MEETING HIGHLIGHT

Efficacy and safety profile of tenofovir alafenamide (TAF) for the treatment of CHB: An inspection of data from global and Chinese subset

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Prof. Lim, Young-Suk

Department of Gastroenterology,
Liver Center, Asan Medical Center,
University of Ulsan College of Medicine,
Seoul, South Korea

Nucleos(t)ide analogues (NAs) have been proven to be highly effective in suppressing the replication machinery of hepatitis B virus (HBV).1 While the first-line NAs effectively suppress the progression of chronic hepatitis B (CHB) infection, functional cure is rare with such treatments.1-3 In view of the indefinite duration of treatment, recent findings suggest that tenofovir alafenamide (TAF) seems to be the optimal choice for minimizing safety concerns whilst suppressing progression of CHB.1 Professor Young-Suk Lim from the University of Ulsan College of Medicine discussed the current problems facing CHB treatment and how tenofovir alafenamide appears to ameliorate them based on real-world data from clinical trials.

Current treatment options for CHB

One of the major hurdles in CHB treatment in terms of demographics is two-fold: Firstly, patients suffering from CHB need to be on medication indefinitely;1 and secondly, the global aging population continues to grow at a swift rate.  From a population projection study conducted in Hong Kong, it was estimated that the proportion of people aged 65 and above would double within the next 20 years – further increasing the likelihood for comorbidities in the aging demographic that suffers from CHB.4,5

Currently, the first-line recommendations for CHB treatment include NAs which have been effective in decreasing and suppressing viral replication in vivo, thus reducing the risk of further disease progression.1,6 Although the NAs have been effective in halting disease progression, long-term use of NAs (especially the older generations) have raised several concerns, consequently producing a novel problem in the process of suppressing the initial one. Of note, the latest recommendations from the American Association for the Study of Liver Diseases (AASLD) include entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF.7

The unmet needs of CHB and the shortcomings of current oral antiviral therapies

As mentioned previously, some of the NAs may lead to certain complications. Firstly, prolonged exposure to NAs often results in drug resistance. ETV resistance was observed after 5 years in 46% of the lamivudine (LAM)-refractory patients.7 To add to that, long-term use of TDF and ETV have been shown to increase renal disease progression as well as incidence of chronic kidney disease (CKD). In a propensity-score matched cohort study conducted in Hong Kong (n=4,458), the 5-year cumulative incidence of CKD progression was 47% in the ETV-treated group and 49% in the TDF-treated group.8

In fact, HBV infection alone is a risk factor for developing bone and renal adverse events. In a nationwide cohort study conducted in Taiwan (n=17,758), investigators found that end-stage renal disease (ESRD) was significantly more prevalent among CHB patients (12-year cumulative incidence, 1.87% vs. 0.49%; p<0.001) compared with the control cohort (Figure 1).9 Upon conducting further analysis, the Taiwanese researchers found that ESRD was 3.85 times more likely in the CHB subjects. Upon inspection of this data, it is evident that HBV infection alone makes for an independent risk factor for ESRD.


Furthermore, CHB has also been shown to play a role in bone toxicity.1,10 A nationwide study in Taiwan showed that the incidence and risk of osteoporosis is higher in patients with CHB compared to the controls, after adjusting for confounding factors such as age, sex, frequency of medical visits, and comorbidities (p for likelihood-ratio test: 0.009).10 There is an urgent need to minimize the risks for such comorbidities: for patient care as well as to reduce the burden on the medical field.

Tenofovir alafenamide (TAF) – The new and improved TFV prodrug

The latest drug approved for CHB treatment, TAF, appears to mitigate the problems associated with other NAs.1,6 One of the key pharmacokinetic issues associated with TDF is that despite a dosage of 300mg, a very small amount of the active form of the drug (TFV) ultimately enters the hepatocytes.11-12 Because the half-life of TDF is short, TFV ultimately gets taken up by the renal tubular cells rather than the hepatocytes. Hence, long-term systemic exposure to this phenomenon would result in increased renal stress and decreased efficacy of the drug on its initial target.12 On the other hand, TAF is characterized by a longer plasma half-life and a greater stability. At a dosage of 25mg, which is approximately one tenth of the dosage of TDF, TAF demonstrates a much better targeted delivery to hepatocytes compared to TDF.11,12

Tenofovir alafenamide (TAF) vs. tenofovir disoproxil fumarate (TDF): A closer examination of the Chinese subset within the clinical trials

TAF demonstrates improved rates of alanine aminotransferase (ALT) normalization, as well as better overall safety profile as compared to TDF.13,14 There are currently two double-blind, active-controlled global clinical trials that are studying TAF and TDF in HBeAg-negative (study 108; n=425) and HBeAg-positive (study 110; n=873) CHB patients.13,14 One of the secondary endpoints of the studies was ALT normalization at week 96, and “very interestingly, the patients who were included in the TAF group showed increased rate of ALT normalization during treatment, both in the HBeAg-negative and HBeAg-positive groups” Prof. Lim said.

For HBeAg-negative patients (in study 108), 50% of the TAF cohort achieved ALT normalization (vs. 40% for TDF; p=0.035) in the overall population, with Chinese patient subset showing similar findings (49% for TAF vs. 41% for TDF).13,15 For HBeAg-positive patients (in study 110), ALT normalization was shown to be much higher in TAF patients compared to TDF patients, both overall (52% for TAF vs. 42% for TDF; p=0.003) and within the Chinese patient subset (57% for TAF vs. 43% for TDF; Figure 2).14,15 These results indicate that for both HBeAg-negative and HBeAg-positive patients, ALT normalization occurs in a greater percentage of patients receiving TAF. The significance of ALT normalization lies in the fact that it would reduce the risk of hepatic events, such as cirrhosis, diabetes mellitus, and hepatocellular carcinomas (HCC).16

 

 

Apart from evaluating ALT levels, the studies also aimed to observe renal and bone safety, since toxicity has been a major concern with CHB patients. At 96 weeks, it was found that TAF treatment had significantly less impact than TDF on estimated glomerular filtration rate by the Cockcroft-Gault method (eGFRGC) in both the HBeAg-negative (a median change in eGFRGC of -3.6mL/min with TDF vs. TAF with -0.6mL/min; p=0.011) and HBeAg-positive studies (a median change in eGFRGC of -5.0mL/min with TDF vs. TAF with -1.8mL/min; p<0.001).13,14 In addition to an improved renal profile, the investigators also sought out to evaluate bone mineral density (BMD) in their subjects. They investigated mean changes in BMD over 96 weeks and found that TAF treatment resulted in smaller declines in hip BMD (-0.33% vs. -2.51% with TDF; p<0.001) as well was in spine BMD (-0.75% vs. -2.57% with TDF; p=0.80).17

Continuous improvement of ALT normalization rate and safety parameters after switching to tenofovir alafenamide (TAF)

At the 96-week point, the investigators conducting studies 108 and 110 switched the subjects receiving TDF treatment to TAF to observe whether the toxicities due to long-term TDF treatment were reversible.18 Studies 108 and 110 were thereby extended for 48 weeks, and patients who had been taking TDF until week 96 were switched to TAF. Whilst viral suppression rates remained relatively unchanged by week 144 (88% at week 96 vs. 89% at week 144), there was a notable increase in patients who achieved ALT normalization after being switched from TDF to TAF.18 At week 96, 47% of the TDF group demonstrated ALT normalization based on AASLD criteria. However, at week 144 (after switching to TAF), a significantly higher percentage of subjects achieved ALT normalization (65%; p<0.001).18 “The mechanism of ALT normalization in the TAF group is not clearly known, however… ALT normalization during treatment has significant clinical implications,” Prof. Lim said.

In addition to improved ALT normalization rates, the researchers also found that switching to TAF at week 96 resulted in reversal of bone and renal damage. Improvements were seen in the BMD of hip (-2.7% at week 96 vs. -1.6% at week 144; p<0.001) and spine (-3.1% at week 96 vs. -1.2% at week 144; p<0.001). 17 Similarly, the eGFRCG increased at week 144 in patients when compared to the value at week 96 (-4.8% at week 96 vs. -1.2% at week 144; p<0.001).18 The notable improvement in ALT normalization and overall safety parameters upon switching to TAF provides a ray of hope for CHB patients who had previously been taking TDF.

Conclusion

Based on the findings from the clinical trials (studies 108 and 110), TAF is recognized to be the preferred treatment option for CHB patients, in view of its high efficacy and favorable safety profile.1,13,14 TAF mitigates the common problems linked to long-term treatment with oral antiviral medication and the aging CHB population, owing to its optimized pharmacokinetic design: a lower drug dosage; lower overall systemic exposure; and higher efficacy in drug delivery.11,12

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