The evolution and adoption of World Health Organization policy guidelines on antiretroviral therapy initiation in sub-Saharan Africa: A scoping review

Background Despite past and present global interventions, the human immunodeficiency virus (HIV) pandemic remains a public health problem in low- and middle-income countries (LMICs). The World Health Organization (WHO) has assisted these countries by providing antiretroviral therapy (ART) policies for adoption and adaptation to local needs. Objectives This article describes the response of countries in sub-Saharan Africa (SSA), to the WHO’s changing CD4-threshold ART-initiation recommendations of the past two decades. Methods Relevant articles published in international peer-reviewed journals were accessed via the following search engines: PubMed, Google Scholar, Cochrane, Embase and EBSCOhost. The study’s inclusion criteria were articles published in the English language between 2000 and 2019 that highlighted changes to the CD4 ART-initiation threshold and that focused on the WHO’s ‘commencement of ART’ policy guidelines. Sixteen studies (n = 16) from SSA were identified and included in this review: four are cross-sectional, four deal with cost-effectiveness, four are retrospective, one is a randomised trial and three are observational studies. Only studies conducted in SSA were assessed. Results Four themes emerged: (1) adoption of the WHO CD4-ART-initiation policy by SSA countries, (2) timely implementation of the changing guideline initiation policy in the region, (3) barriers and facilitators encountered in the implementation of the changing guidelines and (4) description of similarities in policy implementation at country level from 2002 to 2019. Regional studies – cross-sectional, observational, retrospective, cost-effectiveness and randomised have described greater access to ART in SSA. However, barriers remain. The most common barriers to the timely implementation of ‘new’ ART-initiation guidelines were economic constraints, drug stock-outs, delays in obtaining baseline blood-test results and staff shortages. Conclusion Although countries in SSA have adopted the WHO-ART-CD4 initiation-threshold policy guidelines, implementation has seldom occurred in a timely manner. Barriers have been identified. Whilst a small number of countries have implemented recommendations promptly, for many, the barriers still require to be overcome.

200 to 350 cells/mm 3 . In addition, all pregnant women and persons with Stage 3 and 4 infection were offered ART. 3 In 2010, the threshold was raised to CD4 < 350 c/mm 3 for all irrespective of clinical stage. 4,5 By June 2013, the threshold was further increased to CD4 < 500/cells/mm 3 for all children > 5 years and adults irrespective of stage/symptoms. 6 In 2015, the WHO and numerous international organisations removed the CD4 threshold and recommended ART to all regardless of CD4 cell count and clinical stage. 7 Data from two highly influential randomised controlled clinical trials, the START and TEMPRANO studies, underpinned this decision. Both demonstrated survival advantage to those on ART irrespective of clinical stage or CD4 count. 8,9 This led to the introduction by all international agencies, including the WHO, of the policy of 'universal test and treat (UTT)'. The WHO estimates that if these recommendations are adopted globally, 21 million deaths and 28 million new infections could be prevented by 2030. 10 The rate at which countries have aligned their national ART programmes and implemented WHO guidelines since 2002 has varied. Most SSA countries took ± 2 years to implement the WHO's 2010 ART guidelines. 5 From December 2015 to May 2017, Rwanda, Kenya, Uganda, Botswana, Malawi, Zimbabwe and South Africa revised national ART eligibility guidelines to align with the WHO's 2015 guidelines. 11 On average, this integration took 12 months (range, 6-23 months). 11 The implementation of the WHO guidelines in resourceconstrained countries is complex. Consequently, it has not always been possible to implement the guidelines timeously where ART is most needed and where access to health services is limited. 2 In this review, we sought to determine how different SSA countries adapted to the WHO's ART-initiating CD4threshold changes over time and how WHO guidelines have impacted ART in the region.

Search strategy and selection criteria
We carried out a systematic electronic literature search on PubMed, Google Scholar, Cochrane, Embase and EBSCO host for the period, 2000-2019 ( Figure 1). The databases were selected based on our inclusion criteria and the availability of free full-text articles and papers. In this review, we used the preferred reporting items for systematic reviews and metaanalysis (PRISMA) as described by Moher et al., to identify an evidence-based dataset and to provide transparency in the selection process of the articles. 12 The search was based on the combination of the following terms and Boolean operators: WHO-ART guidelines or ARTinitiation guidelines and changes in CD4-initiation guidelines and implementation of WHO guidelines or adoption of WHO-ART guidelines. We also applied a manual country filter to limit our search to SSA. Articles published in a language other than English and articles focusing on ART regimen-change were excluded. The study included articles that focused on CD4-threshold changes and were published between 2000 and 2019. The following articles were not included: duplicates, articles not centered on the WHO and ART initiation guidelines or their adoption and implementation. Exclusion was based on the screening of the title and abstract.
The search process is illustrated in Figure 1. Seventy-nine (79) duplicate articles were removed, which were identical in Google Scholar and PubMed. Fewer articles dealt with the topic in Cochrane and Embase. The articles in PubMed were more detailed, easier to search and free to access. We also excluded 187 articles because they did not specifically address implementation based on CD4-threshold changes. Another 11 were excluded because they focused on only regimen change. Only 16 articles remained. These covered quantitative and qualitative synthesis of how SSA countries adopted the WHO and ART initiation guidelines between 2000 and 2019 and its impact on the management of HIV.

Data extraction and synthesis
The following information was extracted from selected studies using a template: publication details, country of study, objective(s) of the study, study design, summary of findings and theme (Table 1). Two review authors independently assessed the eligibility of the studies identified in the search. Articles with different study designs and objectives were selected to reduce the risk of bias. We used different high-impact databases to search for articles and global authors. The study designs were divided into five groups: cross sectional, cost-effectiveness, retrospective, randomised trial and observational studies. We did not subject the reviewed articles to this quality process because this is a scoping review. For synthesis, extracted information was grouped into themes derived from the articles in line with the review objectives and different study designs. The themes identified were: how different SSA countries adopted WHO and ART initiation policy guidelines at country level, timely implementation levels of the policies by different SSA   Rural KwaZulu Natal, South Africa As temporal changes of guidelines were occurring, percentages of ART initiations significantly increased in newly ART eligible people and did not decrease in those with very low CD4 counts.
It will be crucial to continue to verify the evolution of these percentages of ART initiations with future recommendations reaching near-to-universal access to ART, to ensure that individuals most in need of ART receive it on time. The study was based on data of a large HIV treatment and care programme allowing unbiased findings and giving an accurate representation of the entire population.
Some individuals may have initiated ART outside the programme, which may have led to an underestimation of the ART initiation percentages. However, this bias is likely to be limited as the Hlabisa HIV programme is decentralised in primary healthcare clinics with relatively easy access and this area is rural and poor, making it difficult for people to access ART somewhere else. Another limitation is that amongst included participants, some people may have failed to return to the clinic to receive their CD4 count result after HIV testing and thus were unaware of their status regarding ART eligibility, however we cannot provide a precise figure as this information was not collected in the database. Table 1 continues on the next page → ART initiation thresholds.
In addition, it also evaluated changes to trial characteristics that could bolster the incidence reduction.
KwaZulu Natal, South Africa Implementing the 2013 WHO HIV-treatment threshold could substantially improve the incidence reduction in HIV-population as seen in prevention trials. The feasibility of HIV-population prevention trials should be reassessed as implementation of treatment guidelines evolves. The cross-cluster contamination method that was used proved to be highly influential on trial outcomes.
The model of HIV transmission used was neither age-nor sex-stratified and did not explicitly account for behavioural factors such as concurrent sexual partnerships or sexual networks. Likewise, sex differences in HIV testing frequency and ART uptake were not modelled. Table 1 continues on the next page →

Swaziland
The economic evaluation proved to be a burden on Swaziland's public sector health system with scaling up numbers on early ART initiation. There were continuous drug shortages in most facilities, which resulted in delayed initiations. The study was a randomised control study, which used both quantitative and qualitative methods resulting in high-impact evidence.
ART, antiretroviral therapy; CDC, Centre for Disease Control and Prevention; FGDs, focus group discussions; HCW, healthcare workers; KZN, KwaZulu Natal; SSA, Sub-Saharan Africa; UTT, universal test and treat; WHO, World Health Organization.
countries, the barriers and facilitators to WHO and ART initiation policy adoption in SSA and the similarities in country characteristics in policy implementation in different SSA countries.

Ethical consideration
Ethical approval was obtained from the University of KwaZulu-Natal Biomedical Research Ethics Committee (UKZN BREC, reference number: BREC/00000819/ 2019).

Overview of selected studies
We reviewed 16 studies from an initial collection of 293 articles in Google Scholar, PubMed, Cochrane, Embase and EBSCOhost (Figure 1). We only reviewed studies that examined how different SSA countries adopted changes in WHO and ART initiation guidelines based on CD4 threshold and how the guidelines have impacted ART programmes in SSA. The following four themes were identified from the 16 papers: (1)

Theme 1: Adoption of World Health Organization antiretroviral therapy initiation policy guidelines at country level in sub-Saharan Africa
The results confirm that all the countries in SSA that are part of this review have adopted the WHO  Rwanda implemented the 2006, 2010, 2013 and 2015 WHO and ART initiation guidelines in a timely manner, that is, on an average within 6 months of international release. 25 Part of Rwanda's success is attributed to the cooperation of government and non-governmental service providers.

Theme 3: Barriers to and facilitators of antiretroviral therapy initiation policy implementation
Fourteen studies examined the barriers to and facilitators of ART-initiation policy implementation in SSA. Ambia et al. reported a significant increase in ART initiations, from 42% to 87%, in some facilities in the urban centres of Kenya, Malawi, South Africa (SA), Tanzania, Uganda and Zimbabwe. 13 Healthcare workers' (HCWs) attitudes were found to be both a barrier and a facilitator of implementation at the facility level. Teasdale et al. reported that positive learning attitudes from HCWs were found to be an enabler for WHO policy adoption in Rwanda. Furthermore, the Rwandan government's health department assembled a task team to ensure that the entire country was supported in the implementation of the revised guidelines. 22  Most facilities in SSA failed to fully implement the policy guidelines on time because of limited ARV-stock. 13 In a study from Swaziland, ARV-shortages delayed the implementation of the 2015 WHO guidelines on UTT. The available stock was not sufficient for those already on treatment. 24 24 This review has highlighted delays in aligning and implementing the WHO-ART-initiation guidelines in 20 SSA countries. 14 This suggests a need for greater guidance with regard to strategy and implementation in the communities of SSA.

Discussion
This review provides detailed information regarding WHO and ART initiation guidelines on CD4 count threshold changes and adoption of the guidelines in SSA. There were some variations in study designs, however, all the articles focused on CD4 ART-initiation changes in the WHO guidelines. The findings indicate that delays in adoption and implementation were frequent and widespread throughout SSA. We employed a thematic analysis and identified four crucial themes that were in all the articles. Several barriers to implementing the guidelines were identified. These include costs related to providing ART to eligible individuals, the shortage of staff and drugs in healthcare facilities and limited training of staff when guidelines were changed.
Our findings are consistent with those of Pell et al., who reported that the implementation of the 2015 guidelines took > 12 months to be adopted in all SSA countries after their official release. 1 Mikkelsen et al. noted that in an effort to contain the demand for ART, most African countries were forced to defer treatment-initiation to those eligible PLWH who were well. 26 Whilst policy is well intentioned, it is informed only by epidemiological data. The state of the healthcare system and sociocultural factors are critical for controlling and ending the epidemic. Our analysis of the financial, infrastructural, human resources for health and governance landscape in SSA, the feasibility associated with costs of implementing a UTT programme indicates health systems and societal perceptions related shortcomings. Although with clinical benefits, increasing the CD4 threshold has implications that reverberate across sectors: it affects budgets, infrastructure and human resources.
The WHO-ART guidelines are crafted by an international committee of experts drawn from rich and poor nations whose mandate is to provide the world's low-and middleincome countries (LMICs) with affordable high-quality ART guidelines. Historically, ART-guideline development in highincome countries is independent of the WHO and takes a more local character, for example, the International AIDS Society (IAS)-USA division, the Southern African HIV Clinicians Society, the European AIDS Clinical Society (EACS), the British HIV Association and the ASIA-Pacific HIV Society, etc. Liaison between the WHO and these regional societies and associations is constant. WHO guidelines committee members are also members of their national HIV-agencies. International ART guidelines are almost never produced in isolation.
Local guidelines frequently predate the release of the WHO's guidelines as local bodies require less administration/ bureaucracy and can respond to new data in real time, for example, UTT and the Insight-Start and the Temprano Studies, dolutegravir in first-line ART and the ADVANCE Trial, etc. 27 Mehraj et al. noted that Canada implemented the 2002 WHO and ART guidelines 2 months before its general release. 28 Canada had all the required capacity with regard to resources and regular staff trainings as well as mentoring in implementing the guidelines. Within a space of 1 month after the release of the 2015 WHO and ART initiation guidelines, 60% of the facilities in Spain were already implementing rapid ART initiation. 29 This suggests that Spain had already started preparing for the changes based on EACS guidelines. Larsen et al. revealed that despite significant funding from PEPFAR, the South African National Department of Health is still failing to implement rapid ART initiation. Indeed most SSA countries have experienced fundings cuts in the past few years. 30 There is a worrisome trend in SSA countries concerning the national adoption of the WHO-ART initiation guidelines. This may explain why countries in SSA are still struggling to achieve the 90-90-90 target. Despite the increase in HIV testing, rapid ART initiation based on the 2015 WHO guidelines are yet to be achieved in SSA. Furthermore, there is need for African governments to seriously consider local situations and experiences when embracing global guidelines.

Limitations
One of the limitations of our study is that we reviewed data from SSA and possibly excluded some important articles published in languages other than English. The study included only articles focusing on CD4 threshold changes on ART initiation. More articles might have been captured if language and the CD4 threshold had not been a filter.

Conclusion
We conclude that although countries in SSA have generally adopted the WHO-ART guidelines, implementation has frequently been delayed. We noted that the changes in guidelines were fraught with many challenges like switching from treating at a CD4 count of 200 cells/mm 3 in 2002 to rapid ART initiation in 2015 regardless of the CD4 level. Implementation has been variable across the countries of SSA because of differences in the health systems and the availability of resources. Because of the financial burden on governments, the reduction in donor funding, the rising incidence and prevalence of HIV and sometimes and the attitudes of healthcare workers, the majority of SSA countries have experienced a delay in the implementation of the guidelines. A comprehensive approach to reduce barriers whilst enhancing facilitators may improve the situation of adopting and implementing timely ART initiation guidelines.