To the Editor,
We read with great interest the article by Chuo et al. on the large-scale retrospective study concerning antiretroviral therapy (ART) regimens and advanced liver disease events in people with HIV and hepatitis B virus (HBV) coinfection [1]. The findings, derived from real-world data, suggest that tenofovir alafenamide (TAF)- and tenofovir disoproxil fumarate (TDF)-based therapies reduce liver events compared to non-tenofovir regimens, which provides clinically important insights. However, we would like to raise two critical points regarding the interpretation and clinical application of these results.
First, we believe it is highly probable that the large effect difference reported between regimens reflects severe confounding (i.e., channeling bias) rather than a drug-specific effect. The study by Chuo et al. shows a markedly higher prevalence of baseline renal impairment in the non-tenofovir group (16%) compared to the TAF group (7%) [1]. This strongly suggests that clinicians avoided tenofovir because of renal concerns, resulting in a concentration of patients with higher clinical risk in the non-tenofovir arm. More importantly, the study defines HIV/HBV coinfection based solely on ICD-10 codes, lacking data on disease activity such as HBV DNA levels or the degree of liver fibrosis. Consequently, the non-tenofovir group may represent a heterogeneous population with suboptimal quality of care, where HBV coinfection may have been overlooked, inadequately monitored, or undertreated, thereby including patients with more advanced liver disease at baseline. Indeed, a meta-analysis by Tan et al. comparing TDF and entecavir—both potent anti-HBV agents—found no clinically meaningful difference in the risk of hepatocellular carcinoma (HCC) [2]. This implies that the difference between potent agents is minimal when appropriate HBV treatment is administered, and it is reasonable to interpret the disparity seen in Chuo et al.’s study as a reflection of the presence or absence of adequate HBV management.
Second, an emphasis on the hepatoprotective effect of TAF may increase the risk of clinicians overlooking another critical aspect: its potential contribution to metabolic dysfunction-associated fatty liver disease (MAFLD) in people with HIV (PWH). The prevalence of MAFLD is a growing clinical challenge in the PWH population. A prospective cohort study in Switzerland by Riebensahm et al. found that 51% of PWH had hepatic steatosis, and multivariable analysis revealed that current use of TAF was independently associated with this condition (adjusted odds ratio, 1.70; 95% confidence interval, 1.08–2.69) [3]. This association remained significant even after adjusting for the effect of weight gain, suggesting TAF may influence hepatic lipid metabolism through mechanisms other than weight gain. While the paper by Chuo et al. highlights an important benefit of TAF in suppressing HBV-related liver disease, it does not address its potential to promote metabolic liver disease like MAFLD.
In conclusion, we posit that the superiority of tenofovir-based regimens demonstrated in the study by Chuo et al. is likely a reflection of selection bias and the quality of HBV management rather than a true drug effect. In clinical practice, the decision to prescribe TAF for patients with HIV/HBV coinfection requires a comprehensive assessment that balances the clear benefit of HBV suppression against the potential risk of MAFLD development and progression, necessitating careful judgment based on the individual patient’s metabolic profile.
Sincerely,
Keiji Konishi
Acknowledgments
Medical Writing, Editorial and Other Assistance
The author acknowledges the use of an AI assistant (Gemini 2.5 Pro, Google) for assistance in drafting the response to reviewer comments and implementing the required editorial revisions for formatting and style.
Author Contributions
Keiji Konishi was solely responsible for the conception, literature review, drafting, and critical revision of this letter. The author read and approved the final submitted version.
Funding
No funding was received for the preparation of this letter.
Data Availability
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.
Declarations
Conflict of Interest
Keiji Konishi declares that he has no competing interests.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by the author.
Footnotes
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References
- 1.Chuo CY, Zachry W, de Boer M, et al. Advanced liver disease events in people with HIV and hepatitis B virus coinfection initiating antiretroviral therapy in the United States. Infect Dis Ther. 2025;14:1829–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Tan DJH, Ng CH, Tay PWL, et al. Risk of hepatocellular carcinoma with tenofovir vs entecavir treatment for chronic hepatitis B virus: a reconstructed individual patient data meta-analysis. JAMA Netw Open. 2022;5(6):e2219407. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Riebensahm C, Berzigotti A, Surial B, et al. Factors associated with liver steatosis in people with human immunodeficiency virus on contemporary antiretroviral therapy. Open Forum Infect Dis. 2022;9(11):ofac538. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Data Availability Statement
Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.