A new study released in Annals of Internal Medicine on June 26 demonstrated that people living with HIV who were on antiretroviral therapy (ART) in Madrid, Spain, were less likely to contract SARS-CoV-2, the virus that causes COVID-19 disease. But people who were using tenofovir disoproxil fumarate (TDF) were far less likely to contract SARS-CoV-2 than those taking other ART medications. And while media outlets have published the results of this study, many experts are warning people living with HIV—or using emtricitabine/tenofovir disoproxil fumarate (Truvada, TDF/FTC) or emtricitabine/tenofovir alafenamide (Descovy, TAF/FTC) as pre-exposure prophylaxis (PrEP)—to not take this study as conclusive evidence that ART will protect them from COVID-19, or from becoming gravely ill with the virus.
“While we are very supportive of ongoing efforts to identify potential pre-exposure prophylaxes and treatments for COVID-19 in case efforts to find a vaccine don’t pan out, this is another situation where we need to be very careful before jumping to conclusions as new study results come out,” warned Jeremiah Johnson, M.P.H., HIV project director with Treatment Action Group. “Given the small sample size for those taking TDF/FTC and lack of clarity on any differences in age distribution across different regimens, we cannot say if there is in fact a protective effect or if it is just a chance finding.”
Understanding the Study
The retrospective study reviewed data from 77,590 people living with HIV receiving ART across 60 hospitals in Spain from Feb. 1 through April 15, 2020. They began follow-up with study participants during that period and found 236 PCR-confirmed COVID-19 cases among the larger sample.
“We therefore calculated the 75-day risk (cumulative incidence) and 95% CI (confidence interval) for COVID-19 diagnosis, hospital admission, ICU admission, and death, overall and by age group, sex, and NRTI regimen,” the authors write.
The researchers then looked at which NRTI ART each person with COVID-19 was using, and divided them into people on TDF/FTC, TAF/FTC, ABC/3TC, and other drugs. Of those 236 people with HIV who also were diagnosed with COVID-19, 151 were hospitalized, 15 were admitted to ICU, and 20 individuals died. The researchers found that the risks for COVID-19 diagnosis were 39.1 per 10,000 persons among participants receiving TAF/FTC, 16.9 among participants receiving TDF/FTC, 28.3 among participants receiving ABC/3TC, and 29.7 for participants on other regimens. The researchers note similar correlations between which NRTI backbone regimen people were taking and the rate of hospitalizations, and that “no patient receiving TDF/FTC was admitted to the ICU or died.”
“Our results suggest that the risk for COVID-19 diagnosis is not higher in HIV-positive persons than in the general population, and that HIV-positive patients receiving TDF/FTC had a lower risk for COVID-19 and related hospitalization than other HIV-positive persons,” the researchers write. “These findings warrant further investigation in studies of HIV preexposure prophylaxis and in randomized trials for the treatment and prevention of COVID-19 in persons without HIV.”
The observational cohort study had only a small sample and no control group, so the results are not conclusive enough to give a definitive answer about preventing or treating COVID-19. It does give us some clues into how NRTIs may be active against COVID-19, but other HIV researchers suggest it’s still too early to celebrate—or to give everyone around the world TDF/FTC as PrEP for COVID-19.
Small Sample and Lack of Controlling for Other Risk Factors Makes Drawing Conclusions Difficult
“The number of hospitalizations and deaths in this sample is really small, and while they concluded that regimens including TDF/FTC showed a reduced hospitalization rate and death over the other regimens, I don’t know if they can conclude that TDF/FTC is the reason for that,” said David Malebranche, M.D., M.P.H., associate professor with the Morehouse School of Medicine. “They postulate a lot about it, but this study amounts to a correlation only that warrants further investigation—not definitive evidence that ART works in reducing risk of people living with HIV to COVID-19 illness, hospitalization, and death.”
In addition to the sample size being too small to prove ART prevents SARS-CoV-2 infection or COVID-19 illness, Malebranche and other critics of the study also point to the study’s lack of controlling for older age and comorbidities (like cardiovascular disease, type 2 diabetes, or hypertension), all of which make the risk for COVID-19 greater. Experts who have raised issues with taking this study as conclusive evidence were particularly keen on pointing out that by not controlling for age or comorbidities in the study, it shouldn’t be taken as the final word on whether being on ART, or Truvada in particular, really reduces COVID-19 risk.
“Severity and mortality of COVID-19 has an exceptional dependence on age and prevalence of comorbidities. This cohort study does not appear to adjust for age differences within each NRTI group, rather just PLHIV [people living with HIV], inclusive of all NRTIs, versus the entire Spanish population,” noted activist James Krellenstein, cofounder of #PrEP4All and the COVID-19 Working Group, in a series of tweets about the study.
“They really avoided talking about other comorbidities (other than older age) that was associated with the participants who were hospitalized or died,” said Malebranche. “Were they obese? Had hypertension or DM [diabetes mellitus]? There’s no mention of that in the study, and that’s a huge limitation of many here.”
In essence, if the population in the study was overall younger and had fewer comorbidities, this could be a reason why fewer people in the study contracted COVID-19, and it may not be related to being on ART. Krellenstein also pointed out in his tweets that while the study noted no people with HIV who were on TDF/FTC as part of their backbone regimen were admitted to the hospital or the ICU, there were only 20 individuals in the study who were on that regimen.
“For me, I’m not sure this study really persuades me into thinking that ART and nucelosides, in particular, are somehow protecting people living with HIV from SARS-CoV-2 infection,” said Malebranche. “I need to see more data than this cohort study, and particularly with no control group and no mention of other comorbid conditions—it’s really hard to say that the ART meds were somehow protective.”
There are other studies underway looking at whether ART, or the drugs currently approved for PrEP for HIV, have any benefit as prevention for COVID-19. But until those studies wrap up with more conclusive evidence, people living with HIV or on PrEP should continue to follow protocols for all people, including frequent handwashing, wearing masks, and practicing social distancing in public spaces.