Introduction

Human Immunodeficiency Virus (HIV) continues to be one of a major causes of morbidity and mortality in many countries, especially in sub-Saharan Africa (SSA) [1]. At the end of 2024, approximately 40.8 million people worldwide were living with HIV, including 1.3 million new infections, of whom 31.6 million were receiving antiretroviral therapy (ART). Globally, an estimated 630,000 HIV-related deaths occurred in 2024, of which approximately 60.3% were in the African Region [2]. Projections indicate that sustaining the current levels of HIV control is insufficient to meet the ambitious targets for reducing incidence and mortality by 2030 [3].

Despite the widespread roll-out of ART, many individuals in SSA still cannot access treatment until the later stages of their illness, often presenting with advanced HIV disease (AHD) [4,5]. A CD4 count below 200 cells/mm³ or WHO clinical stage 3 or 4 defines AHD in adults, adolescents, and children aged five and older. All children under five with HIV are considered to have AHD [6,7]. The global prevalence of AHD in healthcare settings, including both inpatient and outpatient care, is estimated at 33.7%, with no evidence of significant change in recent years [8]. From 2016 to 2019, the prevalence of AHD among individuals initiating ART with a baseline CD4 count ranged from 32% to 40% across the four African regions, excluding South Africa [9]. In SSA, an estimated 1.88 million people are living with AHD [10].

Individuals with AHD are more susceptible to opportunistic infections (OIs) such as tuberculosis (TB), severe bacterial infections, and cryptococcal meningitis (CM) [11,12]. Moreover, their risk of mortality increases as CD4 cell counts decline, and this risk has remained stable in recent years [13,14].

Using a Differentiated Service Delivery (DSD) approach, the WHO's recommended intervention package for AHD, which includes screening and diagnosis, early ART initiation, prevention and management of major OIs, and adherence support, should be provided to all individuals presenting with AHD [12,15]. National HIV programs are encouraged to adopt the WHO-recommended package, which will be updated as new evidence and insights emerge [1]. These strategies would help reduce HIV incidence and HIV-related mortality [16].

Despite the high burden of OIs, diagnosing and treating them remains challenging and limited in resource-constrained settings [17]. International funding has been crucial in reducing new HIV infections and related deaths in SSA. Funding cuts could reverse this progress by 2030, disproportionately impacting SSA and vulnerable populations [18–23]. On the other hand, the defunding of conventional lab-based CD4 testing has left treatment programs dependent on a few rapid tests with variable performance, further compounded by the withdrawal of key manufacturers of CD4 cell count tests from the market in low- and middle-income countries [17].

Advanced HIV poses a significant challenge and remains an underexplored area of HIV care [24]. Over the last decade, advanced HIV has become neglected, with insufficient resources and inadequate research focused on its prevention, screening, diagnosis, and treatment [17]. Effective implementation of the AHD care package has the potential to improve the diagnosis of OIs and enhance the overall quality of care for individuals with AHD [25]. Although the implementation of the WHO-recommended package of care is feasible, it has been undertaken to only a limited extent in many sub-Saharan African countries [26].

Understanding the challenges in implementing WHO-recommended package of care for AHD patients in resource-constrained settings can inform policy and programmatic changes to improve care for patients with AHD. Therefore, our study aimed to explore challenges in implementing the WHO-recommended package of care for advanced HIV disease in resource-constrained settings. The findings will help inform strategies to improve the implementation of the WHO-recommended care packages for AHD and support decision-makers in HIV programs to allocate resources more effectively.

Materials and methods

Results

Background characteristics of participants

People living with AHD.

The mean age of the study participants was 33.5 years (SD ± 8.9), with more than half (55.9%) aged between 30 and 49 years. Two-thirds (66.2%) of the participants lived in rural areas. Nearly half (48.9%) had completed primary education, and just over half (53.1%) were married. Additionally, 56.6% of the participants were classified as underweight. The majority of participants (84.1%) were classified as WHO clinical stage 3. Of the 145 AHD cases, only 69 (47.6%) had a recorded baseline CD4 count. Among these 69 cases, two-thirds (n = 46, 66.7%) had a CD4 count between 100 and 199 cells/mm³ (Table 1).

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Table 1. Background characteristics of newly diagnosed people living with AHD initiating ART in the Gedeo Zone, Southern Ethiopia (n = 145).

https://doi.org/10.1371/journal.pone.0341162.t001

Key informant participants

The median (IQR) age of KIs was 36.5 years (34.75–42). The majority were male (7, 87.5%). Half of the KIs were public health officers (4, 50%), while the others included two clinical nurses, one laboratory technologist, and one pharmacist. Most held a bachelor’s degree (6, 75%). The median (IQR) duration of HIV care experience was 3.5 years (2.75–4) (Table 2).

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Table 2. Background characteristics of key informant participants.

https://doi.org/10.1371/journal.pone.0341162.t002

Theme 3: Patient-related concerns as expressed by healthcare workers

Healthcare providers report that certain patient-related factors, including clinical conditions, financial constraints, and psychological unreadiness, hinder the delivery of guideline-recommended care.

Subtheme 3.1: Clinical factors.

Most patients with AHD present with advanced disease and OIs, requiring clinical stabilization before initiating ART. As a result, same-day or rapid ART initiation is often delayed.

“Patients in WHO clinical stages 1 and 2 start ART immediately after giving their consent, while those in stage 3 or 4 face a higher pill burden for managing their condition, so ART initiation is delayed for a short period.” (P2, Senior PHO)

Subtheme 3.2: Psychological unreadiness.

At times, beyond clinical and service-related factors, ART initiation is delayed due to patients’ psychological unreadiness to accept their diagnosis. Some patients are adamant in rejecting the test results, and their enrollment into ART is postponed until they come to terms with the diagnosis and are psychologically prepared to begin treatment. A public health officer described such a scenario as follows:

“Some patients do not accept their test results and request additional testing at other facilities to confirm the diagnosis. In such cases, we allow them for a period of up to one week or more to make an informed decision regarding enrollment in HIV care.” (P5, PHO)

Subtheme 3.3: Financial constraints.

Financial constraints pose a major challenge to the implementation of care packages. Although many patients require OI management, medications are often unavailable in ART pharmacy, forcing patients to purchase them from private pharmacies. Given the severe socioeconomic disadvantage of most AHD patients, many remain untreated, leading to disease progression.

“AHD patients do not purchase medicines from retail drug outlets because they cannot afford them. When they are unable to take their medications, their condition worsens, they get sick, stay at home, and often do not return for follow-up.” (P1, CN)

The three principal challenges in implementing the WHO-recommended package of care for AHD in our study settings are summarized in Table 3.

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Table 3. Summary of challenges in implementing the WHO-recommended package of care for advanced HIV disease.

https://doi.org/10.1371/journal.pone.0341162.t003

Discussion

The primary goal of delivering the WHO’s package of care interventions for individuals with advanced HIV disease is to prevent, diagnose, and treat the most common causes of HIV-related morbidity and mortality. Although the WHO’s intervention package for AHD is based on evidence-based recommendations, implementation of the package of care was sub-optimal in our study settings. Likewise, a study evaluating the screening, diagnosis, and treatment of AHD in an urban setting in Southwestern Uganda demonstrated sub-optimal implementation of the AHD intervention package [31]. Similarly, a study conducted in a rural setting in Malawi evaluating adherence to WHO’s AHD management guidelines found sub-optimal adherence to these guidelines among patients with AHD [32]. Sub-optimal implementation of established recommendations, compounded by recent funding cuts, could reverse global efforts to end the AIDS epidemic as a public health threat by 2030 [18,23].

Individuals with AHD who are eligible for a package of care can be identified using CD4 cell count, which is the best indicator of disease stage and risk of death. Although WHO clinical staging can be used to identify eligible individuals, relying on it alone risks missing a substantial number of people living with HIV who have severe immune suppression. In addition to identifying individuals eligible for the recommended care package, CD4 count testing has the potential to avert deaths from TB and CM, which are two of the most deadly OIs among patients with AHD [33]. Therefore, baseline CD4 count testing remains important for all PLHIV enrolling in ART [7,34].

Despite its critical importance, baseline CD4 cell counts were performed for only 47.6% of advanced HIV cases in our study settings. This implies that more than half of the cases were identified using the WHO clinical staging. Consequently, a considerable proportion of individuals with advanced HIV might have gone unidentified, potentially missing the package of care for which they were eligible. Robust evidence from the two meta-analyses assessing the diagnostic accuracy of the WHO clinical staging system for detecting AHD indicated that a significant proportion of PLHIV may be misclassified, leading to missed opportunities for the prophylaxis, diagnosis, and treatment of opportunistic infections [35,36]. This finding underscores the critical need to enhance CD4 test availability at service delivery points, enabling a comprehensive evaluation of PLHIV enrolling in care. Adequate attention should be given to ensuring the availability of baseline CD4 testing services at spoke facilities. This is supported by evidence from a study that explored global trends in CD4 count measurement at the initiation of ART, highlighting the need for widespread adoption and adequate funding for baseline CD4 measurement at ART initiation [9].

Point-of-care diagnostics theoretically have the potential to reduce mortality by addressing laboratory delays and providing timely same-day results to patients and healthcare workers [37]. Therefore, enhancing the availability of diagnostic resources could potentially improve health outcomes among PLHIV [32]. In spoke facilities lacking diagnostic capacity, mentoring and supporting healthcare professionals to strengthen referral and linkage of newly diagnosed AHD patients to hub centers for essential investigations and care is crucial in resource-constrained settings. Ongoing mentoring and performance monitoring are essential for effective AHD care implementation and improved outcomes [24,38,39]. A growing body of evidence supports that capacity-building training in AHD care can enhance outcomes across the entire care cascade [40].

Screening for OIs, such as TB and CM, is crucial due to the high mortality associated with these co-infections [41]. Strengthening screening and diagnostic efforts for AHD-related OIs is imperative to improve clinical outcomes and ensure progress in HIV care delivery [42]. Adults and adolescents living with HIV should be screened for TB using a clinical algorithm. Those who do not report symptoms such as a current cough, fever, weight loss, or night sweats are unlikely to have active TB and should be offered preventive treatment, regardless of their ART status. After ruling out active TB disease, twenty-one individuals were provided with TB preventive treatment in the current settings. In our study settings, the performance of the four-symptom TB screening aligned with WHO recommendations, ensuring that all individuals with AHD were screened for TB. GeneXpert® MTB/RIF testing was performed on 89.7% (114/127) of individuals who screened positive for TB, while 10.2% (13/127) were not tested. To assist in diagnosing TB, LF-LAM testing was performed among individuals with symptoms and signs of the disease, with 84.4% (78 out of 92) testing positive. There are occasional interruptions in TB diagnostics in the current settings due to resource shortages. To avoid such interruptions and ensure continuity in diagnostic services, well-planned and sustainable strategies should be implemented that guarantee consistent resource availability.

Globally, nearly a fifth (19%) of AIDS-related mortality is attributed to cryptococcal disease [43]. The WHO recommends that countries prioritize reliable access to rapid CrAg diagnostic assays, preferably lateral flow assays, for use in cerebrospinal fluid (CSF), serum, plasma, or whole blood [7]. Screening for cryptococcal infection in PLHIV can identify asymptomatic individuals, allowing for early treatment and prevention of mortality [44]. There is an urgent need to scale up cryptococcal diagnostics, access to effective meningitis treatment, and preventive screening to eliminate cryptococcal meningitis–related mortality by 2030 [43]. Cryptococcal antigen test is affordable, easy to use, and highly sensitive in CM detection [45]. In addition to strengthening diagnostic and treatment capacity for CM, it is necessary to raise awareness among healthcare workers about the impact of fungal infections in AHD and to provide technical assistance and additional training [46][47].

Antiretroviral therapy alone is insufficient for the effective management of CrAg-positive PLHIV; therefore, treatment programs in resource-constrained settings should integrate CrAg screening into HIV care, particularly targeting individuals with CD4 cell count below 100 cells/mm³ [48,49]. Existing evidence supports routine screening for all PLHIV with CD4 cell counts below 100 cells/mm³, and recommends considering screening for those with CD4 counts below 200 cells/mm³ [50]. In our setting, none of the individuals with AHD had been tested for CrAg. This finding is consistent with a study on the management of AHD among individuals initiating ART in Senegal, which reported that no participants underwent CrAg screening or received fluconazole for preventive therapy [51]. A recent study assessing clinical guideline use in CM care among healthcare workers in Ethiopia demonstrated suboptimal uptake, with only 29% reporting routine implementation [46]. Similarly, a study assessing adherence to standards of care in the management of HIV patients at risk of CM in Uganda reported that only 19% of eligible patients underwent CrAg screening [52]. Even when no CrAg testing was performed, 33 individuals with AHD in our study settings received fluconazole primary prophylaxis in accordance with WHO recommendations [29]. This study highlights gaps in CrAg testing for individuals with AHD in resource-limited settings and underscores the urgent need to expand testing and ensure the availability of medications to prevent cryptococcal infections. Failure to screen for CrAg among individuals with AHD represents a critical missed opportunity for early intervention and improved clinical outcomes [53]. Antiretroviral therapy initiation should be deferred for four to six weeks after starting antifungal treatment in individuals with CM to minimize the risk of mortality [54].

Co-trimoxazole prophylaxis is recommended for adults (including pregnant women) with severe or advanced HIV clinical disease (WHO stage 3 or 4) or with CD4 cell count ≤350 cells/mm³ [7]. In the current settings, 92.4% of people with AHD have received co-trimoxazole prophylaxis. Co-trimoxazole prophylaxis should be initiated regardless of CD4 cell count or WHO clinical stage in settings where malaria or severe bacterial infections are highly prevalent [55]. Malaria is highly prevalent in the Gedeo Zone, particularly in Dilla Town and its surrounding areas [56]. According to the recommendation, the implementation of co-trimoxazole prophylaxis in the study settings was satisfactory.

According to consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection, ART should be initiated for all people living with HIV regardless of WHO clinical stage and at any CD4 cell count [57]. Following confirmed HIV diagnosis and clinical assessment, PLHIV should initiate ART without delay. Same-day ART initiation (SDI) should be offered to those who are clinically eligible and ready to begin treatment. Same-day initiation was found to be effective in achieving viral suppression [58,59]. Likewise, rapid initiation of antiretroviral therapy was associated with a significant reduction in mortality [60]. Despite its benefits, same-day initiation was associated with lower retention in care [61,62] and increased rates of medication discontinuation [63]. These detrimental effects, therefore, necessitate improved counseling, capacity-building training for healthcare providers, and patient education to effectively manage concerns and achieve optimal care.

Individuals with AHD should be prioritized for ART initiation due to their heightened risk of mortality. It is advised that the unavailability of same-day CD4 count results should not prevent ART initiation on the same day. In our settings, four patients (2.8%) initiated ART on the same day as their diagnosis, while twenty-nine patients (20%) began treatment through rapid initiation protocols. ART should be deferred for individuals suspected of having TB or CM [7].

Prior to initiating ART, healthcare providers are advised to conduct a comprehensive discussion with patients, addressing their readiness and willingness to begin treatment, selection of the drug regimen, appropriate dosage and schedule, anticipated benefits, potential side effects, and the required follow-up and monitoring appointments. This patient-centered approach can improve treatment outcomes by enhancing adherence, promoting long-term engagement, and reducing loss to follow-up [58,64]. In our study settings, tailored counseling was provided to all individuals starting ART to promote optimal adherence.

A key concern emerging from the qualitative findings is the limited availability of medications for the management of OIs. Multiple interrelated factors appear to contribute to this challenge. First, there has been a marked reduction in the supply of OI medications from the Ethiopian Pharmaceutical Supply Agency (EPSA), the FMoH, and partner organizations supporting the national HIV program. Second, the implementation of the APTS system has restricted the practice of drug exchange between different pharmacy units within health facilities, thereby limiting access to OI medications. Third, the financial inaccessibility of these medications, which is primarily a result of patients’ low socioeconomic status, further compounds the problem. These findings highlight a critical gap in the continuum of care for individuals with AHD and underscore the need for urgent targeted interventions to address this public health concern.

Another critical area is the development of differentiated service delivery models (DSD) for individuals with AHD, who require more specialized and targeted care due to their increased risk of morbidity and mortality. Similar to the approach used for key populations, care for individuals with AHD should be provided separately from the general client population. Differentiated service delivery models are considered acceptable and may contribute to improved retention rates, better viral suppression outcomes, and more efficient service delivery [65]. The implementation of differentiated antiretroviral therapy delivery models enables clinicians to dedicate more time to managing patients with AHD [26]. Furthermore, a differentiated delivery model would help improve both access to and the quality of services. Therefore, national HIV policymakers and program developers should prioritize the adaptation or development of differentiated ART delivery models tailored to the specific clinical and support needs of people with AHD.

Conclusions

The implementation of the WHO-recommended package of care in the current settings remains inconsistent. Although adherence support is routinely provided to all newly diagnosed PLHIV with AHD, the delivery of other components is often impeded by various challenges. Three principal challenges have been identified: structural and organizational obstacles, service delivery constraints, and patient-related concerns as expressed by healthcare workers. The unavailability of essential diagnostic equipments, ineffective referral and linkage, interruptions in the supply of critical resources, significant shortages of OI medications, system-imposed restrictions on drug exchange practices, and the absence of specialized clinics for managing patients with AHD were critical issues. These challenges signify a serious gap in the continuum of care for individuals with AHD and underscore the urgent need for targeted interventions to address this pressing public health concern.

Supporting information

Acknowledgments

We sincerely thank the College of Health Sciences and Medicine at Dilla University for granting ethical clearance for this study. We also extend our heartfelt appreciation to the data collectors and the study participants for their cooperation and valuable time.