Entecavir (Baraclude) Improves Liver Function in Chronic Hepatitis B Patients with Decompensated Cirrhosis

		SUMMARY: The antiviral drug entecavir (Baraclude) worked as well in chronic hepatitis B patients with decompensated liver disease as it did in individuals with less severe liver damage, according to a study published in the February 2010 Journal of Hepatology. Furthermore, over 1 year, entecavir improved underlying liver function in these patients with the most advanced disease.

By Liz Highleyman

Over years or decades, chronic hepatitis B virus (HBV) infection can progress to advanced liver disease including cirrhosis (scarring) and hepatocellular carcinoma. Compensated cirrhosis means the liver is heavily damaged but can still carry out its normal functions; decompensated cirrhosis occurs when the liver fails to perform properly.

Several antiviral agents are used to treat chronic hepatitis B, but therapy can be risky in patients with decompensated cirrhosis. However, this group also stands to benefit most from effective treatment.

Ju Hyun Shim from the University of Ulsan College of Medicine in Seoul and colleagues evaluated entecavir as first-line monotherapy in a group of 70 Korean hepatitis B patients with decompensated cirrhosis who started treatment with 0.5 g/day entecavir between January 2007 and March 2008.

None of the patients had received prior therapy using other antiviral agent or interferon. Participants had HBV DNA viral load levels of at least 4 log copies/mL at baseline. None had evidence of hepatocellular carcinoma the time of treatment initiation and none had undergone prior liver transplantation; individuals with HIV or hepatitis C coinfection were excluded.

Liver cirrhosis was diagnosed based on clinical, radiological, or histological (biopsy) assessments. Decompensated disease was defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher (class B and C) or the presence of portal hypertension complications such as ascites (abdominal fluid accumulation), bleeding varices, or hepatic encephalopathy (brain impairment).

The investigators looked at clinical outcomes among all 70 decompensated patients using an intent-to-treat analysis. They also compared responses in 55 decompensated patients who received entecavir for at least 12 months and 144 patients with compensated liver disease. In both groups, about one-third were women and approximately half were hepatitis B "e" antigen (HBeAg) positive, but the decompensated patients were slightly older on average (53 vs 47 years).

The decompensated and compensated groups were evaluated every 3-6 months with tests for liver function, prothrombin time (a measure of blood clotting), HBeAg, HBe antibodies, and HBV DNA levels.

Results

	6 decompensated patients (8.6%) died during follow-up (all due to liver failure within 6 months of starting entecavir); 3 patients (4.3%) underwent liver transplants 3-4 months after starting entecavir; and 6 patients (8.6%) were lost to follow-up before the 12-month evaluation, but were still alive.
	Among the 70 decompensated cirrhosis, the 1-year cumulative transplant-free survival rate was 87.1%, falling to 83.0% at 2 years.
	After 6 months on entecavir, only 1 decompensated patient died of a liver-related cause (uncontrollable bleeding varices) and no additional patients received liver transplants.
	4 of the 70 decompensated patients developed hepatocellular carcinoma during follow-up, for a cumulative 24-month incidence of 6.9%.
	Entecavir led to a progressive decrease in HBV DNA levels during treatment (-5.52 log copies/mL at 6 months, -6.76 log copies/mL at 12 months).
	The overall 1-year cumulative rate of undetectable HBV DNA among all 199 patients was 84.4% (81.3% in the compensated group vs 92.7% in the decompensated group, not a statistically significant difference; P = 0.099).
	Among the 70 decompensated patients in an intent-to-treat analysis, the 1-year cumulative rate of undetectable HBV DNA was 92.3%.
	Within this same group the rate of HBeAg loss was 54.0%. " Among the decompensated patients, entecavir treatment for 12 months led to improvements in:
	CTP score (8.1 pre-treatment vs 6.6 post-treatment); MELD liver function score (11.1 vs 8.8, respectively); Mean serum albumin (2.8 vs 3.2 g/dL, respectively); Total bilirubin (3.0 vs 1.9 mg/dL, respectively); Prothrombin time (16.3 vs 13.9 seconds, respectively).
	65.5% of decompensated patients reached CTP class A (the least severe level) and 49.1% showed a CTP score improvement of more than 2 points.
	Rates of undetectable HBV DNA, HBeAg seroconversion or loss, and ALT normalization at 1 year were similar in the decompensated and compensated groups.
	Pre-treatment HBeAg seropositivity was the only significant negative predictor of HBV DNA clearance during entecavir therapy (hazard ratio 0.514; P < 0.001).

Based on these findings, the study authors wrote, "One-year initial entecavir therapy was similarly effective in both compensated and decompensated liver disease HBV patients. In addition, it improved underlying liver function in decompensated patients."

"The results presented here clearly confirm that first-line entecavir monotherapy provides comparable overall antiviral benefits in HBV-infected patients with decompensated cirrhosis as has been shown in patients with chronic hepatitis or compensated cirrhosis, regardless of HBeAg serostatus," they elaborated in their discussion.

In conclusion, they wrote, "the present study provides evidence that 1 year of initial entecavir treatment is comparably efficacious in arresting HBV replication and clearing HBeAg in HBV-infected patients with either compensated or decompensated liver disease."

"In addition, entecavir markedly improved the underlying hepatic reserve in decompensated cirrhotic patients, mostly within 6 months of treatment," they continued. "Thus, our findings may establish a rationale for the use of entecavir as a first-line monotherapeutic agent in these patients."

In an accompanying editorial, Robert Fontana from the University of Michigan Medical Center at Ann Arbor wrote that Shim and colleagues "convincingly show that entecavir at a dose of 0.5 mg per day is effective in treating naive decompensated HBV patients with nearly 90% achieving undetectable HBV DNA at month 12. In addition, suppression of HBV DNA was maintained during follow-up with no instances of viral rebound or entecavir-resistant HBV identified."

However, he continued, "the authors also note that not all decompensated patients improved with entecavir therapy," with 12 participants (22%) showing no change in CTP score at 1 year and 4 experiencing worsening CTP scores. "Whether this 'aggravation' was related to entecavir treatment or progression of their underlying liver disease is unclear," he wrote.

All approved oral HBV drugs carry a "black box" warning about their potential to cause mitochondrial toxicity, which can manifest as lactic acidosis, myopathy (muscle damage), neuropathy (nerve damage), or hepatotoxicity (liver toxicity). Laboratory studies suggest that entecavir is less likely to cause mitochondrial damage than other anti-HBV agents, but it has been reported.

Despite this caveat, Fontana concluded, "the study of Shim et al. and others...are bright stars in the horizon for the management of decompensated HBV cirrhosis. The aggregate efficacy and safety data now support the use of entecavir as a first line treatment option for nucleos(t)ide naive patients with decompensated HBV cirrhosis. However, continued follow-up from these ongoing studies including long-term efficacy, safety, and resistance data are needed."

Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

2/9/10

References

JH Shim, HC Lee, KM Kim, and others. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. Journal of Hepatology 52(2): 176-182 (Abstract). February 2010.

RJ Fontana. Entecavir in decompensated HBV cirrhosis: The future is looking brighter (editorial). Journal of Hepatology Hepatology 52(2): 147-149 (Free full text). February 2010.