TAF an alternative to TDF as maintenance for chronic HBV

Patients with chronic hepatitis B virus (HBV) infection who are virologically suppressed after treatment with tenofovir disoproxil fumarate (TDF) could potentially switch to tenofovir alafenamide (TAF), according to a recent phase III study.

“Patients in both groups had very low incidences of treatment failure, and significantly more patients receiving TAF had improved kidney function and increases in hip and spine bone mineral density (BMD) compared with patients in the TDF group,” noted the researchers.

This multinational, double-blind study included 490 adults (mean age 51 years) with chronic HBV infection who had HBV DNA less than the lower limit of quantification for ≥12 weeks (viral suppression; <20 mL/IU at screening) following ≥48 weeks (median 4 years) of TDF* treatment. They were randomized 1:1 to either continue TDF 300 mg QD or receive TAF 25 mg QD for 48 weeks. More than 60 percent of patients had previously received other anti-HBV treatments, including about 50 percent who received non-TDF oral antivirals.

Loss of virological control (HBV DNA ≥20 IU/mL) at week 48 was infrequent and comparable between TDF and TAF recipients (one patient in each group; difference, 0 percent, 95 percent confidence interval [CI], -1.9 to 2.0 percent), with the upper CI limit of <4 percent demonstrating non-inferior efficacy of TAF to TDF. [Lancet Gastroenterol Hepatol 2020;doi:10.1016/S2468-1253(19)30421-2]

At week 48, hip and spine BMD were significantly greater with TAF vs TDF (mean change [from baseline] 0.66 percent vs -0.51 percent; least square means difference [LSMD], 1.17 percent [hip] and mean change 1.74 percent vs -0.11 percent; LSMD, 1.85 percent [spine]; p<0.0001 for both). Estimated creatine clearance was also improved with TAF over TDF (median change 0.94 vs -2.74 mL/min; p<0.0001).

At week 48, more TDF than TAF recipients with stage ≥1 chronic kidney disease (CKD) at baseline experienced ≥1 stage worsening (14 percent vs 6 percent), while more TAF than TDF patients with stage ≥2 CKD experienced improvement in CKD staging (25 percent vs 8 percent; p<0.0001 for both). Fewer TAF than TDF recipients had grade ≥1 proteinuria at week 48 (14 percent vs 22 percent; p=0.013).

“The differences [in bone and kidney parameters] are relevant given that most patients with chronic HBV infection require life-long therapy, and with increasing age, have an increasing prevalence of comorbidities,” said the researchers.

“[Additionally,] no viral resistance developed in either group [and] HBsAg loss was significantly higher in the TDF group than in the TAF group,” they added.

Treatment-emergent adverse events (TEAEs) affected a similar proportion of TAF and TDF recipients (52 percent vs 48 percent), with 9 and 7 percent, respectively, deemed study drug related. The most frequent TEAEs (≥5 percent) occurred at a similar rate between TAF and TDF recipients (upper respiratory tract infection [7 percent in each group] and nasopharyngitis [5 percent in each group)]. One patient in each group developed hepatocellular carcinoma. Serious AEs occurred in 5 and 1 percent of TAF and TDF recipients, respectively; none were deemed treatment related.

The high hepatic levels of TDF that are behind its efficacy can result in high circulating levels and subsequently, kidney and bone toxicity over time. In contrast, circulating levels of TAF can be 90 percent lower than that of TDF. [Aliment Pharmacol Ther 2012;35:1317-1325; Clin Gastroenterol Hepatol 2018;doi:10.1016/j.cgh.2018.06.023; J Hepatol 2015;62:533-540]

Results of this study suggest that some of the negative bone and kidney outcomes from long-term TDF treatment can be reversed by switching to TAF, the researchers noted.

They acknowledged study limitations which included the short follow-up time and the lack of generalizability to patient populations that were excluded in this study such as those with eGFR** <50 mL/min or those with moderate-to-severe renal impairment or decompensated cirrhosis. The increases in lipid parameters in the TAF group, which were not observed in the TDF group, require follow-up, they said.