Study Finds Differences in High-Genetic Barrier Nucleos(t)ide Analogue Efficacy for HBV

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The network meta-analysis found tenofovir disoproxil fumarate was more likely to achieve virologic response at week 48, while entecavir was superior for 48-week biochemical response.

Findings from a recent study are providing clinicians with an overview of differences in the therapeutic efficacy of high-genetic barrier nucleos(t)ide analogues (NAs) for the treatment of chronic hepatitis B virus (HBV) in treatment-naïve patients.1

The systematic search and network meta-analysis compared the efficacy of entecavir (ETV), tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), and besifovir dipivoxil maleate (BSV) and found that although TDF was more likely to achieve virologic response after 48 weeks, ETV provided a superior biochemical response during the same time frame.1

“Previous meta-analyses identified differences between ETV and TDF in achieving complete VR, with favorable outcomes more commonly reported for TDF,” Jaejun Lee, MD, of the division of gastroenterology and hepatology at Seoul St. Mary’s Hospital, College of Medicine at The Catholic University of Korea, and colleagues wrote.1 “There have been fewer publications addressing TAF or BSV, but some studies have shown that these NAs have similar efficacies to those of ETV and TDF.”

According to the World Health Organization, 254 million people were living with chronic hepatitis B infection in 2022, with 1.2 million new infections each year. HBV is preventable with a vaccine, but once infected, most patients must continue on medication for life.2 Thus, understanding the comparative efficacy of prominent HBV medications is important.

To estimate the relative efficacies of ETV, TDF, TAF, and BSV in treatment-naïve patients with chronic HBV, investigators conducted a network meta-analysis of randomized trials and propensity score-matched cohorts. An initial systematic search was performed using PubMed, Cochrane Library, and EMBASE and included randomized controlled trials (RCTs) and cohort studies performed with propensity score matching.1

Investigators collected information on HBV DNA suppression, HBsAg loss, hepatitis B e antigen (HBeAg) seroclearance, and alanine aminotransferase (ALT) normalization from the selected studies. The primary outcomes were virologic response at 48 weeks and 96 weeks after the start of treatment.1

A total of 11,870 articles were initially identified in the systematic search. After excluding 10,934 irrelevant studies, 936 articles were retrieved for abstract review, and 99 full-text articles were reviewed. In total, 7 RCTs and 9 prosperity-score matched cohort studies were selected for the network meta-analysis.1

Across the 16 selected studies, 15,000 patients were included. All of the studies were from Asian countries, including South Korea, Japan, China, Taiwan, and Thailand. Of the included participants, 1434 were from RCTs and 13,566 were from cohort studies.1

Investigators included 15 studies (6 RCTs and 9 cohort studies) for assessment of 48-week virologic response. Although most of the comparisons showed no significant differences in achieving virologic response at this time point, TDF achieved a significantly greater rate than ETV (Odds ratio [OR], 1.38; 95% CI, 1.19–1.59; P <.001). Moreover, using indirect comparison by network meta-analysis, TAF was more efficacious than ETV (OR, 1.48; 95% CI, 1.01–2.17; P = .044).1

For 96-week virologic response, 8 studies (2 RCTs and 6 cohort studies) were included. Investigators noted the efficacy outcomes were similar to those for 48-week virologic response, and the outcomes for TDF were superior to those for ETV (OR, 1.57; 95% CI, 1.15–2.13; P = .004).1

Investigators used a random-effects model meta-analysis to expand the analysis of ETV and TDF to 144 weeks. Consistent with the 48- and 96-week results, TDF again demonstrated a greater rate of virologic response than ETV (OR, 1.45; 95% CI, 1.14–1.85; P = .003).1

In total, 13 studies (6 RCTs and 7 cohort studies) were analyzed for biochemical response. In the 48-week analyses, contrary to the virologic response results, ETV was more likely to achieve 48-week biochemical response than TDF (OR, 0.76; 95% CI, 0.60–0.98; P = .028).1

Further analysis comparing 96-week biochemical response and 144-week biochemical response among patients receiving ETV or TDF was performed using a conventional meta-analysis. Consistent with the 48-week results, patients receiving TDF had a lower likelihood of achieving biochemical response than did those receiving ETV at both the 96- and 144-week time points (96BR: OR, 0.66; 95% CI, 0.55–0.80; P <.001; 144BR: OR, 0.71; 95% CI, 0.58–0.87; P = .001).1

In a sensitivity analysis including only RCTs, investigators observed similar tendencies, with TDF achieving a better outcome than ETV for 48-week virologic response (OR, 1.51; 95% CI, 1.04–2.19; P = .030).1

Investigators described potential limitations to these findings, including the limited number of RCTs eligible for inclusion due to the criteria requiring treatment naïvity; lack of examination of long-term outcomes and safety issues; and the lack of geographic diversity given the studies were all conducted in Asia-Pacific countries.1

“The present study found that TDF and TAF may be preferable to ETV in terms of VR, and ETV showed superior performance in terms of BR,” investigators concluded.1 “Our analyses can serve as a useful reference for NA selection strategies for treatment-naïve CHB patients. Further analyses of high-quality RCTs and long-term outcomes are needed to better understand the efficacy of each of the NA drugs and to guide clinicians in selecting the appropriate option.”


  1. Lee J, Lee A, Sung PS, et al. Efficacy comparison of high-genetic barrier nucleos(t)ide analogues in treatment-naïve chronic hepatitis B patients: a network meta-analysis. KJIM.
  2. World Health Organization. Hepatitis B. Newsroom. April 9, 2024. Accessed June 14, 2024.