By Liz Highleyman

Telbivudine (Tyzeka) is the newest antiviral therapy for chronic hepatitis B virus (HBV) infection, approved by the U.S. Food and Drug Administration (FDA) in October 2006.

Long-term Outcomes

Results

• Pre-treatment serum HBV DNA and ALT levels were significant predictors of virological response at week 24, and predictors of efficacy outcomes and viral breakthrough at week 104.

• Among HBeAg positive telbivudine recipients with ALT

• 2 times the upper limit of normal and HBV DNA < 9 log10 copies/mL at baseline, 47% experienced HBeAg seroconversion and 14% experienced viral breakthrough by week 104, compared with 30% and 29%, respectively, among all HBeAg positive telbivudine recipients regardless of baseline ALT or viral load.

• 71% of patients in this subset had undetectable HBV DNA after 24 weeks on telbivudine, compared with 44% of HBeAg positive telbivudine recipients overall.

• HBV genotype had minor, generally non-significant effects on outcomes.

• Similar relationships were observed in HBeAg negative patients with elevated ALT and serum HBV DNA < 7 log10 copies/mL at baseline.

• However, due to the higher overall rate of viral clearance in this group, baseline parameters had a less pronounced effect on virological responses at weeks 24 and 104.

• After initiation of treatment, multivariate analyses showed a diminished effect of baseline parameters on subsequent outcomes, and confirmed viral load at week 24 as the most significant predictor of outcomes at week 104.

• Among patients with HBV DNA < 9 log10 copies/mL and elevated ALT at baseline, undetectable HBV viral load at week 24 was associated with a 52% rate of HBeAg seroconversion and a 3.6% rate of viral breakthrough after 2 years.

The investigators concluded that, “High rates of efficacy responses after 2 years of telbivudine, and low resistance, occurred in patients with elevated ALT and HBV DNA < 9 log₁₀ (HBeAg positive patients) or < 7 log₁₀ (HBeAg negative patients) copies/mL pretreatment, coupled with optimal viral load reduction at week 24.”

“These results define patient characteristics associated with optimal responses to telbivudine and may contribute to on-treatment patient management strategies,” they added.

Progressors were defined as patients who exhibited a 1-unit increase in Ishak Fibrosis Score or a 2-unit increase in Knodell Necroinflammatory Score (with no decrease in Ishak Score) at week 52. All other patients were classified as non-progressors.

The researchers used stepwise logistic regression to analyze data from 549 telbivudine recipients and 535 lamivudine recipients, comparing 142 progressors to 942 non-progressors after 52 weeks of treatment. Baseline factors included in the model were age, sex, Ishak Fibrosis Score, Knodell Necroinflammatory Score, “e” antigen status, HBV genotype, ALT, body mass index (BMI), and treatment assignment. On-treatment factors analyzed were viral load reduction, undetectable HBV DNA, and ALT decline by at week 24.

Results

• Baseline Ishak Fibrosis Score (OR 5.0) and Knodell Necroinflammatory Score (OR 2.7) were the only significant factors predicting histological progression (P < 0.0001 for both).

• Lower baseline scores were more predictive of progression than higher scores, possibly due to patients with higher scores responding better to treatment.

• The only significant on-treatment predictor of progression was failure to achieve a decline in HBV DNA of at least 5 log10 copies/mL by week 24, which increased the likelihood of progression by 57%.

• HBV genotype, baseline BMI, and treatment assignment were retained in the model, but were not statistically significant.

• However, significantly more telbivudine recipients achieved at least a 5 log10 decline in HBV DNA compared with lamivudine recipients (69% vs 55%; P < 0.05).

“Although baseline histology status was the most important predictor of disease progression at 1 year, the only significant on-treatment factor found to reduce the likelihood of progression was attaining HBV DNA decline > 5 log by week 24,” the investigators concluded.

They added that, “These data suggest that using a more potent antiviral agent can result in histologic improvements over periods as short as one year. Longer-term studies are needed to evaluate the effects over time.”

The drug combinations were evaluated in stably transfected human liver cells expressing replication-competent HBV nucleocapsids and virions. The anti-HBV efficacy of each drug alone and in combination was determined using in vitro endogenous HBV polymerase assays after 10 days of treatment. In vitro cytotoxicity was determined by standard cell viability staining.

Results

• Telbivudine/tenofovir and telbivudine/entecavir combinations exerted greater in vitro anti-HBV activity than telbivudine, tenofovir, or entecavir alone.

• The interaction volumes of all 2-drug combinations suggested that the antiviral activity of the 2 drugs in each combination was additive.

• Telbivudine/tenofovir exhibited an additive interaction in isobolograms, as implied by D-values fluctuating around 0.

• An average D-value of -0.16 was calculated for telbivudine/entecavir, suggesting weak but statistically significant synergy.

• There was no evidence of in vitro cytotoxicity with either combination.

“Telbivudine demonstrated additive to weakly synergistic anti-HBV activity in vitro when combined with tenofovir or entecavir,” the investigators concluded. “These data support the investigation of telbivudine as a component in multi-drug therapy of chronic HBV infection, particularly combinations with drugs exhibiting different resistance patterns such as nucleotide analogs.”

Muscle Toxicity

Myopathy (muscle toxicity) -- indicated by elevated creatine kinase (CK) -- is a potential side effect of nucleoside analogs used to treat HIV. As telbivudine is also a nucleoside analog, investigators with the FDA reviewed the telbivudine approval database for reports of CK elevation and adverse event patterns consistent with muscle toxicity (abstract 940).

Data were reviewed from trials that prospectively measured CK levels and recorded clinical adverse events, in which telbivudine was used in at least 1 arm in New Drug Application 22-011. The researchers also examined the time to onset and frequency of CK elevations in the Phase III GLOBE trial (52-week data). They also reviewed detailed event narratives of clinical adverse events related to CK elevations or events suggestive of myopathy, searched the FDA’s Adverse Event Reporting System for reports of muscle toxicity since telbivudine marketing approval, and looked at preclinical evaluations of mitochondrial toxicity submitted with the New Drug Application.

Results

• The GLOBE trial safety database included 680 telbivudine-treated and 687 lamivudine-treated subjects.

• More telbivudine recipients developed new-onset CK elevations after several months compared with lamivudine recipients (grade 1-4: 72% vs 42%).

• After reviewing narratives for serious adverse events and study drug discontinuations or interruptions, there were a total of 16 telbivudine recipients and 1 lamivudine recipient with CK elevations or muscle symptoms.

• 6 of these patients had a convincing picture of myopathy with muscle weakness and 2 had biopsy confirmation (1 was taking another drug associated with myopathy).

• All symptoms occurred after more than 300 days on the study drug.

• History, degree, and timing of CK elevations and demographic characteristics were variable.

• No reports of telbivudine-associated CK elevations, myopathy, or muscle weakness have been reported to the Adverse Event Reporting System since approval.

• No evidence of mitochondrial toxicity was found in the review of preclinical studies.

“We found an emerging pattern of a cumulative toxicity resulting in myopathy with chronic [telbivudine] that may or may not be associated with mitochondrial toxicity,” the investigators concluded.

“The imperfect relationship between the timing and severity of CK elevations and myopathy, coupled with the variable demography and symptom presentation in these clinical trial settings suggest that further characterization of this toxicity, its mechanism and its predisposing factors is warranted,” they added. “These toxicities may occur more frequently in the general population with longer-term use of [telbivudine].”

11/27/07

References

Benhamou, AM Di Bisceglie, ZD Goodman, and others. On-Treatment Virologic Suppression at Week 24 decreases the Risk of Histologic Progression at 1 Year; Data from the GLOBE Trial AASLD 2007. Abstract 995.