Treatment of Chronic HBV With Entecavir or Tenofovir
Six real-life studies assessing the efficacy and safety of ETV in a total of 1296 NUC-naïve patients have been presented or published, all confirming results reported in clinical trials, with similar rates of virologic and serologic responses and a low incidence of resistance. Importantly, these studies contain a heterogeneous mixture of patients who are differentiated from those in clinical trials as based on a number of criteria (Table 1) and may, therefore, be more reflective of the treatment population and the real efficacy and safety of the drug. Results from these real-life studies are discussed in the following sections and summarized in Table 2.
Results from a retrospective multicentre study conducted at over 25 Spanish centres were presented at the 2010 American Association for the Study of Liver Diseases (AASLD) meeting. The ORIENTE study evaluated 190 mostly HBeAg(−) patients with compensated liver disease who were treated with ETV (0.5 mg) over a 1-year period. Findings were consistent with those observed in Phase III clinical studies over the same time period, with the rate of virologic response (undetectable HBV DNA) being achieved in 61% and 92% of HBeAg(+) and HBeAg(−) CHB patients, respectively, with 21% (12/57) achieving HBeAg seroconversion and 1% (2/190) clearing HBsAg. Furthermore, of the 31 patients with detectable HBV DNA by week 48, five were tested for ETV resistance and none was found.
The European network of excellence for Vigilance against Viral Resistance (VIRGIL) performed a multicentre cohort study at over 10 European referral centres between 2005 and 2010. The cohort included 333 consecutive adult CHB patients treated with ETV monotherapy, of whom 243 were NUC-naïve. Among the NUC-naïve patients, the cumulative probability of achieving virologic response at week 144 was 90% in HBeAg(+) patients and 99% in HBeAg(−) patients, and the proportion of HBeAg(+) patients with HBeAg loss was 34%. Of the five patients experiencing virologic breakthrough, no mutations associated with decreased sensitivity to ETV were found, including in those patients with viral loads >200 IU/mL at the end of follow-up. Additionally, among the 36 patients with detectable viral load at week 48, 81% went on to achieve undetectable levels of HBV DNA after prolonged ETV therapy, suggesting that even patients who only achieve a partial virologic response initially can benefit from continued ETV therapy. A later analysis of data from this cohort, including a total of 372 patients, showed that the decline in HBV DNA over 144 weeks of ETV treatment was comparable among patients with no cirrhosis (n = 274) and those with cirrhosis (n = 89) or decompensated cirrhosis (n = 9). Virologic response to ETV treatment was associated with a significantly reduced probability of disease progression to HCC, hepatic decompensation or death, even in patients with cirrhosis at baseline.
A retrospective, multicentre study was conducted at five centres in Argentina and included 69 treatment-naive chronic HBV patients receiving ETV for an average of 110 weeks. At baseline, patients were 63% HBeAg(+), 16% cirrhotic, mean HBV DNA was 7.094 log IU/mL, and mean alanine transaminase (ALT) was 157 IU/mL. Virologic response was reached by 46%, 77% and 100% of patients at week 24, 48 and 96, respectively. In the HBeAg(+) population, 84% of patients achieved virologic response, with 67% and 100% response rates seen at week 48 and 96, respectively. Among HBeAg(−) patients, 96% achieved virologic response, with 91% and 100% response rates seen at week 48 and 96, respectively. Twenty-three patients (53%) cleared HBeAg with 19 (44%) demonstrating HBeAg seroconversion; seven patients (10%) cleared HBsAg with five (7%) demonstrating HBsAg seroconversion.
This single-centre cohort study included 406 treatment-naïve patients, 154 of whom were treated with ETV monotherapy for a median of 28 months. At baseline, 60% of patients had HBV DNA >4 log10 IU/mL and 34% had cirrhosis. Median HBV DNA declined continuously over the treatment period; 76% of patients had HBV DNA <12 IU/mL by month 12, and this proportion appeared to remain stable through to month 28. HBeAg seroconversion was reported in 8% of patients and 1% cleared HBsAg.
A retrospective/prospective, multicentre study was conducted at 19 Italian centres and included 418 consecutive NUC-naïve CHB patients initiating treatment with ETV. Baseline characteristics differentiated this cohort from clinical trial patients in that they were predominately older (median age 58 years), genotype D HBV carriers (90%), 49% had cirrhosis, approximately 46% had a body mass index over 25 kg/m, and 56% had concomitant diseases (Table 1). Despite these differences, treatment outcomes were similar to those found during Phase III clinical trials, with undetectable HBV DNA achieved by 85% of patients during the first year of treatment. Viral suppression reached 90% and 98% over 42 months of treatment in HBeAg(+) patients and 48 months of treatment in HBeAg(−) patients, respectively (Fig. 1). There were only three (1%) primary nonresponders (<1 log IU/mL drop in HBD DNA at week 12), and partial virologic responses (residual viraemia at week 48) were seen in 12% of patients. Virologic breakthrough was observed in 4% of patients over the full treatment duration. In HBeAg(+) patients, HBeAg seroconversion occurred in 27 patients (cumulative rate of 55%) and HBsAg loss in 12 patients (cumulative rate of 21%). No resistance to ETV was documented over the treatment period.
(Enlarge Image)
Figure 1.
Virologic response by HBeAg status during entecavir (ETV) treatment in the Italian cohort real-life study. Percentage of ETV-treated patients achieving undetectable HBV DNA levels (<12 IU/mL) through 30 months of treatment in an Italian multicentre cohort study [26]. Left, HBeAg(+) patients; right, HBeAg(−) patients.
The single-centre Hong Kong cohort study prospectively analysed 222 treatment-naïve patients receiving ETV (0.5 mg daily) for up to 4 years. This long-term dosage with 0.5 mg ETV, the approved dosage for NUC-naïve patients, differentiates this study from the long-term ETV-901 clinical trial study, which doubled ETV dosage to 1.0 mg after year 1. The cumulative rate of achieving virologic response was 96% by year 4 (Fig. 2), with 86.4% and 100% of patients having HBV DNA >8 log10 copies/mL or <8 log10 copies/mL at baseline achieving undetectable levels of HBV DNA by the end of the therapy, respectively. Only one case of resistance (equating to a 0.6% cumulative resistance rate up to year 4) was reported in this patient cohort, as is consistent with clinical trial findings. HBeAg seroconversion occurred in 53%, but only one case of HBsAg seroconversion (0.5%) was reported; this low rate, by comparison with the Italian results, probably evidences the less frequent occurrence of HBsAg loss (mainly if not exclusively reported in HBeAg(+) patients) in genotypes B and C (the most frequent in Asia) compared with genotypes A and D (the most frequent in Europe).
(Enlarge Image)
Figure 2.
Virologic response by HBeAg status during entecavir (ETV) treatment in the Hong Kong cohort real-life study. Percentage of ETV-treated patients achieving undetectable HBV DNA levels (<12 IU/mL) through 4 years of treatment in the Hong Kong cohort [27]. Left, HBeAg(+) patients; right, HBeAg(−) patients.
Efficacy of Entecavir in Real-life Settings
Six real-life studies assessing the efficacy and safety of ETV in a total of 1296 NUC-naïve patients have been presented or published, all confirming results reported in clinical trials, with similar rates of virologic and serologic responses and a low incidence of resistance. Importantly, these studies contain a heterogeneous mixture of patients who are differentiated from those in clinical trials as based on a number of criteria (Table 1) and may, therefore, be more reflective of the treatment population and the real efficacy and safety of the drug. Results from these real-life studies are discussed in the following sections and summarized in Table 2.
The ORIENTE Study
Results from a retrospective multicentre study conducted at over 25 Spanish centres were presented at the 2010 American Association for the Study of Liver Diseases (AASLD) meeting. The ORIENTE study evaluated 190 mostly HBeAg(−) patients with compensated liver disease who were treated with ETV (0.5 mg) over a 1-year period. Findings were consistent with those observed in Phase III clinical studies over the same time period, with the rate of virologic response (undetectable HBV DNA) being achieved in 61% and 92% of HBeAg(+) and HBeAg(−) CHB patients, respectively, with 21% (12/57) achieving HBeAg seroconversion and 1% (2/190) clearing HBsAg. Furthermore, of the 31 patients with detectable HBV DNA by week 48, five were tested for ETV resistance and none was found.
The VIRGIL Study
The European network of excellence for Vigilance against Viral Resistance (VIRGIL) performed a multicentre cohort study at over 10 European referral centres between 2005 and 2010. The cohort included 333 consecutive adult CHB patients treated with ETV monotherapy, of whom 243 were NUC-naïve. Among the NUC-naïve patients, the cumulative probability of achieving virologic response at week 144 was 90% in HBeAg(+) patients and 99% in HBeAg(−) patients, and the proportion of HBeAg(+) patients with HBeAg loss was 34%. Of the five patients experiencing virologic breakthrough, no mutations associated with decreased sensitivity to ETV were found, including in those patients with viral loads >200 IU/mL at the end of follow-up. Additionally, among the 36 patients with detectable viral load at week 48, 81% went on to achieve undetectable levels of HBV DNA after prolonged ETV therapy, suggesting that even patients who only achieve a partial virologic response initially can benefit from continued ETV therapy. A later analysis of data from this cohort, including a total of 372 patients, showed that the decline in HBV DNA over 144 weeks of ETV treatment was comparable among patients with no cirrhosis (n = 274) and those with cirrhosis (n = 89) or decompensated cirrhosis (n = 9). Virologic response to ETV treatment was associated with a significantly reduced probability of disease progression to HCC, hepatic decompensation or death, even in patients with cirrhosis at baseline.
Argentinean Cohort
A retrospective, multicentre study was conducted at five centres in Argentina and included 69 treatment-naive chronic HBV patients receiving ETV for an average of 110 weeks. At baseline, patients were 63% HBeAg(+), 16% cirrhotic, mean HBV DNA was 7.094 log IU/mL, and mean alanine transaminase (ALT) was 157 IU/mL. Virologic response was reached by 46%, 77% and 100% of patients at week 24, 48 and 96, respectively. In the HBeAg(+) population, 84% of patients achieved virologic response, with 67% and 100% response rates seen at week 48 and 96, respectively. Among HBeAg(−) patients, 96% achieved virologic response, with 91% and 100% response rates seen at week 48 and 96, respectively. Twenty-three patients (53%) cleared HBeAg with 19 (44%) demonstrating HBeAg seroconversion; seven patients (10%) cleared HBsAg with five (7%) demonstrating HBsAg seroconversion.
King's College Cohort
This single-centre cohort study included 406 treatment-naïve patients, 154 of whom were treated with ETV monotherapy for a median of 28 months. At baseline, 60% of patients had HBV DNA >4 log10 IU/mL and 34% had cirrhosis. Median HBV DNA declined continuously over the treatment period; 76% of patients had HBV DNA <12 IU/mL by month 12, and this proportion appeared to remain stable through to month 28. HBeAg seroconversion was reported in 8% of patients and 1% cleared HBsAg.
The Italian Cohort
A retrospective/prospective, multicentre study was conducted at 19 Italian centres and included 418 consecutive NUC-naïve CHB patients initiating treatment with ETV. Baseline characteristics differentiated this cohort from clinical trial patients in that they were predominately older (median age 58 years), genotype D HBV carriers (90%), 49% had cirrhosis, approximately 46% had a body mass index over 25 kg/m, and 56% had concomitant diseases (Table 1). Despite these differences, treatment outcomes were similar to those found during Phase III clinical trials, with undetectable HBV DNA achieved by 85% of patients during the first year of treatment. Viral suppression reached 90% and 98% over 42 months of treatment in HBeAg(+) patients and 48 months of treatment in HBeAg(−) patients, respectively (Fig. 1). There were only three (1%) primary nonresponders (<1 log IU/mL drop in HBD DNA at week 12), and partial virologic responses (residual viraemia at week 48) were seen in 12% of patients. Virologic breakthrough was observed in 4% of patients over the full treatment duration. In HBeAg(+) patients, HBeAg seroconversion occurred in 27 patients (cumulative rate of 55%) and HBsAg loss in 12 patients (cumulative rate of 21%). No resistance to ETV was documented over the treatment period.
(Enlarge Image)
Figure 1.
Virologic response by HBeAg status during entecavir (ETV) treatment in the Italian cohort real-life study. Percentage of ETV-treated patients achieving undetectable HBV DNA levels (<12 IU/mL) through 30 months of treatment in an Italian multicentre cohort study [26]. Left, HBeAg(+) patients; right, HBeAg(−) patients.
The Hong Kong Cohort
The single-centre Hong Kong cohort study prospectively analysed 222 treatment-naïve patients receiving ETV (0.5 mg daily) for up to 4 years. This long-term dosage with 0.5 mg ETV, the approved dosage for NUC-naïve patients, differentiates this study from the long-term ETV-901 clinical trial study, which doubled ETV dosage to 1.0 mg after year 1. The cumulative rate of achieving virologic response was 96% by year 4 (Fig. 2), with 86.4% and 100% of patients having HBV DNA >8 log10 copies/mL or <8 log10 copies/mL at baseline achieving undetectable levels of HBV DNA by the end of the therapy, respectively. Only one case of resistance (equating to a 0.6% cumulative resistance rate up to year 4) was reported in this patient cohort, as is consistent with clinical trial findings. HBeAg seroconversion occurred in 53%, but only one case of HBsAg seroconversion (0.5%) was reported; this low rate, by comparison with the Italian results, probably evidences the less frequent occurrence of HBsAg loss (mainly if not exclusively reported in HBeAg(+) patients) in genotypes B and C (the most frequent in Asia) compared with genotypes A and D (the most frequent in Europe).
(Enlarge Image)
Figure 2.
Virologic response by HBeAg status during entecavir (ETV) treatment in the Hong Kong cohort real-life study. Percentage of ETV-treated patients achieving undetectable HBV DNA levels (<12 IU/mL) through 4 years of treatment in the Hong Kong cohort [27]. Left, HBeAg(+) patients; right, HBeAg(−) patients.
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