Does engagement in HIV care affect screening, diagnosis, and control of noncommunicable diseases in sub-Saharan Africa? A systematic review and meta-analysis

Objective: Low- and middle-income countries are facing a growing burden of noncommunicable diseases (NCDs). Providing HIV treatment may also provide opportunities to increase access to NCD services in under-resourced environments. We sought to investigate whether reported use of antiretroviral therapy (ART) was associated with increased screening, diagnosis, treatment, and/or control of diabetes, hypertension, chronic kidney disease, or cardiovascular disease among people living with HIV (PLWH) in sub-Saharan Africa (SSA). Design: Systematic review and meta-analysis. Methods: We searched 10 electronic literature databases for studies published between 01 January 2011 and 31 December 2022 using a comprehensive search strategy. We sought studies reporting on screening, diagnosis, treatment, and/or control of NCDs of interest by ART use among non-pregnant adults with HIV ≥16 years of age in SSA. Random effects models were used to calculate summary odds ratios (ORs) of the risk of diagnosis by ART status and corresponding 95% confidence intervals (95% CIs), where appropriate. Results: Twenty-six studies, describing 13,570 PLWH in SSA, 61% of whom were receiving ART, were included. ART use was associated with a small but imprecise increase in the odds of diabetes diagnosis (OR: 1.07; 95% CI: 0.71, 1.60) and an increase in the odds of hypertension diagnosis (OR: 2.10, 95% CI: 1.42, 3.09). We found minimal data on the association between ART use and screening, treatment, or control of NCDs. Conclusion: Despite a potentially higher NCD risk among PLWH and regional efforts to integrate NCD and HIV care, evidence to support effective care integration models is lacking.


Introduction
The prevalence of noncommunicable diseases (NCDs) is on the rise globally [1], [2]. In low-and middle-income countries (LMICs), the disease burden has already shifted from predominantly infectious diseases to predominantly NCDs [3], [4]. By 2030, NCDs are expected to account for nearly 46% of deaths in sub-Saharan Africa (SSA), compared to 28% in 2008 [5]-[7]. In SSA where there is already a heavy burden of HIV and other communicable diseases, this creates a challenging multimorbidity disease environment. Co-existence of HIV with one or more NCDs, such as type 2 diabetes mellitus (diabetes) or hypertension, increases the complexity of patients' disease and care management profile, contributing to poorer health outcomes and increased health care costs for both the individual and the country [8]- [10].
People living with HIV (PLWH) may be at increased risk for NCDs. Antiretroviral therapy (ART) has resulted in a decrease in HIV infections and an increase in the lifespan of PLWH [11], [12].
However, chronic inflammation as a result of long-term HIV infection is associated with an increased risk of chronic conditions, including chronic kidney disease (CKD) and cardiovascular disease (CVD) [13], [14]. Moreover, emerging data have demonstrated substantial weight gain associated with newer ART regimens, such as integrase-strand-inhibitors [15]- [17]. As overweight and obesity are known risk factors for numerous NCDs, including hypertension, diabetes, and CVD [18], [19], this ART-associated weight gain could result in an increase of NCD rates in this population.
Though HIV infection and ART use may contribute to increases in NCD risk, the HIV care structure may provide a gateway to improve rates of detection and treatment of NCDs among PLWH. Routine NCD screening among healthy, asymptomatic adults in SSA is not common [20]. Traditionally, however, PLWH on ART have been required to present to a clinic monthly for . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. ;https://doi.org/10.1101https://doi.org/10. /2023 publication bias [30]. Statistical significance of departure from the Egger test null hypothesis of no bias was guided by an alpha level of 0.05.

Sensitivity Analyses
We conducted multiple sensitivity analyses. First, we stratified diabetes and hypertension summary estimates by age group (25-35, 35-45, 45+). Diabetes summary estimates were also stratified by diagnosis method. Additionally, to assess whether the implementation of the WHO Global NCD Action Plan in 2013 had an impact on screening and diagnosis of diabetes and hypertension, we conducted a sensitivity analysis excluding studies with enrollment periods prior to the Action Plan implementation in 2013.
All analyses were performed using STATA v. 15.

Results
The database search yielded a total of 427 potentially relevant studies, of which 83 were duplicates. After screening 344 titles and abstracts, we excluded 303 studies, leaving 41 that met the criteria for full-text review ( Figure 1). Of the 41 articles reviewed, 26 reported on a relevant outcome by ART status for at least one NCD of interest and were included in the final analysis. Some studies reported on multiple diseases of interest and are thus included in the analysis multiple times, once for each relevant outcome. A total of 16 studies reported on diabetes, 18 on hypertension, 6 on CKD, and one on CVD (Table 1). The total population of PLWH in our study was 13,570 [n = 8318 (61%) with reported ART use and n = 5252 (39%) with no reported ART use]. Sample size ranged from 104 to 3170 participants. Enrollment of cohorts began as early as 2008 and continued until at least 2016. Eight studies did not report enrollment . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. ;https://doi.org/10.1101https://doi.org/10. /2023 dates. While a number of longitudinal cohort studies were included in the review, the primary outcomes measured longitudinally were not the outcomes of interest for this review. Outcomes of interest for this review, rather, were reported in Table 1 of the study. As such, all data included in this review is a cross-sectional report of outcomes of interest by ART status.
Similarly, ART use was not the primary exposure of interest in most studies included in this review, therefore detailed reporting on how ART status was assessed was not available in all studies. Of the studies that did report assessment of ART status, most relied upon self-report and/or medical records.

Diabetes
Of the 16 studies addressing diabetes, only one reported screening prevalence by ART status (Table 1). Results of this study showed a slight increase in the likelihood of diabetes screening for PLWH with reported ART use (49%) compared to PLWH with no reported ART use (42%).
The odds of diabetes diagnosis comparing PLWH with reported ART use to PLWH with no reported ART use ranged from 0.32 -32.93 ( Figure 2). Just over half of the studies showed increased odds of diabetes diagnosis among those with reported ART use. The pooled estimate of diabetes diagnosis showed that, among PLWH, reported ART use was associated with a 7% increase in the odds of being diagnosed with diabetes compared to no reported ART use (odds ratio (OR): 1.07; 95% CI: 0.71, 1.60). The confidence interval for this estimate, however, was imprecise and consistent with up to a 29% decrease and 60% increase in odds of diabetes

Chronic Kidney Disease
Six studies reported on CKD diagnosis by ART status. The odds of CKD diagnosis when comparing those with reported ART use to those with no reported ART use ranged from 0.23 to 2.7 (Table 1). The odds of CKD diagnosis was higher in studies using creatine clearance to . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

Age impact
The odds of diabetes diagnosis associated with ART use is generally similar across age groups (Supplemental Figure 1). In the age-stratified analysis of hypertension, the 35-45 age group showed higher odds of hypertension diagnosis (OR: 2.32 (95% CI: 1.72, 3.14)) compared to the 45+ age group (OR: 0.88 (95% CI: 0.73, 1.05)) (Supplemental Figure 2). Only one study reported a mean cohort age <35.

Diagnostic test impact
When stratified by diagnosis method, studies using a glucose test had higher odds of diabetes diagnosis  Figure 3).
. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) Yet, we found no studies in sub-Saharan African reporting on CKD screening rates, and very few reporting on CKD diagnosis rates, among PLWH and engaged in care. Given the established increase in risk, screening for CKD with creatinine clearance and urine dipsticks should be routinely conducted among PLWH, particularly among those on ART. The lack of data on CKD screening and diagnosis rates among PLWH in sub-Saharan Africa suggests a . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. ; https://doi.org/10. 1101/2023 lack of monitoring in this population, despite a well-established care structure that would support frequent screening and early diagnosis of CKD.
We found only one study reporting on CVD diagnosis among a population of PLWH by ART use. Achwoka et al [32] showed a higher proportion of CVD among PLWH with reported ART use. However, the majority of cardiovascular events in this study population were related to elevated blood pressure which is more reflective of hypertension risk than CVD. Emerging data from high-income regions suggest that ART use contributes to an increased risk of CVD through alterations of lipid metabolism [43], [14]. The ART care structure provides a framework for critical monitoring of blood pressure and glucose levels, which would allow for early detection of risk factors of cardiovascular disease and mitigate progression and complications.
Our review should be interpreted in the context of its limitations. First, there is the possibility of incomplete retrieval or abstraction of data, or narrow search criteria resulting in missed studies.
We did not obtain raw data from study investigators for pooled estimation and relied on simple proportions or estimates of association presented in their data. Diagnosis methods for both NCDs varied across studies, and many studies reporting hypertension diagnosis relied on selfreport or medical record review, which could result non-differential outcome misclassification and likely underestimate the true association. Although heterogeneity between studies was high, we used random effects models to account for variability both within and between studies [44], [45]. However, the results may still represent a weighted average of a biased sample. We saw potential publication bias with regards to hypertension, however, given previous research showing higher rates of hypertension among PLWH, this may be related to a causal association rather than reporting bias. Due to lack of data on NCD care among PLWH, we were unable to evaluate the full cascade of care, including screening, treatment initiation, and control.
. CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) 1 6

Conclusion
The existing HIV care framework in SSA offers a promising setting to screen for NCDs among PLWH. A primary objective of the WHO's 2013-2020 Global Action Plan was to not only strengthen existing health systems to address the burden of NCDs, but to also support highquality research for the prevention and control of NCDs [46]. We conclude from this review, however, that evidence supporting that HIV care programs are successfully being leveraged to improve screening, diagnosis, treatment, and control of NCDs is lacking. Continued effort should be made to incorporate NCD services into HIV care programs in sub-Saharan Africa.
Furthermore, efforts to provide reporting on NCD screening, diagnosis, treatment, and control rates, would aid researchers, clinicians, and governments alike in understanding the true NCD risk among PLWH and the overall impact of care integration models.

Acknowledgements
Emma M Kileel: conception and study design, acquisition of data, data analysis, interpretation of data, drafting of work, final approval. Amy Zheng: acquisition of data, interpretation of data, revision of work, final approval. Jacob Bor: interpretation of data, revision of work, final approval.
Matthew P Fox: interpretation of data, revision of work, final approval. Nigel J Crowther: interpretation of data, revision of work, final approval. Jaya A George: interpretation of data, . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. ; https://doi.org/10.1101/2023.01.30.23285196 doi: medRxiv preprint revision of work, final approval. Siyabonga Khoza: interpretation of data, revision of work, final approval. Sydney Rosen: interpretation of data, revision of work, final approval. Willem DF Venter: interpretation of data, revision of work, final approval. Frederick Raal: interpretation of data, revision of work, final approval. Patricia Hibberd: interpretation of data, revision of work, final approval. Alana T Brennan: conception and study design, data analysis, interpretation of data, drafting of work, revision of work, final approval.  . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. ; https://doi.org/10.1101/2023.01.30.23285196 doi: medRxiv preprint . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023. . CC-BY 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

(which was not certified by peer review)
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(which was not certified by peer review)
The copyright holder for this preprint this version posted June 8, 2023.