial conducted among 8200 stable, HIV-infected individuals age 18 years and older on ART in Malawi and Zambia, to compare three ART dispensing intervals on the outcomes of retention in care (primary outcome), virologic suppression, and cost-effectiveness. Thirty clusters will be matched according to country, facility type, and ART cohort size and randomized to one of three study arms: standard of care, 3-month dispensing, and 6-month dispensing. Study participants will be followed, and outcomes will be measured at 12, 24, and 36 months. A subset of participants (n = 240) and providers (n = 180) will also participate in qualitative interviews to evaluate feasibility and acceptability of different ART dispensing intervals. DISCUSSION: This study will be the first to compare 6-month and 3-month ART dispensing intervals for stable, HIV-infected individuals in Malawi and Zambia. We focus on outcomes relevant to country programs, including retention, virologic suppression, and cost-effectiveness. Results from the study will help resource-limited health systems better understand the full scope of outcomes resulting from various ART dispensing intervals and help to inform health policy decisions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03101592 . Registered on 18 March 2017. Pan African Clinical Trials, PACTR201706002336105 . Registered on 2 June 2017.