HBV suppressed on long-term tenofovir alafenamide; switch from TDF improves safety

Tenofovir alafenamide (TAF) keeps chronic hepatitis B virus (HBV) in check through 5 years of treatment, with an added benefit of improving bone and kidney safety outcomes in patients who have switched from tenofovir disoproxil fumarate (TDF), according to data from two ongoing phase III studies.

More than 90 percent of patients maintained virologic control (HBV DNA <29 IU/mL) overall, with the rates not significantly different between patients who used TAF throughout and those initially treated with TDF but switched to TAF at year 2 or 3 (93–96 percent), said presenting author Dr Henry Chan from the Chinese University of Hong Kong during the American Association for the Study of Liver Diseases' (AASLD) The Liver Meeting Digital Experience.

Long-term TAF treatment was safe and well tolerated. Chan highlighted important changes that occurred following the switch from TDF to TAF.

First, kidney function got better, as demonstrated by improvements in estimated glomerular filtration rate by Cockcroft-Gault (eGFR_CG) and markers of proximal tubular function. Second, the early declines in bone mineral density (BMD) seen during TDF treatment steadily increased after the switch, which according to Chan provided evidence that TDF-induced bone loss could be reversed.

The analysis was based on the 5-year results of two identically designed phase III studies: study 108, which comprised 425 HBeAg-negative patients, and study 110, which involved 873 HBeAg-positive patients. Initially, these patients had been randomized to take 25-mg TAF or 300-mg TDF once daily for 2 or 3 years, followed by open-label (OL) TAF until year 5.

In total, 1,157 patients (89 percent) entered the OL phase, but only 999 patients (77 percent) remained on treatment at year 5, including 675 who stayed on TAF and 136 and 288 who switched from TDF and started TAF at year 2 (TDF­–TAF OL 3y) or at year 3 (TDF—TAF OL 2y), respectively.

The majority of the population were men, Asian, and HBeAg-positive. Nearly half had HBV genotype C. At baseline, mean HBV DNA at baseline was ≥7.0 log₁₀ IU/mL, ALT was >60 U/L in men and >38 U/L in women, and eGFR_CG was ≥50 mL/min.

Over 5 years of treatment, TAF normalized ALT, and the rates were similar in the three treatment groups (2018 AASLD Criteria, 74–76 percent; Central Laboratory, 84–88 percent). The same was true for rates of HBeAg loss (37–39 percent) and seroconversion (21–27 percent), which remained low throughout. Fibrosis remained stable, if not improved.

Chan and colleagues found no genotypic resistance to TAF at year 5 among the 44 patients who qualified for sequencing. Eight patients with amino acid changes from baseline are undergoing phenotypic testing with results pending.

Among the treatment groups, grade 3/4 adverse events (AEs; 3–7 percent) and AEs leading to discontinuation (0–1 percent) were infrequent. The changes in fasting lipids with TAF or following TDF-to-TAF switch were not likely to have any clinical impact for most patients, Chan said.

Meanwhile, the eGFR_CG decline was minimal throughout, and hip and spine BMD remained stable in the TAF group.

“The longer-term safety and efficacy data can provide confidence to clinicians to use TAF as a long-term therapy for their chronic hepatitis B patients,” Chan said when contacted for comments by MIMS Doctor.

“TAF will be a better alternative to patients who may require TDF treatment, and TAF can be a first-line treatment for viral hepatitis B,” he added.

TAF is a novel tenofovir (TFV) prodrug, which has greater plasma stability than TDF. It touts enhanced delivery of active drug (TFV-diphosphate) to hepatocytes, with reduced circulating TFV levels relative to TDF. [Mol Pharm 2013;10:459-466; Antimicrob Agents Chemother 2005;49:1898-1906; Antimicrob Agents Chemother 2015;59:3563-3569; J Hepatol 2015;62:533-540]