2012+APASL+丙型肝炎病毒感染共识和治疗程序

GUIDELINES APASL consensus statements and management algorithms for hepatitis C virus infection Masao Omata • Tatsuo Kanda • Ming-Lung Yu • Osamu Yokosuka • Seng-Gee Lim • Wasim Jafri • Ryosuke Tateishi • Saeed S. Hamid • Wan-Long Chuang • Anuchit Chutaputti • Lai Wei • Jose Sollano • Shiv Kumar Sarin • Jia-Horng Kao • Geoffrey W. McCaughan Received: 14 September 2011 / Accepted: 21 January 2012 � Asian Pacific Association for the Study of the Liver 2012 Abstract The Asian Pacific Association for the Study of the Liver (APASL) convened an international working party on the ‘‘APASL Consensus Statements and Man- agement Algorithms for Hepatitis C Virus Infection’’ in December, 2010, in order to revise ‘‘Asian Pacific Asso- ciation for the Study of the Liver consensus statements on the diagnosis, management and treatment of hepatitis C virus infection (J Gastroenterol Hepatol 22:615–633, 2007)’’. The working party consisted of expert hepatolo- gists from the Asian-Pacific region gathered at Makuhari, Chiba, Japan on 19 December 2010. New data were pre- sented, discussed and debated to draft a revision. Partici- pants of the consensus meeting assessed the quality of cited studies. Finalized recommendations are presented in this review. Keywords APASL � DAAs � Guideline � HCV � Treatment Laboratory testing for HCV infection and fibrosis Serologic assays Exposure to hepatitis C virus (HCV) is usually determined by testing for specific antibodies (anti-HCV antibodies) by using an approved enzyme or chemiluminescent immunoassay M. Omata (&) Yamanashi Prefectural Central Hospital, 1-1-1 Fujimi, Kofu-shi, Yamanashi 400-8506, Japan e-mail: momata-tky@umin.ac.jp M. Omata � R. Tateishi The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan T. Kanda � O. Yokosuka Graduate School of Medicine, Chiba University, Chiba, Japan M.-L. Yu Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan M.-L. Yu � W.-L. Chuang Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan S.-G. Lim National University Hospital, Singapore, Singapore W. Jafri � S. S. Hamid The Aga Khan University, Karachi, Pakistan A. Chutaputti Pramongkutklao Hospital, Bangkok, Thailand L. Wei Peking University People’s Hospital, Beijing, China J. Sollano University Santo Tomas Hospital, Manila, Philippines S. K. Sarin GB Pant Hospital, Delhi, India J.-H. Kao National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei, Taiwan G. W. McCaughan Royal Prince Alfred Hospital, Centenary Institute, University of Sydney, Sydney, Australia 123 Hepatol Int DOI 10.1007/s12072-012-9342-y (EIA or CIA). However, antibodies might not be detectable in the first few weeks after initial infection (window period), in patients who are immunosuppressed or in patients in whom resolution of HCV infection occurs over many years [1–7]. Recently, commercial HCV core antigen assays, which show a good correlation with HCV RNA assays, have become available. In some circumstances, these might be an alternative to HCV RNA assays, but due to limited sensitivity, the major role of these assays might be in the identification of blood donors in the seroconversion win- dow. The detection limits of the HCV core antigen assay kit of Ortho Diagnostics and Abbott Diagnostics are 44 and 3 fmol/L, respectively. These assays are currently expen- sive and available in limited countries, but might be available in Asian countries in the near future [8–11]. Molecular assays HCV genotyping HCV genotyping is helpful in epidemiologic studies and necessary for clinical application of personalized therapy for chronic hepatitis C (CHC) [7]. Currently, HCV has been classified into six major genotypes, which can be further divided into subtypes. Genotypes 1, 2, and 3 are widely distributed in the Asia-Pacific region, whereas genotypes 4 and 6 are mainly restricted to the Middle-East and Southeast regions, respectively [12, 13]. Pegylated interferon (peginterferon) plus ribavirin combination therapy has been the standard of care (SOC) for treatment of CHC, and improved outcomes have been achieved using genotype- and response-guided therapy by determination of virus genotype and on-treatment viro- logical responses. A new generation line probe assay designed with both 50 UTR and core-specific oligonucleotides has been shown to overcome the inability to distinguish HCV genotype 6c-l [14, 15]. Qualitative HCV RNA testing HCV RNA is used in determining acute or chronic infection, assessing anti-HCV indeterminate samples, and monitoring and assessing responses to antiviral therapy. HCV RNA testing should be strongly considered in patients at high risk of infection, but who might be anti-HCV negative or inde- terminate because they are in the early phase of acute HCV infection or are immunosuppressed (such as patients on hemodialysis or with HIV infection). The assays used for qualitative HCV RNA testing included end-point PCR and transcription-mediated amplification (TMA) with detection limits of 50 and 10 IU/ mL, respectively. Although negative TMA results were more predictive of sustained virological response (SVR), a single positive TMA result should be interpreted with caution, because patients with positive TMA results may achieve SVR [16]. Recently, with the introduction of more sensitive quantitative real-time PCR assays, qualitative assays may be no longer needed. Quantitative HCV RNA testing HCV viral loads do not appear to be associated with dis- ease activity and progression to chronicity. One study has indicated an association between HCV viral loads and development of hepatocellular carcinoma (HCC) in a pro- spective community-based cohort [17]. Notably, viral load has been shown to be a prognostic indicator of therapy outcome. Monitoring viral load during therapy has also proven useful in individualized HCV therapy. Response-guided therapy based on on-treatment virological responses could provide information about optimal treatment durations and help maximize cost- effectiveness and minimize adverse events [18–22]. A recent study has shown that HCV RNA levels after 4 weeks of peginterferon plus ribavirin therapy (lead-in period) could predict not only treatment outcome, but also the development of drug resistance with subsequent addi- tion of a protease inhibitor to the treatment regimen [23]. Recently introduced real-time PCR assays with a broad dynamic range of quantification are sensitive, specific, precise, and reproducible. Cobas Ampliprep/Cobas Taq- Man is the first FDA-approved real-time PCR assay. However, wide application of this assay requires careful monitoring of HCV-4-infected patients because the assay might underestimate HCV RNA levels in HCV-4-positive samples [24, 25]. Highly sensitive assays have been reported, such as the VERSANT HCV RNA Qualitative Assay (HCV Qual [TMA], Siemens Healthcare Diagnostics, Saint Denis, France) with a detection limit of 9.6 IU/mL and TaqMan 2.0 assay (Roche Diagnostics) with limits of quantification and detection of 25 and 9.3 IU/mL, respectively [26, 27]. Another real-time PCR assay, Abbott Real-Time HCV assay (RealTime HCV; Abbott Molecular, Des Plaines, IL, USA) with limits of quantification of 12 IU/mL, has been approved by FDA for on-treatment monitoring of HCV RNA levels as an aid in the management of HCV therapy [28]. These assays will be useful in clinical practice in Asian countries. Dried blood spots Poor uptake of HCV test materials in injecting drug users (injection drug users; intravenous drug users: IDUs) is Hepatol Int 123 problematic. Dried blood spots (DBSs), which are sampled using a disposable lancet and stable at room temperature, could be employed as first-line diagnostic specimens and are suitable for diagnostic as well as surveillance purposes, especially when freezing equipment is not available. DBS sampling could enhance the public health surveillance of HCV among IDUs and might allow differentiation between individuals with cleared infection, ongoing infection, and recent infection. However, DBS nucleic acid amplification technology (NAT) is not recommended for monitoring treatment responses, because of a tenfold reduction in viral loads yield [29, 30]. Assessment of liver fibrosis Assessment of liver fibrosis is important clinically for decision making. Although liver biopsy remains the ‘‘gold standard’’ to assess liver fibrosis, alternative noninvasive approaches to liver fibrosis have assumed great importance. These include [31, 32]: • Noninvasive imaging (e.g., transient elastography). • Noninvasive blood marker panels (e.g., aspartate ami- notransferase–platelet ratio index (APRI), FibroTest, FIBROSpect II, Hepascore, FibroMeter, and FibroFast). Although noninvasive markers and transient elastogra- phy are useful for identifying only those patients with no fibrosis or with advanced fibrosis, a stepwise algorithm incorporating noninvasive markers and/or transient elas- tography may enhance the accuracy of diagnosis and reduce a significant number of liver biopsies [33–35]. Furthermore, accumulating data provide evidence that noninvasive methods of assessing liver fibrosis can be applied at a single point or repeatedly to provide prog- nostically meaningful distinctions in predicting clinical outcomes, with and without antiviral therapy, in CHC patients [36–41]. Algorithm incorporating noninvasive methods for clinical practice remains to be established. Consensus statements: HCV infection and laboratory testing 1. Anti-HCV antibody testing should be conducted with approved anti-HCV third- or fourth-generation EIA or CIA (II-2)*. 2. Samples that test negative with an approved EIA/CIA can be reported as anti-HCV negative. However, it should be noted that individuals on hemodialysis or those coinfected with HIV might be HCV RNA positive, but anti-HCV negative (II-2). 3. Samples reactive in an approved single EIA can be reported as anti-HCV positive, provided the signal- to-cutoff ratio is sufficiently high to be predictive of a true positive (III). 4. For samples that do not reach this threshold or have reactivity close to the cutoff, a sensitive HCV RNA test should be considered and/or a further follow-up sample be obtained for both anti-HCV and HCV RNA NAT (III). 5. HCV RNA testing requires appropriate contamina- tion controls (II-2). 6. A dedicated sample/aliquot not derived from other test samples is preferred for HCV RNA testing (II-2). 7. HCV RNA quantitation should be reported in IU/mL (optional to include copies/mL) (III). 8. Monitoring of HCV loads during treatment is important for response-guided therapy to determine treatment protocol and duration (I). 9. HCV genotype testing is important for assessing treatment duration and efficacy of antiviral therapy. The use of primers targeting both the 50 UTR and core region is recommended to distinguish some of the genotype 6 subtypes, prevalent in Southeast Asia, from genotype 1 or 1b (II-2). 10. Participation in an external quality assurance program for all testing is ideal (II-2). 11. Internal quality assurance testing is required for all testing (II-2). 12. Testing DBSs that are sampled with a disposable lancet and are stable at room temperature could enhance the public health surveillance of HCV among IDUs (II-2). 13. Noninvasive methods for liver fibrosis are useful for identifying patients with no fibrosis or advanced fibrosis and can provide prognostically meaningful distinctions in predicting clinical outcomes in CHC patients. A stepwise algorithm incorporating nonin- vasive methods may enhance the accuracy of diag- nosis and reduce a significant number of liver biopsies (II-2). *Numbers in parentheses refer to levels of evidence [5]. EIA enzyme immunoassay, CIA chemiluminescent immu- noassay, DBS dried blood spot. The original guidelines were published in [7]. Points 1, 2, 4, 5, 6, 8, 9, 12, and 13 are revised or new recommendations. Prevention of HCV infection The World Health Organization estimates that as many as 170 million persons worldwide might be infected with HCV [42], with prevalence in Southeast Asia at 2.2% and in the Western Pacific at 3.9% [42]. However, these are Hepatol Int 123 crude estimates with significant differences in prevalence rates within provinces even in the same country. True prevention of HCV can only be achieved with an effective prophylactic vaccine, but vaccine trials are in the early phase or in progress [43]. Consequently, the current objective of HCV prevention is to reduce trans- mission through identification and reduction of risk fac- tors. Transmission risk stems from inoculation through the skin or mucous membranes; thus, certain types of risk groups should be identified, such as people with skin or mucous membrane inoculation, or with exposure of bro- ken skin to contaminated blood (household contact, dental work) [44]. In the developing world [45, 46], blood transfusion and intravenous drug use are important, but additional trans- mission groups include acupuncture, body piercing, unsafe injection practices, and familial transmission. Blood safety In 1992, the introduction of second-generation anti-HCV ELISA largely eliminated HCV transmission by screening out infected donors. Nucleic acid testing has reduced the risk of HCV transmission to 0.1–2.33 per million donations [47, 48]. However, the Global Database on Blood Safety shows that testing with anti-HCV ELISA is insufficient, particularly in countries with low human development index—only 51.3% of units of blood are tested for HCV [49]. IDUs Globally, there is variation in the estimated HCV preva- lence rates among IDUs—10–100% in South and Southeast Asia, and 34–93% in East Asia and the Pacific region [50]. In a systematic review, Hagan et al. [51] found no clear association of HCV prevalence with duration of injection use or with age of users. Further, an increased risk of HCV infection was found in non-injecting drug users with the following risk factors: sharing of inhalation tubes for crack cocaine (adjusted odds ratio 3.6, 95%CI 1.3–9.8), presence of tattoos (adjusted odds ratio 3.5, 95%CI 1.3–9.1), and age [34 years (adjusted odds ratio 3.9, 95%CI 1.3–11.6) [52]. Since HCV can be transmitted via needles and syringes as well as drug preparation equipment, a key question was whether the provision of sterile injecting equipment was effective in reducing transmission. A review of meta- analyses concluded that there was insufficient evidence that such interventions were effective [53]. Although the rela- tive risk of HCV infection associated with drug preparation equipment was between 2.0 and 5.9, there exists the limi- tation of the ‘‘sterility’’ from needle and syringe exchange programs [54]. Hemodialysis Hemodialysis units are notorious for HCV outbreaks that are almost certainly attributable to safety breaches [55]. The Centers for Disease Control (CDC) have issued rec- ommendations for infection control in such units [56], but a survey of practices revealed that compliance with these recommendations was suboptimal [57]. Absence of de novo HCV infections in hemodialysis units can, however, be achieved by strict adherence to universal hygiene pre- cautions [58]. Medical procedures According to the Hep-Net acute HCV database, 15% of acute HCV infections are due to medical procedures, while another 13% are caused by needlestick injuries [58]. Such outbreaks are inevitably due to breach of standard safety precautions [49] and involve multi-vial sampling, capillary blood sampling, surgical procedures [59], gastrointestinal endoscopy [60], radiopharmaceuticals [61], and oncology procedures. Unsafe injection practices This is a poorly documented field, but very important in the developing world. A list of unsafe injection practices has been summarized by Kermode [62]. In a meta-analysis, unsafe injection practices were found to be widespread in the developing world and accounted for [50% of injec- tions. Moreover, in Asia, 82% of injections administered were considered unnecessary [63, 64]. Other practices A meta-analysis showed that body piercing was associated with an odds ratio of 1.7–2.7 of acquiring HCV [65]. Another meta-analysis of 124 studies showed that tattooing [66] carried an odds ratio of 2.8 (95%CI 2.4–3.2) of acquiring HCV. Finally, a meta-analysis of acupuncture studies [67] showed a modest risk of HCV infection with odds ratio of 1.3–3.3 with a possible relationship to having more than ten sessions. Familial, sexual, and perinatal transmission A meta-analysis [68] showed that the odds ratio of HCV transmission to the siblings and household contacts of HCV-infected chronic liver disease patients was 9.8 (95%CI 0.9–ad infinitum), while that to the offspring of Japanese HCV carriers was 1.8 (95%CI 1.2–2.6). Male Hepatol Int 123 partners seemed to be more susceptible than female part- ners of HCV-infected males (odds ratio, 20.5; 95%CI 6.1–84.1). The vertical transmission rate was 6.2% in a cohort study of 1,787 mother–child pairs, and cesarean section was not protective [69]. This was confirmed in a meta-analysis [70]. The sexual transmission risk is con- troversial, and a meta-analysis [71] showed no risk in stable heterosexual relationships, but increased risk in those with multiple sexual partners and in HIV-positive gay men. A large sero-epidemiological study of 1,527 female commercial sexual workers from Korea reported an HCV prevalence of only 1.4% with no increased risk due to sexual activity [72], while in a study of 1,699 non-IDU gay men, only 1.5% tested anti-HCV positive, suggesting no increased risk in non-IDU gay men [73]. Consensus statements: prevention of HCV infection 1. All countries must introduce universal screening of blood donors for anti-HCV antibodies, with third- or fourth-generation EIA or CIA*. Regular audit proce- dures should be implemented to ensure compliance at blood-testing facilities. More data on the cost-effec- tiveness of nucleic acid testing for universal screening of blood products is required (II-2). 2. In health-care settings, adherence to universal precau- tions for infection control is essential. Regular audit procedures should be implemented to ensure compli- ance. These should include use of disposable or adequately sterilized materials for invasive procedures, and adequate cleansing and sterilization of instruments (II-2). 3. As transmission of HCV via IDUs is an increasing trend in the Asia-Pacific region, effective strategies to reduce HCV transmission in this group should be explored. Persons undergoing skin/mucosal penetrat- ing procedures such as body piercing, tattooing, and acupuncture should be advised on the increased risk of HCV transmission (II-2). 4. The risk of sexual transmission is unclear, but the use of barrier contraception to reduce potential transmis- sion may be prudent in those who have multiple sexual partners (III). 5. Unnecessary and unsafe injection practices are widely used in the developing world. It is important to reduce unnecessary injections (II-2) and carry out injections using recommended safe procedures. *EIA enzyme immunoassay; CIA chemiluminescent immunoassay; IDU injection drug user, injecting drug users, or intravenous drug user. The original guidelines were published in [7]. All the above points are revised or new recommendations. Natural history of HCV infection Acute HCV infection In the USA, approximately 17% of all new cases of HCV per year present as symptomatic acute hepatitis, based on estimates