This issue of the Journal features the revised Asia–Pacific Consensus Statements on hepatitis C virus (HCV) infection prevention, diagnosis, management and treatment.1 These guidelines have been developed by the region's hepatology society, the Asia–Pacific Association for the Study of the Liver (APASL). They update the original year 2000 consensus statements on prevention and management of hepatitis B and C in the Asia–Pacific region, also written by APASL in collaboration with the Journal.2,3 The present working party, co-chaired by Professors Geoff McCaughan (University of Sydney) and Masao Omata (Tokyo University), must be congratulated on undertaking and completing this ambitious set of statements, and presenting them to the Annual Scientific Meeting of APASL in Kyoto, Japan, on 27–29 March 2007. The need to revise the first set of consensus statements was foreshadowed when they were published in 2000.2,3 The emerging data on superior efficacy with long-acting (pegylated) interferon (peg-IFN) products indicated in 2000 that treatment paradigms would soon change, and in the next 2 years, other sets of hepatitis C management guidelines appeared,4–6 so revisitation of our region's guidelines is appropriate. The 20 experts who assembled in Singapore late 2006 to work on this project came from 11 different Asia–Pacific countries (from all geopolitical zones), and brought expertise from clinical practice, including pediatrics, clinical investigation, laboratory science and diagnostic technology, epidemiology and public health. This was required for tackling the huge range of issues addressed by these guidelines.1 In what way do the present revised statements differ from the JGH-APASL 2000 Guidelines on Hepatitis C, and how do they update management and diagnosis issues compared with French, European and US guidelines of 2002? One improvement is inclusion of a detailed section on laboratory testing. This is contemporary, and offers evidence-based, logical paradigms to make or refute the diagnosis of HCV infection based on initial antibody (anti-HCV) testing, followed by nucleic acid tests for HCV RNA when indicated. Cost-efficient diagnosis is the first step towards management and prevention of HCV infection in a region where mandatory testing of all blood donors may still not always be practiced (see below). The present statements also provide contemporary insights into the natural history of HCV infection, a matter of continuing refinement based on several studies conducted in Japan and Australia. There is recognition of the importance of acute hepatitis C, and refreshingly clear guidelines on what to do about it (Statements 3.1, 4.3, 4.4 and 4.7). This includes the need to confirm the diagnosis of acute HCV infection in high risk settings using HCV RNA detection, the interval (8–16 weeks) that is reasonable to defer treatment to allow for instances of spontaneous resolution, and the treatment options. The latter include high-dose standard IFN or weight-based peg-IFN, given for either 24 weeks (for genotype 1 HCV infection) or 12 weeks (genotype 3); ribavirin is not required. For chronic HCV infection, the factors that impact on clinical outcomes have been discussed with greater clarity than was possible in 2000 or 2002. The duration of HCV infection before cirrhosis and hepatocellular carcinoma (HCC) loom as substantive complications, and the rates of liver failure (hepatic decompensation) and HCC among those with established cirrhosis are iterated in Statement 3.4. This is novel and valuable, although the greater propensity of Japanese to HCC rather than liver failure as a disease outcome, compared to Europeans, is not mentioned.6–8 There is now strong evidence for roles of both prolonged, excessive alcohol intake and obesity/insulin resistance in accelerating fibrotic progression of chronic hepatitis C. This has implications for patient management (Statement 3.3). Finally, there is a statement based on level II (perhaps even level I) evidence that a sustained viral response (SVR) to antiviral therapy impacts positively on the natural history of HCV-related cirrhosis; it largely prevents the ultimate disease complications of liver failure and HCC. One could quibble with Statement 3.5, that the rate of decompensation at 5 years after SVR is still 1%; instances of HCC occurring after SVR are infrequent, except in Japanese men over the age of 60 years with other risk factors for cirrhosis and HCC,9,10 but instances of hepatic failure do not seem to have been reported.7 A disappointing feature of the 2007 statements is the lack of new data and recommendations on prevention of HCV infection compared with the 2000 document.1,3 This may reflect the dearth of good epidemiologic studies of HCV transmission in Asia since the introduction of universal screening of blood donors and introduction of universal precautions against medical spread of blood-borne viruses. The fact that this revision of the guidelines calls for screening of blood donors (Statement 2.1) seems to indicate that such is still not always the case; yet “clean blood”, like clean water, should now be among the most basic requirements for restoring human health in the face of disease. It would be admirable to see APASL and similar bodies working with the World Health Organization and non-government agencies to ensure that this sad neglect is addressed by appropriate targeting of financial and technical resources, as well as laboratory training. Meanwhile, perusal of the pages of the Journal and elsewhere reveals that the epidemiology of HCV infection in the Asia–Pacific region, while it has differed from countries like Egypt and the USA in the past,11,12 now has striking similarities to Europe and North America. As in the USA and Europe,4–6 injection drug use (IDU) is now by far the most important mode of HCV transmission in Australia and New Zealand, accounting for more than 90% of new cases.13 IDU has also become the predominant mode of HCV transmission in Asia, and in areas such as southern China coinfection with HIV is common.14–16 One interesting difference is the pattern of HCV genotypes. Thus, in Japan, there is a much higher proportion of genotype 2 than genotype 1b infections in young male blood donors and people with IDU compared to older HCV-infected patients,17 and in southern China and Hong Kong there are very high rates of genotype 6 infections in HIV-coinfected people with IDU.14,16 If we are to make any progress in prevention of HCV infection, the second most important cause of cirrhosis and HCC in this region, we need to recognize how transmission is currently occurring. More contemporary analysis of the value of harm reduction strategies, including the special instance of HCV transmission in prisons,18 would be appropriate subjects for a next revision of these guidelines. On a more positive aspect, the approach to antiviral therapy has been constructively revised. The changing need for (or not) of liver biopsy (Statement 4.2), and specifically the appropriateness of treating patients without knowing the fibrotic stage of the disease, at least under some circumstances, is acknowledged for the first time in HCV guidelines, although it has been reviewed elsewhere.6 In addition to liberalization of access to treatment by abolishing the mandatory requirement for liver biopsy, Statement 4.9 affirms that treatment is indicated for those with fibrosis (F) stage 1; earlier recommendations are more restrictive (F2 or worse).3,5 The place of alanine aminotransferase (ALT) (normal vs raised) is also addressed (Statement 4.8), and is more explanatory than the earlier recommendation that those with normal ALT should generally not be treated; some of the evidence has been published recently in the Journal.19 The suggested treatment algorithm for genotype 1 HCV (Statement 4.13) as peg-IFN and ribavirin for 48 weeks is now standard of care worldwide, although it could have been useful to spell out the weight-based doses of ribavirin that are usually recommended for this genotype.3–6 These are partly discussed in the preamble, but do not consider the smaller stature of Asians, who often weigh less than 65 kg, and for whom a dose of 800 mg/day is usually regarded as sufficient.5,6 Similarly, with treatment of “responsive” HCV genotypes 2 and 3, the dose of ribavirin could be specified because lower standard doses (800 mg daily) rather than weight-based ones produce equivalent SVR.20 The “12-week stopping rules” according to early viral response (EVR) are now standard of care.4–6 However, a laudable aspect of the new APASL guidelines is a new rule for rapid viral response (RVR) that permits truncation of the treatment course to 24 weeks in some instances of genotype 1 infections. In the future, it may also be worth considering whether RVR should be considered in genotypes 2 and 3, for which no recommendation for viral monitoring during treatment is made, although the evidence for truncation of treatment to 16 weeks in such cases remains controversial. Likewise, determining whether or not EVR is complete could be valuable for cases of these usually treatment-responsive genotypes in which suboptimal SVR to 24 week combination therapy can be anticipated because of insulin resistance.21 In such instances, the value of more prolonged therapy (36–48 weeks) should be studied. Genotypes 4, 6 and 7/8 have not been mentioned in these statements, presumably because evidence is incomplete, but they are common in the broader Asia–Pacific region (including the Middle East) and would be a useful subject for future recommendations. One aspect not usually considered in HCV treatment guidelines is the importance of treatment context—the need for ready access of patients and their families to support services that include nurse specialists, counselors and psychological medical services,22–24 among others. Audits of HCV antiviral treatment outcomes have concluded that such services are now an essential part of managing people affected by this common disease.24 They also allow access to treatment services for subgroups that, until recently, were considered untreatable: those using drugs by injection,23 and those in prisons.4,18 There is no reason why Asia should lag behind in these aspects, because the best results for antiviral therapy of HCV infection come when such supports are in place to ensure continued compliance with therapy, and appropriate dose adjustment or other treatment of side-effects so as to ensure completion of therapy.6,23,24 The new APASL Statements include an excellent contemporary overview about issues of liver transplantation for patients with decompensated cirrhosis or HCC attributable to HCV infection. Although management in the transplant setting is a highly specialized topic, all those treating HCV-infected persons need to keep abreast of these developments, so as to muster our strongest attempts to prevent the need for transplantation by optimal antiviral therapy, and also to ensure timely consultation and referral when treatment has failed or is likely to be dangerous. HCV also plays an important role in renal disease. In addition to causing some glomerular diseases and cryoglobulinemia, rates of HCV infection in dialysis units across the Asia–Pacific region remain extraordinarily high. In Japan and Australia, nosocomial spread of HCV has also been observed in outpatient clinics.25 The role of universal precautions to prevent spread in dialysis units, and the importance of infection of staff in nosocomial transmission are addressed in Statements 5.2. Statement 5.2.4 provides guidance on antiviral therapy against HCV-infected patients with renal failure, the value of liver biopsy, the contraindication of ribavirin and utility of IFN-based mono-therapy. More detail about dosage of IFN among renal failure patients, who experience a high rate of treatment side-effects such as weight loss, and the possibility of using the more potent peg-IFN products, as recommended by the French guidelines and reinforced by a recent report in the Journal,5,6,26 could be considered in future. The last sections of the APASL Statements give due consideration to HCV and its treatment in thalassemia, hemophilia and children, management of those infected with both HBV and HCV, and extrahepatic manifestations of HCV infection. These are important issues that challenge clinical care across the region,27,28 so it is helpful for APASL to have addressed them. Of necessity, the present guidelines must be considered a work-in-progress rather than a set of authoritative, evidence-based statements on these subjects; hopefully, the present Statements will stimulate further research to generate the sort of evidence needed for refinement of guidelines. Likewise, advances in treating HIV-HCV coinfected persons are now coming rapidly, and much clearer guidelines than hitherto promulgated by regional liver societies are presented here.1,4,5 One additional possibility mentioned by European authorities in this field5,29 is to consider HCV antiviral therapy earlier in those HIV-infected persons with preserved CD4 lymphocyte counts who do not yet require antiretroviral therapy. Not only might this produce higher SVR before the onset of immunodeficiency, it reduces the chances of later hepatotoxicity from highly active antiretroviral therapy (HAART) by up to an order of magnitude, particularly for genotype 3 HCV infections.29 In conclusion, the determination of APASL and its President, Professor Omata, to revise these statements on diagnosis, management and treatment of HCV infection is timely; they clarify and endorse new standards of care for the tens of millions of patients in our region infected with HCV. The APASL Statements enter new territory in HCV guidelines by considering the impact of this blood-borne virus infection in such a diverse range of contexts—children, viral co-infections, extra-hepatic manifestations, and the kidney and blood disorders that are common across Asia. Indeed there is more progress to be made in optimal delivery of therapy, particularly in places where it is most needed and least afforded, a topic of recent international media commentary.30 Actions identified for prevention in 2000 have been implemented in several countries, such as Bangladesh, which have introduced universal screening of blood donors in the last few years, but the cry for cooperative research on prevention and better management across the Asia–Pacific region has not yet been heeded conspicuously.2 With a re-invigorated APASL to initiate such studies, and with a regional charitable trust (the JGH Foundation) to help fund them,31 there has never been a better time for concerted action against HCV infection in the Asia–Pacific region.
No takes yet. Share an insight, caveat, or question.
Geoffrey C. Farrell (2007) studied this question.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: