The clinical outcomes of COVID‐19 in HIV‐positive patients: A systematic review of current evidence

Abstract Introduction Patients with chronic underlying diseases are more susceptible to coronavirus disease 2019 (COVID‐19) complications. Recent studies showed people living with HIV (PLWH) are not at greater risk than the general population. Few studies have reviewed the impacts of COVID‐19 on PLWH. The purpose of this systematic review was to investigate the impact of COVID‐19 on patients infected with HIV. Methods We executed a systematic search using four databases of PubMed, Scopus, Science Direct, and Web of Science and screened the records in two steps based on their title/abstract and full text. This study follows the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) checklist to elevate the validity and reliability of its results. Results We reviewed 36 studies. The patients' age was above 20 years in all studies. In almost all studies, the inflammatory parameters were reported high. In most of the studies, all HIV patients completely recovered from the COVID 19 infection. Although CD4 count was not recorded in all studies, the minimum level was reported as 12 cells/µl. Conclusion Based on the current review, we concluded that HIV patients at advanced stages (3 or 4) of the disease, whose CD4 counts are low, may show less severe COVID‐19 infection symptoms. Similarly, Interference can reduce the severity of immune reactions and subsequent cytokine storms and consequently mitigate the symptoms. Therefore, in most of the studies, the majority of HIV patients showed no severe symptoms and completely recovered from COVID 19 infection.

(1) Review articles, letter to the editors, or other studies without original data. (2) Ongoing studies.
(3) Irrelevant to the aims, settings, and design of this study. (4) Abstracts, conference abstracts, errata, or other studies lacking full-texts.

| Quality assessment
We utilized the National Institutes of Health (NIH) tool 22 to evaluate the quality of the studies. A researcher (A. K.) examined all the studies to ensure the quality of evidence. If an element of the criteria was insufficiently addressed, not applicable, or not reported in a study and it could not be identified indirectly, we did not allocate a score to that element. For cohort and cross-sectional studies, 11-14 was considered good, 6-10 fair, and 0-5 poor. We chose 9-12, 5-8, and 0-4 for good, fair, and poor quality in the case-control studies, respectively. The numbers were 7-9, 4-6, and 0-3 for the case series. Case reports were checked with the same checklist as the case series.

| RESULTS
Most of the studies were considered of good quality (25/37). Other studies (12/37) had a fair quality, and we did not classify any studies as poor (Table 1). Thirty-six studies met the inclusion criteria. The results of these 36 studies are summarized in Tables 2 and 3.
T A B L E 1 Quality assessment of the included studies using NIH tool

12/14 Good
Zhang et al. 59 Case report 7/9 Good Forty percent of the studies were from the USA, 20% from China, 11. 4% from Italy, 11. 4% from Spain and the remainder were from Germany, France, UK, South Korea, Poland, and South Africa. All the articles were published between January and December 2020. The study population in the explored articles ranged from one patient (in case reports) to 3,460,932 patients in a large cohort study from South Africa ( Table 2). Among the total studied population of 3,993,400 COVID-19 patients, 89,343 patients had COVID19-HIV coinfection, among which 72% (ranged from 42.3% to 100%) were male, 0.01% (11 patients) were transgender. Patients' gender was not available in two studies. Patients' age was above 20 years in all studies. As the review revealed, nine studies did not mention the ART regimen for HIV + patients. At the time of the COVID-19 diagnosis, the most common symptoms were fever, cough, myalgia, and headache. Additionally, most of the patients had various comorbidities such as hypertension, diabetes mellitus, asthma, renal insufficiency, cardiovascular disease, etc.
Laboratory values including CRP, ferritin, and Interleukins levels were available in about two-third of the studies. But in almost all the studies with inflammatory tests results, the values were elevated. In most of the studies, all HIV patients completely recovered from the COVID-19 infection. In 8 studies, mortality was reported ranging from 1% to 36%. Although CD4 count was not recorded in all the studies, the minimum level was reported as 12 cells/µl.

| DISCUSSION
We found that HIV patients at advanced stages (3 or 4) of the disease with low CD4 count and weak immune systems show less severe COVID-19 symptoms. However, some studies showed controversial results which contradict our primary hypothesis. The main reason for these contradictory results was the scarcity of existent literature and inconsistency of evidence that limited our ability to address and reasonably argue our main hypothesis. This may also be due to simultaneous symptoms and underlying comorbidities that come along at advanced stages of HIV infections and could perplex and obscure the typical presentation of COVID-19 in such patients. Despite these contradictory results, the majority of studies included in this review indicate mild or no typical symptoms of COVID-19 in HIV patients, particularly in those at the advanced stages of HIV disease. This review also found an unexpected high recovery rate in these patients after COVID-19 infection, which contradicts the common knowledge of higher morbidity and mortality rate in immunocompromised patients.
SARS-CoV-2 is a new strain of coronavirus, which is the causal agent of COVID-19. The usual symptoms of COVID-19 are fever, cough, headache, shortness of breath, tiredness, loss of taste or smell, and gastrointestinal symptoms such as diarrhea, anorexia, nausea, and abdominal pain, 1 of which, many are due to the cytokine storm caused by the host's immune system. To control these symptoms, corticosteroids have been used now and then by clinicians around the world which indicates the substantial role of immune system function interfered with SARS-CoV-2. Application of Canakinumab, a humanized monoclonal antibody against IL-1β in a sub-group of hospitalized patients with COVID-19 and subsequent swift reduction in the systemic inflammatory response and oxygenation improvement by Claudio Ucciferri et al. also manifests the fundamental role of the immune system and inflammatory cytokines in the SARS-CoV-2 pathophysiology. 65,66 The human immunodeficiency virus targets the body's natural immune system and causes immune deficiency. This immune deficiency can lower the severity of the immune system reactions such as cytokine storms and subsequently the accompanying symptoms. This could explain the milder symptoms, lower morbidity, and less mortality among HIV-positive patients infected by COVID-19 as the primary fatal condition in COVID patients is caused by the cytokine storm which subsequently leads to multiorgan dysfunction and death. The hypothesis was supported by some of the included studies in the present review, while, some contradictory results were also observed.
In the present review, a CD4 count less than 500 was assumed as a cutoff point. Thus, the patients with a mean CD4 count less than 500 were considered immunedeficient and assumed to be at advanced stage patients. In the study conducted by Calza et al. all the nine HIVpositive patients with CD4 count less than 258 fully recovered, which supports the hypothesis of our study. 26 Additionally, in Kumar et al.'s and Patel RH.'s study, the patients had a CD4 count less than 500 and again completely recovered. 41,47 Similar findings were reported by Mondi A et al. 44 In contrast, in Karmen-Tuohy et al.' study contradictory results were reported. Although the median CD4 count of patients was lower than 500 and the patients were immunodeficient, the mortality rate was higher (28%). 38 Likewise, in the study by Blanco et al., all the patients with CD4 count > 500 were cured, but one of the two patients with CD4 count < 500 remained in the hospital due to the severity of illness that may have been due to comorbidities as is reported by authors. 23 However, the findings of the Ruan L et al' study were completely against our hypothesis. In this study, all the patients with CD4 count > 500 experienced moderate-severity clinical outcomes; while, all the patients with CD4 count < 500 had severe clinical outcomes. 49

| Limitation
Despite the limited available evidence, the findings of the present review authenticate the primary hypothesis arguing less severe clinical outcomes in HIV patients at the advanced stages. Although this could be mainly due to the inability of the immune system in HIV patients to provoke the cytokine storm, which is believed to be the main responsible event for severe clinical outcomes in COVID patients, the contradictory results inform future studies to explore further the possible underlying causes of such an observation.

| CONCLUSION
In conclusion, the results of the present study suggest that HIV patients at advanced stages (3 or 4) of the disease, when CD4 counts are low and their immune system is compromised, manifest less severe symptoms and less mortality following COVID-19. This has been attributed to the inability of HIV-positive individuals' immune systems in provoking the cytokine storm that caused the severe clinical outcome in COVID patients. By a similar mechanism, it seems that corticosteroids mitigate the severity of symptoms in COVID patients with a healthy immune system.