Risk Factors for Coronavirus Disease 2019 (COVID-19) Death in a Population Cohort Study from the Western Cape Province, South Africa

1The effects of the intersecting pandemics of human immunodeficiency virus (HIV), tuberculosis, and coronavirus disease 2019 (COVID-19) in sub-Saharan Africa are unknown. Studies to date suggest no increased risk of adverse outcomes for COVID-19 in patients living with HIV and coinfected with tuberculosis, but these are small studies from Europe and North America, often limited to hospitalized patients, and may not be relevant to sub-Saharan Africa, where people living with HIV (PLWH) are younger, with different comorbidities, frequently including tuberculosis. PLWH may experience more severe COVID-19 disease due to HIV-related immune suppression, which may be exacerbated by transient immune deficiency from coronaviruses. In support of this hypothesis, a large UK cohort study reported an increased risk of COVID-19 death in those with immunosuppressive comorbidities, including PLWH. However, 2 factors may reduce the risk of severe COVID-19 in PLWH: dysfunctional immunity may lessen a virus-induced cytokine storm, and some antiretroviral drugs (tenofovir and some protease inhibitors) have in vitro activity against coronaviruses, with better outcomes reported for PLWH receiving tenofovir disoproxil fumarate (TDF) versus other antiretrovirals. Tuberculosis may exacerbate COVID-19, with impaired immune responses and increased angiotensin converting enzyme 2 receptor expression in respiratory epithelial cells, while COVID-19 pneumonia may enhance tuberculosis progression.

2It is important to establish whether HIV and tuberculosis increase risks of COVID-19 death, so that patients with these conditions can be provided with augmented prevention and potential therapeutic interventions. We used linked data from adults attending public-sector health facilities in the Western Cape Province, South Africa, to identify factors associated with COVID-19 death.

3We conducted a cohort study using deidentified data from the Western Cape Provincial Health Data Centre (WCPHDC) of public-sector patients aged ≥20 years with documented sex and not known to have died before 1 March 2020 (before the first diagnosed COVID-19 case in South Africa, and several weeks before the first documented COVID-19 death) and included all follow-up through 9 June 2020. The outcome was COVID-19–associated death. Our main analysis examined the risk of COVID-19 death in the general population, so all patients were included irrespective of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing. The study was approved by the University of Cape Town and Stellenbosch University Health Research Ethics Committees and the Western Cape Province Department of Health. Individual informed consent requirement was waived for this secondary analysis of deidentified data.

4The Western Cape has nearly 7 million inhabitants, of whom ~520 000 are PLWH, with >90% of them dependent on public-sector health services. The WCPHDC has been described in detail. Briefly, WCPHDC consolidates administrative, laboratory, and pharmacy data from routine electronic clinical information systems used in all public-sector health facilities, with linkage through a unique identifier. Multiple data sources are triangulated to enumerate health conditions such as diabetes mellitus, hypertension, tuberculosis, and HIV, with a label of high- or moderate-certainty evidence assigned for each inferred condition (Supplementary Table 1). High-certainty evidence of HIV comprises a positive HIV diagnostic test, HIV RNA test, triple antiretroviral therapy (ART), and/or registration in the HIV disease management system; moderate certainty is assigned for those with only a CD4 count measure, 2 antiretroviral drugs prescribed (previously used for vertical HIV transmission prevention), and/or an International Classification of Disease, Tenth Revision, diagnosis code of HIV. HIV testing coverage is high, as >90% of PLWH know their HIV diagnosis. High-certainty evidence of tuberculosis comprised laboratory evidence of Mycobacterium tuberculosis infection (any anatomical site, using Xpert RIF/MTB, microscopy, and culture), registration on the electronic tuberculosis registers, combination tuberculosis treatment, and/or admission to a tuberculosis hospital. Comorbidities were based on high- or moderate-certainty evidence but were restricted to high-certainty evidence in sensitivity analyses. The virologic, immunologic, and ART statuses of PLWH on 1 March 2020 were categorized, based on the most recent measures, as “confirmed virologically suppressed on ART” (HIV RNA < 1000 copies/ml in the last 15 months and ART dispensed in the last 6 months), “likely virologically suppressed on ART” (HIV RNA < 1000 copies/ml 15–24 months previously or HIV RNA < 1000 copies/ml > 24 months previously if ART dispensed in the last 6 months), “viremic or immunosuppressed” (HIV RNA > 1000 copies/ml in the last 15 months or CD4 count < 200 cells/µl within 18 months before March 2020), or “unknown.” Until January 2020, adult first-line ART was TDF, emtricitabine/lamivudine, and efavirenz, with abacavir replacing TDF for patients with kidney disease; zidovudine plus an emtricitabine/protease inhibitor were used for second-line ART for most patients. Dolutegravir was introduced in first- and second-line ART in January 2020. Diabetic control was categorized according to glycosylated hemoglobin (HbA1c) measurements within the last 2 years, with <7% indicating diabetes was controlled, 7–8.9% indicating diabetes was poorly controlled, and ≥9% indicating diabetes was uncontrolled.

5All COVID-19 diagnoses were based on a positive SARS-CoV-2 polymerase chain reaction test. Testing was available for all patients with COVID-19 symptoms until 1 June 2020; thereafter, public-sector laboratory testing was restricted to patients requiring admission, aged >55 years, or with comorbidities, due to the temporary limited testing capacity. Hospital admissions and all deaths in SARS-CoV-2–positive cases are recorded and reviewed daily.

6We used Cox proportional hazards models, adjusted for age, sex, and other comorbidities, to examine the associations between HIV, tuberculosis, and COVID-19 death among (1) all public-sector patients with ≥1 health visit in the 3 years before 1 March 2020 (considered “active patients”); (2) laboratory-diagnosed COVID-19 cases; and (3) hospitalized COVID-19 cases. We adjusted for location within Cape Town versus the rest of the province, and by the subdistrict of residence within Cape Town, to account for geographical variation in infection rates and as a proxy for socioeconomic status. Patients were censored on their date of death if deceased without a COVID-19 diagnosis, or on 9 June 2020, whichever was earliest. The database closure was 7 days later to allow for death reporting delays. For the analysis of COVID-19 deaths in laboratory-diagnosed cases, we included cases diagnosed before 1 June 2020, when testing was available for all patients with COVID-19 symptoms, but included all patients diagnosed by 9 June 2020 in the sensitivity analysis. The proportional-hazard assumption was assessed with Schoenfeld residuals. All analyses were conducted using Stata 15.1.

7We also calculated the standardized mortality ratio (SMR) of the actual number of COVID-19 deaths in PLWH versus the number that would be expected if PLWH had the same risk of COVID-19 death as people living without HIV of the same age and sex. We used data on the age, sex, and HIV status of all COVID-19 deaths (public and private sector) and the Thembisa Western Cape HIV model to estimate the Western Cape population size and HIV prevalence, by age and sex, in 2020. We calculated 95% confidence intervals (CI) for the SMR using 1000 bootstrap replications (see Supplementary Appendix 2).

8Since individual socioeconomic status and some comorbidities are not recorded in WCPHDC, we calculated E-values to determine the minimum strength of association that an unmeasured confounder (eg, raised body mass index [BMI] or socioeconomic status) would need to have with HIV/ tuberculosis and COVID-19 death to fully account for any association between HIV/tuberculosis and COVID-19 death. We conducted a quantitative bias analysis to assess the impact of potential confounding by obesity on an association between HIV and COVID-19 death.

9Among 3 460 932 active patients aged ≥20 years on 1 March 2020, 22 308 were diagnosed with COVID-19, of whom 625 (2.8%) died (Table 1). Among COVID-19 cases, 69% were diagnosed and 67% of deaths occurred before the change in testing criteria (1 June). The proportion of men was lower among COVID-19 cases versus noncases (31% vs 42%, respectively), likely due to initial cases being among essential workers in retail and manufacturing sectors that predominantly employ women. The proportion of women peaked (76%) in Week 5 of the epidemic, declining thereafter. Diabetes and hypertension were common in all patients, with higher prevalences among COVID-19 cases than noncases (diabetes, 14% vs 8%, respectively; hypertension, 23% vs 16%, respectively), while proportions of other comorbidities (as listed below) were similar. The COVID-19 patients who died were older than those who survived (median age, 63 years [interquartile range, 54–71] vs 37 [interquartile range, 30–48], respectively); several comorbidities were more common among the deceased patients than survivors (diabetes, 60% vs 14%, respectively; hypertension, 58% vs 23%, respectively; chronic kidney disease, 18% vs 2%, respectively; chronic pulmonary disease/asthma, 13% vs 7%, respectively; current tuberculosis, 4% vs 1%, respectively; previous tuberculosis, 14% vs 8%, respectively).

10Although the proportion of PLWH was similar among surviving and deceased COVID-19 cases, a greater proportion of COVID-19 deaths were in patients aged <50 years in those living with versus without HIV (39% vs 13%, respectively; Table 2). A substantial proportion of PLWH who died from COVID-19 had diabetes (50%) and hypertension (42%); however, these conditions were more common in deceased people living without HIV (62% for each condition). Current and previous tuberculosis were more frequent in PLWH, irrespective of COVID-19 survival status, with 14% and 37% of COVID-19 deceased cases in PLWH having current and/or previous tuberculosis, respectively.

11Among all public-sector patients, the probability of COVID-19 death by 100 days after 1 March 2020 was 180/million (95% CI, 167–196). COVID-19 death was associated with male sex, increasing age, diabetes (with a higher risk with elevated HbA1c), hypertension, and chronic kidney disease (Table 3). Current tuberculosis was associated with an increased hazard of COVID-19 death (adjusted hazard ratio [aHR], 2.70; 95% CI, 1.81–4.04), with a smaller increase for having previous tuberculosis (aHR, 1.51; 95% CI, 1.18–1.93). The increased hazard of COVID-19 death associated with current tuberculosis was present for both microbiologically confirmed and unconfirmed tuberculosis and for rifampicin-sensitive and -resistant disease during intensive phase treatment (Supplementary Table 3).

12After adjusting for age, sex, and other comorbidities, HIV was associated with increased COVID-19 mortality (aHR, 2.14; 95% CI, 1.70–2.70), and this association was similar irrespective of viremia or immunosuppression prior to the COVID-19 episode. However, few patients were viremic or immunosuppressed, as reflected in the wide CIs for the hazard ratios in different groups. Associations with most comorbidities increased when restricting to those with high-certainty comorbidity evidence (Supplementary Table 4). The associations of most comorbidities with COVID-19 death were attenuated when restricting to patients with ≥1 medical visit/year in the last 3 years, as these patients were more likely to have comorbidities warranting regular visits; however, HIV remained significantly associated with COVID-19 death (Supplementary Table 4). Among all public-sector adults, 9.8% of COVID-19 deaths were attributable to HIV (95% CI, 6.2–13.3), 2.6% (95% CI, 1.0–4.2) to current tuberculosis, and 4.7% (95% CI, 1.5–7.8) to previous tuberculosis.

13Among 15 203 COVID-19 cases diagnosed before 1 June 2020, the associations of all comorbidities with COVID-19 death were attenuated compared to the population analysis. However, HIV (aHR, 1.70; 95% CI, 1.32–2.18), current tuberculosis (aHR, 1.62; 95% CI, 1.04–2.51), and previous tuberculosis (aHR, 1.55; 95% CI, 1.19–2.02) remained associated with COVID-19 death (Table 4; Figure 1). Results were similar when including patients diagnosed after the change in testing criteria (Supplementary Table 5). Among COVID-19 cases in PLWH on ART, mortality was lower in patients on TDF (vs abacavir/zidovudine; aHR, 0.41; 95% CI,.21–.78), with no differences in mortality rates for other antiretrovirals.

14Among hospitalized COVID-19 cases, the associations of all mortality risk factors, including HIV, were attenuated, but HIV remained associated with death (aHR, 1.45; 95% CI, 1.14–1.84), as did previous tuberculosis (aHR, 1.40; 95% CI, 1.08–1.82), but not current tuberculosis. Among 601 hospitalized PLWH, 199 (33%) had their CD4 count measured during the COVID-19 episode, of whom 70 (35%) had CD4 count <200 cells/µl, which was associated with COVID-19 death (aHR vs people living without HIV, 2.36 [95% CI, 1.47–3.78]; aHR vs PLWH with CD4 count ≥350 cells/µl, 1.97 [95% CI, 1.14–3.40]). Among the 70 PLWH with a CD4 count < 200 cells/µl during admission, 4 (5%) had no prior evidence of HIV in the WCPHDC; 47% had a previous CD4 count <200 cells/µl, an unsuppressed viral load, or no recent ART; and 47% had a previous CD4 count ≥200 cells/µl or appeared stable on ART (viral load [VL] <1000 copies/ml or ART dispensed in last year; Supplementary Figure 1).

15To assess whether the association between HIV or tuberculosis and COVID-19 mortality could be due to residual unmeasured confounding—for example, by socioeconomic status or unrecorded comorbidities—we calculated the E-value for an unmeasured confounder. For HIV, the E-value for the analysis among all public-sector patients was 3.70 (and 2.79 for the lower bound of the CI), suggesting that only a strong association between HIV and a confounder (eg, socioeconomic status) and between the confounder and COVID-19 death would account for all of the observed association between HIV and COVID-19 death. The effect of HIV on COVID-19 death was similar when restricted to the poorest subdistrict, with the highest HIV prevalence, in Cape Town. Corresponding E-values for current and previous tuberculosis were 4.84 (3.02 for the lower bound of CI) and 2.39 (1.64 for the lower bound of CI), respectively. A quantitative bias analysis showed that the HIV-associated increased risk of COVID-19 death was unlikely due to confounding by raised BMI (Supplementary Appendix 4).

16Among all laboratory-diagnosed COVID-19 cases, there were 135 deaths among an estimated ~520 000 PLWH in the province (260 deaths/million) and 786 deaths among 6.36 million people without HIV (124 deaths/million). The SMR for COVID-19 mortality in PLWH, relative to people living without HIV, was 2.39 (95% CI, 1.96–2.86), and the attributable fraction of public- and private-sector COVID-19 deaths due to HIV was 8.5% (95% CI, 6.1–11.1).

17Among nearly 3.5 million adults (16% PLWH) in South Africa, we found an approximately 2-fold association of COVID-19 death with HIV, irrespective of viremia or immunosuppression prior to the COVID-19 episode, and a similar association between COVID-19 death and current tuberculosis. Among PLWH on ART, receiving TDF was associated with lower COVID-19 mortality, compared to receipt of other antiretrovirals. While the HIV- and tuberculosis-associated increased risks of COVID-19 death may be overestimated if there is residual confounding, due to socioeconomic status or unrecorded comorbidities, our results, supported by sensitivity analyses, demonstrate that PLWH and persons with tuberculosis are at increased risk of severe COVID-19. Nonetheless, despite a high burden of advanced HIV in the province, the attributable fraction of all deaths ascribed to HIV was <10%.

18While most case series of HIV and SARS-CoV-2 coinfection have not shown poor outcomes in PLWH, some cohorts of hospitalized PLWH with COVID-19 have reported substantial morbidity and mortality, including among patients with suppressed VLs on ART. Comparisons by HIV status of hospitalized COVID-19 cases in New York and London have not shown differences in mortality risks. However, the absence of an increased mortality risk in hospitalized patients with comorbidities may be explained by selection bias: risk factors for COVID-19 death may be attenuated by restricting data to the subset of hospitalized patients already at high mortality risk. It is therefore expected that the increased risk of death associated with all comorbidities in our analysis was progressively attenuated when restricting to cases (people with sufficiently severe symptoms to be tested) and hospitalized patients.

19Similar to our findings, several studies have reported a high prevalence of comorbidities among PLWH with severe COVID-19. The high prevalence of comorbidities in deceased PLWH suggests that the effect of HIV may at least partly be due to an increased risk of comorbidities at younger ages, including those not recorded in WCPHDC, such as cardiovascular disease. Persistent immune dysfunction may also be important in severe COVID-19 despite viral suppression; the hazard ratio point estimates for association with COVID-19 death were greater in immunosuppressed or viremic PLWH, although the numbers of these patients with COVID-19 were small, with wide CIs. Further, a CD4 count < 200 cells/µl during admission was associated with COVID-19 death. While this may partly be due to the well-described lymphopenia in severe COVID-19, which is prognostic of poor outcomes, about half of patients with low CD4 counts during admission were either new HIV diagnoses or had previous immunosuppression, viremia, or no recent ART. Among COVID-19 cases in PLWH on ART, the receipt of TDF (vs other therapies) was associated with reduced COVID-19 mortality. However, this association is likely to be overestimated; in South Africa, only patients on second-line ART or with poor renal function would not be on TDF, and both of these factors may themselves increase mortality. Nonetheless, the association remained when adjusting for kidney disease, viral suppression, and ART duration, and concurs with results from a recently published cohort of PLWH on ART from Spain. We found both current and previous tuberculosis to be associated with COVID-19 death, but since current tuberculosis itself causes death, in the absence of autopsy evidence it is difficult to disentangle the effects of COVID-19 versus tuberculosis disease on mortality.

20In our study, the overall high prevalence of diabetes in people with and without HIV, high proportion with poor glycemic control, and very elevated risks for COVID-19 death for diabetics, compared to data reported from other countries, are concerning. Diabetes is often diagnosed late and/or untreated or poorly controlled in resource-limited settings, and the resulting microvascular disease, even in people with good current diabetic control, may increase COVID-19 mortality.

21To our knowledge, this is the largest report on SARS-CoV-2 from Africa, the largest report on HIV and tuberculosis coinfected patients, and the first comparison of COVID-19 outcomes in patients with and without tuberculosis. Strengths include the study size using population-level data, laboratory-confirmed SARS-CoV-2 diagnoses in all COVID-19 cases, and the inclusion of hospitalized and nonhospitalized cases and deaths, as well as modeling the independent associations of HIV and tuberculosis with COVID-19 death. While the population analysis approach is robust to selection bias associated with cases and hospitalized patients only, it may overestimate associations between comorbidities and COVID-19 death if those with comorbidities live in areas with higher transmission or have closer follow-up and are more likely to be diagnosed with COVID-19. Nonetheless the coherence of associations found when analyzing the population cohort and SMR, diagnosed cases and hospitalized patients suggest that the population findings are unlikelyto be solely due to different probabilities of encountering SARS-CoV2 or being diagnosed once infected. Furthermore, an adjustment for subdistrict of residence should address geographic differences in transmission probability. Being an observational study, limitations include the underascertainment of comorbidities in routine administrative data; a lack of data on other potential risk factors, including socioeconomic status, smoking, and BMI; possible underascertainment of all COVID-19 cases and deaths; and potential misclassification of some incidental deaths in patients positive for SARS-CoV-2 as related to COVID-19, although almost all deaths occurred in hospitalized patients with clinical COVID-19. Further, we were unable to systematically exclude other opportunistic infections as contributors to COVID-19 mortality, as investigation for these causes varied by facility, clinical presentation, and time in hospital. Relatively large numbers of PLWH had no recent VL or CD4 count results, limiting our ability to distinguish outcomes for different strata of these measures. In particular, patients with no recent information on disease control (eg, HIV RNA or HBA1c) may have less contact with health services and not reside permanently in the province, with underascertainment of outcomes.

22While our findings of increased COVID-19 mortality risks in those living with HIV or tuberculosis may overestimate associations of these conditions with COVID-19 death due to residual confounding, PLWH and/or those with tuberculosis should nonetheless be considered high-risk groups for COVID-19 management, especially if they have other comorbidities.

23Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.