Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy.

Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg-IFN α-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg-IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 ± 3.73) (day(-1), mean ± SD) but lower daily viral production rate (P = 10(6)-10(12)) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients.

A sustained virologic response is durable in patients with chronic hepatitis C treated with peginterferon alfa-2a and ribavirin.

BACKGROUND & AIMS: A sustained virologic response (SVR) to therapy for hepatitis C virus (HCV) infection is defined as the inability to detect HCV RNA 24 weeks after completion of treatment. Although small studies have reported that the SVR is durable and lasts for long periods, it has not been conclusively shown. METHODS: The durability of treatment responses was examined in patients originally enrolled in one of 9 randomized multicenter trials (n = 1343). The study included patients who received pegylated interferon (peginterferon) alfa-2a alone (n = 166) or in combination with ribavirin (n = 1077, including 79 patients with normal alanine aminotransferase levels and 100 patients who were coinfected with human immunodeficiency virus and HCV) and whose serum samples were negative for HCV RNA (<50 IU/mL) at their final assessment. Patients were assessed annually, from the date of last treatment, for a mean of 3.9 years (range, 0.8-7.1 years). RESULTS: Most patients (99.1%) who achieved an SVR had undetectable levels of HCV RNA in serum samples throughout the follow-up period. Serum samples from 0.9% of the patients contained HCV RNA a mean of 1.8 years (range, 1.1-2.9 years) after treatment ended. It is not clear if these patients were reinfected or experienced a relapse. CONCLUSIONS: In a large cohort of patients monitored for the durability of an SVR, the SVR was maintained for almost 4 years after treatment with peginterferon alfa-2a alone or in combination with ribavirin. In patients with chronic hepatitis C infection, the SVR is durable and these patients should be considered as cured.

HBsAg profiles in patients receiving peginterferon alfa-2a plus ribavirin for the treatment of dual chronic infection with hepatitis B and C viruses.

BACKGROUND: With use of peginterferon alfa-2a and ribavirin combination therapy in patients with dual chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, 11.2% of patients achieved clearance of hepatitis B surface antigen (HBsAg) at 6 months after treatment; however, reactivation of HBV DNA was observed in 36.3%. We investigated the predictive potential of HBsAg quantification. METHODS: HBsAg quantification was performed in 120 e antigen-negative patients dually infected with HBV and hepatitis C virus and treated with peginterferon alfa-2a/ribavirin for 48 weeks (HCV genotype 1; n = 74) or 24 weeks (HCV genotype 2/3; n = 46). HBsAg was quantified at baseline, week 4, week 12, end of treatment, and 24 weeks after treatment. RESULTS: The baseline median serum HBsAg level was 120 IU/mL and decreased gradually during treatment. Low baseline HBsAg was significantly associated with HBsAg clearance (40% for HBsAg level 20 IU/mL vs 2.2% for HBsAg level >20 IU/mL; P < .05). A decrease in HBsAg level from baseline to week 12 of 50% was associated with a reduced likelihood of HBV DNA reactivation in patients with baseline undetectable serum HBV DNA (positive predictive value, 89.5%). CONCLUSIONS: HBsAg quantification appears to be a useful indicator of posttreatment outcome in patients dually infected with HBV and hepatitis C virus.

Pegylated interferon alfa-2a monotherapy for hemodialysis patients with acute hepatitis C.

BACKGROUND: Hemodialysis patients are at risk of hepatitis C virus (HCV) infection. However, little is known about the efficacy and safety of pegylated interferon (IFN) therapy for hemodialysis patients with acute hepatitis C. METHODS: From 2005 through 2008, 35 hemodialysis patients with acute hepatitis C who did not have spontaneous clearance of HCV by 16 weeks were treated with pegylated IFN alfa-2a at a dosage of 135 microg weekly for 24 weeks. In contrast, 7 patients with clearance of HCV by 16 weeks were under observation only. Thirty-six hemodialysis patients from 2002-2005 who had acute hepatitis C but did not receive treatment served as historical controls. The primary efficacy and safety end points were sustained virologic response (undetectable HCV RNA levels at 24 weeks after therapy) by intention-to-treat analysis and treatment-related withdrawal. RESULTS: The rate of sustained virologic response in the treatment group was significantly higher than the rate of spontaneous HCV clearance in the control group (88.6% vs 16.7%; P < .001). Two patients (5.7%) prematurely terminated treatment at 8 and 10 weeks because of constitutional symptoms, and both did not have sustained virologic response. All but one patient had rapid virologic response (undetectable HCV RNA levels at 4 weeks of therapy), and all patients who received >12 weeks of therapy had early and end-of-treatment virologic responses. All patients who had clearance of HCV by 16 weeks had undetectable HCV RNA levels until the end of follow-up. CONCLUSIONS: Pegylated IFN alfa-2a monotherapy is safe and efficacious for hemodialysis patients with acute hepatitis C. It is suggested that patients without spontaneous clearance of HCV by week 16 should receive therapy.

Factors affecting early viral load decline of Asian chronic hepatitis C patients receiving pegylated interferon plus ribavirin therapy.

BACKGROUND: Early viral load decline following pegylated interferon-alpha2a and ribavirin therapy is an important predictor of the treatment responses in chronic hepatitis C (CHC) patients, thus, it is essential to evaluate the influence of host and viral factors on early viral load decline. METHODS: Clinical and serial virological data were collected from 145 consecutive Asian CHC patients with pegylated interferon-alpha2a plus ribavirin therapy. A dose of pegylated interferon-alpha2a was administered at week 1 and then weekly with daily oral ribavirin for 24 or 48 weeks. Genotyping and quantification of hepatitis C virus (HCV) RNA were done using molecular methods. RESULTS: A total of 81 patients were infected with HCV genotype 1,61 with genotype 2 and 3 with both genotypes 1 and 2. At the end of follow-up, 110 patients attained sustained virological response (SVR). In multivariate analyses, body mass index (BMI) and genotype were related to viral load decline at day 2, baseline viral load and high-density lipoprotein (HDL) cholesterol levels were correlated with viral load decline between days 2 and 28. Genotype, baseline viral load, alanine aminotransferase (ALT) levels and BMI independently predicted rapid virological response, whereas only genotype 2, lower baseline viral load and more substantial viral load decline at day 28 predicted a higher SVR. CONCLUSIONS: HCV genotype, baseline viral load, pretreatment BMI, HDL and ALT levels have a significant effect on early viral load decline of Asian CHC patients with interferon-based therapy. Only HCV genotype, baseline viral load and viral load decline at day 28 can independently predict SVR.

HBeAg-negative chronic hepatitis B: cost-effectiveness of peginterferon alfa-2a compared to lamivudine in Taiwan.

OBJECTIVE: In Taiwan, the carrier rate of hepatitis B surface antigen is 15% to 20%, one of the highest in the world. Among chronic hepatitis B (CHB) patients, hepatitis B e antigen (HBeAg)-negative accounts for approximately 40% to 50% of these patients. A recent study found that peginterferon alfa-2a (40 KD) is more effective than lamivudine in treating HBeAg-negative CHB, but its cost-effectiveness has not been evaluated. Our objective is to evaluate the incremental cost-effectiveness of 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine, from the perspective of the Taiwan Bureau of National Health Insurance. METHODS: A Markov model was used to simulate the natural history of HBeAg-negative CHB in a cohort of 40-year-old patients. Efficacy, disease progression, economic, and quality-of-life data were derived from published literature and a survey of clinical experts in Taiwan. Life expectancy, quality-adjusted life expectancy, lifetime costs in New Taiwan Dollars (NTD) (1 USD = 31.96 NTD), and incremental cost-effectiveness ratios (ICERs) were calculated. RESULTS: The gain in quality-adjusted life-years (QALYs) for 48 weeks of peginterferon alfa-2a compared to 48 weeks of lamivudine was 0.45 at an additional cost of 157,000 NTD (4900 USD), resulting in an ICER of 347,000 NTD (10,900 USD) per QALY gained. The 95% central range for the ICER from a probabilistic sensitivity analysis was 228,000-566,000 NTD (7100-17,700 USD). CONCLUSIONS: In HBeAg-negative CHB, 48 weeks of treatment with peginterferon alfa-2a compared to 48 weeks of lamivudine appears to offer life expectancy and quality-of-life improvements at an acceptable cost-effectiveness ratio.

Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B.

BACKGROUND: Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications. METHODS: We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks. RESULTS: After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy. CONCLUSIONS: Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates.

Early viral kinetics during treatment of chronic hepatitis C virus infection with pegylated interferon alpha plus ribavirin in Taiwan.

OBJECTIVES: Early hepatitis C viral (HCV) kinetics following pegylated interferon-alpha (PEG-IFN) and ribavirin help to assess treatment in the Western world. Whether this functions in Taiwanese patients remains unknown. Studying the early HCV kinetics in Taiwanese patients may clarify this issue. METHODS: Six chronic hepatitis C patients were enrolled. A PEG-IFN-alpha dose was administered at week 1, then it was administered weekly with daily ribavirin for 24 weeks. Serum HCV RNA levels were determined frequently during the trial and qualitatively at week 49. Kinetic parameters epsilon (effectiveness at inhibiting viral production)and delta (loss rate of infected cells) were estimated from viral loads and alanine aminotransferase (ALT) kinetics, respectively. RESULTS: All serum HCV RNA levels became undetectable at week 12. The epsilon ranged from 0.4128 to 0.9904 and delta from 0.0019 to 0.1245. The log values of viral load differences between day 7 and 14 ranged from 0.15 to 1.21. Only 1 patient had an abnormal ALT level at week 49. CONCLUSIONS: Viral kinetic parameters in Taiwanese patients were similar to those in Western studies. However, the early viral decline pattern and viral negativity rate in Taiwanese patients might be different from Caucasian patients. Further large-scale studies to clarify this issue are ongoing.

Successful treatment with peginterferon and ribavirin in a patient with acute hepatitis C evolving into chronicity.

Acute hepatitis C has a high frequency of chronic evolution, which may progress to cirrhosis and hepatocellular carcinoma. However, only a small proportion of acute hepatitis C patients are incidentally identified and then treated. Controversial issues regarding treatment of acute hepatitis C include optimal time of treatment initiation, best treatment regimen and appropriate duration of treatment. We report a symptomatic acute hepatitis C patient in the late acute phase evolving into chronicity successfully treated by peginterferon and ribavirin combination therapy for 6 months at late acute phase, with sustained virologic response for up to 18 months. Our findings indicate that combination peginterferon and ribavirin therapy may be as effective in treating acute hepatitis C as it is in chronic hepatitis C.

Mutations in the NS5A and E2-PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin.

BACKGROUND/AIMS: Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN-induced RNA-dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. METHODS: Nucleotide sequences of the PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) and PKR-binding domain (NS5A-PKR bd) of the HCV genome were analyzed by amplification and direct sequencing in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. RESULTS: Nine (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and non-responders. The responders were younger than non-responders (37.2 +/- 10.4 vs. 45.4 +/- 9.5 years, P = 0.017), whereas no significant statistical differences were found in the number of amino acid substitutions in NS5A and E2-PePHD regions between the two groups. CONCLUSIONS: Genetic heterogeneity in NS5A and E2-PePHD regions of the HCV genome may not serve as a predictor for treatment outcome with combination therapy in Taiwanese patients with chronic HCV genotype 1b infection.

The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C.

BACKGROUND/AIMS: Peginterferon alfa-2a plus ribavirin improves sustained virological responses compared with interferon alfa-2b and ribavirin, or peginterferon alfa-2a alone in chronic hepatitis C. We examined the impact of these treatments on health related quality of life (HRQOL). METHODS: Patients (n=1121) were randomized to peginterferon alfa-2a weekly plus ribavirin or placebo, or interferon alfa-2b thrice weekly plus ribavirin. HRQOL was assessed with the SF-36 Health Survey and Fatigue Severity Scale (FSS). RESULTS: Patients receiving peginterferon alfa-2a plus ribavirin reported better HRQOL than those receiving interferon alfa-2b plus ribavirin. These differences were statistically significant for three SF-36 domains and both FSS scores (p<=0.05). Patients receiving peginterferon alfa-2a plus placebo had the least impairment; adding ribavirin significantly decreased five domains of the SF-36 and both FSS scores. Sustained virological response was associated with improvement at follow-up on all SF-36 and FSS scores. CONCLUSIONS: The effects of combination therapy on HRQOL and fatigue are less with peginterferon alfa-2a plus ribavirin than interferon alfa-2b plus ribavirin. Each medication in combination therapy with interferon and ribavirin, affects patients' quality of life differently. Understanding the relationship of specific therapeutic options to HRQOL may help physicians minimize the impact of therapy on HRQOL.