People with hepatitis B who received a combination of experimental
drugs as well as their standard treatment for 48 weeks were significantly less
likely to have high levels of hepatitis B surface antigen (HBsAg) or hepatitis B flares
after discontinuing treatment in a clinical trial compared to people who received
standard treatment alone, Dr Kosh Agarwal of London’s Kings College Hospital reported
at the International Liver Congress.
But the study failed to show that the experimental combination could clear hepatitis B surface antigen in a substantial proportion of participants, the primary outcome of the study.
The study also reported that one patient, a middle-aged
man who had been taking tenofovir for eight years, suffered such an extreme flare-up
of hepatitis B after stopping treatment that he needed a liver transplant. The
serious adverse event highlights the potential risks involved in studies of
experimental hepatitis B treatments that require people with apparently
well-controlled virus to stop treatment.
The REEF-2 study was designed to test whether discontinuing
treatment after 48 weeks of combination treatment with JNJ-3989 and JNJ-6379 and
an NRTI resulted in an increased rate of HBsAg loss 48 weeks after treatment
discontinuation compared to NRTI treatment alone. Achieving HBsAg loss after
stopping treatment is considered a ‘functional cure’, meaning that no further
treatment for hepatitis B is required.
HbsAg loss after discontinuing treatment is rare in people
treated with a nucleotide or nucleoside analogue (NA), the standard form of
treatment for hepatitis B. Drugs that interfere with hepatitis B in several
ways are being tested in early-stage and mid-stage clinical trials to assess
their safety and impact on hepatitis B DNA and HBsAg levels.
JNJ-3989 is a silencing RNA (siRNA) that targets production
of all hepatitis B proteins. JNJ-6379 is a capsid assembly modulator. It promotes
the formation of empty non-infectious viral shells that lack DNA or RNA.
study reported that JNJ-3989 reduced levels of hepatitis B surface antigen
after 48 weeks of treatment in combination with a nucleotide or nucleoside reverse
transcriptase inhibitor (NRTI).
Dr Kosh Agarwal of the Institute of Liver Studies at King’s
College Hospital, London, presented 24-week interim results of REEF-2.
REFF-2 recruited people with hepatitis B who had received NA
treatment for at least two years, had hepatitis B DNA levels below 60 IU/ml,
HBsAg levels above 100 IU/ml at screening and ALT < 2 x upper limit of
normal. All participants received an NA (tenofovir disoproxil (TDF) or tenofovir
alafenamide (TAF) or entecavir) and were randomised in 2:1 proportion to
receive JNJ-3989 and JNJ-6379 or placebos for 48 weeks.
After discontinuing treatment, participants were mandated to
re-start NA treatment if they experienced HBeAg reversion, or a post-treatment
increase HBV DNA above 20,000 IU/ml or a post-treatment increase in HBV DNA
above 2,000 IU/ML coupled with an ALT increase to more than five times the
upper limit of normal, on at least two occasions four weeks apart.
The study recruited 130 participants (85 to the active arm
and 45 to the placebo arm. Two-thirds of participants were male, two-thirds
were white and the median age was 46. Participants had been taking NRTIs for a
median of 8 years (38% were taking etravirine, the remainder TDF or TAF) and
78% had an HBsAg level above 1,000 IU/ml.
The primary endpoint of the study was the proportion of
participants who achieved clearance of HBsAg after treatment discontinuation.
No participants in either study arm achieved the primary outcome.
However, participants in the active treatment arm were significantly
more likely to achieve an HBsAg level below 100 IU/ml by week 48 of treatment
and to maintain this level 24 weeks after stopping treatment. At week 48, 71.1%
of the active treatment arm had an HBsAg level below 100 IU/ml compared to 2.4%
of the placebo arm. By week 24 after discontinuation, 67.1% in the active arm
had an HBsAg level below 100 IU/ml compared to 10.3% in the placebo arm.
Fifty-seven per cent of participants in the active arm maintained
a stable or declining HBsAg level after discontinuing treatment.
Hepatitis B DNA levels tended to rebound higher in people in
the placebo arm after stopping treatment. Just over a third (34.1%) of those in
the placebo arm had an HBV DNA level above 20,00 IU/ml during the 24-week
follow-up period compared to 6.5% in the active treatment arm. Conversely, nearly
30% of participants in the active arm had an undetectable HBV DNA and an HBsAg
level below 100 IU/ml at week 24, compared to 6.5% in the placebo arm.
Flares in ALT, signalling reactivation of hepatitis B virus,
were more common in the placebo arm after discontinuation. Twenty-three per cent
in the placebo arm experienced an ALT increase to at least three times above
the upper limit of normal by week 24 compared to 2.4% in the active treatment
Nineteen per cent of the placebo group resumed treatment by
week 24 due to hepatitis B DNA and ALT increases compared to one patient in the
active treatment arm. The patient resuming treatment in the active treatment
arm did so as a consequence of a diagnosis of cholangiocarcinoma.
The most common serious adverse event during the treatment phase
was reduction in kidney function (measured by eGFR) associated with JNJ-6379 in
the active treatment arm (7%). In the discontinuation phase, the most common
serious adverse event was a severe ALT increase in 9% of the placebo group.
One patient in the placebo arm, a 54-year-old Asian male who
had received tenofovir treatment for eight years, experienced a life-threatening
episode of liver failure after discontinuing treatment. The participant
experienced a severe increase in HBV DNA and ALT eleven weeks after discontinuation
accompanied by jaundice, coagulopathy and sub-acute liver failure. HBV DNA
peaked at over 6 billion IU/ml and HBsAg rose to 124,000 IU/ml. This participant underwent an urgent liver transplant
Dr Agarwal said that the speed and magnitude of the HBV DNA
rebound in this patient has implications for future studies that use treatment
discontinuation as a means of evaluating efficacy. In this study, treatment
resumption criteria were revised to require re-starting of treatment if HBV DNA
levels rose above 5 log, regardless of ALT levels.
In practical terms, this case of rebound has implications for
“the turnaround time for labs and the speed of restarting of NAs”, said Dr
The study findings also raise questions for the design of
future studies, not least the duration of active treatment and the number of
drugs used during the active treatment phase.