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LdT: new drug for HBV, phase II study results
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Results of A One-Year International Phase IIb Comparative Trial of LdT, Lamivudine, and the Combination, in Patients with Chronic Hepatitis B
Ching-Lung Lai (University of Hong Kong, Tokyo) and colleagues reported on this study of LdT (Telbivudine) at AASLD (Oct 2003), which is currently in large Phase III studies, the last step before being reviewed by the FDA for approval. There are several drugs approved for treatment of HBV: lamivudibe (3TC), adefovir, and interferon. Tenofovir is approved for HIV but not yet for HBV, however studies show comparable antiviral activity between adefovir and tenofovir. Entecavir is an HBV drug in phase III studies being developed by Bristol Myers-Squibb. It remains uncertain if combination therapy for HBV will be more effective than monotherapy. Often, the virologists insist combination therapy will be more effective but hepatologists are not yet convinced. Studies have not yet established that combination therapy will be more effective but researchers have just started to explore combination therapy for HBV. In this study, there is an arm consisting of combination therapy. Two keys for successful treatment in HBV are full suppression of viral replication and avoiding drug resistance.
Lai reported background information. LdT is a specific inhibitor of HBV polymerase, and not active against HIV or other viruses. It has favorable preclinical toxicology and is dosed orally once daily. Phase I/II dose escalation studies show: 3.4 to 3.8 log reductions of HBV DNA with 400-800 mg daily. There were no dose-related or dose-limiting toxicities.
This randomized, multicenter, international clinical trial evaluated the efficacy and safety of one year of treatment with standard lamivudine (LAM) monotherapy (100 mg/day) compared to 4 investigational treatment regimens: LdT 400 mg/day, LdT 600 mg/day, LdT 400 mg/day plus LAM (comb400), and LdT 600 mg/day plus LAM (comb600). Patients were HBeAg-positive adults with compensated CHB and baseline ALT >1.3 xULN.
The primary efficacy measure was serum HBV DNA reduction over time, assessed by the COBAS Amplicor PCR assay. Key secondary endpoints included serum ALT normalization, HBeAg loss or seroconversion, and safety.
104 patients were randomized equally to all study treatment arms. 80% were men. 85% were Asian, the rest were African-American, Caucasian, other. Routes of transmission: 64% maternal, 10% horizontal, 26% unknown. Overall mean age: 37 years (18-68). Mean weight: 70 kg (42-119). 100% of patients were HBsAg and HBeAg positive. Baseline viral load (HBV DNA) was about 9 log (8.89-9.66), ALT was 122-152. In 4/5 arms ALT range was 62-400, but in LdT 600+LAM ALT range was 32-1657.
RESULTS
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LAM |
LdT |
LAM+LdT |
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n=19 |
n=42 |
n=41 |
| Mean HBV DNA Ø |
-4.57 |
-6.01 |
-5.99 |
| HBV DNA-neg by PCR |
32%(6) |
61%(27) |
49%(20) |
| ALT Normalization |
63% |
86% |
78% |
| HBeAg loss |
28%(8) |
33%(14) |
17%(7) |
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Lai reported that all study treatments were well-tolerated, with no treatment- or dose-related pattern of adverse events or laboratory abnormalities. In the LdT 600mg arm (n=22) one patient had grade 3/4 ALT elevation, 3 patients had grade 3/4 CPK elevations. There were no grade 3/4 lab toxicities in the LAM or LdT 400 mg arms. In the LdT+LAM arm (n=20) there was 1 grade 3/4 lipase elevation, 2 grade 3/4 elevations in absolute neutrophils, and I grade 3/4 elevation in CPK.
Genotypic Resistance
HBV DNA from patients with confirmed (2-point)virologic breakthrough were amplified by PCR and analyzed by DNA sequencing. 5% of patients receiving LdT developed drug resistance after 52 weeks therapy.
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Total |
Breakthroughs |
Breakthru genotypes |
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M204I |
L180M |
wt +204V |
| Lamivudine |
19 |
4 (21%) |
2 |
1 |
1* |
| LdT |
44 |
2 (5%) |
2 |
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| LdT+LAM |
41 |
5 (12%) |
3 |
1 |
1* |
| *may indicate noncompliance |
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