:::: CASA DA HEPATITE - Universidade Metropolitana de Santos ::::

Hepatite B

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 2010; 51:73-80).

Hepatite C

Randomized Study of Peginterferon-2a Plus Ribavirin vs Peginterferon-2b Plus Ribavirin in Chronic Hepatitis C.
Ribavirin (RBV) combined with either pegylated interferon (PegIFN) a2a or PegIFNa2b is the standard of care for chronic hepatitis C virus (HCV) infection. Due to the lack of head-to-head studies, the 2 PegIFNs have not been directly compared. The endpoints of our study were safety and antiviral efficacy of the 2 regimens. Treatment-naďve patients with chronic hepatitis C were randomly (1:1) assigned after stratification for HCV genotype to receive either 1.5 mcg/Kg/week PegIFNa2b plus RBV 800–1200 mg/day or 180 mcg/week PegIFNa2a plus RBV 800–1200 mg/day for 24 or 48 weeks according to HCV genotype. The study was powered to detect a difference of at least 10% in safety and efficacy of the 2 regimens. The 212 patients on PegIFNa2a and the 219 patients on PegIFNa2b had similar baseline characteristics, including cirrhosis (20% vs 18%, respectively). By intention to treat, the 2 groups showed similar rates of treatment-related serious adverse events (1% vs 1%, respectively) and drop out rates for adverse effects (7% vs 6%, respectively). Overall, sustained virologic response (SVR) rate was higher in PegIFNa2a than in PegIFNa2b patients (66% vs 54%, respectively, P = .02), being 48% vs 32% in the 222 HCV-1 and -4 patients (P = .04), and 96% vs 82%, respectively, in the 143 HCV-2 patients (P = .01). PegIFNa2a independently predicted SVR in the logistic regression analysis (odds ratio, 1.88; 95% confidence interval: 1.20–2.96). Although the 2 regimens showed a similar safety profile, the PegIFNa2a-based treatment yielded significantly more SVR than PegIFNa2b. (GASTROENTEROLOGY 2010; 138:108-115).

Peginterferon Alfa-2a Plus Ribavirin Is More Effective Than Peginterferon Alfa-2b Plus Ribavirin for Treating Chronic Hepatitis C Virus Infection.
Patients with chronic hepatitis C virus (HCV) infection are frequently treated with a combination of pegylated interferon (peginterferon) and ribavirin. This study compared the efficacy and safety of peginterferon alfa-2a and peginterferon alfa-2b, each in combination with ribavirin. A total of 320 consecutive, treatment-naive, HCV RNA–positive patients with chronic hepatitis were randomly assigned to once-weekly peginterferon alfa-2a (180 µg, group A) or peginterferon alfa-2b (1.5 µg/kg, group B) plus ribavirin 1000 mg/day (body weight <75 kg) or 1200 mg/day (body weight =75 kg) for 48 weeks (genotype 1 or 4) or 24 weeks (genotype 2 or 3). The primary end point was sustained virological response (SVR) by intention-to-treat. More patients in group A than group B achieved an SVR (110/160 [68.8%] vs 87/160 [54.4%]; P = .008). Higher SVR rates were obtained in group A than group B among patients with genotype 1/4 (51/93 [54.8%] vs 37/93 [39.8%]; P = .04), with genotype 2/3 (59/67 [88.1%] vs 50/67 [74.6%]; P = .046), without cirrhosis (96/127 [75.6%] vs 75/134 [55.9%]; P = .005), and with baseline levels HCV RNA >500,000 IU/mL (58/84 [69%] vs 43/93 [46.2%]; P = .002). SVR rates in groups A and B were not statistically different among patients with baseline HCV RNA =500,000 IU/mL (52/76 [68.4%] vs 44/67 [65.7%]; P = .727) or in patients with cirrhosis (14/33 [42.4%] vs 12/26 [46.1%]; P = .774). In patients with chronic HCV infection, peginterferon alfa-2a plus ribavirin produced a significantly higher SVR rate than peginterferon alfa-2b plus ribavirin. (GASTOENTEROLOGY 2010; 138:116-1220).

Predicting Clinical and Histologic Outcomes Based on Standard Laboratory Tests in Advanced Chronic Hepatitis C.
Predictors of clinical outcomes and histologic progression among patients with chronic hepatitis C and advanced fibrosis are poorly defined. We developed statistical models to predict clinical and histologic outcomes in such patients. Baseline demographic, clinical, and histologic data from Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial participants were subjected to multivariate analyses to determine their ability to predict clinical outcomes (ascites, spontaneous bacterial peritonitis, Child-Turcotte-Pugh score =7 on 2 consecutive visits, variceal bleeding, hepatic encephalopathy, and liver-related death) and histologic outcome (=2-point increase in Ishak fibrosis stage) during the 3.5 years of the trial. Of 1050 randomized patients, 135 had 1 or more clinical outcomes a median of 23 (range, 1–45) months after randomization. Factors associated with a clinical outcome in multivariate analyses were higher aspartate aminotransferase/alanine aminotransferase ratio, lower albumin, lower platelet count, higher total bilirubin, and more advanced Ishak fibrosis score (P < .0001). The cumulative 3.5-year incidence of a clinical outcome was 2% in the lowest and 65% in the highest risk group. Of 547 patients without cirrhosis at baseline and at least 1 follow-up biopsy, 152 had a histologic outcome. Independent variables associated with a histologic outcome were higher body mass index, lower platelet count, and greater hepatic steatosis (P < .0001). In patients with chronic hepatitis C and advanced fibrosis, risk of clinical complications and fibrosis progression during 3.5 years can be predicted using baseline laboratory tests and histologic data. Our models may be useful in counseling patients and determining the frequency of monitoring. (GASTROENTEROLOGY 2010; 138:136-146).

Shortened treatment duration in treatment-naive genotype 1 HCV patients with rapid virological response: A meta-analysis.
In hepatitis C virus genotype 1 (HCV-1) patients with a rapid viral decline within the first month of therapy, a 24-week course of pegylated interferon (PEG-IFN) alpha and ribavirin treatment has been claimed to be as efficient as the standard 48-week duration. We performed a meta-analysis of 7 randomized controlled trials comparing less than 48weeks to 48weeks PEG-IFN alpha/ribavirin treatment in 807 HCV-1 patients with rapid viral decline. SVR was significantly less frequent with short treatment duration than with 48weeks of therapy, with a mean difference of -13.6% (95% CI: -22.8% to -4.4%, p=0.004). This difference was related to a higher relapse rate (mean difference: 9.9%, 95% CI: 4.1–15.7%, p<0.001). In a sensitivity analysis restricted to studies using only a weight-based ribavirin regimen, shorter therapy was also less efficient. In the subgroup of patients with undetectable HCV-RNA at week 4 and a low baseline HCV-RNA level (?400,000IU/ml), there was no significant difference in SVR rates between 24 and 48weeks of treatment (mean difference: -3.10%, 95% CI: -8.6% to 2.4%, NS). In HCV-1 patients with a rapid virological response, 24weeks of combination therapy with PEG-IFN alpha and ribavirin should be considered only in subjects with low baseline viral load. However, the optimal cut-off defining low baseline viral load and the impact of the presence of other factors capable of altering treatment response, remain subject to debate. (JOURNAL OF HEPATOLOGY 2010; 52:25-31).

Esteatose Hepática

Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis (NASH) is a chronic progressive liver disease that is strongly associated with obesity. Currently, there is no approved therapy for NASH. Weight reduction is typically recommended, but efficacy data are lacking. We performed a randomized controlled trial to examine the effects of lifestyle intervention using a combination of diet, exercise, and behavior modification, with a goal of 7% to 10% weight reduction, on clinical parameters of NASH. The primary outcome measure was the change in NASH histological activity score (NAS) after 48 weeks of intervention. Thirty-one overweight or obese individuals (body mass index [BMI], 25-40 kg/m2) with biopsy-proven NASH were randomized in a 2:1 ratio to receive intensive lifestyle intervention (LS) or structured education (control). After 48 weeks of intervention, participants assigned to LS lost an average of 9.3% of their weight versus 0.2% in the control group (P = 0.003). A higher proportion of participants in the LS group had a reduction of NAS of at least 3 points or had posttreatment NAS of 2 or less as compared with the control group (72% versus 30%, P = 0.03). NAS improved significantly in the LS group (from 4.4 to 2.0) in comparison with the control group (from 4.9 to 3.5) (P = 0.05). Percent weight reduction correlated significantly with improvement in NAS (r = 0.497, P = 0.007). Participants who achieved the study weight loss goal (7%), compared with those who lost less than 7%, had significant improvements in steatosis (-1.36 versus -0.41, P < 0.001), lobular inflammation (-0.82 versus -0.24, P = 0.03), ballooning injury (-1.27 versus -0.53, P = 0.03) and NAS (-3.45 versus -1.18, P < 0.001). Conclusion: Weight reduction achieved through lifestyle intervention leads to improvements in liver histology in NASH. (HEPATOLOGY 2010:51;121-129).

Carcinoma Hepatocelular

Radioembolization for Hepatocellular Carcinoma Using Yttrium-90 Microspheres: A Comprehensive Report of Long-term Outcomes.
Hepatocellular carcinoma (HCC) has limited treatment options; long-term outcomes following intra-arterial radiation are unknown. We assessed clinical outcomes of patients treated with intra-arterial yttrium-90 microspheres (Y90). Patients with HCC (n = 291) were treated with Y90 as part of a single-center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by stage was assessed. Univariate/multivariate analyses were performed. A total of 526 treatments were administered (mean, 1.8; range, 1–5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting (20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 42% and 57% based on WHO and EASL criteria, respectively. The overall TTP was 7.9 months (95% confidence interval, 6–10.3). Survival times differed between patients with Child–Pugh A and B disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child–Pugh B disease who had portal vein thrombosis (PVT) survived 5.6 months (95% confidence interval, 4.5–6.7). Baseline age; sex; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, albumin, and a-fetoprotein; and WHO/EASL response rate predicted survival. Patients with Child–Pugh A disease, with or without PVT, benefited most from treatment. Patients with Child–Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by patient stage at baseline. These data can be used to design future Y90 trials and to describe Y90 as a potential treatment option for patients with HCC.(GASTROENTEROLOGY 2010:138:52-64).

Use of sorafenib in patients with hepatocellular carcinoma before liver transplantation: A cost-benefit analysis while awaiting data on sorafenib safety.
The role of bridging therapies for patients with hepatocellular carcinoma (HCC) on the waiting list for liver transplantation (LT) remains controversial. There is strong evidence to support the effectiveness of sorafenib in extending the time to progression of HCC. Using a Markov model, we compared two strategies: one using sorafenib as neoadjuvant therapy before LT (Strategy A), and the other using no bridging therapy in the first 6 months (Strategy B). Reference case: T2 HCC patient with compensated cirrhosis. The benefit of sorafenib in delaying time to HCC progression was expressed as the hazard ratio (HR) and taken from recently published randomized trials. The endpoints considered were: survival benefit measured in quality-adjusted life days (QALDs), transplant probability, costs (C) in , willingness to pay (WTP), and net health benefit (NHB), where NHB = survival benefit - C/WTP. The calculated WTP of sorafenib in Italy was 346 per QALD. Probabilistic sensitivity analysis showed a median survival benefit of 94 QALDs (10% percentile = 38, 90% percentile = 210). In the base-case scenario (HR = 0.47, monthly dropout probability = 5%, median time to LT = 3 months), the gain in LT probability due to sorafenib was 5% and it increased proportionally with increasing median times to LT and decreasing HR. In the cost-benefit analysis, the incremental NHB of Strategy A versus Strategy B was 37 QALDs; it increased as sorafenib HR decreased and when median times to LT were shorter than 6 months, whereas for longer times it gradually dropped, particularly when Strategy B included effective locoregional treatments. Conclusion: Sorafenib neoadjuvant therapy is cost-effective by comparison with no therapy for T2-HCC patients waiting for LT, particularly for median times to LT under 6 months. (HEPATOLOGY 2010; 51:165-173).

Cirrose Hepática

Increased caffeine consumption is associated with reduced hepatic fibrosis.
Although coffee consumption has been associated with reduced frequency of liver disease, it is unclear whether the effect is from coffee or caffeine and whether there is an effect on hepatic fibrosis specifically. This study was undertaken to use a food-frequency instrument for dietary caffeine consumption to evaluate the relationship between caffeine intake and liver fibrosis. Patients undergoing liver biopsy completed a detailed caffeine questionnaire on three occasions over a 6-month period. Caffeine intake was compared between patients with mild and advanced liver fibrosis (bridging fibrosis/cirrhosis). Logistic regression was used to evaluate the association between caffeine consumption and hepatic fibrosis. One hundred seventy-seven patients (99 male, 104 white, 121 with chronic hepatitis C virus [HCV] infection) undergoing liver biopsy completed the caffeine questionnaire on up to three occasions. Results from repeated questionnaires were consistent. Daily caffeine consumption above the 75th percentile for the cohort (308 mg = approximately 2.25 cups of coffee equivalents) was associated with reduced liver fibrosis (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.14-0.80; P = 0.015) and the protective association persisted after controlling for age, sex, race, liver disease, body mass index, and alcohol intake in all patients (OR, 0.25; 95% CI, 0.09-0.67; P = 0.006), as well as the subset with HCV infection (OR, 0.19; 95% CI, 0.05-0.66; P = 0.009). Despite a modest trend, consumption of caffeine from sources other than coffee or of decaffeinated coffee was not associated with reduced liver fibrosis. A reliable tool for measurement of caffeine consumption demonstrated that caffeine consumption, particularly from regular coffee, above a threshold of approximately 2 coffee-cup equivalents per day, was associated with less severe hepatic fibrosis. (HEPATOLOGY 2010;51:201-209).