COVID‐19 in HIV‐positive patients: A systematic review of case reports and case series

Abstract Introduction Coronavirus disease 2019 (COVID‐19) and acquired immune deficiency syndrome (AIDS) are two viral diseases for which there are currently no definitive treatments. Nowadays, because of the health system's focus on the COVID‐19 epidemic, the control of human immunodeficiency virus (HIV) has received less attention. In this review, we will discuss the characteristics of COVID‐19 in HIV‐positive patients. Material and Methods Using the PRISMA guideline, the databases of Scopus, PubMed, and Web of Science were searched systematically from January 1, 2019 to February 24, 2021. The following keywords were used: “Human Immunodeficiency Virus,” “acquired immune deficiency syndrome,” “HIV,” “AIDS,” “COVID‐19,” “severe acute respiratory syndrome coronavirus 2,” “novel coronavirus,” “SARS‐CoV‐2,” “nCoV disease,” “SARS2,” and “2019‐nCoV disease.” Results Twenty‐one percent of studies were conducted in the USA (n = 13), 16% in China (n = 10), and 13% in Italy (n = 8), respectively. The majority of the patients were men (74.3%). Tenofovir disoproxil fumarate was used in 47.4% of patients, emtricitabine in 58.4%, and lamivudine in 34.8% to treat HIV. Symptoms of HIV patients with COVID‐19 included coughing (81.3%), fever (62.8%), and dyspnea (60%). Hydroxychloroquine (39.34%) and azithromycin (36.58%) were the common treatment options for COVID‐19. The total death rate in HIV‐positive patients with COVID‐19 was about 9%. Conclusion In the current systematic review, we demonstrated that HIV‐positive patients co‐infected with COVID‐19 have high comorbidity of hypertension and diabetes mellitus. HIV/COVID‐19 co‐infection might have negatively influenced the HIV treatment and diagnosis, which indicates the need to regularly screen HIV patients in the COVID‐19 pandemic.


| INTRODUC TI ON
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus, was emerged in December 2019 and COVID-19, as its associated infection was declared as an epidemic in Wuhan, China, which turned into a pandemic in March 2020. 1 Until August 12, 2021, more than 204 million confirmed positive cases and 4.3 million deaths have been reported worldwide. 2 In case of new and emerging diseases, comorbidities are of special interest. It is estimated that 22% of the world's population has at least one disease that increases the risk of severe coronavirus disease 2019 . 3 According to the Centers for Disease Control and Prevention (CDC) report, people living with human immunodeficiency virus syndrome (PLWH) may be at increased risks for COVID-19-related complications and death. 2 Concerns about the increased risks of severe COVID-19 may be related to the immunosuppressive nature of HIV syndrome which makes people more susceptible to infections. 4 There is increasing evidence that PLWH with a low CD4 + T-cell count and those who do not receive antiretroviral therapy (ART) are at a higher risk of severe COVID-19 symptoms, 5,6 even though patients with low CD4 + T-cell count may be more protected against cytokine storming. 7 One study has highlighted the possible protective effects of lymphopenia among PLWH against COVID-19. 8 Another study has shown that patients with low CD4 + T-cell counts have a longer course of COVID-19 and a lower antibody levels. 9 Other risk factors such as age, sex, lung, and kidney diseases might affect the severity of COVID-19 among PLWH. 10 Another factor that may affect the severity of COVID-19 is the use of ART in PLWHs. ART was proposed in 2003 as a protective factor against SARS. 11 It can be assumed that long-term ART may increase the risk of COVID-19 severity,however, due to the small number of the studied cases, variable reports and insufficient data on PLWH co-infected with COVID-19, no certain conclusions have been obtained so far. 12 Therefore, this systematic review was conducted to gather up the current information regarding various risk factors such as age and immune status among PLWH co-infected with COVID-19, as well as different antiretroviral therapies and their impacts on the disease outcome among these patients.

| ME THODS
The current study was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. 13

| Information source and search strategies
The databases Scopus, MEDLINE (via PubMed), and Web of Science were systematically searched from January 1, 2019 to February 24, 2021 to retrieve case series and case reports published in English.

| Study selection
The case series and case reports reporting COVID-19 among HIVpositive patients were included. Other types of articles, including review articles, editorials, letters to editor, and guidelines, were excluded from the analysis. Moreover, duplicate publications, articles reported in languages other than English, and papers with insufficient data or available only in the abstract form were also excluded.
Two different steps were taken by the authors to check the eligibility of all the potentially related articles. First, two independent authors screened the titles and abstracts and eliminated duplicate papers. Next, full text of the papers that met the inclusion criteria was reviewed.

| Data extraction
The extracted data included the first author's name, country of the study, publication time, number of HIV/COVID-19 co-infected patients, HIV diagnosis methods, treatments used for the HIV infection, CD4 lymphocyte count, median duration of the HIV infection, SARS-CoV-2 diagnosis methods, clinical manifestations, comorbidities, therapeutic options for COVID-19, and outcomes. Two authors independently applied the inclusion criteria to the potentially relevant articles, and disagreements between the two authors were resolved by a third author.

| Quality assessment
The case reports/case series appraisal checklist supplied by the Joanna Briggs Institute (JBI) was used to evaluate the quality of the studies. 14

| RE SULTS
As shown in Figure 1, the initial search in the databases resulted in 4502 articles. After removing duplicates, 3599 papers remained, of which 3444 were excluded based on irrelevant titles and abstracts, followed by 155 articles retrieved for detailed full-text evaluation.
Following the full-text evaluation, 65 articles (29 case reports and 36 case series) fulfilled the inclusion criteria and were considered for further analysis. Tables 1 and 2 show the participants' characteristics, clinical manifestation, comorbidities, and treatment regimens obtained from the articles included in this review. Also, the demographics, clinical presentations, and the outcomes of COVID-19 treatment among HIV-infected individuals are summarized in Table 3. Twenty-one percent of the studies were conducted in the USA (13 studies), 16% in China (10 studies), and 13% in Italy (8 studies (17,18).
CD4 count in case reports ranged from 10 to 1,163 cells/mm 3 . About half of the cases had a CD4 count higher than 350 cells/mm 3   (an analog of chloroquine) has been associated with a decrease in the viral load among COVID-19 patients and has shown a comparable effect with azithromycin. 39 There are evidences that suggest ART therapy alleviates COVID-19 severity through immune reconstitution, but these results are not yet proven. 10 There are several limitations to this study, including (1)  Therefore, these studies cannot generate information regarding rates, ratios, incidences, or prevalence of the disease conditions.

| CON CLUS ION
There are many reports of co-infections associated with COVID-19.
In this review, it has been reported that most HIV/COVID-19-coinfected patients, reported so far, have a high comorbidity of hypertension and diabetes mellitus and have ages above 47.9 years.
HIV can increase the severity, morbidity, and mortality rates of COVID-19 infection, but this theory has not been proven yet. On the contrary, HIV/COVID-19 co-infection can probably disrupt HIV treatment and diagnosis. Further studies are needed to assess the impacts of HIV infection in COVID-19 patients.

CO N FLI C T O F I NTE R E S T
The authors declare that there is no conflict of interest.

DATA AVA I L A B I L I T Y S TAT E M E N T
All relevant data are included in the manuscript.