Researchers are also looking at earlier treatment of
chronic hepatitis B. Current guidelines recommend treatment for people with
active liver disease progression, indicated by elevated alanine or aspartate
transaminase (ALT or AST) levels. Much HBV-related liver damage is not caused
by the virus itself, but rather by the body's immune response
Elevated transaminases reflect liver inflammation, which
over time promotes fibrosis as the liver attempts to repair itself.
Typically people with normal ALT levels – known as
immune-tolerant hepatitis B – are not considered candidates for treatment.
But now that highly effective and well-tolerated therapies are available, some
experts propose that treatment during this early stage could lower the risk of
HCC and reduce HBV transmission, as people with immune-tolerant infection may
have high viral loads.
Edward Gane from Auckland General Hospital presented
findings from a study comparing tenofovir monotherapy – the current standard
of care for active chronic hepatitis B – versus combination therapy using
tenofovir plus emtricitabine (marketed as the Truvada coformulation for HIV
treatment).
The study enrolled 126 people with chronic hepatitis B who had
high HBV viral load but ALT below the upper limit of normal. They were evenly
divided between men and women, about 90% were Asian and the average age was 33
years. Though pre-treatment biopsies were not done, they were not known to have
cirrhosis. At baseline the mean HBV DNA level was 9.2 log IU/mL.
About half had HBV genotype B and about 40% had genotype
C.
Participants were randomly assigned to receive 300mg
tenofovir once-daily, either with or without 200mg once-daily emtricitabine,
for 192 weeks.
Viral load declined dramatically in both groups soon after
starting treatment. By week 192, significantly more people achieved
undetectable HBV DNA (< 69 IU/mL) in the combination arm compared with the
tenofovir monotherapy arm (76 vs 55%, respectively). About half the patients
stopped treatment after 192 weeks, however, and their viral load returned to
baseline levels.
Serological response rates were very low in both arms. Six people in the
tenofovir monotherapy arm and two people in the combination arm experienced
HBeAg loss, and five and zero, respectively, had HBeAg seroconversion, but the
differences did not reach statistical significance. No patients in either arm
experienced HBsAg loss or seroconversion.
In a univariate analysis female sex, lower baseline HBsAg
and HBV DNA, and use of combination therapy were associated with a greater
likelihood of viral suppression. In a multivariate analysis, female sex (odds
ratio 6.0) and combination therapy (odds ratio 3.9) remained
the only significant predictors.
Treatment was generally safe and well tolerated. Six
people receiving tenofovir alone and three taking the combination regimen
experienced adverse events, which generally were not considered related to
study drugs. No participants saw elevated creatinine levels or reduced
creatinine clearance suggestive of kidney function impairment (a known
side-effect of tenofovir). No tenofovir resistance mutations were detected
through 192 weeks.
"Prolonged antiviral therapy maintains potent viral
suppression and is safe in immunotolerant patients," the researchers
concluded. "The underlying impaired immune responses to HBV in this population
may explain the poor serological response rates to antiviral therapy."
The treatment advantage for women in this study was
stronger than the effect usually seen in trials of active chronic hepatitis,
leading the investigators to suggest that, "Gender may be an effect
modifier in treating chronic HBV patients with high viral loads and normal ALT
values."
Session chair Mark Thursz asked whether these findings
suggest that treatment guidelines should be revised to recommend treatment for
immune-tolerant patients.
Gane replied that while the study shows we certainly can
treat such individuals, the question is who will benefit? "We need to show
that long-term viral suppression in patients with normal ALT will prevent
progression and HCC," he said.
He noted that many people in this situation are young
women of childbearing potential, who are advised to avoid tenofovir during
early pregnancy due to its association with birth defects. An audience member
further noted that young people with hepatitis B have a very low risk of liver
cancer even without treatment.
"We'd like to know if there's a subset of patients
with high risk of progression – such as family history of liver cancer – who
may benefit from early treatment," Gane concluded.