Contemporary Disengagement From Antiretroviral Therapy in the Western Cape, South Africa: A Cross\u2010Sectional Study

To the Editors: INTRODUCTION South Africa has the largest antiretroviral therapy (ART) program worldwide with 970,000 people receiving ART in 2009.1 As patient numbers have expanded, rising levels of loss to follow-up (LTFU) have significantly reduced the effectiveness of the national ART program, and increasing virological failure has become apparent.2,3 A causal association between increased facility patient caseload and worsening ART outcomes in South Africa is, however, not established.3 A recent study from Mozambique indicated increased attrition from clinics with high pharmacy staff burden.4 However, there is little other sub-Saharan data comparing ART outcomes between facilities with varying patient caseloads. This knowledge is valuable, as the most efficient approaches to further upscale treatment access while maintaining good ART outcomes are critical to the success of ART programs. To determine the effect of increasing facility patient burden on ART program effectiveness, this study compared program outcomes among 54 government primary health care ART facilities in 4 South African provinces. METHODS A multicohort study of adults enrolled at ART facilities supported by a nongovernmental organization (NGO) was conducted. The NGO provides clinical staff, infrastructure, clinical mentoring, community-based adherence support, and electronic data collection systems. Facilities are located in 4 provinces (Western Cape, KwaZulu-Natal, Eastern Cape, and Mpumalanga) in urban and rural areas. All ART-naive adults (16 years and older) enrolled on triple ART between January 2004 and September 2009, with documented date of birth, sex, date of starting ART, at least 1 day of follow-up, and who were enrolled at least 6 months before site database closure were included in the analyses. Patients were followed up until March 2010 or until the NGO exited from a site. Routine patient data were collected prospectively by facility-based data capturers at each clinic visit. Continual data cleaning and quality control routines were implemented to enhance data validity. Outcomes measures were death, LTFU, and virological suppression after starting ART. Attrition was defined as patient losses due to LTFU or death. LTFU was defined as no patient visit for 3 months or more beyond the last missed appointment. Viral load was measured 6 monthly on treatment, and virological suppression was defined as a viral load <400 copies per milliliter. The cumulative total of ART-naive adults enrolled at a facility at the end of the enrollment period was the measure of clinic patient load used. To guide the choice of how to categorize the sample according to facility load to optimize data fit, the Akaike information criterion from Cox models of facility load associated with outcomes was employed. A single cutoff of 950 patients was thus chosen, with facilities enrolling more than 950 patients classified as high caseload clinics and facilities enrolling fewer as low caseload clinics. Subgroup analyses were performed within high caseload clinic patients by comparing outcomes of patients enrolled prior to 6 months before enrollment of the 950th patient per site (the “early period” when the clinics had a low caseload) with patients enrolled thereafter (later period). Sensitivity analyses were conducted by modelling patient load alternatively as a 3-level ordinal variable, split at the tertiles of the sample distribution of cumulative facility enrollment (low tertile < 1067; mid tertile 1067-2031; high tertile > 2031 patients/facility, respectively). Kaplan-Meier estimates of outcomes were calculated. Time till initial virological suppression analyses were limited to patients having 1 or more viral load measurement within the first 12-month measurement period after starting ART. Multivariable Cox regression was used to estimate associations of patient and site-level factors with attrition and LTFU adjusting for baseline patient variables (age, sex, World Health Organization clinical stage, CD4 cell count, year of starting ART, tuberculosis treatment, pregnancy, and initial regimen) and site-related variables (province and rural/urban nature of site). Missing baseline values were classified as separate categories within variables,5 to retain observations in multivariable models. All adjusted models included all available baseline variables. All confidence intervals (CIs) quoted are 95% CIs. Statistical analyses were performed using Stata 11.1 (Stata Corporation, College Station, Texas). The study was approved by the University of Cape Town Research Ethics Committee. RESULTS Overall, 40,861 adults were included, of whom 11,830 (29.0%) were treated at 38 low caseload clinics and 29,031 (71.1%) were treated at 16 high caseload clinics. The median number enrolled per site was 488 [interquartile range (IQR): 291-736) and 2031 (IQR: 1275-3599) at low and high caseload clinics, respectively. The median age was 34.4 years (IQR: 29.3-41.1 years), being equivalent between groups (P = 0.26). Patients at high caseload facilities had a lower proportion of males (30.8% vs. 33.3%; P < 0.0005) and a lower median baseline CD4 cell count [117 cells/μL (IQR: 61-167) vs. 130 cells/μL (IQR: 71-177)]. Availability of baseline CD4 cell count results was 82.5%, with no difference between groups (P = 0.73). A higher proportion of patients were enrolled in earlier calendar years at high caseload facilities (44.5% enrolled pre-2008 vs. 23.7% at low caseload facilities, P < 0.0005). The duration of follow-up was 52,602 person-years. Cumulative LTFU was reduced at low caseload clinics, being 6.4% (CI: 5.9% to 7.0%) and 11.2% (CI: 10.4% to 12.2%) after 12 and 24 months of ART, respectively, vs. 8.6% (CI: 8.3% to 9.0%) and 14.9% (CI: 14.3% to 15.4%) at high caseload facilities, P < 0.0005 (Fig. 1). Mortality was equivalent between the groups, being 5.1% (CI: 4.9% to 5.4%) and 6.8% (CI: 6.5% to 7.1%), after 12 and 24 months overall, respectively (P = 0.40). After 36 months of ART, retention in care (1-attrition) remained superior at low caseload clinics, being 78.8% (CI: 76.7% to 80.8%) vs. 73.9% (CI: 73.1% to 74.7%), P < 0.0005.FIGURE 1: Cumulative probabilities of LTFU at low and high caseload clinics after starting ART. Low caseload clinics enrolled fewer than and high caseload clinics greater than 950 ART-naive adults onto ART.In adjusted multivariable analyses, high caseload clinics had independently increased probabilities of attrition and LTFU, adjusted hazard ratio (AHR) 1.26 (CI: 1.17 to 1.35; n = 40,861) and AHR 1.67 (CI: 1.52 to 1.83), respectively. Patients enrolled in later calendar years had independently increased risks of LTFU [AHR 2.25 (CI: 1.95 to 2.59), 2008-2009 vs. 2004-2005]. The subgroup of patients enrolled at high caseload clinics during the early period (during low caseload) totalled 9200 (31.7%) patients. This subgroup had independently better outcomes compared with patients enrolled during the later (high caseload) period; AHR of attrition and LTFU being 0.81 (CI: 0.75 to 0.88) and 0.74 (CI: 0.67 to 0.82), respectively. Mortality was equivalent, AHR 0.94 (CI: 0.82 to 1.09). In sensitivity analyses using the alternate exposure categorization, patients in the mid and high tertiles of facility caseload had independently increased attrition, AHR 1.20 (CI: 1.12 to 1.29) and AHR 1.37 (CI: 1.23 to 1.52), respectively. LTFU was increased, AHR 1.42 (CI: 1.29 to 1.55) and AHR 2.03 (CI: 1.77 to 2.33) in the mid and high tertiles, respectively. In both cases, a dose-response relationship was evident, with hazards of attrition and LTFU in the high tertile compared with the mid tertile being AHR 1.17 (CI: 1.05 to 1.31) and AHR 1.48 (CI: 1.29 to 1.70), respectively. Viral load result availability after 6 months of ART was better at low caseload clinics, being 61.1% vs. 58.4% (P < 0.0005). The proportion of patients achieving virological suppression at all time points on treatment was 87.2% (CI: 86.8% to 87.5%; n = 42,340), with no difference between groups (P = 0.30). The probability of achieving initial virologic suppression within 12 months of starting ART was, however, increased at low caseload clinics, being 88.3% (CI: 87.5% to 89.2%) vs. 85.0% (CI: 84.4% to 85.5%); P<0.0005, n = 22,251. [Low tertile 89.0% (CI: 88.2% to 89.7%), mid tertile 85.1% (CI: 84.3% to 86.0%), and high tertile 83.4% (CI: 82.5% to 84.3%); log rank trend P < 0.0005]. DISCUSSION Patients at facilities with larger patient loads had increased attrition due to LTFU and reduced initial virologic suppression in this multicohort study. Attrition increased, and initial virological suppression decreased in dose-dependent manners as facility patient loads expanded. LTFU increased in more recent years, similar to other South African cohorts.2,3,6 Low caseload clinics, however, had a decreased probability of LTFU despite having enrolled the majority of their patients in more recent years. Low ART health care provider to patient ratios have been associated with a reduced probability of starting ART after enrollment at HIV care facilities,7 and increased attrition with low pharmacy staff to patient ratios.4 However, no association between nonpharmacy health care provider to patient ratios and ART program attrition was evident in Uganda and Mozambique.4,8 Facility-level factors are nevertheless important determinants of ART outcomes.7 Large patient loads at facilities may overwhelm clinic administration systems and infrastructure, be associated with longer waiting times, and provide a higher caseload for community adherence support counsellors. Dissatisfaction with waiting times is an important predictor of discontent among ART patients.9 Strengths of this study include that a large number of patients from a broad range of sites and settings were analyzed, and individual-level data were collected prospectively, enabling adjustment of patient-level factors associated with outcomes. Limitations include that health care provider to patient ratios and facility infrastructure variables were not included in the analyses as data for all sites were unavailable. Attrition was raised at high caseload sites, although increased misclassification of patients as LTFU instead of deceased at high caseload sites might account for a degree of the raised LTFU observed. Facility patient burden may be assessed using alternate measures such as monthly visit count; cumulative patient enrollment is, however, a useful measure that is currently tracked in South African routine settings. In conclusion, these results further establish an association between increasing facility patient load and poorer ART outcomes. Further research should be conducted to elucidate underlying mechanisms explaining this and to identify potentially remedial interventions. ACKNOWLEDGMENTS The authors acknowledge Emmanuel Okoli, Kheth'Impilo colleagues, PEPFAR, Absolute Return for Kids, and the SA Health Department. Geoffrey Fatti, MBChB, MPH* Ashraf Grimwood, MBChB, MPH* Eula Mothibi, MBChB, FCP* Jawaya Shea, MHPE† *Kheth'Impilo, Cape Town, South Africa †Child Health Unit, School of Child & Adolescent Health, University of Cape Town, Cape Town, South Africa

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BackgroundIn common with other developing countries, South Africa's public health system is characterised by human resource shortfalls. These are likely to be exacerbated by the escalating demand for HIV care and a large-scale antiretroviral therapy (ART) programme. Focusing on professional nurses, the main front-line providers of primary health care in South Africa, we studied patterns of planning, recruitment, training and task allocation associated with an expanding ART programme in the districts of one province, the Free State.MethodsData collection included an audit of professional nurse posts created and filled following the introduction of the ART programme, repeated surveys of facilities providing ART over two years to assess the deployment of staff, and secondary data analysis of government personnel databases to track broader patterns of recruitment and training.ResultsAlthough a substantial number of new professional nurse posts were established for the ART programme in the Free State, nearly 80% of these posts were filled by nurses transferring from other programmes within the same facility or from facilities within the same district, rather than by new recruits. From the beginning, ART nurse posts tended to be graded at a senior level, and later, in an effort to recruit professional nurses for the ART programme, the majority (54.6%) of nurses entering the programme were promoted to a senior level. The vacancy rate of nurse ART posts was significantly lower than that of other posts in the primary health care (PHC) system (15.7% vs 37.1%). Nursing posts in urban ART facilities were more easily filled than those in rural areas, exacerbating existing imbalances. The shift of nurses into the ART programme was partially compensated for by the appointment of additional support staff, task shifting to community health workers, and a large investment in training of PHC workers. However, the use of less-trained, mid-level enrolled nurses and nursing assistants in the ART programme remained low.ConclusionThe introduction of the ART programme has revealed both strengths and weaknesses of human resource development in one province of South Africa. Without concerted efforts to increase the supply of key health professionals, accompanied by changes in the deployment of health workers, the core goals of the ART programme – i.e. providing universal access to ART and strengthening the health system – will not be achieved.

To describe how district-wide access to HIV/AIDS care was achieved and maintained in Thyolo District, Malawi. In mid-2003, the Ministry of Health and Médecins Sans Frontières developed a model of care for Thyolo district (population 587, 455) based on decentralization of care to health centres and community sites and task shifting. After delegating HIV testing and counseling to lay counsellors, uptake of testing increased from 1300 tests per month in 2003 to 6500 in 2009. Shifting responsibility for antiretroviral therapy (ART) initiations to non-physician clinicians almost doubled ART enrollment, with a majority of initiations performed in peripheral health centres. By the end 2009, 23, 261 people had initiated ART of whom 11, 042 received ART care at health-centre level. By the end of 2007, the universal access targets were achieved, with nearly 9000 patients alive and on ART. The average annual cost for achieving these targets was € 2.6 per inhabitant/year. The Thyolo programme has demonstrated the feasibility of district-wide access to ART in a setting with limited resources for health. Expansion and decentralization of HIV/AIDS service-capacity to the primary care level, combined with task shifting, resulted in increased access to HIV services with good programme outcomes despite staff shortages.

The prevalence of diabetes and hypertension has increased in HIV-positive populations, but there is limited understanding of the role that antiretroviral therapy (ART) programs play in the delivery of services for these conditions. The aim of this study is to assess the relationship between ART use and utilization of health care services for diabetes and hypertension. Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa is a cohort of 5059 adults. The baseline study collects biomarker-based data on HIV, ART, diabetes, and hypertension and self-reported data on health care utilization. We calculated differences in care utilization for diabetes and hypertension by HIV and ART status and used multivariable logistic regressions to estimate the relationship between ART use and utilization of services for these conditions, controlling for age, sex, body mass index, education, and household wealth quintile. Mean age, body mass index, hypertension, and diabetes prevalence were lower in the HIV-positive population (all P < 0.001). Multivariable logistic regression showed that ART use was significantly associated with greater odds of blood pressure measurement [adjusted odds ratio (aOR) 1.27, 95% confidence interval (CI): 1.04 to 1.55] and blood sugar measurement (aOR 1.26, 95% CI: 1.05 to 1.51), counseling regarding exercise (aOR 1.57, 95% CI: 1.11 to 2.22), awareness of hypertension diagnosis (aOR 1.52, 95% CI: 1.12 to 2.05), and treatment for hypertension (aOR 1.63, 95% CI: 1.21 to 2.19). HIV-positive patients who use ART are more likely to have received health care services for diabetes and hypertension. This apparent ART advantage suggests that ART programs may be a vehicle for strengthening health systems for chronic care.

The association between maternal HIV and stillbirths in an Era of universal ART access in pregnancy in the Western Cape, South Africa, 2017 \u2013 2021

The extraordinary success of antiretroviral therapy (ART) in the North during the closing years of the last century directly led to the United Nations' resolutions in 2000, about universal access to HIV treatment, and to the inclusion of this target among the Millenium Development Goals [1]. A previous AIDS supplement, supported by the French Agency for AIDS Research (ANRS) and published as early as 2003, presented the evaluation of the first national pilot programs for access to antiretroviral HIV treatment in three African countries (Côte d'Ivoire, Senegal and Uganda). These results contributed to a consensus on the feasibility of scaling-up access to HIV treatment in low-resource settings, an issue that had been heavily debated among clinical, public health and development experts [2]. Since then, antiretroviral therapy coverage rose from 7% in 2003 to 42% in 2008, with especially high coverage achieved in eastern and southern Africa (48%) [3]. There are no longer doubts that access to ART results in a remarkable reduction in mortality, which may be as high as 95% in comparison to no intervention [4]. In addition, retention in care and treatment may exceed levels seen in the North: for example, a remarkable 79% of adults enrolled in the early stages of Botswana's antiretroviral therapy scale-up are alive five years later [5]. On a macro scale, Bendavid and Bhattacharya [6] found that after four years of the US President's Emergency Plan for AIDS Relief (PEPFAR) funding and support for ART, HIV-related deaths decreased in sub-Saharan African focus countries compared with control countries, although trends in adult prevalence did not differ. Despite the community stigma, political denial and tensions between government policy and medical practice, South Africa with the largest number of HIV infected individuals is also home to the largest antiretroviral therapy program in the world with accelerating impact. In the Western Cape Province, six-month mortality among patients at an HIV treatment centre fell from 12.7% to 6.6% between 2001/2002 and 2005 as access expanded [7]. The recent statement, on World AIDS Day on December 1st 2009, about universal access to HIV care and treatment by the new South-African President, Jacob Zuma, raises hope that South Africa will henceforth assume a leadership role in the region [8]. However, scaling-up access to HIV treatment in Africa, home to two thirds of those living with HIV/AIDS, poses new and largely unexplored challenges in the delivery of a complex set of public health, medical and psychosocial interventions. The transition from an emergency response to robust and sustainable health services delivery systems for HIV is a work in progress. Building these systems must be mindful of cultural context and existing health systems in the affected communities. The most recent [9] report on the epidemic describes a highly varied picture of remarkable progress in some African countries and huge unmet needs in others. Access to treatment in Africa is often taking place in the context of fragile states, struggling with social, political and economic turmoil, where investment in healthcare systems has been limited. Particularly in resource limited settings, there is an unavoidable competition for infrastructure, resources and personnel between donor driven programs targeting specific diseases (ie. AIDS, TB and malaria) and long standing programs in primary care, maternal and infant health. The “Maximizing Positive Synergies Collaborative Group” (MPSCG), coordinated by WHO, has recently synthesized the existing evidence regarding interactions between disease-targeted programs and country health systems [10]. Although it concluded that this impact “on health outcomes and health systems, though variable, has been positive on balance and has helped to draw attention to deficiencies in health systems”, available evidence also pointed out that further improvements and efficiency gains are needed especially to strengthen the health workforce, align health information systems, and to reduce out-of-pocket payments for financing health-care expenditures. Operational research encompasses a broad range of investigation, primarily the evaluation of outcomes among the health programs. Systematic observation and analysis of data collected alongside ART programs can provide guidance to implementers and policy makers with the aim of achieving sustainable access to care. Critical in any operational research project is the development of partnerships and capacity building between the wide array of actors who contribute to deliver healthcare, including national health services, community based organizations and advocacy groups, national and transnational NGOs, as well as the international donor agencies on the one hand, and academic researchers and research organizations on the other [11]. There are certainly general principles of treatment that can be broadly applied and evaluated in Africa. But ultimately, in each context, it may be anticipated that the design of programs for access to ART will vary. Critical unanswered questions remain about how access to ART will impact social stigma, individual risk behavior and ultimately the course of the epidemic. Because of the heterogeneity of affected populations and societies, the psychosocial and behavioral consequences of ART access and methods to ensure adherence, retention and to provide sustained treatment across Africa are not likely to be distilled to a single set of best practices. Thus, in the face of the HIV epidemic in Africa, operational research is a process of “learning by doing” in each of the diverse contexts, sharing the outcomes and observations among countries and programs. A myriad of local evaluations of process and outcome may be the most flexible way to effect sustainable implementation of ART access and the development of robust medical and social responses to AIDS in various contexts across a continent. One regrets that in spite of significant investment in evaluation exercises, global health initiatives such as the Global Fund to fight AIDS, Tuberculosis and Malaria (GFATM), PEPFAR or the World Bank still have limited contributions to effective operational research [12,13]. Operational issues in scaling up access to ART This supplement presents original results documenting the progress, as well as obstacles, in scaling up HIV treatment in Africa. Papers from Burkina-Faso and Cameroon are based on operational research carried out alongside the national ART programs of these two countries that have been directly supported by ANRS. Other papers present fruitful experiences from operational research in additional African countries (Botswana, Lesotho, Mozambique and South Africa) while one paper (Celletti et al., S45–S57) focuses on a multi-country effort associating four African countries (Ethiopia; Malawi; Namibia and Uganda) and Brazil. It must be noted that the paper by Bassett et al. (S37–S44) about initiation of ART in Durban, Kwazulu-Natal, South Africa, one of the epicenters of the epidemic, was awarded the joint International AIDS Society (IAS)/ ANRS “Young Investigator Prize” for Operations Research at the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention, that took place in Capetown in July 2009. Finally, one paper (Jerome & Ivers, S73–S78) deals with rural Haiti, a non-African country, whose experience with ART in very deprived and vulnerable populations has been worthwhile for other low-resource settings. The process of improving and sustaining access to ART begins with surveillance and testing to understand the magnitude of the epidemic locally, and requires assessment and consultation with Ministries, healthcare providers, communities and stakeholders to identify the key operational issues in access. Access to ART begins with the effective implementation of voluntary testing on a scale not yet realized, effective post-test counseling, linkage to care, and has already led to monitoring, care and retention of 3 million people on ART in Africa. How to accomplish each of these tasks with health systems that are often insolvent and frequently understaffed is the focus of the papers presented in this supplement. All papers emphasize that advances in access to ART have only been made possible through implementation of innovative ways of delivering and monitoring care, and also illustrate some of these innovations. Clinical research programs continue to evaluate new, less toxic and potentially less costly drug cocktails, more effective monitoring algorithms and programs to reinforce and maintain treatment adherence that would be better adapted to the practical constraints of health systems with very scarce resources. Notably, the DART study results in Uganda and Zimbabwe suggest that some of the accepted guidelines for laboratory monitoring need careful reassessment [14], and the forthcoming results of the STRATALL study in Cameroon will evaluate the impact of the WHO public health approach to monitor ART at a decentralized level of care [15]. Similarly, the management of first-line ART is fraught with issues even in the choice of Non-nucleoside reverse transcriptase inhibitors (NNRTIs). Consideration of Efavirenz and Nevirapine as first line NNRTIs as described in the paper by Wester et al. (S27–S36) in Botswana reflect trade-offs among cost, potency, potential side-effects and concerns about teratogenicity and toxicity. These issues will continue to expand as additional drugs become available and as the price proposed by pharmaceutical firms for new first-line and for second-line regimens, as recommended by WHO, remain prohibitively high compared to those of the “old” generation of antiretroviral drugs [16]. It is estimated that at least 57 countries, mostly in sub-Saharan Africa, face crippling health workforce shortages, and there are simply not enough physicians and nurses on the ground to begin to address the magnitude of the HIV epidemic through traditional clinic based care. Rational redistribution of tasks between physicians and other healthcare personnel, and the introduction of community and family health aids and NGO volunteers, as medical officers, adherence counselors or treatment “buddies” is a key part of the “task-shifting” agenda articulated by WHO [17]. The multi-country paper by Celletti et al. (S45–S57), papers by Sherr et al. (S59–S66) on Mozambique, Jerome and Ivers (S67–S72) on Haiti and Ivers et al. (S73–S78) on the Haiti-Lesotho collaborative model detail the certain conditions that have to be fulfilled for the reorganization of clinical services under a task shifting model to be successful. One of the most innovative contributions of HIV programs has been to promote meaningful multi-stakeholder partnerships between governments, civil society and affected communities at the global and local levels. Civil society has critically important roles ranging from advocacy, demand creation, and service delivery, to policy-setting and providing oversight by emphasizing accountability to service users [18]. Papers by Desclaux et al. (S79–S85) on Burkina-Faso and Ivers et al. (S73–S78) on the south-south collaboration between Haiti and Lesotho illustrate how such involvement of civil society offer opportunities for creative operational research. Quite logically, it is the relationship between scaling up access to HIV treatment and health systems strengthening that bears the greatest scrutiny across most of the papers of this supplement. In a comprehensive evaluation of ART access through a national program in Cameroon, Boyer et al. (S5–S15) present analysis from the EVAL study where the quality and quantity of care at central, provincial and district levels was contrasted. This evaluation clearly shows that decentralization of ART delivery can increase equity in access for the poorest sectors of people living with HIV while maintaining clinical effectiveness, and even improving adherence and quality of life. Experiences in other African countries, like Uganda, suggest that even further decentralization of ART may be effective and cost-effective [19], but this needs more investigation and may differ according to each specific socio-economic and health systems context. Future challenges for long term sustainability of ART In this supplement, another paper on Cameroon by Marcellin et al. (S17–S25) provides compelling evidence that access to ART at higher CD4 levels reduces reported risk behaviors and can improve quality of life. This paper, and the one from Bassett et al. (S37–S44) describing considerable gaps in bringing and retaining people with AIDS into treatment in a well resourced program in South Africa, supports the recent revision of WHO guidelines [20]. These new guidelines increase the recommended CD4 count for starting treatment to 350 cc/mm3 (rather than the previous lower 200 threshold) and imply that an additional number of 5 million HIV-infected patients world-wide should be considered eligible for immediate access to ART. These papers, however, anticipate some of the new challenges and tensions that would logically derive from this extension of treatment eligibility and from the urgent need to revisit the relationship between HIV prevention and treatment. Despite the actions of many agencies and national health autorities, an estimated 1.9 million [1.6 million–2.2 million] new HIV infections occurred in sub-Saharan Africa in 2008. This high incidence, and consequent increase in unmet treatment needs over time, represents an additional key challenge for ART program scale up to remain feasible and sustainable [21]. The recognition that the speed at which people are infected exceeds the speed at which they can be put on treatment has been a powerful message to advocate for enhancing prevention efforts. Treatment programs offer many opportunities to strengthen prevention, through increased uptake of testing, viral load reduction in patients and models of “prevention counseling” for and by positive people. These synergies should be fully recognized and monitored. As an illustration, in a paper on Cameroon in this supplement (Marcellin et al. [S17–S25]), patients not yet on ART reported more frequent inconsistent condom use compared to those on ART, confirming positive effects of intense patient-healthcare worker contact on behavior. (Re)-emphasizing and maximizing synergies between the ART roll out and prevention is essential and urgent but should be seen as a component of a comprehensive “Treatment and Prevention Combination” approach, including behavioral, social and structural interventions. Over the coming decade, the challenges of expanding, enhancing and sustaining treatment for the more than 22.4 million people living with HIV in Africa, will consume immense monetary, human and social resources. Evaluating the long-term outcomes of access to ART on a population level across diverse urban and rural and multiple cultural contexts in Africa present a formidable challenge. If the patterns of behavior and transmission observed in the North are any indication, large-scale access to care may increase transmission of drug resistant viruses [22]. The best way to prevent this will be the development of robust and affordable programs for retention, monitoring and management of ART by skilled providers and robust systems of care. Papers in this supplement support the optimistic view that innovative solutions can be found to tackle the multiple medical, public health, socio-economic and logistic issues related to long term sustainability of ART programs in Africa. Ensuring their financial sustainability through appropriate growth of domestic and international funding however remains a prerequisite for success, and this is far from guaranteed in the context of one of the worst economic crises the world has ever faced. Because overall demand has been higher than anticipated in the funding scenario of its previous replenishment, the Global Fund faces a resource gap for the period 2009–10 for the first time since its creation. Its future contribution to scaling up the response to the HIV epidemic will depend on the willingness of donor governments to provide significantly higher pledges for its next replenishment (2011–2013) than the 9.8 billion US$ obtained for the previous one (2008–2010) [23]. In the US, a debate is growing about whether or not a further expansion of PEPFAR would be the best use of international health funding [24]. Demonstrations, as presented in this supplement, contribute evidence-based advocacy in favor of sustainability of HIV/AIDS treatment and provide clear examples of how health systems are adapting to meet the challenges of HIV. Of course, we also present these examples to underscore the importance of continuing, flexible operational research and evaluation to maintain international and domestic funding, the life-blood of treatment access for millions in Africa, and around the world.

BackgroundRetention in care is an essential component of meeting the UNAIDS “90-90-90” HIV treatment targets. In Khayelitsha township (population ~500,000) in Cape Town, South Africa, more than 50,000 patients have received antiretroviral therapy (ART) since the inception of this public-sector program in 2001. Disengagement from care remains an important challenge. We sought to determine the incidence of and risk factors associated with disengagement from care during 2013–2014 and outcomes for those who disengaged.Methods and findingsWe conducted a retrospective cohort study of all patients ≥10 years of age who visited 1 of the 13 Khayelitsha ART clinics from 2013–2014 regardless of the date they initiated ART. We described the cumulative incidence of first disengagement (>180 days not attending clinic) between 1 January 2013 and 31 December 2014 using competing risks methods, enabling us to estimate disengagement incidence up to 10 years after ART initiation. We also described risk factors for disengagement based on a Cox proportional hazards model, using multiple imputation for missing data. We ascertained outcomes (death, return to care, hospital admission, other hospital contact, alive but not in care, no information) after disengagement until 30 June 2015 using province-wide health databases and the National Death Registry. Of 39,884 patients meeting our eligibility criteria, the median time on ART to 31 December 2014 was 33.6 months (IQR 12.4–63.2). Of the total study cohort, 592 (1.5%) died in the study period, 1,231 (3.1%) formally transferred out, 987 (2.5%) were silent transfers and visited another Western Cape province clinic within 180 days, 9,005 (22.6%) disengaged, and 28,069 (70.4%) remained in care. Cumulative incidence of disengagement from care was estimated to be 25.1% by 2 years and 50.3% by 5 years on ART. Key factors associated with disengagement (age, male sex, pregnancy at ART start [HR 1.58, 95% CI 1.47–1.69], most recent CD4 count) and retention (ART club membership, baseline CD4) after adjustment were similar to those found in previous studies; however, notably, the higher hazard of disengagement soon after starting ART was no longer present after adjusting for these risk factors. Of the 9,005 who disengaged, the 2 most common initial outcomes were return to ART care after 180 days (33%; n = 2,976) and being alive but not in care in the Western Cape (25%; n = 2,255). After disengagement, a total of 1,459 (16%) patients were hospitalized and 237 (3%) died. The median follow-up from date of disengagement to 30 June 2015 was 16.7 months (IQR 11–22.4). As we included only patient follow-up from 2013–2014 by design in order to maximize the generalizability of our findings to current programs, this limited our ability to more fully describe temporal trends in first disengagement.ConclusionsTwenty-three percent of ART patients in the large cohort of Khayelitsha, one of the oldest public-sector ART programs in South Africa, disengaged from care at least once in a contemporary 2-year period. Fifty-eight percent of these patients either subsequently returned to care (some “silently”) or remained alive without hospitalization, suggesting that many who are considered “lost” actually return to care, and that misclassification of “lost” patients is likely common in similar urban populations.A challenge to meeting ART retention targets is developing, testing, and implementing program designs to target mobile populations and retain them in lifelong care. This should be guided by risk factors for disengagement and improving interlinkage of routine information systems to better support patient care across complex care platforms.

Does Antiretroviral Therapy Interfere With the Treatment of Trichomonas vaginalis Among HIV+ Women?

Outcomes of cryptococcal meningitis in antiretroviral naïve and experienced patients in South Africa

We evaluated associations of HIV and antiretroviral therapy (ART) with birth and maternal outcomes at a province-wide-level in the Western Cape, South Africa, in a recent cohort before dolutegravir-based first-line ART implementation. This retrospective cohort study included pregnant people delivering in 2018-2019 with data in the Western Cape Provincial Health Data Centre which integrates individual-level data on all public sector patients from multiple electronic platforms using unique identifiers. Adverse birth outcomes (stillbirth, low birth weight (LBW), very LBW (VLBW)) and maternal outcomes (early and late pregnancy-related deaths, early and late hospitalizations) were compared by HIV/ART status and adjusted prevalence ratios (aPRs) calculated using log-binomial regression. Overall 171,960 pregnant people and their singleton newborns were included, 19% (N = 32 015) identified with HIV. Amongst pregnant people with HIV (PPHIV), 60% (N = 19 157) were on ART preconception, 29% (N = 9276) initiated ART during pregnancy and 11% (N = 3582) had no ART. Adjusted for maternal age, multiparity, hypertensive disorders and residential district, stillbirths were higher only for PPHIV not on ART [aPR 1.31 (95%CI 1.04-1.66)] compared to those without HIV. However, LBW and VLBW were higher among all PPHIV, with aPRs of 1.11-1.22 for LBW and 1.14-1.54 for VLBW. Pregnancy-initiated ART was associated with early pregnancy-related death (aPR 3.21; 95%CI 1.55-6.65), and HIV with or without ART was associated with late pregnancy-related death (aPRs 7.89-9.01). Even in the universal ART era, PPHIV experienced higher rates of LBW and VLBW newborns, and higher late pregnancy-related death regardless of ART status than pregnant people without HIV.

Age in antiretroviral therapy programmes in South Africa: a retrospective, multicentre, observational cohort study

To characterize the relationship of new eosinophilic folliculitis (EF) cases between June 30, 1994, and January 5, 2000, and antiretroviral therapy (ART) status and immune reconstitution. Retrospective cohort analysis. Dermatology clinics at a county hospital. Fifty-seven consecutive subjects with biopsy-proved EF from the pathology database. Subject groups were as follows: naïve to ART, receiving ART without protease inhibitors/nonnucleoside reverse transcriptase inhibitors, and receiving ART containing protease inhibitors/nonnucleoside reverse transcriptase inhibitors. Onset of EF, CD4 cell count and nadir at EF onset, and time of ART initiation. Among the 3 groups previously described, mean CD4 cell counts (86.26/microL vs 113.82/microL vs 145.65/microL, respectively [Kruskal-Wallis rank sum test, P = .15]) and nadir (68.43/microL vs 66.18/microL vs 64.17/microL, respectively [Kruskal-Wallis rank sum test, P = .41]) at EF diagnosis were not statistically different. Fifty-two subjects (91%), regardless of treatment group, had a nadir below 200/microL. Of the subjects undergoing ART, 28 (82%) developed EF within 6 months of initiating ART; their average CD4 cell count increase was 108/microL. Of the 23 subjects receiving protease inhibitor/nonnucleoside reverse transcriptase inhibitor-containing ART regimens, 17 (74%) were diagnosed as having EF within 3 months, with 4 additional subjects diagnosed as having EF within 6 months (a total of 21 [91%] of the 23 subjects). This is not significantly different from the 7 (64%) of 11 subjects diagnosed as having EF at 3 and 6 months of starting ART without protease inhibitors/nonnucleoside reverse transcriptase inhibitors (P = .07) (odds ratio, 0.18; 95% confidence interval, 0.01-1.54). Our study shows an association between low nadir (66.28/microL) and low CD4 cell count (115.54/microL) and the development of EF, regardless of subjects' ART status. However, most subjects receiving ART were diagnosed as having EF within 3 to 6 months of ART initiation, regardless of the regimen.

Background: Antiretroviral therapy (ART) programmes have been extensively scaled-up in countries like Uganda. While success of these programmes largely depends on lasting patient retention, attrition rates are often especially high in the first year after treatment initiation. Our study aimed at analysing recent data of a Ugandan ART patient cohort regarding 12 months ART outcomes and programme retention. Methods: Virika Hospital in Fort Portal, Western Uganda, is offering ART services according to national treatment standards. A routinely collected patient monitoring database was used for retrospective analysis, following-up 369 patients for 12 months after enrolment. Primary outcome indicator was 12 months retention (being alive and active in programme). We assessed clinical ART progress, attrition, mortality and influencing factors, particularly gender differences. Results: From 369 ART patients, two-thirds were female. Overall ART outcomes and adherence in this cohort were satisfying, but in men, improvement of CD4-cell counts and weight gain after 12 months were significantly lower than in female patients. In total, one in eight patients (12.2%) was subject to all-cause attrition after 12 months. We identified low CD4-cell count at ART enrolment as the only independent risk factor for attrition after 12 months (p=0.037), while male patients were at highest risk for this, showing significantly lower CD4-cell counts at ART initiation (p=0.008). Conclusion: We found overall outcomes of this ART programme encouraging, however, attention must be paid particularly to male ART patients. Men were underepresented in our cohort, enrolled in the ART programme at later disease stage, and showed worse ART outcomes after 12 months. Our data suggests that the known challenge of male ART performance is persisting, and that it has not sufficiently been addressed in the past years. Especially the problem of male late-presenters in ART programmes should lead to action in health services planning and implementation, for example by offering more HIV testing opportunities to men.

We explored why people may not reveal their antiretroviral therapy (ART) status when presenting for HIV care, and how a linked electronic system may help address this phenomenon. Data were collected from March to October 2023 from people who presented to clinics for an HIV test in KwaZulu-Natal, South Africa but found to be on ART, as well from staff at those clinics. Themes drawn from the Andersen’s health service utilization framework and the domains of a HIV self-management framework were used to guide the analysis. Twenty five people participated in the interviews (18 individuals on ART and seven clinic staff). People did not reveal ART use due to fear of being reprimanded by clinic staff for interrupting treatment or missing clinic visits, with the main reason being administrative challenges, such as requiring a transfer letter to be allowed to access treatment at a new clinic. Some felt ashamed about actions such as buying ART from the black market due to challenges finding treatment. Others wished to present to new clinics because of employment changes, overcrowding in present clinics, missing clinic visits and experiencing stigma. Participants supported the use of a linked electronic system because all medical records would be accessible to health workers in all facilities. People in HIV care in our study demonstrated resilience, finding creative solutions by moving to new clinics to access ART. A linked electronic system which combines records at all health facilities in KwaZulu-Natal could enable individuals to access treatment from any clinic.