Health service delivery models for the provision of antiretroviral therapy in sub-Saharan Africa: a systematic review.

Tropical Medicine and International Health

doi:10.1111/tmi.12366

volume 19 no 10 pp 1198–1215 october 2014

Health service delivery models for the provision of antiretroviral therapy in sub-Saharan Africa: a systematic review Jeffrey V. Lazarus1, Kelly Safreed-Harmon1, Joey Nicholson2 and Shabbar Jaffar3 1 CHIP, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark 2 New York University Health Sciences Library, NYU School of Medicine, New York, NY, USA 3 Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK

Abstract

objectives In response to the lack of evidence-based guidance for how to continue scaling up antiretroviral therapy (ART) in ways that make optimal use of limited resources, to assess comparative studies of ART service delivery models implemented in sub-Saharan Africa. methods A systematic literature search and analysis of studies that compared two or more methods of ART service delivery using either CD4 count or viral load as a primary outcome. results Most studies identified in this review were small and non-randomised, with low statistical power. Four of the 30 articles identified by this review conclude that nurse management of ART compares favourably to physician management. Seven provide evidence of the viability of managing ART at lower levels within the health system, and one indicates that vertical and integrated ART programmes can achieve similar outcomes. Five articles show that community/home-based ART management can be as effective as facility-based ART management. Five of seven articles investigating community support link it to better clinical outcomes. The results of four studies suggest that directly observed therapy may not be an important component of ART programmes. conclusions Given that the scale-up of antiretroviral therapy represents the most sweeping change in healthcare delivery in sub-Saharan Africa in recent years, it is surprising to not find more evidence from comparative studies to inform implementation strategies. The studies reported on a wide range of service delivery models, making it difficult to draw conclusions about some models. The strongest evidence was related to the feasibility of decentralisation and task-shifting, both of which appear to be effective strategies. keywords antiretroviral therapy, health systems, service delivery, sub-Saharan Africa

Introduction The global community has made great strides towards achieving universal access to antiretroviral therapy (ART), but progress will slow unless there are fundamental changes in the architecture of the treatment scale-up. Eight million people in low- and middle-income countries had initiated ART by the end of 2011 – representing a remarkable 20-fold increase in a span of 8 years – but seven million people remained in need of treatment (UNAIDS 2012). International funding for HIV has largely plateaued since the onset of the economic recession in 2008 (Kaiser Family Foundation 2012). Total annual HIV spending rose to US$ 16.8 billion in 2011, up 11% from 2010, but a much greater increase will be needed to reach the HIV Investment Framework’s 2015 spending 1198

target of US$ 22 billion (Schwartl€ ander et al. 2011; UNAIDS 2012). More than seven million people are on antiretroviral therapy in sub-Saharan Africa (UNAIDS 2013). This is a major achievement given that health systems in the region are weak and fragmented. In particular, there are severe shortages of clinically qualified staff, with many countries having fewer than 10 doctors per 10 000 population (WHO 2013). Accessing health services is also a major challenge for people living with HIV because of transportation costs and long waiting times at health facilities (Govindasamy et al. 2012). The World Health Organization (WHO) called for a departure from the individual case management approach to ART when it published antiretroviral treatment guidelines for resource-limited settings in 2002 (WHO 2002).

© 2014 John Wiley & Sons Ltd



J. V. Lazarus et al. Health service delivery models for ART

Since that time, a large amount of research has been conducted on ART programmes that decentralise services to less specialised health facilities; transfer duties from physicians and nurses to lower-level health workers and lay service providers; link patients to various forms of community support; utilise treatment adherence interventions; and employ other strategies intended to maximise the impact of the global treatment scale-up. The longstanding interest in ART service delivery issues is chronicled in the peer-reviewed literature, but to our knowledge, the lessons learnt have not been synthesised. Policy-makers and programme planners thus lack evidence-based guidance for how to continue scaling up ART in ways that make optimal use of limited resources. We have systematically reviewed the findings of comparative studies that assessed ART service delivery models. We focus specifically on the provision of ART in sub-Saharan Africa because this region has the largest number of people living with HIV worldwide (UNAIDS 2012).

896 citations identified through database searches 79 duplicates eliminated 817 articles identified for first stage of screening Title screening removed 600 articles 217 articles identified for second stage of screening Abstract screening removed 183 articles 34 articles identified for full text review 22 articles added via examination of article references Full-text review removed 26 articles 30 articles retained for inclusion in review

Methods A search was conducted on the topics of HIV drug treatment, health care delivery and sub-Saharan Africa in PubMed/MEDLINE, African Index Medicus, ISI Web of Science, and the OVID Evidence-Based Medicine Resources Database. In each of the four databases, we searched using a combination of subject headings and keywords for each topic area. Studies were considered for inclusion if they compared two or more methods of ART service delivery, defined as a combination of structural and/or organisational interventions and/or actions focused on improving the health outcome of the consumer. Clinical trials, case–control studies, cohort studies and cross-sectional studies were all eligible for inclusion, as were studies of both adult and paediatric populations. Studies comparing clinical monitoring strategies were excluded because they did not address structural or organisational issues. The search was geographically restricted using the names of the 46 countries included in the UNAIDS definition of sub-Saharan Africa (UNAIDS 2012). The review did not limit by language and included studies published anytime before 1 January 2013. The reviewers excluded studies that did not report on one or both of the two primary outcomes of interest: CD4 count and viral load. After duplicate records were eliminated, 817 potentially relevant articles remained (Figure 1). Two of the authors (JL and JN) selected articles for further analysis on the basis of article titles. An article was included if it was selected by one or both reviewers. This process yielded 217 articles. In the next step of screening, the


Figure 1 Study selection process.

same two reviewers examined article abstracts, and each reviewer separately determined which of these articles appeared to meet the inclusion criteria. The reviewers’ decisions were then compared. When there was agreement to include or exclude a study, it was retained for full-text analysis or discarded. When there was disagreement, the article was retained for full-text analysis. A total of 34 articles were retained for full-text analysis. An examination of article references led to the identification of 22 additional articles. The 56 articles were then evaluated based on study design and relevance. Twenty-six studies that did not meet the inclusion criteria were excluded, leaving a final set of 30 articles. A data extraction template was employed to systematically extract information from each study. One author (JN) extracted the data, and a second (JL) reviewed it. Data were extracted for the two primary outcomes of interest as well as for secondary outcomes of interest, including mortality and loss to follow-up. A protocol for this study has been published on the PROSPERO international prospective register of systematic reviews (record number CRD42013005741). Results Thirty articles were included in the review (Table 1). Almost three-fourths (22/30) were published between 1199

1200

Country

South Africa

South Africa

South Africa

Brennan et al. 2011* (AIDS)

Fairall et al. 2012 (Lancet)

Long et al. 2011* (PLoS Medicine)

Type of medical provider managing ART

Author(s); year of publication

Matched cohort analysis compared two groups of stable adult patients who had initiated ART under a physician’s supervision at a large government HIV clinic: those who remained at the clinic for physician-led follow-up care and those who transferred to a down-referral site for nurse-led follow-up care.

Matched cohort analysis compared two groups of stable adult patients who had initiated ART under a physician’s supervision at a large government HIV clinic: those who remained at the clinic for physician-led follow-up care and those who transferred to a downreferral site for nurse-led follow-up care. Cluster-randomised trial compared nurse management of ART to physician management of ART in two groups of adult patients at 31 primary-care ART clinics: those newly initiating ART and those on ART for at least 6 months. 16 clinics were assigned to nurse ART management (‘intervention’) and 15 clinics were assigned to physician ART management (‘standard care’).

Study design

At 12 months of follow-up, downreferred patients who received care from nurses were less likely to experience virological rebound than their counterparts who remained in physician-led care. They also had lower mortality and were less likely to be lost to follow-up. Risk of death was the same for intervention patients newly initiating ART under nurse management and standard care patients newly initiating ART under physician management. In the ART-experienced group, intervention patients and their standard care counterparts had comparable rates of viral load suppression after 12 months. The intervention group had greater CD4 increases. Down-referred patients who received care from nurses were more likely than their counterparts in physician-led care to have a favorable 12-month response to treatment, defined as either undetectable viral load or a stable CD4 count.

4943 patients newly initiating ART at intervention clinics were compared to 3407 patients newly initiating ART at standard care clinics. 2582 patients on ART for at least 6 months prior to trial enrolment at intervention clinics were compared to 2656 patients on ART for at least six months prior to trial enrolment at standard care clinics. 712 down-referred patients were matched at a 1:3 ratio to 2136 patients who remained under physician-led care. All patients were stable on first-line ART, and all had been taking ART for at least 11 months.

Key findings

693 down-referred patients were matched at a 1:3 ratio to 2079 patients who remained under physician-led care. All patients were stable on first-line ART, and all had been taking ART for at least 11 months.

Study participants

Table 1 Articles included in review of studies comparing service delivery methods for the provision of ART in sub-Saharan Africa

Tropical Medicine and International Health volume 19 no 10 pp 1198–1215 october 2014




South Africa

Country Prospective randomised controlled study compared ART management by physicians and nurses in adult patients who had recently initiated ART.

Study design

Ethiopia

Ethiopia

South Africa

Cameroon

Assefa et al. 2012 (J Health Serv Res Policy)

Balcha & Jeppsson 2010 (J Int Assoc Physicians AIDS Care)

Bock et al. 2008 (Trans R Soc Trop Med Hyg)

Boyer et al. 2010 (AIDS)

Cross-sectional survey compared outcomes in a random sample of adult patients receiving ART at national-, provincial- and district-level treatment centres.

Review of routine provincial monitoring data compared outcomes for ART management in children (100 cells/ll. Study arm assignment depended on the location of the nearest primary care clinic. Among the subset of patients for whom mean CD4 changes were measured, no significant difference was found between the primary healthcare arm (N = 122) and the control arm (N = 56) (Humphreys et al. 2010). A Malawian study based in a rural district hospital and 10 primary healthcare clinics found that





after 1 year on ART, 279 adults receiving centralised care and 339 adults receiving decentralised care did not have significantly different odds of achieving either virological suppression or CD4 gains of at least 100 cells/ll (McGuire et al. 2012). Finally, a retrospective cohort study compared data from adults enrolled in vertical HIV programmes with data from programmes where HIV management is integrated into general health services using simplified protocols in nine sub-Saharan African countries. After 12 months on ART, patients in vertical programmes (N = 14 124) and patients in integrated programmes (N = 1279) had similar median CD4 gains (Greig et al. 2012). Managing ART in health facility settings versus community/home settings: Three studies found that homebased ART management delivered by trained community members achieved outcomes comparable to or superior to those seen with conventional facility-based ART management. Jaffar et al. (2009) used a cluster-randomised study design to compare home-based HIV care with standard clinic-based care at The AIDS Support Organisation (TASO) in Jinja, Uganda. In the home-care arm, trained lay workers travelling on motorbikes visited patients in their homes to deliver drugs, provide adherence support and perform checklist-based clinical monitoring. They were supported by healthcare staff based at the clinic. Forty-four geographical clusters comprising 1453 patients were randomised. Patients receiving conventional facilitybased ART management and patients receiving homebased ART management experienced similar virological failure rates and mortality rates. Another Ugandan study compared 200 patients receiving ART management at a district hospital to 185 patients receiving ART management from trained volunteers at weekly home visits. The home-based intervention was designed to reach rural residents who otherwise would have had difficulty accessing ART because of the distance to the hospital. At 6 months of follow-up, successful viral suppression was observed in 89% of hospital-based patients and 90% of community-based patients (Kipp et al. 2010). At 2 years of follow-up, patients in the community-based cohort were more likely to achieve viral suppression, while CD4 increases for the two groups were similar (Kipp et al. 2011, 2012). In Kenya, Selke et al. (2010) used a community-randomised study design to compare outcomes for 112 people (living in 16 clusters) receiving hospital-based ART management and 96 people (living in 8 clusters) receiving ART management in their homes from a cadre of HIVpositive community members trained as ‘community care coordinators’. At 12 months of follow-up, the


proportions of patients with detectable viral load in the hospital-based group and community-based group were not significantly different. Nor was there a significant difference in median CD4 count. Community support services for person taking ART Seven articles (including two based on the same study) examined the role of community support by comparing ART programmes that incorporated community support to ART programmes that did not. A cluster-randomised controlled study in Uganda found that after 96 weeks or more on ART, adults engaging with trained peer health workers (N = 10 clinics; 970 patients) experienced less virological failure than their counterparts who received standard care (N = 5 clinics; 366 patients) (Chang et al. 2010). In Nigeria, Taiwo et al. (2010) found no differences in regard to viral suppression, CD4 count or mortality in an individually randomised trial that compared the use of treatment partners for adult patients on ART (N = 248) to standard care (N = 251). Wouters et al. (2009) studied baseline predictors of treatment success in a cohort of 268 South African adults taking ART. At month 24 of treatment, engagement with any of three forms of community support – treatment buddies, community health workers and peer support groups – was the most important predictor of treatment success (defined as a CD4 count of at least 200 cells/ll and undetectable viral load) compared with other factors such as baseline patient characteristics and health literacy. In a South African study that retrospectively analysed records from 12 HIV treatment sites with patient advocate services and 14 HIV treatment sites without such services, adult ART patients at sites offering the intervention were less likely to experience virological failure than their counterparts at other sites (Igumbor et al. 2011). A large observational study involving 57 primary healthcare facilities in South Africa found that 19 668 adult ART patients who received community-based adherence support from patient advocates had greater viral suppression than 47 285 adult ART patients who did not (Fatti et al. 2012). Lay community health worker support for the caregivers of South African children initiating ART (N = 323) was associated with less patient attrition and mortality in comparison with the non-supported group (N = 1577), while CD4 and virological outcomes were equivalent (Grimwood et al. 2012). Directly observed therapy for ART Four studies assessed the use of directly observed therapy (DOT), with DOT protocols varying widely across the 1209




studies. Idoko et al. (2007) compared three DOT protocols for Nigerian adults to each other and to a control arm. Patients self-selected their intervention arm. At week 48 on ART, no significant differences were found between the daily DOT arm (N = 46), the twice-weekly DOT arm (N = 39), the weekly DOT arm (N = 36) and the control arm (N = 52). In an individually randomised trial in South Africa, Nachega et al. (2010) assessed the benefit of a treatment supporter observing at least one ART dose daily versus non-observed ART. The study was halted early for futility when an interim analysis found no significant differences in viral load suppression between the intervention arm and the control arm. A randomised trial in Mozambique compared patients receiving ART under observation daily for the first six weeks of treatment to patients receiving standard ART management. At 12 months of follow-up, the intervention group (N = 175) and control group (N = 175) had comparable CD4 counts, mortality rates and self-reported medication adherence levels (Pearson et al. 2007). Likewise, both groups in a randomised trial in adults in Kenya experienced comparable 72-week outcomes after the intervention group (N = 116) participated in DOT twice per week for the first 24 weeks of ART (N = 118 for control group) (Sarna et al. 2008). Comparing multiple adherence support strategies Two articles reported on studies that included arms for multiple types of interventions. In a Kenyan study, adults initiating ART were individually randomised to three intervention arms and a control arm, with the interventions consisting of either adherence counselling (N = 92), a pocket alarm device (N = 91) or both adherence counselling and the alarm (N = 83). (N = 96 in the control arm.) Adherence counselling appeared to reduce the likelihood of virological failure, but CD4 increases were comparable for those who received adherence counselling and those who did not (Chung et al. 2011). A trial in an adult population initiating ART in Tanzania compared routine care to two types of interventions. Patients in one intervention arm received treatment calendars that contained educational messages on ART and medication adherence. Patients in the other intervention arm were asked to identify and work with treatment assistants. Patients were randomised according to the study arm in which they could participate (e.g. patients unable to identify treatment assistants were randomly assigned to one of the other arms). The sample sizes ranged from 67 to 312 patients (total N = 621). Outcomes in all three arms were comparable in terms of CD4 counts and self-reported adherence (Mugusi et al. 2009). 1210

Discussion Limited financial and human resources in sub-Saharan Africa make it imperative to ask whether the desired clinical outcomes of antiretroviral therapy – virological suppression and restoration of the immune system – can be routinely achieved using less resource-intensive service delivery models than those that represent the standard of care in wealthy countries. The choice of service delivery model also has implications for efforts to scale up ART equitably, because community-based service delivery has the potential to overcome treatment barriers relating to poverty, rural residence and social marginalisation. This review identified 30 articles reporting on comparative studies that used viral load or CD4 count as an outcome measure to assess features of ART service delivery in sub-Saharan Africa. Four articles conclude that nurse management of ART compares favourably to physician management of ART (Sanne et al. 2010; Brennan et al. 2011; Long et al. 2011; Fairall et al. 2012). Seven articles all provide evidence of the viability of managing ART at lower levels within the health system (Bock et al. 2008; Balcha & Jeppsson 2010; Boyer et al. 2010; Fatti et al. 2010; Humphreys et al. 2010; Assefa et al. 2012; McGuire et al. 2012), and one indicates that vertical and integrated ART programmes can achieve similar outcomes in terms of CD4 gains (Greig et al. 2012). Five articles show that community/home-based ART management can be as effective as facility-based ART management (Jaffar et al. 2009; Kipp et al. 2010, 2011, 2012; Selke et al. 2010). Five of seven articles looking at ART community support interventions were able to link community support to better clinical outcomes (Wouters et al. 2008, 2009; Chang et al. 2010; Igumbor et al. 2011; Fatti et al. 2012). The results of four studies that examined the role of DOT collectively suggest that DOT may not be an important service delivery component in ART programmes (Idoko et al. 2007; Pearson et al. 2007; Sarna et al. 2008; Nachega et al. 2010). Two studies assessed multiple ART adherence-boosting strategies. One indicated a benefit from adherence counselling, but not from the use of pocket alarm devices (Chung et al. 2011); the other did not find significant differences in outcomes for patients using treatment calendars, patients engaging with treatment assistants or patients receiving routine care (Mugusi et al. 2009). With recent funding trends generating concern about whether the momentum driving the ART scale-up can be maintained, the concept of ‘doing more with less’ resonates widely among funders, policy-makers and implementers. As almost two-thirds of ART costs are for





service delivery (Schwartl€ander et al. 2011), identifying the least resource-intensive ways to responsibly initiate and manage ART is crucial. Our review indicates that the evidence base for how to do more with less in relation to ART service delivery is considerably stronger in some regards than others. The service delivery issue receiving the most attention was decentralisation, with seven studies demonstrating the ability of lower-level facilities to manage ART effectively. Similarly, all three task-shifting studies support the strategy of having nurses assume greater responsibility for managing ART. Studies of community-based interventions also identified some promising service delivery models. These findings are especially notable in the context of global policy guidance in recent years. The Treatment 2.0 Initiative, launched by WHO and UNAIDS in 2010, seeks to improve the efficiency and impact of HIV treatment programmes in resource-limited countries. As one of its key priorities, Treatment 2.0 calls for HIV treatment to be decentralised and integrated with other health services, ‘with increased community engagement in service delivery’ (WHO 2011b). The WHO Global Health Sector Strategy on HIV/AIDS, 2011–2015 echoes this message (WHO 2011c). It is important to note, however, that findings from our review might not be highly representative of health systems throughout sub-Saharan Africa. Two of the seven decentralisation studies are from South Africa, and all three task-shifting studies are from South Africa. In fact, a total of 12 articles identified in the review report on 11 studies conducted in South Africa. Another eight articles are based on studies conducted in Kenya and Uganda, which means that fully two-thirds of articles are from three countries. The generalisability of the South African findings is especially questionable because South Africa’s healthcare infrastructure is one of the strongest in subSaharan Africa. A limitation of the evidence presented in this review is that the outcomes are all measured over relatively short periods. Whether decentralised models will continue to be as good as clinic-based models over the longer term is not clear. Our review found only two studies of paediatric ART populations – both set in South Africa (Bock et al. 2008; Grimwood et al. 2012). Sub-Saharan Africa had an estimated 388 000 children below the age of 15 on antiretroviral therapy as of December 2010, with another 1.84 million estimated to be in need of it (WHO 2011a). As some of the medical and psychosocial challenges facing paediatric HIV patients differ markedly from those of their adult counterparts (Baylor International Pediatric AIDS Initiative 2010), the literature about the delivery of


ART to adults can only provide limited guidance for paediatric programme models. Clearly, there is a need for more ART service delivery research using CD4 cell count and viral load as outcome indicators in paediatric populations, including research that acknowledges how children’s and caregivers’ needs change as children progress through different developmental stages between birth and adulthood. We sought to contextualise the findings of this review by relating them to findings from outside of sub-Saharan Africa. However, it appears that few comparative studies of ART service delivery models in other regions have been published in the peer-reviewed literature. In Peru, 60 adult ART patients receiving support from paid community health workers had better 12-month virological suppression than a control group that lacked support (Mu~ noz et al. 2010). In a small Brazilian study, new ART patients who received a motivational intervention did not have better CD4 or viral load outcomes than those who received standard-of-care ART management (Garcia et al. 2005). An issue that undermines efforts to assess the evidence about ART service delivery is the heterogeneity of intervention design. For example, three studies in our review collectively make a strong case for community/home-based ART management, but this type of intervention took quite different forms across these studies (Jaffar et al. 2009; Selke et al. 2010; Kipp et al. 2012). Similarly, another four studies associated community support interventions with good viral control, but again, the interventions varied widely (Wouters et al. 2009; Chang et al. 2010; Igumbor et al. 2011; Fatti et al. 2012). In a 2012 review of studies on community-based ART support services, Wouters et al. (2012) identify a broad array of interventions and furthermore count nine separate types of community support providers, some of whose roles appear to be defined quite similarly. The authors state, ‘The wide range of tasks performed by community members combined with the different descriptions for similar activities indicate that there is a need for further conceptual work to clearly establish a typology of these community support initiatives’. Our review findings affirm this conclusion and furthermore point to the need for researchers to develop uniform study protocols to strengthen the evidence base through multiple studies in a range of contexts. Another shortcoming in the evidence base pertains to the relationship between effectiveness and cost-effectiveness. Some of the studies identified in this review include cost-related information, but often no tangible cost-effectiveness lessons can be derived because researchers do not 1211




present cost analyses for the service delivery models they are comparing. Exceptions include the paper by Jaffar et al. (2009), which reported that the mean annual cost per patient in the home-based ART management arm of the study was US$ 793, compared to US$ 838 per patient in the facility-based arm. In another article comparing home- and facility-based ART management models, Kipp et al. (2011) note that while their home-based intervention was ‘slightly’ more cost-effective, total per-patient programme costs for both models far exceeded Uganda’s average perpatient spending for all health services. Fatti et al. (2012) and Grimwood et al. (2012) report on unit costs in related ART community support studies for South African adults and children, respectively. Long et al. (2011) combine an analysis of treatment outcomes associated with physician-managed and nurse-managed ART in South Africa and a cost-effectiveness analysis. After demonstrating that patients managed by nurses achieve good clinical outcomes in terms of viral load and CD4 measures, the authors go on to report that the management of clinically stable patients at nurse-staffed sites costs 11% less per year than management by physicians at treatment initiation sites. Chang et al. (2013), drawing on their finding that a community support intervention in Uganda is associated with less virological failure, announce in a separate paper that the yearly cost per patient for the intervention is US$ 8.74, and the cost per virological failure averted, US$ 189. However, for most interventions that these studies identify as strategies for advancing the scale-up of ART, further research is needed to assess cost-effectiveness. The evidence gap is notable in light of the growing emphasis on the role of communities in the ART scale-up. For its modelling of how much money will be needed to achieve universal access to HIV prevention, treatment, care and support by 2015 and to maintain the same coverage levels through 2020, the HIV Investment Framework ‘assumes major efficiency gains as delivery of care evolves from facility-based to community-based structures’ (Schwartl€ander et al. 2011). The estimated annual cost of implementing the Investment Framework is expected to peak in 2015 and then decline somewhat over the next 5 years, in part because of ‘cost savings in treatment commodities, simplification of laboratory monitoring, and a shift to community-based approaches in treatment and testing’. If lay community members are to make such a large contribution to the treatment scale-up, then it seems essential to have robust evidence about the merits and drawbacks of community-based interventions such as home-based ART management by lay health workers and 1212

the pairing of people on ART with community supporters. While our review identified nine comparative studies assessing such issues, the lack of accompanying costeffectiveness information for four of those studies makes it difficult for decision-makers to know how to operationalise the findings. Further, evidence on the costs of accessing care incurred by patients is even more scarce. Jaffar et al. (2009) reported that in rural and peri-urban settings, the cost of a single visit to a clinic was US$ 2.30, about 13% of reported monthly cash incomes for men and 20% for women. This has major implications for households and for sustaining people in chronic care programmes. The issue of how HIV-related stigma intersects with different ART service delivery models received relatively little attention in the articles included in our review. This was surprising in light of widespread recognition of the role of stigma as a barrier to accessing HIV services. Only nine articles even mentioned stigma, and few of these articles considered the relationship between stigma and ART programme performance. In a Swazi study comparing nurse-led ART management at primary healthcare clinics to hospital-based ART management, it was noted that one-fourth of people who were invited to attend clinics in their communities refused, with concern about stigma one of the most common reasons cited for continuing to receive ART management at the district hospital (Humphreys et al. 2010). This study is notable for having a design that incorporated an assessment of why patients accepted or refused specific ART service delivery models. Its finding about stigma provides a clear illustration of why researchers and implementers need to carefully consider the social implications of decentralising HIV services. Study limitations With any systematic review, care must be taken to try to retrieve all studies relating to the topic. Naturally, we are limited to those studies with published results, which tend to be more positive in nature than studies that go unpublished, leading to a potential bias. Given the geographic scope and reported treatment outcomes for inclusion criteria, only 30 published articles about 27 studies were part of this systematic review. While this does limit generalizability, the aim of our review was to provide an overall picture of what is known about the effectiveness of various types of service delivery methods in sub-Saharan Africa as a preliminary step towards improving the use of evidence to guide decision-making on this aspect of the antiretroviral therapy scale-up. Therefore, to employ the results in countries or parts of countries that





were not studied, careful consideration will be needed, including the possible piloting of new models of healthcare delivery. Another potential limitation of this study relates to the issue of whether differential mortality or differential loss to follow-up may call into question the effectiveness of some service delivery models that may appear to deliver good CD4 or viral load outcomes. It is also feasible for this dynamic to work in the opposite way, with mortality or loss to follow-up outcomes indicating some possible merit in service delivery models that are not associated with desirable CD4 or viral load outcomes. In recognition of this concern, the authors revisited all mortality and loss to follow-up findings that were reported, comparing them to CD4 and viral load findings for the same studies. Slightly more than two-thirds of the studies in this review compared mortality outcomes across different study arms, and the mortality findings did not often call into question the conclusions suggested by CD4 and viral load findings. Likewise, for most of the 14 studies that examined loss to follow-up in this manner, findings were not at odds with CD4 and viral load findings. The lack of data for other studies leaves open the possibility that some ART service delivery models may be more or less effective than this review appears to suggest because of undocumented differential mortality or differential loss to follow-up. The review did not include comparative studies that reported outcomes using mortality as an indicator unless one or both of the primary outcomes of interest, CD4 and viral load, were reported as well. It was believed that findings about mortality would only make a substantial contribution to the evidence base in this context if HIVspecific mortality could be disaggregated from all-cause mortality, because all-cause mortality rates may differ across study arms for reasons unrelated to the type of ART service delivery model being utilised. When the review protocol was being developed, the authors considered whether including ‘mortality-only’ studies might add substantially to the reviewing workload as well as adding to the scope and length of the paper. Such an approach would only be fruitful if ‘mortality-only’ studies were found to contain disaggregated data for HIV-specific mortality. Ultimately, the most efficient review strategy was determined to be one that focused on CD4 and viral load outcomes. It is possible that further insights may be obtained from studies that only reported on mortality. In this review, the controlled trial was an effective type of study for measuring the benefits of ART service delivery interventions. However, high costs to run such trials are prohibitive in many resource-limited settings. In these areas, observational studies are an important source of


information, particularly with regard to implementation and the further development of models as well as to inform operational research. It is possible that there are other novel service delivery methods being piloted in observational settings that have not been assessed in controlled trials; such new methods would not be captured in this paper. Conclusion Given that the massive scale-up of antiretroviral therapy represents the most sweeping change in healthcare delivery in sub-Saharan Africa in recent years, it is surprising to not find more evidence from comparative studies to inform implementation strategies. Many of the studies identified in this review were small, with low statistical power, and were not randomised trials. The strongest evidence was related to the feasibility of decentralisation and task-shifting, both of which appear to be effective strategies that have a high level of acceptability among patients. Evidence on cost-effectiveness is needed to further inform the development of national ART service delivery policies. More rigorous research on ART service delivery is urgently needed to inform the further scale-up of ART, particularly in sub-Saharan Africa, where research could help guide the allocation of scarce resources to the most cost-effective and most sustainable interventions. Without better evidence regarding some aspects of service delivery, it will be difficult to responsibly manage antiretroviral therapy for millions of additional people. Acknowledgements The abstract was accepted for an oral presentation at the European Congress on Tropical Medicine and International Health in Copenhagen, on 11 September 2013. References Assefa Y, Kiflie A, Tekle B et al. (2012) Effectiveness and acceptability of delivery of antiretroviral treatment in health centres by health officers and nurses in Ethiopia. Journal of Health Services Research and Policy 17, 24–29. Balcha TT & Jeppsson A (2010) Outcomes of antiretroviral treatment: a comparison between hospitals and health centers in Ethiopia. Journal of the International Association of Physicians in AIDS Care 9, 318–324. Baylor International Pediatric AIDS Initiative (2010) HIV Curriculum for the health professional. http://www.bipai.org/WorkArea/DownloadAsset.aspx?id=137. Bock P, Boulle A, White C et al. (2008) Provision of antiretroviral therapy to children within the public sector of South

1213




Africa. Transactions of the Royal Society of Tropical Medicine and Hygiene 102, 905–911. Boyer S, Eboko F, Camara M et al. (2010) Scaling up access to antiretroviral treatment for HIV infection: the impact of decentralization of healthcare delivery in Cameroon. AIDS 24 (Suppl. 1), S5–S15. Brennan AT, Long L, Maskew M et al. (2011) Outcomes of stable HIV-positive patients down-referred from a doctor-managed antiretroviral therapy clinic to a nurse-managed primary health clinic for monitoring and treatment. AIDS 25, 2027–2036. Chang LW, Kagaayi J, Nakigozi G et al. (2010) Effect of peer health workers on AIDS care in Rakai, Uganda: a cluster-randomized trial. PLoS ONE 5, e10923. Chang LW, Kagaayi J, Nakigozi G et al. (2013) Cost analyses of peer health worker and mHealth support interventions for improving AIDS care in Rakai, Uganda. AIDS Care 25, 652–656. Chung MH, Richardson BA, Tapia K et al. (2011) A randomized controlled trial comparing the effects of counseling and alarm device on HAART adherence and virologic outcomes. PLoS Medicine 8, e1000422. Fairall L, Bachmann MO, Lombard C et al. (2012) Task shifting of antiretroviral treatment from doctors to primary-care nurses in South Africa (STRETCH): a pragmatic, parallel, clusterrandomised trial. Lancet 380, 889–898. Fatti G, Grimwood A & Bock P (2010) Better antiretroviral therapy outcomes at primary healthcare facilities: an evaluation of three tiers of ART services in four South African provinces. PLoS ONE 5, e12888. Fatti G, Meintjes G, Shea J et al. (2012) Improved survival and antiretroviral treatment outcomes in adults receiving community-based adherence support: 5-year results from a multicentre cohort study in South Africa. Journal of Acquired Immune Deficiency Syndromes 61, e50–e58. Garcia R, Ponde M, Lima M et al. (2005) Lack of effect of motivation on the adherence of HIV-positive/AIDS patients to antiretroviral treatment. The Brazilian Journal of Infectious Diseases 9, 494–499. Govindasamy D, Ford N & Kranzer K (2012) Risk factors, barriers and facilitators for linkage to antiretroviral therapy care: a systematic review. AIDS 26, 2059–2067. Greig J, O’Brien DP, Ford N et al. (2012) Similar mortality and reduced loss to follow-up in integrated compared with vertical programs providing antiretroviral treatment in sub-Saharan Africa. Journal of Acquired Immune Deficiency Syndromes 59, e92–e98. Grimwood A, Fatti G, Mothibi E et al. (2012) Community adherence support improves programme retention in children on antiretroviral treatment: a multicentre cohort study in South Africa. Journal of the International AIDS Society 15, 17381. Humphreys CP, Wright J, Walley J et al. (2010) Nurse led, primary care based antiretroviral treatment versus hospital care: a controlled prospective study in Swaziland. BMC Health Services Research 10, 229. Idoko JA, Agbaji O, Agaba P et al. (2007) Direct observation therapy-highly active antiretroviral therapy in a resource-limited setting: the use of community treatment sup-

1214

port can be effective. International Journal of STD and AIDS 18, 760–763. Igumbor JO, Scheepers E, Ebrahim R et al. (2011) An evaluation of the impact of a community-based adherence support programme on ART outcomes in selected government HIV treatment sites in South Africa. AIDS Care 23, 231–236. Jaffar S, Amuron B, Foster S et al. (2009) Rates of virological failure in patients treated in a home-based versus a facilitybased HIV-care model in Jinja, southeast Uganda: a clusterrandomised equivalence trial. Lancet 374, 2080–2089. Kaiser Family Foundation (2012) Financing the response to AIDS in low- and middle income countries: international assistance from donor governments in 2011. Kaiser Family Foundation; UNAIDS. http://www.kff.org/hivaids/upload/7347-08.pdf. Kipp W, Konde-Lule J, Saunders LD et al. (2010) Results of a community-based antiretroviral treatment program for HIV-1 infection in Western Uganda. Current HIV Research 8, 179–185. Kipp W, Konde-Lule J, Rubaale T et al. (2011) Comparing antiretroviral treatment outcomes between a prospective communitybased and hospital-based cohort of HIV patients in rural Uganda. BMC International Health and Human Rights 11(Suppl. 2), S12. Kipp W, Konde-Lule J, Saunders LD et al. (2012) Antiretroviral treatment for HIV in rural Uganda: two-year treatment outcomes of a prospective health centre/community-based and hospital-based cohort. PLoS ONE 7, e40902. Long L, Brennan A, Fox MP et al. (2011) Treatment outcomes and cost-effectiveness of shifting management of stable ART patients to nurses in South Africa: an observational cohort. PLoS Medicine 8, e1001055. McGuire M, Pinoges L, Kanapathipillai R et al. (2012) Treatment initiation, program attrition and patient treatment outcomes associated with scale-up and decentralization of HIV care in rural Malawi. PLoS ONE 7, e38044. Mugusi F, Mugusi S, Bakari M et al. (2009) Enhancing adherence to antiretroviral therapy at the HIV clinic in resource constrained countries: the Tanzanian experience. Tropical Medicine and International Health 14, 1226–1232. Mu~ noz M, Finnegan K, Zeladita J et al. (2010) Communitybased DOT-HAART accompaniment in an urban resourcepoor setting. AIDS and Behavior 14, 721–730. Nachega JB, Chaisson RE, Goliath R et al. (2010) Randomized controlled trial of trained patient-nominated treatment supporters providing partial directly observed antiretroviral therapy. AIDS 24, 1273–1280. Pearson CR, Micek MA, Simoni JM et al. (2007) Randomized control trial of peer-delivered, modified directly observed therapy for HAART in Mozambique. Journal of Acquired Immune Deficiency Syndromes 46, 238–244. Sanne I, Orrell C, Fox MP et al. (2010) Nurse versus doctor management of HIV-infected patients receiving antiretroviral therapy (CIPRA-SA): a randomised non-inferiority trial. Lancet 376, 33–40. Sarna A, Luchters S, Geibel S et al. (2008) Short- and long-term efficacy of modified directly observed antiretroviral treatment in Mombasa, Kenya: a randomized trial. Journal of Acquired Immune Deficiency Syndromes 48, 611–619.





Schwartl€ ander B, Stover J, Hallett T et al. (2011) Towards an improved investment approach for an effective response to HIV/AIDS. Lancet 377, 2031–2041. Selke HM, Kimaiyo S, Sidle JE et al. (2010) Task-shifting of antiretroviral delivery from healthcare workers to persons living with HIV/AIDS: clinical outcomes of a community-based program in Kenya. Journal of Acquired Immune Deficiency Syndromes 55, 483–490. Taiwo BO, Idoko JA, Welty LJ et al. (2010) Assessing the viorologic and adherence benefits of patient-selected HIV treatment partners in a resource-limited setting. Journal of Acquired Immune Deficiency Syndromes 54, 85–92. UNAIDS (2012) Global report: UNAIDS report on the global AIDS epidemic 2012. http://www.unaids.org/en/media/unaids/ contentassets/documents/epidemiology/2012/gr2012/ 20121120_UNAIDS_Global_Report_2012_with_annexes_en. pdf. UNAIDS (2013) Update: UNAIDS Special Report. http://www. unaids.org/en/media/unaids/contentassets/documents/document/ 2013/05/20130521_Update_Africa.pdf. WHO (2002) Scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach. WHO. http://apps.who.int/medicinedocs/pdf/s2888e/s2888e.pdf. WHO (2011a) Progress report 2011: global HIV/AIDS response: epidemic update and health sector progress towards universal

access. WHO; UNICEF; UNAIDS. http://whqlibdoc.who.int/ publications/2011/9789241502986_eng.pdf. WHO (2011b) The Treatment 2.0 framework for action: catalysing the next phase of treatment, care and support. WHO; UNAIDS. http://whqlibdoc.who.int/publications/2011/ 9789241501934_eng.pdf. WHO (2011c) Global Health Sector Strategy on HIV/AIDS, 2011–2015. World Health Organization. http://whqlibdoc. who.int/publications/2011/9789241501651_eng.pdf. WHO (2013) World Health Statistics 2013. WHO. http://apps. who.int/iris/bitstream/10665/81965/1/9789241564588_eng. pdf. Wouters E, Van Damme W, van Rensburg D et al. (2008) Impact of baseline health and community support on antiretroviral treatment outcomes in HIV patients in South Africa. AIDS 22, 2545–2548. Wouters E, Van Damme W, Van Loon F et al. (2009) Publicsector ART in the Free State Province, South Africa: community support as an important determinant of outcome. Social Science and Medicine 69, 1177–1185. Wouters E, Van Damme W, van Rensburg D et al. (2012) Impact of community-based support services on antiretroviral treatment programme delivery and outcomes in resourcelimited countries: a synthetic review. BMC Health Services Research 12, 194.

Corresponding Author Jeffrey V Lazarus, CHIP, Centre for Health and Infectious Disease Research, Rigshospitalet, University of Copenhagen, Finsencentret, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Tel.: +45 51 52 99 26; E-mail: [email protected]


1215

Equity in utilization of antiretroviral therapy for HIV-infected people in South Africa: a systematic review.

Annual cost of antiretroviral therapy among three service delivery models in Uganda.

Provision of antiretroviral therapy in South Africa: the nuts and bolts.

Characteristics of Indigenous primary health care models of service delivery: a scoping review protocol.

Identification of Delivery Models for the Provision of Predictive Genetic Testing in Europe: Protocol for a Multicentre Qualitative Study and a Systematic Review of the Literature.

Provision of antiretroviral care to displaced populations in humanitarian settings: a systematic review.

Simulation models for socioeconomic inequalities in health: a systematic review.

Task shifting for the delivery of pediatric antiretroviral treatment: a systematic review.

A systematic review of health system barriers and enablers for antiretroviral therapy (ART) for HIV-infected pregnant and postpartum women.

Epidemiology of Leptospirosis in Africa: A Systematic Review of a Neglected Zoonosis and a Paradigm for 'One Health' in Africa.

Provision of acute general surgery: a systematic review of models of care.

CD4 enumeration technologies: a systematic review of test performance for determining eligibility for antiretroviral therapy.

AIDS service delivery: a systematic review.

Interventions for Enhancing Adherence to Antiretroviral Therapy (ART): A Systematic Review of High Quality Studies.

The survival benefits of antiretroviral therapy in South Africa.

The role of short messaging service in supporting the delivery of healthcare: An umbrella systematic review.

Clinical outcomes of HIV care delivery models in the US: a systematic review.

Impact of Opioid Substitution Therapy on Antiretroviral Therapy Outcomes: A Systematic Review and Meta-Analysis.

Alternate Service Delivery Models in Cancer Genetic Counseling: A Mini-Review.

Mental Health Service Provision in Low- and Middle-Income Countries.

Cross-sector Service Provision in Health and Social Care: An Umbrella Review.

The epidemiology of tuberculosis in health care workers in South Africa: a systematic review.

A Qualitative Study of Service Provision for Alcohol Related Health Issues in Mid to Later Life.

Diabetic nephropathy in Africa: A systematic review.