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.
The purpose of this study was to explore the impact of HIV and SARS-CoV-2 co-infection on mortality.
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.
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],
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.
At the end of December 2019, the first cases of a newly discovered acute respiratory illness named coronavirus disease 2019 (COVID-19) were reported in Wuhan, China.
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 cross-over 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.
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
Literature search strategy.
Database | Keywords | No. of results |
---|---|---|
PubMed | (“hiv”[MeSH Terms] OR “hiv”[All Fields]) OR (“acquired immunodeficiency syndrome”[MeSH Terms] OR (“acquired”[All Fields] AND “immunodeficiency”[All Fields] AND “syndrome”[All Fields]) OR “acquired immunodeficiency syndrome”[All Fields] OR “aids”[All Fields]) AND (“COVID-19”[All Fields] OR “COVID-19”[MeSH Terms] OR “COVID-19 Vaccines”[All Fields] OR “COVID-19 Vaccines”[MeSH Terms] OR “COVID-19 serotherapy”[All Fields] OR “COVID-19 Nucleic Acid Testing”[All Fields] OR “covid-19 nucleic acid testing”[MeSH Terms] OR “COVID-19 Serological Testing”[All Fields] OR “covid-19 serological testing”[MeSH Terms] OR “COVID-19 Testing”[All Fields] OR “covid-19 testing”[MeSH Terms] OR “SARS-CoV-2”[All Fields] OR “sars-cov-2”[MeSH Terms] OR “Severe Acute Respiratory Syndrome Coronavirus 2”[All Fields] OR “NCOV”[All Fields] OR “2019 NCOV”[All Fields] OR ((“coronavirus”[MeSH Terms] OR “coronavirus”[All Fields] OR “COV”[All Fields]) AND 2019/11/01[PubDate] : 3000/12/31[PubDate])) | 1626 |
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” | 9107 |
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
PRISMA diagram of the detailed process of selection of studies for inclusion in the systematic review and meta-analysis.
Characteristics of the included studies.
Study | Sample size | Design | Median age, yr (IQR) | Male |
Black ethnicity |
No. of HIV/AIDS patients: |
|||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
( |
( |
Total |
CD4 cell counts <200 cells/μL |
Receiving ART |
|||||||||
( |
( |
(%) | |||||||||||
Berenguer J et al. |
4035 | Retrospective cohort | 70 (56–80) | 2433 | 61 | 12/3915 | 0.3 | 26/3962 | 0.7 | N/A | - | 21/25 | 84 |
Bhaskaran K et al. |
17 282 905 | Retrospective cohort | 48 (40–55) | 8 632 666 | 49.9 | 340 114/17 282 905 | 1.9 | 27 480/17 282 905 | 0.1 | N/A | - | N/A | - |
Boulle A et al. |
22 308 | Retrospective cohort | 52 (37–63) | 7052 | 31.6 | N/A | - | 3978/22 308 | 17.8 | 70/199 | 35 | 56/70 | 80 |
Braunstein SL et al. |
204 422 | Retrospective cohort | 52 (47–65) | 105 024 | 51.3 | 32 491/204 422 | 15.8 | 2410/204 422 | 1.1 | 379/1419 | 26.7 | 1288/1447 | 89 |
Cabello A et al. |
7061 | Retrospective cohort | 46 (37–56) | 6277 | 88.9 | N/A | - | 63/7061 | 0.9 | 17/63 | 26.7 | 61/63 | 96.8 |
Chilimuri S et al. |
375 | Retrospective cohort | 63 (52–72) | 236 | 63 | 93/375 | 25 | 22/375 | 6 | N/A | - | N/A | - |
Docherty AB et al. |
20 133 | Prospective cohort | 72.9 (58–82) | 12 068 | 59.9 | N/A | - | 83/20 133 | 0.5 | N/A | - | N/A | - |
El-Solh AA et al. |
7816 | Retrospective cohort | 69 (60–74) | 7387 | 94.5 | 3264/7816 | 41.7 | 144/7816 | 1.8 | N/A | - | N/A | - |
Garibaldi BT et al. |
832 | Retrospective cohort | 63 (49–75) | 443 | 53.2 | 336/832 | 41 | 9/832 | 1 | N/A | - | N/A | - |
Geretti AM et al. |
47 592 | Prospective cohort | 74 (60–84) | 27 248 | 57.2 | 1523/42 320 | 3.5 | 122/47 592 | 0.2 | N/A | - | 112/122 | 91.8 |
Gudipati S et al. |
65 271 | Prospective cohort | 52 (45–67) | 30 677 | 47 | 20 886/65 271 | 32 | 278/65 271 | 0.4 | 2/14 | 14.2 | 13/14 | 92.8 |
Hadi YB et al. |
50 167 | Retrospective cohort | 48 (29–67) | 22 636 | 45.1 | 12 729/50 167 | 25.3 | 404/50 167 | 0.8 | N/A | - | 284/404 | 70.2 |
Harrison SL et al. |
31 461 | Retrospective cohort | 50 (35–63) | 14 306 | 45.5 | 8758/31 461 | 27.8 | 226/31 461 | 0.7 | N/A | - | N/A | - |
Hsu HE et al. |
2729 | Retrospective cohort | 54 (40–68) | 1312 | 48.1 | 1218/2729 | 44.6 | 732/2729 | 2.7 | N/A | - | N/A | - |
Huang J et al. |
50 333 | Retrospective cohort | 37 (29–52) | 5427 | 90.4 | N/A | - | 6001/50 333 | 11.9 | 613/5897 | 10.3 | 5527/6001 | 92.1 |
Jassat W et al. |
41 877 | Retrospective cohort | 52 (40–63) | 19 122 | 45.6 | 13 444/19 777 | 68 | 3077/35 550 | 8.7 | 401/1390 | 28.8 | 1271/1278 | 99.5 |
Kabarriti R et al. |
5902 | Retrospective cohort | 58 (44–71) | 2768 | 46.9 | 1935/5902 | 32.7 | 92 | 1.6 | N/A | - | N/A | - |
Karmen-Tuohy S et al. |
63 | Retrospective cohort | 60 (41–81) | 57 | 90.4 | 9 | 14.2 | 21/63 | 33.3 | 6/19 | 31.5 | 21/21 | 100 |
Kim D et al. |
867 | Retrospective cohort | 57 (46–71) | 473 | 54.7 | 267/867 | 30.8 | 24/867 | 2.8 | N/A | - | N/A | - |
Lee SG et al. |
7339 | Retrospective cohort | 47 (28–66) | 2970 | 40.1 | N/A | - | 4/7339 | 0.1 | N/A | - | N/A | - |
Maciel EL et al. |
440 | Retrospective cohort | 53 (42–68) | 240 | 57.1 | 158/279 | 56.6 | 4/440 | 1 | N/A | - | N/A | - |
Marcello RK et al. |
13 442 | Retrospective cohort | 52 (39–64) | 7481 | 56 | 3518/13 442 | 26.1 | 159/13 442 | 2 | N/A | - | N/A | - |
Miyashita H et al. |
8912 | Retrospective cohort | 55 (42–69) | 4922 | 55.2 | N/A | - | 161/8912 | 1.8 | N/A | - | N/A | - |
Ombajo LA et al. |
787 | Retrospective cohort | 43 (33–54) | 505 | 64 | N/A | - | 53/787 | 7 | N/A | - | N/A | - |
Parker A et al. |
113 | Retrospective cohort | 48 (34–62) | 45 | 38.9 | N/A | - | 24/113 | 21.2 | N/A | - | 17/24 | 70.8 |
Sigel K et al. |
493 | Retrospective cohort | 61 (54–67) | 374 | 75.8 | 205/493 | 41.5 | 88/493 | 17.8 | 24/57 | 42.1 | 88/88 | 100 |
Stoeckle K et al. |
120 | Retrospective cohort | 60 (56–70) | 96 | 80 | 36/100 | 36 | 30/120 | 25 | 7/27 | 25.9 | 29/30 | 96.6 |
Tesoriero JM et al. |
377 245 | Retrospective cohort | 53 (45–67) | 51 | 70.5 vs 50.5 | 192 646 | 51 | 2988/377 245 | 0.8 | 270/2887 | 9.3 | 2834/2988 | 94.8 |
USA, United States of America; ART, antiretroviral therapy; HIV/AIDS, human immunodeficiency virus / acquired immunodeficiency syndrome; IQR, interquartile range; N/A, not applicable.
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 HIV-uninfected participants. Two authors independently assessed the quality of each study using the Newcastle–Ottawa Scale.
Newcastle–Ottawa quality assessment of observational studies.
First author | year | Study design | Selection | Comparability | Outcome | Total score | Result |
---|---|---|---|---|---|---|---|
Berenguer J et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Bhaskaran K et al. |
2020 | Cohort | **** | ** | *** | 9 | Good |
Boulle A et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Braunstein SL et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Cabello A et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Chilimuri S et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Docherty AB et al. |
2020 | Cohort | **** | ** | *** | 9 | Good |
El-Solh AA et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Garibaldi BT et al. |
2020 | Cohort | **** | ** | *** | 9 | Good |
Geretti AM et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Gudipati S et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Hadi YB et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Harrison SL et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Hsu HE et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Huang J et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Jassat W et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Kabarriti R et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Karmen-Tuohy S et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Kim D et al. |
2020 | Cohort | *** | ** | **** | 9 | Good |
Lee SG et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Maciel EL et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Marcello RK et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Miyashita H et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Ombajo LA et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Parker A et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Sigel K et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Stoeckle K et al. |
2020 | Cohort | *** | ** | *** | 8 | Good |
Tesoriero JM et al. |
2020 | Cohort | ** | ** | *** | 7 | Good |
Note: Asterisk denotes scores.
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
Our pooled analysis indicated that HIV was associated with mortality from COVID-19 [OR = 1.19 (95% CI 1.01–1.39),
Forest plot that demonstrates the association of HIV with mortality from COVID-19 outcome.
However, meta-regression showed that the association between HIV and mortality from COVID-19 was unaffected by age (
Bubble-plot for meta-regression. Meta-regression analysis showed that the association between HIV and mortality from COVID-19 was not affected by gender (a), CD4 cell count (b) or ART (c).
The subgroup analysis revealed that the association between HIV and mortality from COVID-19 was only statistically significant for studies from African regions [OR = 1.13 (95% CI = 1.04–1.23),
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
Funnel plot for the association of HIV with mortality from COVID-19 outcomes.
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.
Our pooled data confirmed an association of higher mortality from COVID-19 in PLWH.
Firstly, HIV infection may cause severe depletion of the gut-associated lymphoid tissue, with a predominant loss of memory CD4+ T cells.
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 meta-analysis 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.
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.
The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.
T.I.H., J.R., K.C. and A.K. formulated the research questions; T.I.H. and J.R. developed the study protocol, analysed the data and wrote the manuscript. T.I.H., J.R., K.C. and A.K. did the systematic review. A.K. supported and supervised the work. All authors reviewed the manuscript and approved the final version.
This article followed all ethical standards for research without direct contact with human or animal subjects.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
The data analysed in this study were a reanalysis of existing data, which are openly available at the locations cited in the reference section.
The views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.