Is tenofovir more effective than entecavir to prevent hepatocellular carcinoma? The controversy goes on
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LETTER TO THE EDITOR
Is tenofovir more effective than entecavir to prevent hepatocellular carcinoma? The controversy goes on Cheng‑Hao Tseng1 · Mindie H. Nguyen2 · Yao‑Chun Hsu3,4 Received: 18 March 2020 / Accepted: 3 August 2020 © Asian Pacific Association for the Study of the Liver 2020
To the Editor: We read with great interest the recently published article entitled “Tenofovir versus entecavir in lowering the risk of hepatocellular carcinoma development in patients with chronic hepatitis B: a critical systematic review and meta‐ analysis” by Li et al., which concluded that “compared with entecavir, tenofovir disoproxil fumarate treatment tended to have a lower overall cumulative incidence rate of HCC” [1]. In addition, the authors also cautioned that “disparity in follow-up duration may be a key factor to influence the result”. We would like to congratulate the authors on their accomplishment of this study and especially for drawing attention to the key bias that may result from differences in the follow-up duration and thus the differential hepatocellular carcinoma (HCC) incidence rates between the tenofovir disoproxil fumarate (TDF) and the entecavir (ETV) cohorts. Indeed, such differences are inherent due to the rather long delay of drug approval and reimbursement for TDF as compared to ETV in East Asia, where the vast majority of the data on this topic have been derived from. However, we have some concerns. First, this meta-analysis included several studies that may enroll overlapping patient cohorts. For example, patients enrolled in the singcenter study reported by Song and colleagues may also be included in the four-center study reported by Cho and colleagues, given that the two abstracts were similar in design * Yao‑Chun Hsu [email protected] 1
Division of Gastroenterology and Hepatology, E-DA Cancer Hospital/I-Shou University, Kaohsiung, Taiwan
2
Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
3
Center for Liver Diseases, E-Da Hospital, Kaohsiung, Taiwan
4
School of Medicine, College of Medicine, I-Shou University, Kaohsiung, Taiwan
and published in the same year (2018). Second, it is unclear why the authors chose to analyze unmatched and unadjusted data in studies where matched or adjusted data were available. In the REAL-B consortium for example [2], patients treated with ETV were significantly older and sicker than patients treated with TDF prior to matching; and therefore, the unadjusted risk ratio for HCC from unmatched data was obviously confounded and should not have been used as done by Li and colleagues (Fig. 2a) [1] when matched data were available. Third, it is not clear how the authors addressed studies with missing outcome data or no event occurrence in a treatment group. For instance, it was unclear how the risk ratio and confidence interval were estimated from the study by Hsu et al. [3], in which no HCC occurred in the TDF group during the observation period. In addition, this meta-analysis included some studies t
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