Financial incentives for reduced alcohol use and increased isoniazid adherence during tuberculosis preventive therapy among people with HIV in Uganda: an open-label, factorial randomised controlled trial.

BACKGROUND: Alcohol use is common among people with HIV and is a risk factor for tuberculosis disease and non-adherence to isoniazid preventive therapy (IPT). Few interventions exist to reduce alcohol use and increase IPT adherence in sub-Saharan Africa. The aim of this study was to test the hypothesis that financial incentives conditional on point-of-care negative urine alcohol biomarker testing and positive urine isoniazid testing would reduce alcohol use and increase isoniazid adherence, respectively, in people with HIV who have latent tuberculosis infection and hazardous alcohol use. METHODS: We conducted an open-label, 2×2 factorial randomised controlled trial in Uganda. Eligible for the study were non-pregnant HIV-positive adults (aged ≥18 years) prescribed antiretroviral therapy for at least 6 months, with current heavy alcohol use confirmed by urine ethyl glucuronide (biomarker of recent alcohol use) and a positive Alcohol Use Disorders Identification Test-Consumption (AUDIT-C; ≥3 for women, ≥4 for men) for the past 3 months' drinking, no history of active tuberculosis, tuberculosis treatment, or tuberculosis preventive therapy, and a positive tuberculin skin test. We randomly assigned participants (1:1:1:1) initiating 6 months of IPT to: no incentives (group 1); or incentives for recent alcohol abstinence (group 2), isoniazid adherence (group 3), or both (group 4). Escalating incentives were contingent on monthly point-of-care urine tests negative for ethyl glucuronide (groups 2 and 4), or positive on IsoScreen (biomarker of recent isoniazid use; groups 3 and 4). The primary alcohol outcome was non-hazardous use by self-report (AUDIT-C <3 for women, <4 for men) and phosphatidylethanol (PEth; past-month alcohol biomarker) <35 ng/mL at 3 months and 6 months. The primary isoniazid adherence outcome was more than 90% bottle opening of days prescribed. We performed intention-to-treat analyses. This trial is registered with ClinicalTrials.gov (NCT03492216), and is complete. FINDINGS: From April 16, 2018, to Aug 2, 2021, 5508 people were screened, of whom 680 were randomly assigned: 169 to group 1, 169 to group 2, 170 to group 3, and 172 to group 4. The median age of participants was 39 years (IQR 32-47), 470 (69%) were male, 598 (90%) of 663 had HIV RNA viral loads of less than 40 copies per mL, median AUDIT-C score was 6 (IQR 4-8), and median PEth was 252 ng/mL (IQR 87-579). Among 636 participants who completed the trial with alcohol use endpoint measures (group 1: 152, group 2: 159, group 3: 161, group 4: 164), non-hazardous alcohol use was more likely in the groups with incentives for alcohol abstinence (groups 2 and 4) versus no alcohol incentives (groups 1 and 3): 57 (17·6%) of 323 versus 31 (9·9%) of 313, respectively; adjusted risk difference (aRD) 7·6% (95% CI 2·7 to 12·5, p=0·0025). Among 656 participants who completed the trial with isoniazid adherence endpoint measures (group 1: 158, group 2: 163, group 3: 168, group 4: 167), incentives for isoniazid adherence did not increase adherence: 244 (72·8%) of 335 in the isoniazid incentive groups (groups 3 and 4) versus 234 (72·9%) of 321 in the no isoniazid incentive groups (groups 1 and 2); aRD -0·2% (95% CI -7·0 to 6·5, p=0·94). Overall, 53 (8%) of 680 participants discontinued isoniazid due to grade 3 or higher adverse events. There was no significant association between randomisation group and hepatotoxicity resulting in isoniazid discontinuation, after adjusting for sex and site. INTERPRETATION: Escalating financial incentives contingent on recent alcohol abstinence led to significantly lower biomarker-confirmed alcohol use versus control, but incentives for recent isoniazid adherence did not lead to changes in adherence. The alcohol intervention was efficacious despite less intensive frequency of incentives and clinic visits than traditional programmes for substance use, suggesting that pragmatic modifications of contingency management for resource-limited settings can have efficacy and that further evaluation of implementation is merited. FUNDING: National Institute on Alcohol Abuse and Alcoholism. TRANSLATION: For the Runyankole translation of the abstract see Supplementary Materials section.

Seemingly Unrelated Regression Analysis of the Cost and Health-Related Quality of Life Outcomes of the REVAMP Randomized Clinical Trial.

OBJECTIVE: This study aimed to evaluate the 9-month cost and health-related quality of life (HRQOL) outcomes of resistance versus viral load testing strategies to manage virological failure in low-middle income countries. METHODS: We analyzed secondary outcomes from the REVAMP clinical trial: a pragmatic, open label, parallel-arm randomized trial investigating resistance versus viral load testing for individuals failing first-line treatment in South Africa and Uganda. We collected resource data, valued according to local cost data and used the 3-level version of EQ-5D to measure HRQOL at baseline and 9 months. We applied seemingly unrelated regression equations to account for the correlation between cost and HRQOL. We conducted intention-to-treat analyses with multiple imputation using chained equations for missing data and performed sensitivity analyses using complete cases. RESULTS: For South Africa, resistance testing and opportunistic infections were associated with statistically significantly higher total costs, and virological suppression was associated with lower total cost. Higher baseline utility, higher cluster of differentiation 4 (CD4) count, and virological suppression were associated with better HRQOL. For Uganda, resistance testing and switching to second-line treatment were associated with higher total cost, and higher CD4 was associated with lower total cost. Higher baseline utility, higher CD4 count, and virological suppression were associated with better HRQOL. Sensitivity analyses of the complete-case analysis confirmed the overall results. CONCLUSION: Resistance testing showed no cost or HRQOL advantage in South Africa or Uganda over the 9-month REVAMP clinical trial.

Costs of a Brief Alcohol Consumption Reduction Intervention for Persons Living with HIV in Southwestern Uganda: Comparisons of Live Versus Automated Cell Phone-Based Booster Components.

Low-cost interventions are needed to reduce alcohol use among persons with HIV (PWH) in low-income settings. Brief alcohol interventions hold promise, and technology may efficiently deliver brief intervention components with high frequency. We conducted a costing study of the components of a randomized trial that compared a counselling-based intervention with two in-person one-on-one sessions supplemented by booster sessions to reinforce the intervention among PWH with unhealthy alcohol use in southwest Uganda. Booster sessions were delivered twice weekly by two-way short message service (SMS) or Interactive Voice Response (IVR), i.e. via technology, or approximately monthly via live calls from counsellors. We found no significant intervention effects compared to the control, however the cost of the types of booster sessions differed. Start up and recurring costs for the technology-delivered booster sessions were 2.5 to 3 times the cost per participant of the live-call delivered booster intervention for 1000 participants. These results suggest technology-based interventions for PWH are unlikely to be lower cost than person-delivered interventions unless they are at very large scale.

Cost-effectiveness analysis of integrating screening and treatment of selected non-communicable diseases into HIV/AIDS treatment in Uganda.

INTRODUCTION: Despite growing enthusiasm for integrating treatment of non-communicable diseases (NCDs) into human immunodeficiency virus (HIV) care and treatment services in sub-Saharan Africa, there is little evidence on the potential health and financial consequences of such integration. We aim to study the cost-effectiveness of basic NCD-HIV integration in a Ugandan setting. METHODS: We developed an epidemiologic-cost model to analyze, from the provider perspective, the cost-effectiveness of integrating hypertension, diabetes mellitus (DM) and high cholesterol screening and treatment for people living with HIV (PLWH) receiving antiretroviral therapy (ART) in Uganda. We utilized cardiovascular disease (CVD) risk estimations drawing from the previously established Globorisk model and systematic reviews; HIV and NCD risk factor prevalence from the World Health Organization's STEPwise approach to Surveillance survey and global databases; and cost data from national drug price lists, expert consultation and the literature. Averted CVD cases and corresponding disability-adjusted life years were estimated over 10 subsequent years along with incremental cost-effectiveness of the integration. RESULTS: Integrating services for hypertension, DM, and high cholesterol among ART patients in Uganda was associated with a mean decrease of the 10-year risk of a CVD event: from 8.2 to 6.6% in older PLWH women (absolute risk reduction of 1.6%), and from 10.7 to 9.5% in older PLWH men (absolute risk reduction of 1.2%), respectively. Integration would yield estimated net costs between $1,400 and $3,250 per disability-adjusted life year averted among older ART patients. CONCLUSIONS: Providing services for hypertension, DM and high cholesterol for Ugandan ART patients would reduce the overall CVD risk among these patients; it would amount to about 2.4% of national HIV/AIDS expenditure, and would present a cost-effectiveness comparable to other standalone interventions to address NCDs in low- and middle-income country settings.

The REVAMP trial to evaluate HIV resistance testing in sub-Saharan Africa: a case study in clinical trial design in resource limited settings to optimize effectiveness and cost effectiveness estimates.

BACKGROUND: In sub-Saharan Africa, rates of sustained HIV virologic suppression remain below international goals. HIV resistance testing, while common in resource-rich settings, has not gained traction due to concerns about cost and sustainability. OBJECTIVE: We designed a randomized clinical trial to determine the feasibility, effectiveness, and cost-effectiveness of routine HIV resistance testing in sub-Saharan Africa. APPROACH: We describe challenges common to intervention studies in resource-limited settings, and strategies used to address them, including: (1) optimizing generalizability and cost-effectiveness estimates to promote transition from study results to policy; (2) minimizing bias due to patient attrition; and (3) addressing ethical issues related to enrollment of pregnant women. METHODS: The study randomizes people in Uganda and South Africa with virologic failure on first-line therapy to standard of care virologic monitoring or immediate resistance testing. To strengthen external validity, study procedures are conducted within publicly supported laboratory and clinical facilities using local staff. To optimize cost estimates, we collect primary data on quality of life and medical resource utilization. To minimize losses from observation, we collect locally relevant contact information, including Whatsapp account details, for field-based tracking of missing participants. Finally, pregnant women are followed with an adapted protocol which includes an increased visit frequency to minimize risk to them and their fetuses. CONCLUSIONS: REVAMP is a pragammatic randomized clinical trial designed to test the effectiveness and cost-effectiveness of HIV resistance testing versus standard of care in sub-Saharan Africa. We anticipate the results will directly inform HIV policy in sub-Saharan Africa to optimize care for HIV-infected patients.

Randomized Study of Assessment Effects on Alcohol Use by Persons With HIV in Rural Uganda.

OBJECTIVE: Unhealthy alcohol use is a crucial driver of HIV in sub-Saharan Africa, and interventions are needed. The goal of this study was to assess whether assessment itself (assessment reactivity) causes declines in alcohol use in a research study in persons with HIV in Uganda. METHOD: Study participants were adult patients of the Immune Suppression Syndrome (ISS) Clinic in Mbarara, Uganda, who were new to HIV care and reported any alcohol consumption in the prior year. Participants were randomized to (a) a study cohort, with structured interviews, breath alcohol analysis tests, and blood draws conducted quarterly, or (b) a minimally assessed arm that engaged in these procedures only once, at 6 months after baseline. The main outcome was unhealthy drinking at 6 months, defined as Alcohol Use Disorders Identification Test-Consumption [AUDIT-C] positive (≥3 for women, ≥4 for men) or phosphatidylethanol (PEth; an alcohol biomarker) level ≥ 50 ng/ml. We also examined this outcome stratified by gender. RESULTS: We examined 175 and 139 persons in the quarterly assessed versus minimally assessed arms, respectively. Overall, 54.8% were male, the median age was 30 (interquartile range: 25-36), and 58.0% initiated anti-retroviral therapy at 6 months. Nearly equal proportions (53.7% and 51.1% in the study quarterly assessed vs. minimally assessed arm, respectively) engaged in unhealthy drinking in the 3 months before the 6-month study visit (p = .64), and we found no evidence of interaction by gender (p = .36). CONCLUSIONS: We found no evidence of assessment reactivity in a study that included quarterly study visits. Assessment is not sufficient to act as an intervention itself in this population with high levels of unhealthy drinking. Interventions are needed to decrease alcohol consumption in this population.

Diminishing availability of publicly funded slots for antiretroviral initiation among HIV-infected ART-eligible patients in Uganda.

BACKGROUND: The impact of flat-line funding in the global scale up of antiretroviral therapy (ART) for HIV-infected patients in Africa has not yet been well described. METHODS: We evaluated ART-eligible patients and patients starting ART at a prototypical scale up ART clinic in Mbarara, Uganda between April 1, 2009 and May 14, 2010 where four stakeholders sponsor treatment - two PEPFAR implementing organizations, the Ugandan Ministry of Health - Global Fund (MOH-GF) and a private foundation named the Family Treatment Fund (FTF). We assessed temporal trends in the number of eligible patients, the number starting ART and tabulated the distribution of the stakeholders supporting ART initiation by month and quartile of time during this interval. We used survival analyses to assess changes in the rate of ART initiation over calendar time. FINDINGS: A total of 1309 patients who were eligible for ART made visits over the 14 month period of the study and of these 819 started ART. The median number of ART eligible patients each month was 88 (IQR: 74 to 115). By quartile of calendar time, PEPFAR and MOH sponsored 290, 192, 180, and 49 ART initiations whereas the FTF started 1, 2, 1 and 104 patients respectively. By May of 2010 (the last calendar month of observation) FTF sponsored 88% of all ART initiations. Becoming eligible for ART in the 3(rd) (HR = 0.58, 95% 0.45-0.74) and 4(th) quartiles (HR = 0.49, 95% CI: 0.36-0.65) was associated with delay in ART initiation compared to the first quartile in multivariable analyses. INTERPRETATION: During a period of flat line funding from multinational donors for ART programs, reductions in the number of ART initiations by public programs (i.e., PEPFAR and MOH-GF) and delays in ART initiation became apparent at the a large prototypical scale-up ART clinic in Uganda.

Retention in care among HIV-infected patients in resource-limited settings: emerging insights and new directions.

In resource-limited settings--where a massive scale-up of HIV services has occurred in the last 5 years--both understanding the extent of and improving retention in care presents special challenges. First, retention in care within the decentralizing network of services is likely higher than existing estimates that account only for retention in clinic, and therefore antiretroviral therapy services may be more effective than currently believed. Second, both magnitude and determinants of patient retention vary substantially and therefore encouraging the conduct of locally relevant epidemiology is needed to inform programmatic decisions. Third, socio-structural factors such as program characteristics, transportation, poverty, work/child care responsibilities, and social relations are the major determinants of retention in care, and therefore interventions to improve retention in care should focus on implementation strategies. Research to assess and improve retention in care for HIV-infected patients can be strengthened by incorporating novel methods such as sampling-based approaches and a causal analytic framework.