EASL 2016: Tenofovir Alafenamide Works Well Against Hepatitis B with Less Effect on Bones and Kidneys

alt

The new tenofovir alafenamide (TAF) pro-drug is as potent against hepatitis B virus (HBV) as the current tenofovir disoproxil fumarate (TDF) formulation, but with less detrimental effects on bone and kidney biomarkers, according to a pair of studies presented at the European Association for the Study of the Liver's International Liver Congress (EASL 2016) last week in Barcelona.

Gilead Science's tenofovir disoproxil fumarate (Viread) is one of the most effective antiviral drugs for hepatitis B and one of the most widely used antiretrovirals for HIV. It is generally considered safe and well-tolerated, but it can cause a small amount of bone loss soon after starting therapy and can lead to kidney problems in susceptible people.

Nucleoside/nucleotide analogs like tenofovir can effectively suppress HBV replication during treatment, but they usually do not lead to a cure -- as indicated by hepatitis B surface antigen (HBsAg) loss and development of anti-HBs antibodies -- so long-term therapy is generally needed.

TAF is a new pro-drug formulation that produces high levels of the active drug (tenofovir diphosphate) in hepatocytes and CD4 T-cells with smaller doses than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys, bones, and other organs and tissues.

In November the U.S. Food and Drug Administration approved Genvoya, the first combination pill containing TAF for the treatment of HIV; 2 other TAF coformulations, Odefsey and Descovy, have since been approved. In addition, TAF is being developed as a stand-alone drug for hepatitis B treatment.

Maria Buti from Hospital General Universitari Vall d’Hebron in Barcelona and Henry Chan from the Chinese University in Hong Kong presented 48-week results from parallel Phase 3 hepatitis B trials, the first enrolling people with hepatitis B "e" antigen (HBeAg)-negative disease and the second enrolling harder-to-treat HBeAg-positive people.

The HBeAg-negative trial (Study 108) enrolled 425 participants; 61% were men, about 70% were Asian, and the average age was 45 years. About 20% had previously been treated for hepatitis B. Most had HBV genotypes B, C, or D (21%, 40%, and 32%, respectively in the TAF arm). The mean HBV DNA level was approximately 5.7 log, with nearly 20% having 7 log or greater. Participants had alanine aminotransferase (ALT) levels within twice the upper limit of normal, with a median of 67 U/L. About 12% had a FibroTest score suggesting liver cirrhosis.

The HBeAg-positive trial (Study 110) included 873 participants; about 64% were men, 80% were Asian, the mean age was 38 years, and a quarter had prior treatment experience. Genotypes B, C, and D were again most common (17%, 52%, and 23% in the TAF arm). The mean HBV DNA level was higher in this study, at 7.6 log, with about half having 8 log or greater. The median ALT level was 85 U/L and 8% had suspected cirrhosis.

Participants in both studies were randomly assigned (2:1) to receive 25 mg TAF or 300 mg TDF once daily. Buti and Chan reported the proportion of people with undetectable HBV DNA (<29 IU/mL) at week 48, the primary endpoint. The randomized studies will continue through 96 weeks, at which point everyone will receive open-label TAF.

HBeAg-Negative Findings

HBeAg-Positive Findings

Safety Findings

Investigators with both studies reached the same conclusion: In treatment-naive and previously treated HBeAg-negative and HBeAg-positive chronic hepatitis B patients, treatment with TAF for 48 weeks demonstrated non-inferior virological efficacy compared with TDF, higher rates of ALT normalization, and no development of resistance, with significantly less bone loss and less change in markers of kidney function.

Chan noted that higher LDL levels in TAF recipients are expected because TAF does not exert as much of a cholesterol-lowering effect as TDF. Buti said these slight increases likely would have no clinical consequences.

Both presenters were asked the same question about whether these findings suggest that people on long-term hepatitis B treatment should switch from the older form of tenofovir to tenofovir alafenamide.

"For some patients, especially those who are older and have comorbidities, I think [TAF is] a good option," said Buti, noting that further study is needed for hepatitis B but TAF's advantages have been proven for HIV treatment.

"There's no big safety issue with TDF," Chan concurred, but based on more sensitive markers, "in the long run if patients require long-term therapy, I think TAF is a safer option."

4/17/16

References

M Buti, E Gane, WK Seto, et al. A Phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg-negative, chronic hepatitis B: week 48 efficacy and safety results. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract GS06.

HL Chan, S Fung, WK Seto, et al. A Phase 3 study of tenofovir alafenamide compared with tenofovir disoproxil fumarate in patients with HBeAg- positive chronic HBV: week 48 efficacy and safety results. EASL International Liver Congress 2016. Barcelona, April 13-17, 2016. Abstract GS12.

Other Sources

EASL. ILC 2016: Studies demonstrate improved safety results achieved with investigational treatment for hepatitis B. Press release. April 15, 2016.

Gilead Sciences. Gilead Announces Full 48-Week Results From Two Phase 3 Studies Evaluating Tenofovir Alafenamide (TAF) for Patients With Chronic Hepatitis B Infection. Press release. April 15, 2016.