New insights into acute hepatitis C
2003; Elsevier BV; Volume: 125; Issue: 1 Linguagem: Inglês
10.1016/s0016-5085(03)00807-2
ISSN1528-0012
Autores Tópico(s)Hepatitis B Virus Studies
ResumoAcute type C hepatitis represents no more than 15% of all acute hepatitis cases in the United States.1Armstrong G.I. Alter M.J. McQuillan G.M. Margolis H.S. 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 (456) Google Scholar Unlike types A and B, however, which are both easily diagnosed and entirely preventable, acute hepatitis C lacks a reliable serologic tag and cannot be prevented by vaccination. The 4000 new patients in the United States who present annually with acute clinical hepatitis C (an estimated 10% of the total reported cases) may present “symptomatically,” e.g., with constitutional complaints or jaundice, or “asymptomatically.” The asymptomatic patient is often detected via surveillance, such as following a needle-stick exposure to a known carrier. Otherwise, asymptomatic presentation of acute hepatitis is an oxymoron, and accordingly the majority of chronic HCV carriers lack a clinical history of acute hepatitis. The conundrum of an asymptomatic presentation, in essence, is that it is often synonymous with no presentation, and absent a surveillance program, most such patients almost certainly escape detection. Without an accepted serologic definition of acute hepatitis C, and because many individuals will not have had documentation of a previously negative anti-HCV test, the diagnosis of acute type C hepatitis is usually established by inference. Previously normal ALT values, exclusion of other causes of liver dysfunction, etc. represent surrogate parameters that strengthen the diagnosis; the lurking suspicion, of course, is that the “acute” patient was indeed a “silent” HCV carrier all along. Such is especially the case when sexual transmission is alleged. Nevertheless, although a saw-tooth pattern of fluctuating enzymes has long been recognized during the course of chronic hepatitis C, acute reactivation–with precipitous and extreme enzyme elevations such as may be seen with HBV reactivation–is rare. Despite the declining incidence of acute type C hepatitis the importance of this disease, epidemiologically and therapeutically, is enormous. Healthcare workers are particularly vulnerable: the high prevalence of this virus, especially in urban emergency departments,2Kelen G.D. Green G.B. Purcell R.H. Chan D.W. Qaqish B.F. Silvertson K.T. Quinn T.C. Hepatitis B and hepatitis C in emergency department patients.N Engl J Med. 1992; 326: 1399-1404Crossref PubMed Scopus (253) Google Scholar increases the potential risk for needle-stick transmission. Hospitals often lack sophisticated guidelines to prospectively follow high-risk individuals, and when newly diagnosed acute hepatitis C cases are identified, confusion reigns regarding management decisions. Unlike the treatment of chronic hepatitis, controlled trials and practice guidelines for the treatment of acute hepatitis C are lacking. With the intuitive logic that early antiviral intervention will abort the viral replicative process and prevent chronicity, clinicians for the past decade have instinctively started treatment immediately in patients with suspected acute hepatitis C. The literature has largely borne out this plan of management: the NIH Consensus Conference stated that treatment of acute hepatitis C “is warranted,”3National Institutes of Health Consensus Development Conference Statement Management of Hepatitis C: 2002. June 10–12, 2002.Hepatology. 2002; 36: S3-S20Crossref PubMed Scopus (267) Google Scholar and several meta-analyses of published studies have concluded that antiviral therapy during the acute phase of HCV significantly reduces evolution to chronic hepatitis.4Alberti A. Boccato S. Vario A. Benvegnu L. Therapy of acute hepatitis C.Hepatology. 2002; 36: S195-S200Crossref PubMed Google Scholar In the most publicized trial to date, Jaeckel et al.5Jaeckel E. Cornberg M. Wedemeyer H. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (757) Google Scholar from Germany reported the results of their open label trial of a 24-week course of interferon alfa monotherapy to treat acute hepatitis C. Their dramatic finding that 98% of 44 acutely infected patients sustained a complete biochemical and virologic response to what would now be considered suboptimal therapy seemed to settle the controversy. Still, questions remained regarding the wisdom of treating all such cases, even those acutely ill, and calls went out for prospective, multicenter, randomized trials of adequate size and design4Alberti A. Boccato S. Vario A. Benvegnu L. Therapy of acute hepatitis C.Hepatology. 2002; 36: S195-S200Crossref PubMed Google Scholar, 6Orland J.R. Wright T.L. Cooper S. Acute hepatitis C.Hepatology. 2001; 33: 321-327Crossref PubMed Scopus (186) Google Scholar, 7Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl–Munda P. Gangl A. Ferenci P. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (183) Google Scholar with “larger number of patients … and an optimal regimen of therapy.”8Hoofnagle J.H. Therapy for acute hepatitis C.N Engl J Med. 2001; 345: 1495-1497Crossref PubMed Scopus (40) Google Scholar The report by Gerlach et al.9Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. Schraut W.W. Schirren C.A. Waechtler M. Backmund M. Pape G.R. Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar may be as close as we will ever come to a randomized controlled trial for the treatment of patients with acute hepatitis C infection. These investigators (interestingly, also from Germany) waited 7 years to identify 60 individuals with acute hepatitis C. They prospectively enrolled the patients in an observational study investigating the outcome of the natural course of infection in patients with acute hepatitis C in comparison to the outcome of antiviral treatment after acute hepatitis C. After the diagnosis of acute hepatitis C was established by conventional means, usually with documented seroconversion to anti-HCV, patients were informed of their options, including the evolving antiviral therapies that were becoming available during the 1990s. Because the cost of antiviral treatment was completely covered by national health insurance, the decision to treat was not influenced by financial considerations. Based on these conversations, 6 patients chose immediate antiviral therapy. Among the 54 untreated patients, therefore, the natural course of acute hepatitis C was studied. The study provides valuable insight into the immunology, clinical course, and treatment options of acute hepatitis C, and its epidemiology at the turn of the century. Of the 37 of 54 (68%) patients who initially cleared virus spontaneously, 13 patients relapsed and remained viral positive whereas 24 (44%) remained persistently viral negative (“self-limited”). Those with self-limited disease were far more likely to have symptomatic onset of disease (especially flu-like symptoms), whereas no patient who presented asymptomatically lost HCV RNA without treatment (P = 0.007). Antiviral therapy was commenced after 3 to 6 months following onset of symptoms and in 21 of 26 (81%) a sustained response was achieved, often, as in the Jaeckel study,5Jaeckel E. Cornberg M. Wedemeyer H. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (757) Google Scholar with interferon as monotherapy. The Gerlach study therefore supports the contention8Hoofnagle J.H. Therapy for acute hepatitis C.N Engl J Med. 2001; 345: 1495-1497Crossref PubMed Scopus (40) Google Scholar that a substantial proportion of patients with acute hepatitis C will lose virus spontaneously and not require expensive and toxic therapy. The findings of Gerlach et al. that antiviral intervention may be safely delayed in patients with acute hepatitis C will undoubtedly have medical legal implications and will affect practice guidelines, but the study has unavoidable limitations. The relatively small number of patients (although the highest number reported to date), the use of heterogeneous treatment regimens (necessitated by the protracted duration of the study and the advances in treatment over the past decade), and the selection bias toward symptomatic patients (although it is remarkable that so many asymptomatic acute cases were fortuitously diagnosed) unquestionably challenge the findings. Nevertheless, the desired large randomized prospective multicenter trial of acute hepatitis C that will definitively answer the many questions regarding this condition will likely never occur, and the reality is that practice guidelines must rely on such observational reports. An underlying question posed by this study is whether, by delaying therapy, the investigators were actually treating acute or, in reality, chronic hepatitis C. Among patients who cleared virus spontaneously, most did so within the first 12 weeks after the onset of symptoms, and no spontaneous viral clearance was observed after more than 16 weeks. Available evidence therefore suggests that the transition from acute, and potentially self-limited hepatitis C, to chronic disease occurs somewhere between 3 and 4 months after symptomatic onset. Whether one is now treating early chronic infection versus acute hepatitis may be a matter of semantics, but begs the question of whether shorter duration chronic hepatitis responds to therapy more favorably than longer duration disease. Certainly the very high reported sustained response rates in patients with acute hepatitis C, often with abbreviated or otherwise suboptimal therapy, corroborate the generic observation for chronic viral hepatitis in general that shorter disease duration, as opposed to treatment after decades of infection, is in fact a favorable response predictor. In the case of acute hepatitis B, for which antiviral therapy is rarely offered because of its low rate of chronicity, the definition of chronic hepatitis has generally been set, arbitrarily, at 6 months after disease onset. For hepatitis C, that number now appears to be 4 months. Thus, how early is too early and how late is too late? A recent report from Austria provides additional insight into which patients might benefit from early therapy. In this study of 12 consecutive patients with acute hepatitis C, Hofer et al.7Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl–Munda P. Gangl A. Ferenci P. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (183) Google Scholar likewise found that all patients with spontaneous viral clearance developed jaundice, whereas 2 of the 4 patients with viral persistence were anicteric. These investigators noted that, among those patients who cleared virus spontaneously, viral load declined fast and continuously. The study concluded that repeated measurement of serum HCV RNA levels is useful to identify patients with acute hepatitis C who will benefit from antiviral therapy, and suggested that individuals who fail to clear the virus within 35 days after onset of symptoms are the only patients with acute hepatitis C who are justified to receive therapy. While of intellectual interest, repeat viral load determinations, with its inherent cost and long turnaround times, is probably not practical in most clinical settings. The question remains, to treat or not to treat. The clinician tomorrow evaluating a newly diagnosed acute hepatitis C patient will still not know whether to treat with pegylated interferon alfa monotherapy or in combination with ribavirin, 24 weeks or 48 weeks, etc., but the option of delayed treatment following acute symptomatic hepatitis will now become acceptable, if not standard of care. The asymptomatic healthcare worker who becomes HCV RNA positive following a needle-stick injury will be disinclined to wait until the possible development of symptoms, and immediate therapy would seem appropriate. As pointed out by Alberti et al.,4Alberti A. Boccato S. Vario A. Benvegnu L. Therapy of acute hepatitis C.Hepatology. 2002; 36: S195-S200Crossref PubMed Google Scholar however, treating such patients before the onset of marked ALT elevations is theoretically counterproductive if an active host-immune response is required for successful antiviral therapy. The asymptomatic presenter may thus be subdivided into those detected by surveillance, within days of viral conversion, and those diagnosed fortuitously with biochemical hepatitis and anti-HCV seroconversion. For the acutely ill or jaundiced patient, realizing the subjectivity of the word “symptomatic,” introduction of potent antiviral therapy is no longer to be deemed urgent: watchful waiting, possibly with serial viral load determinations and antiviral therapy 3 to 6 months later,7Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl–Munda P. Gangl A. Ferenci P. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (183) Google Scholar is both practical and safe. Also noteworthy is the changing worldwide epidemiology of acute hepatitis C; in recent series, 20%–50% of cases occurred in a nosocomial setting.5Jaeckel E. Cornberg M. Wedemeyer H. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (757) Google Scholar, 7Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl–Munda P. Gangl A. Ferenci P. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (183) Google Scholar, 9Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. Schraut W.W. Schirren C.A. Waechtler M. Backmund M. Pape G.R. Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar In the report by Gerlach et al. 20 (33%) of the patients acquired their infection following recent hospitalization or medical procedure. The findings corroborate a recent case controlled study from Italy10Mele A. Spada E. Sagliocca L. Ragni P. Tosti M.E. Gallo G. Moiraghi A. Balocchini E. Sangalli M. Lopalco P.L. Stroffolini T. Risk of parenterally transmitted hepatitis following exposure to surgery or other invasive procedures results from the hepatitis surveillance system in Italy.J Hepatol. 2001; 35: 284-289Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar that found that invasive procedures, including endoscopy, indeed represent an important mode of HCV transmission. Several sporadic outbreaks of nosocomial acquired acute hepatitis C in the United States within the past 2 years11Meier B. Reuse of needle at hospital infects 50 with hepatitis C. The New York Times, 2002Google Scholar, 12Rabin R. Seeking source of hepatitis C. Investigation of infection in patient who had surgery at St. Francis. Newsday, 2003Google Scholar, 13Rabin R. Patients seek answer on surgeon who spread hepatitis. Newsday, 2002Google Scholar, 14Cardwell D. Patients of Brooklyn clinic are sought after outbreak of hepatitis C. The New York Times, 2001Google Scholar emphasize that the problem is not limited to Europe, and underscore the need for improving infection control practices in all types of health care settings.15Alter M.J. Prevention of spread of hepatitis C.Hepatology. 2002; 36: S93-S98Crossref PubMed Scopus (0) Google Scholar The elimination of the posttransfusion cohort that was described in earlier series, usually older ill patients with age-related and potential transfusion induced immunomodulation,16Gordon S.C. Does source of infection affect outcome in chronic hepatitis C?.Viral Hepatitis Rev. 1999; 5: 205-218Google Scholar may explain the higher proportion of symptomatic acute presenters now being reported. The shift to an otherwise healthy, younger group of patients may also explain the better overall outcome of acute infection, with or without therapy. Recent series5Jaeckel E. Cornberg M. Wedemeyer H. et al.Treatment of acute hepatitis C with interferon alfa-2b.N Engl J Med. 2001; 345: 1452-1457Crossref PubMed Scopus (757) Google Scholar, 7Hofer H. Watkins-Riedel T. Janata O. Penner E. Holzmann H. Steindl–Munda P. Gangl A. Ferenci P. Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load.Hepatology. 2003; 37: 60-64Crossref PubMed Scopus (183) Google Scholar, 9Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. Schraut W.W. Schirren C.A. Waechtler M. Backmund M. Pape G.R. Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar also make clear that acute sexually acquired hepatitis C is a real phenomenon: most of these patients were women, and most of the women in the Gerlach study became ill after having started a new sexual partnership with a chronically infected man. Additional information is needed that can elucidate the mechanisms of transmission in these rare but important cases. Also needed is clarification of risk factors for the substantial proportion of patients with acute hepatitis C (9%–23% in the recent series) who reportedly lacked recognized modes of transmission. The observation that the mode of presentation of acute hepatitis may influence disease outcome was first made in reference to hepatitis B.17Dudley F.J. Scheuer P.J. Sherlock S. Natural history of hepatitis-associated antigen-positive chronic liver disease.Lancet. 1972; 2: 1388Abstract PubMed Scopus (85) Google Scholar Immunosuppressed renal patients when infected were likely to develop chronic infection, whereas healthy hospital personnel developed florid acute attacks, but rarely progressed to chronicity. Patients with a fulminant course of hepatitis B experienced “complete recovery or death.”18Sherlock S. Diseases of the liver and biliary system. 5th ed. Lippincott, Philadelphia, PA1975: 414Google Scholar Among survivors of fulminant hepatitis B, seroconversion to anti-HBs occurred and such patients did not become chronic HBV carriers. Thus, “symptomatic disease” is a surrogate marker of the vigor of the immune response, and the concern is that the immune response weakens once chronic hepatitis evolves. Using this logic, antiviral intervention following acute infection, the sooner the better, has largely dictated clinical management of acute hepatitis C infection for the past decade. The report by Gerlach et al.9Gerlach J.T. Diepolder H.M. Zachoval R. Gruener N.H. Jung M.C. Ulsenheimer A. Schraut W.W. Schirren C.A. Waechtler M. Backmund M. Pape G.R. Acute hepatitis C high rate of both spontaneous and treatment-induced viral clearance.Gastroenterology. 2003; 125: 80-88Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar reinforces the observations of the past concerning outcomes of acute viral hepatitis, it sheds light on the epidemiology of acute hepatitis C in 2003, and it provides reassurance to clinicians that a prudent period of observation following acute symptomatic hepatitis C infection is a reasonable treatment strategy.
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