Outcomes and cost-effectiveness of different models of delivery of antiretroviral therapy

Background: HIV remains a major contributor to the burden of disease in the Eastern and Southern African region, where around half of those with HIV/AIDS reside, according to the 2016 UNAIDS estimates. Data on the direct costs and outcomes of providing health care are important due to competing health needs and limited budgets in resource-limited settings, especially if we are to reach the UNAIDS 90-90-90 goals. This thesis presents a series of studies, which together represent the typical journey followed within an economic evaluation, starting with the establishment of a cohort, then onto cost and outcome analyses and, finally, the development of a Markov model for the purpose of establishing the cost-effectiveness of a particular intervention. Methods: Data for this thesis come from several cohorts within South Africa, with patients commencing ART between 1998 and 2014, and with care provided within a number of different models: private (Aid for AIDS), public-private partnerships or PPP (BroadReach), and public sector (Khayelitsha). The study design for all were retrospective cohort analyses. These cohorts had important strengths in their data: adherence measures (private, PPP); initiating ART at CD4 counts > 200 cells/µL (private); detailed cost data (private); long duration of follow-up with a larger proportion on second-line ART (private); ability to assess health care utilization pre-ART and in patient loss to ART follow-up (private); and availability of national identity numbers, allowing us to confirm mortality from national death register data (private, PPP). Results: The results sections of this thesis are presented in the form of published papers and chapters. In the first analysis (Chapter 4), we present a cohort profile for Aid for AIDS, where we describe the history of the programme and contrast it with the public sector programme in South Africa. In the second analysis (Chapter 5), we present a paper highlighting the profile and determinants of costs on ART over time in the private cohort. We draw attention to the impact of baseline stage and adherence to ART on early and late costs respectively. In the third analysis (Chapter 6), we explore different models of HIV care: GP versus clinic for public sector patients and courier versus collect pharmacy for private sector patients. In the third analysis (Chapter 7), we present a paper which reviews cost-effectiveness studies in LMICs and explores the relative impact of various factors on costs and mortality in preparation for the final analysis (Chapter 8), which required the development of a novel HIV Markov model. Conclusion: Interventions, such as public-private partnerships with GPs or home-refill by courier, which we have found to be associated with lower costs and improved outcomes respectively, should be considered for implementation in South Africa, especially in light of the proposed National Health Insurance. The focus of this thesis on models of ART delivery and the inclusion of under-represented or novel models are significant strengths

Dosage adjustment in medical patients with renal impairment at Groote Schuur Hospital

BACKGROUND: Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment. The need for dose adjustment is frequently neglected by prescribers. METHODS: We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration rate (eGFR) or = 1 day after renal function tests were performed. We determined what proportion of these prescriptions required dose adjustment and whether drug doses were appropriately adjusted. RESULTS: We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients, 69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no doses had been correctly adjusted. CONCLUSION: Consistent with international studies, drug dose adjustment in patients with renal impairment in a South African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in renal impairment should be considered, including automated eGFR reporting and computerised aids to guide drug dosing, that account for renal impairment

Factors influencing retention in care after starting antiretroviral therapy in a rural South African programme

The prognosis of patients with HIV in Africa has improved with the widespread use of antiretroviral therapy (ART) but these successes are threatened by low rates of long-term retention in care. There are limited data on predictors of retention in care, particularly from rural sites. METHODS: Prospective cohort analysis of outcome measures in adults from a rural HIV care programme in Madwaleni, Eastern Cape, South Africa. The ART programme operates from Madwaleni hospital and seven primary care feeder clinics with full integration between inpatient and outpatient services. Outreach workers conducted home visits for defaulters. RESULTS: 1803 adults initiated ART from June 2005 to May 2009. At the end of the study period 82.4% were in active care or had transferred elsewhere, 11.1% had died and 6.5% were lost to follow-up (LTFU). Independent predictors associated with an increased risk of LTFU were CD4 nadir >200, initiating ART as an inpatient or while pregnant, and younger age, while being in care for >6 months before initiating ART was associated with a reduced risk. Independent factors associated with an increased risk of mortality were baseline CD4 count 6 months before initiating ART and initiating ART while pregnant were associated with a reduced risk. CONCLUSIONS: Serving a socioeconomically deprived rural population is not a barrier to successful ART delivery. Patients initiating ART while pregnant and inpatients may require additional counselling and support to reduce LTFU. Providing HIV care for patients not yet eligible for ART may be protective against being LTFU and dying after ART initiation

Mobile Health Technology for Enhancing the COVID-19 Response in Africa: A Potential Game Changer?

Disclosure: J. B. N. is also a coprincipal investigator of TOGETHER, an adaptive randomized clinical trial of novel agents for treatment of high-risk outpatient COVID-19 patients in South Africa; supported by the Bill & Melinda Gates Foundation; and a member of COVID-19 Scientific Committee of the Democratic Republic of the Congo. R. T. L. is an infectious disease specialist and global health researcher with support from the Canadian Institutes of Health Research, Michael Smith Foundation, for Health Research and Grand Challenges Canada, and is cofounder of the WelTel (www.weltelhealth.com), as well as a member of the roster of experts for the WHO Task Force for Digital Health. He served on the front lines of the 2003 SARS epidemic and led a consortium on the Ebola outbreak response in 2014. Sir Zumla is co-PI of the Pan-African Network on Emerging and Re-Emerging Infections (PANDORA-ID-NET: https://www.pandora-id.net/) funded by the European and Developing Countries Clinical Trials Partnership the EU Horizon 2020 Framework Programme for Research and Innovation. Sir Zumla is recipient of a National Institutes of Health Research senior investigator award

A novel Markov model projecting costs and outcomes of providing antiretroviral therapy to public patients in private practices versus public clinics in south Africa

Introduction Providing private antiretroviral therapy (ART) care for public sector patients could increase access to ART in low- and middle-income countries. We compared the costs and outcomes of a private-care and a public-care ART program in South Africa. METHODS: A novel Markov model was developed from the public-care program. Patients were first tunneled for 6 months in their baseline CD4 category before being distributed into a dynamic CD4 and viral load model. Patients were allowed to return to ART care from loss to follow up (LTFU). We then populated this modeling framework with estimates derived from the private-care program to externally validate the model. RESULTS: Baseline characteristics were similar in the two programs. Clinic visit utilization was higher and death rates were lower in the first few years on ART in the public-care program. After 10 years on ART we estimated the following outcomes in the public-care and private-care programs respectively: viral load 500 cells/μl 33% and 37%, LTFU 14% and 14%, and death 27% and 32%. Lifetime undiscounted survival estimates were 14.1 (95%CI 13.2-14.9) and (95%CI 12.7-14.5) years with costs of 18,734 (95%CI 12,588-14,022) and 13,062 (95%CI 12,077-14,047) USD in the private-care and public-care programs respectively. When clinic visit utilization in the public-care program was reduced by two thirds after the initial 6 months on ART, which is similar to their current practice, the costs were comparable between the programs. CONCLUSIONS: Using a novel Markov model, we determined that the private-care program had similar outcomes but lower costs than the public-care program, largely due to lower visit frequencies. These findings have important implications for increasing and sustaining coverage of patients in need of ART care in resource-limited settings

Dosage adjustment in medical patients with renal impairment at Groote Schuur Hospital

Background. Many drugs are eliminated by the kidneys and therefore may require dose adjustment in patients with renal impairment. The need for dose adjustment is frequently neglected by prescribers. Methods. We reviewed folders of patients admitted to the Groote Schuur Hospital general medical wards between January and March 2008. Patients with renal impairment, defined as an estimated glomerular filtration rate (eGFR) ≤50 ml per minute per 1.73 m2, were identified. In-patient prescriptions were captured if they were written after clinical notes indicated impaired renal function, or ≥1 day after renal function tests were performed. We determined what proportion of these prescriptions required dose adjustment and whether drug doses were appropriately adjusted. Results. We found renal impairment in 32% (97/301) of medical admissions. There were 615 prescription entries for the 97 patients with renal impairment. Dose adjustment was required in 19% (117/615) of prescription entries, and only 32% (37/117) of these prescription entries were correctly dose adjusted. Of 97 patients, 69 received one or more drugs that required dose adjustment (median 1, range 1 - 5). All drug doses were correctly adjusted in 12% (8/69) of patients. Importantly, in the majority of patients (59% (41/69)) no doses had been correctly adjusted. Conclusion. Consistent with international studies, drug dose adjustment in patients with renal impairment in a South African hospital was frequently neglected. Strategies to alert clinicians of the need for dose adjustment in renal impairment should be considered, including automated eGFR reporting and computerised aids to guide drug dosing, that account for renal impairment

El límite en la ciudad ilustrada: la ordenación de un espacio urbano

Al aproximarnos al estudio de las ciudades españolas de la segunda mitad del XVIII, nos enfrentamos a un material que resulta ser de muy distinta naturaleza: referencias cartográficas, memorias de proyección, información facilitada por los censos, descripciones en libros de viajes o guías para forasteros, grabados, perspectivas o vistas a vuelo de pájaro de núcleos urbanos... ; aparentemente su conjunto ofrece una imagen global de la ciudad: existe, sin embargo, un problema debido al carácter contradictorio de los documentos citados; a menudo los planos tan sólo son siluetas de población, donde no se detalla la configuración de la trama ni se define cual fue la ocupación real de manzanas; en otras, el autor decídió integrar en su diseño proyectos que no llegaron a realizarse; en los grabados o perspectivas se cambia, a menudo, la escala o se incluyen fantásticos equipamíentos, con los que la referencia aparece distorsíonada; si leemos las guias de forasteros o almanaques veremos como, en su mayoría, se concibieron como largas listas donde se enumeraban calles, se daba referencia de palacios e iglesias más importantes, fíjándose a continuación posibles recorridos que permitiesen ver, comodamente, los hitos mencionados, pero nada se decía sobre la cíudad. Por último, tampoco los libros de viajeros son referencia fidedigna puesto que, a menudo, sus opiniones sobre una misma ciudad eran contradictorias, bien por valorar distintos aspectos, o, caso de coincidir, por expresar opiniones diferentes

Short term adherence tool predicts failure on second line protease inhibitor-based antiretroviral therapy: an observational cohort study

Background: Most patients who experience virologic failure (VF) on second line antiretroviral therapy (ART) in low-middle income countries fail due to poor adherence rather than antiretroviral resistance. A simple adherence tool designed to detect VF would conserve resources by rationally limiting need for viral load (VL) testing and, in those countries with access to third line ART, the need for resistance testing. Methods: We conducted an observational cohort study of patients who initiated second line ART at a clinic in Kwazulu-Natal, South Africa. Using clinical and pharmacy refill data extracted from the clinic’s electronic database, we determined risk factors for VF. Three different methods of calculating short term pharmacy refill adherence were evaluated and compared with long term adherence since second line initiation. We also explored the ability of differing durations of short term pharmacy refill to predict VF on second line ART. Results: We included 274 patients with a median follow up of 27 months on second line ART. VF ranged between 3% and 16% within each six month interval after initiating second line ART. 243 patients with at least one VL after 4 months on second line were analysed in the statistical analysis. Pharmacy refill adherence assessed over shorter periods (4 to 6 months) predicted virologic suppression as well as pharmacy refill assessed over longer periods. The risk of VF fell 73% with each 10% increase in adherence measured from pharmacy refills over a 4 month period. Low CD4 count at second line ART initiation was a significant independent risk factor for VF. Conclusion: Patients identified as poorly adherent by short term pharmacy refill are at risk for VF on second line ART. This pragmatic adherence tool could assist in identifying patients who require adherence interventions, and help rationalize use of VL monitoring and resistance testing among patients on second line ART

Improving the evidence base of Markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings

<p>Abstract</p> <p>Background</p> <p>Despite concerns about affordability and sustainability, many models of the lifetime costs of antiretroviral therapy (ART) used in resource limited settings are based on data from small research cohorts, together with pragmatic assumptions about life-expectancy. This paper revisits these modelling assumptions in order to provide input to future attempts to model the lifetime costs and the costs of scaling up ART.</p> <p>Methods</p> <p>We analysed the determinants of costs and outcomes in patients receiving ART in line with standard World Health Organization (WHO) guidelines for resource poor settings in a private sector managed ART programme in South Africa. The cohort included over 5,000 patients with up to 4 years (median 19 months) on ART. Generalized linear and Cox proportional hazards regression models were used to establish cost and outcome determinants respectively.</p> <p>Results</p> <p>The key variables associated with changes in mean monthly costs were: being on the second line regimen; receiving ART from 4 months prior to 4 months post treatment initiation; having a recent or current CD4 count <50 cells/µL or 50-199 cells/µl; having mean ART adherence <75% as determined by monthly pharmacy refill data; and having a current or recent viral load >100,000 copies/mL. In terms of the likelihood of dying, the key variables were: baseline CD4 count<50 cells/µl (particularly during the first 4 months on treatment); current CD4 count <50 cells/µl and 50-199 cells/µl (particularly during later periods on treatment); and being on the second line regimen. Being poorly adherent and having an unsuppressed viral load was also associated with a higher likelihood of dying.</p> <p>Conclusions</p> <p>While there are many unknowns associated with modelling the resources needed to scale-up ART, our analysis has suggested a number of key variables which can be used to improve the state of the art of modelling ART. While the magnitude of the effects associated with these variables would be likely to differ in other settings, the variables influencing costs and survival are likely to be generalizable. This is of direct relevance to those concerned about assessing the long-term costs and sustainability of expanded access to ART.</p