TAF is an investigational treatment (Gilead Sciences) for CHB while TDF is an approved treatment option and is one of the two guideline-recommended nucleos-(t)-ide analogue (NA) therapies for CHB. Both have been approved in treating HIV infection.
TAF, like TDF, is prodrug of tenofovir- the active ingredient responsible for the drug’s antiviral activity, but delivers 90% lower plasma tenofovir compared with standard TDF. This pharmacology might reduce the off-target effects of tenofovir, in particular renal and bone toxicities.5 Riding on this, recent comparative RCT has demonstrated that TAF (as part of HAART) significantly reduced effects on CrCl (-2.0 vs -7.5ml/min from baseline, p<0.001), proteinuria and bone mineral density (BMD) compared to TDF in patients with HIV infection over 2 years.3,4
For CHB, two randomized comparative phase III trials are being conducted over a period of 96 weeks in 873 HBeAg(+) and 425 HBeAg(-) patients, of which were randomized 2:1 to TAF 25 mg daily or TDF 300 mg daily. The primary efficacy endpoint was virologic response with HBV DNA≤29IU/ml at week 48 and non-inferiority in efficacy within 10% margin and key safety endpoints were changes in hip and spine BMD, change of serum creatinine (SCr) and dipstick proteinuria.
Primary data of the 48-week studies on HBeAg(-) and HBeAg(+) CHB were presented on 14-April at General Session of the European Association for the Study of Liver’s International Liver Congress 2016 by Maria Buti, MD, PhD, professor of the Hospital General Universitari Vall d’Hebron in Barcelona, Spain1 and Henry Chan, MD, professor of medicine from the Chinese University of Hong Kong, Hong Kong2 respectively.
For the 425 HBeAg(-) patients, 19% had HBV DNA ≥7logIU/ml, 21% were treatment-experienced, 72% were Asian, and mean age was 46 years.
For 873 HBeAg(+) patients, 47% had HBV DNA ≥8logIU/ml, 26% were treatment-experienced, 82% were Asian and mean age was 38 years.
48-week TAF vs TDF: Improved bone and renal safety while sustaining efficacy in CHB1,2
Overall, response rates in both HbeAg(-) and HBeAg(+) studies met the primary endpoint of non-inferiority of TAF compared to TDF in CHB. In the HBeAg(-) study, 94.0% and 92.9% of patients on TAF and TDF respectively achieved virologic response (difference: +1.8%, 95%CI: -3.6% to +7.2%, p=0.47), while in the more difficult HBeAg(+) study, 63.9% and 66.8% of patients on TAF and TDF achieved virologic response (difference: -3.6%, 95%CI: -9.8% to +2.6%, p=0.25).
In terms of safety, patients in TAF on both studies experienced a significantly smaller mean % decrease from baseline in hip and spine bone mineral density at week 48 (p<0.001), and had smaller changes in renal tubular markers (p<0.001) than TDF. Additionally, the mean change in eGFRCG (CrCl) over 48 weeks was in favour of TAF (-0.3 to -1.4 ml/min) in both studies (p<0.01). However, more patients experienced elevated LDL cholesterol in TAF arm (4-6%) than in TDF arm (<1%) for both studies. The rates of treatment-emergent discontinuations (1%) and serious adverse events (4-6%) were low and similar in the two arms of both studies.
No viral resistance were detected in patients qualified for mutation surveillance, i.e., virologic breakthrough or viremia at the time of discontinuation [4 in HBeAg(-) study and 33 in HBeAg(+) study].
With the improved pharmacology- lower administrated dosage and less off-target exposure of tenofovir, TAF can be considered as a successor of TDF.5
“These two studies have demonstrated that treatment with TAF is as effective and yet safer than treatment with TDF,” concluded both Professors Buti and Chan, and agreed Professor Tom Hemming Karlsen, the EASL Vice Secretary who was not involved in these studies. “Patients with HBV require long-term treatment and we are pleased that these results could provide a potentially safer treatment regimen in the future”, Professor Buti expected.6
Regarding the higher incidence of elevated cholesterol in TAF recipient, “this is expected because TAF does not exert as much cholesterol-lowering effect as TDF”, said Professor Chan. And “these are slight increase and would likely have no clinical significant consequences”, added Professor Buti.7
When asked for whether CHB patients on long-term TDF treatment should switch to TAF based on these findings, Professor Buti believed that “it’s a good option for some patients, especially those who are older and having comorbidity”. “Regarding the safety”, Professor Chan added, “there is no big issue with TDF”, based on his experience, “but if patients require long-term therapy (as most patients do), I think TAF is a safer option”.7
“Further and longer studies are needed to ascertain the long-term safety and efficacy of TAF” closed the discussion by two presenters. In fact, results from the 2nd year of double-blind phase and the further open-label extension of current two studies will shed more light on these important aspects.