Cardiovascular risk of tenofovir disoproxil fumarate or tenofovir alafenamide in patients with chronic hepatitis B: More questions than an answer

Hepatitis B virus (HBV) infection has been associated with lower cardiometabolic risks and even a protective factor for major adverse cardiovascular events (MACE) when compared with hepatitis C virus infected patients or controls [1-3]. Antiviral treatment also provides a lower risk of MACE than those without antiviral treatment in patients with chronic hepatitis B [4]. As the lipid-lowering effect has been unexpectedly and uniquely observed in patients treated with tenofovir disoproxil fumarate (TDF) but not in those treated with tenofovir alafenamide (TAF), their impact on long-term MACE has been raised. A recent retrospective study from Korea by Hong et al. investigated the risk of MACE in patients with chronic hepatitis B (CHB) treated by TDF or TAF. After propensity score matching to control confounding factors, a comparable risk of long-term MACE between TDF- and TAF-treated patients was observed despite different lipid profiles between the two groups [5]. This study provides important information to some degree to answer the uncertain association of TDF or TAF with cardiovascular outcomes. However, unresolved issues remain and need to be investigated.

In Hong’s study, significantly lower lipid profiles were observed in TDF-treated patients rather than in TAF-treated patients [5], which was consistent with a previous study that showed TDF reduced lipid profiles in HBV patients, when compared to TAF [6]. A Recent study further demonstrated that the lipid profiles greatly increased in HBV patients switching from TDF to TAF, but not in patients switching from entecavir to TAF [7]. Meanwhile, the presence of metabolic traits, including gain of body weight, worsening of insulin resistance, and a trend towards increased atherosclerotic cardiovascular disease scores, may possibly predispose to cardiovascular diseases in TDF-switch patients. These results indicated that TDF and TAF may exert effects on metabolic risk factors other than lipid profiles. In contrast to the lipid-lowering effects of TDF, TAF monotherapy could greatly increase lipid profiles when compared with entecavir monotherapy [8]. In patients with human immunodeficiency virus infection, the TAF-containing regimen did show an increase in lipids compared to the non-TAF-containing regimen [9]. The two phase 3 studies also showed progressively increased low-density lipoprotein and triglycerides, but decreased high-density lipoprotein during 5-year TAF treatment for CHB patients [10]. These results may imply that TAF alone may induce changes in lipid profiles, increasing the risk of MACE. Therefore, the investigations on mechanisms of lipid changes associated with TDF or TAF treatment are important not only to clarify the mechanisms of changes in lipid profiles but also to understand the detailed changes in lipid components that are beneficial or harmful to the occurrence of MACE. From these points of view, more studies addressing the association between TDF/TAF and MACE are needed.

The established common risk factors for MACE include hypertension, diabetes, obesity, hyperlipidemia, tobacco smoking, a sedentary lifestyle, and a lack of adequate physical activities [11]. As expected, Hong’s study showed that active smoking and a history of cardiovascular events were the two independent factors associated with an increased risk of MACE. As the HBV infection has been known not to be a risk factor for MACE, the association between long-term TDF/TAF treatment and changes in lipid profiles may influence or add impacts on cardiovascular risk for certain degree, if any, but not serve as one of the major determinants. For long-term outcomes in CHB patients, liver-related complications remain the main causes of morbidity and mortality. In addition to chronic viral hepatitis, metabolic derangements also contribute to the progression of liver diseases. Traditional risk factors for developing MACE still play a central and important role. Furthermore, HBV infection has been reported to be inversely associated with hepatic steatosis [12]. As MACE and metabolic dysfunction-associated fatty disease (MAFLD) share common risk factors, cardiovascular disease is the leading cause of mortality in patients with MAFLD [13]. Patients with simultaneous CHB and MAFLD tend to have accelerated progression of liver disease, exhibit more liver-related complications, and have a higher death rate than patients with CHB alone or MAFLD alone [14]. In Hong’s study, the prevalence of HBV patients with the diagnosis of fatty liver was much lower than the reported prevalence in the general population of Korea (15.4% vs. 32.9%) [15]. The impact of MAFLD on MACE may be underestimated; hence, the effect of TDF/TAF on MACE is supposed to be further minimized in CHB patients. In this aspect, risk factors for MACE may play a more dominant role. Moreover, Hong’s study conducted a retrospective design with chart review in one medical hospital, which may introduce selection bias and confounding factors. The cohort effect due to the late introduction of TAF to the market might also contribute to the imbalance in the proportion of patients taking lipid-lowering agents and the misinterpretation of the effect on MACE between the TAF- and TDF-treated groups.

There are several issues that need to be further clarified. First, long-term use of TDF/TAF is always required for the majority of CHB patients. Safety concerns should be taken into account. Unclear mechanisms of TDF/TAF make the impact of lipid changes on MACE uncertain. At present, whether the lipid profiles related to TDF/TAF are truly “benefit” or “bad” for MACE remains to be resolved. Second, the risk of MAFLD in CHB patients warrants stratification of MACE risk according to the grade of cardiometabolic risk factors. In the current era, metabolic derangements contribute to diseases of different organs and have become an important determinant of outcome measurements. Evaluation of MACE risk in the presence of cardiometabolic risk factors is warranted in the long-term care of CHB patients under antiviral therapy.

Authors’ contribution

PN Cheng drafted the manuscript. ML Yu reviewed and finalized the manuscript.

Acknowledgments

Prof ML Yu receives research grant from the “Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung” from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.

Conflicts of Interest

The authors have no conflicts to disclose.

Abbreviations

HBV, hepatitis B virus; MACE, major adverse cardiovascular events; TDF, tenofovir disoproxil fumarate; TAF, tenofovir alafenamide; CHB, chronic hepatitis B; MAFLD, metabolic dysfunction-associated fatty disease

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