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TDF Exposure and COVID-19 Protection: Association or Causation?

Josep M. Llibre, MD, PhD

Senior Consultant
Infectious Diseases Division
Fight Infections Foundation
University Hospital Germans Trias
Badalona, Barcelona, Spain

Josep M. Llibre, MD, PhD, has disclosed that he has served on an advisory board or panel and as a consultant for Gilead Sciences, Janssen, MSD, and ViiV.

View ClinicalThoughts from this Author

Released: August 16, 2021

Studies indicating that tenofovir and emtricitabine interfere with the SARS CoV-2 RNA–dependent RNA polymerase have fueled interest in ascertaining their potential role in COVID-19 prevention or treatment.

Effects of TDF/FTC in Persons Coinfected With HIV and SARS-CoV-2
A Spanish multicenter cohort study of 77,590 people with HIV (PWH) that included 236 people with polymerase chain reaction (PCR)–confirmed SARS-CoV-2 coinfection reported that patients receiving tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (but not tenofovir alafenamide [TAF]/FTC) had a lower risk for COVID-19 and related hospitalization than those receiving other therapies. Persons receiving TDF/FTC vs TAF/FTC had the lowest risk for COVID-19 diagnosis (16.9 vs 39.1 per 10,000) and hospitalization (10.5 vs 20.3 per 10,000), respectively. In addition, no patient receiving TDF/FTC was admitted to the ICU or died. But median age, comorbidities, and baseline characteristics of the subjects receiving TDF or TAF were not reported or were not known in this study. It should be noted that TDF is preferentially prescribed to younger subjects without comorbidities, establishing a prescription channeling bias.

Another Spanish retrospective cohort identified an independent association between TDF vs TAF use and SARS-CoV-2 seropositivity among 1076 PWH (adjusted odds ratio: 0.49; P = .031). Again, the baseline characteristics of TDF and TAF users were not reported. How 2 compounds with the same active drug (tenofovir) could have variable impacts on COVID-19 is currently unknown, although distinctive pharmacokinetic or immunomodulatory effects have been postulated.

A third study in South Africa with 3978 PWH with COVID-19 identified a significantly lower risk of COVID-19–related death in PWH receiving TDF vs abacavir (ABC) or zidovudine (ZDV) (adjusted HR 0.41; P = .007) in multivariate analysis. First-line antiretroviral therapy (ART) in adults included TDF plus FTC, lamivudine plus efavirenz (or dolutegravir), with ABC replacing TDF for patients with kidney disease. Second-line ART for most patients consisted of ZDV plus FTC and a protease inhibitor, and both of these factors may themselves increase mortality. In addition, there was a strong association between COVID-19 death and current tuberculosis, which could be more prevalent among PWH on second-line ART. Receipt of TDF (vs ZDV) was associated with reduced COVID-19 mortality even after adjusting for renal disease, viral suppression, and ART duration, but other nonadjusted factors (previous virologic failure, tuberculosis) could be associated with ZDV use.

The association between TDF use and a potentially lower COVID-19 infection rate or better outcomes has sparked much debate ever since.

Effects of TDF in Persons Coinfected With Hepatitis B and SARS-CoV-2
A multicenter study in subjects with chronic hepatitis B (without HIV infection) has also reported significantly lower rates of severe COVID-19, ICU admission, ventilatory support, and fewer days in the hospital in those receiving TDF vs entecavir. However, TAF was not approved for chronic hepatitis B in Spain at that time, and again, people receiving TDF had significantly lower comorbidity rates than people taking entecavir (hypertension, diabetes, obesity, coronary heart disease, and chronic kidney disease―all significant), indicating a prescription bias that relates to patient characteristics affecting COVID-19 prognosis. The study performed a multivariate logistic regression analysis adjusted by age, sex, obesity, and comorbidities, but it is unlikely that such a strong underlying bias was completely removed.

Effects of TDF/FTC in Persons Using PrEP vs Not Using PrEP
In 2 other observational studies performed in Madrid and Paris, TDF/FTC and TAF/FTC pre-exposure prophylaxis (PrEP) users (without HIV infection) presented a similar or even higher seroprevalence to SARS-CoV-2 vs the control group with no PrEP, with no significant differences in the rates of symptomatic COVID or duration of symptoms between TDF/FTC and TAF/FTC in the Madrid study. Likewise, in a substudy of French PREVENIR-ANRS and SAPRIS-Sero, SARS-CoV-2 antispike immunoglobulin G prevalence was similar in 1688 TDF-exposed PrEP users and in 1460-person fully matched non-PrEP users, suggesting that when there is no channeling bias in TDF prescription, the potential protective role of TDF is lost.

Trial of TDF/FTC in Outpatients With COVID-19
Finally, in a recent pilot, randomized, open-label phase II trial (AR0-CORONA study in France) in 60 adult outpatients with reverse transcriptase ­PCR–confirmed nonsevere SARS-CoV-2 infection of ≤7 days, TDF did not accelerate the natural clearance of nasopharyngeal SARS-CoV-2 at Day 4 (primary endpoint) vs the standard-of-care arm. However, it did it at Day 7, with an effect corresponding to approximately 0.8 log10 decrease of SARS-CoV-2 RNA. Of note, this reduction has unknown microbiological or clinical relevance and patients actually had no individual benefit. The time to symptom resolution and rates of hospitalization were similar between groups, and TDF was associated with higher rates of drug-related adverse events.

Take-home Points
In summary, selection biases were present in the aforementioned cohort studies because it is unlikely that TDF is prescribed to older PWH or those with known comorbidities such as cardiovascular disease, diabetes, or kidney disease, each of which has been identified as an independent risk factor for poorer outcomes with COVID-19.

So, do the current data support a protective role of TDF in SARS-CoV-2 infection? I don’t think so. To date, this association cannot be considered causation, but further clinical trials are ongoing (NCT04712357, NCT04334928, NCT04359095, and NCT04890626).

Your Thoughts?
Do you think TDF has promising anti–SARS-CoV-2 activity? Answer the polling question and join the conversation by posting in the discussion section.

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