Role of TAF in the potentially lifelong treatment of CHB
Oral antiviral treatments with nucleos(t)ide analogues (NAs) are highly effective in suppressing hepatitis B virus (HBV) replication.1 However, most patients with chronic HBV (CHB) infection still require a long-term therapy, as viral suppression with NAs rarely leads to functional cure.1,2 Considering the successful achievement of hepatitis C virus (HCV) cure with a simple drug regimen,3 current investigations on novel molecules may bring us closer to achieving functional cure (and even complete cure) in CHB infection. In the meantime, I would like to share the benefits of using tenofovir alafenamide (TAF) in our clinical practice, in view of its high efficacy and more favorable safety profile as compared to tenofovir disoproxil fumarate (TDF).
Long-term use of NAs is still required to treat CHB
Although the HBV prevalence in people who were born after the introduction of universal childhood vaccination has been markedly reduced, CHB remains a major health burden in the Asia-Pacific region.4,5 In fact, a territory-wide study of 4,803 subjects has revealed that the overall hepatitis B surface antigen (HBsAg) positive rate remained high (8.7%) in Hong Kong.6 As expected, a higher proportion of subjects with HBsAg-positive were those in middle-age.6 Highest proportion of HBsAg-positive (12.2%) was aged 36-45 years, while the lowest (4.4%) was aged less than 26 years (i.e. those who had received HBV vaccine).6
The findings described above were relatable to our routine clinical practice, with newly diagnosed patients with CHB usually being in their 40s. As the number of comorbidities increases as the patients age further,7 this necessitates the importance of a CHB treatment that is safe over a long period of time, at least until we find a cure for HBV.
Concerns have been raised regarding the long-term use of the older generations of NAs.1 For example, bone and renal toxicities in patients receiving adefovir or TDF, muscle toxicity and peripheral neuropathy in patients receiving telbivudine, and potential carcinogenic effects (based on animal studies) of entecavir.1 Sporadic reports have also suggested that NAs may contribute to the occurrence of lactic acidosis, especially in patients with renal or liver impairment.1 As CHB infection was reported to affect ~257 million people worldwide, even a small risk of toxicities could possibly translate into a major medical issue.1
Impact of CHB on bone and renal health
To make matters even worse, bone and renal toxicities have always been a major concern in CHB patients, even without the involvement of NAs. It has been postulated that the increased levels of proinflammatory cytokines in patients with viral hepatitis, such as tumor necrosis factor (TNF), may activate osteoclast precursors which leads to an increased bone resorption.8 As a consequence, osteoporosis was reported to affect up to 53% of patients with viral hepatitis at the time of their assessment for liver transplantation.8
Meanwhile, even in the absence of cirrhosis, untreated CHB infection appears to be associated with an increased risk of chronic kidney disease (CKD) such as membranous glomerulonephritis.1,9 Studies have been conducted to elucidate the mechanisms responsible for it, but the pathogenesis of HBV-associated nephropathy probably depends on virus-host interactions.9 Given that CHB infection might worsen insulin resistance and hyperglycemia, it could potentially confound the renal outcomes as well.9
TAF vs. TDF in clinical trials: What do we know so far?
The availability of TAF, the new phosphonate prodrug of tenofovir (TFV) and the latest addition to the armamentarium of NAs, may lessen concerns on the bone and renal toxicities of TDF.1 Current guidelines emphasize on the importance of profound and durable suppression of HBV replication,10,11 and there is no doubt that TDF has fulfilled this. A review article by Buti et al noted that 96-98% of patients achieved undetectable serum HBV DNA after continuous treatment with TDF for up to 10 years.12 No resistance and no clear pattern of resistance-associated mutations was observed with TDF in clinical trials or real-life studies.12 Nonetheless, TAF should be considered as the preferred option to achieve and maintain a prolonged suppression of HBV replication.
In the two ongoing phase 3 studies for HBeAg-negative (in study 108) and HBeAg-positive (in study 110) CHB patients, the proportion of patients with HBV DNA suppression (defined as plasma HBV DNA <29IU/mL) was comparable between the TAF and TDF arms.13,14 At week 96, similar rates of mean HBV DNA decline (log10 change) was observed at all time points across both studies.13,14 No resistance was detected through 96 weeks of treatment.13,14 An earlier analysis done at week 48 also revealed that the viral suppression rate was similar in patients receiving TAF vs. TDF in any of the major subgroup evaluations, such as age, sex, ethnicity, baseline HBV DNA level, treatment status, HBV genotype, or baseline alanine aminotransferase (ALT) levels.12
Bone and renal parameters were better with TAF than with TDF at week 96 in both studies.13-15 Smaller decrease in bone mineral density (BMD) in the hip (-0.33% with TAF vs. -2.51% with TDF; p<0.001) and spine (-0.75% with TAF vs. -2.57% with TDF; p<0.001) was observed at week 96.13,14 Multivariate analysis identified the study drug treatment as one of the independent predictors for >3% BMD decline in hip or spine (TAF vs. TDF, OR: 0.232; 95% CI: 0.170-0.317; p<0.0001).15 Other independent predictors not described here were age, gender, and baseline renal function.15 A reduced impact of TAF over TDF on bone safety was also supported by the minimal changes of markers of bone turnover such as C-type collagen sequence (CTX) and procollagen type 1 N-terminal propeptide (P1NP).15
At week 96, the median change in estimated glomerular filtration rate with Cockcroft-Gault formula (eGFRCG) was -1.2mL/min with TAF (vs. -4.8mL/min with TDF; p≤0.001).13,14 Compared to TDF-treated patients, significantly smaller median percentage changes in retinol-binding protein to creatinine (RBP:CR) ratio and β2-microglobulin to creatinine (β2M:CR) ratio in the urine (p<0.001 for both) were found in TAF-treated patients.15 Of note, an increased concentration of RBP and β2M in urine are considered as a sensitive and specific marker of a proximal tubular dysfunction.15
Normal on-treatment ALT equals improved clinical outcomes in CHB
Rates of normal on-treatment ALT levels were also assessed and compared between patients receiving TDF and TAF.13,14 At week 96, both studies 108 and 110 found a significantly higher rate of ALT normalization in patients receiving TAF than TDF, regardless of the criteria used (Figure 1).13,14 This begs the question: What are the implications of achieving normal on-treatment ALT levels in CHB patients?
Based on a territory-wide cohort of ~21,000 patients who received ETV and/or TDF (followed for 4.0 ± 1.7 years), we found that the risk of hepatic events was reduced by achieving normal on-treatment ALT during the first year of treatment.16 After adjustment for baseline ALT and other important co-variates, the adjusted HRs (95% CI) for those with normal on-treatment ALT at 3, 6, 9, and 12 months were 0.61 (0.49-0.77), 0.55 (0.45-0.67), 0.54 (0.44-0.65), and 0.51 (0.42-0.61), respectively; all p<0.001 vs. those without normal on-treatment ALT.16 Cumulative incidence of composite hepatic events (including hepatocellular carcinoma) at 6 years were also significantly reduced in those achieving on-treatment ALT, as compared to those who did not achieve it (Figure 2).16
As a matter of fact, the 2017 European Association for the Study of the Liver (EASL) guidelines recommend that biochemical response, defined as ALT normalization, should be achieved as an additional endpoint of therapy.11 It is therefore beneficial to achieve normal on-treatment ALT, as it does not only cater to physician’s objectives, but to the patient’s as well. Indeed, with an elevated ALT level, the treating physician would have to confirm or exclude possible causes to it, therefore causing the patient to worry whether the treatment is working or not.
Bone and renal toxicities of TDF are reversible upon switching to TAF
As per US Food and Drug Administration (FDA) request, the double-blind phase duration of studies 108 and 110 was extended from 2 to 3 years.15 However, some patients have already reached the 96-week visit before the protocol was updated, thus allowing investigators to assess the outcomes in patients who were switched from TDF to TAF.15 The 24-week switch data (24 weeks of TAF after 96 weeks of TDF) reported that viral suppression was maintained, but with a significantly higher rate of ALT normalization by AASLD criteria (47% vs. 63%; p<0.001).15
It is also reassuring to see that the bone and renal toxicities of TDF are readily reversible upon switching to TAF, equaling levels seen in patients who received TAF from the beginning of the study.15 Improvements in eGFR (+2.43mL/min), mean BMD at the hip (+0.71%; p=0.0004) and spine (+1.41%; p<0.0001), as well as biomarkers of bone formation and reabsorption were reported in those who switched from TDF to TAF.15 These findings were further supported by the 48-week switch data (48 weeks of TAF after 96 weeks of TDF) which were presented at the 2017 AASLD Annual Meeting, suggesting that the benefits of switching to TAF were maintained over the 48-week course of TAF, consistent with those reported in the 24-week switch data.15
What do the guidelines recommend?
TAF can be prescribed in any kinds of patients with CHB, but there are certain groups of patients who would receive the most benefits from the medication. These include patients with existing risk factors for bone or kidney diseases, such as diabetes or chronic kidney disease (CKD), who might be at an increased risk for side effects.1
For the use of TAF in pregnancy, human safety data is currently lacking (pregnant women who are currently taking TAF should be registered at the Antiretroviral Pregnancy Registry [APR]).1 Nonetheless, given that no adverse developmental effects were observed in animal studies, TAF is presumably a suitable alternative to TDF for pregnant patients with CHB.1 This is also taking into consideration the reduced systemic toxicity and superior safety profile of TAF when compared to TDF.1
The 2017 EASL guidelines, being the first to include TAF in their recommendations as one of the first-line regimens, pointed out that “an optimised safety profile of long-term NA therapy might be preferred, particularly in an ageing CHB population, with accruing co-morbidities”.11 The use of TAF over TDF is notably preferred in CHB patients, particularly in older age, who are at risk for bone or renal disease.11
The more recent 2018 AASLD guidance, meanwhile, utilized an expert panel to generate consensus, following a formal review and analysis of published literature.10 Intended to complement the 2016 guidelines, which were based on a comprehensive systematic review, the panel noted that the guidance should not replace clinical judgment for a unique patient.10 TAF also joins the list of preferred HBV therapies, but the guidance does not dictate a one-size-fits-all approach, suggesting that patients at risk for renal dysfunction or bone disease would receive more benefits from TAF.10
Therapeutic strategies aiming to achieve functional cure in CHB infection, which includes persistent transcriptionally inactive covalently closed circular DNA (cccDNA), is currently a matter of intense research.15,17 With investigations on molecules that manipulate the host’s immune system or directly inhibit replication (via fundamental steps such as entry, cccDNA formation/stability, viral transcripts, and capsid assembly/secretion), curative treatments for CHB may become available in the near future.15,17 As we wait for the availability of such curative treatments, TAF is perhaps the ideal oral therapy for most of CHB patients, in view of its high antiviral efficacy and more favorable safety profile over a long period of time.1,15
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