continues to be safe and effective for treating chronic hepatitis B through eight
years of follow-up, researchers reported at The Liver Meeting 2012, the 63rd Annual Meeting
of the American Association for the Study of Liver Diseases (AASLD) last week in
Boston. Another study showed minimal bone loss among tenofovir-treated patients
using the FRAX method.
Several nucleoside/nucleotide analogues are
active against hepatitis B virus (HBV), but with long-term use HBV develops
resistance to older drugs such as lamivudine (Epivir-HBV), thereby compromising sustained effectiveness.
Tenofovir – which
has demonstrated potent activity against both HBV and HIV – has a higher barrier to resistance. Gilead Sciences'
Study 102 and Study 103showed that tenofovir maintains HBV viral load suppression, is well tolerated
and shows no evidence of resistance through six years for previously untreated
chronic hepatitis B patients.
Fung, fromToronto General Hospital, and colleagues conducted a phase
3b study of tenofovir for treatment-experienced hepatitis B patients.
Participants were receiving lamivudine at study entry but had HBV viral load of
1000 IU/ml or more and documented lamivudine resistance (e.g., M204I/V or L180M
mutations); some had also used adefovir (Hepsera)
for 48 weeks or less.
This analysis included 280 participants, about half of whom were
hepatitis B 'e' antigen (HBeAg) positive. Approximately two-thirds
were enrolled in Europe and one-third in North America. They had been infected
with HBV for ten years on average and had been taking lamivudine for about four
About three-quarters of participants were men, about 60% were white,
about 35% were Asian and the average age was 47 years. HBV genotype A was most
common (22%), followed by B (14%), C (19%) and D (45%). At baseline, the mean
HBV DNA level was about 6.5 log10 copies/mL.
About 60% of participants had elevated alanine aminotransferase (ALT) at
study entry. People with pre-existing kidney function impairment (creatinine
clearance < 50 ml/min) were excluded, as were individuals with HIV or
hepatitis C co-infection. At baseline about 30% of participants had evidence of low
bone density (osteopenia or osteoporosis) on spine DEXA scans and about 20% had
bone loss shown on hip scans.
Participants were randomly assigned to take tenofovir alone or co-formulated
approved for HIV treatment). Safety and efficacy were evaluated over 96 weeks. About
90% of participants in both study arms completed all 96 weeks.
Assessments included kidney biomarkers (serum creatinine, creatinine
clearance, serum phosphorus) because tenofovir can cause kidney toxicity in
susceptible individuals, as well as DEXA bone density scans because the drug
has been linked to bone loss in people with HIV.
An intent-to-treat analysis showed good – and
statistically equivalent – efficacy in
the tenofovir monotherapy and tenofovir/emtricitabine arms: 89 and 86%,
respectively, had undetectable HBV DNA at 96 weeks (< 400 copies/ml or <
69 IU/ml). ALT normalisation, indicating reduced liver inflammation, occurred
in 62 vs 63%, respectively.
Other measures of response to hepatitis B treatment were less
impressive. HBeAg loss occurred in 15% of tenofovir monotherapy and 13% of tenofovir/emtricitabine
recipients. HBeAg seroconversion occurred in 11 and 10%, respectively. Only
one person in the combination arm experienced hepatitis B surface antigen
(HBsAg) loss, considered the best indication of a cure for hepatitis B.
Amongst 18 participants who underwent drug resistance testing, no
tenofovir resistance was detected in either treatment arm through 96 weeks.
Tenofovir monotherapy and tenofovir/emtricitabine were both generally safe
and well tolerated. Only one participant experienced a serious adverse event, and
three people (1%) discontinued treatment due to adverse events.
Looking specifically at kidney-related side-effects, no participants saw
a confirmed serum creatinine increase of 0.5 mg/dL or more from baseline. Just
1% had reduced serum phosphorus below 2 mg/dL, whilst 3% had creatinine
clearance below 50 ml/min (most of whom had sub-normal kidney function at
The researchers judged that no study participants developed clinically
relevant bone loss according to spine and hip bone mineral density T-scores and
Z-scores, which compare bone density to population norms. Although five people
sustained trauma-associated bone fractures, none had non-traumatic fractures
due to bone fragility in the absence of injury.
"A high rate of HBV DNA suppression with no detectable [tenofovir]
resistance was achieved with [tenofovir] in patients with documented lamivudine
resistance through 96 weeks," the researchers concluded. "[Tenofovir]
was safe and well tolerated, with a low rate of renal events and no evidence of
clinically relevant bone loss."
Given the similar safety and effectiveness of the tenofovir monotherapy
and combination therapy arms, Dr Fung said that tenofovir alone should be