This study presents the clinical characteristics and outcomes of COVID-19 in PLHIV and matched controls, admitted in participating hospitals from 14 Brazilian cities in 2020 and 2021. Clinical characteristics were similar between groups, except for comorbidities such as obesity, chronic obstructive pulmonary disease and cancer and laboratory results of total leukocytes and neutrophils, which showed important differences in the first period under analysis. Although patients with HIV admitted in 2020 had higher mortality than matched controls without the disease, this finding has not been observed among those admitted in 2021. This indicates that measures such as large-scale immunization programs have successfully contributed to reducing the excess mortality seen in PLHIV in the early stages of the pandemic.
Despite the conflicting evidence regarding the influence of HIV infection on the clinical course and outcome of COVID-19, most studies – including systematic reviews and meta-analyses – agree that PLHIV have a higher risk of death from COVID-19 [7, 13, 14, 33–36]. However, a thorough analysis of the literature demonstrates that most of the available studies comprise samples from the year 2020, when there were a large number of publications due to the urgency of updates on Covid-19. These studies do not include the vaccination period, as the World Health Organization issued the first document supporting the approval of a COVID-19 vaccine on 31 December 2020. Additionally, the most recent studies evaluating COVID-19 outcomes in PLHIV include data collected no later than July 2021, and therefore do not cover a more advanced stage of COVID-19 vaccination [8, 33, 34, 36–38].
Although the vaccination program in Brazil began in January 2021, the immunization rates advanced slowly in the first half of that year due to the limited disponibility of vaccines. By the end of 2021, with a significant advance in immunization, the country had reached the coverage of 67.9% of the population fully vaccinated and 78.2% with at least one vaccine dose [39]. Regarding the definition of target groups for immunization by the Ministry of Health, the PLHIV were considered a priority if they had a CD4 + count < 350 mm³, otherwise, the vaccination followed the age criteria, with older people being vaccinated first [40]. In our cohort, which includes patients admitted through December 2021, we assume that the mass vaccination program, especially when considering the prioritization of PLHIV with immunodeficiency, may have contributed to the differences in mortality seen between both study periods (before and after the vaccination program started in Brazil).
Regarding specific information related to HIV infection, we obtained data from 99 (76.1%) patients in study. Most patients with available data were on antiretroviral therapy (100.0%) and had suppressed viral loads (2020: 78.1% and 2021: 71.4%). Similarly, in a meta-analysis that analyzed the outcomes of COVID-19 in HIV-infected individuals from seven countries, 96.0% were on antiretroviral therapy, and about 80.0% were suppressed [7]. Brazil is a country that stands out in Latin America for a strong HIV response, with an established national public program designated for the identification, monitoring, surveillance, and access to free antiretrovirals since the 1990s [41]. Currently, 650,000 PLHIV are on antiretroviral therapy and 66.0% have suppressed viral load in the country, being observed constant efforts to reach the global goal of viral suppression to 90.0% [42].
Our results also showed that only 54.7% of PLHIV admitted in 2020, with available data, had CD4 + T lymphocyte counts above 500 cells/µL, a condition that may have contributed to the finding of greater severity of COVID-19 among PLHIV compared to controls. Notably, the immune dysregulation resulting from HIV infection is a contributing factor to the severity of COVID-19 [8]. According to Davanzo et al. (2020)[9], the binding of SARS-CoV-2 to the defense cells of patients with HIV coinfection is capable of inducing a pronounced cell death process. Liu et al. (2021)[43] and Hoffman et al. (2021)[6] also describe an exacerbated expression of cytokines and chemokines in patients with SARS-CoV-2 and HIV coinfection, which may trigger a hyperinflammatory response and potentiate the negative outcomes of COVID-19. Furthermore, it is known that immunocompromise may be established before the initiation of antiretroviral therapy and, therefore, even with adherence to treatment, HIV-infected patients may find themselves in a state of persistent immune dysregulation and, consequently, present a higher risk of severity during the course of COVID-19 [5].
In 2021, 70.0% of PLHIV, with available data, had a CD4+ T lymphocyte count greater than or equal to 500 cells/µL, a period in which there was no significant difference in mortality between the groups under analysis. The clinical trial developed by [44], provides clear evidence of the efficacy and immunogenicity of vaccination against COVID-19 for PLHIV with CD4+ T lymphocyte counts greater than 350 cells/µL. Thus, the considerable percentage of patients with high CD4+ T lymphocyte counts in 2021, as well as access to vaccination programs in this period, may be related to the absence of a significant difference in mortality for patients admitted to the study in 2021.
Information regarding the clinical history obtained for patients admitted for COVID-19 in 2020 indicates that PLHIV had a higher frequency of comorbidities, such as chronic obstructive pulmonary disease (9.3% vs 3.8%; p = 0.049) and cancer (15.1% vs 7.1%; p = 0.032), in relation to patients not infected with HIV. According to Maciel et al. (2018)[45], PLHIV are susceptible to premature aging as a result of the inflammatory process associated with HIV infection and, even at younger ages, have a higher prevalence of chronic conditions common in older populations not infected with the virus. Therefore, it is believed that advanced age and the presence of a greater number of comorbidities are capable of influencing the severity of COVID-19 in PLHIV, which may explain the higher mortality observed in this specific population in 2020 [7, 46]. In 2021, no significant difference was found for any of the comorbidities investigated in the groups under analysis. Although patients with comorbidities are known as high-risk groups for COVID-19, clinical trials show that vaccination against COVID-19 is highly effective in reducing the severity of the disease in these individuals with comorbidities, a result that is also observed in investigations involving PLHIV [47].
During the assessment of aspects related to lifestyle habits, PLHIV showed a higher frequency of smoking compared to controls in both periods (12.8% vs 4.7%, p = 0.013 in 2020; 13.6% vs 4.0%, p = 0.027 in 2021). It is valid to consider that there is concrete evidence that PLHIV are two to three times more exposed to smoking than the general population [48–51]. Studies involving patients with Covid-19 demonstrate greater disease severity among smokers [52]. Thus, the higher frequency of comorbidities such as chronic obstructive pulmonary disease and cancer, as well as the high number of smokers among PLHIV in this study, may have an influence on findings of higher mortality in this population compared to patients not infected with HIV.
As for clinical signs and symptoms upon hospital presentation, the findings were similar between both groups, with dyspnea and fever being the most prevalent symptoms. These findings are in accordance with previous studies and reinforce that the screening and clinical suspicion of COVID-19 for the HIV-infected population should be similar to the general population [53, 54]. Clinical assessment data on admission for COVID-19 were similar for HIV infected and non-HIV infected patients in the two study periods. Laboratory findings also were mostly similar to non-HIV infected patients. However, we found that the HIV-infected group in 2020 had lower counts of leukocytes and neutrophils compared to the non-infected population, but that difference did not maintain in 2021. Although chronic HIV infection might lead to lower neutrophil counts [55], it is unclear the clinical significance of this finding in the context of an acute SARS-CoV-2 infection.
Most patients included in both study periods were on antiretroviral therapy, with lamivudine (96.9%), tenofovir (61.5%) and dolutegravir (57.3%) being the most used antiretrovirals. In this regard, it is worth noting that evidence points to the activity of antiretrovirals such as tenofovir against COVID-19 [17, 18, 56, 57]. In vitro and molecular docking studies suggest that tenofovir inhibits the ribonucleic acid (RNA)-dependent RNA polymerase of SARS-CoV-2 [58, 59]. This antiretroviral also has immunomodulatory effects, including decreased production of interleukin (IL)-8 and IL-10 [60], cytokines that are clearly associated with COVID-19 severity and mortality [43, 61]. Although subject to confounding factors, the results of the previously described studies are sufficient to encourage the inclusion of certain antiretrovirals in randomized clinical trials to investigate their potential for preventing and treating COVID-19.
Concerning the study limitations, the sample of PLHIV was small, which indicates the need for a careful interpretation of the results. Even so, the point estimate for mortality in 2021 was approximately the same for patients with HIV and matched controls. Despite the restricted sample size, this study presents great relevance since until now there are no publications directed to the investigation of patients with coinfection by SARS-COV-2 and HIV in Latin America in different waves of the pandemic. In this context, it is noticeable that knowledge about the clinical course of COVID-19 in this specific population is crucial to ensure the appropriate management of the disease, as well as to improve the management of health care costs, which is relevant for many countries of the continent that had great restriction of resources during the pandemic of COVID-19 [62].
Another limitation is the retrospective review as the primary means of obtaining data on the patients under study. Information such as the vaccination status from patients and specific data related to HIV infection could not be fully recovered in the hospital records and other records under analysis. The resources used to obtain the variables of interest in the study are secondary sources of information, and since they were not specifically designed for data collection, the absence of indispensable information for the study is inevitable. Additionally, the work overload of health professionals can make it difficult to assiduously record information about the assistance provided to the patient, directly affecting the quality of the data source [63].
The major advantage of this study focuses on the involvement of two Brazilian cohorts, including patients from 27 hospitals in 14 cities and 4 different states (Minas Gerais, São Paulo, Rio Grande do Sul and Pernambuco), ensuring the diversity of the population studied. Another relevant factor is the comparison of clinical characteristics and outcomes in patients with SARS-CoV-2 and HIV co-infection in two consecutive years (2020 and 2021), which has not been observed in other cohorts published until the moment.