Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis
Articles in Press
Jnl of Hepatology Jan 2010
Ju Hyun Shim, Han Chu Lee, Kang Mo Kim, Young-Suk Lim, Young-Hwa Chung, Yung Sang Lee, Dong Jin Suh
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
Received 8 May 2009; received in revised form 31 July 2009; accepted 1 September 2009. published online 19 November 2009.
Background & Aims
The effect of entecavir (ETV) therapy on viral suppression and hepatic function in hepatitis B virus (HBV) patients with decompensated cirrhosis has not been established. We evaluated ETV as first-line monotherapy in these patients.
We consecutively enrolled 70 HBV-infected patients with decompensated cirrhosis primarily treated with 0.5mg/day ETV, and evaluated the clinical outcomes by intention-to-treat analyses. We also compared the virological responses of 55 patients treated for 12months (decompensated group) with those of 144 chronic hepatitis or compensated cirrhosis patients (compensated group).
The cumulative transplantation-free survival was 87.1% at 1year. ETV treatment for 12months resulted in improved Child-Turcotte-Pugh (CTP) and model for end-stage liver disease (MELD) scores. Sixty-six percent (36/55) of patients achieved CTP class A and 49% (27/55) showed improvement in the CTP score of 2 points after 12months of ETV. The 1-year cumulative rates of HBV DNA negativity and HBeAg loss were 92.3% and 54.0%, respectively, by intention-to-treat analysis. The rates of HBV DNA negativity, HBeAg seroconversion/loss and ALT normalization at month 12 were similar for the decompensated and compensated groups. Cox regression analysis showed that pretreatment HBeAg seropositivity was a negative predictor of HBV DNA clearance during ETV therapy (hazard ratio, 0.514; 95% confidence interval 0.367-0.719; p<0.001).
One-year initial ETV therapy was similarly effective in both compensated and decompensated liver disease HBV patients. In addition, it improved underlying liver function in decompensated patients.
Approximately 15-40% of hepatitis B virus (HBV) carriers are at increased risk of serious sequelae such as cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC) , . In Korea, 5-7% of individuals within the general population are identified as HBV carriers , accounting for about 70% of liver cirrhosis and HCC cases . The 5-year survival rate in decompensated cirrhosis patients is a low 14% compared with 84% for those with compensated cirrhosis .
A high viral load may be predictive of future progression to cirrhosis or HCC in HBV-infected patients , . The oral antiviral drug lamivudine (LAM) slows deterioration in chronic hepatitis B (CHB) and advanced liver disease patients by delaying hepatic decompensation and HCC development . However, LAM is no longer considered an optimal first-line therapy in CHB patients, owing to its higher resistance rate and lower potency compared to entecavir (ETV) and telbivudine , , , . Latest recommendations suggest using ETV and tenofovir as primary oral agents irrespective of hepatitis B e antigen (HBeAg) serostatus .
ETV is considered an excellent treatment alternative for nucleos(t)ide-naïve patients due to insignificant resistance rates and strong antiviral effects , , and is thus widely prescribed. In recent 48-week trials of ETV treatment for CHB, 67% of HBeAg-positive and 90% of HBeAg-negative patients showed HBV DNA reduction to undetectable levels , , consistent with data obtained from patients with advanced liver fibrosis or compensated cirrhosis . Furthermore, over 5years of treatment, the cumulative probability of development of mutations in the virus conferring genotypic resistance to ETV was only 1.2% in nucleos(t)ide-naïve patients . Hence, early ETV therapy may halt disease progression more effectively in chronically infected patients compared with LAM.
At present, limited information is available on the impact of ETV therapy on viral suppression and hepatic function in CHB patients, particularly those with decompensated cirrhosis. In addition, the issue of when to use ETV as a first-line option in CHB therapy remains to be established.
In the present study, we evaluated the efficacy of ETV monotherapy in HBV-infected patients. We compared outcomes between decompensated cirrhosis patients and those with CHB or compensated cirrhosis. In addition, we investigated the effect of ETV therapy on hepatic function in patients with decompensated cirrhosis.
Patients and methods
From January 2007 to March 2008, 70 consecutive treatment-naive patients with HBV-related decompensated cirrhosis were orally treated with 0.5mg/day ETV alone at our institution. Of these patients, 6 (8.6%) died during the follow-up period, and all deaths were due to hepatic failure within 6months of ETV therapy (Fig. 1). Three patients (4.3%) underwent orthotopic liver transplantation (OLT) 3 or 4months after the commencement of ETV therapy. At the time of OLT, all three had intractable ascites and/or grade 3 or 4 hepatic encephalopathy, with model for end-stage liver disease (MELD) score 15. Six patients (8.6%) were lost to follow-up before evaluation at 12months, but were still alive. We analyzed clinical data from the remaining 55 patients with decompensated cirrhosis (decompensated group; Fig. 1), along with those from 144 consecutive patients with CHB or compensated cirrhosis (compensated group) who underwent 0.5mg/day ETV treatment for at least 12months during the same period. None of these patients had evidence of HCC at the time of initiation of ETV. CHB patients showing hepatic decompensation during acute exacerbation, defined as an elevation of alanine aminotransferase (ALT) activity to more than 10 times the upper limit of normal and more than twice the baseline value  were not included in the decompensated group. No patient had been previously administered antiviral therapy involving interferon-α or nucleos(t)ide analogs. All patients with or without HBeAg were persistently positive for hepatitis B surface antigen (HBsAg) for more than 6months, and contained serum HBV DNA levels of 4log10copies/ml or greater at baseline. Patients displaying antibodies against hepatitis C (anti-HCV) or human immunodeficiency virus (anti-HIV) or who had undergone liver or other organ transplants were excluded.
Decompensated liver disease was established based on a Child-Turcotte-Pugh (CTP) score7 (class B and C) or the presence of portal hypertension complications such as ascites, variceal bleeding or hepatic encephalopathy , . Liver cirrhosis was diagnosed based on clinical, radiological, or histological assessments. The study was approved by the institutional review board of our hospital.
Laboratory and radiological testing
Baseline serological and imaging data such as ultrasonography (USG) or spiral computed tomography (CT) were obtained for all subjects. Serum hepatitis viral markers, including HBsAg, anti-HBs, HBeAg, anti-HBe, anti-HCV and anti-HIV, were confirmed using commercially available enzyme immunoassays (Abbott Laboratories, Chicago, IL). Serum HBV DNA levels were quantified using the Abbott Real-Time PCR assay (Abbott Laboratories, Chicago, IL) with a linear dynamic range of detection of 5.1x101-3.4x109copies/ml, according to the manufacturer's instructions. Other laboratory parameters were assayed using standard analytical procedures.
Compensated and decompensated groups were followed-up every 3-6months with tests for liver function, prothrombin time (PT), HBeAg, anti-HBe, and HBV DNA levels, in company with USG or spiral CT. Clinical examination and counseling regarding treatment adherence were performed for all patients at every clinic visit.
The two groups were compared using Student's t-test or Mann-Whitney test for continuous variables and chi-square or Fisher's exact test for categorized variables, where appropriate. Covariates with p-values<0.20 in univariate analysis were included in multivariate analysis using Cox proportional hazards models to determine whether pretreatment clinical and laboratory variables were significant in predicting HBV DNA clearance during ETV treatment. A p-value<0.05 was considered to indicate significance.
The baseline characteristics of the two study groups are shown in Table 1. The 199 total patients comprised 131 males and 68 females, and the gender ratio was similar for each group. The mean age was greater in the decompensated than the compensated group (52.6 vs. 46.8years, p<0.001). The two groups were similar in terms of serum HBV DNA levels. The mean serum ALT levels were lower in the decompensated group (101.9 vs. 156.5IU/L, p=0.021). The proportion of subjects positive for HBeAg was similar in both groups (49.1% vs. 62.5%, p=0.086). As anticipated, the decompensated group showed lower scores than the compensated group in terms of CTP and MELD scores, hepatic function (total bilirubin, albumin, PT) and platelet counts (p<0.001 for all). In the decompensated group, 31 (56.4%) patients had ascites, 7 (12.7%) had episodes of hepatic encephalopathy, and 13 (23.6%) experienced variceal bleeding. No patient in either group discontinued ETV during the study period.
The 70 patients with decompensated cirrhosis (Table 2) had a mean serum HBV DNA concentration at baseline of 7.18log10copies/ml and 34 (48.6%) patients were positive for HBeAg. All components of the CTP score, except for hepatic encephalopathy, were significantly poorer in the 9 patients (12.9%) who died or underwent OLT within 6months of ETV therapy than in the other 61 patients (87.1%) with decompensated cirrhosis (p<0.05 for all). These two subgroups, however, did not differ in serum HBV DNA or ALT levels, HBeAg serostatus, MELD score, or number of episodes of variceal bleeding.
Virological, serological, and biochemical responses
Viral and host responses to ETV therapy in the decompensated and compensated groups are presented in Table 3. Overall, ETV therapy over 12months resulted in a progressive decrease in serum HBV DNA levels (-5.52log10copies/ml at month 6, and -6.76log10copies/ml at month 12). The mean reductions in serum HBV DNA levels at months 6 and 12 did not differ significantly between the decompensated and compensated groups (Fig. 2). Undetectable serum HBV DNA levels were observed in 162 of the total 199 (81.4%) patients during the 12months of ETV therapy, and in each group a similar proportion of patients achieved undetectable viremia. Virological breakthrough (>1log10 increase in serum HBV DNA level from the nadir) was not noted in any patient throughout the follow-up period.
Of the 117 patients initially positive for HBeAg, 21 (17.9%) and 28 (23.9%) exhibited HBeAg seroconversion at months 6 and 12, respectively, with similar proportions being observed in both decompensated and compensated groups (18.5 vs. 17.8% at month 6, p=0.930; and 22.2 vs. 24.4% at month 12, p=0.812). This distribution was consistent with the HBeAg clearance rate (33.3 vs. 25.6% at month 6, p=0.427; and 48.1 vs. 41.1% at month 12, p=0.517). With regard to ALT response, the frequency of ALT normalization occurred uniformly at 12months of ETV therapy in both groups (76.4% vs. 75.0%, p=0.535). No differences were also observed in terms of the likelihood of HBV DNA suppression to undetectable levels and ALT normalization at 12months between the groups when stratified according to HBeAg serostatus (Table 4).
When all 70 patients with decompensated cirrhosis receiving ETV therapy were included in an intention-to-treat analysis of efficacy, the cumulative rates of HBV DNA negativity and HBeAg loss at 12months were 92.3% and 54.0%, respectively (Fig. 3A and B).
Pretreatment factors predicting HBV DNA negativity during ETV therapy
The overall 1-year cumulative rate of HBV DNA negativity was 84.4% in all 199 patients (Fig. 4A), i.e., 81.3% and 92.7% in the decompensated and compensated groups, respectively (p=0.099; Fig. 4B). During 12months of ETV therapy, the cumulative rate of HBV DNA negativity was significantly higher in HBeAg-negative than in HBeAg-positive patients (97.6% vs. 75.2%, p<0.001; Fig. 4C). Cox regression analysis with adjustment for baseline potential confounders (age, HBeAg status, serum HBV DNA levels, and categories of liver disease) showed that baseline HBeAg seropositivity was the only independent predictive factor adversely affecting HBV DNA negativity during ETV therapy (hazard ratio, 0.514; 95% confidence interval, 0.367-0.719, p<0.001; Table 5).
Changes in hepatic function after 12months of ETV therapy in the decompensated group
To evaluate the influence of ETV therapy on hepatic function reserve in the decompensated group, we measured the CTP score and its components (i.e., total bilirubin, albumin, and PT), along with MELD score and compared these values pre- and post-treatment (Fig. 5). For all 55 patients, the mean albumin (2.8 vs. 3.2g/dl), total bilirubin (3 vs. 1.9mg/dl), PT (16.3 vs. 13.9s), CTP score (8.1 vs. 6.6), and MELD score (11.1 vs. 8.8) improved after 12months of ETV treatment than at baseline (p<0.05 for all). Twenty-seven patients (49.1%) showed an improvement of >2 points in CTP score. Of the remaining 28 patients (50.9%), 9 achieved CTP class A with 1 point of improvement; 3 did not achieve CTP class A despite 1 point in improvement; 12 showed no change; and 4 experienced aggravation. Of the 27 patients who showed >2 point CTP score improvement, 15 (55.6%) improved within 3months and 20 (74.1%) improved within 6months of commencing ETV. As a result, 36 (65.5%) of the 55 patients achieved CTP class A (score 5 or 6) after 12months of ETV.
On-treatment outcomes of HCC occurrence and OLT-free survival in patients with decompensated cirrhosis
The 70 patients with decompensated cirrhosis had a cumulative incidence of HCC of 6.9% at month 24, with 4 patients developing HCC during the entire follow-up period (Fig. 6). In addition, the cumulative incidence of mortality or OLT was 12.9% at month 12 and 17.0% at month 24, respectively (Fig. 6), with 36.4% at month 24 in patients with CTP class C. After 6months of ETV therapy, only one patient in the decompensated group died of uncontrollable variceal bleeding and no patient received a liver transplant.
The results presented here clearly confirm that first-line ETV 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. Moreover, ETV monotherapy improved hepatic function significantly, especially in patients with decompensated cirrhosis. Previous studies showed that LAM was also effective in viral suppression with no serious adverse effects in HBV-related decompensated cirrhosis and resulted in improved hepatic function and reduced morbidity , , , . However, the antiviral effects of ETV in cirrhotic patients with hepatic decompensation in the clinical setting have not been established , , .
Using real-time PCR analysis, we found that 1year of ETV therapy resulted in HBV DNA levels that were undetectable in 81.5% of HBeAg-positive and 96.4% of HBeAg-negative patients with decompensated cirrhosis. These values are considerably better than other published rates in compensated CHB patients. These figures were achieved despite the lack of patients achieving undetectable HBV DNA at a wider detection limit of below 51copies/ml in our study using real-time PCR analysis compared with previous studies using commercial assays , . Similar findings were observed regarding ALT normalization which occurred in 77.8% of HBeAg-positive and 75.0% of HBeAg-negative patients with decompensated cirrhosis. Interestingly, the proportions of compensated and decompensated patients showing ALT normalization at 12months were similar despite poorly matched pretreatment ALT levels. In general, patients with advanced liver disease often have relatively lower liver enzyme elevations despite a higher viral load compared to patients with well-compensated liver disease .
Notably, HBeAg seropositivity was an important predictor for suboptimal viral response to ETV treatment. The reasons underlying this finding remain to be established. This result is consistent with previous data showing that in terms of virological and biochemical responses, ETV therapy was more favorable for CHB patients negative for HBeAg than those positive for HBeAg, although not when compared head-to-head , , which may be conceivable since the long-term natural course is reported to be poorer in HBeAg-negative patients compared with HBeAg-positive patients , .
In contrast to similar outcomes in HBeAg seroconversion at 12months (23.9% vs. 21%), the overall rate of HBeAg loss in our study subjects was much higher than that reported in other study populations (46.8% vs. 22%) . The high HBeAg rate of loss may reflect the lower HBeAg titer in Korean CHB patients. Indeed, a Korean study reported that 22% of HBeAg-positive patients had a mixed infection of precore mutant and wild-type . In addition, our prior data showed that HBeAg seroconversion was 34% in patients with pretreatment serum ALT levels over twice the ULN, compared with 5% in those with pretreatment ALT levels less than twice the ULN . In the present study, serum ALT values over twice ULN were identified in 63.8% of all patients.
Emerging data have revealed the positive effect of LAM therapy on the functional enhancement of underlying liver disease in patients with HBV-related decompensated cirrhosis and HCC, thus leading to improvements in the biochemical and clinical parameters of patients , , . Similarly, the CTP and MELD scores, both of which reflect liver function, and their components, including serum albumin and total bilirubin levels as well as PT, dramatically improved during the period of ETV treatment in our patients with decompensated cirrhosis. All practice guidelines suggest that antiviral treatment should be considered in decompensated cirrhosis patients regardless of HBV DNA levels , , . In HBV-infected patients with significant functional compromise, corresponding early intervention with ETV may possibly prevent clinical progression to hepatic failure, taper complication risk, and even delay or avoid OLT as a bridging therapy by substantially stabilizing the HBV status.
In Korea, living donor-OLT is currently performed in approximately 80% of the liver transplant because of a cadaveric organ shortage. Therefore, OLT is generally recommended for patients with CTP class C or a MELD score >15. We initially recommend OLT if the patients are under the above conditions, and start ETV therapy if a donor liver is not available. When donor livers become available, we reevaluate the patients' status and perform OLT if the patients are still in CTP class C or a MELD score >15. In our series, the 2-year OLT-free survival was 83%. There were six deaths and three liver transplants within 6months of starting ETV treatment. Of these, the three transplanted patients and three of the patients who died were evaluable for virological response at month 3, and all showed a marked decrease in serum HBV DNA to <103copies/ml. The early antiviral response to LAM at week 8 did not predict 6-month mortality in patients with decompensated CHB . Although significant clinical improvement with ETV therapy was achieved most frequently within 6months of therapy, approximately 80% of early mortality or OLT in our population occurred within 4months of onset of ETV therapy. This observation is consistent with the previous LAM therapy data , , . Given that patients who died or underwent OLT early in ETV treatment had significantly higher pretreatment CTP scores, OLT should not be delayed in patients with CTP class C or a MELD score >15 at baseline, or be urgently considered in patients displaying suboptimal improvement in hepatic reserves after 3months of ETV treatment.
Whereas the LAM studies of Yao and colleagues ,  showed a dramatic decline in CTP scores of >3 points in more than 60% of patients, less than half of our patients showed significantly improved CTP scores (>2 points). These dissimilar results may reflect that decompensated patients with acute exacerbation of CHB were excluded from the present study in contrast to the previous studies , .
In the context of clinical antiviral resistance, virological breakthrough was not noted throughout our study period, although genotypic analysis of ETV-resistant HBV variants was not performed. A previous study on 17 Korean patients matched with ours for pretreatment characteristics found that 7 patients (41.2%) experienced virological breakthrough during approximately 2years of LAM treatment, including 6 (86%) with YMDD mutants .
The long-term efficacy of ETV in vivo is unclear at present. Since the potency and resistance rates of ETV outweigh those of LAM , , similar or better outcomes are expected. However, this requires confirmation in further studies.
In conclusion, the present study provides evidence that 1year of initial ETV treatment is comparably efficacious in arresting HBV replication and clearing HBeAg in HBV-infected patients with either compensated or decompensated liver disease. In addition, ETV markedly improved the underlying hepatic reserve in decompensated cirrhotic patients, mostly within 6months of treatment. Thus, our findings may establish a rationale for the use of ETV as a first-line monotherapeutic agent in these patients. Further ongoing follow-up investigations are necessary to obtain long-term data in conjunction with genotypic assays of ETV resistance.