Scale-Up of HIV Antiretroviral Therapy and Estimation of Averted Infections and HIV-Related Deaths - Uganda, 2004-2022.

On January 28, 2003, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR), the largest commitment by any nation to address a single disease in history, was announced.* In April 2004, the first person in the world to receive PEPFAR-supported antiretroviral therapy (ART) was a man aged 34 years in Uganda. Effective ART reduces morbidity and mortality among persons with HIV infection (1) and prevents both mother-to-child transmission (MTCT) (2) and sexual transmission once viral load is suppressed to undetectable levels (<200 viral copies/mL) (3). By September 2022, more than 1.3 million persons with HIV infection in Uganda were receiving PEPFAR-supported ART, an increase of approximately 5,000% from September 2004. As indicators of the ART program's effectiveness, a proxy MTCT rate decreased 77%, from 6.4% in 2010 to 1.5% in 2022, and the viral load suppression rate (<1,000 viral copies/mL) increased 3%, from 91% in 2016 to 94% in September 2022. During 2004-2022, ART scale-up helped avert nearly 500,000 HIV infections, including more than 230,000 infections among HIV-exposed infants, and approximately 600,000 HIV-related deaths. Going forward, efforts will focus on identifying all persons with HIV infection and rapidly linking them to effective ART. PEPFAR remains committed to continued strong partnership with the Government of Uganda, civil society, and other development partners toward sustainable solutions aligned with the Joint United Nations Programme on HIV/AIDS (UNAIDS) fast-track strategy to ending the global AIDS epidemic by 2030† and safeguarding impact achieved in the long term.

Changes in the timing of antiretroviral therapy initiation in HIV-infected patients with tuberculosis in Uganda: a study of the diffusion of evidence into practice in the global response to HIV/AIDS.

BACKGROUND: We aimed to determine the extent to which emerging evidence and changing guidelines regarding timing of antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected patients with tuberculosis influenced "real-world" clinical practice in Uganda. METHODS: We evaluated ART-naive, HIV-infected adults starting tuberculosis therapy at 2 HIV clinics in Uganda between 26 August 2006 and 29 September 2012. We used multivariate regression to calculate associations between 4 calendar periods reflecting publication of seminal clinical studies or changes in guidelines and timing of ART after tuberculosis therapy initiation. RESULTS: For patients with CD4 counts <50 cells/µL, the fraction starting ART within 14 and 30 days of initiating tuberculosis therapy increased from 7% to 14% and from 14% to 86% over the period of observation. The fraction of patients with CD4 counts >50 cells/µL starting ART within 60 days increased from 16% to 28%. After adjustment for sociodemographic factors, when comparing the most recent with the earliest calendar period, the rate of ART initiation increased by 4.57-fold (95% confidence interval [CI], 1.76-fold to 11.86-fold) among patients with baseline CD4 counts ≤ 50 cells/µL and by 5.43-fold (95% CI, 3.16- fold to 9.31-fold) among those with baseline CD4 counts >50 cells/µL. CONCLUSIONS: We observed large changes in clinical practice during a period of emerging data and changing guidelines among HIV-infected patients with tuberculosis. Nonetheless, a significant proportion of individuals with higher CD4 cell counts do not start ART within recommended time frames. Targeted dissemination and implementation efforts are still needed to achieve target levels in practice.

High retention in care among HIV-infected patients entering care with CD4 levels >350 cells/µL under routine program conditions in Uganda.

BACKGROUND: In Africa, human immunodeficiency virus (HIV)-infected patients who present to care with CD4 levels >350 cells/µL (ie, current antiretroviral treatment thresholds) are often thought to be poorly retained in care, but most estimates do not account for outcomes among patients lost to follow-up. METHODS: We evaluated HIV-infected adults who had made a visit in the last 2.5 years in a program in Uganda. We identified a random sample of patients lost to follow-up (9 months without a visit). Ascertainers sought patients in the community in this sample and outcomes were incorporated into revised survival estimates of mortality and retention for the clinic population using a probability weight. RESULTS: Of 6473 patients, (29% male, median age 29 years, median CD4 count 550 cells/µL), 1294 (20%) became lost to follow-up over 2.5 years. Two hundred seven (16%) randomly selected lost patients were sought, and in 175 (85%) vital status was ascertained. In 19 of 175 (11%), the patient had died. Of the 156 (89%) alive, 74 (47%) were interviewed in person, and 38 of 74 (51%) reported HIV care elsewhere, whereas 36 of 74 (49%) were not in care. Application of weights derived from sampling found that at 2.5 years, retention among patients who enrolled with CD4 levels >350 cells/µL was 88.2% and mortality was 2.5%. Lower income, unemployment, and rural residence were associated with failure to be retained. CONCLUSIONS: Retention in patients entering care with high CD4 counts under routine program conditions in Africa is high in a Ugandan care program and may be systematically underestimated in many other settings.

Protocol for the 3HP Options Trial: a hybrid type 3 implementation-effectiveness randomized trial of delivery strategies for short-course tuberculosis preventive therapy among people living with HIV in Uganda.

BACKGROUND: Recently, a 3-month (12-dose) regimen of weekly isoniazid and rifapentine (3HP) was recommended by the World Health Organization for the prevention of tuberculosis (TB) among people living with HIV (PLHIV) on common antiretroviral therapy regimens. The best approach to delivering 3HP to PLHIV remains uncertain. METHODS: We developed a three-armed randomized trial assessing optimized strategies for delivering 3HP to PLHIV. The trial will be conducted at the Mulago Immune Suppression Syndrome (i.e., HIV/AIDS) clinic in Kampala, Uganda. We plan to recruit 1656 PLHIV, randomized 1:1 to each of the three arms (552 per arm). Using a hybrid type 3 effectiveness-implementation design, this pragmatic trial aims to (1) compare the acceptance and completion of 3HP among PLHIV under three delivery strategies: directly observed therapy (DOT), self-administered therapy (SAT), and informed patient choice of either DOT or SAT (with the assistance of a decision aid); (2) to identify processes and contextual factors that influence the acceptance and completion of 3HP under each delivery strategy; and (3) to estimate the costs and compare the cost-effectiveness of three strategies for delivering 3HP. The three delivery strategies were each optimized to address key barriers to 3HP completion using a theory-informed approach. We hypothesize that high levels of treatment acceptance and completion can be achieved among PLHIV in sub-Saharan Africa and that offering PLHIV an informed choice between the optimized DOT and SAT delivery strategies will result in greater acceptance and completion of 3HP. The design and planned evaluation of the delivery strategies were guided by the use of implementation science conceptual frameworks. DISCUSSION: 3HP-one of the most promising interventions for TB prevention-will not be scaled up unless it can be delivered in a patient-centered fashion. We highlight shared decision-making as a key element of our trial design and theorize that offering PLHIV an informed choice between optimized delivery strategies will facilitate the highest levels of treatment acceptance and completion. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03934931 ; Registered 2 May 2019.

Closing the gap: A novel metric of change in performance.

BACKGROUND: Interventions to improve performance of global programs in the HIV cascade of care are widespread and increasing the focus of implementation science. At present, however, there is no clear consensus on how to conceptualize their improvement at the program level. The commonly used measures of association, based on ratios of probabilities (or odds), have well-known defects in public health applications. They yield large effect sizes even when the absolute effects, and therefore the public health impact, are small. On the other hand, risk differences create problems because settings with higher baseline values are penalized. We aim to examine ways of quantifying improvement in each health center of a cluster-randomized trial in Uganda to accelerate antiretroviral therapy initiation among HIV-infected adults. METHODS: We formalize the concept of the 'improvement index,' defined as the fraction of gaps closed as a metric of improvement, and suggest that it has unique features and strengths when compared to risk ratios and risk differences. RESULTS: Overall agreement between the different indices was not high, especially among health centers that were among the top 5 or 10. However, all ranking showed broad similarities at the far ends of the spectrum. On scatter plots, there was a positive linear relationship between the metrics, and the Bland Altman (B-A) plots were in agreement. CONCLUSION: The improvement index can be used as an alternative measure of association in implementation science interventions. It can be useful for public health purposes as it demonstrates how much can be covered from the baseline.

Understanding uptake of an intervention to accelerate antiretroviral therapy initiation in Uganda via qualitative inquiry.

INTRODUCTION: The Streamlined Antiretroviral Therapy Initiation Strategy (START-ART) study found that a theory-based intervention using opinion leaders to inform and coach health care providers about the risks of treatment delay, provision of point of care (POC) CD4 testing machines (PIMA) and reputational incentives, led to rapid rise in ART initiation. We used qualitative research methods to explore mechanisms of provider behaviour change. METHODS: We conducted in-depth interviews (IDIs) with 24 health care providers and nine study staff to understand perceptions, attitudes and the context of changes in ART initiation practices. Analyses were informed by the Theoretical Domains Framework. RESULTS: Rapid dissemination of new practices was enabled in the environmental context of an existing relationship based on communication, implementation and accountability between Makerere University Joint AIDS Program (MJAP), a Ugandan University-affiliated organization that provided technical oversight for HIV service delivery at the health facilities where the intervention was implemented, and a network of health facilities operated by the Uganda Ministry of Health. Coaching carried out by field coordinators from MJAP strengthened influence and informal accountability for carrying out the intervention. Frontline health workers held a pre-existing strong sense of professional identity. They were proud of attainment of new knowledge and skills and gratified by providing what they perceived to be higher quality care. Peer counsellors, who were not explicitly targeted in the intervention design, effectively substituted some functions of health care providers; as role models for successful ART uptake, they played a crucial role in creating demand for rapid ART initiation through interactions with patients. Point of care (POC) CD4 testing enabled immediate action and relieved providers from frustrations of lost or delayed laboratory results, and led to higher patient satisfaction (due to reduced costs because of ability to initiate ART right away, requiring fewer return trips to clinic). CONCLUSIONS: Qualitative data revealed that a multicomponent intervention to change provider behaviour succeeded in the context of strong institutional and individual relationships between a University-affiliated organization, government facilities, and peer health workers (who acted as a crucial link between stakeholders) and the community. Fostering stable institutional relationships between institutional actors (non-governmental organization (NGOs) and ministry-operated facilities) as well as between facilities and the community (through peer health workers) can enhance uptake of innovations targeting the HIV cascade in similar clinical settings.

Effects of a multicomponent intervention to streamline initiation of antiretroviral therapy in Africa: a stepped-wedge cluster-randomised trial.

BACKGROUND: In Africa, up to 30% of HIV-infected patients who are clinically eligible for antiretroviral therapy (ART) do not start timely treatment. We assessed the effects of an intervention targeting prevalent health systems barriers to ART initiation on timing and completeness of treatment initiation. METHODS: In this stepped-wedge, non-blinded, cluster-randomised controlled trial, 20 clinics in southwestern Uganda were randomly assigned in groups of five clinics every 6 months to the intervention by a computerised random number generator. This procedure continued until all clinics had crossed over from control (standard of care) to the intervention, which consisted of opinion-leader-led training and coaching of front-line health workers, a point-of-care CD4 cell count testing platform, a revised counselling approach without mandatory multiple pre-initiation sessions, and feedback to the facilities on their ART initiation rates and how they compared with other facilities. Treatment-naive, HIV-infected adults (aged ≥18 years) who were clinically eligible for ART during the study period were included in the study population. The primary outcome was ART initiation 14 days after first clinical eligibility for ART. This study is registered with ClinicalTrials.gov, number NCT01810289. FINDINGS: Between April 11, 2013, and Feb 2, 2015, 12 024 eligible patients visited one of the 20 participating clinics. Median CD4 count was 310 cells per µL (IQR 179-424). 3753 of 4747 patients (weighted proportion 80%) in the intervention group had started ART by 2 weeks after eligibility compared with 2585 of 7066 patients (38%) in the control group (risk difference 41·9%, 95% CI 40·1-43·8). Vital status was ascertained in a random sample of 208 patients in the intervention group and 199 patients in the control group. Four deaths (2%) occurred in the intervention group and five (3%) occurred in the control group. INTERPRETATION: A multicomponent intervention targeting health-care worker behaviour increased the probability of ART initiation 14 days after eligibility. This intervention consists of widely accessible components and has been tested in a real-world setting, and is therefore well positioned for use at scale. FUNDING: National Institute of Allergy and Infectious Diseases (NIAID) and the President's Emergency Fund for AIDS Relief (PEPFAR).