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  The International Liver Congress™
EASL - European Association for the
Study of the Liver
June 23-26 2021
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Tenofovir May Trim COVID-19 Severity in People With Chronic HBV
  EASL International Liver Congress, June 23-26, 2021
Mark Mascolini
Compared with COVID-19 patients taking entecavir (ETV) for chronic hepatitis B virus (HBV) infection, those taking tenofovir disoproxil fumarate (TDF) had significantly lower rates of severe COVID-19, intensive care unit (ICU) admission, and ventilatory support, and fewer days in the hospital [1]. Researchers from Hospital Universitario Ramon y Cajal and colleagues across Spain suggested that TDF "seems to exert a protective effect in patients with chronic HBV infected with COVID-19."
Prior research documented a lower risk of COVID-19 and related hospital admission in HIV-positive people taking TDF/emtricitabine (FTC) than in those taking tenofovir alafenamide (TAF)/FTC or other antiretrovirals [2]. Spanish investigators conducted this new retrospective analysis to see whether TDF cuts incidence and severity of COVID-19 when compared with ETV in people with chronic HBV.
Researchers scoured records of 28 Spanish hospitals to find adults with COVID-19 taking TDF or ETV for chronic HBV between February 1 and November 30, 2020. They defined COVID-19 infection by a positive polymerase chain reaction. Severe COVID-19 meant bilateral severe pneumonia, acute respiratory distress syndrome, sepsis, or septic shock. The investigators used inverse probability of treatment weighting propensity score to estimate the effect of TDF or ETV on risk of severe COVID-19. They used bivariate analysis to compare associations between the two drugs and other outcomes.
Among 4736 adults with chronic HBV infection, 117 got diagnosed with COVID-19 (2.5%, 95% confidence interval [CI] 2.1 to 2.9). Of those 117 people, 67 (57.3%) took TDF and 50 (42.7%) took ETV. During the study period, 41 people with HBV and COVID-19 (35%) got admitted to the hospital, 5 (4.3%) got admitted to the ICU, and 6 (5.1%) died. People taking TDF had lower comorbidity rates than those taking ETV: obesity (9% vs 22%), diabetes (12% vs 32%), ischemic cardiomyopathy (3% vs 14%), and arterial hypertension (18% vs 44%) (P < 0.05 for all comparisons). People taking TDF had a nearly significant trend toward lower prevalence of advanced (F3-F4) fibrosis (18% vs 35%, P = 0.06).
In the chronic HBV population, incidence of COVID-19 was similar in the TDF group and the ETV group (0.023 vs 0.026, P = 0.44). But prevalence of severe COVID-19 (as defined above) was significantly lower in people taking TDF than in those taking ETV (list below). And other markers of COVID-19 severity favored the TDF group:
- Severe COVID-19: 6% TDF vs 36% ETV, P < 0.01
- ICU admission: 0% TDF vs 10% ETV, P = 0.01
- Ventilatory support: 3% TDF vs 20% ETV, P < 0.01
- Average hospital days: 3.1 TDF vs 10.8 ETV, P < 0.01
- Death: 1.5% TDF vs 10% ETV, P = 0.08 (not significant)
Multivariate analysis adjusted for age, sex, obesity, comorbidities, and fibrosis stage linked TDF use to about a 6-fold lower risk of severe COVID-19 (adjusted-IPTW-OR 0.17, 95% CI 0.04 to 0.67, P = 0.01).
The Spanish collaborators proposed that people with chronic HBV and COVID-19 appear to run a lower risk of severe COVID-19 if taking TDF rather than ETV. The researchers surmised that TDF may "exert a protective effect" against severe COVID-19 in people with HBV. At a press conference, presenting author Beatriz Mateos Munoz suggested that protective activity could reflect the cell-study finding that the active form of TDF inhibits SARS-CoV-2 polymerase [3]. Or, she added, certain antiinflammatory or immunomodulatory effects of TDF could ease COVID-19 severity.
A 60-hospital February 1-April 15, 2020 Spanish analysis of 77,590 people with HIV found a lower risk of hospital admission for COVID-19 in people taking TDF/FTC than in those taking TAF/FTC, abacavir/lamivudine, or other regimens [2]. Risk of COVID-19 diagnosis was also lower in people taking TDF/FTC than in those taking other regimens. No one taking TDF/FTC got sent to the ICU or died because of COVID-19.
These investigators floated the theory that "persons who received TDF/FTC in February 2020 in Spain are a highly select group from which those most susceptible to SARS-CoV-2 infection have been removed" [2]. But they admitted that could not "think of any mechanisms that might explain such an extreme form of depletion of susceptible persons."
These Spanish researchers noted that tenofovir diphosphate, the active form of TDF and TAF, may fit better into the active site of SARS-CoV-2 RNAdRNAp because of its smaller size compared with other antiretrovirals [2,3]. They added that tenofovir has immunomodulatory effects in some animal and human cell lines, and tenofovir may quell production of inflammatory cytokines that contribute to COVID-19 severity [2].
1. Munoz BM, Buti M, Vazquez IF, et al. Tenofovir reduces severity of COVID-19 infection in chronic hepatitis B patients. EASL International Liver Congress, June 23-26, 2021. Abstract PO-1449.
2. Del Amo J, Polo R, Moreno S, et al. Incidence and severity of COVID-19 in HIV-positive persons receiving antiretroviral therapy: a cohort study. Ann Intern Med. 2020;173:536-541. doi: 10.7326/M20-3689. https://www.acpjournals.org/doi/full/10.7326/M20-3689
3. Jockusch S, Tao C, Li X, et al. Triphosphates of the two components in DESCOVY and TRUVADA are inhibitors of the SARS-CoV-2 polymerase. bioRxiv. Preprint posted online 5 April 2020. doi:10.1101/2020.04.03.022939. https://www.biorxiv.org/content/10.1101/2020.04.03.022939v1