MEETING HIGHLIGHT

Tenofovir alafenamide (TAF) and updates on the management of HBV

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Prof. Tsai, Naoky

Clinical Professor of Medicine,
John A. Burns School of Medicine,
University of Hawaii, United States

Chronic hepatitis B (CHB) is effectively managed with nucleos(t)ide analogues (NAs), yet the treatment is given over an indefinite period of time as functional cure is still difficult to achieve.1 Since the aging demographic continues to grow in population size, the use of CHB treatment that is safe over a long period of time is increasingly becoming more important.2,3 Due to a more efficient uptake of the intracellular active metabolite (tenofovir diphosphate [TFV-DP]), the use of tenofovir alafenamide (TAF) has been proposed as a solution for suppressing the hepatitis B virus (HBV) whilst minimizing the risks of bone or renal adverse events.4-7 In this meeting, Professor Naoky Tsai from the University of Hawaii discussed the clinical benefits of switching from tenofovir disoproxil fumarate (TDF) to TAF.

Bone and renal toxicities in the aging demographic of CHB patients

“A lot of CHB patients who we treat are actually getting old, you are going to have to see many comorbid conditions that come with age… that should be a concern regarding what you need to do when you are treating somebody with certain medications,” Prof. Tsai said. Bone and renal toxicities, in particular, are always the concern in an aging demographic of CHB patients.2,3 The risk of developing end-stage renal disease (ESRD) in elderly patients infected with HBV was reported to be 3.85-fold higher as compared to non-infected patients.3 Furthermore, another study has reported that osteoporosis was 1.13-fold more likely in HBV-infected patients compared to non-infected patients.2

Pre-existing bone and renal impairments are therefore an important consideration when selecting an appropriate treatment for CHB. As shown in ReCoRd, a multicentre, retrospective, cohort study that assessed the renal safety of TDF and entecavir (ETV) in patients with moderate or severe renal impairment, similar rates of renal serious adverse events (SAEs) and decline in renal function were observed in both the TDF and ETV arms (Figure 1).8 Among patients who received TDF, 11 of them had proximal renal tubulopathy (PRT) or renal tubular dysfunction (RTD).8

 

 

TAF vs. TDF: What are the differences?

The greater plasma stability of TAF allows for a more efficient delivery of TFV-DP to the hepatocytes with the dosage of 25mg, which is considerably smaller than the 300mg dose of TDF.6,7 Effective therapy is therefore achieved with ~90% lower plasma tenofovir exposure, which translates into the clinical benefits shown in the two phase 3 clinical trials of TAF (study 108 for HBeAg-negative; study 110 for HBeAg-positive).6,7

In the 96-week analysis of studies 108 and 110, TAF was found to be non-inferior to TDF in terms of achieving virologic suppression, defined by HBV DNA level of <29IU/mL (HBeAg-positive: 73% vs. 75% with TDF; p=0.47 and HBeAg-negative: 91% vs. 90% with TDF; p=0.84).5 However, there were notable differences between TDF and TAF with regard to safety.6,7

At week 96, a pooled analysis of both studies showed that patients who received TAF had smaller changes in the estimated glomerular filtration rate as measured by the Cockcroft-Gault equation (eGFRCG) as compared to those who received TDF (-1.2mL/min vs. -4.8mL/min with TDF; p<0.001).9 Treatment with TAF resulted in significantly smaller changes in renal markers of tubular functions as compared to TDF, particularly in the urine retinol-binding protein to creatinine (RBP:CR) ratio (median change: 21.8% vs. 49.1% with TDF; p<0.001) as well as the β2-microglobulin to creatinine (β2M:CR) ratio (median change: 8.4% vs. 48.9% with TDF; p<0.001).9

In addition to TAF displaying benefits in renal safety, the pooled analysis showed that treatment with TAF also resulted in smaller changes in the hip and spine bone mineral density (BMD) (hip: -0.33% vs. -2.52% with TDF; p<0.001 and spine: -0.75% vs. -2.59% with TDF; p<0.001).9

Switching patients from TDF to TAF resulted in the reversal of toxicities

Although FDA had extended the double-blind phase duration of studies 108 and 110 from 2 to 3 years, some patients were already switched from TDF to TAF before the protocol was updated.5 The assessment of this group of patients led to the discovery that the bone and renal toxicities of TDF were in fact reversible upon switching to TAF.5,10

Interestingly, while viral suppression was maintained at week 144 (i.e. 48 weeks of TAF after 96 weeks of TDF), alanine aminotransferase (ALT) normalization rates were significantly improved from 47% at week 96 to 65% at week 144 (p<0.001).10

With regard to renal safety, positive results were seen in both eGFRCG and renal tubular markers (Figure 2). Patients who were switched from TDF to TAF had a significant decrease in the median change of eGFRCG (-4.8 mL/min at week 96 vs. -1.2 mL/min at week 144; p<0.001).10 Similarly, improvements were noted in bone toxicities.10 The BMD for both spine (-3.1% at week 96 vs. -1.2% at week 144; p<0.001) and hip (-2.7% at week 96 vs. -1.6% at week 144; p<0.001) were improved in patients upon switching from TDF to TAF.10

Given that the bone and renal adverse events could lead to a major medical issue, especially in the aging population, it is reassuring to see that these are reversible upon switching the treatment to TAF. “If [patients] are on [TDF], you probably want to switch them so as to avoid added side-effects”, Prof. Tsai said.

TAF for prophylaxis of HBV reactivation in candidates for immunosuppressive treatment

Prof. Tsai then discussed about CHB management in patients who are candidates for immunosuppressive (IS) treatment. Based on the risk gradient with different IS drugs (Figure 3), the guidelines released by the American Gastroenterological Association (AGA) in 2015 recommended antiviral prophylaxis for those with moderate- or high-risk of HBV reactivation.11

 

For patients at moderate-risk (1-10%), antiviral prophylaxis should be given during IS treatment and for at least 6 months after discontinuation of IS treatment.11 For patients at high-risk (>10%), antiviral prophylaxis should be given during IS treatment and for at least 6-12 months after discontinuation of IS treatment.11 The AGA recommended prophylaxis with antiviral drugs that have a high barrier to resistance in particular.11 In line with the more recent guidelines by both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), TAF is included as one of the preferred options.12,13

Take-home message

In conclusion, bone and renal toxicities need to be thoroughly considered when assessing the treatment options for the management of CHB, particularly in the aging population.1-3 Given the improved safety profile of TAF, this could be a more suitable option for CHB patients who would need a lifelong treatment to effectively manage their disease.

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