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MANAGEMENT O F V I R A L H E PAT I T I S

:
A CANADIAN CONSENSUS CONFERENCE 2003/2004

Funding for this publication/multimedia project was provided by Health Canada and Correctional Service Canada. The opinions expressed in this publication are those of the authors/researchers and do not necessarily reflect the official views of Health Canada or of Correctional Service Canada.

Address for Correspondence:

Morris Sherman

Toronto General Hospital 200 Elizabeth Street Toronto, ON M5G 2C4 Tel: (416) 340-4756 Fax: (416) 591-2107 Email: morris.sherman@uhn.on.ca

© Morris Sherman MB BCH PhD, FRCP(C), University of Toronto; Vincent Bain MD FRCP(C), University of Alberta; Jean-Pierre Villeneuve MD FRCP(C), University of Montreal; Robert P. Myers MD FRCP(C), University of Calgary; Curtis Cooper MD FRCP(C), University of Ottawa; Steven Martin MD FRCP(C), University of Montreal; Catherine Lowe MD FRCP(C), Queen's University. Cat. Number: H39-4/39-2004 ISBN: 0-662-68145-2 Publication Number: 4409

In collaboration with:

Canadian Association for the Study of the Liver

Association of medical Microbiology and Infectious Disease Canada

Canadian Association of Hepatology Nurses

Canadian Viral Hepatitis Network

MANAGEMENT OF VIRAL HEPATITIS:
A CANADIAN CONSENSUS CONFERENCE 2003/2004

Prepared by: Morris Sherman MB BCH PhD, FRCP(C), University of Toronto, Vincent Bain MD FRCP(C), University of Alberta, Jean-Pierre Villeneuve MD FRCP(C), University of Montreal, Robert P. Myers MD FRCP(C), University of Calgary, Curtis Cooper MD FRCP(C), University of Ottawa, Steven Martin MD FRCP(C), University of Montreal, Catherine Lowe MD FRCP(C), Queen’s University.

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................................................................................................................... 15 Pegylated interferon .................... 14 Interferon in HBeAg-positive patients ............................................................................... 14 Lamivudine in HBeAg-negative patients.............................................................. 17 Special situations .......................................................................... 15 Hepatitis B in children ................................................ 15 3 . 13 Prevention of hepatitis B virus infection...................................................................................................................................................................................................................................................................... 13 Treatment of chronic hepatitis B.................................................................................................................................................................................................................................................................................................................................................................................................. 14 Lamivudine in HBeAg-positive patients...................................................................................................................................... 6 Conference program................................. 9 Introduction.................................................... 16 Chemotherapy and bone marrow transplant (BMT) ................... 13 Hepatitis B and hepatocellular carcinoma ...................................................... 16 HIV-HBV co-infection................................................................................................................................................................................. 16 Renal transplant candidates... 15 Adefovir dipivoxil....................................................................................................................................................................... 7 Preamble................................................................................................................................................... 13 How to assess response to treatment?.................................................................................................................. 5 Members of the conference organizing committee ..........................................................................................................................................................................................................M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Table of Contents Acknowledgements ........................................................................................................................... 14 What treatment should be used?............................................................ 15 Pregnant women .................... 16 HBV-HCV co-infection.......... 14 Interferon in HBeAg-negative patients. 13 Who should be treated? ................. 16 Decompensated cirrhosis ...................................................................................................... 11 HEPATITIS B............................................................................................ 13 Initial assessment........................................................................................................................................................................................................................................................................................

................................................................................................................................................................................................34 Table 1.....................................................................................................................22 Extrahepatic manifestations of hepatitis C ......................21 Early virological response (EVR)........................................................................................................................................................................................................................................................23 Conclusions ....26 Tables .........................................................................................................................................25 References..............................................................................................................22 Renal impairment and renal transplantation.......................24 Use of antiretrovirals..........................................................23 Children with chronic hepatitis C....................................................................................20 Normal ALT .................................................................................19 Initial assessment ............................................24 Adjuvant therapy....................................................................... Contraindications to antiviral treatment.......................21 Cytopenias.................................................................................................................................................................................................................................................................................................25 Addendum ................................................................................21 Acute hepatitis C .....................25 Vaccination................................................................................................................................................................................................................................19 Choosing patients for antiviral therapy ...........................19 Drug treatment ..........23 Treatment environment............................................................34 Table 2..........................M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 HEPATITIS C............ Grading system for ranking recommendations and clinical guidelines .............................................................................................................................................................................................................................................................................................20 Evaluation and monitoring during treatment .........................................................................................................................................................................................................................................25 4 .....................................25 Transplantation.........................35 Screening and investigations.....................................22 Re-treatment of patients.24 Hepatitis C drug therapy......................................................................21 Special situations..............................................................................................................24 Which therapy first.....................................................................................................................................................................................................................................................................................................................................................................................................................21 Cirrhosis ...............................................23 HIV-HCV co-infection.............................................................................................................................................................................

5 . Dr. who provided the very latest information about the efficacy of anti-HCV therapy in HIV co-infected patients after the conference and as soon as it was available. David Wong. and Dr.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Acknowledgements The authors would like to thank Dr. Steve Shafran. Marina Klein.

Stephen Shafran Canadian Viral Hepatitis Network Dr.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Members of the conference organizing committee Canadian Association for the Study of the Liver Dr. Mel Krajden Canadian Association of Hepatology Nurses Vera Simon Correctional Service Canada Dr. Morris Sherman Warren Hill PhD British Columbia Centre for Disease Control Dr. Dr. Francoise Bouchard Josephine Muxlow Health Canada Dr. Winnie Wong Vince Bain Marc Deschênes Sam Lee Association of Medical Microbiology and Infectious Disease Canada Dr. Lacoursière 6 . Dr. Dr. Tom Wong Gregory Zaneiwski Tracey Donaldson Cathy Sevigny Annie J.

David Wong Treatment of HIV/HCV Co-infection: Timing. Kurt Williams Dr. Sam Lee Dr. and Maintenance Therapy Treatment in Patients With "Relative Contraindications" Management of Extrahepatic Manifestations Dr. Linda Scully Dr. Marc Deschênes Dr. Steven Wong Dr. Stephen Shafran Dr. Mark Swain Dr. Winnie Wong Dr. Chair: Dr. Dennis Kunimoto Dr.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Conference program Management of Hepatitis B Virus (HBV). Kevork Peltekian Dr. Jenny Heathcote Summary of National Institutes of Health (NIH) Consensus Recommendations Optimal Treatment for Genotypes 2 and 3 Management of Patients with "Normal" ALT Dose Reduction and Use of Adjunctive Therapy Comparison of the 2 Pegylated Interferon Regimens Controversial/Difficult Management Issues. Non-Responder. Kelly Kaita Dr. Chair: Dr. and Contraindications Treatment of HIV/HCV Co-infection: Treatment Results and Drug Interactions Re-treatment: Relapses vs. Andrew Mason 7 . Karen Doucette Treatment of HCV. Indications. Chair: Dr. Cameron Ghent Summary of European Association for the Study of the Liver (EASL) Consensus Recommendations Lamivudine or Interferon? Adefovir and Other Antivirals Around the Corner Use of Pegylated Interferon in Chronic HBV Infection HBV/Hepatitis C Virus (HCV) Co-infection and HBV in Immunocompromised Dr. Marina Klein Dr. Paul Marotta Dr.

Mel Krajden Dr. Future Directions and Initiatives 8 . Public/Patients What is out there? What is needed? Gaps in Prevention Counselling. Chair: Dr. Steve Martin Dr.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Dr. Health Providers. Eric Yoshida Dr. Mel Krajden Geri Hirsch Katherine Dinner and Cathy Sevigny Protocol for the Follow-up of Patients on Treatment (Clinical and diagnostic testing algorithm) Monitoring Protocols for the "Watch and Wait" Group (Clinical and diagnostic testing algorithm) Tracking Patient Outcomes and Adverse Events Database Requirements (Canadian Viral Hepatitis Network (CVHN)) Effective Education Medium for Physicians. Bernard Willems Dr. Jenny Heathcote Treatment in Active Injection Drug Users (IDU)/Addictions Treatment in Pediatrics Treatment in Patients with Cirrhosis Treatment Settings and Clinician Support. Pierre Lauzon Dr.

in addition to drug therapy measures. For this to occur. Treatment. In order to maximize the chances of successful therapy and minimise the long-term consequences of the disease. it is anticipated that 60% to 70% of new cases will be related to substance use with 10% to 20% of these cases being co-infected with HIV and other infections. There is also a need for targeted social and behavioural research to determine the most effective strategies to prevent risk behaviour. an estimated 250. such as Aboriginal people. It is recognised that the disproportionate number of new infections anticipated in these populations in the future requires special attention to ensure adequate care. incarcerated populations. Medical treatment is an important component of the management of viral hepatitis but it represents only one element of what needs to be a comprehensive approach. the diverse and vulnerable populations affected by hepatitis need to be engaged to articulate their healthcare needs across the continuum of prevention. effective physician and nursing educational programs need to be developed to provide primary care providers with a basic knowledge and understanding of the wide spectrum of management issues. 9 . counselling or treatment for hepatitis requires the development of a broad partnership approach. help in dealing with alcohol and other addictions. This limits the number of patients an individual physician can manage. this consensus conference also provided an opportunity to identify gaps in the overall management of viral hepatitis in Canada and to set the stage for future strategic direction. including social and behavioural factors that influence risky behaviour. is "labour intensive". The effective management of individuals undergoing screening. and to determine the cost-effectiveness of treatment. care and treatment. and immigrants. and through use of unsterile medical equipment in foreign countries. The provision of specialized nursing care will allow a larger number of patients to be treated. This is particularly true for patients whose health care falls under federal jurisdiction. Hepatitis B in Canada.000 individuals are infected with the hepatitis C virus (HCV) and probably a similar number are infected with hepatitis B. The model of service delivery is important for some populations and can impact on health status and outcomes. In developing these models. especially for hepatitis C. including persons with low incomes and unstable housing. This could be used to inform the development of comprehensive counselling guidelines and innovative models of service delivery. Analysis of the data could be used to define program and support needs for hepatitis virus-infected individuals. in contrast. There is the need for a national database to track prevention/care and hepatitis-targeted research. is largely a disease of immigrant populations with up to 70% of infected individuals born in foreign countries. The HCV-infected population is heterogeneous and includes those infected through the blood supply. such as Aboriginal people and inmates in the federal correctional system. the provision of adequate housing and nutrition. In addition to addressing patient care issues. street youth. the root determinants of health need to be considered. including vulnerable populations. the conference also identified the importance of monitoring outcomes of prevention and care programs. Primary and secondary prevention best practices and models of care for chronic disease "self" management are required. dietary management and weight reduction. In the future. In addition to meeting the need for updated treatment information for health care professionals. A significant proportion of the current infections are in vulnerable populations. The management of the patient with viral hepatitis includes. to guide best prevention and comprehensive care practices. These factors provide the patient with a variety of possible treatment settings and support issues. and in some cases. through contaminated injection drug use equipment. There is a new appreciation of the complexities involved in managing viral hepatitis in some patient subgroups.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Preamble Presently in Canada.

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New assays have been introduced for the measurement of viral load. the Canadian Viral Hepatitis Network. Therefore. provincial and territorial ministries of health and professional associations. The treatment of viral hepatitis is rapidly changing. However. and Blood Safety Surveillance and Health Care Acquired Infections Division of Health Canada. Since the introduction of interferon-␣ for the therapy of chronic viral hepatitis. Invited presenters reviewed the literature. and new information has emerged regarding the natural history of the diseases caused by these viruses. and presented expert opinions where literature was not available.2) and the Canadian Journal of Infectious Diseases. even in cases when this therapy was appropriate. Ontario. and these changes need to be quickly incorporated into practice. This consensus conference was not intended to provide an exhaustive overview of all of the complex issues involved in the management of viral hepatitis. and then revised the draft to produce the final document. which included experts in the field. hepatitis C community and advocacy groups. the guidelines were also used to define categories of patients and forms of therapy that would be excluded from reimbursement. In addition. The current document is meant as a guide to therapy and does not claim to define the only way in which patients can be treated. a significant number of studies have been referred to that have so far only been published in abstract form. The suitability of treatment for each patient cannot be described by this or any document. Correctional Service Canada. this consensus conference also provided an opportunity to identify gaps in the overall management of viral hepatitis in Canada and to set the stage for future national strategic direction (see Preamble). with a relatively small proportion covered by private insurance. These grades are given in brackets at the end of the sentence. the guidelines were adopted by some provincial/territorial reimbursement plans to define categories of patients who were eligible for reimbursement of treatment costs. primary care physicians. Several new drugs have become available. appropriate off-label uses of medication to 11 . the Community Acquired Infections Division. the Canadian Association of Hepatology Nurses. The result was that it became very difficult to obtain reimbursement for antiviral therapy if the patient did not meet the guideline criteria. 2003. These have been published in the Canadian Journal of Gastroenterology (1. A writing committee prepared a first draft of the recommendations and presented this draft to the audience. The document will provide levels of evidence for the statements and recommendations made according to the Infectious Diseases Society of America’s quality standards (Table 1) (3). the Canadian Association for Study of the Liver has sponsored a series of conferences at which local experts reviewed the available literature on the subject and issued clinical practice guidelines on the management of chronic viral hepatitis. and the conclusions from these abstracts are generally accepted as valid. and treatment costs should be reimbursed where treatment is appropriate. Funding was provided by Health Canada and Correctional Service Canada. the Association of Medical Microbiology and Infectious Disease Canada. The major intent was to address some of the changes in the medical management and treatment of chronic hepatitis B and C where the changes since the last consensus conference have been most significant.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Introduction The management of infection by hepatitis viruses has undergone rapid change in the recent past. This issue is particularly significant in Canada given that the high cost of hepatitis treatment is borne predominantly by governments. in Ottawa. The writing committee accepted feedback from participants. This current conference was jointly planned by the Canadian Association for Study of the Liver. The data have been presented at international meetings in all cases. In addition to meeting the need for updated treatment information for health care professionals. as well as on various Web sites. and the response to treatment. Following publication of the last consensus conference proceedings. Pharmaceutical medical directors and representatives were invited as observers. The needs of each patient should be assessed individually. and to obtain concomitant reimbursement for growth factor therapy. The conference was held from November 7 to November 9.

Managing patients with chronic viral hepatitis is time and labour-intensive and cannot be adequately provided by physicians working alone. The weighing of the benefits of therapy versus the likelihood of response and of significant side effects is left to the individual physician.g. In all cases. it is strongly recommended that there be support for training and deployment of nurses trained in hepatitis. consisting at a minimum of physicians and nurses. Governments should establish mechanisms to allow reimbursement of such offlabel uses where appropriate. and that financial support be provided for the development of hepatitis clinics. does not exclude active injection drug users from therapy. the decision to treat has to be individualized. cancer and to provide palliative care.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 support patients with chronic viral hepatitis should be available (B)(III). This document deliberately does not specify particular groups of patients who should be treated or excluded from treatment. Thus. just as there are nurses trained to manage. The best outcomes are obtained when patients are managed by a team. but should also establish mechanisms to ensure that patients are appropriately treated when using compounds for which evidence of benefit has not been established by high levels of evidence (C)(III). 12 . this document. unlike previous documents. Therefore. One such mechanism may be to establish committees of experts who could review individual requests for reimbursement that fall outside of the guidelines.. e. diabetes.

20). Although the prevalence of HIV is low in some populations (e. In neonates.18). Furthermore. the impact of monotherapy with lamivudine. There is also Canadian economic data indicating that this is a highly cost-effective strategy (13). Such patients may not require surveillance. where chronic hepatitis B infection is largely a disease of immigrants (6). Viral replication (quantitative HBV-DNA measurement) should be measured in patients with evidence of active disease (elevated ALT) (A)(II).000 copies/ml are candidates for therapy (A)(I). adefovir or tenofovir in a patient with Who should be treated? Acute hepatitis B infection does not require antiviral therapy (B)(III). Liver histology. Therefore. Hepatitis B-infected individuals.5). Anti-HCV antibodies should also be measured since HBV-HCV co-infection may impact on the selection of treatment (A)(I)(14). the risk is not equal in all infected individuals.22).10). horizontal transmission in childhood is more likely (II)(7. albumin. and tests of disease activity (AST. the risk of a neonate developing chronic infection is greater than 90% (II)(11. However.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 HEPATITIS B Prevention of hepatitis B virus infection Universal vaccination against hepatitis B is effective in preventing transmission of disease (I)(4. disease severity (clinical evaluation. but patients with non-cirrhotic liver disease may also be at risk. prothrombin. 13 . The distinction between HBeAg-positive and negative patients may impact on the choice and duration of therapy. screening of pregnant women in the third trimester of pregnancy for HBsAg is mandatory (A)(I).. it is recommended that patients with chronic hepatitis B undergo regular surveillance to detect early HCC (C)(III)(17. Hepatitis B and hepatocellular carcinoma Because of the increased risk of developing hepatocellular carcinoma (HCC). In these populations. However. once infected. Patients with mild disease may not require treatment despite active viral replication. such patients should be followed at close intervals. and HBV DNA >100. South East Asians). In Canada.12). HBeAg/anti-HBe). However.g.000 copies/ml. When the HBV DNA <100. Hepatitis A vaccination is recommended in patients with chronic hepatitis B (B)(II)(15. All hepatitis B carriers should be offered testing for anti-HIV antibodies (A)(I). neonatal vaccination may be preferable in provinces with a high proportion of immigrants from areas of the world highly endemic for hepatitis B. undiagnosed HIV infection is great due to the potential for the HIV to develop drug resistance. Patients with established cirrhosis are at highest risk. although not mandatory. The decision to treat or not may also be influenced by the severity of disease on liver biopsy. and complete blood count). bilirubin. Treatment of chronic hepatitis B Initial assessment Baseline assessment should include hepatitis B serology (HBsAg/anti-HBs. what little evidence exists suggests that annual surveillance is just as effective (21. Observation without treatment is appropriate in patients with mild disease.16). the use of the hepatitis B vaccine and hepatitis B immune globulin is highly effective in preventing hepatitis B transmission (I)(9. surveillance with abdominal ultrasound and serum alphafetoprotein every six months is common practice. some provinces offer neonatal vaccination. Although there is no evidence that surveillance for HCC reduces disease-specific or all-cause mortality. ALT). is highly recommended in patients with active disease (A)(II). while others offer preadolescent vaccination.8). Patients who have been documented as having inactive disease for many years and who are not cirrhotic (usually anti-HBe-positive and usually Caucasian) are at much lower risk (A)(II)(19. whether HBeAgpositive or HBe-negative with elevated AST and/or ALT. Since chronic hepatitis B is the largest reservoir for transmission of disease. the likelihood of hepatitis Binduced injury is thought to be low (23).

Lamivudine in HBeAg-positive patients The recommended dosage is 100 mg p. However. but this occurs only rarely (I)(24). response is also assessed after completion of therapy. particularly in the absence of cirrhosis. until a partial virological response (HBeAg seroconversion) occurs.37). The response rate is lower than for HBeAg-positive patients.000 copies/ml in a PCR assay. Phenotypic resistance is defined as the reappearance of HBV DNA following initial disappearance using a non-PCR-based assay. interferon). The effect of interferon therapy on survival in Asian populations may not be as pronounced (35. A partial virological response (HBeAg seroconversion) may be expected in 25-40% of patients six months after completion of therapy. daily for up to five years or more. East Asian). A biochemical response is defined as a normalization of serum AST and ALT.. The optimal time post therapy for assessing this response has not been defined. the durability of seroconversion may be lower (III)(34.5 times the upper limit of normal [xULN]). and the durability of response is also less well established (II)(38-40).28-32). In Caucasian populations. Genotypic resistance refers to the demonstration of mutations in the YMDD motif of the HBV polymerase gene.g. Patients with Interferon in HBeAg-positive patients Treatment should be with 10 million international units (MIU) interferon alpha subcutaneously (sc) three times per week (TIW) or 5 MIU sc daily for 16 weeks (I)(26. mild hepatic inflammation (AST or ALT <1. A partial virological response (HBeAg seroconversion) can be expected in 18-25% of patients within the first year of therapy. Interferon in HBeAg-negative patients The recommended dosage of interferon is 5-10 MIU TIW sc for one to two years. Liver biopsy is not mandatory to assess treatment efficacy (B)(II)(26). as it may impact on treatment efficacy. but there is no consensus on this issue. The utility of determining HBV genotype needs to be explored. or by a rise in HBV DNA concentration to >100.o. Continuing treatment for six months after seroconversion may improve the durability of seroconversion (II)(44).000 copies/ml (26). presence of cirrhosis and male gender. A complete virological response is defined as the sustained loss of HBsAg after treatment. such as those with high viral loads (>108 copies/ml). There are several areas of uncertainty concerning lamivudine resistance. An alternate endpoint for a partial virological response is a decrease in serum HBV-DNA below 100. Interferon may be more appropriate than lamivudine as initial treatment in young patients. a partial virological response is defined as the sustained loss of HBeAg with gain of anti-HBe after treatment (HBeAg seroconversion)(25). What treatment should be used? Lamivudine or interferon are both acceptable as initial treatment (A)(I). Response is initially assessed while on therapy (on-treatment response).g. interferon therapy has been shown to enhance overall survival and complication-free survival in HBeAg-positive patients who maintain post-treatment seroconversion (II)(36). The durability of HBeAg seroconversion after interferon treatment in Caucasian populations is high (68% three years after stopping therapy) (II)(33).. One rationale is that it may be preferable to use a time-limited form of therapy in a young patient who might otherwise have to be on therapy for many years.35).M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 How to assess response to treatment? Response to treatment can be defined virologically or biochemically. Response rates are decreased in the presence of high viral loads (>108 copies/ml). Some believe that longer duration therapy (up to 24 weeks) may be justified in selected cases (27). age over 40 years. in other populations (e. and who can tolerate the side effects of interferon. South 14 . rising to about 60% after three years of therapy. In HBeAg-positive carriers. The durability of HBeAg seroconversion after lamivudine is not as good as after interferon therapy. For patients treated with time-limited regimens (e. or until lamivudine resistance develops (I)(41-43).

which could be fatal in patients who have underlying cirrhosis. as in patients with HBeAgpositive chronic hepatitis B. No recommendation can be made regarding whether lamivudine should be withdrawn or not once lamivudine resistance develops.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 phenotypic resistance have a 97% probability of having genotypic resistance (45) and therefore. its role as first-line treatment in patients remains unclear. Once resistance occurs (approximately 60% after four years of therapy) (46). However. It . lamivudine is used at the same dosage (100 mg PO daily) (I)(48-50). In Mediterranean and Alaskan populations.000 copies/ml) on therapy. the utility of confirming phenotypic resistance by genotyping is unclear. but experience is limited. Special situations Hepatitis B in children The principal goals of therapy of hepatitis B in children are to reduce horizontal transmission of infection as well as to minimize long-term diseaseassociated morbidity. Pegylated interferon The efficacy of pegylated interferon in the treatment of HBV infection is being investigated. Preliminary data suggest that the efficacy of pegylated interferon is at least comparable to that of standard interferon (55). but the available data are too limited to allow specific recommendations to be made. Similarly.52) that will soon be available in Canada. For patients with a biochemical and virological response (i. Combination therapy with adefovir and lamivudine to limit the development of resistance (by analogy with HIV-positive patients) needs to be explored. it is unclear whether treatment should be stopped or continued once lamivudine resistance develops. normal AST. seems to be less effective than lamivudine in inducing HBeAg seroconversion. The optimal duration of treatment is uncertain. but it is uncertain whether the rate of progression is slower than in the absence of lamivudine. The decision to treat a child must take into account that there is a significant rate of spontaneous seroconversion in childhood.e.. and HBV-DNA <100. Disease severity does appear to progress once resistance develops (46. flares of hepatitis can occur after cessation of therapy. the rate may be 2-5% per year and 11% per year in those with elevated ALT (58. As with all forms of hepatitis B therapy. and possibly no more than about 13% of patients remain in remission.59). as many as 80% of children will undergo spontaneous HBeAg seroconversion in regions of low or moderate endemicity and 25-70% in regions of high endemicity (57. it is unclear whether lamivudine should be withdrawn. There is also a concern that lamivudine withdrawal may precipitate a flare of hepatitis. In patients in whom treatment is stopped after one year. the options to use interferon or adefovir remain. there are no guidelines as to when treatment should be stopped. patients can be offered treatment with interferon (if they have not previously failed interferon) or adefovir dipivoxil (see below). Although initially studied as first-line therapy for chronic hepatitis B. 8-16% of children per year will undergo HBeAg seroconversion (56. HBeAg seroconversion has also been reported after the development of lamivudine resistance (46). In Asian children with normal ALT. Lamivudine in HBeAg-negative patients In HBeAg-negative patients. the evidence supporting this is only anecdotal. there are still several areas of uncertainty. Its use as a first line drug may also be limited because of cost considerations. Thus.57). It is indicated for therapy of lamivudine-resistant infection and in patients who have failed to respond to lamivudine initially and who do not tolerate or have failed interferon (53). As adefovir is a new therapy.60). and may also be less potent in inducing viral suppression. The durability of seroconversion in HBeAg-positive patients remains unknown. Once resistance has developed. by twenty years of age. ALT.59. Predictors 15 Adefovir dipivoxil Adefovir dipivoxil is a new nucleotide analogue that is effective in both treatment-naïve and lamivudineresistant HBV infection (I)(51. However.47). the relapse rate is high. which differs in different populations. Possible endpoints for stopping treatment might be negative HBV DNA by PCR or negative HBcAg on liver biopsy. Renal toxicity can occur in some cases and dose adjustments are required for patients with established renal disease. The rate of development of resistance to adefovir appears to be much lower than with lamivudine (54).

The most appropriate way of combining interferon and ribavirin has not been established. and. treatment may be appropriate in HBeAg-positive adolescents who have failed to undergo spontaneous HBeAgseroconversion despite ALT >2x ULN for 6-12 months. with partial virological (HBeAg seroconversion) response rates of 23% but with the development of lamivudine resistance in 19% (I)(62). in adolescents. The long-term benefits of a three-year seroconversion advantage afforded by treatment have not been established. suggesting that treatment mainly accelerates seroconversion by about three years. Children should also be entered into long-term monitoring programs.000 copies/ml) (I)(64. Similar considerations apply in other circumstances where immunosuppressive therapy is used for immunologically-mediated diseases. the benefit of lamivudine in patients with advanced cirrhosis and inactive or low-level viral replication (<100. Other studies have shown that. preemptive lamivudine treatment should be used to prevent flares of HBV that can occur with these treatments (II)(67). However. all children should continue to be followed at one to two-year intervals to monitor for durability of response (III). Since flares of hepatitis Pregnant women Some recommend the use of lamivudine in pregnant women with high HBV DNA levels to reduce the risk of neonatal transmission (III)(63). Lamivudine may reduce or delay the need for liver transplantation in these patients. In contrast.e. Decompensated cirrhosis Interferon is contraindicated in these patients. no firm recommendations can be made regarding the use of interferon vs. Chemotherapy and bone marrow transplant (BMT) All patients undergoing chemotherapy or BMT should be screened for HBV markers prior to treatment (B)(II). Regardless of type of therapy. and lamivudine should not be used under these circumstances (B)(III). Similarly. Whether lamivudine should be used in patients with markers of past HBV infection (anti-HBs-positive and/or anti-HBc-positive) to prevent reactivation is not clear. Interferon-␣ 6MIU/m2 sc (maximum 10MIU) TIW for 24 weeks has been approved for children with HBeAg-positive hepatitis B. Clinical trials of treatment with interferon or lamivudine provided insufficient follow-up of control groups. Cirrhosis and HCC are rare in children (usually <5%). In those who are positive for HBsAg. moderate or severe inflammation on liver biopsy may also justify treatment (III).M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 of spontaneous seroconversion include ALT >3 xULN. no reports of fetal injuries due to lamivudine. to detect complications such as HCC (III). children who get HCC usually achieve HBeAg seroconversion in the first few years of life. To date. Lamivudine may be more appropriate for younger patients due to its ease of administration and better side effects profile.000 copies/ml) is doubtful. the rate of maternalfetal transmission is approximately 30% despite neonatal vaccination (63).60). This will achieve a partial virological response in approximately 35% (I)(61). In younger patients. although HBsAg should be monitored to detect reactivation. do not always present after a long period of inflammatory activity. high histological activity index. HBV-HCV co-infection Some favour the use of interferon. Therefore. the same predictors of treatment response).. Lamivudine is the first choice in patients with active viral replication (HBV DNA >100. female gender and low HBV-DNA (i. 3 mg/kg/day (maximum 100 mg) for one year has also been approved. there are 16 . as it may be effective in both infections (III). A single study has shown that if the HBV DNA levels are very high (>109 copies/ml).65). by three years of follow-up. Interferon may be more suitable in some older children in whom short-term therapy and monitoring may be required. treated and controlled patients have the same rates of seroconversion (59. Lamivudine. lamivudine. Renal transplant candidates Lamivudine treatment is recommended in all HBsAgpositive patients prior to and following kidney transplant to avoid HBV reactivation following immunosuppression after transplantation (II)(66). Cirrhosis is well described in young children with short duration disease.

and the treatment of hepatitis B in hemodialysis patients. including specialists in infectious diseases and hepatology or gastroenterology (C)(III). simply to allow control of their hepatitis B (C)(III). For patients in whom immunosuppression continues (e.. Because the HIV population in general is hyporesponsive to hepatitis B vaccination. once all courses of chemotherapy have been completed. is advised (A)(II). 17 . HBV is more active and liver fibrosis is often more advanced in HBV-HIV co-infection compared to HBV infection alone (70. A multidisciplinary approach for the delivery of care is ideal for the management of HIV-HBV co-infection. either a schedule using a double dose (72). Whether subjects with markers of past HBV infection should also be treated is unclear. The rates of aminotransferase normalization.75). Furthermore. The prevalence of HBV-HIV co-infection is approximately 5% but variable depending on location (69). HIV-HBV Co-infection In the case of HIV-HBV co-infection.g.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 occur mostly as a result of immune recovery. Adefovir and tenofovir. and tenofovir (7779). highly active antiretroviral therapy (HAART) regimens containing the reverse transcriptase inhibitors (NRTI) lamivudine and/or tenofovir are ideal given that these drugs possess virologic activity against both HIV and HBV and infrequently cause hepatotoxicity (B)(II)(76). or six standard doses (73). Vaccination is recommended for those negative for HBsAg and antiHBs. interferon could be used.80). and the doses appropriate for HIV are associated with significant toxicity. These include the management of hepatitis D. treatment with lamivudine can be started a few days before starting immunosuppressive therapy. Lamivudine should never be used as monotherapy for HBV infection in untreated HIV patients as the rapid development of HIV resistance to lamivudine may jeopardize future treatment in these cases (II). However. the bone marrow donor should be screened for markers of HBV infection to determine whether adoptive transfer of immunity would be a possibility (II). the prevention and treatment of hepatitis B infection in liver transplant recipients. after BMT). lamivudine can be withdrawn (C). there is crossresistance between adefovir and tenofovir. Hepatitis A virus vaccination is also recommended (B)(II)(74. Alternatively. There are patients who require therapy for their hepatitis B. Adefovir should not be used because the dose used to treat hepatitis B (10 mg/day) is inadequate to control HIV. loss of HBeAg and development of anti-HBe are comparable between interferon. There are additional treatment issues around hepatitis B that were not addressed in this conference. Since nucleoside analogue monotherapy is not acceptable. Some suggest a period of maintenance therapy of a few months after chemotherapy before withdrawal (C). lamivudine therapy should also continue. There is no information to guide how long patients should be treated. Anti-HBs and HBsAg screening should be performed in all HIV sero-positive individuals (A)(II). In BMT recipients who are HBsAg-positive. another nucleotide analogue developed to treat HIV that is effective against both wild-type and lamivudine-resistant HBV strains. but who would not otherwise qualify for HAART. should also not be used as monotherapy for HBVHIV co-infected patients (II). lamivudine. these patients may need to go onto HAART. reduction in HBV DNA to undetectable levels. Tenofovir is preferred to adefovir in the HBV-HIV co-infected patient. An advantage of tenofovir over lamivudine may be the slower evolution of drug resistance and the efficacy of tenofovir in HBV-infected individuals with lamivudine-resistant HBV (79. Chronic HBV infection in the BMT recipient can be cured by adoptive transfer of immunity from a bone marrow donor with evidence of past hepatitis B infection (II)(68).71).

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M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Hepatitis C Initial Assessment Initial evaluation of suspected hepatitis C infection involves serologic testing for antibodies against enzyme-linked hepatitis C (3rd generation immunoassay [EIA]). Contraindications to antiviral treatment for hepatitis C are listed in Table 2 (B)(II). risk of adverse effects. glucose. In anti-HCV-positive patients. in that they allow early termination of costly therapies where appropriate. In many countries from which Canada draws immigrants. albumin. even if remote and only occasional. The initial evaluation should also include a careful review of the patient’s history to exclude contraindications to therapy and identify areas that need attention during treatment. Second. Therefore. no matter what the apparent state of their liver disease. must agree to use a highly effective method of contraception during therapy and for six months following completion of therapy for the same reasons. Patients with genotype 2 and 3 infection. seizure disorders. Patients with mild disease. Sexually-active females must have a pregnancy test prior to initiation of therapy. bilirubin. AST. who have a high likelihood of cure. HBsAg. because of the teratogenicity of ribavirin (B). Additional tests include abdominal ultrasound and ECG (if age over 50 or history of cardiac disease) (B)(II). creatinine. and of course. especially minimal fibrosis. Studies have indicated that patients who achieve this outcome no 19 . transfusion of blood products prior to 1990. PT. Particular attention should be paid to a previous or current history of psychiatric disorders. alcohol and drug addiction. This recommendation is different than previous recommendations. have the best response to therapy. male or female. large numbers of patients were infected with hepatitis C 30-50 years ago.84).82. the possibility of declining treatment with the hope of future advances in antiviral therapy should be discussed. HIV. Although some have advocated the selective treatment of only those patients with advanced fibrosis or severe inflammation on liver biopsy. ANA. Therefore. These assays are essential to the proper management of patients and are cost efficient. the large registration trials that have been published included a significant proportion of patients with mild inflammation and/or fibrosis. However. cardiac and renal disease. viral load and genotype testing has to be available in a timely fashion (A)(I). related to medical procedures using improperly sterilized syringes and needles (81. ALT. should undergo evaluation to determine whether therapy is appropriate (A)(I). retinopathy. HCV RNA levels where appropriate (see later). alkaline phosphatase. It is impossible to treat hepatitis C properly without viral load and genotype testing. serum or urine ␤-HCG (to exclude pregnancy) and urinalysis (B)(II). CBC. infection should be confirmed with a highly sensitive qualitative HCV RNA assay (A)(II). autoimmune disease. for patients with mild hepatitis. These include prior injection drug use. and the presence of co-infections such as hepatitis B and HIV. defined as a negative serum HCV RNA by a qualitative test sensitive to <50 IU/ml six months after the completion of therapy (83. serologic testing is preferred. Sexually-active patients. and immigrants from countries with high prevalence rates of hepatitis C. TSH. patient symptoms. The decision to treat or not to treat is complex and must consider factors such as the risk for liver disease progression. Because urinary pregnancy testing has limited sensitivity and can result in false negative readings. The primary endpoint of therapy is an SVR. INR. may not need a liver biopsy prior to treatment (B)(I). Liver biopsy remains the most sensitive measure of disease severity and is recommended but is not mandatory prior to the initiation of therapy (B)(II). the patient’s wishes.127). Choosing patients for antiviral therapy With recent improvements in sustained virological response (SVR) using combination treatment with pegylated interferon and ribavirin. the exclusion of this group from treatment would lead to overall SVR rates that are inferior to usually quoted values. simply because a patient has not been infected long enough to develop significant liver injury is not a reason to withhold treatment. Testing for hepatitis C should be undertaken in all patients with abnormal aminotransferase levels and in those with risk factors for hepatitis C infection (A)(II). Laboratory assessment prior to treatment should include genotype. likelihood of treatment response. all patients.

The initial registration studies for pegylated interferon/ribavirin did not distinguish between genotype 1 and genotypes 4. the major drawback is a loss of flexibility to tailor the ribavirin dose as required. Fried et al. the ribavirin dose used in this study was likely too low. Therapy should be stopped for patients who fail to achieve EVR.␣.5 ␮g/kg sc weekly. 180-␮g sc weekly or peginterferon alpha-2b. The large trials differed with respect to the proportion of patients with genotype 1.87. (86) have reported an SVR of 42% in genotype 1 patients using peginterferon alpha-2b at a dose of 1. Given the uncertainties of comparing outcomes from separate trials.8 log compared to baseline at 12 weeks of therapy (B)(III). There are currently two preparations of pegylated interferon. Genotype 2 and 3 infection is optimally treated with a 24-week regime using peginterferon alpha-2a. SVRs of 78-82% may be achieved. EVR should be defined as failure to achieve a decline in HCV RNA of 1. At the time of writing. no conclusions can be reached regarding the superiority of one agent over the other. Drug treatment The best results have been obtained using a combination of pegylated interferon and ribavirin (A)(I)(86. However. 20 pegylated interferon and ribavirin are available separately. Furthermore. and do not relapse in the ensuing years (85). a sustained virological response is equivalent to a cure with less than 2% suffering a late relapse (I)(85). This was superior to combination treatment using standard interferon and ribavirin (SVR 33% in genotype 1). While there are advantages to bundling. Quantitative HCV RNA assays have an inherent variability that might be as high as 0.5 logs. different adverse event definitions were used.90). together with ribavirin 800 mg daily for 48 weeks.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 longer have detectable HCV RNA in the liver. Patients who achieve a 1. 2a. This so-called bundling only occurs in Canada. Patients failing to achieve an EVR have only a 0-3% chance of achieving an SVR.87). depending on whether the patient is less than or heavier than 75 kg (I)(88). In the USA and in Europe. the two drugs. .g. (87) have reported a similar SVR of 44% in genotype 1 patients using peginterferon alpha-2a at a dose of 180 ␮g sc per week plus ribavirin. or 6. Both manufacturers have chosen to bundle the interferon and ribavirin. although the adverse effect profiles seem comparable. less than about 800. In retrospect.5 ␮g/kg sc (I). Although these predictive rules were devised for genotype 1 patients. as they are extremely unlikely to achieve SVR (A)(I)(88. Viral genotype has the most profound influence on the likelihood of treatment response. There are no direct comparisons of the efficacy of peginterferon alpha-2a and peginterferon alpha-2b. 1000-1200 mg PO daily. Manns et al. 1.8 or 2-log drop. EVR was defined in the registration studies as either undetectable HCV RNA or at least a 2-log drop in HCV-RNA concentration. current practice is to treat genotypes 4. A fixed dose of 800 mg ribavirin PO daily is sufficient when using either pegylated interferon. The consensus conference speakers and attendees strongly recommend to the manufacturers that the two products be available in an unbundled form.. Therefore. Those achieving an EVR have a 65-72% chance of achieving an SVR. Those who fail to clear the virus at 24 weeks should have therapy withdrawn. Therefore. For practical purposes. The other major factor influencing the SVR is viral load. there are preliminary data that suggest that the EVR rule is useful in genotype 4 patients as well (91). but who do not clear HCV RNA from serum at week 12 should be tested with a qualitative HCV RNA at 24 weeks (C)(III).86). or 2b (A)(84. the likelihood that an individual patient will not have an SVR can be reliably predicted after 12 weeks of therapy by assessing the EVR (I). with better results being observed in patients with lower viral loads (e. Subsequent studies have suggested that 1000-1200 mg PO is a more suitable dose for genotype 1.90). mean body weight and proportion with advanced fibrosis (METAVIR stage F3 or F4) (86. 5. Therapy should therefore be stopped for these patients (A)(I)(87. so that direct comparisons of the side effect profiles are not possible. so that a fixed ribavirin dose is provided with each dose of interferon.000 IU/ml)(86-88). only one is available in Canada.89). the EVR rule cannot be applied too strictly. 5. and 6 as genotype 1 until more data are available (B)(II). Early virological response (EVR) For patients infected with genotype 1. The second preparation is expected in 2004.

M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Patients infected with genotype 2 and 3 achieve EVR in 97% of cases. For patients receiving less than 80% of the intended dose. The manufacturers also suggest that if the neutrophil count falls below 0. the reduction in SVR rates is small (87. It may be important. the diagnosis requires the demonstration of HCV RNA in serum (111). and then monthly. infection is rare (96). The common laboratory abnormalities requiring intervention are anemia and neutropenia. Patients who prematurely withdraw from therapy have very low SVR rates. patients whose baseline levels of red and white cells and platelets in blood were low were excluded from therapy. and add significant expenses. there are no data on the effect that this might have on SVR rates. infectivity concerns. The effect of dose reduction on SVR has not been fully evaluated. Therefore. ALT.8 x109/L. but might be appropriate in some patients (99-101). Unacceptable declines in cell counts during therapy may respond to growth factor therapy (see above). 21 . In addition. These patients should no longer be automatically refused treatment (C)(II). patients must be evaluated carefully and monitored vigilantly during and after treatment. 6.5x109/L. compared to patients with abnormal ALT (110). who might prefer to wait for newer therapies to be developed. extrahepatic disease. For patients with ribavirininduced anemia. and urinalysis should be done monthly. 2. 4. Approximately 40-50% of symptomatic patients (e. Since some patients may present prior to the development of anti-HCV antibodies. erythropoietin can be used to maintain hemoglobin concentration (98). Pregnancy tests must be done regularly. As yet however. whether a patient was a non-responder to interferon and relapsed during or after treatment. the dose of interferon should be reduced. erythropoietin and GM-CSF or G-CSF are controversial. The use of Cytopenias Interferon and ribavirin therapy induces declines in red blood cells. 8. Evaluation and monitoring during treatment Treatment of hepatitis C has numerous side effects that can be severe. Special situations Normal ALT Approximately 30% of HCV patients have persistently normal ALT (at least three normal ALT values when measured over a period of several months) (102-104). severe symptoms. and occupational concerns should be considered in the decision to treat patients with normal ALT. As long as patients receive more than 80% of the intended dose of all therapy.95). but develop breakthrough viremia before the end of therapy. All patients who complete a course of therapy should have HCV RNA measured at the end of therapy to define the nature of their treatment response (C)(III). There is therefore no merit to measuring HCV RNA at 12 weeks in this group.g. A liver biopsy is helpful to determine those with significant disease who would benefit from treatment and will identify patients with mild disease. Treatment with pegylated interferon and ribavirin results in equivalent SVR rates in patients with normal ALT. other factors such as favourable genotype. life threatening. Therefore. but remains acceptable. studies suggest that even at neutrophil counts of 0. but who continue on therapy. Acute hepatitis C Acute hepatitis C is rarely identified since the majority of patients are asymptomatic during the initial stage of infection. those with jaundice. and irreversible. This included patients with thalassemia and constitutional neutropenia (common in Blacks) (96). a few may have significant fibrosis (105-109). In the past. Some patients will achieve EVR. TSH and weight every three months (B)(I)(92. glucose. patients with persistently normal ALT should be considered for therapy (A)(I). when considering future therapy. GM-CSF and G-CSF have been used to treat interferon-induced neutropenia. However. the SVR rate drops.97). Studies show that the use of erythropoietin allows the ribavirin dose to be maintained. and discontinuation is required if the hemoglobin level falls below 85 g/L (94. Laboratory assessments include CBC at week 1. The manufacturers recommend that dose reduction of ribavirin is required for hemoglobin levels below 100 g/L. white blood cells and platelet counts. bilirubin. Although the majority of these patients have mild disease on biopsy.93).

right upper quadrant discomfort.118).87). flu-like symptoms) will clear the virus spontaneously (112. In order to avoid the unnecessary treatment of such patients. Extrahepatic manifestations of hepatitis C There are several conditions related to hepatitis C that might require therapy. The latter group is more resistant to re-treatment with interferon-based regimens. but data are limited. 22 . Although data from randomized controlled trials are lacking. Re-treatment of Patients Selected patients who have failed to respond to interferon-based therapy should be considered for retreatment. vomiting. re-treatment with peginterferon alpha and ribavirin can be considered. therapy should be deferred until three to four months following presentation if persistent HCV RNA positivity is demonstrated (B)(II)(114). In relapsers and nonresponders to interferon and ribavirin combination therapy. In patients with a relatively good likelihood of response who have relapsed or not responded to interferon monotherapy. Neither the dose nor duration of therapy has been determined. however. The decision to re-treat patients should consider the previous therapy received. Subgroup analyses of the large registration trials of this therapy revealed rates of sustained virologic response of 43-44% (in patients with bridging fibrosis and cirrhosis combined) (86. but may well be necessary in asymptomatic patients. the highest rate of sustained virologic response (98%) has been reported with high dose induction therapy with standard interferon monotherapy (5 million units (MU) sc daily for 4 weeks followed by 5 MU sc TIW for 20 weeks)(B)(II)(114). the tolerance of and response to prior treatment (non-response versus relapse). and hepatocellular carcinoma. such patients are probably best treated in specialized centres. The efficacy of combination therapy with ribavirin and the role of peginterferon alpha has yet to be established. dosage reductions may be necessary in patients with pre-existing cytopenias. The optimal dose and Cirrhosis Although the majority of patients with chronic hepatitis C have mild disease. although efficacy data from randomized controlled trials are not currently available (III). In patients with compensated cirrhosis. the optimal therapy is the combination of peginterferon and ribavirin (B)(II). The dosage and duration of therapy should be the same as in non-cirrhotic patients. Therefore. occur exclusively in these patients (115). the treatment of these conditions has not been standardized. However. Patients with advanced fibrosis (stage 2 or greater) should be given priority for re-treatment (C)(II). However. but have reappearance of HCV RNA following the withdrawal of therapy. However. immediate treatment can be considered due to the low probability of spontaneous viral clearance (113) and high rates of successful treatment when administered during the early period of infection (II)(114). Treatment of patients with decompensated cirrhosis with interferon-based regimens is contraindicated outside specialized care environments due to the risk of precipitating severe liver failure and potential death (B)(II)(116).M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 nausea. combination therapy with peginterferon alpha and ribavirin at standard dosages and duration is the preferred re-treatment strategy (B)(II). Preliminary data suggest that about 10% of non-responders and about 20% of relapsers achieve an SVR (117. In asymptomatic patients. cirrhotic patients have the most to gain from successful antiviral therapy. Therefore. The majority of the complications of chronic hepatitis C including liver failure. no recommendations can be made about how to treat these patients. even in the absence of significant liver disease. The role of maintenance interferon-based therapy is under study and cannot currently be recommended (D)(III). a large proportion of these patients were symptomatic so the efficacy of therapy in asymptomatic patients is unclear. and factors predictive of an SVR. These include cryoglobulinemia and glomerulonephritis.113). a significant proportion will progress to cirrhosis. Adjunctive therapy with growth factors including erythropoeitin and G-CSF may be useful in these patients. Unfortunately. "Non-responders" fail to achieve HCV RNA negativity during treatment. "Relapsers" become HCV RNA-negative during treatment (as manifested by an EVR or end-oftreatment virologic response). rates of sustained virologic response are lower and tolerance is generally poorer in patients with advanced disease. variceal bleeding.

These findings suggest that antiviral treatment may be warranted in selected patients. although patients should receive at least the minimum therapy recommended for treatmentnaïve patients. Children with hepatitis C are typically asymptomatic and the majority have normal or minimally-elevated serum aminotransferases (II)(122). three quarters of HIV-HCV co-infected subjects were found to have METAVIR stage 2 or 3 fibrosis and 10% were cirrhotic. Since the introduction of HAART liver disease secondary to HCV infection has become a leading cause of morbidity and mortality in HIV-HCV co-infection (129). a liver biopsy should be considered in the management of infected children. As in adults. Liver biopsies in HIV-HCV co-infection identify at least some disease activity in most patients (> 95%)(139).138).124). and liver fibrosis may be improved in HIV-HCV co-infected subjects receiving potent and durable HAART. with weight loss being the only side effect presenting more frequently than in adults. A biopsy is strongly recommended to stage fibrosis. In one study. this rate is at least 50% and up to 80% in some regions (128). Interferon is generally well-tolerated in children. The resultant growth inhibition is not permanent (125). Children under three years of age should not be treated due to concerns regarding the potential neurotoxicity of interferon on the developing brain (126) and the higher rates of spontaneous viral clearance observed in this subgroup.. The influence of HCV on HIV infection is less pronounced (133. however. patients with abnormal liver enzymes in the absence of other causes of liver disease or patients with high risk for acquiring HCV infection. Peginterferon alpha-2a can be administered at full dosage (180 ␮g/week) in patients with a creatinine clearance above 20 mL/min. Since the correlation between ALT and hepatic histologic lesions is poor. HCV RNA testing by PCR should be done in the setting of patients who are anti-HCV negative but at high risk of HCV. CD4 T cell recovery following initiation of HAART may be blunted in comparison to HCV sero-negative individuals with HIV (135. preferably at specialized centres (C)(III). particularly after ten years of infection (C)(III). and a reduced dosage (135 ␮g/week) in those with more severe renal dysfunction (95). Patients with moderate to severe fibrosis and/or necroinflammatory activity on liver biopsy should be targeted for therapy. i. Ribavirin is contraindicated in patients with significant renal dysfunction (creatinine clearance <50 mL/min) due to altered pharmacokinetics and the risk of severe anaemia. 2 and 3) (II)(123. Immunodeficiency (CD4 <200 cells/ml) and excess alcohol consumption (>50 grams per day) are independently associated with rapid progression to cirrhosis.122). in specialized care centres at low dosages with therapeutic monitoring of plasma ribavirin concentration (119).136). the indications for therapy are poorly defined. some children have significant fibrosis on liver biopsy (II). Among HIV seropositive injection drug users.e.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 duration of therapy has yet to be identified. HIV-HCV co-infection Approximately one-quarter of Canadian HIVinfected individuals are seropositive for HCV (127). In patients with previous renal transplantation. the decision for treatment must consider the efficacy and adverse effects of therapy and the severity of the underlying liver disease. Screening and investigations Children with chronic hepatitis C Although the progression of chronic hepatitis C appears slower in children than adults (121). Progression to cirrhosis and decompensated liver disease is accelerated in HIV-HCV co-infected patients (130-132). compared to baseline (137. Renal impairment and renal transplantation Peginterferon alpha-2b is relatively contraindicated in patients with a creatinine clearance below 50 mL/min because peginterferon alpha-2b is excreted by the kidney (94). however. interferon is contraindicated due to the risk of precipitating irreversible graft dysfunction (II)(121)(120. Standard interferon (3 MU/m2 three times weekly) and ribavirin (15 mg/kg/day) for 48 weeks yields rates of sustained virologic response similar to that observed in adults (40-60% overall.134). biopsy inflammation scores. assist in the decision regarding the need 23 . 70-100% in genotypes HCV screening by serology is recommended in all HIV-infected individuals (B)(II). Ribavirin has been used. Mildly-elevated aminotransferases. The efficacy of peginterferon and ribavirin has yet to be conclusively demonstrated.

The SVR rate with 48 weeks of pegylated interferon alpha-2 plus ribavirin for genotype 1 infection is under 30% (I)(139-143). Because HCV progresses more rapidly in HIV-HCV co-infected patients. However. defined as at least a 2-log drop in HCV viral load. the strategy of first treating HCV and then HIV in order to avoid the combined toxicities of coadministration of these medications may be considered (C)(III). Treatment limiting hepatotoxicity is rare with all classes of antiretrovirals (156.150). In those with CD4 T cell count between 200 and 350 x 109cells/L. of mitochondrial toxicity (lactic acidosis and pancreatitis) (I)(144-146). and elevated ALT has also been described but is observed infrequently (154. are usually asymptomatic and resolve without interruption of antiretroviral therapy. high HIV viral load). . The constitutional and cognitive toxicities related to therapy are significant (143). Which therapy first In cases in which CD4 T lymphocyte count is below 200 cells/µL. It is unclear if 24 weeks of therapy is sufficient. and identify cirrhotics who may be at more risk of treatment-related hepatotoxicity (A)(II). but in general. rash. Severe elevation of aminotransferases (defined as >10x the upper limit of normal) occurs in between 5-10% of patients. These toxicities are mediated by NRTI inhibition of mitochondrial DNA replication (151). Severe adverse interactions between antiretrovirals and HCV drug therapy occur rarely and can usually be prevented by careful laboratory monitoring and avoiding combinations of certain medications. a coordinated multidisciplinary approach for the delivery of care is strongly recommended (C)(II). should be determined as lack of an early virologic response predicts failure to achieve SVR (A)(I).141).157). A 2-4% incidence of rise in aminotransferases is reported in treatment-naïve subjects receiving nonnucleosidase reverse transcriptase inhibitors (151). and uncontrolled substance abuse. Given the low rates of SVR. for most protease inhibitors (152154). Initiation of both therapies simultaneously is not recommended. In cases in which the CD4 T lymphocyte count has never fallen below 350 x 109 cells/L. the patient should be monitored closely for signs of liver failure. as a 29% relapse rate has been reported after the end of therapy for genotype 3 infection (139).. neither increased treatment side effects nor loss of HIV virologic suppression have been reported in NRTI-treated subjects initiating ribavirin. As both zidovudine and ribavirin can cause anemia.. Caution should be exercised when didanosine and ribavirin are used in combination because of the risk 24 There is a risk of hepatotoxicity with antiretroviral therapy (149.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 for drug therapy. given the potential for combined toxicity (D)(III). Although ribavirin may alter the intracellular levels of several nucleoside reverse transcriptase inhibitors (NRTI)(148). careful attention is warranted if co-administered (C)(II)(147). predict the likelihood of response to therapy. HCV therapy should be initiated using the full recommended doses of interferon and ribavirin with aggressive supportive therapy for drug-induced side effects as SVR rates are reduced with sub-therapeutic dosing in HCV mono-infected patients (B)(II). HAART represents the most beneficial initial intervention in those with HIV-HCV coinfection (III). Therefore. stage 1) and/or normal ALT (C)(II). The early virologic response. Hepatic steatosis and fulminant hepatitis are rare complications of HIV NRTI treatment (150-154). Therapy in this population is often contraindicated because of co-morbid illnesses such as psychiatric illness.e. treatment may be considered in those with minimal fibrosis (i. Hepatitis C drug therapy Use of antiretrovirals A decision to initiate therapy should be based on similar criteria to that used in HCV mono-infected individuals (A)(I). An early nevirapine hypersensitivity syndrome consisting of fever. there may be cases in which HAART can be deferred in favour of initial HCV therapy. Treatment environment The management of HIV-HCV co-infection is more complex than management of either disease alone. severe cytopenias. are not more frequent or severe in comparison to those infected with HCV alone. The SVR rate with 48 weeks treatment for genotype 2 and 3 infection may be as high as 62% with low virological relapse rates between end of therapy to 72-week follow-up (I)(140. This is reasonable in the absence of opportunistic infection and markers of rapidly progressive HIV disease (i.155).e.

Management of injection drug use. It is therefore incumbent on non-specialists caring for these populations to familiarize themselves with the contents of this document. There are insufficient hepatologists.2002.html Vaccination HAV and HBV vaccination are recommended (C)(II). Only in this manner will the population with chronic viral hepatitis in Canada receive the care they deserve. Conclusions The management of chronic viral hepatitis is complex. additional scientific data to support the efficacy of these interventions in HIV-HCV co-infection is required. Patients with liver failure should be assessed individually and referred for transplantation.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Adjuvant therapy Although there may be situations in which adjunctive therapies including pre-HCV drug therapy antidepressants and erythropoietin may be of value in improving quality of life (158). and to refer patients for specialist attention when required. if appropriate. Addendum The recommendations for screening in pregnancy contained in this document differ from the recommendations of the National Advisory Committee on Immunization and the Health Canada Canadian Immunization Guidelines . whether it be hepatitis B or hepatitis C. gastroenterologists and infectious disease specialists in Canada to allow all patients to receive specialist care.ca/pphb-dgspsp/publicat/ std-mts98/index. Further research into the efficacy and safety of this therapeutic option is required.hc-sc. alcohol use. For guidance in assessing high-risk behaviours for Hepatitis B infection see the 1998 Canadian STD Guidelines available on the Health Canada website: http://www. Transplantation Liver transplant for the HIV-HCV co-infected subjects with liver failure is being evaluated in a research setting. 25 . Health Canada recommends adherence to the following guidelines: All pregnant women should be routinely tested for HBsAg at the first prenatal visit and repeat testing before delivery may be considered in uninfected and unimmunized women with continuing high-risk behaviour. and depression should be optimized prior to initiating HCV drug therapy as these negatively impact therapeutic success (C)(II).gc. to recognize the limitations of their knowledge.

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Grading system for ranking recommendations and clinical guidelines (3) Strength of Recommendation A B C D E Definition Good evidence to support a recommendation for use/action Moderate evidence to support a recommendation for use/action Poor evidence to support a recommendation for use/action Moderate evidence to support a recommendation against use/action Good evidence to support a recommendation against use/action Quality of Evidence I Evidence from controlled trial one or more properly randomized II Evidence from one or more well-designed clinical trials. or reports from expert committees. descriptive studies.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Table 1. or from dramatic results from uncontrolled experiments Evidence from opinions of respected authorities. based on clinical experience. or from cohort or case-controlled analytic series (preferably from >1 centre). III 34 . without randomization. or from multiple time series.

especially autoimmune hepatitis Hemoglobinopathy Severe anemia Poorly controlled epilepsy Neutrophils <0. Contraindications to antiviral treatment Alpha Interferon Severe or uncontrolled psychiatric disease Ribavirin Pregnancy or inadequate contraception (males and females) Both interferon and ribavirin Documented poor compliance Hepatic decompensation Severe heart disease Solid organ transplantation (except liver) Ongoing and untreated alcohol or drug abuse Advanced renal failure Any other uncontrolled serious medical illness Certain autoimmune diseases.M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Table 2.75 x 109/l Platelet count <40 x 109/l Active serious infection 35 .

M A N A G E M E N T O F V I R A L H E PAT I T I S : A C A N A D I A N C O N S E N S U S C O N F E R E N C E 2 0 0 3 / 2 0 0 4 Notes 36 .