Viral Hepatitis - part 7 pot

Chapter 33532 to be closely monitored by an individual who has the time to interact and support them throughout treatment. Physicians are rarely able to achieve this, and this role is best performed by a specially trained nurse. Under their tutelage, the patient can learn to control the fevers associated with IFN by taking prophylactic acetami- nophen. The irritating cough and dry skin associated with ribavirin therapy can be considerably reduced by encouraging the patient to maintain a high fl uid intake. The troublesome depression that particularly affects in- dividuals whose pretreatment history indicates past de- pressive illness, can be greatly helped by prophylactic use of antidepressant medications. Appropriate dose reduction of IFN and/or ribavirin Dose reduction is most often required because of ad- verse laboratory events, particularly a fall in haemo- globin and/or absolute neutrophil count. Sometimes symptoms, particularly overwhelming fatigue and shortness of breath, may occur when the haemoglobin is not very low but the haemolysis caused by ribavirin has been particularly rapid. Under these circumstances, it may be necessary to reduce ribavirin dosage for a short period of time. Addiction medicine counselling A recent study of antiviral therapy given to patients with hepatitis C who fell into various psychiatric risk groups indicated that adherence rates could be easily maintained in individuals with well controlled psychi- atric illnesses or in those with prior addiction habits that were controlled on methadone. But in those who were former injecting drug users (IDUs), but not on metha- done, the drop-out rate was higher and hence SVR rates were much lower. 32 Unfortunately, methadone is only useful in injecting drug users who are addicted to opio- ids, and at present there is no medication which helps curb addiction to other compounds such as cocaine. In some centres, antiviral treatment given to current IDUs is said to be successful, 45 although few current IDUs are motivated to seek and maintain medical help. Predicting response to antiviral therapy for hepatitis C Retrospective analysis of outcomes following treatment with standard IFN and ribavirin suggested that it was possible early on in treatment to predict who may not attain an SVR by examining the fall in viral load from baseline to 4 weeks. 46 It was shown that 50–60% of sub- sequent non-responders could have been predicted ear- ly into treatment. 47 Prospective analysis of PEG-IFNα-2a plus ribavirin has shown that the likelihood of achieving an SVR can also be reliably predicted at 12 weeks into therapy. 14 Clinical implications of improved predictability of antiviral treatment in hepatitis C Our ability to reliably predict outcome at 12 weeks into treatment means that the burden of therapy to patients can be limited to those who are most likely to respond. In those who do attain an EVR, this information may help to sustain them through the ongoing unpleasant side-ef- fects of treatment required for a further 36 weeks, i.e. it acts as an incentive for patient counselling and educa- tion. An improvement in cost-benefi t ratio will also be achieved if therapy is stopped at 12 weeks in those who do not achieve an EVR. However, as all those infected with genotype 2 or 3 achieve an EVR, testing at 12 weeks into treatment is not recommended, rather 6 months of treatment is given to all. Barriers to antiviral therapy for hepatitis C Accessibility The major pool of infected individuals worldwide live in situations which are either hard to access, e.g. home- less individuals, impoverished individuals in the devel- oping world, those living in isolated areas such as on reservations, and individuals not isolated, but in a social situation where the need for therapy is often ignored, i.e. individuals incarcerated in prisons. An equally dis- turbing situation is the inability of an individual to af- ford the cost of antiviral therapy in any part of the world because their insurance system fails to cover their costs. The complex requirements of both repeated injections and serial blood monitoring, with the need to access pa- tients immediately if the drug dose needs to be reduced or stopped, really precludes employing the current ther- apies in many individuals. But unless this large source of potential transmission for virus is controlled, there is no hope that we will signifi cantly impact the burden of hepatitis C. Thus, clean needle exchange programmes have been initiated in many countries. Many govern- ments have recognized the inadvisability of withhold- ing antiviral therapy from the prison population. In such a controlled environment, there is no reason why antiviral therapy should not be successful. 48,49 Contraindications to current therapies There remain many infected individuals who either have co-morbidities that preclude current antiviral therapies, e.g. severe seizure disorder which cannot be 1405130059_4_033.indd 5321405130059_4_033.indd 532 30/03/2005 12:39:5230/03/2005 12:39:52 Treatment of chronic hepatitis C 533 adequately controlled, or who are unable to tolerate the treatment-associated side-effects. It is hoped that such individuals will be able to be successfully treated with the second generation of antiviral therapy for hepatitis C, namely enzyme inhibitors. There are others who can- not tolerate current therapies because their liver disease is too advanced, in which case if there are no other con- traindications, liver transplantation may be the optimal route. Need for adjunctive therapy With appropriate adjunctive and supportive therapy, the number of patients in whom treatment is recom- mended, but in whom co-morbid conditions have in the past precluded therapy, may be signifi cantly reduced with the use of agents to control depression and support blood components. Special populations of patients with hepatitis C requiring antiviral therapy Patients with cirrhosis Potentially, individuals with cirrhosis due to hepati- tis C have the most to gain in the short and possibly the long term, were they to be successfully treated for their hepatitis C. Whereas therapy with standard IFN monotherapy was very disappointing, particularly in cirrhotic patients, the chance of achieving an SVR with PEG-IFN-α and ribavirin is markedly better, i.e. 40–50%. Those most likely to die from their hepatitis C are those with cirrhosis. Both early 50 and long-term 51 follow-up liver biopsy data indicate that regression of hepatic fi brosis may be observed following antiviral therapy most often when an SVR is achieved. If liver transplantation is still required, recurrence of hepatitis C post-transplant is much less in those who have unde- tectable HCV RNA. 22 Analysis of very large numbers of patients with hep- atitis C treated with all forms of antiviral therapy do suggest that the rate of subsequent hepatocellular car- cinoma (HCC) is signifi cantly less in those who at the time of therapy had a hepatic fi brosis score of 3 out of 4. 52 However, the benefi t seems to be mainly in Japanese patients, in whom the risk of HCC in chronic hepatitis C is so much higher. A signifi cant benefi t in terms of reduction in HCC in Caucasians is disputed. 53,54 There are reports that following successful antiviral therapy the rate of hepatic decompensation is reduced in both Japanese and Caucasians – but all these data are from observational studies, where the less severe patients tend to be those treated. 55,56 It is logical to assume that if the inciting agent is removed, there will be a long-term benefi t – just as there is when appropriate reduction in copper or iron overload is achieved in individuals with Wilson’s disease or haemochromatosis. HIV/HCV co-infection Liver-related mortality in individuals with HIV/HCV co-infection has become more overt since the introduc- tion of effective therapy for HIV infection. Although the mortality from liver disease remains highest in co-in- fected individuals not treated for their HIV infection, liv- er disease remains a signifi cant problem in those whose HIV infection is well controlled. 20 There is an urgent need to introduce effective antiviral therapy for hepa- titis C in the co-infected individual, because the rate of liver disease progression in co-infected individuals is al- most double that seen with HCV infection alone. However, there are many problems encountered dur- ing treatment for hepatitis C in those who also are in- fected with HIV. Because of the background immune suppression, HCV RNA titres tend to be high. There are reports of untoward drug interactions between ribavirin and various components of HAART therapy, particu- larly with the ‘d’ drugs, which are probably related to competition for intracellular metabolism. 57,58 Such drug interactions may cause severe mitochondrial injury, he- patic steatosis and even liver failure, but less overt drug interactions may just destabilize the HAART. As many co-infected individuals either have been or currently re- main IDUs, the issue of adherence to both HIV and HCV antiviral therapy is problematic. Co-infected individuals generally have as their pri- mary physician an individual who is not trained in the management of liver disease or skilled in the practice of liver biopsy. Without a liver biopsy, patients with cirrhosis will be missed, as compensated cirrhosis can- not be reliably assessed with non-invasive techniques. Antiviral therapy in HCV/HIV co-infection in an indi- vidual with cirrhosis who has even only mild evidence of hepatic impairment in terms of minimal elevation of serum bilirubin and/or low serum albumin, may lead to rapid hepatic decompensation and death. 59 Thus, it is advised that co-infected patients be managed in a multi- disciplinary clinic which includes experts in HIV and liver disease as well as addiction medicine. 60 Timing of treatment for hepatitis C in individuals co-infected with HIV Management guidelines suggest that in individuals co-infected with HCV and HIV, it is generally best to consider the need for treatment of the HIV fi rst and if anti-retroviral therapy is not required, then this is the ideal time for introducing treatment for hepatitis C. If anti-retroviral treatment is required, then this should be started before any antiviral therapy for hepatitis C is 1405130059_4_033.indd 5331405130059_4_033.indd 533 30/03/2005 12:39:5230/03/2005 12:39:52 Chapter 33534 given, and the HIV infection should be stabilized be- fore introducing treatment with IFN and ribavirin (this is discussed in more detail in Chapter 50). Those with normal ALT with or without other non-hepatic, hepatitis C-related co-morbidities At least 25% of individuals infected with hepatitis C have consistently or intermittently normal ALT levels, over a period of several years. Some may have signifi - cant hepatic fi brosis on liver biopsy, indicating that they are at risk for further disease progression and thus may warrant therapy. 61 Effi cacy of PEG IFN-α-2a 180 µg/ week plus ribavirin (800 mg/day) for 48 weeks indicates that SVR rates are not dissimilar to those observed in individuals with elevated ALT. 17 There are other individuals who have signifi cant co- morbidity caused by hepatitis C which may improve were the virus to be eradicated. Serum ALT values may well be normal, and liver biopsy may show only mild liver disease, but nevertheless treatment is warranted, particularly if the patient suffers from symptomatic vas- culitus caused by cryoglobulinaemia with or without a complicating non-Hodgkin’s lymphoma (NHL). A re- cent meta-analysis suggests that the association between hepatitis C and NHL appears real. 62 Symptoms of cryoglobulinaemia caused by a vasculi- tus affecting most often the skin, kidneys or peripheral nerves are well controlled in 70% of those undergoing antiviral therapy, even when viraemia persists. 63 Re- lapse after cessation of therapy occurs if viral clearance has not been achieved, but symptoms may remain con- trolled even in the presence of persistent viraemia in many 64 without the need for immunosuppressive ther- apy and/or plasmapheresis. This particular co-mor- bidity may be one of the few indications for prolonged antiviral therapy in the face of persistent viraemia. Complete resolution of splenic lymphoma associated with a chronic hepatitis C infection may be observed fol- lowing a sustained viral response, not so if SVR is not achieved. 65 The seroprevalence of hepatitis C in patients with end-stage renal disease is high. 66 As IFN is generally not recommended in patients with a kidney transplant because this drug may promote rejection of this small organ, 67 antiviral therapy needs to be given as early into the course of an individual’s chronic renal disease as possible, as antiviral therapy is poorly tolerated in end-stage renal disease. However, the pharmacokinet- ics of the PEG-IFN-α-2a is such that these drugs may be better tolerated than standard IFN-α (Fig. 33.3) Liver transplant patients End-stage liver disease caused by chronic hepatitis C is now the major indication for liver transplantation in Eu- rope and North America. With no active intervention, graft reinfection is inevitable and, in the setting of the anti-rejection therapy, rapidly progressive disease can occur – threatening graft and patient survival. Pre-transplant Ideally, the physician should aim for a sustained viral clearance before transplant, but this is rarely feasible as the patients frequently have decompensated disease and, in patients with HCC, the urgent need for trans- plant limits the use of effective antiviral therapy prior to the procedure. With careful supervision and dose modifi cation some patients can benefi t from pre-transplant treatment. 22 Post-transplant Despite the immunostimulatory effects of IFN-α and the theoretical risks of graft rejection, IFN is success- fully used in many recipients of liver transplants. Most of the published studies have featured trials of standard IFN and ribavirin, and there is increasing use of PEG- IFN with ribavirin. Overall, the success rates are lower in the post-transplant patients and discontinuation rates are much higher than those seen in the non-transplant setting. In one French study, 68 52 liver transplant recipients were randomized to receive standard IFN in combina- tion with ribavarin or placebo. The SVR was 21% in those who received the combination and 0% in those who re- ceived placebo. Signifi cant side-effects, particularly se- vere anaemia, led to treatment discontinuation in 43%. Another study compared treatment with IFN and ribavirin for 6 months versus 12 months. 69 Fifty-seven patients (68% genotype 1b) were treated, and the SVR was 22% in those who received therapy for 6 months and 17% in those who received therapy for 1 year, sug- gesting that a subgroup of patients may benefi t from a relatively short course of treatment. This study also demonstrated that in the virological non-responders with a biochemical response there was also histological improvement, and there may be a role for ‘maintenance therapy’ in this group of patients. In view of the poor tolerance of antiviral regimens and the low antiviral response in this group, other approach- es have been tried such as ribavirin monotherapy. Short- term use of ribavirin monotherapy 70 has been shown to lead to a biochemical response and a decrease in the in- fl ammatory score on liver histology, but longer-term fol- low-up will be required to ascertain whether this is also associated with a reduction in fi brosis development. Most studies now feature PEG-IFN and ribavirin. One pilot study 71 described high levels of discontinuation 1405130059_4_033.indd 5341405130059_4_033.indd 534 30/03/2005 12:39:5230/03/2005 12:39:52 Treatment of chronic hepatitis C 535 because of side-effects (43.6%) but an SVR of 66.7% in those who completed therapy. For those patients unable to tolerate IFN and ribavi- rin, there are prospects of future therapy with protease and helicase inhibitors or alternative approaches with anti-fi brotic rather than antiviral agents. Ongoing drug use The patient who continues to inject drugs can vary from the stable patient on a supervised (oral or injected) methadone or heroin programme to the erratic patient who injects from time to time and who continues to share needles and syringes with others. Delivery of care to the more chaotic patient is a considerable challenge and requires substantial resources. In the more erratic patient, there are risks of missing doses and monitoring visits and also the risk of reinfection at any time dur- ing the treatment course. A multidisciplinary approach is vital. Most would advise that the priority with such a patient is to work closely with the drug treatment centres and to encourage the patient to follow their pre- scribed drug stabilization programme before embarking on a treatment course for hepatitis C. Alcohol consump- tion, polydrug use, nutritional problems, anxiety and depression are common in this group and psychiatric input is therefore valuable. Many of the studies report- ing benefi cial effects of IFN and ribavirin in drug users exclude those with active drug or alcohol use. 72 In a Nor- wegian study 73 27 ex-intravenous drug users who had been successfully treated for hepatitis C were followed up. Although 33% of the group had returned to injecting drugs, only one had evidence of reinfection, suggesting that at least some behaviour modifi cation had occurred. It is also argued that treating drug users may have some benefi ts beyond the individual patient, and that reduc- ing the viral load in a drug user reduces the chance of infection spreading to others. Early treatment guidelines counselled against treat- ing active drug users, and the wisdom and ethics of this have been questioned by Edlin and others. 74 They emphasize that adherence to treatment regimens is re- duced in many chronic illnesses and that the risk versus benefi t of side-effects, risk of reinfection and timing of treatment must be assessed for each individual. Supervised drug treatment programmes may involve daily visits and can be combined with directly observed hepatitis C treatment programmes. This approach could also be adapted to the prison environment. The longer half-lives of PEG-IFNs lend themselves to the concept of once-weekly supervised therapy. African-American patients African-American patients are more likely to have geno- type 1 infection, lower ALT values and less rapid disease progression. 75 African-Americans also have lower neu- trophil counts, which may lead to exclusion from ther- apy or to inappropriate dose reductions. 76 They are also less likely to have an elevated alpha-fetoprotein with HCC development. 77 The chance of responding to anti- viral therapy is reduced and this is not fully understood, although the prevalence of ‘hard-to-treat genotypes’ tends to be high. Two clinical trials 78 were pooled to ana- lyze this further. There were 53 black patients among the total of 1744 patients, and 96% of them had genotype 1 infection compared with 65% of the white patients. The overall response rate was 27% in the white patients and only 11% in the black patients. The SVR rates in the black patients were 20% with 24 weeks of standard IFN and ribavirin, 23% with 48 weeks of this therapy, and no patients responded to IFN monotherapy. For geno- type 1 infection, the sustained response rates of 23% in the black patients and 22% in the white patients suggest that in this study the genotype was a major factor in the overall responses. Increased iron stores have been reported in African-Americans, 79 which may infl uence immune response. One study compared the virological kinetics in 19 Af- rican-American and 16 white patients with genotype 1 infection and reported a decreased viral load reduction in the African-American group. 80 Similarly, intensifi ca- tion of the IFN dosing with daily administration also demonstrated a decreased response in this group. 81 Children Earlier experiences with higher doses of IFN in children with chronic hepatitis B have shown that children tol- erate such therapy surprisingly well. There are limited clinical trial data for children, and many of the children treated have underlying conditions such as haemophil- ia, thalassaemia or malignancy, which may impair their response and reduce their chance of tolerating antiviral therapy. In one study of 41 children, an SVR of 61% was reported following 1 year of standard IFN and ribavi- rin. 82 As yet, there are limited data on the use of PEG- IFN regimens in this group. Thalassaemia and iron overload Thalassaemia patients with hepatitis C are challenging to treat as they may be unable to tolerate the haemolysis associated with ribavirin and may have advanced liver disease and a substantial iron overload at baseline – fac- tors which generally reduce the chance of responding to treatment. In one IFN monotherapy study, 83 six of thirteen chil- dren responded and a favourable response was more likely in those with less severe liver disease and lower 1405130059_4_033.indd 5351405130059_4_033.indd 535 30/03/2005 12:39:5330/03/2005 12:39:53 Chapter 33536 baseline ferritin levels. An Australian study, 84 however, found that the baseline hepatic iron concentration did not affect the chance of a sustained response. In a pilot study, 85 11 patients with thalassaemia were treated with a combination of standard IFN and riba- virin. Five patients had a sustained response although, probably as a result of the ribavirin, transfusion and iron chelation requirements were increased during the treatment period. In another study, 86 18 patients (14 with genotype 1b) received 12 months of combination of standard IFN and ribavirin and the SVR was 72.2% with a 30% increase in supportive blood transfusion. Studies are underway with PEG-IFN and ribavirin, and PEG-IFN monotherapy may be an option for those who are unable to tolerate ribavirin. Non-responders and relapsers to standard IFN monotherapy or combination regimens with ribavirin Several studies have shown that for those who have previously failed to respond to IFN monotherapy there is a reasonable chance of responding to combination therapy. The benefi t is particularly seen in those who initially responded and then relapsed. In one study 87 of 345 pa- tients who had relapsed following IFN monotherapy, the sustained response rate was 49% in those who received IFN and ribavirin combination therapy and only 5% in those who were retreated with IFN monotherapy. Response rates in previous non-responders are much lower at 15–20%. 88–92 Other studies have tried other ap- proaches such as an induction period with high dose IFN. Another approach has been the addition of aman- tadine to the regimen. In a large study of 225 non-re- sponders, 93 IFN and ribavirin was compared with IFN, ribavirin and amantadine. There was a trend towards a higher response rate in the group who received triple therapy (25% versus 18%). The use of other types of IFNs has also been tried in this group of patients. A pilot study of treatment with consensus IFN and ribavirin 94 in patients who had failed to respond to standard IFN and ribavirin reported SVRs of 33% in the previous non-responders and 42% in the previous relapsers. There are limited data on PEG-IFN ribavirin regimens as retreatment, but preliminary results suggest signifi - cant benefi ts for those who have received IFN mono- therapy and more modest gains for those who have already received IFN and ribavirin. The early virologi- cal response will hopefully also prove useful in deter- mining the chance of an SVR in these patients, but more data are required to ascertain whether the predictors in previously treated patients undergoing retreatment re- main valid. Overall, the factors associated with a higher chance of responding to retreatment are previous relapse (rather than non-response), genotypes 2 and 3, lower levels of HCV RNA and an early virological response to treat- ment. Negative factors include being African-American and/or cirrhotic. Those with only mild liver damage can afford to wait for the development of new antiviral agents, but for those with more severe disease a more realistic priority may be to inhibit fi brosis and maintain liver function. Long-term maintenance regimens may need to be con- sidered. References 1 Kenny-Walsh E. Clinical outcomes after hepatitis C infection from contaminated anti-D immune globulin. N Engl J Med 1999;340:1228–33. 2 Di Bisceglie AM. 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Is an ‘à la carte’ combination interferon alfa-2b plus ribavirin regi- men possible for the fi rst line treatment in patients with chronic hepatitis C? Hepatology 2000;31:211–18. 47 Liu WCL, Tomlinson G, Mazzulli T, Murray A, Heathcote J. Early prediction of non-responders to treatment with interferon alpha-2b and ribavirin in patients with chronic hepatitis C. Can J Gastroenterol 2003;17:483–7. 48 Skipper C, Guy JM, Parkes J, Roderick P, Rosenberg WM. Eval- uation of a prison outreach clinic for the diagnosis and preven- 1405130059_4_033.indd 5371405130059_4_033.indd 537 30/03/2005 12:39:5330/03/2005 12:39:53 Chapter 33538 tion of hepatitis C. Implications for the national strategy. Gut 2003;52:1500–4. 49 Hammett TM. Adapting more systematic approaches to hep- atitis C treatment in correctional facilities. Ann Intern Med 2003;138:235–6. 50 Poynard T, McHutchison J, Manns M et al. Impact of pegylated interferon alfa-2b and ribavirin on liver fi brosis in patients with chronic hepatitis C. Gastroenterology 2002;122:1303–13. 51 Shiratori Y, Imazeki F, Moriyama M et al. Histologic improve- ment of fi brosis in patients with hepatitis C who have sustained response to interferon therapy. Ann Intern Med 2000;132:517– 24. 52 Yoshida H, Shiratori Y, Moriyama M et al. Interferon therapy reduces the risk for hepatocellular carcinoma: national sur- veillance program of cirrhotic and non-cirrhotic patients with chronic hepatitis C in Japan. Ann Intern Med 1999;131:174–81. 53 Camma C, Giunta M, Andreone P, Craxi A. Interferon and pre- vention of hepatocellular carcinoma in viral cirrhosis: an evi- dence-based approach. J Hepatol 2001;34:593–602. 54 Papatheodoridis GV, Papadmitripoulos VC, Hadziyannis SJ. Ef- fect of interferon therapy on the development of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis: a meta analysis. 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Management and guidelines for the HCV & HIV co-infected adult: recommendations of a multidis- ciplinary expert panel. Can J Infect Dis 2001;12:67–71. 61 Martinot-Peignoux M, Boyer N, Cazals-Hatem D et al. Pro- spective study on anti-hepatitis C virus positive patients with persistently normal serum alanine transaminase with or without detectable serum hepatitis C virus RNA. Hepatology 2001;34:1000–5. 62 Gisbert JP, Carcia-Buey L, Pajares JM, Moreno-Otero R. Preva- lence of hepatitis C virus infection in B-cell non-Hodgkin’s lym- phoma: systematic review and meta-analysis. Gastroenterology 2003;125:1723–32. 63 Cacoub P, Lidove O, Maisonobe T et al. Interferon-alpha and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitus. Arthritis Rheum 2002;46:3317–26. 64 Joshi S, Heathcote EJ. The morbidity of symptomatic cryoglob- ulinemia and hepatitis C and response to treatment. Gastroenter- ology 2003;124(Suppl. 1):(Abstract). 65 Hermine O, Lefrere F, Bronowicki J-P et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepati- tis C virus infection. N Engl J Med 2002;347:89–94C. 66 Centers for Disease Control and Prevention. Recommendations for preventing transmission of infections among chronic hemo- dialysis patients. Morbid Mortal Wkly Rep 2001;50(RR-5):1–43. 67 Luciani G, Bossola M, Muscaritoli M et al. Sustained response with negative serum HCV RNA and disappearance of antibod- ies after interferon-alpha therapy in a kidney transplant recipi- ent with chronic active viral hepatitis. J Nephrol 2003;16:417–20. 68 Samuel D, Bizollon T, Feray C et al. Interferon-alpha 2b plus rib- avirin in patients with chronic hepatitis C after liver transplan- tation: a randomized study. Gastroenterology 2003;124:642–50. 69 Lavezzo B, Franchello A, Smedile A et al. Treatment of recur- rent hepatitis C in liver transplants: effi cacy of a six versus a twelve month course of interferon alfa 2b with ribavirin. J Hepa- tol 2002;37:247–52. 70 Gane EJ, Lo SK, Riordan SM et al. A randomized study compar- ing ribavirin and interferon alfa monotherapy for hepatitis C recurrence after liver transplantation. Hepatology 1998;27:1403. 71 Mukherjee S, Rogge J, Weaver L, Schafer DF. Pilot study of pegylated interferon alfa-2b and ribavirin for recurrent hepati- tis C after liver transplantation. Transplant Proc 2003;35:3042–4. 72 Sylvestre DL. Treating hepatitis C in methadone maintenance patients: an interim analysis. Drug Alcohol Depend 2002;6:117– 23. 73 Dalgard O, Bjoro K, Hellum K et al. Construct Group. Treatment of chronic hepatitis C in injecting drug users: 5 years’ follow-up. Eur Addict Res 2002;8:45–9. 74 Edlin BR, Seal KH, Lorvick J et al. Is it justifi able to withhold treatment for hepatitis C from illicit-drug users? N Engl J Med 2001;345:211–15. 75 Wiley TE, Brown J, Chan J. Hepatitis C infection in African Americans: its natural history and histological progression. Am J Gastroenterol 2002;97:700–6. 76 Soza A, Everhart JE, Ghany MG et al. Neutropenia during com- bination therapy of interferon alfa and ribavirin for chronic hepatitis C. Hepatology 2002;36:1273–9. 77 Nguyen MH, Keeffe EB. Screening for hepatocellular carcino- ma. J Clin Gastroenterol 2002;35(5 Suppl. 2):S86–S91. 78 McHutchison JG, Poynard T, Pianko S et al. The impact of in- terferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interven- tional Therapy Group Gastroenterology 2000;119:1317–23. 79 Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV. Racial differences in the relationship between hepatitis C infection and iron stores. Hepatology 2003;37:795–801. 80 Layden-Almer JE, Ribeiro RM, Wiley T, Perelson AS, Layden TJ. 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A placebo controlled randomized trial of ribavirin monotherapy versus combination therapy with ribavirin and interferon in 121 patients in the Benelux. BMC Gastroenterol 2003;3:24. 93 Teuber G, Pascu M, Berg T et al. Randomized, controlled trial with IFN-alpha combined with ribavirin with and without amantadine sulphate in non-responders with chronic hepatitis C. J Hepatol. 2003;39:606–13. 94 Barbaro G, Barbarini G. Consensus interferon for chronic hepa- titis C patients with genotype 1 who failed to respond to, or re- lapsed after, interferon alpha-2b and ribavirin in combination: an Italian pilot study. Eur J Gastroenterol Hepatol 2002;14:477– 83. 1405130059_4_033.indd 5391405130059_4_033.indd 539 30/03/2005 12:39:5430/03/2005 12:39:54 540 hepatitis C infection, the ideal therapy would be highly effective, orally bioavailable, without major side-effects and affordable. While such a drug is unlikely to be de- veloped in the near future, a number of novel and prom- ising compounds may signifi cantly improve current options for therapy. Many were designed on the basis of insights into the mechanics of HCV replication, entry into cells and host cellular immune responses. Others may slow the progression of liver disease. In this chap- ter, we highlight and summarize many of these ongoing developments and research. Chapter 34 New drugs for the management of hepatitis C John G McHutchison, Jennifer M King, Amany Zekry Introduction Approximately 170 million people worldwide are in- fected with hepatitis C virus (HCV). 1 Current therapies for chronic HCV infection (Table 34.1) are only effective in approximately 50% of patients. In addition, therapies are costly, prolonged, associated with signifi cant side-ef- fects, and not suitable for all patients. Fortunately, many new treatments for HCV infection are currently being designed and evaluated in preclini- cal, animal and human studies. For patients with chronic Table 34.1 Hepatitis C drugs in various phases of development Drug type Compound Phase of development Comments Small molecules and viral enzyme inhibitors NS3 helicase inhibitors Preclinical and phase 1 Numerous agents in preclinical stages. Development of one compound halted in early dose-ranging studies NS5B polymerase inhibitors JTK-003 Phase 1 and 2 Inhibits HCV RNA replication in cell culture JTK-109 Preclinical Inhibits HCV RNA replication in cell culture NM-283 Phase 1 and 2 Inhibits HCV RNA replication in cell culture. Up to 1 log reduction preliminarily reported in early short-term clinical trials p7 inhibitors Long-alkyl-chain iminosugar derivatives Phase 2 Have antiviral activity against bovine viral diarrhoea virus. Clinical data pending in HCV-infected patients Ribozymes Directed at IRES Phase 1 and 2 Further development halted because of animal toxicology fi ndings Antisense oligonucleotides ISIS-14803 Phase 2 >1 log reductions observed in some HCV non-responder patients, associated with transient asymptomatic ALT elevations siRNA and eiRNA Preclinical Uses double-stranded RNA to downregulate post- translational gene expression NS3 serine protease inhibitors Preclinical and phase 1 A multitude of agents from different classes are in preclinical development. One agent, BILN-2061, has entered a phase 1 trial and is associated with profound viral inhibition, but further development has been halted (Continued.) 1405130059_4_034.indd 5401405130059_4_034.indd 540 30/03/2005 12:40:2130/03/2005 12:40:21 New drugs for the management of hepatitis C 541 Drug type Compound Phase of development Comments Non-specifi c immune activators Interferons IFN-α-2a Approved Roferon-A (Roche), 3 MU three times/week, SC IFN-α-2b Approved Intron A (Schering-Plough), 3 MU three times/week, SC IFN-alfacon-I Approved Infergen (InterMune), 9 µg three times/week, SC PEG-IFN-α-2a Approved Pegasys (Roche), 180 µg once/week, SC PEG-IFN-α-2b Approved Peg-Intron (Schering Plough), 1.0–1.5 µg/kg once/week, SC Albuferon Phase 2 Fusion of interferon with albumin to increase half-life. Preliminary data suggest prolonged half-life and similar antiviral effi cacy Omega-interferon (IFN-ω) Phase 2 Alternate type 1 IFN. Early studies suggest similar antiviral effects to type 1 IFNs and similar side-effect profi le Gamma-interferon (IFN-γ) Phase 2 Combination studies with type 1 IFNs for non-responder patients in progress Oral IFNs Phase 1 Absorption of IFN via oral route Oral interferon inducers Imiquimod Preclinical Approved for use as a topical agent in dermatology Resiquimod Phase 2 Studies show no antiviral effects or cytokine induction, but doses may have been inadequate ANA 245 Phase 1 Low molecular weight nucleoside analogue ANA 971 Phase 1 Delivers ANA 245 to plasma of various animals Nucleoside analogues Ribavirin* Approved Copegus (Roche), 0.8–1.4 g/day, orally† Rebetol (Schering-Plough), 0.8–1.4 g/day, orally† Levovirin Development is halted because of absorption and delivery issues Viramidine Phase 3 Ribavirin ‘prodrug’ with preferential liver uptake. Large- scale international multicentre trials in combination with PEG-IFNs in progress ANA 246 Preclinical Oral compound that enhances the type 1 cytokine response IMPDH inhibitors VX-497 Phase 2 Specifi c IMPDH inhibitor, no haemolysis, further trials with IFNs and ribavirin in progress Mycophenylate mofetil Phase 2 Evaluation of effi cacy combined with IFN-α in non- responders in progress Broad-spectrum antivirals Amantadine Phase 2 Numerous clinical trials evaluating effi cacy with IFN or IFN and ribavirin in naïve and non-responder populations Rimantadine Phase 2 Similar trials to those for amantadine Other immunomodulators Histamine dihydrochloride Phase 2 NK cell activator. Combined with PEG-IFN and ribavirin in clinical trials in non-responder patients Thymosin α-1 Phase 2 and 3 Two large-scale trials comparing PEG-IFN alone or with thymosin α-1 in non-responders IL-10 Phase 2 and 3 Anti-infl ammatory cytokine. Randomized controlled trial failed to show benefi t in terms of fi brosis; IL-10 was associated with decreased ALT values and hepatic infl ammation, but increased viral concentrations IL-12 Phase 2 and 3 Proinfl ammatory cytokine. Phase 2 trial indicated lack of effi cacy and signifi cant toxicity Passive immunization HCIg Phase 1 and 2 Inactivated pooled high-titre HCV RNA-negative immunoglobulin. Initial trial to evaluate recurrence of HCV post-liver transplantation Therapeutic vaccination E1 therapeutic vaccine Phase 2 Administration of E1 vaccine in HCV patients after 28 weeks produced detectable levels of E1 antibody and specifi c T-cell responses (Continued.) Table 34.1 (Continued) 1405130059_4_034.indd 5411405130059_4_034.indd 541 30/03/2005 12:40:2530/03/2005 12:40:25 [...]... hypervariable region 1 in acute self-limiting and chronic infections due to hepatitis C virus J Virol 19 97; 71:4123 7 75 Bjoro K, Froland SS, Yun Z, Samdal HH, Haaland T Hepatitis C infection in patients with primary hypogammaglobulinemia 1405130059_4_035.indd 565 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 565 after treatment with contaminated immune globulin N Engl J Med 2002;331:16 07 11 Christie JM, Healey... 2003;100:6104–8 17 Carrere-Kremer S, Montpellier-Pala C, Cocquerel L, Wychowski C, Penin F, Dubuisson J Subcellular localization and topology of the p7 polypeptide of hepatitis C virus J Virol 2002 ;76 : 372 0–30 18 Harada T, Tautz N, Thiel HJ E2-p7 region of the bovine viral diarrhea virus polyprotein: processing and functional studies J Virol 2000 ;74 :9498–9506 19 Durantel D, Branza-Nichita N, Carrouee-Durantel... non-A, non-B post-transfusion hepatitis Role of gamma-globulin prophylaxis in its prevention Gastroenterology 1 977 ;72 (5 Pt 1):902–9 70 Feray C, Gigou M, Samuel D et al Incidence of hepatitis C in patients receiving different preparations of hepatitis B immunoglobulins after liver transplantation Ann Intern Med 1998;128:810–16 71 Piazza M, Sagliocca L, Tosone G et al Sexual transmission of the hepatitis. .. Med 19 97; 1 57: 15 37 44 72 Krawczynski K, Alter MJ, Tankersley D et al Effect of immune globulin on the prevention of experimental hepatitis C virus infection J Infect Dis 1996; 173 :822–8 73 Allander T, Beyene A, Jacobson SH, Grillner L, Persson MA Patients infected with the same hepatitis C virus strain display different kinetics of the isolate-specific antibody response J Infect Dis 19 97; 175 :26–31 74 Zibert... a proviral effect, despite a positive antifibrotic effect in an initial pilot study .74 ,75 In a phase 2 study of IL-12, a different and proinflammatory drug, the results suggested that IL-12 was associated with additional toxicity and lacked efficacy .76 ,77 Hyperimmune anti-HCV immunoglobulins It has been hypothesized that multiple infusions of hyperimmune anti-HCV immunoglobulins (HCIg) may modify viral. .. Baumert TF, Liang TJ Hepatitis C virus-like particles induce virus-specific humoral and cellular immune responses in mice Hepatology 2001;34:4 17 23 Blanchard E, Brand D, Trassard S, Goudeau A, Roingeard P Hepatitis C virus-like particle morphogenesis J Virol 2002 ;76 :4 073 –9 Roccasecca R, Folgori A, Ercole BB et al Mimotopes of the hyper variable region 1 of the hepatitis C virus induce cross-reactive antibodies... decrease in viral RNA levels These activated CD8+ cells did not secrete gamma-interferon (IFN )- Shortly afterwards, a 5 log reduction in viral load occurred commensurate with the appearance of HCV-specific, IFN-γ-secreting CD8+ cells with a nonactivated phenotype (CD38-negative) This large reduction in viral load was not accompanied by an increase in serum ALT levels, suggesting that a non-cytolytic viral. .. al Different clinical behaviors of acute hepatitis C virus infection are associated with different vigor of the anti -viral cell-mediated immune response J Clin Invest 1996;98 :70 6–14 47 Tsai SL, Liaw YF, Chen MH, Huang CY, Kuo GC Detection of type 2-like T-helper cells in hepatitis C virus infection: implications for hepatitis C virus chronicity Hepatology 19 97; 25:449– 58 48 Lechner F, Wong DK, Dunbar... with hepatitis C virus The HENCORE group Hepatitis C European Network for Cooperative Research Lancet 1999;354:2119–24 62 Harcourt G, Hellier S, Bunce M et al Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection J Viral Hepat 2001;8: 174 –9 63 Thio CL, Gao X, Goedert JJ et al HLA-Cw*04 and hepatitis C virus persistence J Virol 2002 ;76 : 479 2 7 64... acid (Cellcept) and VX-4 97, 70 are also currently being studied in patients with chronic hepatitis C As with ribavirin, preliminary results with these agents have shown no direct antiviral efficacy in short-term studies Recent results from a small European study suggest a higher on-treatment response rate with a triple therapy strategy includ- 1405130059_4_034.indd 5 47 5 47 ing VX4 97, which was not associated . Lancet 2003;362:12 67 74 . 21 Sulkowski MS, Thomas DL. Hepatitis C in the HIV-infected per- son. Ann Intern Med 2003;138:1 97 2 07. 22 Forns X, Garcia-Retortillo M, Serrano T et al. Antiviral therapy. (Schering-Plough), 3 MU three times/week, SC IFN-alfacon-I Approved Infergen (InterMune), 9 µg three times/week, SC PEG-IFN- -2 a Approved Pegasys (Roche), 180 µg once/week, SC PEG-IFN- -2 b Approved. -1 and IFN-α were inconclusive. Thy- mosin -1 is currently being evaluated in large phase 2 and 3 trials in combination with PEG-IFN-α. 73 In a randomized controlled trial, IL-10, an anti-infl