Chen-Hua Liu

High Levels of Hepatitis B Surface Antigen Increase Risk of Hepatocellular Carcinoma in Patients With Low HBV Load

BACKGROUND & AIMS Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen (HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase risk for HCC. METHODS We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to the known risk factors of HCC, we investigated the association between levels of HBsAg and development of HCC. RESULTS Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC during 10-year and 15-year periods (both, P < .001). However, when we evaluated hepatitis B e antigen-negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase and HBsAg (≥1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≥1000 IU/mL versus <1000 IU/mL was 13.7 (95% confidence interval: 4.8-39.3). CONCLUSIONS Among patients infected with HBV genotype B or C, determinants of HCC risk include their sex, age, hepatitis B e antigen status, HBV genotype, and levels of alanine aminotransferase and HBV DNA, but not level of HBsAg. Among hepatitis B e antigen-negative patients with low viral loads, HCC risk is determined by levels of HBsAg and alanine aminotransferase and age, but not HBV DNA.

Pegylated Interferon-α-2a plus Ribavirin for Treatment-Naive Asian Patients with Hepatitis C Virus Genotype 1 Infection: A Multicenter, Randomized Controlled Trial

BACKGROUND Comparable sustained virologic response (SVR) rates have been documented between Asian patients who received 24 weeks of pegylated interferon (IFN) plus ribavirin and white patients who received 48 weeks of combination therapy for hepatitis C virus genotype 1 (HCV-1) infection. Whether a 48-week course of combination therapy shows a better SVR rate than a 24-week course of such therapy among Asian patients with HCV-1 infection has not been confirmed in multicenter, randomized studies. METHODS In this multicenter, randomized trial, 308 treatment-naive HCV-1-infected Asian patients were randomly assigned to receive either 24 or 48 weeks of pegylated IFN-alpha-2a (180 microg per week) plus ribavirin (1000-1200 mg/day) therapy. The primary end point was SVR, defined as an undetectable serum HCV RNA level 24 weeks after discontinuation of therapy. In addition, rapid virologic response (RVR) was defined as an undetectable serum HCV RNA level at week 4 of therapy, and complete early virologic response was defined as an undetectable serum HCV RNA level at 12 weeks of therapy in the absence of RVR. RESULTS By intention-to-treat analysis, patients who received 48 weeks of therapy had a significantly higher SVR rate than did those who received 24 weeks of therapy (76% vs. 56%; P < .001). Among patients with a baseline serum HCV RNA level <800,000 IU/mL and RVR, SVR rates were comparable between 24- and 48-week courses of therapy (94% vs. 100%; P = .13). In contrast, 48 weeks of therapy was associated with a significantly higher SVR rate than was 24 weeks of therapy among patients without RVR (39% vs.16%; P = .01) and among those who achieved a complete early virologic response (44% vs. 20%; P = .02). CONCLUSIONS In treatment-naive Asian patients with HCV-1 infection, 48 weeks of pegylated IFN-alpha-2a plus ribavirin therapy is associated with a higher SVR rate, compared with 24 weeks of such therapy. Patients with a baseline serum HCV RNA level <800,000 IU/mL and who have achieved an RVR can receive a 24-week course of therapy without compromising the SVR rates; however, those who have not achieved an RVR but who have achieved a complete early virologic response should receive a 48-week course of therapy.

Peginterferon Alfa-2a Plus Ribavirin for the Treatment of Dual Chronic Infection With Hepatitis B and C Viruses

BACKGROUND & AIMS Dual chronic infection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is common in areas endemic for either virus. Combination therapy with ribavirin and pegylated interferon (peginterferon) is the standard of care for patients with HCV monoinfection. We investigated the effects of combination therapy in patients infected with both HBV and HCV (genotypes 1, 2, or 3). METHODS The study included 321 Taiwanese patients with active HCV infection; 161 also tested positive for hepatitis B surface antigen (HBsAg) and 160 were HBsAg-negative (controls). Patients with HCV genotype 1 infection received peginterferon alfa-2a (180 mug) weekly for 48 weeks and ribavirin (1000-1200 mg) daily. Patients with HCV genotypes 2 or 3 received peginterferon alfa-2a weekly for 24 weeks and ribavirin (800 mg) daily. At 24 weeks posttreatment, patient samples were examined for a sustained virologic response (SVR) against HCV (serum HCV levels decreased to <25 IU/mL). RESULTS In patients with HCV genotype 1 infection, the SVR was 72.2% in dually infected patients vs 77.3% in monoinfected patients after treatment. For patients with HCV genotype 2/3 infections, the SVR values were 82.8% and 84.0%, respectively, after treatment. Serum HBV DNA eventually appeared in 36.3% of 77 dual-infected patients with undetectable pretreatment levels of HBV DNA; this was not accompanied by significant hepatitis. Posttreatment HBsAg clearance was observed in 11.2% of 161 dual-infected patients. CONCLUSIONS Combination therapy with peginterferon alfa-2a and ribavirin is equally effective in patients with HCV monoinfection and in those with dual chronic HCV/HBV infection.

Serum hepatitis B surface antigen levels help predict disease progression in patients with low hepatitis B virus loads

Chronic hepatitis B patients with high viral loads are at increased risk of cirrhosis and hepatocellular carcinoma (HCC). In patients with low viral loads, higher hepatitis B surface antigen (HBsAg) levels have been shown to predict HCC development. However, little is known about the difference in risk for other hepatitis B virus (HBV)‐related adverse outcomes with varying HBsAg levels. A total of 1,068 Taiwanese hepatitis B e antigen (HBeAg)‐negative HBV carriers with serum HBV DNA level <2,000 IU/mL at baseline were followed for a mean duration of 13.0 years. Patients were categorized based on their HBsAg levels, and the relationships between HBsAg level and development of HBeAg‐negative hepatitis, hepatitis flare, and cirrhosis were investigated. Of the 1068 patients with low viral loads, 280 developed HBeAg‐negative hepatitis, with an annual incidence rate of 2.0%. HBsAg level, but not HBV DNA level, was found to be a risk factor for HBeAg‐negative hepatitis. Multivariate analysis showed that the adjusted hazard ratio in patients with an HBsAg level ≥1,000 versus <1000 IU/mL was 1.5 (95% confidence interval, 1.2–1.9). The positive correlation was present when evaluating other endpoints, including hepatitis flare and cirrhosis, and remained consistent when the study population was restricted to those with normal alanine aminotransferase (ALT) level at baseline. The annual incidence rate of HBeAg‐negative hepatitis was lowered to 1.1% in patients with low levels of HBV DNA, HBsAg, and ALT. Conclusion: In HBeAg‐negative patients with low viral loads and genotype B or C virus infection, a higher HBsAg level can predict disease progression. HBsAg <1,000 IU/mL in combination with low levels of HBV DNA and ALT help define minimal‐risk HBV carriers. (HEPATOLOGY 2013)

Determinants of spontaneous surface antigen loss in hepatitis B e antigen-negative patients with a low viral load.

Loss of hepatitis B surface antigen (HBsAg) usually indicates the cure of hepatitis B virus (HBV) infection. In spontaneous hepatitis B e antigen (HBeAg) seroconverters, lower serum HBsAg and HBV DNA levels have been shown to be associated with HBsAg loss over time. However, little is known about their impacts on HBsAg loss in HBeAg‐negative patients with limited viral replication. A total of 688 HBeAg‐negative patients with baseline serum HBV DNA levels <2000 IU/mL were enrolled in Taiwan. The relationships of HBsAg and HBV DNA levels with subsequent HBsAg loss were investigated. In a mean follow‐up of 11.6 years, the average annual rate of HBsAg loss was 1.6%. Baseline HBsAg and HBV DNA levels were inversely associated with subsequent HBsAg loss. When compared to patients who had HBsAg levels >1000 IU/mL, the rates of HBsAg loss were significantly higher in patients with HBsAg levels of 100‐999, 10‐99, and <10 IU/mL, with hazard ratios of 2.5 (95% confidence interval [CI], 1.6‐4.0), 2.8 (95% CI, 1.6‐5.0), and 13.2 (95% CI, 8.1‐21.5), respectively. Multivariate analysis showed that HBsAg level, but not HBV DNA, remained as an independent factor. The adjusted hazard ratio of HBsAg loss was 13.2 (95% CI, 7.8‐22.1) for HBsAg level <10 versus ≥1000 IU/mL. When compared to HBV DNA level by receiver operating characteristic curve analysis, HBsAg level served as a better predictor of both 5‐year and 10‐year HBsAg loss. Conclusion: In HBeAg‐negative patients with HBV genotype B or C infection who have HBV DNA level <2000 IU/mL, HBsAg level <10 IU/mL is the strongest predictor of HBsAg loss. (HEPATOLOGY 2012;55:68–76)

High hepatitis C viral load is associated with insulin resistance in patients with chronic hepatitis C

Background and Aims: Although insulin resistance affects liver fibrosis progression and treatment response in chronic hepatitis C (CHC), the relationship between chronic hepatitis C virus (HCV) infection and insulin resistance (IR) remains to be firmly established. We thus studied the impact of host, metabolic and viral factors on IR in CHC patients.

Serum hepatitis B surface antigen concentration correlates with HBV DNA level in patients with chronic hepatitis B

BACKGROUND Serum HBV DNA level is crucial in the management of chronic hepatitis B (CHB); however, the assay is expensive and cannot be used widely. Therefore, we explored the possibility of hepatitis B surface antigen (HBsAg) quantification as a surrogate marker for HBV DNA level in CHB patients. METHODS A total of 289 CHB patients were enrolled, 251 were evaluated at baseline and 75 of them were also evaluated during anti-HBV treatment. Another 38 on-treatment patients were used for validation. Serum HBsAg titre was quantified by an immunoassay and HBV DNA level by a PCR-based method. Baseline and on-treatment data were analysed. RESULTS In parallel to log(10) HBV DNA, the log(10) HBsAg was high in both immune tolerance and immune clearance phases, and significantly decreased in the inactive carrier state and was again increased in the reactivation phase of the CHB infection. There was a positive correlation between log(10) HBsAg and log(10) HBV DNA, which was greater in patients with chronic hepatitis, hepatitis B e antigen-positivity, greater alanine aminotransferase or HBsAg levels at baseline and during pegylated interferon treatment. Log(10) HBsAg could predict log(10) HBV DNA independently. An HBsAg titre of >900 IU/ml at baseline or >1,500 IU/ml within the first year of treatment could predict an HBV DNA level of >20,000 IU/ml, especially in subgroups of chronic hepatitis with alanine aminotransferase levels >40 IU/l. The dynamics of HBsAg might also predict serial HBV DNA changes. In the validation group, 64% of patients with on-treatment HBV DNA levels >20,000 IU/ml could be correctly predicted. CONCLUSIONS Serum HBsAg concentration might serve as a surrogate marker of HBV DNA level in CHB patients.

Pegylated interferon α-2a versus standard interferon α-2a for treatment-naïve dialysis patients with chronic hepatitis C: a randomised study

Background: Chronic hepatitis C virus (HCV) infection is prevalent in dialysis patients, and standard interferon monotherapy is the current standard of care for such patients. Aim: To investigate whether pegylated interferon has a better therapeutic efficacy and safety profile than standard interferon in dialysis patients with chronic hepatitis C. Methods: 50 such patients were randomly assigned to receive either pegylated interferon α-2a 135 μg subcutaneously once per week or standard interferon α-2a 3 million units subcutaneously thrice per week for 24 weeks. The primary efficacy and safety end points were sustained virological response (SVR) by intention-to-treat analysis and treatment-related withdrawal rate during the study. Results: In univariate analysis, patients receiving pegylated interferon α-2a tended to have a higher sustained virological response (SVR) than those receiving standard interferon α-2a (48% vs 20%, p = 0.07). By using multivariate analysis, treatment with pegylated interferon α-2a (p = 0.02) and pretreatment HCV RNA level <800 000 IU/ml (p = 0.007) were independently predictive of an SVR. All patients failing to achieve a rapid virological response (RVR) could not achieve an SVR. In addition, patients receiving pegylated interferon α-2a had a significantly lower treatment-related withdrawal rate than those receiving standard interferon α-2a (0% vs 20%, p = 0.04). Conclusions: Pegylated interferon α-2a once weekly provides more effective and safer therapy than standard interferon α-2a thrice weekly for treatment-naïve dialysis patients with chronic hepatitis C.

Pegylated Interferon-α2a With or Without Low-Dose Ribavirin for Treatment-Naive Patients With Hepatitis C Virus Genotype 1 Receiving Hemodialysis: A Randomized Trial

BACKGROUND Data are limited on the efficacy and safety of pegylated interferon plus ribavirin for patients with hepatitis C virus genotype 1 (HCV-1) receiving hemodialysis. OBJECTIVE To compare the efficacy and safety of combination therapy with pegylated interferon plus low-dose ribavirin and pegylated interferon monotherapy for treatment-naive patients with HCV-1 receiving hemodialysis. DESIGN Open-label, randomized, controlled trial. (ClinicalTrials.gov: NCT00491244). SETTING 8 centers in Taiwan. PATIENTS 205 treatment-naive patients with HCV-1 receiving hemodialysis. INTERVENTION 48 weeks of pegylated interferon-α2a, 135 µg weekly, plus ribavirin, 200 mg daily (n = 103), or pegylated interferon-α2a, 135 µg weekly (n = 102). MEASUREMENTS Sustained virologic response rate and adverse event-related withdrawal rate. RESULTS Compared with monotherapy, combination therapy had a greater sustained virologic response rate (64% vs. 33%; relative risk, 1.92 [95% CI, 1.41 to 2.62]; P < 0.001). More patients receiving combination therapy had hemoglobin levels less than 8.5 g/dL than those receiving monotherapy (72% vs. 6%; risk difference, 66% [CI, 56% to 76%]; P < 0.001). Patients receiving combination therapy required a higher dosage (mean, 13 946 IU per week [SD, 6449] vs. 5833 IU per week [SD, 1169]; P = 0.006) and longer duration (mean, 29 weeks [SD, 9] vs. 18 weeks [SD, 7]; P = 0.004) of epoetin-β than patients receiving monotherapy. The adverse event-related withdrawal rates were 7% in the combination therapy group and 4% in the monotherapy group (risk difference, 3% [CI, -3% to 9%]). LIMITATION Open-label trial; results may not be generalizable to patients on peritoneal dialysis. CONCLUSION In treatment-naive patients with HCV-1 receiving hemodialysis, combination therapy with pegylated interferon plus low-dose ribavirin achieved a greater sustained virologic response rate than pegylated interferon monotherapy. PRIMARY FUNDING SOURCE National Center of Excellence for Clinical Trial and Research.

Association of pre-S deletion mutant of hepatitis B virus with risk of hepatocellular carcinoma

Background:  Pre‐S deletion mutant of hepatitis B virus (HBV) affects the expression of middle and small surface proteins, resulting in intracellular accumulation of large surface protein. The correlation between pre‐S deletion mutant and risk of hepatocellular carcinoma (HCC) in hepatitis B virus carriers remains unclear.