The cyclical cascade of HIV care: Temporal care engagement trends within a population-wide cohort.

BACKGROUND: The traditional HIV treatment cascade aims to visualise the journey of each person living with HIV from diagnosis, through initiation on antiretroviral therapy (ART) to treatment success, represented by virological suppression. This representation has been a pivotal tool in highlighting and quantifying sequential gaps along the care continuum. There is longstanding recognition, however, that this may oversimplify the complexity of real-world engagement with HIV services in settings with mature high-burden HIV epidemics. A complementary "cyclical" cascade has been proposed to represent the processes of disengagement at different points on the care continuum, with multiple pathways to re-engagement, although the feasibility of implementing this at scale has been uncertain. This study aimed to populate, refine, and explore the utility of a cyclical representation of the HIV cascade, using routine data from a high-burden HIV setting. METHODS AND FINDINGS: This observational cohort study leveraged person-level data on all people living with HIV in the Western Cape (WC), South Africa, who accessed public health services in the 2 years prior to 31 December 2023. Programme data from disease registers were complemented by data from pharmacy and laboratory systems. At study closure, 494 370 people were included, constituting 93% of those of those estimated to be living with HIV in the province, of whom 355 104 were on ART. Substantial disengagement from HIV care was evident at every point on the cascade. Early treatment emerged as a period of higher risk of disengagement, but it did not account for the majority of disengagement. Almost all those currently disengaged had prior experience of treatment. While re-engagement was also common, overall treatment coverage had increased slowly over 5 years. The transition to dolutegravir-based regimens was dramatic with good virological outcomes for those in care, notwithstanding a clearly discernible impact of the Coronavirus Disease 2019 (COVID-19) pandemic on viral load (VL) testing. People currently engaged and disengaged in care are similar with respect to age and gender. Those who died or disengaged recently were previously distributed across a range of cascade statuses, and a substantial proportion of those newly initiating and re-initiating treatment were no longer on treatment 6 months later. The main limitation of this study was incomplete evidence of HIV testing, linkage to HIV-specific services, and out-of-facility mortality. CONCLUSIONS: Using routine data, it was possible to populate and automate a cyclical cascade of HIV care that continuously captured the nonlinear care journeys of individuals living with HIV. In this generalised mature HIV epidemic, most people are treatment experienced. Disengagement is common and occurs at various points along the cascade, making it challenging to identify high-impact intervention opportunities. While historical HIV cascades remain valuable for target setting and service monitoring, they can be complemented with insights from more detailed cyclical cascades.

COVID-19 among adults living with HIV: correlates of mortality among public sector healthcare users in Western Cape, South Africa.

INTRODUCTION: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower-income settings. We studied the association of mortality with characteristics of HIV severity and management, and vaccination, among adult PWH. METHODS: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with evidence of antiretroviral therapy (ART) collection, time since first HIV evidence, CD4 cell count, viral load (among those with evidence of ART collection) and COVID-19 vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. RESULTS: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17,831 first-diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis (especially more recent episodes of tuberculosis), chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. CONCLUSIONS: Mortality was strongly associated with suboptimal HIV control, and the prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimized.

COVID-19 among adults living with HIV: Correlates of mortality in a general population in a resource-limited setting.

Introduction: While a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower income settings. We studied the association between mortality and characteristics of HIV severity and management, and vaccination, among adult PWH. Methods: We analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with CD4 cell count, viral load, evidence of ART, time since first HIV evidence, and vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period. Results: Mortality occurred in 5.7% (95% CI: 5.3,6.0) of 17 831 first diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load (among those with ART evidence), and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis, chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults. Conclusions: Mortality was strongly associated with suboptimal HIV control, and prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimised.

A longitudinal analysis of the completeness of maternal HIV testing, including repeat testing in Cape Town, South Africa.

INTRODUCTION: The virtual elimination of mother-to-child transmission of HIV cannot be achieved without complete maternal HIV testing. The World Health Organization recommends that women in high HIV prevalent settings repeat HIV testing in the third trimester, and at delivery or directly thereafter. The Western Cape Province (South Africa) prevention of mother-to-child transmission (PMTCT) guidelines recommend a repeat maternal HIV test between 32 and 34 weeks gestation and at delivery in addition to testing at the first antenatal visit (ideally <20 weeks gestation). There are few published longitudinal studies on the uptake of initial and repeated maternal HIV testing programmes in sub-Saharan Africa. We aimed to investigate the implementation of initial and repeat maternal HIV testing guidelines in Cape Town, South Africa. METHODS: Between 2013 and 2016 we established an electronic PMTCT register that consolidated routine data from a primary healthcare facility and its secondary and tertiary referral sites in Cape Town. This provided a longitudinal record for each participant, from first antenatal visit to delivery. Utilizing these data, we conducted a retrospective analysis investigating the completeness of maternal HIV testing according to the PMTCT HIV testing guidelines in Cape Town, and predictors of complete testing, from 2014 to 2016. RESULTS: Among 8558 enrolled pregnant women, 7213 (84%) were not known to be HIV positive at their first visit and thus eligible for HIV testing; 91% of them received ≥1 HIV test during pregnancy/delivery. Testing at the first visit was 98% among the 85% of women who attended antenatal care. Among women eligible to receive all three recommended HIV tests, only 11% achieved all three tests. Delivery HIV testing completion among all women without an HIV-positive diagnosis was 23%. HIV prevalence at delivery was 21% and HIV incidence between first visit and delivery in those with ≥2 HIV tests was 0.2%. Women who enrolled after 2014 were more likely to receive the three recommended tests (aOR: 1.41; 95% CI: 1.10 to 1.81) and retest at delivery (aOR: 1.20; 95% CI: 1.05 to 1.39). CONCLUSIONS: Implementation of maternal HIV testing in Cape Town improved between 2014 and 2016 but major gaps remain, particularly at delivery.

Neonatal and infant diagnostic HIV-PCR uptake and associations during three sequential policy periods in Cape Town, South Africa: a longitudinal analysis.

INTRODUCTION: To strengthen the early infant diagnosis (EID) programmes and timeously identify and treat HIV-infected infants, birth HIV-PCR for some/all infants has been recommended in the Western Cape, South Africa since 2014. Operational data on the implementation of such programmes in low- and middle-income countries are limited. METHODS: Utilizing the electronic records platform at primary care facilities, we developed an electronic register which consolidated obstetric and HIV-related data, allowing us to track a cohort of HIV-infected/exposed mother/infant dyads longitudinally from antenatal care through delivery to infant HIV-PCR. We assessed guideline implementation and impact on EID of three sequential EID policies in a referral chain of facilities in Cape Town (primary-tertiary care). Birth HIV-PCR was indicated in period 1 if symptomatic; period 2 if meeting high-risk criteria for transmission; and period 3 for all HIV-exposed neonates. RESULTS: We enrolled 2012 HIV-exposed infants; 89.2% had at least one HIV-PCR at any point. The majority of birth tests were performed in hospital versus primary care regardless of policy period. Almost half of all infants (47.9%) had at least one high-risk criterion for vertical infection; of these, 39.7% had a birth test. Infants with more risk factors were more likely to have birth EID. Receipt of a birth HIV-PCR significantly reduced the likelihood of receiving a follow-up test at six to ten weeks, even after adjusting for potential confounders (aOR 0.18 (0.12 to 0.26)). The proportion of infants tested at six to ten weeks old dropped from 92.9% (period 1) to 80.2% in period 3 and those receiving birth HIV-PCR increased, peaking at 67.4% during period 3. The proportion of positive birth tests was highest (2.9%) when birth tests were restricted to infants meeting high-risk criteria, with a low proportion positive for the first time at six to ten weeks. During period 3, the proportion positive at six to ten weeks was high (2.4%), highlighting the importance of follow-up to detect intrapartum and early postpartum infections. CONCLUSIONS: Over all policy periods, EID guidelines were incompletely implemented across all levels of care but especially in primary care. Birth HIV-PCR reduced return for follow-up testing, such follow-up testing is critical for the effectiveness of the programme.

The epidemiology of adolescents living with perinatally acquired HIV: A cross-region global cohort analysis.

BACKGROUND: Globally, the population of adolescents living with perinatally acquired HIV (APHs) continues to expand. In this study, we pooled data from observational pediatric HIV cohorts and cohort networks, allowing comparisons of adolescents with perinatally acquired HIV in "real-life" settings across multiple regions. We describe the geographic and temporal characteristics and mortality outcomes of APHs across multiple regions, including South America and the Caribbean, North America, Europe, sub-Saharan Africa, and South and Southeast Asia. METHODS AND FINDINGS: Through the Collaborative Initiative for Paediatric HIV Education and Research (CIPHER), individual retrospective longitudinal data from 12 cohort networks were pooled. All children infected with HIV who entered care before age 10 years, were not known to have horizontally acquired HIV, and were followed up beyond age 10 years were included in this analysis conducted from May 2016 to January 2017. Our primary analysis describes patient and treatment characteristics of APHs at key time points, including first HIV-associated clinic visit, antiretroviral therapy (ART) start, age 10 years, and last visit, and compares these characteristics by geographic region, country income group (CIG), and birth period. Our secondary analysis describes mortality, transfer out, and lost to follow-up (LTFU) as outcomes at age 15 years, using competing risk analysis. Among the 38,187 APHs included, 51% were female, 79% were from sub-Saharan Africa and 65% lived in low-income countries. APHs from 51 countries were included (Europe: 14 countries and 3,054 APHs; North America: 1 country and 1,032 APHs; South America and the Caribbean: 4 countries and 903 APHs; South and Southeast Asia: 7 countries and 2,902 APHs; sub-Saharan Africa, 25 countries and 30,296 APHs). Observation started as early as 1982 in Europe and 1996 in sub-Saharan Africa, and continued until at least 2014 in all regions. The median (interquartile range [IQR]) duration of adolescent follow-up was 3.1 (1.5-5.2) years for the total cohort and 6.4 (3.6-8.0) years in Europe, 3.7 (2.0-5.4) years in North America, 2.5 (1.2-4.4) years in South and Southeast Asia, 5.0 (2.7-7.5) years in South America and the Caribbean, and 2.1 (0.9-3.8) years in sub-Saharan Africa. Median (IQR) age at first visit differed substantially by region, ranging from 0.7 (0.3-2.1) years in North America to 7.1 (5.3-8.6) years in sub-Saharan Africa. The median age at ART start varied from 0.9 (0.4-2.6) years in North America to 7.9 (6.0-9.3) years in sub-Saharan Africa. The cumulative incidence estimates (95% confidence interval [CI]) at age 15 years for mortality, transfers out, and LTFU for all APHs were 2.6% (2.4%-2.8%), 15.6% (15.1%-16.0%), and 11.3% (10.9%-11.8%), respectively. Mortality was lowest in Europe (0.8% [0.5%-1.1%]) and highest in South America and the Caribbean (4.4% [3.1%-6.1%]). However, LTFU was lowest in South America and the Caribbean (4.8% [3.4%-6.7%]) and highest in sub-Saharan Africa (13.2% [12.6%-13.7%]). Study limitations include the high LTFU rate in sub-Saharan Africa, which could have affected the comparison of mortality across regions; inclusion of data only for APHs receiving ART from some countries; and unavailability of data from high-burden countries such as Nigeria. CONCLUSION: To our knowledge, our study represents the largest multiregional epidemiological analysis of APHs. Despite probable under-ascertained mortality, mortality in APHs remains substantially higher in sub-Saharan Africa, South and Southeast Asia, and South America and the Caribbean than in Europe. Collaborations such as CIPHER enable us to monitor current global temporal trends in outcomes over time to inform appropriate policy responses.

e-PC101: an electronic clinical decision support tool developed in South Africa for primary care in low-income and middle-income countries.

Health technology is increasingly recognised as a feasible method of addressing health needs in low and middle-income countries (LMICs). Primary Care 101, now known as PACK (Practical Approach to Care Kit), is a printed, algorithmic, checklist-based, comprehensive clinical decision support tool. It assists clinicians with delivering evidence-based medicine for common primary care presentations and conditions. These assessment and treatment guides have been adopted widely in primary care clinics across South Africa. This paper focuses on the process of designing, developing, and implementing a digital version of the clinical decision support tool for use on a tablet computer. Lessons learnt throughout its development and pilot implementation could apply to the creation of electronic health interventions and the digitisation of clinical tools in LMICs.

Educational Outreach with an Integrated Clinical Tool for Nurse-Led Non-communicable Chronic Disease Management in Primary Care in South Africa: A Pragmatic Cluster Randomised Controlled Trial.

BACKGROUND: In many low-income countries, care for patients with non-communicable diseases (NCDs) and mental health conditions is provided by nurses. The benefits of nurse substitution and supplementation in NCD care in high-income settings are well recognised, but evidence from low- and middle-income countries is limited. Primary Care 101 (PC101) is a programme designed to support and expand nurses' role in NCD care, comprising educational outreach to nurses and a clinical management tool with enhanced prescribing provisions. We evaluated the effect of the programme on primary care nurses' capacity to manage NCDs. METHODS AND FINDINGS: In a cluster randomised controlled trial design, 38 public sector primary care clinics in the Western Cape Province, South Africa, were randomised. Nurses in the intervention clinics were trained to use the PC101 management tool during educational outreach sessions delivered by health department trainers and were authorised to prescribe an expanded range of drugs for several NCDs. Control clinics continued use of the Practical Approach to Lung Health and HIV/AIDS in South Africa (PALSA PLUS) management tool and usual training. Patients attending these clinics with one or more of hypertension (3,227), diabetes (1,842), chronic respiratory disease (1,157) or who screened positive for depression (2,466), totalling 4,393 patients, were enrolled between 28 March 2011 and 10 November 2011. Primary outcomes were treatment intensification in the hypertension, diabetes, and chronic respiratory disease cohorts, defined as the proportion of patients in whom treatment was escalated during follow-up over 14 mo, and case detection in the depression cohort. Primary outcome data were analysed for 2,110 (97%) intervention and 2,170 (97%) control group patients. Treatment intensification rates in intervention clinics were not superior to those in the control clinics (hypertension: 44% in the intervention group versus 40% in the control group, risk ratio [RR] 1.08 [95% CI 0.94 to 1.24; p = 0.252]; diabetes: 57% versus 50%, RR 1.10 [0.97 to 1.24; p = 0.126]; chronic respiratory disease: 14% versus 12%, RR 1.08 [0.75 to 1.55; p = 0.674]), nor was case detection of depression (18% versus 24%, RR 0.76 [0.53 to 1.10; p = 0.142]). No adverse effects of the nurses' expanded scope of practice were observed. Limitations of the study include dependence on self-reported diagnoses for inclusion in the patient cohorts, limited data on uptake of PC101 by users, reliance on process outcomes, and insufficient resources to measure important health outcomes, such as HbA1c, at follow-up. CONCLUSIONS: Educational outreach to primary care nurses to train them in the use of a management tool involving an expanded role in managing NCDs was feasible and safe but was not associated with treatment intensification or improved case detection for index diseases. This notwithstanding, the intervention, with adjustments to improve its effectiveness, has been adopted for implementation in primary care clinics throughout South Africa. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials (ISRCTN20283604).

Socioeconomic predictors and consequences of depression among primary care attenders with non-communicable diseases in the Western Cape, South Africa: cohort study within a randomised trial.

BACKGROUND: Socioeconomic predictors and consequences of depression and its treatment were investigated in 4393 adults with specified non-communicable diseases attending 38 public sector primary care clinics in the Eden and Overberg districts of the Western Cape, South Africa. METHODS: Participants were interviewed at baseline in 2011 and 14 months later, as part of a randomised controlled trial of a guideline-based intervention to improve diagnosis and management of chronic diseases. The 10-item Center for Epidemiologic Studies Depression Scale (CESD-10) was used to assess depression symptoms, with higher scores representing more depressed mood. RESULTS: Higher CESD-10 scores at baseline were independently associated with being less educated (p = 0.004) and having lower income (p = 0.003). CESD-10 scores at follow-up were higher in participants with less education (p = 0.010) or receiving welfare grants (p = 0.007) independent of their baseline scores. Participants with CESD-10 scores of ten or more at baseline (56 % of all participants) had 25 % higher odds of being unemployed at follow-up (p = 0.016), independently of baseline CESD-10 score and treatment status. Among participants with baseline CESD-10 scores of ten or more, antidepressant medication at baseline was independently more likely in participants who had more education (p = 0.002), higher income (p < 0.001), or were unemployed (p = 0.001). Antidepressant medication at follow up was independently more likely in participants with higher income (p = 0.023), and in clinics with better access to pharmacists (p = 0.053) and off-site drug delivery (p = 0.013). CONCLUSIONS: Socioeconomic disadvantage appears to be both a cause and consequence of depression, and may also be a barrier to treatment. There are opportunities for improving the prevention, diagnosis and treatment of depression in primary care in inequitable middle income countries like South Africa. TRIAL REGISTRATION: The trial is registered with Current Controlled Trials ( ISRCTN20283604 ).

Innovating to improve primary care in less developed countries: towards a global model.

One of the biggest problems in global health is the lack of well trained and supported health workers in less developed settings. In many rural areas there are no physicians, and it is important to find ways to support and empower nurses and other health workers. The Knowledge Translation Unit of the University of Cape Town Lung Institute has spent 14 years developing a series of innovative packages to support and empower nurses and other health workers. PACK (Practical Approach to Care Kit) Adult comprises policy-based and evidence-informed guidelines; onsite, team and case-based training; non-physician prescribing; and a cascade system of scaling up. A series of randomised trials has shown the effectiveness of the packages, and methods are now being developed to respond cost-effectively and sustainably to global demand for implementing PACK Adult. Global health would probably benefit from less time and money spent developing new innovations and more spent on finding ways to spread those we already have.

Effect of antiretroviral treatment on the risk of tuberculosis during South Africa's programme expansion.

OBJECTIVE: The objective of this study is to estimate the effectiveness of antiretroviral treatment (ART) in preventing tuberculosis (TB) in HIV-infected people during the first 6 years of ART programme expansion. DESIGN: A cohort study comparing TB risk without ART and after ART initiation. SETTING: Public sector HIV programme of the Free State province, South Africa. PARTICIPANTS: Seventy-four thousand and seventy-four HIV-infected people enrolled from 2004 until 2010, of whom 43 898 received ART and 30 176 did not. INTERVENTION: Combination ART. MAIN OUTCOME MEASURES: Time to first TB diagnosis, adjusted for CD4 cell count, weight, age, sex, previous TB, district and year, with ART, CD4 cell count and weight as time-varying covariates and with death as a competing risk. RESULTS: Three thousand eight hundred and fifty-eight first TB episodes occurred during 78 202 person-years at risk with ART and 5669 episodes occurred during 62 801 person-years without ART [incidence rates 4.9 and 9.0 per 100 person-years, crude incidence rate ratio 0.55 (95% confidence interval 0.52-0.57)]. The adjusted subhazard ratio (SHR) of time to first TB episode after starting ART, compared with follow-up without ART, was 0.67 (0.64-0.70). Within CD4 cell count subgroups (<50, 50-199, 100-199, 200-349 and >350 cells/µl), the respective SHRs were 0.64 (0.57-0.71), 0.63 (0.57-0.70), 0.66 (0.61-0.72), 0.67 (0.62-0.72), 0.72 (0.63-0.83) and 0.97 (0.60-1.59). Adjusted SHRs for ART decreased with each year of enrolment, from 0.90 (0.77-1.04) in 2004 to 0.54 (0.43-0.67) in 2010. CONCLUSION: ART was effective in preventing TB in HIV-infected patients with CD4 cell counts below 350 cells/µl, but less so than previously estimated. Effectiveness increased each year.

Multimorbidity, control and treatment of noncommunicable diseases among primary healthcare attenders in the Western Cape, South Africa.

BACKGROUND: South Africa (SA) is facing a heavy burden of non-communicable diseases (NCDs). Few studies address multimorbidity, control and treatment of NCDs in patients attending primary healthcare (PHC) clinics. OBJECTIVES: To describe multimorbidity, related risk factors, disease severity and treatment status of patients with four important NCDs attending public sector PHC clinics in two districts in SA. METHODS: A cross-sectional sample of patients completed baseline data collection for a randomised controlled trial of a health systems intervention. The study population comprised adults attending PHC clinics in the Eden and Overberg districts of the Western Cape in 2011. Four subgroups of patients were identified: hypertension, diabetes, chronic respiratory disease and depression. A total of 4 393 participants enrolled from 38 clinics completed a baseline structured questionnaire and had measurements taken. Prescription data were recorded. RESULTS: Of participants with hypertension, diabetes, respiratory disease and depression, 80%, 92%, 88% and 80%, respectively, had at least one of the other three conditions. There were low levels of control and treatment: 59% of participants with hypertension had a blood pressure ≥140/90 mmHg, the mean haemoglobin A1c (HbA1c) value in participants with diabetes was 9%, 12% of participants in the depression group were prescribed an antidepressant at a therapeutic dose, and 48% of respiratory participants were prescribed a b2-agonist and 34% an inhaled corticosteroid. CONCLUSION: Considerable multimorbidity and unmet treatment needs exist among patients with NCDs attending public sector PHC clinics. Improved strategies are required for diagnosing and managing NCDs in this sector.

Temporal trends in the characteristics of children at antiretroviral therapy initiation in southern Africa: the IeDEA-SA Collaboration.

BACKGROUND: Since 2005, increasing numbers of children have started antiretroviral therapy (ART) in sub-Saharan Africa and, in recent years, WHO and country treatment guidelines have recommended ART initiation for all infants and very young children, and at higher CD4 thresholds for older children. We examined temporal changes in patient and regimen characteristics at ART start using data from 12 cohorts in 4 countries participating in the IeDEA-SA collaboration. METHODOLOGY/PRINCIPAL FINDINGS: Data from 30,300 ART-naïve children aged <16 years at ART initiation who started therapy between 2005 and 2010 were analysed. We examined changes in median values for continuous variables using the Cuzick's test for trend over time. We also examined changes in the proportions of patients with particular disease severity characteristics (expressed as a binary variable e.g. WHO Stage III/IV vs I/II) using logistic regression. Between 2005 and 2010 the number of children starting ART each year increased and median age declined from 63 months (2006) to 56 months (2010). Both the proportion of children <1 year and ≥10 years of age increased from 12 to 19% and 18 to 22% respectively. Children had less severe disease at ART initiation in later years with significant declines in the percentage with severe immunosuppression (81 to 63%), WHO Stage III/IV disease (75 to 62%), severe anemia (12 to 7%) and weight-for-age z-score<-3 (31 to 28%). Similar results were seen when restricting to infants with significant declines in the proportion with severe immunodeficiency (98 to 82%) and Stage III/IV disease (81 to 63%). First-line regimen use followed country guidelines. CONCLUSIONS/SIGNIFICANCE: Between 2005 and 2010 increasing numbers of children have initiated ART with a decline in disease severity at start of therapy. However, even in 2010, a substantial number of infants and children started ART with advanced disease. These results highlight the importance of efforts to improve access to HIV diagnostic testing and ART in children.

Cost-effectiveness of nurse-led versus doctor-led antiretroviral treatment in South Africa: pragmatic cluster randomised trial.

OBJECTIVE: To estimate the cost-effectiveness of nurse-led versus doctor-led antiretroviral treatment (ART) for HIV-infected people. DESIGN: Cost-effectiveness analysis alongside a pragmatic cluster randomised controlled trial in 31 primary care clinics (16 intervention, 15 controls) in Free State Province, South Africa. Participants were HIV-infected patients, aged ≥16 years. Cohort 1 (CD4 count ≤350 cells/µl, not yet receiving ART at enrolment): consisted of 5 390 intervention patients and 3 862 controls; Cohort 2 (already received ART for ≥6 months at enrolment) of 3 029 intervention patients and 3 202 controls. Nurses were authorised and trained to initiate and represcribe ART. Management and ART provision were decentralised to primary care clinics. In control clinics, doctors initiated and re-prescribed ART, nurses monitored ART. Main outcome measure(s) were health service costs, death (cohort 1) and undetectable viral load (<400 copies/ml) (cohort 2) during the 12 months after enrolment. RESULTS: For Cohort 1, the intervention had an estimated incremental cost of US$102.52, an incremental effect of 0.42% fewer deaths and an incremental cost-effectiveness ratio (ICER) of US$24 500 per death averted. For Cohort 2, the intervention had an estimated incremental cost of US$59.48, an incremental effect of 0.47% more undetectable viral loads and an ICER of US$12 584 per undetectable viral load. CONCLUSIONS: Nurse-led ART was associated with higher mean health service costs than doctor-led care, with small effects on primary outcomes, and a high associated level of uncertainty. Given this, and the shortage of doctors, further implementation of nurse-led ART should be considered, although this may increase health service costs.

Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, cluster-randomised trial.

BACKGROUND: Robust evidence of the effectiveness of task shifting of antiretroviral therapy (ART) from doctors to other health workers is scarce. We aimed to assess the effects on mortality, viral suppression, and other health outcomes and quality indicators of the Streamlining Tasks and Roles to Expand Treatment and Care for HIV (STRETCH) programme, which provides educational outreach training of nurses to initiate and represcribe ART, and to decentralise care. METHODS: We undertook a pragmatic, parallel, cluster-randomised trial in South Africa between Jan 28, 2008, and June 30, 2010. We randomly assigned 31 primary-care ART clinics to implement the STRETCH programme (intervention group) or to continue with standard care (control group). The ratio of randomisation depended on how many clinics were in each of nine strata. Two cohorts were enrolled: eligible patients in cohort 1 were adults (aged ≥16 years) with CD4 counts of 350 cells per µL or less who were not receiving ART; those in cohort 2 were adults who had already received ART for at least 6 months and were being treated at enrolment. The primary outcome in cohort 1 was time to death (superiority analysis). The primary outcome in cohort 2 was the proportion with undetectable viral loads (<400 copies per mL) 12 months after enrolment (equivalence analysis, prespecified difference <6%). Patients and clinicians could not be masked to group assignment. The interim analysis was blind, but data analysts were not masked after the database was locked for final analysis. Analyses were done by intention to treat. This trial is registered, number ISRCTN46836853. FINDINGS: 5390 patients in cohort 1 and 3029 in cohort 2 were in the intervention group, and 3862 in cohort 1 and 3202 in cohort 2 were in the control group. Median follow-up was 16·3 months (IQR 12·2-18·0) in cohort 1 and 18·0 months (18·0-18·0) in cohort 2. In cohort 1, 997 (20%) of 4943 patients analysed in the intervention group and 747 (19%) of 3862 in the control group with known vital status at the end of the trial had died. Time to death did not differ (hazard ratio [HR] 0·94, 95% CI 0·76-1·15). In a preplanned subgroup analysis of patients with baseline CD4 counts of 201-350 cells per µL, mortality was slightly lower in the intervention group than in the control group (0·73, 0·54-1.00; p=0·052), but it did not differ between groups in patients with baseline CD4 of 200 cells per µL or less (0·94, 0·76-1·15; p=0·577). In cohort 2, viral load suppression 12 months after enrolment was equivalent in intervention (2156 [71%] of 3029 patients) and control groups (2230 [70%] of 3202; risk difference 1·1%, 95% CI -2·4 to 4·6). INTERPRETATION: Expansion of primary-care nurses' roles to include ART initiation and represcription can be done safely, and improve health outcomes and quality of care, but might not reduce time to ART or mortality. FUNDING: UK Medical Research Council, Development Cooperation Ireland, and Canadian International Development Agency.

Differences in access and patient outcomes across antiretroviral treatment clinics in the Free State province: a prospective cohort study.

OBJECTIVE: To assess differences in access to antiretroviral treatment (ART) and patient outcomes across public sector treatment facilities in the Free State province, South Africa. DESIGN: Prospective cohort study with retrospective database linkage. We analysed data on patients enrolled in the treatment programme across 36 facilities between May 2004 and December 2007, and assessed percentage initiating ART and percentage dead at 1 year after enrolment. Multivariable logistic regression was used to estimate associations of facility-level and patient-level characteristics with both mortality and treatment status. RESULTS: Of 44 866 patients enrolled, 15 219 initiated treatment within 1 year; 8 778 died within 1 year, 7 286 before accessing ART. Outcomes at 1 year varied greatly across facilities and more variability was explained by facility-level factors than by patient-level factors. The odds of starting treatment within 1 year improved over calendar time. Patients enrolled in facilities with treatment initiation available on site had higher odds of starting treatment and lower odds of death at 1 year compared with those enrolled in facilities that did not offer treatment initiation. Patients were less likely to start treatment if they were male, severely immunosuppressed (CD4 count ≤50 cells/µl), or underweight (<50 kg). Men were also more likely to die in the first year after enrolment. CONCLUSIONS: Although increasing numbers of patients started ART between 2004 and 2007, many patients died before accessing ART. Patient outcomes could be improved by decentralisation of treatment services, fast-tracking the most immunodeficient patients and improving access, especially for men.

Outcomes in patients waiting for antiretroviral treatment in the Free State Province, South Africa: prospective linkage study.

OBJECTIVE: In South Africa, many HIV-infected patients experience delays in accessing antiretroviral therapy (ART). We examined pretreatment mortality and access to treatment in patients waiting for ART. DESIGN: Cohort of HIV-infected patients assessed for ART eligibility at 36 facilities participating in the Comprehensive HIV and AIDS Management (CHAM) program in the Free State Province. METHODS: Proportion of patients initiating ART, pre-ART mortality and risk factors associated with these outcomes were estimated using competing risks survival analysis. RESULTS: Forty-four thousand, eight hundred and forty-four patients enrolled in CHAM between May 2004 and December 2007, of whom 22 083 (49.2%) were eligible for ART; pre-ART mortality was 53.2 per 100 person-years [95% confidence interval (CI) 51.8-54.7]. Median CD4 cell count at eligibility increased from 87 cells/µl in 2004 to 101 cells/µl in 2007. Two years after eligibility an estimated 67.7% (67.1-68.4%) of patients had started ART, and 26.2% (25.6-26.9%) died before starting ART. Among patients with CD4 cell counts below 25 cells/µl at eligibility, 48% died before ART and 51% initiated ART. Men were less likely to start treatment and more likely to die than women. Patients in rural clinics or clinics with low staffing levels had lower rates of starting treatment and higher mortality compared with patients in urban/peri-urban clinics, or better staffed clinics. CONCLUSIONS: Mortality is high in eligible patients waiting for ART in the Free State Province. The most immunocompromised patients had the lowest probability of starting ART and the highest risk of pre-ART death. Prioritization of these patients should reduce waiting times and pre-ART mortality.

Towards universal ARV access: achievements and challenges in Free State Province, South Africa.

OBJECTIVE: To study the progress and challenges with regard to universal antiretroviral (ARV) access in Free State Province, South Africa. METHODS: Data from the first 4 years of the public sector ARV roll-out and selected health system indicators were used. Data were collected from the public sector ARV database in Free State Province for new patients on ARVs, average waiting times and median CD4 counts at the start of treatment. Information on staff training, vacancy rates and funding allocations for the ARV roll-out was obtained from official government reports. Projections were made of expected new ARV enrolments for 2008 and 2009 and compared with goals set by the National Strategic Plan (NSP) to achieve universal access to ARVs by 2011. RESULTS: New ARV enrolments increased annually to 25% of the estimated need by the end of 2007. Average waiting times to enrolment decreased from 5.82 months to 3.24 months. Median CD4 counts at enrolment increased from 89 to 124 cells/mm3. There is a staff vacancy rate of 38% in the ARV programme and an inadequate increase in budget allocations. CONCLUSION: The current vertical model of ARV therapy delivery is unlikely to raise the number of new enrolments sufficiently to achieve the goals of universal access by 2011 as envisaged by the NSP. The Free State is implementing a project (STRETCH trial) to broaden the ARV roll-out in an attempt to increase access to ARVs.

Effectiveness of antiretroviral treatment in a South African program: a cohort study.

BACKGROUND: The effectiveness of the South African government's expanding antiretroviral treatment program is unknown. Observational studies of treatment effectiveness are prone to selection bias, rarely compare patients receiving antiretroviral treatment with similar patients not receiving antiretroviral treatment, and underestimate mortality rates unless patients are actively followed up. METHODS: We followed up 14 267 patients in the Public Sector Anti-Retroviral Treatment project in Free State, South Africa, for up to 20 months after enrollment. A total of 3619 patients received highly active triple antiretroviral treatment (HAART) for up to 19 months (median, 6 months; interquartile range, 3-9 months) after enrollment. Patients' clinical data were linked with the national mortality register. Marginal structural regression models adjusted for baseline and time-varying covariates. RESULTS: Of 4570 patients followed up for at least 1 year, 53.2% died. Eighty-seven percent of patients who died had not received HAART. HAART was associated with lower mortality (hazard ratio, 0.14; 95% confidence interval [CI], 0.11-0.18) and with the presence of tuberculosis (hazard ratio, 0.61; 95% CI, 0.46-0.81) after adjusting for age, sex, weight, clinic, district, CD4 cell count, cotrimoxazole therapy, tuberculosis at baseline, and previous antiretroviral therapy. Cotrimoxazole therapy was associated with lower mortality (hazard ratio, 0.37; 95% CI, 0.32-0.42). Each month of HAART was associated with an increase in CD4 cell count of 15.1 cells/microL (95% CI, 14.7-15.5 cells/microL) and with an increase in body weight of 602 g (95% CI, 548-658 g). CONCLUSIONS: HAART provided through these South African government health services seems as effective as that provided in high-income countries. Delays starting HAART contributed to high mortality rates. Faster expansion and timely commencement of HAART are needed.