2006丙肝治疗（英文）-AGA

A so S of H de res pla len su th (H ne he pr me inf for ne ach eff ve he ate wi sh lem ate ma inc Am tec pr pr car wi ap tit intended to assist physicians and other health care workers in arriving at reasoned patient care decisions,2 are designed to be flexible rather than rigidly inflex- ibl th cas ph sta lin soc rel wh no jec be HC rec fre co an ch son rec pa Sp can wh can for co an rec co co sev asp for therapy. All candidates for antiviral therapy should be tested for HCV RNA with a quantitative amplifi- GASTROENTEROLOGY 2006;130:225–230 e universally applied “standards of care.” Although ese recommendations should be followed in most es, management decisions are left to the individual ysician and health care worker based on the circum- cation assay and should be tested for HCV genotype. Patients in whom antiviral therapy is being considered are candidates for liver biopsy, the gold standard for merican Gastroenterological As tatement on the Management epatitis C accounts for a sizable proportion of cases of chronic liver disease, liver disease aths, and cases of hepatocellular carcinoma and rep- ents the most common indication for liver trans- ntation. Projections based on the current preva- ce of infection and anticipated rates of progression ggest that the morbidity and mortality, as well as e medical care costs attributable to hepatitis C virus CV) infection, will escalate alarmingly during the xt 2 decades. The substantial clinical and economic impact of patitis C focuses attention on the critical need to event and control HCV infection. Public health asures, changes in behavior to avoid blood-borne ections, and screening of donated blood and organs HCV have reduced dramatically the frequency of w infections, and substantial progress has been ieved in antiviral therapy for hepatitis C. Applied ectively, contemporary antiviral therapy can pre- nt chronic infection in almost all persons with acute patitis C and can cure chronic liver disease associ- d with HCV infection in as many as half of patients th compensated, HCV-associated liver disease. In ort, hepatitis C is an important public health prob- whose consequences can be reduced by appropri- application of antiviral therapy. Because the de- nd for management of chronic hepatitis C has reased so considerably over the past decade, the erican Gastroenterological Association developed a hnical review1 and this medical position statement. This medical position statement, which contains actice guidelines intended for physicians, nurse actitioners, physician assistants, and other health e workers who participate in the care of patients th hepatitis C, includes suggestions for preferable proaches to the management of persons with hepa- is C. These guidelines, which are recommendations nces of the individual patient. As in previous guide- es issued by the American Gastroenterological As- ciation Medical Position Hepatitis C iation, specific recommendations are based on evant published information. Screening Routine screening of all asymptomatic adults, o have a low prior probability of HCV infection, is t recommended. Among high-risk groups (eg, in- tion drug users, persons who received a transfusion fore 1992 [when donor screening for antibody to V was introduced], persons with hemophilia who eived clotting factors before 1987, persons with quent percutaneous exposures, immigrants from untries with a high prevalence of HCV infection, d persons with clinical or biochemical evidence for ronic liver disease, even among asymptomatic per- s), diagnostic testing for HCV infection has been ommended by the US Public Health Service, expert nels, and professional medical specialty societies. ouses of persons with chronic hepatitis C are also didates for HCV serologic testing. Persons in om the diagnosis of hepatitis C is established are didates for hepatitis A and hepatitis B vaccines. Pretreatment Diagnostic Evaluation of Patients With Chronic Hepatitis C Persons with a reactive enzyme immunoassay antibody to HCV, the presence of HCV RNA, and mpensated liver disease are potential candidates for tiviral therapy. Currently, antiviral therapy is not ommended routinely for patients with hepatic de- mpensation; patients with a history of severe, un- ntrolled psychiatric disorder; and/or patients with ere hematologic cytopenias. Elevation of alanine aminotransferase (ALT) and artate aminotransferase levels is not a requirement © 2006 by the American Gastroenterological Association 0016-5085/06/$32.00 doi:10.1053/j.gastro.2005.11.011 de ten tie ME his me dis mo in me lik tre con lin to liv da pra of C by vir rib ap PE 1.5 ter tri alf vir 42 of PE cat th th me we (10 kg an do esp pa 2 a 80 th wh th wi ge ge ad rec tio nic or tak lev pa PE rin br ba PE tie RN liv sta or VI am res tol th off in Ta No Low Abs Du Age Lig No Adh Abs NO sta rela com 226 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 130, No. 1 termining histologic grade and stage, unless the po- tial for complications is unacceptably high. For pa- nts with moderate to severe fibrosis (Ishak stage �3, TAVIR stage �F2; please see technical review1 for tologic scoring systems), antiviral therapy is recom- nded uniformly. For patients with milder histologic ease, progression may be sufficiently slow to justify nitoring without imminent therapeutic intervention a proportion of these patients (see Treatment Recom- ndations). For patients with genotypes 2 and 3, the elihood of response is so high that the benefits of atment may outweigh the importance of histologic siderations; therefore, some authorities forego a base- e liver biopsy in patients with genotypes 2 and 3. Data support routine ultrasonography for localization of the er before liver biopsy are insufficient to justify man- ting prebiopsy ultrasonography in all cases and for all ctitioners regardless of levels of skill and experience. Treatment of Chronic Hepatitis C The current standard of care for the treatment previously untreated patients with chronic hepatitis is combination pegylated interferon (PEG-IFN) alfa subcutaneous injection once a week and oral riba- in daily. For patients with contraindications to avirin but who have indications for antiviral ther- y, PEG-IFN represents the best available treatment. Two PEG-IFN alfa preparations are available: (1) G-IFN alfa-2b, administered at a weight-based, -�g/kg dose, and (2) PEG IFN alfa-2a, adminis- ed at a fixed, 180-�g dose. Randomized controlled als (RCTs) have shown that combination PEG-IFN a and ribavirin therapy can achieve a sustained ologic response (SVR) in 54%–56% of patients: %–52% of patients with genotype 1 and 76%–84% those with genotypes 2 and 3. Whether one of these G-IFN/ribavirin regimens or weight-based modifi- ions of the 2 regimens will prove to be superior is e subject of ongoing trials. Predictors of response to erapy in these large RCTs are displayed in Table 1. The results of a single, large RCT support a recom- ndation that patients with genotype 1 require 48 eks of therapy with higher daily doses of ribavirin 00–1200 mg, depending on weight �75 or �75 ) (some clinicians may wish to adhere to the Food d Drug Administration–approved 800 mg daily se of ribavirin when used with PEG-IFN alfa-2b, ecially in patients who weigh �65 kg), while tients with the more treatment-favorable genotypes nd 3 can be treated for only 24 weeks and with only 0 mg of ribavirin daily. Moreover, 12 weeks of his da his erapy suffices in patients with genotypes 2 and 3 in om HCV RNA levels are undetectable at week 4. In e group of patients with genotypes 2 and 3, patients th genotype 2 are more likely than those with notype 3 to achieve an SVR; for patients with notype 3 who have high levels of HCV RNA or vanced fibrosis on liver biopsy, many authorities ommend treatment for 48 weeks. Pending addi- nal data, in patients with genotypes 2 and 3, cli- ians may wish to consider higher doses of ribavirin a longer duration of therapy on an individual basis, ing into account considerations such as high viral el, cirrhosis, or delayed response to therapy. For tients with genotype 4, 48 weeks of treatment with G-IFN alfa plus full-dose (1000–1200 mg) ribavi- is recommended. The potential added benefit of a oader range (800–1400 mg) of ribavirin weight- sed dosing as part of combination therapy with G-IFN is currently being studied. Therapy is indicated for previously untreated pa- nts with chronic hepatitis C, circulating HCV A, elevated aminotransferase levels, evidence on er biopsy of moderate to severe hepatitis grade and ge (METAVIR stage �F2, Ishak stage �3, septal bridging fibrosis), and compensated liver disease. Patients with milder histologic changes (META- R stage F1, Ishak stage �3) (and normal serum inotransferase activity; see following text) appear to pond as well as patients with more advanced his- ogic changes; such patients can be counseled about e reduced risk of disease progression but still can be ered therapy. If a decision is made to defer therapy patients with mild disease, periodic laboratory and ble 1. Predictors of Response to PEG-IFN Plus Ribavirin Therapy in RCTs Conducted in Previously Untreated, Immunocompetent Patients With Compensated Chronic Hepatitis C n-genotype 1 HCV RNA levels ence of cirrhosis/bridging fibrosis ration of therapy (for genotype 1) 40 years or younger hter body weight nblack ethnicity erence ence of steatosis on liver biopsy TE. Non-genotype 1 is the most influential predictor of response to ndard of care therapy with combination PEG-IFN plus ribavirin. The tive weighting of variables analyzed in RCTs of PEG-IFN/ribavirin bination therapy is presented in the technical review.1 tologic monitoring should be pursued; however, ta to support a recommendation on the frequency of tologic monitoring are wanting. co un tiv pa car co mu oth RN tit sp HC is EV go dis Po ab be ach res sp ap lim RN sho mo mo tro sti thy Ta ace dr nia Fo fic lat it ne tat of HC ing in va cie do pe pr tio lev pa no ap mi pa log wh In Ta Re F M E A H R D S V W S H P I I Re H C P S R G N D T January 2006 AMERICAN GASTROENTEROLOGICAL ASSOCIATION 227 Current contraindications to therapy include de- mpensated cirrhosis (see following text), pregnancy, controlled depression or severe mental illness, ac- e substance abuse in the absence of concurrent rticipation in a drug treatment program, advanced diac or pulmonary disease, severe cytopenias, poorly ntrolled diabetes, retinopathy, seizure disorders, im- nosuppressive treatment, autoimmune diseases, or er inadequately controlled comorbid conditions. Monitoring Response to Antiviral Therapy Baseline and 12-week monitoring of HCV A levels should be performed with the same quan- ative amplification assay. An early virologic re- onse (EVR), defined as a �2-log10 reduction in V RNA levels during the first 12 weeks of therapy, a valuable clinical milestone. In the absence of an R, the likelihood of an SVR is 0–3%. If the only al of therapy is to achieve an SVR, therapy can be continued after 12 weeks if an EVR is not achieved. tentially, histologic benefit can accrue even in the sence of an SVR; therefore, some authorities treat yond 12 weeks even in patients who have not ieved an EVR. For documentation of a virologic ponse at the end of therapy (end-of-treatment re- onse) or an SVR �6 months after completing ther- y, a more sensitive quantitative assay with a lower it of �50 IU/mL, if available, or a qualitative HCV A assay is recommended. Clinical and virologic monitoring during therapy uld be conducted at intervals ranging from once a nth to once every 3 months. Frequent hematologic nitoring is necessary to identify marked anemia, neu- penia, and thrombocytopenia; monitoring of thyroid- mulating hormone level is indicated to identify hypo- roidism or hyperthyroidism. Management of Side Effects of Antiviral Therapy Side effects of antiviral therapy are listed in ble 2. Flu-like side effects of IFN can be managed with taminophen or nonsteroidal anti-inflammatory ugs, sleep-promoting agents can be used for insom- , and antidepressants can be used for depression. r management of neutropenia, dose reduction suf- es, and the addition of granulocyte colony-stimu- ing factor is generally not recommended, although may be considered in individual cases of severe utropenia. Ribavirin is contraindicated in pregnancy, necessi- ing strict precautions and contraception in women th tra de childbearing age and their sexual partners and in V-infected men with female partners of childbear- age. Treatment with ribavirin should be avoided patients with ischemic cardiovascular and cerebro- scular disease and in patients with renal insuffi- ncy. If anemia occurs, options include ribavirin se reduction or the addition of erythropoietin. Approach to Other Patient Populations Normal aminotransferase activity. Patients with rsistently normal ALT levels generally do not ogress histologically, while responses to combina- n antiviral therapy in patients with normal ALT els are indistinguishable from response rates in tients with elevated ALT activity. Patients with rmal ALT activity are candidates for antiviral ther- y or for monitoring without intervention, as deter- ned on an individual basis and as influenced by tient factors such as motivation, genotype, histo- ic activity, and fibrosis. Cirrhosis. Patients with compensated cirrhosis o can tolerate therapy are candidates for treatment. patients with decompensated cirrhosis, antiviral ble 2. Side Effects of Antiviral Therapy lated to IFN lu-like symptoms arrow suppression (especially leukopenia and thrombocytopenia) motional effects (irritability, difficulty concentrating, memory disturbances, depression) utoimmune disorders (especially thyroiditis) air loss ash iarrhea leep disorders isual disorders (rarely retinal hemorrhages, especially in diabetic patients and hypertensive patients) eight loss eizures earing loss ancreatitis nterstitial pneumonitis njection site reactions lated to ribavirin emolytic anemia hest congestion, dry cough, and dyspnea ruritus inus disorders ash out ausea iarrhea eratogenicity erapy is not recommended; instead, referral for liver nsplantation is indicated. Although patients with compensated cirrhosis are not routine candidates for IF he do wi th ou ter in en th a r th ho is pa eff IF pa sta lon a r plu IF rib to ou me fre Ex low ba fac th sh div no no da cal sp lim dis era th ass an ati tri ma ad SV aft de me acu aft sp ma ter PE to rib ab he ini ad lis lik en au mo wo me me rev jun ran fol reg an clu vir an alc he con est pr un th cu ma th rib 228 AMERICAN GASTROENTEROLOGICAL ASSOCIATION GASTROENTEROLOGY Vol. 130, No. 1 N-based antiviral therapy, attempts to eradicate patitis C viremia with progressively escalated, low- se antiviral therapy before transplantation have met th limited, early success; however, data supporting is approach are insufficient to justify its adoption tside of clinical trials conducted at established cen- s by experienced investigators. Previous relapsers and nonresponders. Patients whom HCV RNA is undetectable during and at the d of therapy but reappears again after completion of erapy (relapsers) are likely to respond and experience elapse again with a subsequent course of the same erapy. The chance of achieving an SVR in relapsers, wever, may be as high as 40%–50% if re-treatment pursued with more effective therapy. If this group of tients is to be re-treated, ideally, a different, more ective regimen should be used. Therapy with PEG- N and ribavirin should be strongly considered for tients who experienced a relapse after a course of ndard IFN/ribavirin combination therapy, while a ger duration of therapy in patients who experienced elapse after 12 months of treatment with PEG-IFN s ribavirin is of unproven efficacy. For nonresponders to a previous course of standard N monotherapy, re-treatment with PEG-IFN plus avirin can increase the frequency of responsiveness approximately 20%; for nonresponders to a previ- s course of standard IFN plus ribavirin, re-treat- nt with PEG-IFN plus ribavirin can increase the quency of responsiveness to approximately 10%. pectations for responsiveness to re-treatment are er in patients with genotype 1, cirrhosis, high seline HCV RNA levels, and black ethnicity. Such tors, in addition to a patient’s tolerance to previous erapy and severity of underlying liver disease, ould be taken into consideration when making in- idualized decisions about the re-treatment of prior nresponders. Given the difficulty of clearing hepatitis C viremia, nresponder patients have been considered as candi- tes for long-term maintenance therapy. Hypotheti- ly, maintenance IFN alfa therapy in prior nonre- onders might retard the progression of fibrosis and it the progression of cirrhosis to end-stage liver ease and hepatocellular carcinoma. Therefore, sev- l large, multicenter RCTs of long-term (2–4 years) erapy with low-dose PEG-IFN are in progress to ess the effect of maintenance therapy on histologic d clinical end points in patients with chronic hep- tis C and advanced fibrosis. The results of these als will be required before recommendations can be de for chronic maintenance therapy in those with are plu sp vanced histologic fibrosis who fail to achieve an R. Acute hepatitis C. The risk of HCV infection er an accidental needlestick is sufficiently low to lay antiviral therapy until HCV infection is docu- nted virologically and biochemically. Patients with te hepatitis C are candidates for antiviral therapy er a period of observation to allow for potential ontaneous clearance. Case series have focused pri- rily on IFN or PEG-IFN monotherapy adminis- ed for 12–24 weeks. Although combination IFN or G-IFN/ribavirin has not been shown to be superior IFN monotherapy, conventional doses of PEG-IFN/ avirin combination therapy may represent a reason- le approach to treatment of patients with acute patitis C. In fact, the optimal regimen, dose, time to tiate therapy, duration of therapy, or benefit of ding ribavirin to IFN therapy has not been estab- hed, and the infrequency of acute hepatitis C will ely confound the prospective comparison of differ- t treatment regimens. Based on available data, most thorities would initiate treatment no later than 2–3 nths after presentation with acute hepatitis and uld extend therapy for at least 24 weeks. Injection drug or alcohol use. Therapy is recom- nded for recovered drug users, including those on thadone maintenance, and, based on a case-by-case iew, for active drug users, especially when in con- ction with drug treatment programs. Additional domized trials will be required to evaluate the lowing: the safest and most effective treatment imens; the levels of and factors favoring compli- ce; the risk of recidivism; side effect profiles, in- ding the risk of depression; and the effect of anti- al therapy on methadone requirements. Abstinence should be recommended before and during tiviral treatment in alcoholic persons, and treatment of ohol abuse should be linked with efforts to treat patitis C in alcoholic patients. A safe level of alcohol sumption in patients with hepatitis C has not been ablished. Hematologic disorders. The therapeutic ap- oach in this group of patients may depend on the derlying hematologic disorder. For example, in alassemic patients, primary therapy should be fo- sed on reducing iron overload. Chronic hepatitis C y be treated with PEG-IFN plus ribavirin, al- ough data supporting the safety and efficacy of avirin, at full or reduced doses, in these populations limited, because registration trials of PEG-IFN s ribavirin excluded patients with these disorders ecifically. In patients with a genetic predisposition to pr ma vid ab are tio bu log ma tre 3 y co ev an PE pa fin th tox ter tri 18 for th