Viral Hepatitis - part 5 pptx

Chapter 22350 after 1 year of treatment and 1-year patient survival reached 92%. 50 Combination prophylaxis with low dos- es of intramuscular HBIg and lamivudine has also been shown to be highly effective (Table 2.2) with recurrence rates of <10% in most studies. 24,34,44,51–55 Higher rates of recurrence are typically found in patients who have developed lamivudine resistance prior to transplanta- tion. 44 This strategy is becoming the standard of care in most transplant programmes. However, the best proto- col is still unknown as doses, routes, type and lengths of administration vary substantially from centre to centre. Moreover, the amount of HBIg infused ranges from 2800 to 80 000 IU during the fi rst week, and from 7600 to 200 000 IU during the fi rst year. Some centres continue to use the intravenous (i.v.) route while others switch to the intramuscular (i.m.) injection. Fixed i.m. or i.v. HBIg doses are utilized in some centres, while others prefer to individualize this therapy to achieve predefi ned serum anti-HBs concentrations. Finally, some centres continue HBIg indefi nitely, while others stop HBIg at different time intervals from transplantation. Future studies are needed to assess these aspects, in particular the benefi ts of fi xed versus individualized therapy and the need for indefi nite versus limited durations of HBIg therapy. Long-term prophylactic therapy At present, the main unanswered question relates to long-term prophylaxis. In patients receiving combina- tion therapy, there is a need to defi ne the optimal du- ration of HBIg. Two different approaches have been investigated. The fi rst is active HBsAg vaccination with the aim of inducing active immunity against HBV without the need for additional antiviral treatment. Results from preliminary studies are disparate, 56–59 with good results being achieved in some studies, and poor response to HBV vaccination observed in others. Reasons for these apparently discrepant results likely include differences in study populations, differences in methodologies and differences in defi nitions of seroprotection. In the fi rst study by Sanchez-Fueyo et al., 56 17 patients at low risk for HBV recurrence (non-replicative before transplantation, HBIg for at least 18 months without evidence of allograft HBV infection, and on low immunosuppressive doses) were vaccinated against HBV at a median of 30 months post-transplantation. The maintenance dose of HBIg prior to vaccination was approximately 2000 IU given i.m. every 1–2 months so as to maintain anti-HBs titres >100 IU/L. Then 1–4 weeks after the last dose of HBIg, three i.m. doses of 40 µg of recombinant HBsAg were given at 0, 1 and 6 months. Seroconversion to anti-HBs (antiHBs titres >10 IU/L) occurred in 82% of the patients (six after the fi rst three doses, eight after a second course of three additional doses). A recently updated report showed that among 22 vaccinated transplant recipients, the percentage of seroconversion decreased to 64%. 57 In contrast to this initial study, a second study by Angelico et al. did not confi rm these fi ndings and the rate of sero- protection (defi ned as anti-HBs titres >10 IU/L) was only 23%. 58 The main differences between these two studies include the differences in the study population (all pa- tients in the Italian study underwent transplantation for cirrhosis) and the use of lamivudine following HBIg dis- continuation (in the Italian study). More recently, a third group has reported the results of HBV vaccination using a more immunogenic vaccine. 59 In that study, 10 patients received repeated doses of recombinant HBV vaccine (20 µg) in combination with a new adjuvant, monophos- phoryl lipid A. Vaccination was performed at least 2 days prior to HBIg administration and titres of anti-HBs concentrations were determined before HBIg injections. HBIg was then discontinued whenever levels were >500 IU/L. Five of the 10 patients developed anti-HBs levels ranging from 721 to 45 800 IU/L, thus allowing HBIg withdrawal. After 1 year of follow-up, all responders had serum anti-HBs concentrations >900 IU/L. Larger Table 22.2 Combined prophylaxis with hepatitis B immune globulins at low doses and lamivudine in the prevention of recurrent hepatitis B Author, year (ref. no.) Patient no. HBV DNA-positive pre-LT Pre-LT lamivudine (%) Follow-up (months) HBV recurrence (%) Yao et al. 1999 (51) 10 2 100 16 10 Yoshida et al. 1999 (52) 6 4 100 18 0 McGaughan et al. 1999 (55) 9 8 NA Han et al. 2001 (54) 59 NA 41 15 0 Angus et al. 2000 (53) 32 16 100 18 3 Rosenau et al. 2001 (44) 21 13 90 20 11* Marzano et al. 2001 (24) 25 25 100 30 4 Seehofer et al. 2001 (45) 17 17 100 25 18* LT, liver transplantation; NA, not available. *The patients with recurrent hepatitis B despite prophylaxis had lamivudine resistance prior to transplantation. 1405130059_4_022.indd 3501405130059_4_022.indd 350 30/03/2005 12:33:1730/03/2005 12:33:17 Liver transplantation in the management of chronic viral hepatitis 351 trials using different vaccination protocols over a longer observation period are needed to determine the real ef- fi cacy of this approach, particularly in low-risk patients without active viral replication pre-transplantation. Once established in this group, the applicability of this approach will have to be tested in patients at high risk for treatment failure. Other issues will need to be ad- dressed, including the optimal vaccine doses, the timing of booster injections, as well as the potential benefi t of using more immunogenic vaccines. Finally, the scientifi c basis for this approach may be questioned, as these pa- tients with previous chronic HBV cirrhosis have already been exposed to high levels of naturally occurring HB- sAg and have failed to develop protective immunity to HBV. It is therefore unclear why vaccination of these im- munocompromised individuals would be likely to now result in immune protection. A less risky alternative may be to substitute HBIg with lamivudine in the long term. Successful results using this alternative have already been reported by some authors in low-risk patients without markers of viral replication prior to transplantation. 25,60,61 More data are needed to defi ne the optimal timing for HBIg withdrawal and the potential applicability in high-risk individuals. In summary, an individualized multi-step prophylac- tic regimen may be used to prevent HBV recurrence. In patients at low-risk for recurrence, i.e. those undergoing transplantation for HBV HDV cirrhosis, fulminant hep- atitis B and HBV cirrhosis with undetectable HBV DNA by PCR assays, there may be no need for pre-transplan- tation antiviral therapy. In contrast, for those with de- tectable HBV DNA prior to transplantation, suppression with oral antiviral appears to be appropriate. Following transplantation, three alternatives may be proposed: (1) indefi nite high-dose HBIg starting with i.v. HBIg 10 000 UI in the anhepatic phase and daily during the fi rst week, followed by the administration of variable amounts of HBIg aimed at achieving anti-HBs titres >100–150 UI/L; (2) indefi nite low-dose HBIg in association with lamivu- dine (100 mg/day) using the same dose of HBIg during the fi rst week followed by i.m. monthly administration of low-dose HBIg (2000–4000 UI/L); (3) high-dose HBIg in association with lamivudine (100 mg/day) during the fi rst 6–12 months, followed by lamivudine alone for up to 2–3 years, and subsequently active HBV vaccination. In those who develop protective immunity, lamivudine may be stopped, and booster doses may be adminis- tered to maintain anti-HBs levels (at least, >100 UI/L). If there is no response to vaccine, the prophylaxis should continue with lamivudine. In high-risk patients, i.e. those with detectable HBV DNA by hybridization assay and/or HBeAg, pre-transplantation antiviral therapy with lamivudine is required for at least 1 month. Follow- ing transplantation, two alternatives may be proposed: (1) indefi nite high-dose HBIg in association with lami- vudine (100 mg/day) starting with i.v. HBIg 10 000 UI in the anhepatic phase and daily during the fi rst week, followed by the administration of variable amounts of HBIg aimed at achieving anti-HBs titres >500 UI/L dur- ing the fi rst 3 months, and 100–150 IU/L subsequently; (2) high-dose HBIg in association with lamivudine (100 mg/day) during the fi rst 12–24 months, followed by lamivudine alone for up to 2–3 years, and subsequently active HBV vaccination. HBIg discontinuation should only be proposed for patients with undetectable serum HBV DNA by PCR assay. Treatment of HBV disease of the graft There are three categories of patients who are potential candidates for HBV therapy after liver transplantation: (1) those who have undergone liver transplantation in the pre-HBIg and/or lamivudine era; (2) those who have undergone liver transplantation in the post-HBIg/lami- vudine era and who have broken through treatment; (3) those with apparent ‘de novo’ acquisition of HBV. Selec- tion of therapy likely depends on the category to which the patient belongs. For example, treatment options for patients in the fi rst category include lamivudine, ente- cavir or adefovir. These patients may have developed ‘vaccine escape mutants’, but they are likely to be sensi- tive to all three antiviral agents. The proportion of pa- tients falling into the second category today is small, yet if these patients have ‘broken through’ both HBIg and lamivudine, they are likely to have developed resistance and as such may be appropriate candidates for antiviral agents such as adefovir or entecavir that have activity against resistance variants. Finally, patients that fall into the third category with ‘de novo’ infection, are likely to be infected with virus that is sensitive to all currently available agents. 27,62 Lamivudine is the most widely used nucleoside ana- logue. In most studies, liver transplant recipients with documented HBV recurrence (elevated serum ALT lev- els, and detectable HBsAg and HBV DNA) have been treated with lamivudine 100 mg daily (adjusted for re- nal function) with good tolerance and rapid loss of HBV DNA in serum. 27,62–66 Good biochemical and virological responses have been achieved not only in patients with chronic hepatitis B following transplantation but also in the setting of acute hepatitis B of the graft and in the most severe cases of fi brosing cholestatic hepatitis. His- tological improvements in the infl ammatory grade are also achieved with therapy. In a multicentre study based on 52 patients with detectable DNA after liver transplan- tation, lamivudine therapy for 1 year resulted in 60% loss of HBV DNA in serum and 31% ‘e’ seroconversion. 63 Other studies have confi rmed these results, showing HBV DNA loss in 68–100% of patients treated for peri- ods of 12–36 months. 27,64–66 The downside of this agent is 1405130059_4_022.indd 3511405130059_4_022.indd 351 30/03/2005 12:33:1730/03/2005 12:33:17 Chapter 22352 the need for continuous treatment, as relapse is the rule once the drug is discontinued. Prolonged therapy is, in turn, associated with the development of breakthrough due to the emergence of HBV escape mutants, which has been shown to reach 50% with long-term therapy. 62–68 Famciclovir (500 mg three times daily with dosing ad- justed to renal function) has also been used to treat liver transplant recipients with HBV recurrence. 64,67 Although initially good results were obtained with this drug both in terms of HBV DNA reduction and transaminase nor- malization, viral clearance was observed in a lower per- centage of patients than has been seen for lamivudine. In addition, famciclovir-resistant virus may not be sen- sitive to lamivudine, a situation recently described in several patients. 42 Emergence of nucleoside analogue resistance Monotherapy with both lamivudine and famciclovir has resulted in the emergence of HBV variants that are resistant to these compounds. This resistance gener- ally occurs after prolonged therapy (>6 months). 27,62–68 In both instances, the appearance of resistant mutants is associated with a rise in serum HBV DNA and ALT levels, indicating a breakthrough in therapy. Molecular analysis has shown mutations in the gene encoding the viral DNA polymerase. Because of the overlapping na- ture of the HBV open reading frames (ORFs), nucleotide changes in the polymerase may result in amino acid changes not only in the polymerase protein but also in the surface protein, which could in turn theoretically al- ter binding of HBIg at the time of transplantation. 42 When the antiviral drugs are stopped, the wild-type variant re-emerges as the dominant viral population, but retreatment is again associated with the development of resistant mutants at an accelerated rate. Drug-resistant mutants are not consistently associated with hepatic dis- ease progression. In vitro studies have shown that the M 204 V/I mutants have decreased replication fi tness com- pared with wild-type HBV. 39 However, in some cases, severe and fatal hepatitis B infection can occur during lamivudine therapy and may be associated with certain HBV mutants selected during sequential nucleoside and HBIg treatment. 42 It has been suggested that these changes may represent compensatory mutations that restore the replication fi tness of HBV. The lamivudine- enhanced replication shown by these mutants suggests that continuation of therapy with lamivudine could be deleterious in some patients. From a clinical point of view, patients who are maintained on lamivudine thera- py after the emergence of lamivudine resistance should be closely monitored to detect fl ares of the underlying disease. Fortunately, the availability of new hepatitis B antivirals such as adefovir has resulted in viral suppres- sion of lamivudine-resistant variants. 46 Thus far, resist- ance to adefovir is unusual (<2% after 2 years). It is not yet known whether patients who are treated for lamivu- dine resistance with adefovir post-transplantation need to continue on lamivudine, but given the potential for progressive liver disease with overt recurrence, it seems prudent to continue both drugs for some period after the institution of adefovir. For patients who have become HBsAg-positive after liver transplantation despite therapy in the pre- and/or peri-transplantation period, possible interventions in- clude adefovir or entecavir. Experience with adefovir (at a dose of 10 mg per day) has shown that this drug is viral suppressive but that treatment may be limited by toxici- ties, possibly associated with impaired renal function. 46 Experience with entecavir is limited. As this nucleoside is devoid of renal toxicity, it may play an important role in the future management of these recipients. Prevention and treatment of de novo HBV infection The prevalence of de novo HBV hepatitis ranges from 2% to 8%, and is generally related to transmission from an HBsAg-negative, anti-HBc-positive donor to an unin- fected recipient. The most signifi cant factor associated with transmission is the serologic status of the recipient, so that the risk is almost null in patients who are anti- HBs-positive, minor (≅ 10%) in those who are anti-HBs- negative but anti-HBc-positive, and high (≅ 50–70%) in those without markers of previous exposure to HBV. 69,70 Although there have been reports of severe progression, the natural history of de novo hepatitis B is generally more benign than that described for recurrent hepatitis B. In order to avoid de novo HBV infection, two com- plementary approaches may be undertaken. (1) HBV vaccination prior to liver transplantation of all anti-HBs- negative candidates. Accelerated vaccination regimen with double doses (40 µg) has been adopted at 0, 1 and 2 months with a follow-up vaccine at 6 months. Unfor- tunately, as with other immunosuppressed populations, the results of vaccination in these patients have been dis- appointing with response rates that barely reach 40%. 71 A second course of vaccination may slightly increase these results. (2) Anti-HBc determination of the donor with use of organs from anti-HBc-positive donors only in re- cipients already infected with HBV. In order to obtain a maximum benefi t from these organs while at the same time reducing the risk of HBV transmission, these organs may be used in special circumstances in recipients not infected with HBV. The following criteria should then be applied. 72 As the risk of HBV transmission is low if the recipient is anti-HBs- and anti-HBcore-positive, selec- tion of an anti-HBs-positive recipient may be suffi cient without other interventions. However, there is concern 1405130059_4_022.indd 3521405130059_4_022.indd 352 30/03/2005 12:33:1730/03/2005 12:33:17 Liver transplantation in the management of chronic viral hepatitis 353 that vaccine-induced immunity may not be as effective as innate immunity in preventing acquisition of HBV from an infected donor. Livers from anti-HBc-positive donors can be directed next to recipients with isolated anti-HBc, although a low risk of HBV transmission ap- pears to exist if no specifi c HBV prophylactic measures are taken. While initiating prophylaxis with HBIg and/ or lamivudine to all patients will prevent transmission, this strategy has the potential for treating a high pro- portion of recipients who would have never developed infection. When no individuals with the above criteria exist in the waiting list, anti-HBc-positive donors can be offered to naïve recipients with critical clinical needs or with HCC although, in such cases, HBV prophylaxis with either lamivudine or HBIg or a combination of both agents is advisable given the high likelihood of HBV ac- quisition. Treatment of de novo hepatitis B is similar to that described for recurrent hepatitis B. If started at early time-points, the results are generally better than those obtained with recurrent hepatitis B. Unfortunately, re- sistant mutants develop at the same rate, and adefovir or entecavir may prove to be preferred therapy for the primary management of this disease. Re-transplantation The initial results on re-transplantation for patients with graft failure due to recurrent hepatitis B were discourag- ing due to high rates of HBV reinfection and even more aggressive disease in the second graft. Improved out- comes have been achieved with specifi c interventions, mainly with the use of aggressive immunoprophylaxis to prevent HBV reinfection in combination with lamivu- dine that is typically started prior to re-transplantation in order to suppress viral replication. 73–75 Fortunately, re- transplantation for recurrent HBV disease is rare, given the effective measures described above that prevent re- current infection in the vast majority of those with pre- transplantation infection. If it is needed, three measures should be followed in order to improve the outcome: (1) avoid late re-transplantations when the hepatic failure is too advanced and renal insuffi ciency has developed; (2) use antiviral therapy to clear the virus prior to retrans- plantation; and (3) choose an aggressive prophylactic regimen to prevent reinfection. Living-related liver transplantation (LRLT) There are no data regarding HBV recurrence following LRLT. Given the availability of excellent therapies to prevent and treat recurrence, it is likely that the results obtained with this technique will be similar to those ob- tained with cadaveric organs. In addition, adequate tim- ing of pre-transplantation antiviral therapy is a potential advantage, as transplantation can be performed when HBV DNA has been cleared in serum but before the de- velopment of resistant mutants. 76 Transplantation in patients co-infected with HDV Historically, patients with HBV and HDV infection were considered to be better candidates for liver transplan- tation than those with HBV infection alone, because of the lower HBV DNA levels and consequent lower risk of recurrent infection in the former than in the lat- ter group. 9 Delta infection is an uncommon indication for liver transplantation. In the absence of HBIg, both HBV and delta virus can infect the graft, but HDV is not pathogenic until HBV replication also occurs. Interest- ingly though, HDV is detected early post-transplanta- tion either in serum (HDV RNA) or liver (HDV RNA and/or delta antigen) in 80% of HBsAg-negative liver transplant recipients. 77,78 With prolonged follow-up and absence of HBV recurrence, these markers of HDV in- fection disappear. If HBV recurs, HDV is also detected leading to chronic hepatitis. HDV-HBV-related hepatitis is generally less severe than in patients with HBV alone. HBIg prophylaxis is effective at preventing recurrence in the majority of those with pre-transplantation co-in- fection. 77,78 The additional benefi t of pre-transplantation treatment with lamivudine is largely unstudied but is commonly administered in clinical practice. Thus, cur- rent recommendations would be to pre-empt HBV and HDV infection of the graft as is undertaken for the pre- vention of recurrent HBV infection described above. Recurrent hepatitis C virus (HCV) infection Once considered an excellent indication for liver trans- plantation, enthusiasm for liver transplantation in pa- tients with end-stage HCV cirrhosis is waning, due to the growing evidence that recurrent HCV disease is an important cause of morbidity and even mortality in the post-transplantation period. 79 In contrast to HBV disease, there are no effective interventions to prevent post-trans- plantation HCV recurrence. 80 HCV-related liver disease with or without alcohol and with or without HCC now represents the major indica- tion for liver transplantation in the United States and Europe. 1,79 Historically, rates of HCV recurrence were modest (70%) and typically resulted in benign liver in- jury with no effect on survival. In contrast, more recent natural history studies based on strict histological fol- low-up, updated virological techniques and prolonged follow-up, have demonstrated that viral recurrence is universal, histological recurrence is very frequent, and advanced graft HCV disease occurs in a substantial 1405130059_4_022.indd 3531405130059_4_022.indd 353 30/03/2005 12:33:1830/03/2005 12:33:18 Chapter 22354 ance clearly favours this option and not merely because the patient meets minimal listing criteria for transplan- tation. Thus, as the outcome of compensated HCV-cir- rhotic patients is suffi ciently good, liver transplantation should be reserved ideally for those with progressive liver disease that cannot be managed medically. Thus, while indications and contraindications for transplanta- tion in these patients do not differ from those applied to other forms of liver diseases, decompensated patients should be aggressively managed with traditional medi- cal therapy in an effort to avoid the premature trans- plantation of some of these patients. This is also true in the new era of living donor liver transplantation. Criteria for selecting patients with HCC do not dif- fer from those with HCC who are not HCV-infected. 89 However, because recurrent HCV will likely compli- cate the post-transplantation management of these pa- tients, aggressive medical and surgical management of HCC including chemoembolization and hepatic resec- tion should be undertaken before consideration of liver transplantation. Thus, resection may be considered the treatment of choice, particularly in those with compen- sated cirrhosis without relevant portal hypertension, with liver transplantation remaining as ‘adjuvant’ thera- py. 89,90 The addition of antiviral therapy in these patients could potentially lead to viral eradication and improve- ment of hepatic fi brosis, 91 eliminating the future need for transplantation. Recurrence of HCV infection While recurrence of HCV infection is based on virologi- cal parameters, the recurrence of HCV disease requires protocol and/or clinically indicated liver biopsies that number of patients, leading to an adverse effect on graft and patient survival. 79,81,82 Due to the magnitude of the problem, with a preponderance of HCV as the primary indication for liver transplantation, the worsening pa- tient and graft survival in HCV recipients, 81,83,84 and the growing demand for re-transplantation in recipients with recurrent HCV, 85 a Consensus Conference was re- cently held to overview the state of the art concerning liver transplantation and HCV disease. The conference participants examined the defi nition of recurrent HCV, the natural history of HCV after liver transplantation, the potential clinical predictors of adverse outcomes, treatment and management strategies, the contribution of different immunosuppressive regimens to outcome, and the role of re-transplantation for recurrent HCV in the face of an overall donor shortage. 86 Indications for liver transplantation Cirrhosis due to chronic hepatitis C infection is associ- ated with reduced survival, due to the development of hepatic complications, namely clinical decompensa- tion and HCC. In the absence of decompensation, the 10-year survival approximates 80%, but survival de- creases markedly once hepatic decompensation occurs (approximately 50% at 5 years). 87–89 The cumulative risk of clinical complications is 30% over a 10-year period. The risk of clinical decompensation unrelated to HCC has been estimated to be 15–20% after 4 years of follow- up, while the risk of developing HCC is 6–24% over the same time. Given the potential for an aggressive form of recurrent hepatitis C, timing of liver transplantation is a major challenge in transplant centres. Liver transplanta- tion should only be offered when the risk-benefi t bal- 99% 25-45% 50-98% 8-44% 42% HCV acute chronic graft cirrhosis decompensated RNA + hepatitis hepatitis in 5-7 years 1 year LT HCV RNA (-) 2% Fibrosing Cholestatic hepatitis 2-6% Minimal injury 30-50% Delayed injury 30% Viral factors Viral load Genotype Quasi-species Donor factors Age, sex, steatosis Surgical factors Warming ischaemic time Host factors HLA, race, gender, age, immune genetic background, immune system External factors Immunosuppression, alcohol, viral co-infection, antiviral therapy Immune mechanism of liver damage Cytopathic mechanism of liver damage Figure 22.1 Natural history of recurrent hepatitis C: mechanisms of liver lesion and factors that determine outcome. LT, liver transplantation. 1405130059_4_022.indd 3541405130059_4_022.indd 354 30/03/2005 12:33:1830/03/2005 12:33:18 Liver transplantation in the management of chronic viral hepatitis 355 report both grade and stage of disease. Indeed, recur- rence of HCV infection is defi ned as the presence of virus in serum and liver. It occurs nearly universally fol- lowing transplantation 92 and is characterized by a steep rise in levels of HCV RNA, that typically are 10–20-fold higher than before transplantation. 93 Recurrence of HCV disease, in contrast, occurs at various time points and exhibits a wide spectrum of histological fi ndings from trivial infl ammation in the absence of fi brosis to severe and progressive liver disease 94 (Fig. 22.1) Pathogenesis A rapid and sharp decline in viral load occurs imme- diately after removal of the infected liver. 95 Following reperfusion, HCV RNA levels typically decrease further at a rate that exceeds the decrease observed during the previous anhepatic phase. HCV binding to and/or up- take by hepatocytes may contribute to this early post- transplant decrease in viraemia. Following this initial decline, HCV RNA levels either increase exponentially reaching pre-transplantation levels as soon as day 4, or continue a decline in the fi rst post-transplant week to increase thereafter, peaking by the fourth postoperative month. 95 These differences in kinetics appear to be re- lated to the use of corticosteroids, so that HCV RNA lev- els increase rapidly in patients receiving corticosteroids as part of the immunosuppressive regime, while they continue to decrease in those not receiving this drug. At 1 year post-transplantation, the levels are 10–20-fold higher than pre-transplantation. 93 The mechanisms by which HCV leads to liver injury are incompletely understood. Several lines of indirect evidence support a role for the cellular immune re- sponse in shaping outcome following transplantation. It is likely that the increased levels of HCV replication typically observed – in conjunction with the altered host immune responsiveness – contribute to the pathogenesis of liver damage, particularly to the severe course of dis- ease of the grafted liver. In addition, there is a spectrum of severity of recurrent HCV disease that may differ in pathogenesis and clearly differs in outcome. 94 Recurrent chronic hepatitis C disease, which can lead to cirrhosis, should be distinguished from recurrent cholestatic HCV disease. In the former, it is possible that the relative an- tiviral control by the immune response prevents cyto- pathic injury while perpetuating chronic liver injury. 96 In contrast, a direct cytopathic mechanism of liver injury appears to predominate in patients with severe choles- tatic hepatitis. 97 Natural history of HCV recurrence Early short-term survival is comparable to that obtained with other aetiologies. However, emerging data are demonstrating that the long-term outcome is not as be- nign as previously thought. 79,81–83 Acute lobular hepatitis develops in approximately two-thirds of the patients within the fi rst 6 months post- transplantation. By the fi fth postoperative year, >80% of recipients will develop chronic recurrent HCV disease, characterized histologically by portal and periportal in- fl ammation with or without the presence of portal and/ or periportal fi brosis. Lobular hepatitis can also be part of the pathological picture. 98–102 The natural history of this chronic hepatitis C is more aggressive than that observed in the immunocompetent population. Indeed, in the non-transplantation setting, it is estimated that approximately 20% of the infected pa- tients will develop cirrhosis after a mean duration of in- fection of 30 years. In the transplant setting, this course is accelerated, and progression to cirrhosis occurs in a percentage of recipients that ranges, depending on the series, from 6% to 23% after a median of 3–4 years since transplantation. 81,83,84,98–104 The development of cirrhosis is associated with reduced graft and patient survival. 94 A recent study has estimated that the median time to develop cirrhosis after transplantation is approximately 9–12 years, 105 a duration signifi cantly shorter than that described in the immunocompetent population. The progressive nature of liver disease in the transplant set- ting is also evident once the cirrhosis is established, with a higher likelihood of developing clinical decompensa- tion and death compared with that observed in non- transplant patients with cirrhosis. 106 The 1-year actuarial risk of decompensation in patients with post-transplan- tation HCV cirrhosis is 42%, a percentage that is higher than the 28% at 10 years observed in HCV-infected non- transplant patients with cirrhosis. In addition, in 5–10%, an accelerated course of liver injury leading to rapid development of liver failure has been observed, 107 reminiscent of that previously de- scribed in HBV-infected recipients with fi brosing chole- static hepatitis. Recurrent cholestatic HCV disease can occur as the initial manifestation of recurrent HCV dis- ease or can emerge in the setting of chronic HCV disease. The defi nition of fi brosing cholestatic hepatitis includes all of the following criteria: 1 month post-transplant, se- rum bilirubin >100 µmol/L, serum alkaline phosphatase and GGT more than fi ve times the upper limits of nor- mal, characteristic histology of central ballooning (not necrosis or fallout), a paucity of infl ammation ± cholan- giolar proliferation without bile duct loss, very high serum HCV RNA levels and absence of surgical biliary complications or hepatic artery thrombosis. 86 Delayed hepatitis C-related severe liver damage may occur in recipients following initial benign recurrence. This acceleration in disease progression develops in 1405130059_4_022.indd 3551405130059_4_022.indd 355 30/03/2005 12:33:1830/03/2005 12:33:18 Chapter 22356 one-third of patients who have relatively slow fi brosis progression in the fi rst 3–5 years of post-transplantation disease. 108 Emerging data suggest that the rate of fi brosis progres- sion, and thus the rate of development of graft cirrhosis due to recurrent hepatitis C, is accelerated in patients transplanted in recent years. 81,83,84,105 Based on all these data, it is not surprising that in several centres a reduction in patient and graft survival among HCV-infected recipients has been observed, with a 5-year survival signifi cantly lower among HCV-infect- ed recipients than in those not infected with HCV (60– 70% vs 76–77%). 81,82 In addition, the worse histological outcome seen in recent years is beginning to translate in some centres into a reduced survival among those trans- planted recently. 81 Histological changes Liver function tests are not correlated with either virae- mia or with histological disease severity, 98–101,109,110 and protocol liver biopsies are generally needed to identify progression to severe forms of chronic hepatitis. Early histological fi ndings may be helpful in selecting the patients at high risk of disease progression. 98–101,109–113 In particular, the degree of activity and fi brosis staging observed in the fi rst-year liver biopsy is associated with the subsequent risk of developing cirrhosis with only 3–10% of those with mild hepatitis developing cirrhosis compared with 30–60% in those with moderate to severe activity in their fi rst-year liver biopsy. 98,99 Furthermore, not only the severity of initial histological fi ndings, but also some specifi c histological features such as signifi - cant steatosis, ballooning degeneration, cholestasis and confl uent necrosis observed on early biopsies may be helpful in predicting progression of disease. 98–101,111–113 Fi- nally, the presence of some degree of fi brosis at baseline (i.e. F = 1 in the fi rst-year liver biopsies) appears to pre- dict the delayed onset of severe liver damage. 108 Pre- and post-liver transplant risk factors impacting on HCV recurrence While some patients have an accelerated course to cirrho- sis, there are others, approximately one-third, who remain stable with normal or near-normal histology during 5–10 years of follow-up. Identifying patients at risk of acceler- ated allograft loss is paramount to the decision about the timing of antiviral agents and/or need for re-transplan- tation. Factors which have been described as predictors of disease severity/progression and/or survival include those related to the host (demographics, genetic back- ground, immune status, co-morbidities, hepatic function at transplantation), those related the virus (genotype, vi- ral replication, viral quasi-species), those that are donor- related (age, degree of hepatic steatosis, weight, living vs cadaveric) and those related to the environment (surgical- related factors, immunosuppression, alcohol). 79,86 The immune status Several indirect fi ndings point towards the deleterious effect of the immunosuppressed status, a variable in- trinsically related to the transplant setting (Table 22.3). It has even been suggested that the recent worsening in disease progression may be related to over-immuno- suppression following the introduction of more potent immunosuppressive agents. 81,83,105 However, the true adverse effect of more potent immunosuppression on disease outcomes, immunosuppressive agents such as mycophenolate mofetil, lymphocyte-targeting immu- noglobulins (e.g. daclizumab and basiliximab), as well as the newer agents with dose-dependent antiprolifera- tive properties, 114–121 needs to be defi ned. Table 22.3 Indirect fi ndings supporting the role of immunosuppression in the natural history of recurrent hepatitis C The course of hepatitis C is accelerated in liver transplant recipients as compared with that observed in immunocompetent patients: Higher rate of fi brosis progression – 0.3/year (0.004–2.19/year) vs 0.2/year (0.09–0.8/year) – and higher risk of developing severe hepatitis Shorter duration to cirrhosis from time of infection (median of 9–12 years vs 20–40 years) Higher risk of clinical decompensation once HCV-related cirrhosis is established (50% in 1 year vs 20–25% in 10 years) The course of hepatitis C is worse in recent years when signifi cant changes have mainly occurred in the immunosuppressive therapy: Use of newer and more potent fi rst-line immunosuppressive drugs Earlier and more abrupt discontinuation post-transplantation of second-line immunosuppressive drugs The course of recurrent hepatitis C is worse in other immunosuppressed populations such as HIV-co-infected patients or those with hypogammaglobulinaemia 1405130059_4_022.indd 3561405130059_4_022.indd 356 30/03/2005 12:33:1930/03/2005 12:33:19 Liver transplantation in the management of chronic viral hepatitis 357 There is already ample evidence that severity of re- currence of HCV is linked in part to the degree of im- munosuppression, with most studies showing a positive correlation between a high rate of cirrhosis development and potent immune suppression (high number of boluses of methyl-prednisolone, use of anti-lymphocytic prepa- rations, high total cumulative doses of steroids). 122–125 Immunogenetic background There is now strong evidence for the important role of genetics in host immune responses to infectious path- ogens and in susceptibility to infection as well as in outcomes after exposure to microbial agents. Both the major histocompatibility complex (MHC) genes and non-MHC genes are increasingly identifi ed as candi- date genes with signifi cant importance in outcome of infectious diseases. In HCV, specifi c HLA class II alle- les, such as HLA B14 and HLA DRB1*04 have emerged as possible modulators of disease severity. Regulatory mechanisms that control cytokine production, includ- ing tumour necrosis factor (TNF)-α, operate in part at the gene level. It has been shown that cytokine genes are polymorphic at specifi c sites. These mutations may infl uence the production of cytokines encoded by the polymorphic gene. In one study, Rosen et al. evaluated the signifi cance of polymorphisms at positions –238 and –308 of the TNF-α gene promoter (mutations associated with susceptibility to active hepatitis after HCV expo- sure in immunocompetent patients) in liver donors on the severity/outcome of recurrent HCV. They found that time to recurrence was shorter and the hepatic ac- tivity index greater in those who received an organ from donors with TNF-α –308 allele. 126 These data suggest that a specifi c donor TNF-α genotype, known to be as- sociated with high TNF-α production, may contribute to the accelerated graft injury observed in liver transplant recipients with HCV infection. Furthermore, some but not all authors have suggested that while HLA-B sharing between the donor and the re- cipient reduces the incidence of acute cellular rejection, it also promotes the recurrence of viral hepatitis. 127,128 Discrepancies may be explained by differences between studies in HLA typing methods, selection and ethnic backgrounds of patients as well as differences in immu- nosuppressive regimens used. Donor-related variables The age of the donor was recently found to be independ- ently associated with disease severity, disease progres- sion and survival. 81,83,84,129 In one series, only 14% of the recipients who received an organ from a donor younger than 30 developed recurrent HCV-related cirrhosis. In contrast, 45% and 52% of those receiving the organ from donors aged 31–59 or older than 59 developed graft cir- rhosis, respectively (p <0.0001). 81 The changing organ donor profi le with increasing age of the donors in recent years may explain the observed worsening in outcomes over the same time period. This observation has impor- tant implications for donor liver allocation, in that older donors might be more appropriate for HCV-negative re- cipients in whom the adverse effects of donor age appear to be less deleterious. In addition, the effect of donor age correlates with data from the immunocompetent popula- tion where age at the time of infection is an important and powerful determinant of fi brosis development. Age-re- lated changes in liver response may be the key factor that determines the increased susceptibility of the older liver to HCV-related fi brosis. The anti-HCV status of the donor may also infl uence the post-transplantation outcome. Superinfection has been described in this setting, 130 but it appears that his- tological outcome and survival do not differ from those observed in patients receiving organs from anti-HCV- negative donors. 131–133 Viral-related variables HCV RNA levels prior to and/or soon after transplanta- tion may predict survival and the rate/severity of hepa- titis C of the graft. 105,134 These fi ndings parallel those previously described for hepatitis B. In one study, pa- tients with higher pre-transplantation HCV RNA levels (>log 1 mEq/mL) experienced mortality and graft loss rates 30% more frequently than those with lower lev- els. 134 Studies evaluating the relationship between severity of liver disease post-transplantation and HCV genotypes are confl icting. 135–137 Some but not all studies have impli- cated genotype 1b in a more aggressive post-transplan- tation disease than non-1b genotype. It may possible that different strains belonging to genotype 1b may be implicated. 138,139 HCV heterogeneity may be implicated in the pathogen- esis of progressive HCV disease. However, results from the few studies published to date are inconclusive and somewhat discrepant, 94,140,141 and may be related to the small number of patients included, the different meth- odologies applied to assess HCV heterogeneity, the type of end-points chosen, the region of the genome evalu- ated, and the defi nition of disease severity. Other host variables Race was recently found to infl uence outcome in pa- tients with HCV recurrence, with non-Caucasians doing worse than Caucasians. 105,134 In some studies, female gender has been associated with a severe course of recurrent hepatitis C and subse- 1405130059_4_022.indd 3571405130059_4_022.indd 357 30/03/2005 12:33:1930/03/2005 12:33:19 Chapter 22358 quent low survival. 82,83 Reasons that might explain this association are lacking. In one study, a lack of association was observed be- tween the rate of fi brosis progression prior to transplantation and that observed after transplantation, 105 suggesting that variables present at the time of transplantation and those related to post-transplantation management are more important in infl uencing disease progression than genetic or viral variables unique to the individual. The in- terpretation of these results is complicated, however, by diffi culties in measuring accurately the duration of infec- tion prior to liver transplantation. In some studies, the presence of HCC was found to be a signifi cant predictor of reduced patient and graft sur- vival. 103 This may be explained by differences in patient and tumour selection criteria. 142 Prolonged re-warming time during allograft implanta- tion has been associated with severe recurrent disease. 143 If these data are confi rmed, special emphasis should be placed on techniques to minimize re-warming time, such as vena cava preservation. Timing of recurrence appears also to be related to the outcome, with early recurrence within the fi rst 6 months associated with worse prognosis. 100 Patients who develop cytomegalovirus (CMV) viraemia may be at increased risk of severe HCV recurrence. 84,144 The reasons for this association are unknown but proba- bly relate to the degree of immune defi ciency, the release of TNF by CMV and/or the existence of cross-reactive im- munological responses. Co-infection with other hepatotropic viruses such as HBV may infl uence histologic disease severity but results are confl icting. While no effect was found in an initial study, 145 co-infected patients appeared to have milder histological course than patients infected only with HCV. 103 Although viral interactions could explain this phenomenon, the passive transmission of antibodies against HCV in co-infected patients receiving HBIg dur- ing the pre-HCV era is a more likely explanation. 146 In contrast, co-infection with other viruses such as hepatitis G virus (HGV) does not seem to infl uence the post-transplantation course of HCV disease. 147 In summary, it is likely that the interaction between all these variables accounts for the differences in out- comes observed between different centres with cumula- tive rates of developing HCV-related graft cirrhosis that range from 10% to 50%. Prevention of HCV graft reinfection Given the increasing number of patients progressing to HCV-related graft cirrhosis and the shortage of organ donors, development of strategies to improve the out- come of these recipients is mandatory. These strategies include an adequate timing of liver transplantation in patients with HCV-related end-stage liver disease (see above), antiviral therapy, and the use of specifi c immu- nosuppression regimens that may be less deleterious to HCV-infected patients than others. Hepatitis C immunoglobulins (HCIg) In contrast to HBV, there is currently no available inter- vention to prevent universally HCV recurrence. In one study, polyclonal immunoglobulins containing anti-HCV were shown to decrease the incidence of recurrent HCV viraemia measured 1 year post-transplantation. 146 How- ever, given the humoral immune failure in providing ad- equate and long-lasting neutralizing immunity against HCV, one would predict that additional approaches will be necessary. Indeed, a recent randomized controlled study of hepatitis C immunoglobulin found no benefi t in terms of post-transplant clinical reinfection rate or HCV RNA levels. 148 Whether this negative study is a function of the dose of HCIg used, the timing of administration or the type of preparation used (non-neutralizing anti- bodies) is unknown. It is also possible if not likely, that diverse quasi-species nature of HCV makes this virus in- herently more diffi cult to neutralize than the more stable HBV virus populations present in any individual. Pre-transplantation antiviral therapy In theory, the rationale for treating patients with de- compensated HCV-related cirrhosis is the same as for hepatitis B, i.e. (1) to slow down clinical disease progres- sion and improve the hepatic synthetic function, and in doing so, to reverse the complications of liver disease and obviate/delay the need for liver transplantation; and (2) to achieve an improvement in post-transplanta- tion outcome by clearing the virus prior to transplan- tation. While the fi rst aim has become a reachable goal in patients with HBV-related decompensated cirrhosis, it remains to be proven in patients infected with HCV, at least with current antiviral agents. In contrast, clear- ance of HCV prior to transplantation may prevent viral recurrence, and reduction of HCV RNA levels could po- tentially improve post-transplantation disease progres- sion. Patients waiting for liver transplantation due to HCV-related liver disease typically include two types of patients, those with compensated cirrhosis and HCC and those with decompensated cirrhosis. While in the former group it is likely that a complete course of anti- viral therapy may be achieved with currently available drugs, it is less so in those with advanced hepatic insuf- fi ciency. Treatment of compensated cirrhosis (for HCC) Therapy of chronic hepatitis C has improved in recent 1405130059_4_022.indd 3581405130059_4_022.indd 358 30/03/2005 12:33:1930/03/2005 12:33:19 Liver transplantation in the management of chronic viral hepatitis 359 years with the addition of ribavirin and development of pegylated forms of IFN (PEG-IFNs). Sustained virologi- cal responses are achieved in 54–56% of patients com- pared with 44–47% of those treated with standard IFN and ribavirin. Response is strongly related to the infect- ing genotype, so that it may reach 78% in those infect- ed with non-1 genotypes compared with 51% in those infected with genotype 1. Other factors that have been shown to infl uence virological response include viral load, body mass index, race and the degree of liver fi - brosis. Although tolerance is adequate, the response rate to these therapies appears to be lower in patients with compensated cirrhosis or transition to cirrhosis than in patients with less advanced liver disease (43–50% vs 57– 65% in non-cirrhotic patients). 149 In addition, histological analysis has shown that 49% of cirrhotic patients with a sustained virological response have an improvement in the fi brosis score, suggesting that advanced fi brosis can be reversed with therapy. It remains to be shown wheth- er improvements in fi brosis can be reliably achieved in patients without a virological response who are treated with long-term, maintenance IFN therapy. Tolerabil- ity and side-effects are similar to those observed with standard IFN, with the exception of cytopenias, particu- larly neutropenia, that are more frequently seen with the PEG-IFNs. These side-effects may become a limitation when treating cirrhotic patients with marginal counts. The use of growth factors (i.e. erythropoietin and neu- trophil stimulating factor) may be helpful in some cases and avoid the reduction and/or discontinuation of anti- viral drugs. However, the potential benefi t of these com- pounds needs to be tested in prospective randomized trials. Thus, in summary, combination therapy with PEG- IFN and ribavirin should be recommended in patients with cirrhosis provided that no contraindications are present. 80 For patients infected with genotype 1, the op- timal length of therapy and dose of ribavirin are prob- ably 48 weeks and 1000–1200 mg. In contrast, for those infected with genotypes 2 and 3, 24 weeks and 800 mg of ribavirin are probably suffi cient. Treatment of patients with decompensated cirrhosis (Table 22.4) The data available on treatment outcomes of antiviral therapy in patients with decompensated liver disease are limited to small uncontrolled case series. 150–152 How- ever, it is clear from these studies that antiviral therapy should be administered with extreme caution in this population, as treatment may increase the risk of infec- tious complications and increase the likelihood of he- patic decompensation. In two studies, therapy was started with low doses of IFN ± ribavirin, and doses were increased slowly as tolerated. 10,151 In contrast, complete doses of both drugs were used in a third study by Forns and colleagues. 152 These studies emphasize the advantages and disadvan- tages of this approach. In the multicentre study by Crippin and colleagues, 150 HCV-infected patients at or near the top of their respec- tive waiting lists were randomly assigned to one of three treatment arms, two involving therapy with IFN in monotherapy, and one in combination with ribavirin. Less than half the patients screened met entry criteria, with thrombocytopenia and leukopenia being the most common reasons for exclusion. Eventually, only 15 pa- tients from fi ve large transplant centres were treated. Nine patients received IFN monotherapy while six re- ceived combination therapy with ribavirin (400 mg twice daily). While on treatment, loss of detectable HCV RNA was seen in 33%. Unfortunately, recurrence of in- fection was not prevented in the single patient who un- derwent liver transplantation at the time when he was HCV RNA-negative (although he was negative by the relatively insensitive bDNA assay). In addition, a signif- icant number of adverse effects occurred (n = 23), many of which were considered severe. While thrombocyto- penia was the most frequent adverse event, infection was the most severe one. These side-effects, particularly life-threatening infections, ultimately led to the early termination of the study. There are several interesting conclusions from this study. (1) A large proportion of Table 22.4 Therapy of patients with HCV-related decompensated cirrhosis Author, year (number of patients) ref Eligibility Genotype 1 Child A VR* Adverse events Treatment DC Prevention of recurrence of those HCV RNA-negative at transplantation Crippin et al. 2002 (n = 15) 150 47% 67% 0% 33% 87% 100% No (n = 1) Everson et al. 2000 (n = 91) 151 NA 77% 50% 38% ND 28% 100% (n = 8) Forns et al. 2003 (n = 30) 152 62% 83% 50% 30% 63% 20 67% (6/9) DC, discontinuation; VR, virological response; NA, not available; ND, not done. *HCV RNA clearance while on therapy. 1405130059_4_022.indd 3591405130059_4_022.indd 359 30/03/2005 12:33:2030/03/2005 12:33:20 [...]... primary hepatocellular carcinoma (HCC). 15 GBV-A 100% GBV-C GBV-B 98% Figure 24.1 Phylogenetic relationship between HCV and other members of the Flaviviridae This figure shows a comparison of the predicted polymerase regions of HCV-1a, -2 a, -3 a, -4 a, -5 a and -6 a, GBV-A, GBV-B, GVB-C, classical swine fever virus (CSFV), bovine viral diarrhoea virus (BVDV), tick-borne encephalitis virus (TBEV), yellow... Simmonds.11,12) HCV-3a HCV-5a HCV-6a HCV-4a HCV-1a HCV-2a 100% BVDV CSFV 100% 100% Hepaciviruses Pestiviruses TBEV YFV Flaviviruses WNV DV 381 14 051 30 059 _4_024.indd 381 30/03/20 05 12:34:29 382 Chapter 24 RNA ~9,600 nt AUG UAG UTR 5 UTR 3¢ Open reading frame NH2 C E1 S C E1 E2 S E2 Structural proteins p7 NS2 S S NS3 4A NS4B 2–3 3 3 NS5A NS5B 3 3 4A NS4B NS5A CO2H p7 NS2 NS3 NS5B Non-structural proteins... patients. 155 One small, uncontrolled series has evaluated the effect of pre-emptive combination therapy In this case series, 36 recipients were treated with IFN-α2b and ribavirin starting the third post-transplant week and continued for 1 year. 156 After a median follow-up of 52 months, the actu- 30/03/20 05 12:33:20 Liver transplantation in the management of chronic viral hepatitis arial 5- year survival... Oon C-J, Tan K-L, Harrison TJ, Zuckerman AJ Natural history of hepatitis B surface antigen mutants in children Lancet 1996;348: 152 4 Wilson JN, Nokes DJ, Carman WF The predicted pattern of emergence of vaccine-resistant hepatitis B: a cause for concern? Vaccine 1999;17:973–8 Zuckerman AJ Effect of hepatitis B virus mutants on efficacy of vaccination Lancet 2000; 355 :1382–4 30/03/20 05 12:33 :58 14 051 30 059 _4_023.indd... prophylaxis with very low-dose hepatitis B immune globulin Liver Transpl Surg 1999;6 :51 2–19 56 Sanchez-Fueyo A, Rimola A, Grande L et al Hepatitis B immunoglobulin discontinuation followed by hepatitis B virus vaccination: a new strategy in the prophylaxis of hepatitis B virus recurrence after liver transplantation Hepatology 2000;31:496– 50 1 57 Sanchez-Fueyo A, Martinez-Bauer E, Rimola A Hepatitis B vaccination... containing pre-S components of the HBV coat protein with non-pre-S containing vaccines J Gastroenterol Hepatol 19 95; 10 :51 5 Ferrari C, Cavalli A, Penna A et al Fine specificity of the human T-cell response to hepatitis B virus preS1 antigen Gastroenterology 1992;103:2 25 63 Suzuki H, Limo S, Shirak K et al Safety and efficacy of a recombinant pre-S2 and S-containing hepatitis B vaccine (TGP-943): phase... 14 051 30 059 _4_023.indd 378 30/03/20 05 12:33 :58 Section V Hepatitis C Virus 14 051 30 059 _4_024.indd 379 30/03/20 05 12:34:27 14 051 30 059 _4_024.indd 380 30/03/20 05 12:34:29 Chapter 24 Structure and molecular virology Michael J McGarvey, Michael Houghton The relationship between hepatitis C virus and the Flaviviridae family Hepatitis C virus (HCV) is an enveloped positive-strand RNA virus of the genus Hepacivirus... liver transplantation for patients with hepatitis B-related liver disease Hepatology 2002; 35: 152 8– 35 30/03/20 05 12:33:23 Chapter 23 Prevention Jane N Zuckerman Introduction Hepatitis B, which is a major public health problem throughout the world, is preventable by immunization First-generation vaccines were prepared from the 22-nm hepatitis B surface antigen (HBsAg) particles purified and inactivated from... Consensus Group on hepatitis B Immunity Are booster immunisations needed for lifelong hepatitis B immunity? Lancet 2002; 355 :56 1 5 10 Whittle H, Jaffar S, Wansborough M et al Observational study of vaccine efficacy 14 years after trial of hepatitis B vaccination in Gambian children BMJ 2002;3 25: 569–72 11 Alpen CA, Kruskall MS, Marcus-Bagley D et al Genetic prediction of nonresponse to hepatitis B vaccine... influence pre-S1, pre-S2, S hepatitis B vaccine Vaccine 1999;17:330–9 15 Milich DR, McNamra NK, McLachlan A, Thornton GB, Chisari FV Distinct H-2 linked regulation of T-cell responses to the preS and S regions of the same hepatitis B surface polypeptide al- 30/03/20 05 12:33 :58 Prevention 16 17 18 19 20 21 22 23 lows circumvention of nonresponsiveness to the S region Proc Natl Acad Sci USA 19 85; 82:8168–72 . 14 051 30 059 _4_022.indd 355 14 051 30 059 _4_022.indd 355 30/03/20 05 12:33:1830/03/20 05 12:33:18 Chapter 22 356 one-third of patients who have relatively slow fi brosis progression in the fi rst 3 5 years. decompensated RNA + hepatitis hepatitis in 5- 7 years 1 year LT HCV RNA (-) 2% Fibrosing Cholestatic hepatitis 2-6 % Minimal injury 3 0 -5 0% Delayed injury 30% Viral factors Viral load Genotype Quasi-species Donor. transplantation. 14 051 30 059 _4_022.indd 354 14 051 30 059 _4_022.indd 354 30/03/20 05 12:33:1830/03/20 05 12:33:18 Liver transplantation in the management of chronic viral hepatitis 355 report both grade