Most people with chronic hepatitis B who are
treated with tenofovir for eight years continued to maintain viral suppression,
researchers reported at the American
Association for the Study of Liver Diseases (AASLD) Liver Meeting earlier this month in
Boston, United States. Serological response rates continued to increase
over time and kidney and bone-related side-effects remained uncommon.
Antiviral therapy
using nucleoside/nucleotide analogues like tenofovir (Viread), entecavir (Baraclude),
adefovir (Hepsera) or lamivudine (Epivir) is the mainstay of chronic hepatitis
B treatment. Although these drugs can effectively suppress
hepatitis B virus (HBV) replication during therapy, they typically do not
eradicate the virus and therefore may need to be taken long term. Viral
suppression has been shown to improve liver fibrosis and reduce the risk of
complications such as liver cancer.
Patrick Marcellin from Hôpital Beaujon in
Paris and colleagues presented the latest findings from Gilead Sciences'
Study 102 and Study 103, a pair of phase 3 trials evaluating tenofovir in hepatitis B 'e'
antigen (HBeAg)-negative and HBeAg-positive patients, respectively.
Glossary
- phosphate
Phosphorus combined with oxygen in the blood forms a variety of phosphates, vital for energy
production, muscle and nerve function, and bone growth. Raised levels can
be a sign of conditions such as kidney disease and diabetes.
Together, the
studies enrolled more than 600 participants, most previously untreated. Nearly
three-quarters were men, about 60% were white, about 30% were Asian, the mean
age was approximately 40 years and 24% had liver cirrhosis. A majority of
HBeAg-negative participants (64%) had HBV genotype D, with 11% having genotypes
A, B and C; genotypes were more evenly distributed in the HBeAg-positive study.
Participants in both trials were randomly assigned to receive 300mg
tenofovir or 10mg adefovir for 48 weeks, after which they could elect to
continue on open-label tenofovir. People with continued detectable HBV DNA
while on tenofovir had the option of adding emtricitabine (Emtriva) at week 72 or later. Safety and efficacy were assessed
every three months, resistance testing was performed annually and DEXA bone
mineral density scans were done starting at year 4 of follow-up.
About 90% of
participants completed the initial blinded 48-week phase and entered the
open-label phase. A total of 266 HBeAg-negative patients (71% of those
initially randomised and treated) and 146 HBeAg-positive patients (55%)
completed follow-up through week 384, or approximately eight years – the original
planned study duration.
At 384 weeks, 75% of HBeAg-negative participants and
58% of HBeAg-positive patients had viral suppression (HBV DNA <69 IU/ml) in
an intent-to-treat analysis. In an as-treated or observed analysis of those who
stayed on treatment, the corresponding rates reached 99% and 98%, respectively.
Looking at serological markers, 1.1% of HBeAg-negative
participants and 13% of HBeAg-positive patients experienced hepatitis B surface
antigen (HBsAg) loss, while 0.7% and 10%, respectively, achieved HBsAg
seroconversion – the closest indicator of a cure for hepatitis B.
Predictors of HBsAg loss in a multivariate analysis included
white race/ethnicity, HBV genotype A or D, being HBV-infected for four years or
less and a lower baseline HBsAg level.
In the HBeAg-positive study, 32% of patients
experienced HBeAg loss and 21% achieved HBeAg seroconversion.
In a subset of 90 patients evaluated at 165 time
points over eight years, there was no evidence of tenofovir resistance.
Tenofovir remained generally safe and well-tolerated
throughout the course of follow-up. There were seven (1.2%) drug-related
serious adverse events and 13 (2.2%) adverse events leading to treatment
discontinuation during the open-label phase.
Twenty patients (3.4%) reduced their tenofovir doses
or interrupted or discontinued treatment due to kidney-related side-effects
including elevated creatinine (2.2%), elevated phosphate (1.7%) and reduced creatinine
clearance (1.0%).
Turning to effects on bone, 2.0% and 3.1% of patients
developed osteopenia (low bone mineral density) at the hip and spine,
respectively; 1.2% and 1.9% progressed from osteopenia to more severe
osteoporosis, but none went from normal bone density to osteoporosis over four
years. Conversely, 2.0% and 4.4% improved from
osteopenia to normal bone density at the hip and spine, respectively; 0.8% and
1.1% improved from osteoporosis to osteopenia. A total of 34 bone fractures
occurred in 31 patients (5.3%), but these were mostly due to trauma rather than
bone loss.
Over an eight-year period of treatment with
tenofovir, "virologic and serologic responses were durable" and viral
suppression was "consistently maintained," the researchers concluded.
"Renal events were uncommon," they added, and there was "no
clinically relevant bone loss over four-year follow-up."
Another
study presented at the meeting found that adding pegylated interferon to
tenofovir increased the likelihood of HBsAg loss in people with chronic
hepatitis B.