HIV status is a risk factor for worse COVID-19 outcomes—but it remains uncertain the extent to which antiretroviral therapy (ART), viral load, and CD4 count can reduce that risk, according to a new flurry of research presented this week at the 11th International AIDS Society Conference on HIV Science (IAS 2021).
This new research adds to the growing body of data about the relationship between HIV and SARS-CoV-2 infection, specifically whether people living with HIV (PLWH) are at greater risk of worse COVID-19 outcomes. But in total, it leaves us with few definitive conclusions beyond a general understanding that COVID-19 severity is higher within the global community of people living with HIV.
This lack of absolute clarity is due to the fact that many studies—as with most HIV-focused research over the past year and a half of the COVID-19 pandemic—didn’t stratify PLWH by viral load, CD4 cell count, or antiretroviral therapy status, thus “lumping apples and oranges together in the same study,” according to Dave Wessner, Ph.D., a professor of biology specializing in HIV at Davidson College in North Carolina.
Still, based on a few studies that have weighted for these factors, including new research presented at IAS 2021 and prior science presented or published elsewhere, a clearer picture about the risk factors for PLWH experiencing worse COVID-19 outcomes is emerging. Here’s what we can say at the moment about the relationship, and what it could mean for public health policy.
Dueling Studies Offer Different Conclusions on HIV and COVID-19 Severity
Two large studies presented at IAS 2021 gave conflicting conclusions about the risk of more severe COVID-19 outcomes among PLWH. Importantly, neither weighted their results for ART status or CD4 count among the participants who were living with HIV.
Silvia Bertagnolio, M.D., an infectious disease physician with the World Health Organization (WHO), presented an analysis of data reported to the WHO Global Clinical Platform to determine the risk of severe outcomes for PLWH who had been hospitalized with COVID-19. Using the health records of more than 268,000 patients hospitalized with COVID-19 between January 2020 and April 2021 across 24 countries, Bertagnolio and colleagues focused on 15,000 people living with HIV from that pool.
Researchers reached a rather frightening conclusion: PLWH were more likely to be hospitalized with severe COVID-19 symptoms than people who were not living with HIV, and they had a 30% higher risk of dying in the hospital—independent of age, gender, or comorbidities. But there is a huge caveat: Due to insufficient data on CD4 count or HIV treatment status, researchers did not consider these factors to assess the risk for PLWH. (The study notes that nearly 92% of PLWH reported that they were on ART, but Bertagnolio noted that this statistic was misleading: ART status was only available for 40% of PLWH in the study, thus rendering the 92% figure moot.)
The data did reveal some additional risk factors among PLWH, however. Males, people over 65 years of age, and those with comorbidities such as diabetes and hypertension faced a particularly increased risk of death from COVID-19, the report noted.
A surprising contradiction to the WHO survey was presented by Matt Durstenfeld, M.D., who summarized a U.S. study concluding that there was little difference in COVID-19 outcomes between PLWH and people without HIV.
In the largest study to date of PLWH hospitalized with COVID-19 in the U.S., Durstenfeld and colleagues the University of California-San Francisco (UCSF) used the American Heart Association’s COVID-19 Cardiovascular Disease Registry—comprising more than 21,000 hospitalizations from 127 hospitals—to look at data from 221 PLWH hospitalized with COVID-19 between March and December 2020 in search of any associations between HIV and in-hospital mortality, major cardiac events, severity of illness, or length of stay.
When adjusted for demographics (age, sex, race/ethnicity, and health insurance) and for medical history (body mass index, smoking, chronic kidney disease, and lung disease), researchers found little difference between PLWH and people not living with HIV in terms of in-hospital mortality. As with the WHO study, however, subjects were not stratified by CD4 count or HIV treatment status. Durstenfeld also said that registry-participating hospitals might not be representative of all hospitals in the U.S.
Smaller Studies Suggest That HIV Treatment, Viral Load Play Role in COVID-19 Severity
One study of the COVID-HIV connection presented at IAS 2021 did include HIV viral load, CD4 cell count, and ART status, as well as other health variables, in its analysis of risk for severe outcomes of COVID-19 for PLWH.
Daniel Kwakye Nomah, M.D., a physician and researcher at the Centre for Epidemiological Studies of Sexually Transmitted Disease and HIV (CEEISCAT) in Catalonia, Spain, presented findings from a large study that considered sociological and clinical data of 749 patients coinfected with HIV and SARS-CoV-2 across 16 collaborating hospitals in Catalonia.
Researchers noted that the risk of severe COVID-19 outcomes increased with the number of comorbidities (e.g., chronic liver disease, hypertension, chronic kidney disease, diabetes, metabolic disease, and respiratory disease) as well as age (i.e., older patients faced more risk of poor health outcomes). Among people coinfected with HIV and SARS-CoV-2, worse outcomes were associated with people who had a detectable HIV viral load, regardless of whether their CD4 count was above or below 200 cells/mm3.
Another presentation at IAS 2021 looked at 429 PLWH coinfected with COVID-19 in Colombia; it concluded that ART significantly reduced the risk of death from COVID-19 and also helped with recovery.
Monica Mantilla, M.D., M.Sc., the national medical director of the HIV/hepatitis program at CEPAIN IPS in Colombia, stated that, among this cohort, 1.7% of patients who were on ART died, compared to 27% who were not receiving ART. Although there were no data on CD4 count or viral load, these results may give comfort to PLWH who are on effective treatment.
Making Sense of the Wide Array of HIV-COVID Outcome Study Results
HIV can disrupt the body’s immune defenses, but so can many other factors. It’s thus been challenging to assess and accurately weigh the risk of every possible body stressor in COVID-19 outcomes to reach a clear conclusion.
For example: Studies looking at the COVID-HIV relationship presented at IAS 2021, along with many other studies for the past 16 months, have used data from people hospitalized with COVID-19, which might not give the clearest picture of the risks for all PLWH, according to Matthew Spinelli, M.D., an infectious disease and HIV physician at UCSF.
“I think we need to evaluate studies that only include hospitalized individuals with caution; I think many of the early studies were likely biased,” Spinelli told TheBodyPro. “I find the population-based studies that include the entire population of PLWH in an area or health system more convincing, such as the Tesoriero New York State analysis.” That study (the primary author of which was James M. Tesoriero, Ph.D.) concluded that HIV, regardless of CD4 count, may play a direct role in severe COVID-19 outcomes—but it also acknowledged that a greater understanding of the role of comorbidities and other medical conditions is needed.
In a recent commentary for The Lancet, Spinelli argued for more research on a related question: How well are COVID-19 vaccines protecting PLWH compared to the general population? There is a dearth of data answering this question thus far.
Rachel A. Bender Ignacio, M.D., M.P.H., an assistant professor of medicine in the University of Washington’s Division of Allergy and Infectious Diseases, coauthored a study presented earlier this year by her colleague Adrienne Shapiro, M.D., Ph.D., which focused on health outcomes among PLWH coinfected with SARS-CoV-2. Bender Ignacio and her colleagues found that PLWH with a CD4 count of less than 350 are at greater risk of hospitalization for COVID-19 complications. But she said she understands the challenges within the research community in coming to a clear conclusion about all of the risk factors for severe COVID-19. Specifically, she said, the reliance on aggregated database data makes it hard to capture useful information on viral load, CD4 count, or ART status, as well as even more subtle factors that could affect risk of severe COVID outcomes for coinfected people.
“Careful use of data is especially important, as acute viral infections—or any form of acute stressor, even a car accident—could depress the CD4 count, so it is important to use CD4 counts obtained as part of routine care and not drawn on hospital admission for COVID-19 illness,” Bender Ignacio told TheBodyPro.
“Because PLWH also bear a disproportionate burden of medical comorbidities, substance abuse, low socioeconomic status, and biologic stressors like allostatic loading that comes from experiencing racism or anti-LGBTQ discrimination, etc., it is hard to piece out what is due to the immunologic effects of HIV itself, or may be woven into comorbidities or other factors more common in PLWH,” she continued. “Analyses may differ depending on how they accounted for these other factors, and the locale of the study, including access to care/disparities in care in those settings.”
Stratifying PLWH by CD4 Count or Viral Load Might Not Matter When Prioritizing COVID-19 Vaccination
In the United States, where COVID-19 vaccination appointments are easy to get and vaccine doses are going unused, the issue of prioritizing people based on HIV status, or any health status, has become moot. The increasingly urgent message from federal, state, and local health officials is that everyone who hasn’t been vaccinated should do so as soon as possible.
But in many countries where vaccine access is still extremely low, prioritizing PLWH for vaccination matters—and stratification by viral load, CD4 count, or ART status might not. This is in large part because, in the same way that many researchers have found it challenging to access data on CD4 count or ART status when assessing COVID-19 severity in PLWH, it is similarly difficult for countries to differentiate PLWH by ART status or viral suppression when prioritizing their PLWH citizens for a COVID-19 vaccine.
“I think [countries] would need to prioritize all PLWH [for the vaccine], as it would be too logistically complicated otherwise,” Spinelli said.
Wessner offered that it’s reasonable to believe that high viral load is a risk factor for severe COVID-19 outcomes among PLWH. “But if CD4 count is unknown, there’s still a good argument for putting PLWH at the front of the vaccination line, worldwide.”
Steven Deeks, M.D., a professor of medicine and HIV researcher at UCSF, said that based on the emerging data, it’s logical to make vaccinations a priority for all people living with HIV. “This is particularly true for low- and middle-income countries, given recent data suggesting those living in those regions who have HIV do poorly with COVID.”
These opinions align with the World Health Organization guidance.
“WHO will continue monitoring the data and is actively encouraging data contribution and sharing through the WHO Global Clinical Platform to assess the situation on an ongoing basis and regularly update this report, hopefully with an analysis by ART status,” Bertagnolio told TheBodyPro. “Until more robust evidence become available, all PLHIV [people living with HIV], regardless of ART, will be considered as a group at risk for severe/critical COVID-19.”
The WHO Clinical Management Guidelines for COVID-19 are currently under revision; they should be finalized and distributed by the end of August, Bertagnolio said.
Advice for HIV Clinicians: Support Vaccination and ART
Experts who spoke with TheBodyPro said that there are a few clear guidelines for PLWH and their health care providers: Get vaccinated for COVID-19 and get HIV under control with antiretroviral therapy.
Beyond that, Spinelli said he doesn’t recommend sending patients who are coinfected with HIV and COVID-19 to the hospital earlier than patients who are not living with HIV, unless they have other clinical features like oxygen saturation and respiratory distress.
“As the overall effect of HIV on risk is modest and inconsistent, I would not support routinely hospitalizing in treating everyone with HIV who gets COVID,” agreed Deeks. He noted that clinicians may be inclined to triage PLWH differently, i.e., having a lower threshold for hospitalization and perhaps treatment. But he suggested that when it comes to COVID-19 management, HIV is best treated “like other risk factors, including age, obesity, and the presence of co-morbidities.”
Bender Ignacio urged PLWH with COVID-19 who are at higher risk for severe COVID-19 outcomes to help prevent hospitalization by seeking out clinics or hospitals providing infusions of monoclonal antibodies that have been granted emergency authorization by the U.S. Food and Drug Administration. Alternatively, she suggested, patients could consider signing up for one of the many COVID-19 treatment trials studying how to prevent severe illness. Unlike many historical trials, most—if not all—of these are actively recruiting people who are coinfected with HIV and COVID-19, she noted.