Human immunodeficiency virus and mortality from coronavirus disease 2019: A systematic review and meta-analysis

Background Persons living with human immunodeficiency virus (PLWH) constitute a vulnerable population in view of their impaired immune status. At this time, the full interaction between HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been incompletely described. Objective The purpose of this study was to explore the impact of HIV and SARS-CoV-2 co-infection on mortality. Method We systematically searched PubMed and the Europe PMC databases up to 19 January 2021, using specific keywords related to our aims. All published articles on coronavirus disease 2019 (COVID-19) and HIV were retrieved. The quality of the studies was evaluated using the Newcastle–Ottawa Scale for observational studies. Statistical analysis was performed with Review Manager version 5.4 and Comprehensive Meta-Analysis version 3 software. Results A total of 28 studies including 18 255 040 COVID-19 patients were assessed in this meta-analysis. Overall, HIV was associated with a higher mortality from COVID-19 on random-effects modelling {odds ratio [OR] = 1.19 [95% confidence interval (CI) = 1.01–1.39], p = 0.03; I2 = 72%}. Meta-regression confirmed that this association was not influenced by age (p = 0.208), CD4 cell count (p = 0.353) or the presence of antiretroviral therapy (ART) (p = 0.647). Further subgroup analysis indicated that the association was only statistically significant in studies from Africa (OR = 1.13, p = 0.004) and the United States (OR = 1.30, p = 0.006). Conclusion Whilst all persons ought to receive a SARS-CoV-2 vaccine, PLWH should be prioritised to minimise the risk of death because of COVID-19. The presence of HIV should be regarded as an important risk factor for future risk stratification of COVID-19.


Research methods and design Eligibility criteria
This is a systematic review and meta-analysis of published observational studies. Articles were selected if they fulfilled the following entry criteria: compliance with the PICO framework, namely P = confirmed positive COVID-19 patients, I = patients living with HIV, C = HIV-uninfected persons and O = mortality in COVID-19-confirmed patients not attributable to unrelated conditions such as trauma. The studies included were randomised clinical trials, cohort, case-cohort and crossover design, and the full-text paper had to be available and to have been published. Excluded studies included non-original research such as review articles, letters or commentaries; case reports; studies in a language other than English; studies of children and youths <18 years of age and pregnant women.

Search strategy and study selection
A systematic search of PubMed and Europe PMC provided many papers. Additional articles were located by analysing the papers cited by the authors of the identified studies. The search terms included 'HIV' or 'human immunodeficiency virus' or 'immunocompromised' or 'immune-deficient' or 'AIDS' or 'acquired immunodeficiency syndrome' and 'SARS-CoV-2' or 'coronavirus disease 2019' or 'COVID-19' or 'novel coronavirus' or 'nCoV'. The selected time-range included 01 December 2019 to 19 January 2021. Only English-language articles were evaluated. Details of the search strategy are listed in Table 1. Studies of HIV and SARS-CoV-2 co-infection with a valid definition of 'mortality' were included. The search strategy is presented in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) diagram.
The initial investigation located 10 733 studies. After the removal of duplicates, 8653 records remained. A further 8585 studies were excluded after screening of the titles and abstracts failed to match with the inclusion and exclusion criteria. Of the 68 full-text articles evaluated for eligibility, 22 that lacked control or comparator groups were excluded, and 15 more were excluded because they lacked outcomes pertinent to our study. Three articles that were not in the English language were rejected. The final meta-analysis  included 28 observational studies 21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,3  7,38,39,40,41,42,43,44 that reported on 18 255 040 COVID-19-infected persons, of whom 48 703 were co-infected with both HIV and SARS-CoV-2 (see Figure 1). Of the included articles, 25 were retrospective and 3 were prospective (see Table 2).

Data extraction and quality assessment
The study's outcome of interest was mortality from COVID-19. This was defined as the number of patients with COVID-19 whose death could not be attributed to a cause other than COVID-19. Two authors performed the data extraction. Relevant demographic, laboratory and clinical information was recorded on a dataform: age, gender, ethnicity, the number of PLWH, the number of patients with a CD4 cell count of <200 cells/µL, the use of antiretroviral therapy (ART) and the mortality outcomes of both HIV-infected and HIVuninfected participants. Two authors independently assessed the quality of each study using the Newcastle-Ottawa Scale. 45 The selection, comparability and outcome of each study were assigned a score from zero to nine. Studies with scores of ≥7 were considered to be of good quality (see Table 3). All included studies were rated 'good'. In summary, all studies were deemed fit to be included in the meta-analysis.

Statistical analysis
Review Manager version 5.4 (Cochrane Collaboration) and the Comprehensive Meta-Analysis version 3 software were used in the meta-analysis, and Mantel-Haenszel's formula gave odds ratios (ORs) and 95% confidence intervals (CIs). The heterogeneity was assessed using the I 2 statistic with values of <25%, 26% -50% and >50% providing low, moderate and high degrees of heterogeneity, respectively. Significance was obtained if the two-tailed P-value was ≤0.05. Europe PMC "HIV" OR "human immunodeficiency virus" OR "immunocompromised" OR "immunodeficient" OR "AIDS" OR "acquired immunodeficiency syndrome" AND "SARS-CoV-2" OR "coronavirus disease 2019" OR "COVID-19"  The qualitative risk of publication bias was assessed using Begg's funnel plot analysis.

Subgroup analysis
The subgroup analysis revealed that the association between HIV and mortality from COVID-19 was only statistically significant for studies from African regions

Publication bias
The funnel plot analysis revealed a qualitatively symmetrically inverted funnel plot for the association between HIV and a mortality outcome, suggesting no publication bias. This is demonstrated in Figure 4.

Discussion
This systematic review and meta-analysis of 28 studies not only analyse the association between HIV and mortality from COVID-19 but evaluate the role of confounding factors such as age, gender, ethnicity, CD4 cell count and ART in this cohort.
An association was found between HIV and mortality from COVID-19. However, this did not appear to be influenced by the confounding factors above. Instead, the subgroup analysis found that mortality from COVID-19 in PLWH was more likely to be reported in studies from Africa and the USA, rather than Asia or Europe. Factors unique to Africa, such as the large background prevalence of HIV, delayed access to healthcare (poor health 'awareness', an inadequate healthcare infrastructure and logistical challenges to accessing care) and ready access to alternate, non-Western, traditional health practitioners and medicines, are likely to have influenced outcomes. 46,47 Similarly, the COVID-19 epidemic in the USA disproportionately affected the poor, people of colour and the socially marginalised such as drug users and the institutionalised.
In both regions, PLWH may have been 'over-represented' in published studies.
Our pooled data confirmed an association of higher mortality from COVID-19 in PLWH.
Firstly, HIV infection may cause severe depletion of the gutassociated lymphoid tissue, with a predominant loss of memory CD4+ T cells. 48    adaptive immune response, may predispose patients to Mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent tuberculosis reactivation by 20-fold. 49

Limitations
Firstly, only a limited number of our included studies reported on CD4 cell counts, viral loads and ART -a fact that is likely to have impacted the precision of the meta-regression analysis of this study. Indeed, most studies focussed on the characteristics of COVID-19 patients rather than its effects on PLWH. Secondly, the studies utilised in this review and metaanalysis were primarily observational and thus, may reflect occult confounders or biases unique to the particular study. Finally, we included some preprint studies to minimise the risk of publication bias; however, we made exhaustive efforts to ensure that only sound studies were included that we expect will eventually be published. We hope that this study can give further insight into the management of COVID-19 patients.

Conclusion
Our meta-analysis of observational studies indicates that HIV had an association with a mortality outcome from COVID-19; however, larger observational studies or even randomised clinical trials are needed to confirm our results and elucidate additional associations. Patients living with HIV must take extra precautions and always adhere to health-promoting protocols. They must be prioritised to receive COVID-19 preventive therapy: the SARS-CoV-2 vaccine. Where feasible, practical use must be made of telemedicine and virtual-based practice to provide continuous care to PLWH throughout this pandemic. Every effort must be made to identify co-infected PLWH and to link them with clinicians and treatment centres skilled in COVID-19 care. Gaps in ART-related care, such as medicine stockouts, must be identified by local healthcare providers and authorities. Finally, HIV co-infection must be included in future risk stratification models for COVID-19 management.