Tenofovir amibufenamide: A potential alternative for chronic hepatitis B treatment

Abstract

Tenofovir amibufenamide (TMF) is a novel prodrug of tenofovir that demonstrates a promising safety and efficacy profile. A recent study by Peng et al compared TMF with tenofovir alafenamide in the treatment of chronic hepatitis B. The findings indicated that both medications offer similar efficacy in terms of viral response and alanine aminotransferase normalization. Notably, TMF showed potential advantages in lipid management, as it did not significantly affect cholesterol levels, unlike tenofovir alafenamide. This correspondence highlights the need for further research to evaluate the long-term safety and efficacy of TMF, its impact on cardiovascular risk, and its use in specific patient populations.

Key Words: Tenofovir amibufenamide; Tenofovir alafenamide; Chronic hepatitis B; Antiviral efficacy; Safety profile; Hyperlipidemia

Core Tip: Tenofovir amibufenamide demonstrates comparable efficacy to tenofovir alafenamide in the treatment of chronic hepatitis B. Tenofovir amibufenamide offers improved safety, particularly in lipid management, with minimal effects on bone and renal health. Its favorable metabolic profile makes it an attractive option for patients with hyperlipidemia, providing antiviral efficacy without compromising metabolic health. Large-scale, multicenter studies are essential to validate long-term outcomes and its suitability for special patient populations.

TO THE EDITOR

This article provides insights from the recent publication by Peng et al[1], published in the World Journal of Gastroenterology. In their retrospective analysis, Peng et al[1] compared the efficacy and safety of tenofovir alafenamide (TAF) and tenofovir amibufenamide (TMF) in 215 chronic hepatitis B (CHB) patients over 48 weeks. The results revealed no significant differences in virological response (78.57% vs 78.65%) rate and alanine aminotransferase (ALT) normalization (78.30% vs 74.31%) between the two groups. However, the study identified a notable increase in total cholesterol levels in the TAF group, suggesting a potential advantage of TMF in lipid management. The findings of this study have important implications for clinical practice. TMF’s comparable efficacy and safety to TAF, along with its potential benefit in lipid profiles, make it a promising option for certain patient populations, particularly those requiring long-term treatment and facing cardiovascular risks. Clinicians should adopt a comprehensive approach when selecting antiviral therapy, carefully weighing antiviral efficacy against potential effects on overall health, including renal function and lipid metabolism.

Strength and limitations of the study

The study’s strength lies in its real-world comparison of TMF and TAF, offering valuable insights into their clinical utility. TMF’s efficacy and safety profile, similar to that of TAF, supports its consideration as a viable treatment option. The observed impact of TAF on lipid profiles underscores the importance of monitoring and individualized treatment approaches, particularly in patients with pre-existing cardiovascular risks. However, while the study provides valuable data, several limitations should be taken into account. The relatively short follow-up period of 48 weeks may not capture the long-term effects of the drugs. Especially in the case of CHB, the clearance of the virus and the therapeutic efficacy of antiviral treatment may take a considerable amount of time to manifest. Evaluating the effectiveness of antiviral therapy in the short term can be challenging, as issues such as drug resistance and viral relapse may emerge during treatment. Thus, short-term observation may not fully reflect these long-term outcomes.

Additionally, as a single-center retrospective study with a small sample size, the study may be subject to selection bias, limiting its external validity and generalizability. Given the increasing global availability of TMF, it is important to assess the broader applicability of the findings. Future multi-center, large-sample prospective studies are recommended to enhance the study’s external validity and generalizability, alongside longer follow-up periods to evaluate the long-term effects of treatment. For example, Liu et al’s study[2] found that patients with CHB maintained robust virological and biochemical responses, with hepatitis B virus (HBV)-DNA concentrations remaining below 20 IU/mL after 144 weeks of treatment (86.2% vs 83.3%), whether after 144 weeks of TMF treatment or following a switch from 96 weeks of tenofovir disoproxil fumarate (TDF) to 48 weeks of TMF. This research not only confirms the findings of Peng et al’s study[1] but also underscores the need for additional studies with larger, multicenter cohorts and longer follow-up periods.

Liu et al[3] reported that TDF may induce weight loss, while TMF is associated with minor weight gain. In contrast, Peng et al’s study[1] did not examine the effects of TMF and TAF on patient weight. The reliance on serum creatinine and estimated glomerular filtration rate (eGFR) as renal function markers is also limited, as creatinine clearance is insensitive to mild impairment. Furthermore, the eGFR (Chronic Kidney Disease Epidemiology Collaboration) formula, which does not account for body weight, may introduce bias. Using the non-indexed eGFR (Chronic Kidney Disease Epidemiology Collaboration) would have offered a more accurate evaluation of TMF’s renal impact[4]. To improve the study’s reliability, it would be beneficial to incorporate additional indicators of renal tubular function, as suggested by clinical pharmacological research. Additionally, the omission of bone health data, such as dual-energy X-ray absorptiometry scan results, limits a comprehensive safety assessment, which is essential for evaluating long-term treatment effects in chronic diseases.

In their assessment of TMF and TAF in cirrhotic patients, Peng et al[1] relied on fibrosis-4 (FIB-4) and liver stiffness measurement (LSM) scores to evaluate efficacy and safety. The study found that the TAF group exhibited a more significant decrease in FIB-4 scores compared to TMF, with no notable differences in LSM values. However, the use of LSM and FIB-4 to assess fibrosis regression during antiviral therapy in CHB patients is questionable, as these metrics may not reliably reflect fibrosis reversal. In contrast, the age-male-albumin-bilirubin-platelets score has emerged as a promising noninvasive diagnostic tool for fibrosis in CHB patients. Moreover, the age-male-albumin-bilirubin-platelets-LSM model has demonstrated greater accuracy in estimating the liver fibrosis stage in treated CHB patients[5]. This limitation in Peng et al’s study[1] underscores the potential inaccuracies in using LSM and FIB-4 as sole indicators of treatment efficacy in fibrotic CHB.

Comparison of TMF and TAF

CHB represents a significant global health burden, leading to liver fibrosis, cirrhosis, hepatocellular carcinoma, and approximately 820000 deaths each year[1]. The persistence of viral DNA in the liver necessitates long-term nucleoside analog therapy for most patients[6]. TAF and TMF are notable nucleoside analog prodrugs of tenofovir. Once converted to tenofovir-diphosphate in hepatocytes, they inhibit HBV polymerase/reverse transcriptase. TAF results in 90% lower circulating tenofovir levels compared to TDF, improving renal and bone safety, though it may impact lipid metabolism[7]. TMF, with an added methyl group, potentially increases stability in peripheral blood and more effectively targets hepatocytes, while maintaining the efficacy of TDF[8]. However, direct comparisons between TMF and TAF are limited. To address this gap, we conducted a comparative analysis of the two drugs based on the study by Peng et al[1] (Table 1).

Table 1 Comparison of drug characteristics between tenofovir amibufenamide and tenofovir alafenamide.

	TMF	TAF
Safety	Safe, well-tolerated long-term	Safe, effective, tolerable long-term
Efficacy	Superior long-term efficacy to TAF	Better than TDF, not as good as TMF
Cost-effectiveness	Research data lacking	Cost-effective vs tenofovir, entecavir in wealthier regions
Lipid profiles	Minimal impact on blood lipids, no increased ASCVD risk	May cause dyslipidemia, monitor blood lipids
Special populations	Safe for ages 65+, data lacking for pregnant women, children	Suitable for pregnant women, children aged 12 and older

TMF: Tenofovir amibufenamide; TAF: Tenofovir alafenamide; TDF: Tenofovir disoproxil fumarate; ASCVD: Atherosclerotic cardiovascular disease.

Safety: Peng et al[1] found that TMF and TAF have comparable safety profiles in the treatment of CHB. Chan et al[7] reported that long-term TAF treatment effectively suppressed HBV, showed no resistance, and preserved renal and bone safety. Similarly, Liu et al[3] observed favorable safety outcomes after 144 weeks of TMF treatment, with improved renal and bone safety following a switch from TDF.

Efficacy: TMF appears to outperform TAF in terms of efficacy. Liu et al[2] found that 88.7% of CHB patients on TMF for 144 weeks exhibited superior virological and biochemical responses, with HBV DNA levels below 29 IU/mL. Furthermore, switching from TDF to TMF after 96 weeks enhanced these responses without resistance. In contrast, the TAF registration study conducted in mainland China reported that 87.6% of TAF-treated patients achieved similar HBV DNA levels, though direct comparison with TMF was limited by differences in patient populations. Hepatitis B e antigen seroconversion rates were higher for both the TMF-naive (37.0%) and TDF-switch groups (34.4%) compared to TAF’s rate of 23% in mainland China and 24% internationally at 144 weeks. Chan et al[7] reported a seroconversion rate of 33.8% for TAF after 240 weeks. Additionally, after 240 weeks of TAF, 68.4% of patients normalized ALT, which was less than the 78.5% normalization rate in the TMF group after 144 weeks as reported by Liu et al[2].

Tolerability: Both TMF and TAF are well-tolerated. Liu et al[2] found TMF treatment well-tolerated from 96 to 144 weeks in both TMF-naive and TDF-experienced patients. Chan et al[7] reported no resistance after switching from 2-3 years of TDF to 5 years of TAF.

Medication uses in special populations: Pan et al’s systematic review[9] revealed no significant difference between TAF and TDF in preventing HBV transmission from mother to child. The 2022 China CHB prevention and treatment guidelines suggest TAF as a treatment option for children aged 12 and older with advanced liver disease or cirrhosis[10]. To date, there is no data supporting the use of TMF in pregnant women or children. Chu et al[11] evaluated TMF’s effectiveness and safety in CHB and cirrhosis patients aged 65 and older, finding that TMF significantly reduced HBV DNA replication, normalized ALT levels, and was well-tolerated.

Patients with cirrhosis: Rong et al[12] demonstrated that both TMF and TAF can rapidly suppress HBV replication, improve liver function, and have no negative impact on renal function in HBV-related decompensated cirrhosis patients. Regarding lipid metabolism, both drugs demonstrated favorable safety profiles, with regular blood lipid level monitoring recommended.

Economy: Dai et al[13] conducted a cost-effectiveness analysis of first-line therapies for CHB in China, including TAF, TDF, entecavir, and pegylated interferon. Among nucleotide analogs, TAF was the most effective and showed higher acceptability for achieving optimal outcomes in eastern China (under the 1 × gross domestic product per capita threshold). Given the relatively recent market launch of TMF, sufficient clinical or economic research data may not yet be available.

Conclusion

TMF emerges as a promising alternative for CHB treatment, offering comparable efficacy to TAF with potential advantages in lipid management. While current evidence suggests TMF’s favorable safety and efficacy profiles, further research is crucial to fully evaluate its long-term impact and suitability for all patient populations. Specifically, large-scale, multicenter studies with extended follow-up periods are required to evaluate the safety and efficacy of TMF, particularly in comparison with TAF. Additionally, research is essential to explore the mechanisms underlying TMF’s effects on lipid profiles and to investigate its use in special populations, including pregnant women and children. By addressing these knowledge gaps, TMF could become a valuable treatment option for CHB, especially for patients with hyperlipidemia or those requiring antiviral therapy with minimal impact on bone and renal health.