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Hep C Online News: recently reported studies in HCV
Reported by Jules Levin
  This online newsletter is a selection of summaries of interesting studies reported in 2002 in published medical journals. See the NATAP website for the special Hepatitis Section and numerous articles, both simple and scientific, on HCV.
Impact of peginterferon (PEG) alfa-2b and ribavirin on liver fibrosis.
summary abstract: Thierry Poynard and colleagues pooled data from 4 randomized trials that investigated 10 different regimens ranging from interferon (IFN) x 24 wk to optimized PEG/ribavirin. These studies included 3,010 patients with pre- and post-treatment liver biopsies. Treatment impact was estimated by the percentage of patients with 1-3 grade improvement in the necrosis and inflammation score, the percentage of patients with 1-3 stage worsening in the fibrosis score, and by the fibrosis progression rate per year. All regimens reduced the rate of fibrosis progression. Necrosis and inflammation improved in 73% of optimized PEG/ribavirin patients compared to 39% of patients treated with IFN x 24 wk (p<0.001), and fibrosis worsened in only 8% of PEG/ribavirin patients versus 23% of IFN-treated patients (p<0.001). Moreover, reversal of cirrhosis was observed in 75 (49%) of the 153 patients with baseline cirrhosis. Factors independently associated with the absence of significant fibrosis after treatment included: stage of fibrosis at baseline; sustained viral response; age<40 years; body mass index <27 kg/m2; and viral load <3.5 million copies/mL. These data demonstrate that the combination of PEG and ribavirin therapy effectively reduces the rate of fibrosis progression in HCV patients. (Poynard T, et al. Gastroenterology 2002;122:1303-1313.)
Read detailed NATAP report of this study at discussing nonresponders:
Lower risk of cirrhosis in wine drinkers.
summary abstract: Ulrik Becker and associates analyzed data from 3 prospective studies involving 30,630 subjects from the Copenhagen area by means of multiplicative Poisson regression models. They found that individuals who drank more than 5 drinks daily had a relative risk of 14 to 20 for developing cirrhosis. However, compared to those who drank no wine (relative risk = 1.0), individuals for whom wine made up at least 51% of their alcohol intake had a relative risk for developing cirrhosis of 0.3. These data indicate that all types of excessive alcoholic intake increased the risk for cirrhosis, but the risk for wine drinkers was lower. (Becker U, et al. Hepatology 2002;35:868-875).
Natural history of HCV in African Americans.
summary abstract: Thelma Wiley and coworkers retrospectively reviewed the records of 355 patients with HCV infection (112 African Americans and 243 non-African Americans). African Americans were more likely to be older at presentation, to be women (p = 0.02), and to be infected with genotype 1 virus (p = 0.001). In addition, serum baseline alanine aminotransferase (ALT) levels were lower and piecemeal necrosis was less frequently found in African Americans. These findings suggest that the immunologic recognition of HCV infected hepatic cells may not be as strong in African Americans as in non-African Americans. (Wiley TE, et al. Am J Gastroenterol 2002;97:700-706). Results rom studies show African-Americans don't respond as well to interferon/ribavirin therapy. an NIH study is examining this question now to understand why.
PEGINTERFERON ALFA-2a (Pegasys) plus ribavirin: 24 vs. 48 weeks and 800 vs. 1000/1200 mg ribavirin
At the EASL (European liver meeting) in April results were reported from a large phase III study of Pegasys + ribavirin. Important conclusions from this study are that: 1) Pegasys plus ribavirin yielded a sustained viral response SVR of 61% overall; 2) the SVR in non-cirrhotics was 65% versus 50% in cirrhotics; 3) in genotype 1 patients, 48 weeks of Pegasys plus ribavirin at a dose of 1000/1200 mg/d achieved a SVR of 51% (the SVR in patients with a high viral load was 46% [35% receiving 800mg ribavirin] vs. 61% in those with a low viral load [53% receiving 800 mg ribavirin]); 4) in non-genotype 1 patients, a shorter duration of therapy (24 week) and a lower dose of ribavirin (800 mg/d) was adequate therapy (73% to 78% SVR), with no increased efficacy with longer therapy or higher doses of ribavirin.
A more detailed report of this study at NATAP website:
Predictability of Sustained Virological Response & Adherence
At EASL, Dr. Donald Jensen from Rush Presbyterian in Chicago addressed the issue of predictability of SVR in patients receiving Pegasys and ribavirin therapy. In a study of 453 patients receiving this combination for 48 weeks, 86% had an early virological response (EVR) defined as serum HCV RNA negativity or at least a 2-log drop in HCV RNA levels after 12 weeks of therapy. Patients who took 80% or more of their medication doses and completed at least 38 weeks of therapy, which was defined as "full dose", and who also had an EVR ultimately had a SVR of 75%. In genotype 1 patients, the group with an EVR and meeting the full dose criteria had a SVR of 67%. For patients with genotypes 2 or 3, patients who had an EVR and satisfied the full dose criteria had a SVR of 88%.
These data suggest that the EVR after 12 weeks of therapy is highly predictive of a SVR and is more useful than baseline parameters in determining response rates. Absence of EVR was useful in predicting non-response, with a negative predictive value of 97%. Use of EVR will allow individualization of treatment regimens and provide a basis for advocating adherence to therapy.
Additional reported studies:
PegIntron at FDA Hearing, December 2001
Review of HCV Therapy at NIH HCV Consensus Conference (June 2002)
Cost-effectiveness of hepatitis A virus (HAV) vaccination in patients with chronic hepatitis C.
HAV infection in patients with chronic HCV infection is associated with a high case fatality rate. Thus, Miguel Arguedas et al evaluated the cost-effectiveness of HAV vaccination by cost estimates based on published data and Medicare reimbursement rates. Results were sensitive to the incidence of HAV, the probability of fulminant hepatic failure, and the cost of HAV antibody screening and vaccination. Compared with no vaccination, targeted vaccination was associated with an incremental cost-effectiveness ratio of $51,000 per quality-adjusted life-year (QALY). Compared to targeted vaccination, universal vaccination was associated with an incremental cost-effectiveness ratio of $3,900,000 per QALY. These results indicate that universal HAV vaccination is not a cost-effective strategy, while targeted HAV vaccination may be a cost-effective means to decrease the morbidity and mortality of HAV superinfection in patients with chronic hepatitis C. (Arguedas MR, et al. Am J Gastroenterol 2002;97:721-728)
Interferon alfa-2b therapy of acute hepatitis C.
Elmar Jaeckel and the German Acute Hepatitis C Therapy Group report that interferon alfa-2b (6 MU subcutaneously daily for 4 weeks and then tiw for 20 weeks) was effective treatment of 44 patients with acute HCV infection. The average time from infection to start of therapy was 89 days. At the end of therapy and after 24 weeks of follow-up, 43 patients (98%) had undetectable serum HCV RNA and normal ALT levels. Serum HCV RNA levels became undetectable after an average of 3.2 weeks of interferon treatment. Therapy was well tolerated, with only 1 patient stopping treatment due to side effects. This study demonstrates that the treatment of acute hepatitis C with interferon alfa-2b has a high sustained response rate and prevents the development of chronic infection. (Jaeckel E, et al. N Engl J Med 2001;345:1452-1457)
More detailed report on this study at NATAP website:
Barriers to therapy for chronic hepatitis C.
Yngve Falck-Ytter and colleagues retrospectively reviewed the case records of HCV-infected patients referred to a metropolitan liver clinic to investigate the overall rate of antiviral treatment and the reasons for not undergoing treatment. Of 293 patients with detectable serum HCV RNA, only 83 patients (28%) underwent antiviral treatment (13% achieved a sustained virological response). The remaining 72% of patients were not treated for the following reasons: 37% did not follow evaluation directions; 34% had medical or psychiatric contraindications; 13% abused drugs or alcohol; 11% declined therapy; and 5% had normal liver enzyme levels. These findings show that most HCV-infected patients in a county hospital are not candidates for interferon therapy, and alternate strategies are needed. (Falck-Ytter Y, et al. Ann Intern Med 2002;136:288-292). I would suggest that these findings also say that these patients need proper guidance, support, and education. Sylvestri has recently reported a study at DDW 2002 showing for patients on methadone maintenance and in support group who experience IVD relapse intervention can prevent continued IVDU and patients can respond to HCV therapy. Studies have shown that some patients with psychiatric conditions can be managed and receive HCV treatment. Education about HCV and treatment can address a number of barriers to care and treatment. So the author's conclusion that most HCV-infected patients were not candidates needs to be modified. There are barriers but with programs to bridge the gaps many of these patients can be treated and since HCV is an epidemic and the largest blood-borne disease in the US we need to develop these programs.
Cognitive and neuropsychological impairment.
Daniel Forton and colleagues tested viremic patients with mild chronic hepatitis C (n = 27) and patients who cleared HCV, either spontaneously or after antiviral therapy, (n = 16) with a computer-based cognitive assessment battery. The results of these tests showed that HCV-infected patients were impaired on more cognitive tasks than the patients who cleared HCV (p = 0.02). Further, cerebral proton magnetic resonance spectroscopy (MRS) revealed the choline/creatine ratio to be elevated in the basal ganglia and white matter of HCV-infected patients. This preliminary investigation demonstrated cognitive impairment in HCV patients with mild liver disease; the abnormal findings on MRS suggest a biological basis of this impairment. Robin Hilsabeck and coworkers administered neuropsychological tests to patients with either chronic hepatitis C (n= 66) or other chronic liver diseases (n = 14). Cognitive impairment was observed in areas measuring sustained attention and concentration. Test scores of patients with chronic hepatitis C were similar to those of patients with other chronic liver diseases. Greater hepatic fibrosis was associated with poorer performance, however patients with and without cirrhosis exhibited cognitive dysfunction. These findings indicate that progressive hepatic injury (whether or not due to HCV infection) may result in cognitive impairment. Both of these studies are provocative but must be considered preliminary; larger studies with further controls are needed in this important area of research. (Forton DM, et al. Hepatology 2002;35:433-439 and Hilsabeck RC, et al. Hepatology 2002;35:440-446)
More details on this study/report at NATAP site:
Neuropsychological Impairment in Patients with Chronic Hepatitis C
Fatty Liver, HIV and Lipodystrophy
Association with the insulin resistance syndrome. NASH is associated with disorders that are characterized by hyperinsulinemia and insulin resistance (IR). Recent data indicate that NASH may be a feature of the IR syndrome (central obesity, impaired glucose tolerance, dyslipidemia, and hypertension). Shivakumar Chitturi et al. utilized the homeostasis model assessment (HOMA) to determine IR in 66 patients with NASH and 36 age- and sex-matched controls with chronic hepatitis C. IR was confirmed in 65 NASH patients (98%), and 55 (87%) of these patients fulfilled minimum criteria for the IR syndrome. The IR values and prevalence of IR syndrome (75% vs 8.3%) were significantly higher in NASH patients than in comparable cases of chronic hepatitis C. In a second study, Gianfranco Pagano and colleagues analyzed 38 subjects (19 patients with NASH and 19 age- and sex-matched normal controls). NASH patients were found to have lower insulin sensitivity (p = 0.0003) and higher total insulin secretion (p = 0.001) than controls. Furthermore, 9 NASH patients (47%) had at least 2 criteria required to define the metabolic syndrome according to the European Group for the Study of Insulin Resistance (EGIR). The data from these 2 studies further support the concept that NASH is specifically associated with the IR syndrome. Finally, Kimberly Woodcroft and associates conducted studies of molecular regulatory mechanisms showing that insulin mediates hepatic CYP2E1 expression by enhancing CYP2E1 mRNA degradation and by decreasing CYP2E1 gene transcription. CYP2E1 has been implicated in the generation of tissue-damaging hydroxyl radicals, a potential "second hit" in patients with NASH. (Chitturi S, et al. Hepatology 2002;35:373-379; Pagano G, et al. Hepatology 2002;35:367-372; Woodcroft KJ, et al. Hepatology 2002;35:263-273) In HIV and on HAART, cholesterol, tryglicerides and sugar can become elevated. Insulin resistance also can occur on HAART. Certain HIV drugs may be more or less associated with this occurence. Patients on HAART may be more prone to NASH or fatty liver but we need more research to understand this concern and how to address it. starting HCV therapy before HAART in the appropriate setting may be one approach.
Human immunodeficiency virus (HIV) coinfection.
To determine the influence of HIV on HCV infection, Vincent Di Martino and colleagues retrospectively analyzed the 52-month clinical course of 80 HIV+ and 80 HIV- injection drug users identified between 1980 and 1995. These two cohorts were matched for age, gender, and duration of HCV infection. Higher serum HCV RNA levels, higher total Knodell histologic index activity scores, and poorer sustained responses to interferon therapy were found in the HIV+ patients. An accelerated progression to cirrhosis was also seen in HIV+ patients with low CD4 cell counts and in patients who had not received interferon. The risk of cirrhosis-related death was increased in both heavy drinkers and HIV+ patients with CD4 cell count <200. These data show that HIV coinfection worsens the outcome of chronic HCV infection and that interferon therapy has a protective effect against cirrhosis in both HIV+ and HIV- patient cohorts. (Di Martino V, et al. Hepatology 2001;34:1193-1199). While this study was not very well done it found what a number of other studies have found. But, we certainly need prospective large studies to understand the course of HCV progression in HCV untreated coinfected pstients so we can be more certain about ig HIV accelerates HCV and how much more quickly it progresses in coinfection.
Correlates of liver disease in HCV-infected injection drug users (IDUs).
Rudra Rai and associates assessed liver biopsies from 207 evaluable IDUs with chronic hepatitis C. They found severe liver disease to occur uncommonly in this population, especially in younger patients and those with repeatedly normal serum enzyme levels. (Rai R, et al. Hepatology 2002;35:1247-1255)
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