Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

Studies have suggested that African American patients infected with hepatitis C virus (HCV) do not respond as well to treatment with interferon (IFN) as white patients. Here we analyzed the difference in the viral kinetic response between genotype 1 HCV-infected African American patients (n ‫؍‬ 19) and white patients (n ‫؍‬ 16). Patients were treated with 10 mIU IFN-␣2b daily with or without ribavirin for 1 month followed by 3 mIU IFN-␣2b 3 times a week with ribavirin. The kinetic parameters (⑀, treatment effectiveness at inhibiting virion production; ␦, loss rate of virus-producing cells; c, clearance rate of free virions; , delay until viral decline starts) were estimated from the viral load decay profiles using a previously described mathematical model. Differences in early kinetic parameters and viral negativity frequencies at weeks 4, 12, and 48 were compared. Ribavirin did not appear to enhance any of the viral kinetic parameters, although this may have been due to the high dose of IFN used. African American patients exhibited significantly (P ‫؍‬ .005) lower drug effectiveness (88.6% vs. 98.2%) compared with white patients, accounting for a 0.8 log lower HCV RNA decrease in the first 24 hours of treatment. Significant differences (P ‫؍‬ .006) were also noted for ␦. There was no correlation between any of the viral kinetic parameters and either age, body mass index (BMI), or genotype 1 subtype. No patient achieved viral negativity at weeks 4, 12, or 48 without an ⑀ greater than 90%. The mean viral decline and viral negativity rates were statistically different between the two races; however, when controlling for treatment effectiveness, these differences were no longer apparent. In conclusion, the failure of IFN response in African American patients infected with genotype 1 HCV is in part due to an impaired ability to inhibit viral production. ( H epatitis C virus (HCV) infects 1.0% to 1.5% of the white population and 2.5% to 3.5% of the African American population in the United States. 1,2 In infected white patients, 65% to 75% have genotype 1 virus; in infected African American patients, 90% to 95% are infected with this subtype. [2][3][4] In 1999, Reddy et al. reported that African American patients failed to respond as well to consensus interferon (IFN) and IFN-␣2b treatment as white patients, in part due to a greater rate of genotype 1 infection in African American patients. 4 These lower response rates have been confirmed by others for African American patients treated with IFN monotherapy. [5][6][7] McHutchison et al. reported that combination therapy with IFN plus ribavirin partly overcame these impaired response rates, 5 although preliminary results from other sites have not shown consistently improved results with combination therapy. [7][8][9] The kinetics of HCV RNA decline following the initiation of IFN therapy have recently been described. [10][11][12][13][14] Following an initial dose of IFN, there is a rapid dosedependent decline in HCV RNA levels of 0.5 to 2.0 logs over the first 24 hours...

Studies of the kinetics of hepatitis C virus (HCV) decline during interferon (IFN)-based therapy have led to insights into treatment efficacy. However, the kinetics of serum alanine aminotransferase (ALT), an enzyme used as a surrogate of liver damage, have not been closely monitored, and it is not known if they correlate with those of HCV RNA. Here we describe the associations between ALT and HCV dynamics. We analyzed 35 patients treated daily with 10 mIU IFN-␣2b with or without ribavarin for 28 days followed by standard IFN/ ribavirin therapy. Patients exhibited 4 patterns of ALT change: (1) exponential decay of ALT, (2) transient increase in ALT followed by a decrease to pretreatment or normal levels, (3) increase in ALT to a new level, and (4) no significant change. By simultaneously modeling HCV and ALT dynamics, we successfully fit the observed changes. We found ALT decays with t 1/2 ‫؍‬ 12.7 hours. The transient increase in ALT observed in some patients suggested a mild hepatotoxic effect of IFN. However, patients with a smaller initial ALT increase achieved higher rates of viral negativity by week 72 (P ‫؍‬ .02). The week-4 ALT decline correlated with the HCV log drop (P ‫؍‬ .006) and the efficacy of therapy (P ‫؍‬ .025). In conclusion, our results suggest the use of ALT as a surrogate marker for treatment effect in patients with elevated ALT. (HEPATOLOGY 2003;38:509-517.) H epatitis C virus (HCV) is the most common cause of blood-borne viral hepatitis, 1,2 with acute HCV infection progressing to the chronic state 60% to 70% of the time. 1,3 Chronic HCV infection can lead to cirrhosis and/or hepatocellular carcinoma and is the leading cause of liver transplantation in the United States. 1,3 While treatment options have greatly improved, they are still not effective in all patients.Prior to the advent of HCV-RNA testing, alanine aminotransferase (ALT) levels served as a surrogate marker of HCV infection and liver injury. 4,5 This cytosolic enzyme functions in a transamination reaction, which is important for carbohydrate and protein metabolism. 6 With a normally functioning liver, the activity of this soluble enzyme is at low levels in the serum. With hepatic injury, ALT leaks from the liver, causing an elevation of serum ALT activity, thus serving as an indicator of hepatocellular injury. 6,7 However, the specificity and sensitivity of elevated ALT levels as a marker for hepatic injury are low. Consequently, the ALT serum level does not always correlate with the extent of hepatic injury, 8 and in fact 20% of patients infected with HCV have normal ALT values despite histologic injury on biopsy. 3 The determination of what constitutes "normal" serum ALT levels has been controversial; this is in part because the distribution of ALT levels is influenced by such factors as gender, race, obesity, diet, and geographic region. 6,[9][10][11][12] In addition, diurnal variations in this enzyme's serum levels have been noted. 13 Despite the variations noted in the normal levels of this enzyme, the measurement of ...

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for posttransplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in 410% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53 þ (P ¼ 0.0007) and Ki-67 þ cases (P ¼ 0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level Z100 ng/ml at time of diagnosis, compared to those with an AFP level o100 ng/ml (P ¼ 0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level Z100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

Background & Aims-Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA) >6 log IU/ml or cirrhosis have a reduced probability of a sustained-virological response (SVR). We examined the relationship between bHCV-RNA, cirrhosis and SVR using a mathematical model that includes the critical-drug efficacy (ε c ; the efficacy required for a drug to clear HCV), the infectionrate constant (β) and the percentage of HCV-infected hepatocytes (π).