Both tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are the first-line treatments for chronic hepatitis B (CHB). We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase (ALT) improvement, but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis.

To assess the benefits of TDF switching to TAF for 3 years on ALT, aspartate aminotransferase (AST), and hepatic fibrosis improvement in patients with CHB.

A single center retrospective study on 53 patients with CHB who were initially treated with TDF, then switched to TAF to determine dynamic patterns of ALT, AST, AST to platelet ratio index (APRI), fibrosis-4 (FIB-4) scores, and shear wave elastography (SWE) reading improvement at switching week 144, and the associated factors.

The mean age was 55 (28-80); 45.3%, males; 15.1%, clinical cirrhosis; mean baseline ALT, 24.8; AST, 25.7 U/L; APRI, 0.37; and FIB-4, 1.66. After 144 weeks TDF switching to TAF, mean ALT and AST were reduced to 19.7 and 21, respectively. From baseline to switching week 144, the rates of ALT and AST < 35 (male)/25 (female) and < 30 (male)/19 (female) were persistently increased; hepatic fibrosis was also improved by APRI < 0.5, from 79.2% to 96.2%; FIB-4 < 1.45, from 52.8% to 58.5%, respectively; mean APRI was reduced to 0.27; FIB-4, to 1.38; and mean SWE reading, from 7.05 to 6.30 kPa after a mean of 109 weeks switching. The renal function was stable and the frequency of patients with glomerular filtration rate > 60 mL/min was increased from 86.5% at baseline to 88.2% at switching week 144.

Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement, but also hepatic fibrosis improvement by APRI, FIB-4 scores, as well as SWE reading, the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

Hepatitis B virus (HBV) infection is a major global health concern that involves the risk of cirrhosis and hepatocellular carcinoma (HCC). World Health Organization estimates that approximately 296 million people were living with chronic HBV infection in 2019, with approximately 1.5 million people become newly infected each year. In 2019, chronic hepatitis B (CHB) resulted in an estimated 820000 deaths, mostly from cirrhosis and HCC[1]. Antiviral therapy with nucleos(t)ide analogues (NAs) is currently the main treatment option that has significantly improved the outcomes in patients with CHB. The NAs, tenofovir disoproxil fumarate (TDF), approved in 2008, and entecavir (ETV), approved in 2005, have been recommended by international guidelines and used as first-line therapy for CHB. Prolonged treatment with these NAs has been associated with reduction in progression to cirrhosis, lower risk of HCC, and reversal of hepatic decompensation by sustained suppression of HBV DNA[2-4]. Tenofovir alafenamide (TAF), approved in 2016, provided another treatment option for patients with CHB. Compared to TDF, TAF is a prodrug of tenofovir with greater plasma stability, allowing for more efficient uptake by hepatocytes with less peripheral and renal exposure of metabolites, tenofovir diphosphate, thus, better safety profile and has becomes one of the first line options for HBV treatment[5,6].

Stage of liver fibrosis is very important to determine severity and prognosis, and prioritize for treatment in CHB patients. Previously, the only method of staging fibrosis was liver biopsy, which has been the gold standard[7]. In addition to staging fibrosis, it can grade necrosis, and inflammatory activities. However, there are limitations of this procedure, including cost, risk of serious complications, sampling errors, and observer technical differences[8]. Various non-invasive methods ranging from serum markers to imaging techniques have been developed over the past decade to stage liver fibrosis. Several scoring systems, such as aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis index based on four factors (Fibrosis-4 index, FIB-4) have been widely validated in large cohort studies[9,10]. Liver stiffness measurement (LSM) is another option to stage liver fibrosis noninvasively, including transient elastography (TE) and shear wave elastography (SWE)[11,12].

Prior studies have demonstrated the benefits of switching from TDF to TAF, including better renal profile and bone safety[13-16]. Previously, we have showed switching from TDF to TAF treatment for 96 weeks resulted in alanine aminotransferase (ALT) improvement, but data remain lacking on its long-term effect on biochemical changes and hepatic fibrosis[17]. The present study assessed the effect of TDF switching to TAF for 3 years (144 weeks) on dynamic changes of ALT, AST, APRI, FIB-4 scores and SWE reading, and the associated factors.

To our knowledge, few real-world studies have thus far reported the benefits of switching from TDF to TAF for up to week 96[17,18], but there is limited data on long-term benefit of this switching to beyond 96 weeks, including fibrosis improvement. Our study evaluated the clinical benefits after 144 weeks of TDF switching to TAF by assessing the changes in biochemical markers ALT and AST, non-invasive fibrosis score APRI and FIB-4, and LSM by SWE.

ALT normalization under antiviral treatment has been associated with a decrease in viral replication, tissue damage and necroinflammation. A significant reduction of liver enzymes was observed after switching from TDF to TAF for 6 months[22]. Our previous and other studies showed that switching from TDF to TAF resulted in high rates of ALT and AST improvement at switching week 96[17,18,23]. The present study further assessed the benefit of switching from TDF to TAF for 144 weeks. We demonstrated that the mean ALT was further reduced from 24.8 to 19.6 and 19.7 U/L, and the mean AST was also reduced from 25.7 to 21.2 and 21 U/L from baseline to week 96 and week 144 switching, respectively. Our study showed further persistent improvement rate of both ALT/AST to < 35/25 from baseline to post-switching week 144. These results were not only consistent with Toyoda et al[23] study which showed great improvement of ALT/AST < 35/25 at switching week 96, but also demonstrated further persistent improvement from week 96 to week 144 after the switching. In addition, we found the improvement rates of ALT, AST, and both ALT/AST to < 30/19 were also persistently increased from baseline to post-switching week 144. Our data demonstrated the additional benefit of ALT/AST improvement by both < 35/25 and < 30/19 criteria with overall 21% reduction in mean ALT and 18% reduction in mean AST, and improved rates of both ALT and AST normalization, after TDF to TAF switching for 144 weeks.

Our study showed that ALT and AST improvement to < 30 (U/L) for men and < 19 (U/L) for women of at switching week 144 was significantly associated with male gender, ALT < 30/19 and < 35/25, APRI < 0.5 at 24 week switching, but not age, BMI, cirrhosis, pre-Rx spleen size > 12 cm, platelet < 120 × 10⁹/L, AST < 30/19, and < 35/25 at 24 week switching. Our real world data confirmed results from the published studies which show TAF results in continued improvement not only viral suppression, but also ALT and AST normalization[14,16], a unique benefit of long-term TAF treatment.

Besides ALT/AST normalization, another goal of HBV treatment is to slow down the progression of liver fibrosis and even to achieve resolution of liver fibrosis[24,25]. Our previous study showed that HCV direct acting antiviral treatment resulted in highly durable improvement rates of ALT and AST, APRI and FIB-4 scores in HCV patients[26]. Liu et al[27] reported a significant decrease of both APRI and FIB-4 after 5 years of treatment with ETV in HBeAg-negative CHB patients. There were limited studies on the effect of switching TDF to TAF on the improvement of APRI and FIB-4 scores. Our study demonstrated the mean APRI was significantly reduced from 0.37 to 0.27 and the improvement rate of APRI to < 0.5 was increased from 79.2% to 96.2%, equal to 27% reduction in mean APRI and 1.2-times improvement rate of APRI to < 0.5. Likewise, we also found that the mean FIB-4 score was significantly reduced from 1.66 to 1.38 and the improvement rate of FIB-4 to < 1.45 was increased from 52.8% to 58.5%, equal to 16.9% reduction in mean FIB-4, and 1.1-times improvement rate of FIB-4 to < 1.45 after the switching to TAF for 144 weeks. Univariate analysis showed that the improvement of APRI to < 0.5 and FIB-4 to < 1.45 was both significantly associated with absence of clinical cirrhosis. Our study demonstrated switching from TDF to TAF for 144 weeks resulted in hepatic fibrosis regression in CHB patients with persistent improvement by APRI and FIB-4 scores, another important benefit of such treatment switch. Additionally, our data provided supportive evidence of clinical application of both APRI and FIB-4 scores in assessing the effectiveness of HBV antiviral treatment.

LSM, including TE and SWE, has become a standard clinical practice for liver fibrosis assessment. To further determine the long-term clinical benefit of TDF switching to TAF in liver fibrosis improvement as indicated by APRI and FIB-4 scores, we assessed if 144 weeks switching could also impact SWE reading. We found that after switching from TDF to TAF for a mean of 109 weeks, the mean SWE reading was improved from 7.05 to 6.30 kPa, equal to 10.6% score improvement, and the rate of fibrosis stage 0-1 was increased from 64% to 86%, equal to 34.4% improvement. Together with APRI and FIB-4 scores improvement, the above SWE results further confirmed clinical benefits and superiority in liver fibrosis improvement after switching from TDF to TAF for 144 weeks. These benefits might be due to TAF has greater stability in plasma than TDF that allows more efficient uptake by hepatocytes and higher circulating intra-hepatocytic concentration of active metabolites allowing more prominent liver targeting ability[5,6]. In addition, TAF enters hepatocytes by passive diffusion and efficiently taken up by hepatocytes and then hydrolyze to form tenofovir which undergoes phosphorylation to active metabolite, tenofovir diphosphate, provides more persistent intracellular level of tenofovir diphosphate, a potent inhibitor of HBV replication[28,29] and results in more reduced hepatic inflammation and liver fibrosis.

In the present study, our results also showed the renal benefits after switching from TDF to TAF. After 144 weeks of switching, the renal function was stable and even further improved as indicated by stable mean serum creatinine and increased rate of GFR > 60 mL/min from 86.5% at baseline to 88.2%. Our data was consistent with previous studies on the renal benefits of TAF switching[13,14].

Some limitations should be noted in our study. First, this was a single-center retrospective study with small sample size, especially the patients with advanced liver fibrosis. Secondly, we did not have follow-up liver biopsy data to reference the non-invasive fibrosis test results. However, it is the first study to further assess the long-term benefits of switching TDF to TAF on biochemical changes of ALT, AST, APRI, FIB-4 scores and SWE reading. Future studies with larger sample size are warranted to confirm our findings.

In summary, the present study demonstrated that switching from TDF to TAF for 3 years results in not only persistent ALT and AST improvement, but also hepatic fibrosis improvement assessed by APRI and FIB-4 scores, as well as SWE reading, the important clinical benefits of long-term HBV antiviral treatment with TAF.