To our knowledge, these are the first externally validated clinical scores for ART care intensification generated for SSA. The scores, which have superior screening accuracy characteristics in predicting early mortality risk than WHO-recommended advanced disease eligibility criteria, are not dependent on CD4 testing access, can differentiate mortality risk into three risk groups, could improve access to evidence-based early ART care packages, improve efficiency of advanced disease DSD models, and facilitate improved differentiated care .
The CD4-independent clinical score, designed for settings where CD4 is unavailable at ART intitiation, with a cut-off score of ≥ 4 was largely as sensitive (86–95%) in screening in persons at risk of death by 6 months as the current WHO advanced disease eligibility criteria (83–100%) and nearly twice as sensitive as WHO eligibility criteria that would rely on WHO stage alone (48%). Compared with the CD4-based WHO advanced disease eligibility criteria, the CD4-independent clinical score had higher specificity and would screen 8–26% fewer ART enrollees into intensified care pathways, suggesting the screening tool could also increase efficiency of investments in DSD models for advanced disease. Therefore, in the many settings in SSA that lack access to rapid CD4 testing, the CD4-independent clinical score should be considered for scale-up to facilitate early ART care intensification, with the potential for reductions in early ART mortality . In addition, in those settings where CD4 is available, using the CD4-dependent clinical score with a cut-off score of ≥ 5 could have similar or increased sensitivity and superior specificity compared with WHO advanced disease eligibility criteria, with the potential to both reduce early ART mortality and improve efficiency of DSD algorithms.
In contrast to current WHO guidelines, which recommend only the use of CD4 count and WHO HIV disease staging to identify patients at high risk for morbidity and mortality, our composite risk score provides both more comprehensive and specific information on the magnitude of risk for each patient by integrating additional objective variables into the assessment . The additional variables included in our score are both clinical and demographic. The clinical variables of WHO TB symptom screen, temperature, and anemia severity are known to be associated with serious comorbidities that significantly increase early mortality risk, while the demographic variable in the scores (the gender variable of male, female non-pregnant, and female pregnant) captures important generalizable differences in early mortality risk in SSA, which are due to both psychosocial and biological factors [28, 29]. Our risk scores are careful to be simple (5 or 6 variables assessed), use objective covariates rather than variables that are more open to interpretation, and use variables that should be available, or could easily be made available, at the POC in LMIC. Our score could be relatively easily included in paper medical records relevant for the first HIV clinic or ART initiation visit and should not require a calculator, unlike clinical scores developed for resource-rich settings that require either electronic medical record or website access to calculate the score (e.g., the Veterans Aging Cohort Study (VACS) or EuroSIDA scores) [30,31,32].
The hemoglobin concentration variable in our scores is more available in LMIC than POC CD4 testing, although scale-up of CD4 testing is needed and ongoing. Notably, WHO has long designated hemoglobin testing one of four essential laboratory services in SSA , and hemoglobin tests are the most commonly performed laboratory test globally [34, 35]. For example, in Malawi, one of the most resource-constrained countries in the world which is ranked 172 out of 189 countries on the human development index, hemoglobin testing through point-of-care HemoCue®  or the WHO Hemoglobin Color Scale is relatively widely available . In the 2014 Malawi national health facility survey to assess access to diagnostic tests, 82% of hospitals had access to hemoglobin testing, with access only superseded by malaria diagnostic testing (95%) and HIV diagnostic testing (95%), whereas CD4 testing was only available in 43% of hospitals . Across all health facility types (hospitals, health centers, clinics, and health posts), hemoglobin testing was three times more widely available than CD4 testing , although there is a need for scale-up of both tests. In addition to being currently more widely accessible in SSA than CD4 testing, POC hemoglobin testing is currently easier to scale up than CD4 testing. Available POC hemoglobin measurement devices tend to be durable, easy to use, and not reliant on electricity supply, and require minimal training and supervision  while also providing good accuracy in LMIC [37, 38]. To date, these POC hemoglobin devices have been less expensive than currently available POC CD4 systems and are useful for non-HIV-related care (e.g., <$100/POC hemoglobin measurement device and $0.12–0.75/test  vs. about $7430/POC CD4 device and about $8.70/test ). Both CD4 testing and hemoglobin testing are important at the point of care, and less expensive POC CD4 lateral flow assays and transcutaneous spectrophotometry solutions for hemoglobin level measurement may become available in the future [40,41,42].
Additional advantages of developing clinical scores with a variety of cut-offs are that it allows program managers to choose cut-offs with associated screening accuracy characteristics, allowing program managers to choose cut-offs based on funding availability, by trading sensitivity for improved specificity .
Another potential advantage of the combined clinical score over the WHO advanced disease criteria is the ability to differentiate three risk groups (low, moderate, and high), with the highest risk group having 6-month mortality rates of 16–30% versus 0–3% in the low and 4–5% in the moderate risk groups. While all patients with moderate or high scores might benefit from standardized outpatient intensified early ART care, patients in the highest risk group might be candidates for additional interventions to help navigate the relatively complex time of early ART. During this time, clinicians need to rapidly search for, diagnose, or rule out comorbidities, and both choose and time appropriate therapies, all within the context of ART-driven immune reconstitution [43, 44]. Our clinical score could be used to inform a clinical trial of such interventions.
Moderate to severe anemia was a stronger predictor than CD4 count and overall was the strongest predictor of early ART mortality in our cohort, similar to other studies in SSA [21, 45, 46]. Anemia is the most common hematological complication of HIV disease among PLHIV  and develops through several mechanisms including direct HIV infection of hematopoietic progenitor cells, dysregulated erythropoiesis through indirect effects of proinflammatory cytokines, and through anemia of chronic disorders (ACD), which is thought to be the most common pathway . ACD is driven by hepatic expression of hepcidin, an acute phase reactant that causes iron to be diverted from the circulation and sequestered within cells of the reticuloendothelial system through downregulation of ferroportin channels . TB also drives ACD through this hepcidin-ferroportin interaction [49, 50]. In turn, sequestration of iron inside macrophages and T cells might support both intracellular mycobacterial growth [46, 49] and HIV viral replication , showing the potential for rapid worsening of HIV, TB, and severe hepcidin-driven anemia. Therefore, although ART is the most important treatment of HIV-associated anemia, early treatment of any associated co-infections is crucial . In a separate analysis, we show that moderate to severe anemia was also predictive of active TB infection in the XPRES cohort, similar to other analyses . Given the strong association between moderate to severe anemia, early mortality, and active TB, which is the most common cause of early mortality in SSA , the scores associated with observed moderate-severe anemia in this analysis (2–4 points) appropriately bring the total clinical score very close to the threshold for ART care intensification. Per current WHO guidelines, care intensification should include further investigations for TB, especially disseminated TB, through the use of the urine TB-LAM assay and Xpert MTB/RIF [46, 50, 53, 54].
Another notable finding is that measured temperature at > 37.5 °C at ART initiation was strongly predictive of early ART mortality, independent of the WHO TB symptom screen for fever or night sweats, which was also predictive of mortality. This indicates the importance of objective measures of fever in addition to patient history . In addition, our analysis shows that in those settings where measured temperature measurement is not available, measured heart rate (> 120 versus ≤ 120/min) is a suitable replacement variable. Notably, some of the key inflammatory cytokines that drive hepcidin release and fever are the same (e.g., interleukin (IL)-6, tumor necrosis factor which stimulates IL-6 release, interferons, and microbial-derived Toll-like receptors) and are important for both pathways [49, 55]. Disseminated undiagnosed TB or TB diagnosed late is the most common infectious cause of death among PLHIV in sub-Saharan Africa, accounting for about 40% of deaths . However, a recent autopsy study of causes of death among new HIV clinic enrollees in SA found that 59% of decedents had evidence of two or more concurrent infections . Most bacterial infections were due to common pathogens, such as Klebsiella spp., Salmonella spp., Haemophilus influenzae, and Staphylococcus aureus, while cryptococcal infection was found in 13% . Targeting an antimicrobial package of interventions to patients who screen positive for our proposed clinical scores, such as the package of interventions recommended by WHO or trialed in the REALITY trial (continuous trimethoprim–sulfamethoxazole, ≥ 12 weeks of isoniazid–pyridoxine (once active TB is ruled out), 12 weeks of fluconazole, 5 days of azithromycin, and a single dose of albendazole), could significantly reduce mortality for patients who screen positive .
The prognostic importance of male gender in predicting mortality was correlated with older age and smoking history in our model, and we chose to include the single gender variable rather than two additional variables (age ≥ 55 and smoking) in the CD4-dependent clinical score to make the most parsimonious clinical score and because male gender is a more generalizable predictor of poor outcomes in SSA [29, 57, 58]. In addition, similar to many ART programs in SSA [20, 59], pregnant women in XPRES, who were (1) more likely to be diagnosed at an earlier disease stage through routine testing at antenatal care and (2) able to initiate ART immediately once diagnosed unlike non-pregnant women diagnosed with HIV at the time , had lower mortality than non-pregnant women starting ART in bivariate analysis [20, 59]. However, if ART programs in SSA are able in the future to achieve earlier testing and ART initiation for male and non-pregnant female PLHIV, it is likely gender and pregnancy status could become less important predictors, while predictors like smoking and older age will become more important . Although smoking is not part of the clinical score, this article provides additional evidence for the need for tobacco smoking reduction programs for PLHIV, separate or included in early ART care intensification algorithms, to minimize not only the risk of ischemic cardiovascular diseases but also the risk of malignancies and bacterial infections, including TB .
Strengths of this study include the use of data from prospective cohorts nested within clinical trials, meaning there was minimal missing covariate data and strong ascertainment of the primary outcome of interest (6-month ART mortality) (e.g., only one patient was LTFU from the XPRES cohort and was excluded from this analysis ). Additional strengths include the relatively high screening accuracy in both the XPRES and TBFT cohorts, from two geographically separate cohorts, with very different cohort characteristics (e.g., XPRES enrollees represent general outpatient ART enrollees while TBFT enrollees had homogenously low CD4 counts (< 150/μL)). Notably, discrimination, as measured by the AUROC of the clinical scores, was lower in the TBFT than in the XPRES cohort, but at the chosen clinical score cut-offs, the clinical score still provided similar sensitivity and superior specificity in predicting early ART mortality compared with the WHO advanced disease eligibility criteria. The lower discriminatory capacity of the clinical scores in the TBFT cohort is not surprising given the TBFT cohort reflects a relatively homogenous ART population with advanced HIV disease. Notably, while in the XPRES cohort 6% of ART enrollees were newly diagnosed and treated for TB, in the TBFT cohort 62% were treated for TB through a risk-based TB-treatment algorithm , suggesting that the risk score is likely to be generalizable across a wide range of new ART enrollee cohorts. However, additional validation exercises are needed and planned to further assess generalizability.
Limitations include that the risk score has not yet been validated in a cohort enrolled under HIV test-and-treat guidelines, something which is planned in the near future. Other limitations include the fact that while the gender and pregnancy variable is relevant in SSA and many resource-limited settings, it is not generalizable to cohorts in resource-rich settings like the USA and Europe, where males often have better outcomes than female ART enrollees. Although the specificity of the clinical scores is superior to the WHO advanced disease eligibility criteria, a substantial percentage of ART enrollees (36–38% in the XPRES cohort) would be screened into receiving an advanced disease care package, which would require a monitoring system to assess implementation fidelity. In addition, these screening tools were validated in clinical trial cohorts that received relatively intensive TB screening and treatment services, and therefore, those that died did so despite access these services. Finally, although the clinical score is highly sensitive in screening in almost all patients with low CD4 count and advanced WHO disease stage at risk of death into intensification of care pathways, and has superior or similar sensitivity to current WHO advanced disease screening criteria, it is possible for some patients with a very low CD4 count and advanced WHO stage to have a clinical score that falls below the specified cut-off, and clinical discretion to screen these rare patients missed by the screening tool into intensification of care pathways is warranted.