Tenofovir alafenamide (TAF) remains effective against hepatitis B virus (HBV) for 96 weeks, with no resistance detected, according to studies presented at the 2017 AASLD Liver Meeting last month in Washington, DC.
Researchers also reported that people with hepatitis B who switched from the old tenofovir disoproxil fumarate (TDF) to TAF saw improvements in kidney function and bone density.
Nucleoside/nucleotide analogues like tenofovir suppress HBV replication during treatment but usually do not lead to a cure. Therefore, ongoing therapy is generally required and long-term safety is important.
A protein made in the liver, needed to maintain a balance of the fluids in the body. In a blood test, lower than normal levels of albumin and total protein may indicate liver damage or disease. If there is not enough albumin, fluid may accumulate in the abdomen (ascites).
drug that is broken down into another active form inside the body.
TDF (Viread) is among the most effective antiviral drugs for hepatitis B, as well as one of the most widely used antiretrovirals for HIV. It is generally considered safe and well tolerated, but it can cause bone loss and kidney problems in susceptible individuals.
TAF (Vemlidy) is a new pro-drug formulation of tenofovir that produces high levels of the active drug in liver cells and CD4 T-cells using smaller doses than TDF, which means lower concentrations in the blood and less drug exposure for the kidneys and bones. The latest European Association for the Study of the Liver (EASL) hepatitis B guidelines recommend that people at risk for kidney or bone disease should consider switching from TDF to TAF or entecavir (Baraclude).
Maria Buti of Vall d’Hebron University Hospital in Barcelona presented 96-week results from a pair of randomised phase 3 studies comparing the safety and efficacy of TAF versus TDF, focusing on participants with risk factors for kidney problems or bone loss.
Gilead Sciences' Study 108 enrolled 425 hepatitis B 'e'-antigen (HBeAg)-negative people and Study 110 enrolled 873 harder-to-treat HBeAg-positive people. In both studies a majority of participants were men, most were Asian and the average age was around 40 years. About a quarter were previously treated before starting tenofovir. Participants were randomly assigned to receive once-daily TAF (25mg) or TDF (300mg) for 144 weeks, after which everyone could continue on open-label TAF.
Among these 1298 people, 239 had at least one risk factor that could make TDF inadvisable. These included being age 60 or older, having an estimated glomerular filtration rate (eGFR) < 60 ml/min, a urine albumin-to-creatinine ratio > 30 mg/g, serum phosphorus < 2.5 mg/dl or osteoporosis (bone loss). The average age in this subgroup was around 48 years and nearly a third were over 60. About 40% had osteoporosis at the hip or spine. Most had one risk factor, but some had two or more.
The full 96-week results from these two studies were presented at this year's EASL International Liver Congress. In the HBeAg-negative study, 90% of TAF recipients and 91% of TDF recipients had undetectable HBV DNA (< 29 lU/ml), while in the HBeAg-positive study 73% of TAF recipients and 75% of TDF recipients had undetectable viral load. In both studies, hepatitis B surface antigen (HBsAg) loss was rare (three people total). Normalisation of ALT liver enzyme levels was more likely in people taking TAF.
Efficacy results were similar in the subset of patients with kidney or bone risk factors. In the HBeAg-negative study, 85% of TAF recipients and 90% of TDF recipients had undetectable HBV DNA, as did 76% and 75%, respectively, in the HBeAg-positive study. Here too, ALT normalisation occurred more often in the TAF arm.
Overall safety and tolerability in people with kidney or bone risk were comparable to that of the study population as a whole. Participants receiving TAF showed smaller declines in eGFR and smaller increases in proteinuria (protein in the urine, a marker of kidney tubule dysfunction) than those taking TDF. TAF recipients also had smaller declines in bone mineral density at the hip and spine and smaller changes in biomarkers of bone formation and reabsorption.
"In chronic hepatitis B patients considered to be at risk for TDF toxicity, TAF showed significantly less impact on bone and renal parameters while efficacy was maintained in this subgroup through 96 weeks," the researchers concluded.
Calvin Pan of New York University Langone Medical Center presented kidney and bone safety data for a subset of patients in the two studies who remained on open-label TAF (n = 361) or switched from TDF to TAF (n = 180) after 96 weeks of randomised treatment. Dual-emission x-ray absorptiometry (DXA) bone scans were done every six months and creatinine clearance was assessed regularly.
A year after the protocol change, both the TDF to TAF switch group and the group that stayed on TAF continued to have high rates of HBV suppression (88% and 89%, respectively). The rate of ALT normalisation rose in the switch group (from 47% to 65%) while remaining stable at 65% in the continued TAF group.
Creatinine clearance improved significantly in people who switched from TDF to TAF while remaining stable in those who stayed on TAF. Bone mineral density according to DXA scans improved among people who switched to TAF (+0.94% at the hip and +1.54% at the spine), while again remaining stable in the continued TAF group.
Finally, Henry Chan of the Chinese University of Hong Kong presented a pooled analysis of drug resistance in Study 108 and Study 110.
The researchers performed HBV genetic sequencing for participants who had a detectable viral load (HBV DNA >69 IU/ml) at week 96 or who stopped treatment early with a viral load above this level. Phenotypic resistance testing was done for people who experienced viral breakthrough despite good adherence to treatment and those with certain viral mutations.
A similar proportion of participants in the TAF and TDF arm qualified for resistance testing (11% in both groups). Among the 87 qualified people in the TAF arm, 31 had no viral sequence changes from baseline, 15 were unable to sequence, 32 had polymorphic site substitutions and nine had conserved site substitutions. Among the 45 qualified people in the TDF arm, 26 had no sequence changes, six were unable to sequence, 11 had polymorphic site substitutions and two had conserved site substitutions. Most of these mutations were seen in only a single participant. The rtA181T substitution (associated with adefovir resistance), seen in two people, was not associated with increased viral load.
At 96 weeks, 23 people (2.8%) taking TAF and 13 people (3.1%) on TDF experienced a viral breakthrough. This was associated with non-adherence in 22% of TAF recipients and 46% of TDF recipients. Of the 19 people on TAF and eight on TDF who qualified for phenotypic analysis, none of the virus samples showed reduced susceptibility to tenofovir.
In people with chronic hepatitis B treated with TAF or TDF, "virologic breakthrough was infrequent and often associated with nonadherence to study drug," Chan's team concluded. "No amino acid substitutions detected by sequence analysis were associated with phenotypic resistance."