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New Hepatitis B Drugs
Written by Jules Levin
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Entecavir vs 3TC Resistance
A more detailed report is forthcoming but here are a few highlights from this
meeting. several apparently promisingly drugs for treating HBV are in human
development and moving along and had data presented on them here at AASLD:
LDT, FTC (not good for 3TC resistance), adefovir, and entecavir. This morning
data was presented on entecavir in 3TC resistant patients. Previous study
data showed 0.5 mg (highest of 3 doses) dose of ETV reduced viral load by
over 4 log in treatment-naive at week 20. The data this morning was presented
in oral session. 85% reportedly had YMDD mutation. Three ETV doses were used:
0.1mg, 0.5mg and 1.0mg. Mean HBV DNA was about 9 log. About 40 patients in
each arm. 79% in the high dose arm (1.0 mg) had undetectable HBV-DNA at week
24 by bDNA, and a 4.4 log reduction in HBV-DNA. By PCR 17% had undetectable
HBV-DNA. 93% had 2 or more log reduction. There was a dose response. The
group receiving 3TC 100mg had little HBV-DNA response. 11% in the high dose
group (n=27) had loss of HBeAg compared to 6% in the 3TC continuation arm.
There were 67 adverse events in the ETV 1.0 mg arm: headache (19), fatigue
(5), abdominal pain (10), rhinitis (7). 5 discontinued and 5 had serious AE.
The incidence of AEs was not different than in the 3TC arm. Although there
were 2 serious AEs in the 3Tc arm. Several patients had elevated ALT.
Adefovir
This morning an oral talk was presented on a study for adefovir (ADV) for
patients with HBeAg+ chronic HBV. This study looked at changes in liver
histology. This 48+ week study looks at fibrosis, Knodell score, and
necroinflammation. HBV-DNA was 8.4 log at baseline ALT 95. About 20% were
nonresponders to IFN and <1%-3% had prior 3TC. Median Knodell scores were
about the same in placebo 10mg and 30mg ADV arms: 9.5-10.0, necroinflammation
7.0-8.0, fibrosis 1.0. Cirrhosis: 4% in 30mg arm, 7% in 10mg arm, 8% in
placebo. The 10 and 30 mg arms had about the same response measured by
Knoedell (Histology): 53-59% showed improvement compared to 25% in placebo
arm. 28%-36% showed no improvement in ADV arms compared to 65% in placebo
arm. 10-12% of patients across the 3 arms had missing data. The difference
between ADV 10 mg and placebo was significant (p<0.001). Necroinflammation:
similar results--71-77% showed improvement in ADV arms vs 41% in placebo;
12-15% in ADV arms showed no imprivement compared to 26% in placebo. 34% in
placebo showed worsening compared to 10-13% in ADV arms. Fibrosis: 41% showed
improvement in 10mg ADV arm, 54% in ADV 30mg arm, and 26% in placebo. 26%
worsened in placebo while 14% worsened in 10mg arm and 19% in 30mg arm. 50%
remained the same in placebo vs 45% in 10mg and 37% in 30 mg arm. HBV-DNA:
reduced by median 3.52 log in 10 mg arm (n=172) (21% <400 copies/ml HBV-DNA),
4.76 in 30 mg arm (n=173) (39% <400 HBV-DNA) and .55 in placebo (0%). 14%
HBeAg seroconverted in 30mg arm, 12% in 10mg arm, and 6% in placebo. 33% exp
erienced HBeAg loss in 30mg arm, 23% in 10mg arm, 17% in placebo. Serious
AEs, AEs, and discontinuations were about the same in all 3 arms (5% serious
AE, 87-95% AE, 7-8% disct. Dose reduction was 25% in 30mg ADV arm vs 3% in
10mg arm. 8% in 30 mg arm had confirmed increase 0.5 or more serum creatinine
increase from baseline. No serum phosphorous confirmed decreases <1.5 mg/dL
in any arm. Resistance reported later in conference. ADV 10 mg selected for
development due to renal lab abnormalities with 30mg dose.
Data on FTC is also being presented showing viral load reductions. Maureen
Myers reported median HBV-DNA reduction of 3.63 log at week 4 using highest
dose og 400mg per day. In lower doses 2-3 log reductions seen. She reported
no serious adverse events, toxicities.
It seems apparent that combination therapy for HBV should be the approach.
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