Effectiveness of entecavir in chronic hepatitis B NUC-naive patients in routine clinical practice

Authors


  • Disclosures None.

Ezequiel Ridruejo MD, Hepatology Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno ‘CEMIC’, Avda, Las Heras 2981, (C1425ASG) Buenos Aires, Argentina
Tel.: + 54 11 5299 1221
Fax: + 54 11 5299 0600 (ext. 5900)
Email: eridruejo@gmail.com

Summary

Introduction:  Registration studies showed entecavir (ETV) to be effective and safe in NUC-naïve patients with chronic hepatitis B virus (HBV), but its effectiveness in routine clinical practice is unknown.

Materials and methods:  Sixty-nine HBeAg positive and negative NUC naïve chronic HBV patients were treated with ETV for 110 weeks. 63% were HBeAg positive, 16% were cirrhotics, mean HBV-DNA was 7.09 log IU/ml and mean ALT was 157 IU/ml.

Results:  Sixty-one (88%) patients achieved undetectable DNA, with 46%, 77% and 100% virological response rates at week 24, 48 and 96 of treatment, respectively. Thirty-seven (84%) patients in the HBeAg-positive population achieved undetectable DNA, with 67% and 100% virological response rates at week 48 and 96 of treatment, respectively. Twenty-four (96%) patients in the HBeAg-negative population achieved undetectable DNA, with 91% and 100% virological response rates at week 48 and 96 of treatment, respectively. Twenty-three (53%) patients cleared HBeAg and 19 (44%) patients seroconverted to antiHBe positive status; seven (10%) patients cleared hepatitis B surface antigen and five (7%) patients developed antiHBs. At the end of the study, 10 patients successfully stopped therapy: nine HBeAg positive (four developed antiHBs positive) and one HBeAg negative. None of the patients had primary non-response. ETV resistance was not tested. None of the patients developed hepatocellular carcinoma, underwent liver transplantation or died because of liver-related events. No serious adverse events were reported.

Conclusion:  The ETV monotherapy showed high virological response rates, a favourable safety profile for NUC-naive HBeAg-positive and negative patients treated in routine clinical practice.

What’s known

There is information about treatment of chronic hepatitis B in randomised clinical trials (RCT). All these trials show that treatment in highly selected patients is safe and effective. There is little information about treatment in daily clinical practice with ‘real life’ patients. There are some abstracts presented at medical meetings but there is no publication about this topic.

What’s new

This is the first study to be published as a full article about treatment of hepatitis B in routine clinical practice. There is a debate about translating results of RCT to clinical practice. Our results confirm that treatment of chronic hepatitis B with ETV is safe and effective.

Introduction

The hepatitis B virus (HBV) is estimated to have infected more than two billion people worldwide, of whom 400 million are chronically infected today and are at an increased risk of liver-related complications, including cirrhosis, liver failure, liver transplantation, hepatocellular carcinoma (HCC) and death (1,2). In America, HBV prevalence is relatively low, with hepatitis B surface antigen (HBsAg) positivity ranging from < 2% to 7% compared with Asia, Africa and the Middle East, where HBV prevalence rates reach 5–20% of the general population (2,3).

Indications for treatment have been established by several international guidelines. PEG-IFN-alfa, tenofovir and entecavir have been selected as the first-line therapy to initiate treatment in naïve chronic HBV infected patients. When choosing which antiviral agent to use, consideration should be given to the safety and efficacy, risks of drug resistance, costs (medication, monitoring tests and clinic visits), as well as patient and provider preferences (3,4).

Entecavir is a potent inhibitor of HBV replication, which is commercially available since 2005. In phase III randomised clinical trials (RCT) entecavir at a dose of 0.5 mg/day in treatment-naive patients suppressed HBV-DNA to undetectable levels by year 1 in 67% of HBeAg-positive and in 90% of HBeAg-negative patients (5,6). Recent reports showed that when entecavir was administered for 96 weeks treatment, it resulted in a better HBV-DNA suppression and higher rates of HBeAg seroconversion (7,8). Entecavir has a high genetic barrier to resistance and a strong resistance profile. Recently reported results of more than 6 years of therapy showed that in nucleos(t)ide-naive patients, the cumulative probability of genotypic resistance to entecavir was 1.2% (9). Also, entecavir treatment has been shown to improve fibrosis of the liver and can cause fibrosis and cirrhosis regression (10).

A multicentre Italian study demonstrated that entecavir treatment for NUC-naïve, HBeAg-negative chronic hepatitis B patients might be effective in clinical practice (11). The objective of the study is to evaluate the efficacy and safety of entecavir in chronic hepatitis B NUC-naïve HBeAg-positive and negative patients in routine clinical practice.

Material and methods

We included 69 patients with chronic hepatitis B treated with entecavir for at least 6 months in five centres in Argentina. Each centre included all patients treated since January 2005. We report our virological and serological results with continued treatment up to 1 September 2010 or until stopping it according to international recommended stopping rules. We evaluated the effect of entecavir treatment on HBV-DNA negativization, HBeAg negativization, antiHBe seroconversion, HBsAg negativization and antiHBs seroconversion. We also evaluated the influence of baseline demographic characteristics, ALT values (mean and ≥ 5 times upper limit of normal-ULN), HBV-DNA values (mean and ≥ 7 log IU/ml), Metavir A and F scores; presence of cirrhosis and entecavir treatment duration of treatment outcomes. Treatment duration was defined according to current stopping rule guidelines: discontinuation after 24 to 48 weeks of antiHBe seroconversion in HBeAg-positive patients and indefinitely in HBeAg-negative/antiHBe positive patients (3,4). At baseline and at a 6-month interval the following parameters were recorded: liver functional tests, cellular blood counts, serum HBV-DNA levels; HBsAg, antiHBs, HBeAg and antiHBe status.

Patients older than 18 years; HBV-DNA positive; HBeAg positive or negative; and treatment naïve were included. We excluded patients treated in RCTs, those with decompensated liver disease; HIV and/or HCV coinfection; solid organ transplantation; on haemodialysis or with other associated liver disease. Data were obtained from the medical records, and anonymously entered in a database.

Diagnosis of chronic hepatitis B was defined as a positive serum HBsAg and detectable HBV-DNA for more than 6 months, independent of ALT levels and HBeAg status. Quantitative HBV-DNA was determined by Cobas Taqman HBV ‘Real Time PCR’ test (Roche Molecular systems Inc, Branchburg, NJ, USA) with a limit of detection of 6 IU/ml (0.78 log). HBsAg, antiHBs, HBeAg, antiHBe and antiHBc were assessed by microparticule enzyme immunoassay assay (MEIA) (Abbott Diagnostics Division, Wiesbaden-Delkenheim, Germany).

Treatment was indicated and monitored according to national and international guidelines. In some cases doses might be different to those recommended, according to individual medical judgment.

Management of adverse events, including dose modifications or treatment suspension was decided by the treating physicians according to national and international guidelines and to their own clinical judgment.

Statistical analysis

Microsoft Excel 2007® software (Microsoft, Seattle, WA, USA) was used for the database. stata® statistical software was used for the analysis (version 7.0; Stata Corporation, TX, USA). The chi-squared test was employed to compare categorical variables, and continuous variables were compared using the t-test. Logistic regression test was used to explore base line factors predicting a virological response. p-Value < 0.05 was considered statistically significant.

Results

We included 69 NUC-naïve patients in the study: 51 (74%) were men, 60 (87%) were Caucasian, with a mean age of 46 ± 11 years. Forty-four patients (63%) were HBeAg positive and the mean viral load was 7.09 ± 1.85 log IU/ml. ALT was elevated in 64 patients (93%) before treatment, with a mean value of 157 ± 211 IU/ml. Fifty-two patients (75%) underwent a liver biopsy: mean Metavir A score was 2 ± 0.69 and mean F score was 2.25 ± 1.11; 11 patient (15%) had cirrhosis. HBeAg-positive patients were younger (44 ± 12 95% CI 40–47 vs. 49 ± 8 years 95% CI 45–53, p = 0.049), have higher HBV-DNA values (7.98 ± 1.39 log IU/ml, 95% CI 7.55–8.41 vs. 5.55 ± 1.55 log IU/ml, 95% CI 4.92–6.18; p < 0.001), and had a lower incidence of cirrhosis (36 vs. 64%, p = 0.03) than HBeAg-negative ones. Baseline ALT values (184 ± 250 IU/ml 95% CI 108–260 vs. 110 ± 104 IU/ml 95% CI 67–153, p = 0.13) and mean fibrosis scores (2.1 ± 0.9, 95% CI 1.8–2.5 vs. 2.4 ± 1.2 95% CI 1.8–2.9, p = 0.47) were similar in both HBeAg-positive and negative patients (Table 1).

Table 1.   Demographics characteristics of the overall population
 HBeAg positiveHBeAg negativep value
Male/female35/916/90.158
Caucasian/Asian38/622/30.846
Age (years)44 ± 1249 ± 80.049
Mean Metavir F score2.1 ± 0.92.4 ± 1.20.47
Cirrhosis (%)36640.03
Mean ALT values (IU/ml)184 ± 250110 ± 1040.13
Mean HBV DNA (log (IU/ml)7.98 ± 1.395.55 ± 1.55<0.001
Mean ETV treatment time (weeks)106 ± 55116 ± 540.5

Mean entecavir treatment period was 110 ± 54 weeks: 65 (92%) patients were treated for 48 or more weeks and 31 (45%) were treated for 96 or more weeks. There was no difference in treatment duration between HBeAg-positive and negative patients (106 ± 55 weeks, 95% CI 90–123 vs. 116 ± 54 weeks, 95% CI 93–138, p = 0.5).

Sixty-one (88%) patients in the overall population achieved undetectable HBV-DNA, with 46%, 77% and 100% virological response rates at week 24, 48 and 96 of treatment, respectively. Thirty-seven (84%) patients in the HBeAg-positive population achieved undetectable HBV-DNA, with 67% and 100% virological response rates at week 48 and 96 of treatment, respectively. Twenty-four (96%) patients in the HBeAg-negative population achieved undetectable HBV-DNA, with 91% and 100% virological response rates at week 48 and 96 of treatment, respectively (Figure 1).

Figure 1.

 Response to entecavir in the overall population and according to treatment duration

Twenty-three (53%) patients cleared HBeAg and 19 (44%) patients seroconverted to antiHBe positive status in the overall population. In patients treated for 96 weeks or more, 70% cleared HBeAg and 50% seroconverted to antiHBe positive status (Figure 1). Comparisons of baseline characteristics between HBeAg and antiHBe responders are shown in Table 2. Seven (10%) patients cleared HBsAg (six HBeAg positive and one HBeAg negative) in the overall population: 12% of those treated for 24 weeks and 20% of those treated for 96 weeks or more (Figure 1). Five (7%) patients developed protective titres of antiHBs (four HBeAg positive and one HBeAg negative) in the overall population: 8% of those treated for 24 weeks and 14% of those treated for 96 weeks or more (Figure 1). Comparisons of baseline characteristics between HBsAg and antiHBs responders are shown in Table 3. At the time of the study, 10 patients successfully stopped therapy: nine HBeAg positive (four developed antiHBs positive) and one HBeAg negative.

Table 2.   Baseline characteristic according to HBeAg/antiHBe response
 HBeAg negativizationAntiHBe seroconversion
YesNop valueYesNop value
Patients 23 20  19 24 
Age (years)46 ± 1141 ± 130.1046 ± 1141 ± 130.11
Mean Metavir A score2.3 ± 0.61.6 ± 0.60.00172.3 ± 0.61.8 ± 0.60.02
Mean Metavir F score2.6 ± 0.81.7 ± 10.0062.5 ± 0.72 ± 10.08
Mean ALT values (IU/ml)150 ± 90138 ± 880.34168 ± 95129 ± 810.10
Mean HBV DNA (log (IU/ml)8.1 ± 1.77.8 ± 1.20.287.9 ± 1.28 ± 1.20.53
Mean ETV treatment time (weeks)126 ± 15884 ± 440.01115 ± 60100 ± 530.21
Table 3.   Baseline characteristic according to HBsAg/antiHBs response
 HBsAg negativizationAntiHBs seroconversion
YesNop valueYesNop value
Patients762 564 
Age (years)48 ± 1545 ± 110.2752 ± 945 ± 110.08
HBeAg positive/negative (%)85/1560/400.1980/2062/380.43
Mean Metavir F score2.33 ± 2.022.22 ± 1.030.432.4 ± 1.892.22 ± 1.080.86
Mean ALT values (IU/ml)403 ± 570131 ± 1020.001479 ± 677132 ± 1020.001
Mean HBV DNA (log (IU/ml)7.39 ± 1.43 7.03 ± 1.190.197.33 ± 1.717.07 ± 1.880.31
Mean ETV treatment time (weeks)118 ± 26108 ± 570.33130 ± 16108 ± 580.19

None of the patients had primary non-response; in patients with partial virological response median residual viraemia was 3.05 log IU/ml (1.57–6.09). ETV resistance was not tested.

Sixty-three (93%) patients in the overall population normalised ALT values; mean ALT value at the time of evaluation was 30 ± 21 IU/ml. All HBeAg-negative patients achieved normal ALT values, while 87% (6/44 pts) of HBeAg positive normalised ALT (p = 0.053).

When evaluating baseline predictors of treatment outcome we found that: Metavir F score (OR 3.05, p = 0.021, 95% CI 1.18–7.86) and time with entecavir treatment (OR 1.02, p = 0.037 95% CI 1.001–1.056) were associated with HBV-DNA negativization; Metavir F score (OR 2.89, p = 0.025 95% CI 1.14–7.35), Metavir A score (OR 6.53, p = 0.014, 95% CI 1.47–29.04), and ALT values > 5 times upper limit of normal (OR 4.5, p = 0.035 95% CI 1.10–18.27) were associated with HBeAg negativization/antiHBe seroconversion; and ALT values > 5 times upper limit of normal (OR 5.44 p = 0.041 95% CI 1.07–27.63) were associated with HBsAg negativization.

None of the patients developed HCC, underwent liver transplantation or died because of liver-related events. No serious adverse events were reported. None of the patients abandoned treatment or were lost to follow up.

Discussion

In this small study, we have demonstrated that treatment with entecavir in routine clinical practice can be as effective as in RCT. Pivotal studies demonstrated that entecavir is an antiviral agent of high clinical potency. At a dose of 0.5 mg/day in treatment-naive patients suppressed HBV-DNA to undetectable levels by year 1 in 67% of HBeAg-positive and in 90% of HBeAg-negative patients (5,6). The mean reduction in HBV-DNA at year 1 from baseline was 6.9 log copies/ml (∼ 6.2 log IU/ml) in HBeAg-positive patients receiving entecavir vs. 5.0 log copies/ml (∼ 4.3 log IU/ml) in HBeAg-negative patients. A recent report showed that prolonging treatment resulted in a better HBV-DNA suppression. When administered for 96 weeks in HBeAg-positive patients, 80% of the patients achieved HBV-DNA levels < 300 copies/ml (∼ 59 IU/ml). In addition, approximately 31% of patients achieved HBeAg seroconversion, 5% achieved HBsAg negativization and 2% achieved HBsAg seroconversion by week 96 (7). In a Japanese study, long-term treatment with entecavir (more than 96 weeks) revealed that 83% of patients suppressed HBV-DNA to undetectable levels, and 20% of HBeAg-positive patients achieved HBeAg seroconversion. One patient in this cohort achieved HBsAg negativization, and another achieved HBsAg seroconversion by week 96 (8).

Entecavir has a high genetic barrier to resistance and a strong resistance profile. Recently reported results of more than 6 years of therapy showed that in nucleos(t)ide-naive patients, the cumulative probability of genotypic resistance to entecavir was 1.2% whereas the 6-year cumulative risk of genotypic resistance to entecavir among lamivudine-refractory patients was 57% (9). We did not perform tests to evaluate genetic resistance, but we found no evidence of clinical resistance to treatment (e.g. reappearance of HBV-DNA during treatment in previous responders).

There is little information about HBV treatment in routine clinical practice. Lampertico et al. showed that entecavir treatment for NUC-naïve, HBeAg-negative chronic hepatitis B patients might be effective in clinical practice: Ninety-nine per cent of patients achieved undetectable HBV-DNA, 87% normalised ALT values and 0,6% seroconverted to antiHBs positive status (11); and that HBV suppression can be maintained over time (12). Lim et al. showed that entecavir treatment can be effective in HBeAg-positive and negative patients, NUC-naive patients or those who have had previous treatment (13). Also Lampertico et al. showed that tenofovir, another NUC used for the treatment of chronic HBV, can also reach in clinical practice same results as in clinical trials (14).

Our results showed that HBV negativization rates are similar to those obtained in RCT and in two studies in clinical practice. Rates of HBeAg seroconversion, HBsAg negativization and seroconversion are slightly higher than previously reported (7,8,10,12). But, this is a small sample to draw definitive conclusions. At least, responses are not lower, showing the same efficacy as in RCT and in previous experience in routine clinical practice. We also found that predictors of response previously reported, predicted treatment outcome in our cohort. Surprisingly, higher levels of fibrosis are associated with HBV-DNA negativization and HBeAg seroconversion.

Argentina is considered a low HBV endemic country, and lots of patients are probably not diagnosed yet (15). Given this situation, and because of lack of accessibility to diagnosis and treatment, number of treated patients is small. A bigger multicentre study might be needed to confirm these results.

There is a discussion if results of RCTs can be extrapolated to the everyday clinical practice. These studies, despite sound internal validity, may not have good external validity (generalisability) in general population (16). As we and other authors have shown, treatment of chronic HBV in real life can be as safe and effective as in RCT. More studies are needed to confirm these results.

Acknowledgements

We are indebted to Dr Hugo Krupitzky for his help with the statistical analysis.

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