Robert A. de Man

Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial

BACKGROUND Treatment of HBeAg-positive patients with chronic hepatitis B is not effective in most. A combination of immunomodulatory pegylated interferon alfa-2b and antiviral lamivudine might improve the rate of sustained response. METHODS 307 HBeAg-positive patients with chronic hepatitis B were assigned combination therapy (100 microg/week pegylated interferon alfa-2b and 100 mg/day lamivudine) or monotherapy (100 microg/week pegylated interferon alfa-2b and placebo) for 52 weeks. During weeks 32-52 the pegylated interferon dose was 50 microg/week in both treatment groups. The analyses were based on the modified intention-to-treat population after exclusion of 24 patients from one centre withdrawn for misconduct, ten who lost HBeAg before the study start, and seven who received no study medication. All included patients were followed up for 26 weeks after treatment. FINDINGS 49 (36%) of 136 patients assigned monotherapy and 46 (35%) of 130 assigned combination therapy had lost HBeAg at the end of follow-up (p=0.91). More of the combination-therapy than of the monotherapy group had cleared HBeAg at the end of treatment (57 [44%] vs 40 [29%]; p=0.01) but relapsed during follow-up. Patterns were similar when response was assessed by suppression of serum hepatitis B virus (HBV) DNA or change in concentrations of alanine aminotransferase. Response rates (HBeAg loss) varied by HBV genotype (p=0.01): A, 42 (47%) patients; B, ten (44%); C, 11 (28%); and D, 26 (25%). INTERPRETATION Treatment with pegylated interferon alfa-2b is effective for HBeAg-positive chronic hepatitis B. Combination with lamivudine in the regimen used is not superior to monotherapy. HBV genotype is an important predictor of response to treatment.

Tenofovir Disoproxil Fumarate versus Adefovir Dipivoxil for Chronic Hepatitis B

BACKGROUND Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. METHODS In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. RESULTS At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. CONCLUSIONS Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)

Survival and Prognostic Indicators in Hepatitis B Surface Antigen-Positive Cirrhosis of the Liver

To evaluate indications for new therapies such as liver transplantation and antiviral therapy, survival of histologically proven hepatitis B surface antigen (HBsAg)-positive cirrhosis of the liver was assessed in a cohort of 98 patients followed up for a mean of 4.3 years. The overall survival probability was 92% at 1 year, 79% at 3 years, and 71% at 5 years. Variables significantly associated with the duration of survival were age, serum aspartate aminotransferase levels, presence of esophageal varices, and all five components of the Child-Pugh index (bilirubin, albumin, coagulation factors, ascites, encephalopathy). Multivariate analysis showed that only age, bilirubin, and ascites were independently related to survival. Survival of patients with decompensated cirrhosis (determined by the presence of ascites, jaundice, encephalopathy, and/or a history of variceal bleeding) and those with compensated cirrhosis at 5 years was 14% and 84%, respectively. For patients with compensated liver cirrhosis, hepatitis B e antigen (HBeAg) positivity was also a prognostic factor with a 5-year survival of 72% for HBeAg-positive cirrhosis and 97% for HBeAg-negative cirrhosis; the risk of death was decreased by a factor of 2.2 when HBeAg seroconversion occurred during follow-up. It is concluded that liver transplantation should be considered for patients with decompensated HBsAg-positive liver cirrhosis and antiviral therapy for patients with HBeAg-positive compensated cirrhosis.

Three-Year Efficacy and Safety of Tenofovir Disoproxil Fumarate Treatment for Chronic Hepatitis B

BACKGROUND & AIMS Tenofovir disoproxil fumarate (TDF), a nucleotide analogue and potent inhibitor of hepatitis B virus (HBV) polymerase, showed superior efficacy to adefovir dipivoxil in treatment of chronic hepatitis B through 48 weeks. We evaluated long-term efficacy and safety of TDF monotherapy in patients with chronic hepatitis B who were positive or negative for hepatitis B e antigen (HBeAg(+) or HBeAg(-)). METHODS After 48 weeks of double-blind comparison of TDF to adefovir dipivoxil, patients who underwent liver biopsy were eligible to continue the study on open-label TDF for 7 additional years; data presented were collected up to 3 years (week 144) from 85% of participants. Primary efficacy end points at week 144 included levels of HBV DNA and alanine aminotransferase, development of resistance mutations, and presence of HBeAg or hepatitis B surface antigen (HBsAg). RESULTS At week 144, 87% of HBeAg(-) and 72% of HBeAg(+) patients treated with TDF had levels of HBV DNA <400 copies/mL. Among patients who had previously received adefovir dipivoxil and then received TDF, 88% of the HBeAg(-) and 71% of the HBeAg(+) patients had levels of HBV DNA <400 copies/mL; overall, 81% and 74%, respectively, maintained normalized levels of alanine aminotransferase and 34% had lost HBeAg. Amino acid substitutions in HBV DNA polymerase that are associated with resistance to tenofovir were not detected in any patient. Cumulatively, 8% of HBeAg(+) patients lost HBsAg. TDF maintained a favorable safety profile for up to 3 years. CONCLUSIONS TDF was safe and effective in the long-term management of HBeAg(+) and HBeAg(-) patients with chronic hepatitis B.

Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.

Data on the long‐term effects of interferon alfa (IFN) treatment on disease progression and mortality in patients with chronic hepatitis B (CHB) are limited. To evaluate factors that influence clinical outcome and survival, we performed a follow‐up study on 165 hepatitis B e antigen (HBeAg) positive CHB patients treated with IFN between 1978 and 2002. The median IFN dose was 30 megaunits (MU)/week (range, 2–70 MU/week), and the median duration of therapy was 16 weeks (range, 1–92 weeks). Response to treatment was defined as HBeAg loss within 12 months after the end of IFN therapy. Median follow‐up was 8.8 years (range, 0.3–24 years). Fifty‐four patients (33%) responded to IFN treatment. Relapse (HBeAg reactivation) occurred in 7 of the 54 (13%) responders. Fifty‐two percent of the responders lost hepatitis B surface antigen (HBsAg) as compared with 9% of the nonresponders (P < .001). Liver histology showed a decreased necroinflammatory activity and less progression of fibrosis in responders. Twenty‐six patients died during follow‐up. Hepatocellular carcinoma (HCC) was found in 8 patients, 6 of whom were nonresponders. Of the two responders who developed HCC, one patient had relapsed after discontinuation of therapy. Multivariate analysis showed significantly improved survival (relative risk (RR) of death 0.28, 95% CI 0.10–0.78) and reduced risk of developing HCC (RR 0.084, 95% CI 0.09–0.75) in responders. In conclusion, response to IFN therapy results in a prolonged clinical remission with an increased rate of HBsAg seroconversion and improved liver histology. Our results indicate that after correction for baseline factors, response to IFN therapy increases survival and reduces the risk of developing HCC. (HEPATOLOGY 2004;39:804–810.)

Lamivudine resistance inimmunocompetent chronic hepatitis B

Abstract Background: Lamivudine is a non-toxic, potent inhibitor of hepatitis B virus replication. Recently, hepatitis B virus resistance to lamivudine has been described in patients using immunosuppressive drugs after liver transplantation. Methods: From our cohort of 81 consecutive patients treated with lamivudine, we selected all immunocompetent patients who received lamivudine monotherapy for a period over 26 weeks ( n =14). Results: Lamivudine resistance with the characteristic mutation in the YMDD motif was observed in four patients (actuarial cumulative incidence: 39%). Two patterns of viral resistance were observed; incomplete response ( n =2) and viral breakthrough ( n =2). Conclusions: The observed high frequency of lamivudine resistance may have implications for the concept of long-term virus-suppressive therapy of chronic hepatitis B by lamivudine monotherapy.

Long‐term efficacy of tenofovir monotherapy for hepatitis B virus‐monoinfected patients after failure of nucleoside/nucleotide analogues

Tenofovir disoproxil fumarate (TDF) has demonstrated high antiviral efficacy in treatment‐naive patients with chronic hepatitis B virus (HBV) infection but experience in nucleoside/nucleotide analogue (NA)‐experienced patients is limited. In this retrospective multicenter study we therefore assessed the long‐term efficacy of TDF monotherapy in patients with prior failure or resistance to different NA treatments. Criteria for inclusion were HBV DNA levels >4.0 log10 copies/mL at the start and a minimum period of TDF therapy for at least 6 months. In all, 131 patients (mean age 42 ± 12 years, 95 male, 65% hepatitis B e antigen [HBeAg]‐positive) were eligible. Pretreatment consisted of either monotherapy with lamivudine (LAM; n = 18), adefovir (ADV; n = 8), and sequential LAM‐ADV therapy (n = 73), or add‐on combination therapy with both drugs (n = 29). Three patients had failed entecavir therapy. Resistance analysis in 113 of the 131 patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, respectively. The mean HBV DNA level at TDF baseline was 7.6 ± 1.5 log10 copies/mL. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/mL was 79% after a mean treatment duration of 23 months (range, 6–60). Although LAM resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/mL, respectively). However, virologic breakthrough was not observed in any of the patients during the entire observation period. Loss of HBeAg occurred in 24% of patients and HBsAg loss occurred in 3%. No significant adverse events were noticed during TDF monotherapy. Conclusion: TDF monotherapy induced a potent and long‐lasting antiviral response in NA‐experienced patients with previous treatment failure. Our data may have implications for current add‐on strategies. (HEPATOLOGY 2009.)

Treatment with Peg-Interferon α-2b for HBeAg-Positive Chronic Hepatitis B: HBsAg Loss Is Associated with HBV Genotype

BACKGROUND AND AIMS:Hepatitis B surface antigen (HBsAg) loss is the hallmark of a complete response to antiviral therapy for chronic hepatitis B. In this study, we investigated the frequency of HBsAg loss after treatment with pegylated (Peg)-interferon α-2b.METHODS:In a multicenter randomized controlled trial, 266 HBeAg-positive patients were treated for 52 wks with Peg-interferon α-2b (100 μg/wk) in combination with either lamivudine (100 mg/day) or placebo. Posttreatment follow-up was 26 wks.RESULTS:At the end of follow-up, 95 (36%) of the 266 patients exhibited HBeAg loss, 18 (7%) HBsAg loss, and 16 (6%) HBsAg seroconversion. Addition of lamivudine did not enhance HBeAg loss, HBsAg loss, or development of anti-HBs. All 18 patients who showed HBsAg loss had normal ALT; 11 (61%) of these patients were also hepatitis B virus (HBV) DNA negative (<;400 copies/mL) at the end of follow-up. Loss of HBsAg differed according to HBV genotype: 14% for genotype A, 9% for genotype B, 3% for genotype C, and 2% for genotype D (A vs D: p= 0.006).CONCLUSIONS:One year of Peg-interferon α-2b for HBeAg-positive patients led to HBsAg loss in 7%. Our study indicates that treatment with Peg-interferon α-2b is the best therapy to achieve HBsAg clearance in patients with genotype A.

Lanreotide Reduces the Volume of Polycystic Liver: A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND & AIMS Therapy for polycystic liver is invasive, expensive, and has disappointing long-term results. Treatment with somatostatin analogues slowed kidney growth in patients with polycystic kidney disease (PKD) and reduced liver and kidney volume in a PKD rodent model. We evaluated the effects of lanreotide, a somatostatin analogue, in patients with polycystic liver because of autosomal-dominant (AD) PKD or autosomal-dominant polycystic liver disease (PCLD). METHODS We performed a randomized, double-blind, placebo-controlled trial in 2 tertiary referral centers. Patients with polycystic liver (n = 54) were randomly assigned to groups given lanreotide (120 mg) or placebo, administered every 28 days for 24 weeks. The primary end point was the difference in total liver volume, measured by computerized tomography at weeks 0 and 24. Analyses were performed on an intention-to-treat basis. RESULTS Baseline characteristics were comparable for both groups, except that more patients with ADPKD were assigned to the placebo group (P = .03). The mean liver volume decreased 2.9%, from 4606 mL (95% confidence interval (CI): 547-8665) to 4471 mL (95% CI: 542-8401 mL), in patients given lanreotide. In the placebo group, the mean liver volume increased 1.6%, from 4689 mL (95% CI: 613-8765 mL) to 4895 mL (95% CI: 739-9053 mL) (P < .01). Post hoc stratification for patients with ADPKD or PCLD revealed similar changes in liver volume, with statistically significant differences in patients given lanreotide (P < .01 for both diseases). CONCLUSIONS In patients with polycystic liver, 6 months of treatment with lanreotide reduces liver volume.

The prognostic significance of subclinical hepatic encephalopathy

OBJECTIVE:Subclinical hepatic encephalopathy may have prognostic significance with regard to the development of clinical hepatic encephalopathy and survival.METHODS:We studied 116 consecutive patients with histologically proven cirrhosis of the liver for subclinical hepatic encephalopathy, using Number Connection Test A, Digit Symbol Test, and spectral analysis of the electroencephalogram.RESULTS:Twenty-five patients (22%) were diagnosed as having subclinical hepatic encephalopathy. Patients with subclinical hepatic encephalopathy were older, had a higher Child-Pugh score, and more often had esophageal or gastric varices and episode(s) of clinical hepatic encephalopathy in their history. During a median follow-up of 29 months (range, 1–49 months), patients with subclinical hepatic encephalopathy significantly more often had episodes of clinical hepatic encephalopathy; survival, however, was similar to that of patients without subclinical hepatic encephalopathy, and was determined mainly by the Child-Pugh score. The Child-Pugh score was also superior to subclinical hepatic encephalopathy in predicting episodes of clinical hepatic encephalopathy.CONCLUSIONS:The prognostic significance of subclinical hepatic encephalopathy appears limited.