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Standard of care in advanced HIV disease: review of HIV treatment guidelines in six sub-Saharan African countries



The World Health Organization (WHO) recommends an evidence-based package of care to reduce mortality and morbidity among people with advanced HIV disease (AHD). Adoption of these recommendations by national guidelines in sub-Saharan Africa is poorly documented. We aimed to review national guidelines for AHD management across six selected countries in sub-Saharan Africa for benchmarking against the 2021 WHO recommendations.


We reviewed national guidelines from six countries participating in an ongoing randomized controlled trial recruiting people with AHD. We extracted information addressing 18 items of AHD diagnosis and management across the following domains: [1] Definition of AHD, [2] Screening, [3] Prophylaxis, [4] Supportive care, and [5] HIV treatment. Data from national guideline documents were compared to the 2021 WHO consolidated guidelines on HIV and an agreement score was produced to evaluate extent of guideline adoption.


The distribution of categories of agreement varied for the national documents. Four of the six countries addressed all 18 items (Malawi, Nigeria, Sierra Leone, Uganda). Overall agreement with the WHO 2021 guidelines ranged from 9 to 15.5 out of 18 possible points: Malawi 15.5 points, Nigeria, and Sierra Leone 14.5 points, South Africa 13.5 points, Uganda 13.0 points and Botswana with 9.0 points. Most inconsistencies were reported for the delay of antiretroviral therapy (ART) in presence of opportunistic diseases. None of the six national guidelines aligned with WHO recommendations around ART timing in patients with tuberculosis. Agreement correlated with the year of publication of the national guideline.


National guidelines addressing the care of advanced HIV disease in sub-Saharan Africa are available. Besides optimal timing for start of ART in presence of tuberculosis, most national recommendations are in line with the 2021 WHO standards.


Despite enormous advances in antiretroviral therapy (ART) and prevention of opportunistic infections, about 650 000 people died from human immunodeficiency virus (HIV)-related causes in 2021. The World Health Organization (WHO) African Region is the most affected, contributing to 25.6 million people living with HIV (PWH) and 420 000 HIV-related deaths in 2021 [1, 2]. The mortality burden largely comprises adults with advanced HIV disease (AHD), defined as CD4 + count < 200 cells/mm3 or a WHO stage 3 or 4 event [3], who experience 10 to 20% mortality [4].

The number of patients with AHD in sub-Saharan Africa is persistently high. In some areas more than half of people with a new diagnosis of HIV present with advanced disease [5,6,7,8] and an increasing number of people presenting with AHD are ART experienced [9]. Mortality in this group is mainly driven by opportunistic infections including tuberculosis, cryptococcal meningitis, and severe bacterial infection, all of which are potentially preventable and curable [3, 10].

To reduce the burden of preventable morbidity and mortality, and related health care costs in people with AHD, the WHO in 2017 published the first international guideline providing evidence-based diagnostic, prophylaxis, and treatment recommendations for people with AHD to be delivered as a package of care [3]. To translate WHO guidance into health outcomes, specific recommendations need to be adopted into national practice guidelines and implemented in ART programs. It is unclear to what extent evidence-based WHO recommendations on AHD have been adopted in national guidelines.

The objective of this study is to review and document national guidelines for AHD management across selected countries in sub-Saharan with a high burden of advanced HIV for benchmarking against WHO recommendations. Findings may help to identify gaps in care and areas for health system investment.


Search strategy

Investigators representing six sub-Saharan African countries (Botswana [11], Malawi [12], Nigeria [13], South Africa [14], Sierra Leone [15], and Uganda [16]) participating in an ongoing trial of azithromycin prophylaxis for AHD (“REVIVE”, NCT05580666) were asked to provide published national guideline documents that included recommendations on management of AHD. We also searched the WHO website for the most recent guideline documents that related to management of AHD and included two publications for comparison [3, 17].

Data extraction

To compare the different documents (two WHO documents, six national documents) for management of AHD, we defined 18 items grouped in six categories: [1] Definition of AHD (1 item), [2] Screening (6 items), [3] Prophylaxis (6 items), [4] Supportive care (1 item) and [5] HIV treatment (4 items) (Tables 1, 2, 3). Available information was extracted from each guideline document and entered onto a spreadsheet for analysis. The national investigator of each country reviewed and confirmed the accuracy of data extraction from national guidelines and one author (SW) independently reviewed and confirmed the accuracy of data extraction from the WHO guidelines.

Table 1 Extracted data country specific guidelines
Table 2 Extracted data WHO documents
Table 3 Agreement of country specific guidelines to WHO 2021

Evaluation of guideline agreement

All documents were compared to a WHO reference guideline. We categorized items in each guideline as follows:

Not addressed. No information for the respective item was found within the national guidelines.

Agreement. The extracted data for an item in the country guideline matched the WHO 2021 guideline recommendations.

Partial agreement. The data of the national guideline included at least the same, but non-identical, criteria (e.g., WHO 2021: CD4 +  < 100 cells/mm3, National guideline: CD4 +  < 200 cells/mm3).

No agreement. National recommendation not in line with the WHO 2021 guidelines.

We used a scoring system to quantitatively rate the agreement. Agreement was assigned 1-point, Partial agreement 0.5-points, and No agreement and Not addressed 0-points.


The categories of overall agreement were displayed as bar graphs. Points on the scoring system were aggregated for each document to obtain an overall score.


Reference guideline documents

Data from following WHO documents was extracted:

  • 2017: “Guidelines for managing advanced HIV disease and rapid initiation of antiretroviral therapy” published in 2017 (hereinafter called WHO 2017). This guideline provides specific recommendations about management of people presenting with AHD and timing of initiation of ART for all PWH [3].

  • 2021: “Consolidated guidelines on HIV prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach” published in 2021 (hereinafter called WHO 2021). This document includes existing and new clinical and programmatic recommendations and brings together all relevant WHO guidance on HIV produced since 2016. Information about HIV prevention, testing, treatment, service delivery and monitoring is provided across different ages, populations and settings [17].

WHO 2021 was selected as a reference to define the gold standard for guideline comparison. This document was chosen because it is a consolidated guideline including all relevant WHO guidance on HIV produced since 2016 and therefore also incorporated and superseded WHO 2017. “Providing care to people with advanced HIV disease who are seriously ill” [18] was published in 2023 as a policy brief and was not included in this manuscript.

WHO 2021 provides recommendations for all defined items (Tables 1 and 2). Agreement with the national guidelines is shown in Table 3.

National guideline documents

Data was extracted from six national guidelines (Table 4). All countries established country specific guidelines, which were published between 2016 and 2023. Only the guidelines of Nigeria and Uganda include a specific section for AHD. The extracted data from national guidelines is presented in Table 1.

Table 4 Index of national guidlines

Definition AHD

WHO 2021 defines advanced HIV as CD4 + count < 200 cells/mm3 or WHO clinical stage 3 or 4. Nigeria, Sierra Leone, and Uganda use the same definitions. Botswana uses a CD4 + cut-off of less than 100 cells/mL and Malawi includes additional criteria for the diagnosis, including virological failure, hospitalization status and clinical danger signs. South African guidelines do not provide a definition of AHD.

Screening for opportunistic infections

agreement was found for at least four of the six items for all countries. All national guidelines recommend testing for CD4 + at baseline, if available. However, guidelines differ in their recommendations for screening for cryptococcal antigen and tuberculosis (Tables 1 and 3). Both screening procedures are recommended in every document, but the targeted population groups vary slightly.

Cryptococcal screening

According to WHO 2021, screening for cryptococcal disease is recommended in PWH and a CD4 +  < 100 cells/mm3 and should be considered in PWH with CD4 < 200 cells/mm3. Recommendations of Botswana and South Africa are in line with WHO 2021. Malawi, Nigeria, Sierra Leone, and Uganda screen a wider population group than recommended. Malawi includes all patients with AHD, Nigeria uses a threshold of CD4 + 200 cells/mm3, and Sierra Leone also screens PWH on ART with suspected or confirmed treatment failure. Uganda assesses clinical information, either positive symptom screening or danger signs, or a CD4 + count < 100 cells/mm3.

Tuberculosis screening

WHO 2021 recommends screening for tuberculosis with urine lipoarabinomannan (LAM) for inpatients (CD4 +  < 200 cells/mm3) or outpatients (CD4 +  < 100 cells/mm3), any CD4 count with symptoms, or if seriously ill. Routine tuberculosis symptom screening is recommended in all countries. The use of urine LAM is not addressed in the guideline documents from Botswana. None of the remaining countries uses an approach stratified by CD4 + cell count for in- and outpatient LAM screening. In contrast to WHO 2021, Nigeria and Sierra Leone do not include clinical criteria as an indication for urine LAM testing, both using a CD4 + threshold of 100 cells/mm3 only. Malawi includes all patients with AHD, and South Africa recommends urine LAM screening for patients with CD4 count < 200 cells/mm3 within the last 6 months, AHD or current serious illness.

Prophylaxis of opportunistic infections

Malawi, Nigeria, Sierra Leone (all agreement), South Africa (4 agreement, 2 no agreement), and Uganda (4 agreement, 1 partial agreement, 1 no agreement) addressed all six items. Botswana addressed only 4 items, of which two were described as no agreement.

Cotrimoxazole prophylaxis

In WHO 2021, cotrimoxazole prophylaxis is recommended for PWH with a CD4 + count < 350 cells/mm3, clinical stage 3 or 4, or to any PWH in settings with high prevalence of malaria or severe bacterial infection. All national documents recommend use of cotrimoxazole, but the targeted population group varies. Sierra Leone, Nigeria, and Malawi include all HIV infected adults for cotrimoxazole prophylaxis, which is in line with WHO 2021 because malaria or severe bacterial infection are highly prevalent in those countries. Botswana and South Africa use a lower CD4 + cut off (CD4 +  < 200 cells/mm3). Uganda recommends cotrimoxazole for all people newly initiating ART and for people with ART treatment failure (Table 1).

Malawi and Sierra Leone recommend lifelong prophylaxis with cotrimoxazole. In Nigeria, prophylaxis can be discontinued once clinically stable on ART. Both approaches are in line with WHO 2021. In national recommendations from Uganda five criteria need to be met to discontinue prophylaxis: age, pregnancy status, duration of ART, viral load, and current clinical status (Table 1). In contrast, Botswana and South Africa recommend discontinuing prophylaxis once CD4 + cell count reaches 200 cells/mm3.

Tuberculosis preventive therapy

All national guidelines, except Botswana (not addressed), recommend preventive therapy for tuberculosis for all adults living with HIV.

Supportive care interventions

Intensified treatment adherence support for people with AHD is recommended in all documents. Interventions include adherence counseling in Botswana or home visits—if feasible – in Nigeria.

Antiretroviral therapy (ART)

All national documents addressed items in this domain. All national guidelines include dolutegravir (DTG), emtricitabine (FTC) or lamivudine (3TC), and tenofovir disoproxil fumarate (TDF) as the recommended first line regimen. Guidelines vary in recommendations to defer ART start in patients requiring treatment for tuberculosis.

Start ART in PWH and tuberculosis

In contrast to WHO 2021, which makes recommendations without taking CD4 + levels into account (tuberculosis at non-neurological site, start ART within 2 weeks; tuberculosis meningitis, start at 4–8 weeks), Malawi, Nigeria, and Uganda require a CD4 + count to define when to start ART. South Africa further differentiates according to drug-sensitive or drug-resistant tuberculosis.

Start ART in PWH and cryptococcal meningitis

All national documents agree with WHO 2021 for timing of ART in cryptococcal meningitis, recommending a delayed start of ART for 4–6 weeks after diagnosis.

Overall agreement

Botswana obtained 9 points (9 Agreement, 5 No agreement, 4 Not addressed), Malawi 15.5 points (14 Agreement, 3 Partial agreement, 1 No agreement), Nigeria and Sierra Leone 14.5 points (14 Agreement, 1 Partial agreement, 3 No agreement), South Africa 13.5 points (13 Agreement, 1 Partial agreement, 3 No agreement, 1 Not addressed) and Uganda 13 points (12 Agreement, 2 Partial agreement, 4 No agreement) (Table 2, Fig. 1). Alignment with WHO 2021 recommendations varies over time, but shows an increasing trend (Fig. 2).

Fig. 1
figure 1

Categories of agreement for national guidelines

Fig. 2
figure 2

Overall agreement according to year of publication


This review evaluates national guideline documents from six sub-Saharan African countries to describe the standard of care for AHD. Overall, national guidelines addressed between 14 and 18 items and at least 60% of the addressed items were in agreement with the WHO reference document across all six national documents.

Various enhanced clinical care approaches, including prophylaxis, screening procedures or intensified adherence counselling, have been shown to reduce mortality in AHD [19, 20]. We defined a set of 18 items to reflect these broad areas. All items were addressed in the national guidelines from Malawi, Nigeria, Sierra Leone, and Uganda. Gaps were documented in the guidelines from Botswana and South Africa.

The number of items not addressed at a national level (range 0–4) could be explained by local circumstances and policies or presence of other national documents dealing with defined topics of our items, such as national tuberculosis guidelines, that were not included in our review.

AHD is defined by CD4 + count and clinical stage. Only half of the country-specific guidelines were in line with the definition provided by WHO 2021. CD4 + testing at baseline is important to identify patients at highest risk for morbidity and mortality, especially since nearly half of people presenting with CD4 + counts < 100 cells/mm3 have WHO clinical stage 1 or 2 [19]. However, there has been a decrease of pre-ART CD4 + testing in the treat-all era in low/lower-middle-income countries and the determination of CD4 count varies widely across Africa [21, 22]. Malawi is the only country to provide additional clinical criteria to define advanced HIV disease, a tacit and pragmatic acknowledgement that CD4 testing might not be available in many clinics in that country.

The agreement of national guidelines compared to WHO 2021 varies. We established different categories of agreement to quantify and summarize differences; importantly, these categories are not a measure of clinical importance or guideline quality. The highest agreement was shown for Malawi, followed by Nigeria, and Sierra Leone. Most no agreement scores were in the ART domain, with all national documents showing differences in comparison to WHO 2021. The choice of first line ART is aligned in all documents, reflecting wide availability of highly effective and well tolerated drugs. In contrast, the optimal timing for ART initiation with concomitant tuberculosis does not align with WHO recommendations and varies across countries. This discrepancy may reflect a reluctance of countries to implement rapid (same day) ART initiation for PHW undergoing tuberculosis screening or within 2 weeks for those starting tuberculosis treatment given the increased risk of immune reconstitution inflammatory syndrome and the absence of mortality benefit for patients with CD4 + count > 50 cells/mm3 in randomized controlled trials [23].

The reviewed national guidelines were published between 2016 and 2023 and WHO recommendations published in 2017 and 2021. The changes seen in the WHO documents, such as indication for the use of urine LAM or timing of ART with tuberculosis, reflect the ongoing scientific advances in this area. Overall agreement between national documents and WHO 2021 increased over time, reflecting the importance of providing regular updates to national guidelines in a rapidly changing field.

The strength of this survey is the close collaboration with leading clinicians and researchers situated in the evaluated countries. Furthermore, we included WHO documents, issued over a period of 6 years, to highlight changes in international guidance documents.

A limitation of this work is that only one guideline for each country was assessed, and relevant recommendations from other topic-specific guidelines may have been missed. Furthermore, we restricted our evaluation of national guidelines to the six countries participating in the vanguard phase of the REVIVE trial, limiting the generalizability of findings to other countries. The included countries however account for roughly 350 million people, representing nearly one third of the total population of sub-Saharan Africa [24]. Our study did not collect information around guideline implementation. It is estimated that only 28% of national policy documents of countries in the WHO African region adhere to the WHO HIV testing strategy [25] and that most of the 25 sub-Saharan countries do not appear to have widely implemented specific interventions regarding the care of AHD [26]. A study in Senegal showed that there are missed opportunities to prevent HIV-associated morbidity and mortality in AHD due to various barriers including diagnostic evaluation [27]. Implementation research to measure uptake and understand implementation barriers is needed.


In conclusion, we found that national guidelines of six countries in sub-Saharan Africa address most recommendations relevant in the care of patients living with AHD. However, level of agreement with the 2021 WHO recommendations varied across countries. The largest discrepancies were in the recommendations for timing of ART in relation to tuberculosis. Encouragingly, agreement appears to be increasing over time.

Availability of data and materials

All data generated or analysed during this study are included in this published article [and its supplementary information files].





Advanced HIV disease


Antiretroviral therapy






Human immunodeficiency virus




People living with HIV


Tenofovir disoproxil fumarate


World Health Organization


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SW is supported by the National Institutes of Health (K43TW011421 and U01AI170426) and the Wellcome Trust through core funding from the Wellcome Centre for Infectious Diseases Research in Africa (203135/Z/16/Z). For the purposes of open access, the authors have applied a CC-BY public copyright to any author-accepted manuscript arising from this submission.

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TCS, SW, JWE designed the research project and performed data extraction. TCS, JWE, SW, SL, DM, GM analyzed the data and drafted the manuscript. NY, MM, CK, OA, SL, CKM, GM, DM revised the manuscript and provided interpretation. NY, MM, CK, OA, SL, CKM, GM, SW assisted in data acquisition. All authors approve the submission of the final draft of the manuscript.

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Correspondence to Sean Wasserman.

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Scheier, T.C., Youssouf, N., Mosepele, M. et al. Standard of care in advanced HIV disease: review of HIV treatment guidelines in six sub-Saharan African countries. AIDS Res Ther 20, 83 (2023).

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