Effects of entecavir and tenofovir disoproxil fumarate on the incidence and severity of COVID-19 in patients with chronic hepatitis B | BMC Infectious Diseases

In this study, we investigated the incidence, duration, and severity of COVID-19 in 630 CHB patients receiving ETV or TDF. Our results indicate that ETV or TDF treatment has similar effects on the incidence, duration, and severity of COVID-19 in patients with chronic hepatitis B. After adjusting for multiple confounding factors, the conclusions remained consistent.

In the current study, 64.3% (405/630) of patients with chronic hepatitis B had COVID-19. The vast majority of COVID-19 patients self-reported mild and moderate symptoms, with only 8.4% (34/405) reporting severe symptoms. Notably, no one required hospitalization, ICU admission, oxygen or died due to COVID-19. This is significantly different from another study conducted in Spanish CHB, where the incidence of COVID-19 was 2.5%, of which 39.3% required hospitalization, and 18.8% developed severe COVID-19, of which 4.3% required ICU admission. 10.3% (12/117) received ventilatory support and 5.1% (6/117) died (3). This discrepancy may be due to differences in study populations, study periods, and circulating strains. As the SARS-CoV-2 virus continues to mutate, omicron mutant strains are widely prevalent, and the fatality rate of omicron mutant strains has been significantly reduced. An increasing number of infected people are presenting with non-severe cases. Previous studies have shown that patients infected with the omicron variant have a significantly reduced risk of hospitalization (0.2%-4.1%), ICU admission (0.1%-0.5%), and death (0.46%) compared with the delta variant. 20,21,22,23,24). In the current study, we assessed the incidence, duration, and severity of COVID-19 in the Chinese CHB population during the omicron epidemic, while another study investigated these incidence, duration, and severity of COVID-19 in the first year of the COVID-19 epidemic. index. This may explain the inconsistent incidence and severity of COVID-19 between the two studies.

Furthermore, it is worth mentioning that although the proportion of severe COVID-19 patients was lower, we found that the rate of symptomatic COVID-19 remained high during the omicron epidemic. In our study, the proportion of patients experiencing at least one COVID-19-related symptom was approximately 90%, with the corresponding proportion for each symptom ranging from 5.0% to 77.6%. Previous studies also reported that when omicrons were dominant, the incidence of each symptom (i.e., nasal congestion, headache, sore throat, cough, etc.) in patients who tested positive for SARS-CoV-2 ranged from 4.3% to 76.5%. Similar to our results (21).

Furthermore, in this study, the incidence of COVID-19 was comparable between patients treated with ETV and those treated with TDF. This result is partially supported by previous studies, which found that TDF was not associated with a reduction in COVID-19 incidence (4,5,6,7,8,9). Although one study showed that antiviral drugs, including TDF and ETV, were associated with decreased SARS-CoV-2 positivity (16). However, it is worth noting that only 50 patients in the latter study received antiviral drugs, and the effective sample size was small, which may bias the results. Furthermore, the results of our subgroup analysis showed that TDF was effective in reducing the incidence of COVID-19 in women before matching for confounders, but after matching, this effect disappeared. This is consistent with another prospective multicenter cohort study of people living with HIV. They found that the potential protective effect of TDF/FTC on COVID-19 incidence disappeared after using an adjusted Cox regression model (8). Therefore, based on the evidence from the current study, we believe that TDF and ETV have similar effects on the incidence of COVID-19.

Furthermore, our findings showed that there were no significant differences in the proportion of patients with concurrent COVID-19-induced symptoms, symptom duration, symptom severity scores, and symptom severity between ETV and TDF-treated patients before and after matching. These results are consistent with previous studies. In the Korean national cohort, among 7,723 SARS-CoV-2-positive patients, 480 (6.2%) patients were diagnosed with severe COVID-19, and 237 (3.1%) patients died during hospitalization. Among patients with chronic hepatitis B, 26 (5.4%) developed severe COVID-19 and 12 (5.1%) died (16). Researchers found that antiviral drugs, including TDF and ETV, were not associated with severe clinical outcomes in COVID-19 (16). Beyond this, results from an open-label, double-randomized, phase 3 pragmatic clinical trial of 355 subjects showed that TDF had no beneficial effect on severe COVID-19 (15). Based on the above evidence, we believe that the impact of ETV and TDF on COVID-19 in patients with CHB is not seriously different.

Interestingly, there are also studies that differ from our results. The reason behind this may be differences in the distribution of COVID-19 severity among subjects. The main population evaluated in this study was patients with non-severe COVID-19, while most previous studies have focused on patients with severe COVID-19. For example, a study of a Spanish chronic hepatitis B population found 117 cases of COVID-19, of which 39.3% required hospitalization and 18.8% developed severe COVID-19 (3​​​). They found that patients with ETV more often had severe COVID-19, required ICU, ventilatory support, had longer hospital stays, or died. And compared with ETV, TDF can exert a protective effect on COVID-19 patients with CHB (3). The inverse probability of treatment-weighted propensity score also showed that TDF reduced the risk of severe COVID-19 by 6-fold (3). Additionally, multiple studies have found that TDF prevents COVID-19-related events such as hospitalization and ICU admission in HIV-positive patients compared with other antiretroviral drugs (4,5,6,7,8,9,25) . Taken together, the above studies indicate that TDF is beneficial for severe COVID-19.

Computer simulations and in vitro studies have shown that TDF inhibits SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) (10,11,12) and that TDF plus emtricitabine can accelerate the natural spread of SARS-CoV-2 virus in the nasopharynx. Clear burden (14). Additionally, TDF reduces the production of interleukin-8 and interleukin-10, which have been shown to reduce the severity of COVID-19 (26). However, a comprehensive set of in vitro data suggests that tenofovir (TFV), tenofovir alafenamide (TAF), TDF, and FTC are inactive against SARS-CoV-2 (17). None of these drugs showed any significant in vitro anti-SARS-CoV-2 effect at concentrations 100-fold higher than clinically relevant levels (17). Furthermore, structural modeling further demonstrates that these nucleoside/tidal reverse transcriptase inhibitor (NRTI) active metabolites are a poor fit at the active site of the SARS-CoV-2 RdRp (17). Their data suggest that TDF is unlikely to be a direct antiviral agent against SARS-CoV-2 (17). More research is needed to confirm whether TDF is beneficial for COVID-19.

This study does have some limitations. First, this is a single-center cross-sectional study, and the results of subgroup analysis with a small sample size may not be unreliable and need to be verified with a larger sample size. Secondly, the use of VAS to evaluate the severity of COVID-19 is greatly affected by patient subjective factors and may cause certain biases. Third, this study did not collect biochemical and virological information, so it was not possible to evaluate the incidence of liver and kidney injury and changes in HBV-related virological markers in CHB patients during COVID-19 infection. Worth further investigation.

In summary, the vast majority of CHB patients experience non-severe COVID-19 during the current pandemic. There is no serious difference between ETV and TDF in the impact of COVID-19 in patients with chronic hepatitis B. Better study designs are needed to further explore the impact of both drugs on COVID-19.

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