- Email: [email protected]
Management of hepatitis C: current and future perspectives
Journal oj-Hepatology1999: 31: (Suppl. 1): 264268 Printed in Denmark All rights reserved Munksgaard Copenhagen
Copyright0 EuropeanAssociation for the Studyof the Liver1999 Journal of Hepatology
ISSN 0169-5185 ISBN 87-16-16386-9
Management of hepatitis C: current and future perspective Jay H. Hoofnagle Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Chronic hepatitis C is now a major cause of chronic liver disease, cirrhosis and hepatocelhdar carcinoma. In March 1997, the National Institutes of Health sponsored a Consensus Development Conference entitled “Management of Hepatitis C”. The final statement from the Consensus Panel set forth clear, evidence-based guidelines and recommendations regarding the diagnosis, evaluation, prevention and therapy of hepatitis C. The conclusions of the Consensus Panel have been widely accepted and have brought some degree of uniformity to the management of hepatitis C. An important issue is how to keep such recommendations current in such a rapidly evolving area of medicine. In the 2 years since the Consenus Conference there have been important advances in the management of chronic hepatitis C. Two recommendations of the Consensus Panel deserve modification: lirst, on the clinical usefulness of genotyping of hepatitis C virus and second, on the optimal therapeutic regimen. Two large multicenter,prospectivecontrolled
The 1997 National Institutes of Health Consensus Development Hepatitis C
Conference: Management
of
In the United States as in Europe, chronic hepatitis C is one of the leading causes of cirrhosis, end-stage liver disease and hepatocellular carcinoma. The discovery of the hepatitis C virus (HCV) in 1989 (1) the development of sensitive assays for its detection (2), and the evolution of antiviral therapy have led to an important need to provide accurate and evidence-based recommendations regarding diagnosis, management and treatment. For these reasons, in March 1997, the National Institutes of Health sponsored a Consensus DeCorrespondence: Jay H. Hoofnagle, M.D., Bldg 31, Room 9A23, NIH, Bethesda, MD, USA, 20892. Tel: + 1 301 496 1333. Fax: + 1 301496 2830. e-mail: [email protected]
264
trials have shown that the combination of alpha interferon with ribavirin provides higher sustained virologic responses than interferon alone and that optimal therapy is a 24-week course for patients with genotypes 2 and 3 and a 4Sweek course for patients with genotype 1. Furthermore, therapy can be stopped at 24 weeks if HCV RNA is still present. Many clinical challenges remain. Major current needs are for accurate means of assessing the grade and stage of disease, for the likelihood of disease progression and of response to therapy as well as for viral eradication by treatment. Also important are new therapies for hepatitis C that might be used alone or in combination with interferon and ribavirin; therapies that could be applied to a wide variety of patients, with different stages of disease and with other co-morbitities. Key words: Cirrhosis; Consensus conferences; Controlled trials; Hepatitis C; Hepatitis C virus; Interferon; Ribavirin.
velopment Conference entitled “Management of Hepatitis C” (3). A panel of unbiased and independent professional and lay persons were provided with the published literature on hepatitis C and listened to 2 days of oral presentations on the virology, clinical features, course and natural history, epidemiology and therapy of hepatitis C. The panel then prepared a consensus statement that addressed six pre-selected questions: (1) What is the natural history of hepatitis C? (2) What is the most appropriate approach to diagnose and monitor patients with hepatitis C? (3) What is the most effective therapy for hepatitis C? (4) Which patients with hepatitis C should be treated? (5) What recommendations can be made to patients to prevent transmission of hepatitis C? (6) What are the most important areas for future research? The Consensus Development process insured a fair and unbiased set of recommendations that were based on firm scientific grounds. Areas
Future perspectives
of uncertainty were clearly delineated in the recommendations and comments. The recommendations and conclusions of the NIH Consensus Panel have been widely accepted and have brought some degree of uniformity to the management of hepatitis C.
Modification of the consensus recommendations An important and difficult problem now arises as to how to keep the recommendations made by the 1997 consensus panel current, particularly in view of the rapidly evolving understanding of the hepatitis C virus, its spread and treatment. Review of the consensus statement almost 2 years after it was written reveals that most of the conclusions and recommendations are still valid; for instance, recommendations regarding screening in high risk persons, diagnostic tests and their interpretation, indications for therapy and avoidance of transmission. Many of the statements were written with a view towards future progress for instance, the recent licensing and approval of a third generation enzyme immunoassay (EIA-3) and confirmatory test (RIBA-3) for detection of anti-HCV Two major recommendations of the consensus panel, however, warrant comment and possible modification: (1) the statement that genotyping of HCV is not clinically useful, and (2) the conclusion that the optimal regimen for therapy of hepatitis C is a 12month course of alpha interferon with testing for HCV RNA after 3 months and early discontinuation if viremia is still present. The modifications needed are largely the result of three large, multicenter, randomized controlled trials on the combination of alpha interferon and ribavirin as therapy of hepatitis C (4 6). Clearly, in all groups of patients, this combination resulted in higher sustained response rates than with alpha interferon alone. Importantly, genotyping for HCV appeared to be clinically important in determining the optimal duration of therapy. In both the U.S. and the international trials of alpha interferon and ribavirin, the rates of sustained virological response were 67% and 64% among patients with genotypes 2 and 3 and rates were similar with a 24-week course as with a 48week course of therapy. In contrast, the rates of response to the combination therapy were lower among patients with genotype 1, and rates were significantly higher with 48 weeks (28% and 31%) than 24 weeks of therapy (16% and 18%). Thus, the optimal regimen of therapy is currently the combination of alpha interferon and ribavirin given for 6 months for patients with genotypes 2 and 3 and for 12 months for patients genotype 1. For patients with genotype 1 who have low levels of HCV RNA or who had previously been treated and had a transient response and relapse, it is
not clear whether a 1Zmonth course provides additional benefit over a 6-month course. In both the U.S. and the international trials, sustained responders to combination therapy were all HCV RNA negative by 6 months (but not at 3 months). For this reason, therapy can be terminated at 6 months if HCV RNA is still present. Therapy with interferon alone should be reserved for patients with contraindications to ribavirin therapy such as anemia, renal insufficiency, inability to practice birth control and significant cerebral or cardiovascular disease. The appropriate dose and safety of ribavirin has not been shown for children; thus children should not be treated with this combination outside of controlled trials. Of great importance is that ribavirin is teratogenic and must be carefully used in women of child-bearing potential, with strict attention to birth control during and for at least 6 months after therapy. To help in the continuing review of optimal management of hepatitis C, the National Institutes of Health have formulated an ad hoc advisory group to review possible modifications in recommendations. Also valuable will be recommendations prepared by other scientific and regulatory groups using expert panels or the consensus conference mechanism to propose management guidelines from evidence-based review of current literature. For instance, recommendations regarding screening for hepatitis C and diagnosis were updated and expanded by the Centers for Disease Control and Prevention based upon the advice of expert consultants and several public meetings, which resulted in publication of a MMWR report (7): “Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease”. In the same way, the International Consensus Conference on Hepatitis C sponsored by the European Association for the Study of the Liver (EASL) will provide another unbiased, evidence-based update of the National Institutes of Health Consensus Panel statement.
Clinical challenges in management of hepatitis C While there have been important advances in diagnosis, management and therapy of hepatitis C, there remain many clinical challenges (Table 1). The central clinical challenges are to improve means of assessing the severity (grade) and stage of disease and evaluating prognosis of chronic hepatitis C, to increase the sustained response rates to therapy, to decrease the adverse side effects of current treatments and to decrease the financial and personal burden of therapy for all populations of patients with this disease. At present, the most pressing challenge is the low
265
J. H. Hoofnagle TABLE 1 Central clinical challenges in hepatitis C research l
l
l
l l
l
l
l
Better means of assessing disease severity and stage, predicting progression, predicting response before, and likelihood of relapse during treatment. More effective and better tolerated therapies; new antiviral agents, immune approaches, cytoprotective medications. Means of decreasing the side effects of therapy, such as the neuropsychiatric effects of interferon and the hemolysis of ribavirin. Reducing the burden of therapy, personally and financially. Finding optimal therapies for patients with co-morbid conditions, such as HIV infection and hepatitis B, as well as renal, cerebrovascular, cardiovascular, and neuropsychiatric diseases. Developing treatments for special types of patients: the elderly, children, post-transplant patients. Developing treatments for special situations: acute hepatitis C, post-exposure prophylaxis, mild hepatitis or hepatitis with normal aminotransferases, advanced hepatitis C and hepatitis C after liver transplantation. Developing means of treatment and delivering care to special groups of patients: indigent, public assistance, homeless and institutionalized populations.
rate of sustained response, even to an optimal course of therapy: more than half of patients treated do not have a sustained response to therapy with alpha interferon, with or without ribavirin. Current therapy is also poorly tolerated and expensive. Furthermore, combination therapy has many adverse side effects, some of which are life-threatening. Finally, current regimens are effective largely in highly selected groups of patients, adults with typical hepatitis C, without other complicating illnesses, who are often quite educated and highly motivated. The most pressing clinical need in hepatitis C is to develop more effective and better tolerated therapies. Major efforts are being made to develop potent antivirals, focusing upon inhibitors of the replicative enzymes of HCV, protease, helicase and polymerase inhibitors that might be used alone or in combination with alpha interferon. Other approaches to treatment include the use of agents that block other steps in replication, such as the internal ribosomal entry site (IRKS) or the cell surface receptor of HCV Cytokines and cytokine modulators may affect the life cycle of HCV and also deserve evaluation in chronic hepatitis C. Persistence of HCV infection and the associated hepatocellular injury are strongly influenced by immune mechanisms; thus immune modulators or stimulants may eventually prove effective in treating hepatitis C. Means of stimulating specific immune responses to HCV or viral antigens may also be critical in developing effective means of controlling this disease. Finally, non-specific cytoprotective agents, by acting through common intracellular pathways of hepatocyte 266
injury and repair, may ultimately play an important role in the management of hepatitis C. Indeed, the mechanism by which ribavirin increases the antiviral actions of alpha interferon is not currently known. Ribavirin might act by direct inhibition of viral replication (perhaps by interfering with the RNA polymerase), by modulation of the immune response (by affecting the balance of Thl and Th2 cell responses) or by direct cytoprotection (which might promote the normal intracellular actions of interferon in inducing an antiviral state). All of these approaches to the management of hepatitis deserve full evaluation. Perhaps as important as finding new agents to treat hepatitis C are approaches to improve the responses to current medications, in particular alpha interferon. Higher doses or different dose regimens may provide more optimal inhibition of HCV RNA and better long-term responses (8). Indeed, interferons with a better profile of pharmacokinetics are now being evaluated in clinical trials (9). Several forms of alpha interferon have been successfully pegylated; a process that gives interferon a longer half-life and more sustained period of action. Pegylated interferons can be given once weekly and have been shown to induce prolonged antiviral activity. Thus, improvements in the dosing, doses, regimens and formulations of both alpha interferon and ribavirin may improve response rates and decrease side effects. Prospective trials with direct, unbiased comparisons of these regimens are needed. An important clinical challenge is to develop viral and serologic markers that accurately predict the severity and stage of disease, the likelihood of progression of hepatitis, the likelihood of a response to treatment and, more importantly, the likelihood of a sustained response once a response has occurred in therapy. The latter issue is a critical clinical problem. The usual analysis of results of therapy trials show the end-oftreatment and sustained reponse rates, both of which were found to be higher with combination therapy as recently shown in the two controlled trials of interferon and ribavirin (Fig. 1). For the individual patient being treated, however, it is important also to analyze results in terms of relapse rates (Fig. 2). Relapse is defined as a return of HCV RNA during the 6 months after therapy has been stopped in patients who are nonreactive for this viral marker at the end of therapy. Thus, even after a year of combination therapy, relapses occur in at least 20% of patients. Furthermore, there are no reliable markers to predict the likelihood of a relapse other than the duration of therapy and genotype, which do not help in the individual case. A clinical marker of the likelihood of relapse would be helpful to accurately assess whether an individual patient who is
Future perspectives
lFN-6
IFN-12
W)
(503)
comb-6 Ws)
comb-12
(*
Fig, 1. End-of-treatment (total height of bars) and sustained (dark areas of bars) response rates to alpha interferon alone for 6 or 12 months (IFN-6 and IFN-12) compared with the rates with the combination of alpha interferon and ribavirin for either 6 or 12 months (Comb-6 and Comb-12). The number of patients in each group is given in parentheses, Combined results from the U. S. (4) and the international (6) trials of alpha interferon and ribavirin.
IFN-6
IFN-12
Comb-6
Comb-12
(66)
(147)
(278)
(260)
Fig. 2. The relapse rate after treatment with either 6 or 12 months of alpha interferon alone (IFN-6 and IFN-12) compared with the rates after treatment with either 6 or 12 months of the combination of alpha interferon and ribavirin (Comb-6 and Comb- 12). Relapse is defined as the rate of return of HCV RNA positivity 6 months after treatment among patients who were HCV RNA negative at the end of treatment. The number of patients in each group is given in parentheses. Combined results from the U.S. (4) and the international (6) trials of alpha interferon and ribavirin.
HCV RNA negative at the end of treatment will remain negative after therapy is stopped. Such a marker could be used to decide when combination therapy can be stopped. Most appropriate would be a “super-sensitive” polymerase chain reaction (PCR) assay for HCV RNA that would accurately demonstrate virus eradication. Other markers might be serologic tests (antibody titers, such as anti-E2) or immunologic markers (reactivity to HCV core or NS3) that indirectly reflect the presence on ongoing viral replication at low levels.
Management of hepatitis C would also greatly benefit by a reduction in the adverse side effects of therapy. A 1Zmonth course of the combination of alpha interferon and ribavirin is rarely well-tolerated. In the two large trials of combination therapy, dose reductions were reported in 7% and 25% and early termination of therapy in 19% and 21% of patients receiving 48 weeks of therapy (4, 6). It should also be stressed that patients entering controlled trials are usually quite committed to therapy; thus dose reductions and early terminations of therapy are likely to be much more frequent once therapy is used in general practice. Investigation of the cause of the adverse side effects of alpha interferon and ribavirin are needed, as well as means of preventing or ameliorating these adverse events. In particular, better information is needed on the management of the neuropsychiatric effects of alpha interferon and the basis of the autoimmune phenomena that occur during therapy. The pathogenesis of the anemia of ribavirin also deserves investigation. These adverse events are the major reasons for intolerance to combination therapy. Finally, a critical need in the management of hepatitis C is to improve the efficacy and safety of therapy in special groups, special populations and special situations that occur with this infection. For instance, the response rate and safety of therapy has not been established for children or for the elderly. Other groups with hepatitis C that have not been adequately evaluated are patients with other medical problems, with HIV coinfection, with ongoing alcohol or substance abuse, psychiatric or neurologic illnesses, autoimmune disease, renal failure, hemophilia, thalassemia and those who are receiving chemotherapy, immunosuppression or after bone marrow or solid-organ transplant. Evaluation of therapy at the different stages of hepatitis C is also needed. The efficacy and safety of therapy have not been studied and are not well known in acute hepatitis C, in cases of mild chronic hepatitis, in patients with normal aminotransferases, and, at the other end of the spectrum, in patients with cirrhosis and particularly with decompensated cirrhosis. Furthermore, the role and efficacy of interferon and combination therapy have yet to be shown in patients with cryoglobulinemia or glomerulonephritis due to hepatitis C. A critical issue is how to manage acute, accidental exposures to hepatitis C, such as needlestick exposures. Should these patients be treated preventively, once HCV RNA becomes detectable, only if clinical evidence of hepatitis appears, or only once the disease is clearly chronic? Finally, an important challenge is the management and therapy of special groups of patients, the indigent, the homeless, patients on public assist267
J. H. Hoofnagle
ante, in institutions and in prisons. The clinical challenges in management of hepatitis C are many. Until there are more effective and better tolerated therapies for hepatitis C, these challenges will remain.
References 1. Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. Isolation of a cDNA clone derived from a bloodborne non-A, non-B viral hepatitis genome. Science 1989: 244: 359-362. 2. Kuo G, Choo Q-L, Alter HJ, Gitnick GL, Redeker AG, Purcell H et al. An assay for circulating antibodies to a major etiologic virus of human non-A, non-B antibodies. Science 1989: 244: 362364. 3. National Institutes of Health Consensus Development Conference Panel. Management of hepatitis C. Hepatology 1997: 26 (Suppl 1): 2S16S. 4. McHutchison JG, Gordon SC, Schiff ER, Shiffman ML, Lee WM, Rustgi VK et al. for the Hepatitis Interventional Therapy Group. Interferon alpha 2-b alone or in combination with ribavi-
268
rin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339: 1485-1492. 5. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C et al. for the International Hepatitis Interventional Therapy Group. N Engl J Med 1998: 339: 1493-1499. 6. Poynard T, Marcellin P Lee SS, Niederau C. Minuk GS. Ideo G et -al. for the International Hepatitis Interventional Therapy Group. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998: 352: 14261432. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR (Morb Mort Wkly Rep) 1998: 47 (No. RR-19): l-39. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-a therapy. Science 1998: 282: 103-109. Hu Z-X, Hoffman J, Pate1 I, Joubert P Single-dose, safety-tolerability and pharmacokinetic-pharmacodynamics following administration of ascending subcutaneous doses of pegylated-interferon and interferon alpha-2a to healthy subjects. Hepatology 1998: 28: 708A [abstract].
Copyright0 EuropeanAssociation for the Studyof the Liver1999 Journal of Hepatology
ISSN 0169-5185 ISBN 87-16-16386-9
Management of hepatitis C: current and future perspective Jay H. Hoofnagle Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA
Chronic hepatitis C is now a major cause of chronic liver disease, cirrhosis and hepatocelhdar carcinoma. In March 1997, the National Institutes of Health sponsored a Consensus Development Conference entitled “Management of Hepatitis C”. The final statement from the Consensus Panel set forth clear, evidence-based guidelines and recommendations regarding the diagnosis, evaluation, prevention and therapy of hepatitis C. The conclusions of the Consensus Panel have been widely accepted and have brought some degree of uniformity to the management of hepatitis C. An important issue is how to keep such recommendations current in such a rapidly evolving area of medicine. In the 2 years since the Consenus Conference there have been important advances in the management of chronic hepatitis C. Two recommendations of the Consensus Panel deserve modification: lirst, on the clinical usefulness of genotyping of hepatitis C virus and second, on the optimal therapeutic regimen. Two large multicenter,prospectivecontrolled
The 1997 National Institutes of Health Consensus Development Hepatitis C
Conference: Management
of
In the United States as in Europe, chronic hepatitis C is one of the leading causes of cirrhosis, end-stage liver disease and hepatocellular carcinoma. The discovery of the hepatitis C virus (HCV) in 1989 (1) the development of sensitive assays for its detection (2), and the evolution of antiviral therapy have led to an important need to provide accurate and evidence-based recommendations regarding diagnosis, management and treatment. For these reasons, in March 1997, the National Institutes of Health sponsored a Consensus DeCorrespondence: Jay H. Hoofnagle, M.D., Bldg 31, Room 9A23, NIH, Bethesda, MD, USA, 20892. Tel: + 1 301 496 1333. Fax: + 1 301496 2830. e-mail: [email protected]
264
trials have shown that the combination of alpha interferon with ribavirin provides higher sustained virologic responses than interferon alone and that optimal therapy is a 24-week course for patients with genotypes 2 and 3 and a 4Sweek course for patients with genotype 1. Furthermore, therapy can be stopped at 24 weeks if HCV RNA is still present. Many clinical challenges remain. Major current needs are for accurate means of assessing the grade and stage of disease, for the likelihood of disease progression and of response to therapy as well as for viral eradication by treatment. Also important are new therapies for hepatitis C that might be used alone or in combination with interferon and ribavirin; therapies that could be applied to a wide variety of patients, with different stages of disease and with other co-morbitities. Key words: Cirrhosis; Consensus conferences; Controlled trials; Hepatitis C; Hepatitis C virus; Interferon; Ribavirin.
velopment Conference entitled “Management of Hepatitis C” (3). A panel of unbiased and independent professional and lay persons were provided with the published literature on hepatitis C and listened to 2 days of oral presentations on the virology, clinical features, course and natural history, epidemiology and therapy of hepatitis C. The panel then prepared a consensus statement that addressed six pre-selected questions: (1) What is the natural history of hepatitis C? (2) What is the most appropriate approach to diagnose and monitor patients with hepatitis C? (3) What is the most effective therapy for hepatitis C? (4) Which patients with hepatitis C should be treated? (5) What recommendations can be made to patients to prevent transmission of hepatitis C? (6) What are the most important areas for future research? The Consensus Development process insured a fair and unbiased set of recommendations that were based on firm scientific grounds. Areas
Future perspectives
of uncertainty were clearly delineated in the recommendations and comments. The recommendations and conclusions of the NIH Consensus Panel have been widely accepted and have brought some degree of uniformity to the management of hepatitis C.
Modification of the consensus recommendations An important and difficult problem now arises as to how to keep the recommendations made by the 1997 consensus panel current, particularly in view of the rapidly evolving understanding of the hepatitis C virus, its spread and treatment. Review of the consensus statement almost 2 years after it was written reveals that most of the conclusions and recommendations are still valid; for instance, recommendations regarding screening in high risk persons, diagnostic tests and their interpretation, indications for therapy and avoidance of transmission. Many of the statements were written with a view towards future progress for instance, the recent licensing and approval of a third generation enzyme immunoassay (EIA-3) and confirmatory test (RIBA-3) for detection of anti-HCV Two major recommendations of the consensus panel, however, warrant comment and possible modification: (1) the statement that genotyping of HCV is not clinically useful, and (2) the conclusion that the optimal regimen for therapy of hepatitis C is a 12month course of alpha interferon with testing for HCV RNA after 3 months and early discontinuation if viremia is still present. The modifications needed are largely the result of three large, multicenter, randomized controlled trials on the combination of alpha interferon and ribavirin as therapy of hepatitis C (4 6). Clearly, in all groups of patients, this combination resulted in higher sustained response rates than with alpha interferon alone. Importantly, genotyping for HCV appeared to be clinically important in determining the optimal duration of therapy. In both the U.S. and the international trials of alpha interferon and ribavirin, the rates of sustained virological response were 67% and 64% among patients with genotypes 2 and 3 and rates were similar with a 24-week course as with a 48week course of therapy. In contrast, the rates of response to the combination therapy were lower among patients with genotype 1, and rates were significantly higher with 48 weeks (28% and 31%) than 24 weeks of therapy (16% and 18%). Thus, the optimal regimen of therapy is currently the combination of alpha interferon and ribavirin given for 6 months for patients with genotypes 2 and 3 and for 12 months for patients genotype 1. For patients with genotype 1 who have low levels of HCV RNA or who had previously been treated and had a transient response and relapse, it is
not clear whether a 1Zmonth course provides additional benefit over a 6-month course. In both the U.S. and the international trials, sustained responders to combination therapy were all HCV RNA negative by 6 months (but not at 3 months). For this reason, therapy can be terminated at 6 months if HCV RNA is still present. Therapy with interferon alone should be reserved for patients with contraindications to ribavirin therapy such as anemia, renal insufficiency, inability to practice birth control and significant cerebral or cardiovascular disease. The appropriate dose and safety of ribavirin has not been shown for children; thus children should not be treated with this combination outside of controlled trials. Of great importance is that ribavirin is teratogenic and must be carefully used in women of child-bearing potential, with strict attention to birth control during and for at least 6 months after therapy. To help in the continuing review of optimal management of hepatitis C, the National Institutes of Health have formulated an ad hoc advisory group to review possible modifications in recommendations. Also valuable will be recommendations prepared by other scientific and regulatory groups using expert panels or the consensus conference mechanism to propose management guidelines from evidence-based review of current literature. For instance, recommendations regarding screening for hepatitis C and diagnosis were updated and expanded by the Centers for Disease Control and Prevention based upon the advice of expert consultants and several public meetings, which resulted in publication of a MMWR report (7): “Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease”. In the same way, the International Consensus Conference on Hepatitis C sponsored by the European Association for the Study of the Liver (EASL) will provide another unbiased, evidence-based update of the National Institutes of Health Consensus Panel statement.
Clinical challenges in management of hepatitis C While there have been important advances in diagnosis, management and therapy of hepatitis C, there remain many clinical challenges (Table 1). The central clinical challenges are to improve means of assessing the severity (grade) and stage of disease and evaluating prognosis of chronic hepatitis C, to increase the sustained response rates to therapy, to decrease the adverse side effects of current treatments and to decrease the financial and personal burden of therapy for all populations of patients with this disease. At present, the most pressing challenge is the low
265
J. H. Hoofnagle TABLE 1 Central clinical challenges in hepatitis C research l
l
l
l l
l
l
l
Better means of assessing disease severity and stage, predicting progression, predicting response before, and likelihood of relapse during treatment. More effective and better tolerated therapies; new antiviral agents, immune approaches, cytoprotective medications. Means of decreasing the side effects of therapy, such as the neuropsychiatric effects of interferon and the hemolysis of ribavirin. Reducing the burden of therapy, personally and financially. Finding optimal therapies for patients with co-morbid conditions, such as HIV infection and hepatitis B, as well as renal, cerebrovascular, cardiovascular, and neuropsychiatric diseases. Developing treatments for special types of patients: the elderly, children, post-transplant patients. Developing treatments for special situations: acute hepatitis C, post-exposure prophylaxis, mild hepatitis or hepatitis with normal aminotransferases, advanced hepatitis C and hepatitis C after liver transplantation. Developing means of treatment and delivering care to special groups of patients: indigent, public assistance, homeless and institutionalized populations.
rate of sustained response, even to an optimal course of therapy: more than half of patients treated do not have a sustained response to therapy with alpha interferon, with or without ribavirin. Current therapy is also poorly tolerated and expensive. Furthermore, combination therapy has many adverse side effects, some of which are life-threatening. Finally, current regimens are effective largely in highly selected groups of patients, adults with typical hepatitis C, without other complicating illnesses, who are often quite educated and highly motivated. The most pressing clinical need in hepatitis C is to develop more effective and better tolerated therapies. Major efforts are being made to develop potent antivirals, focusing upon inhibitors of the replicative enzymes of HCV, protease, helicase and polymerase inhibitors that might be used alone or in combination with alpha interferon. Other approaches to treatment include the use of agents that block other steps in replication, such as the internal ribosomal entry site (IRKS) or the cell surface receptor of HCV Cytokines and cytokine modulators may affect the life cycle of HCV and also deserve evaluation in chronic hepatitis C. Persistence of HCV infection and the associated hepatocellular injury are strongly influenced by immune mechanisms; thus immune modulators or stimulants may eventually prove effective in treating hepatitis C. Means of stimulating specific immune responses to HCV or viral antigens may also be critical in developing effective means of controlling this disease. Finally, non-specific cytoprotective agents, by acting through common intracellular pathways of hepatocyte 266
injury and repair, may ultimately play an important role in the management of hepatitis C. Indeed, the mechanism by which ribavirin increases the antiviral actions of alpha interferon is not currently known. Ribavirin might act by direct inhibition of viral replication (perhaps by interfering with the RNA polymerase), by modulation of the immune response (by affecting the balance of Thl and Th2 cell responses) or by direct cytoprotection (which might promote the normal intracellular actions of interferon in inducing an antiviral state). All of these approaches to the management of hepatitis deserve full evaluation. Perhaps as important as finding new agents to treat hepatitis C are approaches to improve the responses to current medications, in particular alpha interferon. Higher doses or different dose regimens may provide more optimal inhibition of HCV RNA and better long-term responses (8). Indeed, interferons with a better profile of pharmacokinetics are now being evaluated in clinical trials (9). Several forms of alpha interferon have been successfully pegylated; a process that gives interferon a longer half-life and more sustained period of action. Pegylated interferons can be given once weekly and have been shown to induce prolonged antiviral activity. Thus, improvements in the dosing, doses, regimens and formulations of both alpha interferon and ribavirin may improve response rates and decrease side effects. Prospective trials with direct, unbiased comparisons of these regimens are needed. An important clinical challenge is to develop viral and serologic markers that accurately predict the severity and stage of disease, the likelihood of progression of hepatitis, the likelihood of a response to treatment and, more importantly, the likelihood of a sustained response once a response has occurred in therapy. The latter issue is a critical clinical problem. The usual analysis of results of therapy trials show the end-oftreatment and sustained reponse rates, both of which were found to be higher with combination therapy as recently shown in the two controlled trials of interferon and ribavirin (Fig. 1). For the individual patient being treated, however, it is important also to analyze results in terms of relapse rates (Fig. 2). Relapse is defined as a return of HCV RNA during the 6 months after therapy has been stopped in patients who are nonreactive for this viral marker at the end of therapy. Thus, even after a year of combination therapy, relapses occur in at least 20% of patients. Furthermore, there are no reliable markers to predict the likelihood of a relapse other than the duration of therapy and genotype, which do not help in the individual case. A clinical marker of the likelihood of relapse would be helpful to accurately assess whether an individual patient who is
Future perspectives
lFN-6
IFN-12
W)
(503)
comb-6 Ws)
comb-12
(*
Fig, 1. End-of-treatment (total height of bars) and sustained (dark areas of bars) response rates to alpha interferon alone for 6 or 12 months (IFN-6 and IFN-12) compared with the rates with the combination of alpha interferon and ribavirin for either 6 or 12 months (Comb-6 and Comb-12). The number of patients in each group is given in parentheses, Combined results from the U. S. (4) and the international (6) trials of alpha interferon and ribavirin.
IFN-6
IFN-12
Comb-6
Comb-12
(66)
(147)
(278)
(260)
Fig. 2. The relapse rate after treatment with either 6 or 12 months of alpha interferon alone (IFN-6 and IFN-12) compared with the rates after treatment with either 6 or 12 months of the combination of alpha interferon and ribavirin (Comb-6 and Comb- 12). Relapse is defined as the rate of return of HCV RNA positivity 6 months after treatment among patients who were HCV RNA negative at the end of treatment. The number of patients in each group is given in parentheses. Combined results from the U.S. (4) and the international (6) trials of alpha interferon and ribavirin.
HCV RNA negative at the end of treatment will remain negative after therapy is stopped. Such a marker could be used to decide when combination therapy can be stopped. Most appropriate would be a “super-sensitive” polymerase chain reaction (PCR) assay for HCV RNA that would accurately demonstrate virus eradication. Other markers might be serologic tests (antibody titers, such as anti-E2) or immunologic markers (reactivity to HCV core or NS3) that indirectly reflect the presence on ongoing viral replication at low levels.
Management of hepatitis C would also greatly benefit by a reduction in the adverse side effects of therapy. A 1Zmonth course of the combination of alpha interferon and ribavirin is rarely well-tolerated. In the two large trials of combination therapy, dose reductions were reported in 7% and 25% and early termination of therapy in 19% and 21% of patients receiving 48 weeks of therapy (4, 6). It should also be stressed that patients entering controlled trials are usually quite committed to therapy; thus dose reductions and early terminations of therapy are likely to be much more frequent once therapy is used in general practice. Investigation of the cause of the adverse side effects of alpha interferon and ribavirin are needed, as well as means of preventing or ameliorating these adverse events. In particular, better information is needed on the management of the neuropsychiatric effects of alpha interferon and the basis of the autoimmune phenomena that occur during therapy. The pathogenesis of the anemia of ribavirin also deserves investigation. These adverse events are the major reasons for intolerance to combination therapy. Finally, a critical need in the management of hepatitis C is to improve the efficacy and safety of therapy in special groups, special populations and special situations that occur with this infection. For instance, the response rate and safety of therapy has not been established for children or for the elderly. Other groups with hepatitis C that have not been adequately evaluated are patients with other medical problems, with HIV coinfection, with ongoing alcohol or substance abuse, psychiatric or neurologic illnesses, autoimmune disease, renal failure, hemophilia, thalassemia and those who are receiving chemotherapy, immunosuppression or after bone marrow or solid-organ transplant. Evaluation of therapy at the different stages of hepatitis C is also needed. The efficacy and safety of therapy have not been studied and are not well known in acute hepatitis C, in cases of mild chronic hepatitis, in patients with normal aminotransferases, and, at the other end of the spectrum, in patients with cirrhosis and particularly with decompensated cirrhosis. Furthermore, the role and efficacy of interferon and combination therapy have yet to be shown in patients with cryoglobulinemia or glomerulonephritis due to hepatitis C. A critical issue is how to manage acute, accidental exposures to hepatitis C, such as needlestick exposures. Should these patients be treated preventively, once HCV RNA becomes detectable, only if clinical evidence of hepatitis appears, or only once the disease is clearly chronic? Finally, an important challenge is the management and therapy of special groups of patients, the indigent, the homeless, patients on public assist267
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ante, in institutions and in prisons. The clinical challenges in management of hepatitis C are many. Until there are more effective and better tolerated therapies for hepatitis C, these challenges will remain.
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rin as initial treatment for chronic hepatitis C. N Engl J Med 1998: 339: 1485-1492. 5. Davis GL, Esteban-Mur R, Rustgi V, Hoefs J, Gordon SC, Trepo C et al. for the International Hepatitis Interventional Therapy Group. N Engl J Med 1998: 339: 1493-1499. 6. Poynard T, Marcellin P Lee SS, Niederau C. Minuk GS. Ideo G et -al. for the International Hepatitis Interventional Therapy Group. Randomised trial of interferon a2b plus ribavirin for 48 weeks or for 24 weeks versus interferon a2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. Lancet 1998: 352: 14261432. Centers for Disease Control and Prevention. Recommendations for prevention and control of hepatitis C virus (HCV) infection and HCV-related chronic disease. MMWR (Morb Mort Wkly Rep) 1998: 47 (No. RR-19): l-39. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-a therapy. Science 1998: 282: 103-109. Hu Z-X, Hoffman J, Pate1 I, Joubert P Single-dose, safety-tolerability and pharmacokinetic-pharmacodynamics following administration of ascending subcutaneous doses of pegylated-interferon and interferon alpha-2a to healthy subjects. Hepatology 1998: 28: 708A [abstract].