Update on Chronic Hepatitis C
2005; Elsevier BV; Volume: 3; Issue: 6 Linguagem: Inglês
10.1016/s1542-3565(05)00247-8
ISSN1542-7714
Autores Tópico(s)Liver Disease and Transplantation
ResumoThe burden of chronic hepatitis C infection remains significant in the United States and worldwide. Increased knowledge regarding the natural history of acute and chronic infection and the key factors responsible for disease progression, risk for cirrhosis, and risk for hepatocellular carcinoma are critical in guiding secondary and tertiary prevention measures. The past decade has seen substantial improvement of antiviral therapy for chronic hepatitis C virus with an increasing number of individuals achieving viral eradication. Decisions regarding whom, when, and how to use antiviral therapy have become more complex and change as new studies become available. This review focuses on the current status of hepatitis C virus patient management and future treatment directions. The burden of chronic hepatitis C infection remains significant in the United States and worldwide. Increased knowledge regarding the natural history of acute and chronic infection and the key factors responsible for disease progression, risk for cirrhosis, and risk for hepatocellular carcinoma are critical in guiding secondary and tertiary prevention measures. The past decade has seen substantial improvement of antiviral therapy for chronic hepatitis C virus with an increasing number of individuals achieving viral eradication. Decisions regarding whom, when, and how to use antiviral therapy have become more complex and change as new studies become available. This review focuses on the current status of hepatitis C virus patient management and future treatment directions. There are an estimated 170 million individuals worldwide with chronic hepatitis C virus (HCV) infection. In the United States, the incidence of HCV has decreased since the late 1980s,1Williams I. Epidemiology of hepatitis C in the United States.Am J Med. 1999; 107: 2S-9SAbstract Full Text Full Text PDF PubMed Google Scholar but models based on known prevalent cases and the increased risk for cirrhosis and hepatocellular carcinoma with longer duration of infection predict that the rate of liver-related complications in the next 10–20 years will increase.2Armstrong G. Alter M. McQuillan G. et al.The past incidence of hepatitis C virus infection implications for the future burden of chronic liver disease in the United States.Hepatology. 2000; 31: 777-782Crossref PubMed Scopus (457) Google Scholar, 3Davis G. Albright J. Cook S. et al.Projecting future complications of chronic hepatitis C in the United States.Liver Transpl. 2003; 9: 331-338Crossref PubMed Scopus (511) Google Scholar Preventing these complications of chronic infection is dependent on identification of infected individuals, modification of factors that negatively influence disease progression (eg, alcohol use), and treatment of infected individuals. Ultimately, the burden of infection and complications of chronic liver disease will be prevented most effectively by the development of a vaccine for HCV.Epidemiology and Natural HistoryRisk factors for HCV acquisition in the United States has changed over time, with a decrease in the number of infections attributable to blood transfusion and an increased proportion attributed to sexual contact.4Alter M. Prevention of spread of hepatitis C.Hepatology. 2002; 36: S93-S98Crossref PubMed Scopus (0) Google Scholar Sharing of contaminated needles and paraphernalia among injection drug users remains the most common mode of HCV transmission, both past and present. Screening for HCV infection is targeted toward risk groups with an HCV prevalence rate greater than that of the general population, including all patients with a history of transfusion of clotting factor before 1987, patients who received blood products or an organ transplant before 1992, patients with a history of injection drug use, chronic dialysis recipients, infants born to HCV-positive mothers, all human immunodeficiency virus (HIV)-infected persons, and any patient with clinical evidence of liver disease.5Centers for Disease ControlRecommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease.MMWR Morb Mortal Wkly Rep. 1998; 47: 1-38PubMed Google Scholar, 6Sulkowski M.S. Thomas D.L. Hepatitis C in the HIV-infected person.Ann Intern Med. 2003; 138: 197-207Crossref PubMed Scopus (369) Google Scholar The identification of infected individuals is dependent on health care providers recognizing persons at risk and offering testing. Although knowledge of HCV screening guidelines is high, physicians do not inquire consistently regarding HCV risk factors nor do they always screen those identified with risk factors.7Pratt C. Paone D. Carter R. et al.Hepatitis C screening and management practices a survey of drug treatment and syringe exchange programs in New York City.Am J Public Health. 2002; 92: 1264-1266Crossref PubMed Google Scholar, 8Shehab T. Sonnad S. Lok A. Management of hepatitis C patients by primary care physicians in the USA results of a national survey.J Viral Hepat. 2001; 8: 377-383Crossref PubMed Scopus (101) Google Scholar, 9Boaz K. Fiore A. Schrag S. et al.Screening and counseling practices reported by obstetrician-gynecologists for patients with hepatitis C virus infection.Infect Dis Obstet Gynecol. 2003; 11: 39-44Crossref PubMed Scopus (21) Google Scholar, 10Navarro V. St Louis T. Bell B. Identification of patients with hepatitis C virus infection in New Haven County primary care practices.J Clin Gastroenterol. 2003; 36: 431-435Crossref PubMed Scopus (22) Google Scholar The absence of increased liver enzymes may be one factor influencing screening in persons with recognized risk factors,8Shehab T. Sonnad S. Lok A. Management of hepatitis C patients by primary care physicians in the USA results of a national survey.J Viral Hepat. 2001; 8: 377-383Crossref PubMed Scopus (101) Google Scholar but the primary barrier to identifying infected individuals is the lack of inquiry into current and past risk factors for HCV acquisition.The natural history of HCV is quite variable. After exposure to HCV, 55%–80% of persons become chronically infected. The age of infection is linked with risk for chronicity and rate of disease progression. Among children and young adults, spontaneous clearance of infection occurs in approximately 40%–45% and cirrhosis develops in 2%–4% after 20 years of infection.11Vogt M. Lang T. Frosner G. et al.Prevalence and clinical outcome of hepatitis C infection in children who underwent cardiac surgery before the implementation of blood-donor screening.N Engl J Med. 1999; 341: 866-870Crossref PubMed Scopus (447) Google Scholar, 12Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. Irish Hepatology Research Group.N Engl J Med. 1999; 340: 1228-1233Crossref PubMed Scopus (843) Google Scholar, 13Rodger A. Roberts S. Lanigan A. et al.Assessment of long-term outcomes of community-acquired hepatitis C infection in a cohort with sera stored from 1971 to 1975.Hepatology. 2000; 32: 582-587Crossref PubMed Scopus (173) Google Scholar In contrast, older individuals clear virus spontaneously less often (∼20%), and 20%–30% progress to cirrhosis after 20 years or more.14Freeman A.J. Dore G.J. Law M.G. et al.Estimating progression to cirrhosis in chronic hepatitis C virus infection.Hepatology. 2001; 34: 809-816Crossref PubMed Scopus (524) Google Scholar Among those with cirrhosis, risks for liver decompensation are estimated to be 3%–4% annually and liver cancer occurs at an annual incidence of 1.4%–6.9%.15Serfaty L. Aumaitre H. Chazouilleres O. et al.Determinants of outcome of compensated hepatitis C virus-related cirrhosis.Hepatology. 1998; 27: 1435-1440Crossref PubMed Scopus (394) Google Scholar, 16Benvegnu L. Gios M. Boccato S. et al.Natural history of compensated viral cirrhosis. 2004; 53: 744-749Google Scholar The prevention of liver-related complications, including cirrhosis and hepatocellular carcinoma, is an important goal of antiviral therapy.The risk-benefit of antiviral therapy requires an understanding of the natural history of infection and the anticipated future risk for liver complications. Factors most consistently linked with a higher risk for developing cirrhosis are older age at infection, long duration of infection, male sex, heavy alcohol use, and HIV co-infection (Table 1).17Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2755) Google Scholar, 18Benhamou Y. Di Martino V. Bochet M. et al.Factors affecting liver fibrosis in human immunodeficiency virus-and hepatitis C virus-coinfected patients impact of protease inhibitor therapy.Hepatology. 2001; 34: 283-287Crossref PubMed Scopus (396) Google Scholar, 19Kamal S. Fehr J. Roesler B. et al.Peginterferon alone or with ribavirin enhances HCV-specific CD4 T-helper 1 responses in patients with chronic hepatitis C.Gastroenterology. 2002; 123: 1070-1083Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, 20Benhamou Y. Bochet M. Di Martino V. et al.Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group.Hepatology. 1999; 30: 1054-1058Crossref PubMed Scopus (1147) Google Scholar Other immunocompromised populations, including transplant recipients, are at a higher risk for progressive liver disease than nonimmunocompromised populations. Steatosis21Monto A. Alonzo J. Watson J. et al.Steatosis in chronic hepatitis C; relative contributions of obesity, diabetes mellitus, and alcohol.Hepatology. 2002; 36: 729-736Crossref PubMed Scopus (330) Google Scholar, 22Hourigan L.F. Macdonald G.A. Purdie D. et al.Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.Hepatology. 1999; 29: 1215-1219Crossref PubMed Scopus (602) Google Scholar, 23Castera L. Herode C. Roudot-Thoraval F. et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.Gut. 2002; 52: 288-292Crossref Scopus (267) Google Scholar, 24Rubbia-Brandt L. Fabris P. Paganin S. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Crossref PubMed Scopus (238) Google Scholar and possibly race25Wiley T.E. Brown J. Chan J. Hepatitis C infection in African Americans its natural history and histological progression.Am J Gastroenterol. 2002; 97: 700-706Crossref PubMed Google Scholar, 26Crosse K. Umeadi O. Anania F. et al.Racial differences in liver inflammation and fibrosis related to chronic hepatitis C.Clin Gastroenterol Hepatol. 2004; 2: 463-468Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 27Sterling R. Stravitz R. Luketic V. et al.A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans.Clin Gastroenterol Hepatol. 2004; 2: 469-473Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 28Nguyen M. Whittemore A. Garcia R. et al.Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis.Clin Gastroenterol Hepatol. 2004; 2: 820-824Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 29Davila J. Morgan R. Shaib Y. et al.Hepatitis C infection and the increasing incidence of hepatocellular carcinoma a population-based study.Gastroenterology. 2004; 127: 1372-1380Abstract Full Text Full Text PDF PubMed Scopus (424) Google Scholar are additional factors influencing fibrosis progression. Recent studies suggest African Americans may have less severe histologic disease compared with Caucasians,25Wiley T.E. Brown J. Chan J. Hepatitis C infection in African Americans its natural history and histological progression.Am J Gastroenterol. 2002; 97: 700-706Crossref PubMed Google Scholar, 26Crosse K. Umeadi O. Anania F. et al.Racial differences in liver inflammation and fibrosis related to chronic hepatitis C.Clin Gastroenterol Hepatol. 2004; 2: 463-468Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar, 27Sterling R. Stravitz R. Luketic V. et al.A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans.Clin Gastroenterol Hepatol. 2004; 2: 469-473Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar but appear to have higher rates of hepatocellular carcinoma.28Nguyen M. Whittemore A. Garcia R. et al.Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis.Clin Gastroenterol Hepatol. 2004; 2: 820-824Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 29Davila J. Morgan R. Shaib Y. et al.Hepatitis C infection and the increasing incidence of hepatocellular carcinoma a population-based study.Gastroenterology. 2004; 127: 1372-1380Abstract Full Text Full Text PDF PubMed Scopus (424) Google ScholarTable 1Factors Associated With a Higher Risk of Fibrosis Progression or CirrhosisEstablished factorsEmerging factorsMale sexPresence of fibrosis on initial biopsy examinationOlder age of infection (>40 y)SteatosisHepatitis B virus co-infectionCaucasian race (vs African American)HIV coinfection (CD4 count 50 g/dayData from Poynard et al,17Poynard T. Bedossa P. Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups.Lancet. 1997; 349: 825-832Abstract Full Text Full Text PDF PubMed Scopus (2755) Google Scholar Monto et al,21Monto A. Alonzo J. Watson J. et al.Steatosis in chronic hepatitis C; relative contributions of obesity, diabetes mellitus, and alcohol.Hepatology. 2002; 36: 729-736Crossref PubMed Scopus (330) Google Scholar Hourigan et al,22Hourigan L.F. Macdonald G.A. Purdie D. et al.Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis.Hepatology. 1999; 29: 1215-1219Crossref PubMed Scopus (602) Google Scholar Castera et al,23Castera L. Herode C. Roudot-Thoraval F. et al.Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies.Gut. 2002; 52: 288-292Crossref Scopus (267) Google Scholar Rubbia-Brandt,24Rubbia-Brandt L. Fabris P. Paganin S. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Crossref PubMed Scopus (238) Google Scholar Wiley et al,25Wiley T.E. Brown J. Chan J. Hepatitis C infection in African Americans its natural history and histological progression.Am J Gastroenterol. 2002; 97: 700-706Crossref PubMed Google Scholar Crosse et al,24Rubbia-Brandt L. Fabris P. Paganin S. et al.Steatosis affects chronic hepatitis C progression in a genotype specific way.Gut. 2004; 53: 406-412Crossref PubMed Scopus (238) Google Scholar Sterling et al,27Sterling R. Stravitz R. Luketic V. et al.A comparison of the spectrum of chronic hepatitis C virus between Caucasians and African Americans.Clin Gastroenterol Hepatol. 2004; 2: 469-473Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Ryder et al,101Hinrichsen H. Benhamou Y. Wedemeyer H. et al.Short-term antiviral efficacy of BILN 2061, a hepatitis C virus serine protease inhibitor, in hepatitis C genotype 1 patients.Gastroenterology. 2004; 127: 1347-1355Abstract Full Text Full Text PDF PubMed Scopus (315) Google Scholar and Wright et al.102Godofsky E. Afdhal N. Rustgi V. et al.A phase I/II dose escalation trial assessing tolerance, pharmacokinetics, and antiviral activity of NM283, a novel antiviral treatment for hepatitis C.Gastroenterology. 2004; 126: A681Google Scholar Open table in a new tab Initial Evaluation of the Anti-Hepatitis C Virus-Positive PatientThe initial evaluation of an anti-HCV-positive individual serves to determine the following: (1) if chronic infection is present or whether spontaneous viral clearance has occurred, (2) exclusion of concomitant causes of liver disease, (3) the severity of liver disease, and (4) suitability for antiviral therapy. Identification of risk factors for acquisition of infection may help to estimate the duration of infection. Counseling regarding prevention of transmission to others and lifestyle modifications to reduce the risk for disease progression are required. Alcohol and drug dependency are important comorbidities to identify and treat.30Sylvestre D. Loftis J. Hauser P. et al.Co-occurring hepatitis C, substance use, and psychiatric illness treatment issues and developing integrated models of care.J Urban Health. 2004; 81: 719-734Crossref PubMed Scopus (79) Google Scholar Review of systems focuses on hepatic and extrahepatic manifestations of HCV infection, and relevant comorbid medical and psychiatric conditions.In all anti-HCV-positive individuals, the persistence of infection should be confirmed by detection of HCV-RNA in serum using a sensitive qualitative assay. The confirmation of viremia also is necessary before initiation of antiviral therapy. There is no correlation between genotype or viral load31Poynard T. Ratziu V. Charlotte F. et al.Rates and risk factors of liver fibrosis progression in patients with chronic hepatitis C.J Hepatol. 2001; 34: 730-739Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 32Fanning L. Kenny E. Sheehan M. et al.Viral load and clinicopathological features of chronic hepatitis C (1b) in a homogeneous patient population.Hepatology. 1999; 29: 904-907Crossref PubMed Scopus (79) Google Scholar and disease severity, but these virologic parameters have great relevance in the determination of treatment duration, ribavirin dose, and likelihood of response.33McHutchison J. Gordon S. Schiff E. et al.Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C.N Engl J Med. 1998; 339: 1485-1492Crossref PubMed Scopus (3343) Google Scholar, 34Hadziyannis S. Sette H.J. Morgan T. et al.Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C a randomized study of treatment duration and ribavirin dose.Ann Intern Med. 2004; 140: 346-355Crossref PubMed Scopus (2738) Google Scholar, 35Fried M.W. Shiffman M.L. Reddy K.R. et al.Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.N Engl J Med. 2002; 347: 975-982Crossref PubMed Scopus (5859) Google Scholar, 36Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar Therefore, quantitative HCV-RNA levels and genotyping should be measured in those being considered for antiviral therapy. Other causes of liver disease should be ruled out if liver enzyme levels are increased. In general, a baseline abdominal ultrasound is used to assess for radiologic signs of cirrhosis and portal hypertension, especially if the duration of infection is unknown or estimated to be in excess of 20 years.Role of Liver Biopsy ExaminationWhether a liver biopsy examination is necessary in all HCV-infected patients is controversial. The 2002 National Institutes of Health Consensus Statement considers the liver biopsy examination to be a “useful part of informed consent,” and in most patients with chronic hepatitis C, “the value of pretreatment liver biopsy outweighs its risks.”37Consensus Development PanelNational Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10–12, 2002.Hepatology. 2003; 36: S3-S20Google Scholar Patient groups in which the role of biopsy examination is more debatable are patients with persistently normal alanine transaminase (ALT) levels and those with genotypes 2 and 3. In those with clinical evidence of cirrhosis or portal hypertension, a liver biopsy examination may add little further information unless an additional diagnosis is suspected, and may be associated with more complications.38Bravo A. Sheth S. Chopra S. Liver biopsy.N Engl J Med. 2001; 344: 495-500Crossref PubMed Scopus (1807) Google Scholar, 39Terjung B. Lemnitzer I. Dumoulin F. et al.Bleeding complications after percutaneous liver biopsy. An analysis of risk factors.Digestion. 2003; 67: 138-145Crossref PubMed Scopus (171) Google ScholarThe biopsy examination remains the most reliable method to assess the extent of necroinflammatory activity (grade) and fibrosis (stage).37Consensus Development PanelNational Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10–12, 2002.Hepatology. 2003; 36: S3-S20Google Scholar The degree of fibrosis has prognostic value in predicting treatment response, although this effect has diminished as therapies have improved,36Manns M.P. McHutchison J.G. Gordon S.C. et al.Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C a randomised trial.Lancet. 2001; 358: 958-965Abstract Full Text Full Text PDF PubMed Scopus (5871) Google Scholar, 40Poynard T. Marcellin P. Lee S. et al.Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.Lancet. 1998; 352: 1426-1432Abstract Full Text Full Text PDF PubMed Scopus (2392) Google Scholar, 41Heathcote E. Shiffman M. Cooksley W. et al.Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.N Engl J Med. 2000; 343: 1673-1680Crossref PubMed Scopus (869) Google Scholar and may influence the timing of antiviral therapy. Individuals with more severe histologic disease are at greater risk for liver-related complications, in the short term, than those with early disease. A person with early histologic disease may choose to defer treatment, awaiting more effective or easier-to-tolerate therapies. It is recommended that a biopsy examination be considered in those who are over the age of 40, those who wish to defer treatment, or those in whom the risk-benefit of antiviral therapy is unclear.37Consensus Development PanelNational Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10–12, 2002.Hepatology. 2003; 36: S3-S20Google ScholarRecently, fibrosis indices calculated by using a combination of biomarkers such as the Fibrotest (Fibrosure; Biopredictive, Paris, France),42Rossi E. Adams L. Prins A. et al.Validation of the FibroTest biochemical markers score in assessing liver fibrosis in hepatitis C patients.Clin Chem. 2003; 49: 450-454Crossref PubMed Scopus (217) Google Scholar, 43Poynard T. Imbert-Bismut F. Munteanu M. et al.Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C.Comp Hepatol. 2004; 3: 8Crossref PubMed Scopus (312) Google Scholar Forns’ index,44Forns X. Ampurdanes S. Llovet J. et al.Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model.Hepatology. 2002; 36: 986-992PubMed Google Scholar or the AST/platelet ratio index45Wai C. Greenson J. Fontana R. et al.A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C.Hepatology. 2003; 38: 518-526Crossref PubMed Scopus (3047) Google Scholar have been proposed as an alternative to liver biopsy examination. These indices appear most accurate at the extremes of the fibrosis spectrum (minimal fibrosis and bridging fibrosis/cirrhosis).46Fontana R. Lok A. Noninvasive monitoring of patients with chronic hepatitis C.Hepatology. 2002; 36: S57-S64Crossref PubMed Google Scholar With the increased understanding of hepatic fibrogenesis, new biomarkers of matrix metabolism that predict accurately fibrosis and risk for fibrosis progression are likely to be identified, and the future role of the liver biopsy examination in managing patients with chronic HCV infection is likely to change.Considerations for TherapyThe National Institutes of Health Consensus Conference concluded that all patients with chronic HCV infection should be considered for antiviral therapy,37Consensus Development PanelNational Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10–12, 2002.Hepatology. 2003; 36: S3-S20Google Scholar but it was recognized that the decision to treat must be individualized. Factors influencing this decision include the expected rate of disease progression in the absence of treatment, the likelihood of achieving viral eradication or other treatment benefits, the presence of relative or absolute contraindications to receipt of interferon or ribavirin, and the motivation and expected compliance of the patient.Because only a proportion of patients with chronic hepatitis C progress to cirrhosis, and antiviral therapy is not effective in all patients, identification of those at increased risk for cirrhosis and liver-related complications may be useful in evaluating the risks vs benefits of antiviral therapy. Although certain factors have been associated with worse disease severity (Table 1), they are not predictive enough to be used in individual treatment decisions. The finding of moderate inflammation and portal or bridging fibrosis on liver biopsy examination usually is indicative of increased risk for disease progression.37Consensus Development PanelNational Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C: 2002—June 10–12, 2002.Hepatology. 2003; 36: S3-S20Google Scholar For patients with cirrhosis, treatment is indicated if the disease is well compensated. For patients with decompensated cirrhosis, antiviral therapy is not recommended outside of clinical trials because of poor tolerability and a risk of serious complications, especially infections.47Hoofnagle J. DiBisceglie A. Waggoner J. et al.Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B.Gastroenterology. 1993; 104: 1116-1121PubMed Google Scholar, 48Crippin J.S. McCashland T. Terrault N. et al.A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation.Liver Transpl. 2002; 8: 350-355Crossref PubMed Scopus (310) Google ScholarApproximately 30% of HCV-infected individuals have persistently normal ALT levels and such patients typically have mild histologic disease.49Persico M. Persico E. Suozzo R. et al.Natural history of hepatitis C virus carriers with persistently normal aminotransferase levels.Gastroenterology. 2000; 118: 760-764Abstract Full Text Full Text PDF PubMed Scopus (209) Google Scholar, 50Bacon B. Treatment of patients with hepatitis C and normal serum aminotransferase levels.Hepatology. 2002; 36: S179-S184Crossref PubMed Google Scholar Nonetheless, some may have or progress to advanced liver disease. Treatment results in patients with persistently normal ALT levels are equivalent to those with abnormal ALT levels, and increases in ALT levels during or after treatment occur in the minority of patients.51Martinot-Peignoux M.N.B. Cazals-Hatem D. Pham B. et al.Prospective study on anti-hepatitis C virus-positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA.Hepatology. 2001; 34: 1000-1005Crossref PubMed Scopus (142) Google Scholar, 52Jacobson I. Ahmed F. Russo M. et al.Interferon alpha-2b and ribavirin for patients with chronic hepatitis C and normal ALT.Am J Gastroenterol. 2004; 99: 1700-1705Crossref PubMed Scopus (39) Google Scholar, 53Hui C. Monto A. Belaye T. et al.Outcomes of interferon alpha and ribavirin treatment for chronic hepatitis C in patients with normal serum aminotransaminases.Gut. 2003; 52: 1644-1648Crossref PubMed Scopus (47) Google Scholar Therefore, patients with normal ALT levels require an individualized assessment of risk-benefit regarding liver biopsy examination and antiviral treatment.54Bacon B. Chronic hepatitis C and normal ALT considerations for treatment.Am J Gastroenterol. 2004; 99: 1706-1707Crossref PubMed Scopus (9) Google ScholarLastly, in considering antiviral therapy, one needs to consider potential contraindications to the use of interferon (IFN) and ribavirin (Table 2). Historically, active substance use or depression was considered absolute contraindications for treatment with IFN-based therapy. However, more recent trials have shown that comparable efficacy and tolerability can be achieved in these patients, especially with use of concomitant treatment for drug use and depression.55Schaefer M. Schmidt F. Folwaczny C. et al.Adherence and mental side effects during hepatitis C treatment with interferon alfa and ribavirin in psychiatric risk groups.Hepatology. 2003; 37: 443-451Crossref PubMed Scopus (310) Google Scholar, 56Mauss S. Berger F. Goelz J. et al.A prospective controlled study of interferon-based therapy of chronic hepatitis C in patients on methadone maintenance.Hepatology. 2004; 40: 120-124Crossref PubMed Scopus (159) Google Scholar, 57Backmund M. Meyer K. Von Zielonka M. et al.Treatment of hepatitis C infection in injection drug users.Hepatology. 2001; 34: 188-193Crossref PubMed Scopus (284) Google Scholar Therefore, the populations being considered for antiviral therapy are expanding.Table 2Contraindications to Peginterferon and Ribavirin TherapyAbsolute contraindicationsSevere or uncontrolled psychiatric diseasePoorly controlled epilepsyActive serious infection
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