Over the past year, studies have revealed that certain pre-existing conditions, such as cancer, diabetes and high blood pressure, can increase a person’s risk of dying from COVID-19. New research shows that individuals living with human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS)—an estimated 38 million worldwide, according to the World Health Organization—have an increased risk of SARS-CoV-2 infection and fatal outcomes from COVID-19.
In a new study, Penn State College of Medicine researchers found that people living with HIV had a 24% higher risk of SARS-CoV-2 infection and a 78% higher risk of death from COVID-19 than people without HIV.
They assessed data from 22 previous studies that included nearly 21 million participants in North America, Africa, Europe and Asia to determine to what extent people living with HIV/AIDS are susceptible to SARS-CoV-2 infection and death from COVID-19.
The majority of the participants (66%) were male and the median age was 56. The most common comorbidities among the HIV-positive population were hypertension, diabetes, chronic obstructive pulmonary disease and chronic kidney disease. The majority of patients living with HIV/AIDS (96%) were on antiretroviral therapy (ART), which helps suppress the amount of HIV detected in the body.
“Previous studies were inconclusive on whether or not HIV is a risk factor for susceptibility to SARS-CoV-2 infection and poor outcomes in populations with COVID-19,” said Dr. Paddy Ssentongo, lead researcher and assistant professor at the Penn State Center for Neural Engineering. “This is because a vast majority of people living with HIV/AIDS are on ART, some of which have been used experimentally to treat COVID-19.”
“As the pandemic has evolved, we’ve obtained sufficient information to characterize the epidemiology of HIV/SARS-CoV-2 coinfection, which could not be done at the beginning of the pandemic due to scarcity of data,” said Vernon Chinchilli, fellow researcher and chair of the Department of Public Health Sciences.
“Our findings support the current Centers for Disease Control and Prevention guidance to prioritize persons living with HIV to receive a COVID-19 vaccine.”
Emily Heilbrunn, Anna Ssentongo and Jonathan Nunez of Penn State College of Medicine; Ping Du of Takeda Pharmaceuticals and Shailesh Advani of Georgetown University also contributed to this research. The researchers declare no conflicts of interest.
Immune status in people living with HIV and SARS-CoV-2 response
A favourable clinical course of COVID-19 has been associated with appropriate class-I interferon responses and timely production of neutralising antibodies and specific cell-mediated immunity.15 On the contrary, low or delayed immune responses allow viral dissemination and are associated with hyperinflammatory states, or cytokine storms, leading to massive pneumonia, respiratory failure, and death.16
However, much remains to be learned regarding SARS-CoV-2 immunity,17 and reports suggest that, in patients with severe COVID-19 infection, sustained interferon responses in combination with IL-1 and tumour necrosis factor production in lung monocytes could exacerbate the cytokine storm.18 Therefore, the effect of immunodeficiency in chronic HIV infection on the appropriate immune response to COVID-19 might be a matter of concern or might offer potential protection against severe forms of disease.
Immune response to SARS-CoV-2 mediated by interferon in people living with HIV
Interferon is the first barrier to infection, which SARS-CoV-2 is sensitive to in vitro. In response, SARS-CoV-2 has developed several mechanisms to counteract the interferon response.19 Accordingly, poor COVID-19 prognosis has been associated with decreased interferon response,20 frequently observed in older patients, genetic defects in interferon-associated pathways, and anti-interferon antibody generation.20, 21
HIV infection triggers interferon responses in acute infection, contributing to HIV-replication control and transmitted/founder virus selection.22 However, in chronic phases of HIV infection, persistently high interferon concentrations and interferon-stimulated gene activation might correlate with disease progression, low CD4 counts, and long-term immunoactivation.
These factors could suggest a detrimental role of chronic interferon signalling in HIV infection, normalised by ART.23
HIV-infected response: adaptive immunity and potential gaps against SARS-CoV-2
Early generation of robust functional IgG antibodies against the SARS-CoV-2 spike protein is associated with survival in severe COVID-19 infection.24 In addition, broad, strong CD4 and CD8 memory cell responses are observed in recovered patients, suggesting that coordinated antigen-specific B-cell and T-cell responses provide protective immunity against severe COVID-19 infection and death.24
In people living with HIV, active replication of HIV is associated with T-cell activation, increased CD8 T cells, inflammation, and lymphocytic exhaustion.25 These parameters are normalised by ART, particularly when treated early. Profound defects in B-cell function have been reported – eg, polyclonal activation, absence of and dysfunction of memory B cells, and defective follicular helper T-cell activity.26 Some of these defects are not fully recovered after ART, and long-term antibody production and decreased responses to neoantigens or recall antigens can persist in patients with HIV, representing a potential threat to vaccine response.
These defects in T-cell and B-cell functions can potentially result in severe clinical course and poor COVID-19 prognosis in patients with HIV, particularly when low CD4 counts and viral replication persist despite ART. Two studies have shown that the concentration and duration of IgG, IgM, and neutralising antibodies in people living with HIV after SARS-CoV-2 infection are similar to the population that are HIV-negative,27, 28 although a third study showed a lower rate of neutralising antibodies in people living with HIV.29
Proinflammatory status in people living with HIV
Patients with COVID-19 and severe clinical course develop dysfunctional immune responses characterised by profound lymphopenia (including both low CD4 and CD8 T-cell counts), increased cytokines and chemokines, massive natural killer cell and lymphocytic activation, and subsequent exhaustion. At the pulmonary level, macrophage activation and endothelial damage lead to cellular recruitment, increased inflammation, and activation of complement and coagulation pathways, leading to aggravated viral pneumonia, respiratory failure, systemic injury, and death.
This cytokine storm is also present with lower intensity in acute HIV infection in which strong immune-system activation is triggered by high viraemia.25, 30 ART restores interferon, cytokine, and chemokine concentrations, although some patients present low-level persistent activation and inflammatory markers. Although evidence is scarce, restoration of interferon concentrations might be beneficial for responses to SARS-CoV-2.
Overall, full viral suppression with ART ensures near-complete immune recovery in people living with HIV. Therefore, for well controlled infections in people with well controlled HIV infection, SARS-CoV-2 infection should be managed as in the HIV-negative population. However, persistent viral replication, low CD4 counts, and increased concentrations of inflammatory markers have been described in a subgroup of patients treated with ART, a scenario potentially leading to severe COVID-19 disease progression.
Additionally, defective B-cell functioning, not completely recovered by ART, might contribute to decreased COVID-19-vaccine response. Moreover, increased rates of cancer, neurological disease, and cardiovascular disease have been described in people living with HIV, adding potential risk factors to COVID-19 disease progression.31, 32 There is also a progressive increase in the median age of people living with HIV, particularly in high-income countries,33 and the natural immune-senescence process should be also considered in older people living with HIV, which might also impair immune responses.34
Advantages and disadvantages of immune HIV status in tackling COVID-19
People living with HIV with CD4 counts less than 200 cells per μL, unsuppressed HIV RNA, or opportunistic illnesses in the preceding 6 months, have been considered an at-risk population since the COVID-19 pandemic began.35 As declining CD4 cells are associated with COVID-19 severity, people living with HIV with low CD4 cells might face a higher risk of severe COVID-19 infection.36, 37
Similarly, untreated HIV infections might worsen the immunological effect of COVID-19 infection.38 At present, effective ART is universally recommended and immunological recovery is expected in most patients with HIV infection,39 but COVID-19 might occur in people living with HIV unaware of their HIV status. In the largest published cohorts, the potentially higher risk for poorer COVID-19-related outcomes in people living with HIV with lower CD4 cell counts40, 41 might be driven by concomitant comorbidities,42 more common in people living with HIV than in uninfected people,43 the prevalence of which is inversely proportional to CD4 counts in people living with HIV.44
reference link : https://www.thelancet.com/journals/lanhiv/article/PIIS2352-3018(21)00070-9/fulltext
More information: Paddy Ssentongo et al. Epidemiology and outcomes of COVID-19 in HIV-infected individuals: a systematic review and meta-analysis, Scientific Reports (2021). DOI: 10.1038/s41598-021-85359-3
