Expert Commentary on:

Abstract

Modeling the Impact of Interferon Alfa Treatment on Liver Fibrosis Progression in Chronic Hepatitis C: A Dynamic View Rodolphe Sobesky, Philippe Mathurin, Frederic Charlotte, Joseph Moussalli, Martine Olivi, Michel Vidaud, Vlad Ratziu, Pierre Opolon, Thierry Poynard, for the MULTIVIRC Group. Gastroenterology 116:378-386, 1999. Background & Aims: Impact of hepatitis C treatment has never taken into account the dynamics of fibrosis progression. This study assessed the impact of interferon on liver fibrosis progression in patients with chronic hepatitis C according to 3-month aminotransferase activity response. Methods: We recruited 287 patients, 185 treated and 102 control, with paired biopsy specimens. Before follow-up, the fibrosis progression rate per year was estimated as the ratio between fibrosis stage in METAVIR units (1 U, 1 stage; 4 U, cirrhosis) and the duration of infection. During follow-up, fibrosis progression was assessed by the observed difference between stages divided by duration between biopsies. Results: The median fibrosis progression rate in treated patients decreased compared with the rate before treatment from 0.103 F METAVIR U/yr (95% confidence interval [CI], 0.087-0.120) to 0.000 (95% CI, 0.000-0.000; P =< 0.0001). Among 91 treated responders, fibrosis stage worsened in 19 (22%), compared with 21 (22%) of 94 treated nonresponders and 57 of 102 controls (56%; P =< 0.0001 compared with treated patients), and improved in 26 (29%), 17 (18%), and 8 (8%; P = 0.0002 compared with 29% and P = 0.03 compared with 18%), respectively. These observed differences persisted after genotype, viremia, sex, age at infection, duration of infection, and alcohol consumption were taken into account. Conclusions: Interferon treatment changes the natural fibrosis progression rate in patients with chronic hepatitis C independently of genotype and early response.

Expert Commentary

Hepatitis C virus (HCV) is recognized as a growing public health threat in the US and worldwide. Already the main cause of chronic liver disease and leading indication for orthotopic liver transplants in the US, HCV is predicted to cause accelerated rates of hepatic morbidity in the coming decades. The introduction of alfa interferon therapy has allowed a subset of patients to clear HCV from their sera and livers. However, efficacy rates, when determined by traditional measures such as alanine aminotransferase (ALT) activity and presence of HCV RNA, have been disappointing. Even the recently approved combination of alfa interferon and ribavirin for chronic hepatitis C results in sustained clearance of HCV RNA in less than 40% of treated patients (see Expert Commentary on: Interferon Alfa-2b Alone or in Combination With Ribavirin as Initial Treatment for Chronic Hepatitis C).This study, from the French MULTIVIRC group, expands on the premise that chronic hepatitis C can and should be viewed not only as an infectious disease, but as a histologic disease, the natural history of which leads to hepatic fibrosis. Methods This retrospective study examined data from a large cohort of patients with chronic hepatitis C in whom paired biopsy samples were available. Untreated controls were matched with the treated cohort according to baseline fibrosis rate and genotype. Liver fibrosis during the treatment period was estimated using the METAVIR scoring system, which assigns numerical values to inflammatory activity and fibrosis. Results One hundred eighty-five treated patients were compared to 102 matched, untreated controls. Fibrosis progression rate in the treated group was significantly reduced compared to that of the untreated group. Although the decrease in fibrosis progression was most impressive in those with biochemical (ALT) response, there was still a benefit regarding fibrosis progression in the group with lack of response to interferon. This histologic progression remained significant when controlling for genotype, age, sex, viral load, and alcohol consumption.

Conclusion

This study adds to the growing body of literature portraying HCV infection as a progressive disease of hepatic fibrogenesis. Much of our current emphasis has been on normalization of serum ALT and clearance of HCV RNA from the serum. Using these criteria, the majority of patients are destined to "fail" therapy. If, as this study implies, fibrogenesis can be delayed or forestalled by interferon therapy, cessation of such treatment based on lack of virologic clearance at 12 weeks may be premature. Future trials will be strengthened by determination of histologic measures, especially over a prolonged period of observation. This study did have several weaknesses, many of which are readily acknowledged by the authors. Alcohol consumption was not objectively assessed in the two groups. Viral load was measured in a minority of patients, using a relatively insensitive method (bDNA). Most important, patients have naturally differing rates of fibrosis progression. Understanding and predicting this variation is indeed one of the most difficult challenges in the management of patients with chronic HCV infection. Nonetheless, the authors' estimate of the mean time (7 years) elapsed between METAVIR fibrosis stages is a sobering reminder that our therapies need to address these sort of histologic issues. Future work may well address histologic assessment of those patients receiving combination interferon/ribavirin therapy and those on longer or suppressive interferon regimens. Steven K. Herrine, MD Clinical Assistant Professor of Medicine Jefferson Medical College Division of Gastroenterology and Hepatology Thomas Jefferson University Hospital Philadelphia, Pa.

American Association for the Study of Liver Diseases 50th Annual Meeting

[Medscape, 1999. © 1999 Medscape, Inc.]
New Trends in Liver Transplantation Michael R. Lucey, MD

Introduction:  Three broad themes about liver transplantation were discernable at the 50th annual meeting of the American Association for the Study of Liver Diseases (AASLD). The first of these was the growing problem of inadequate donor organ supply; the second focused on new advances in managing the allograft response. Last, many presentations addressed the challenges resulting from recurrence of the original disease. The first two of these topics will be reviewed in this summary, and Paul Martin will review the issue of disease recurrence, of which recurrent hepatitis is perhaps the most challenging.

The Donor-Recipient Imbalance

The number of livers available for transplantation in the United States has remained relatively constant at about 4000 per annum for the past several years. At the same time, however, the number of patients on the UNOS (United Network for Organ Sharing) waiting list has continued to grow every year. The perception that patients with end-stage liver disease are dying while on the transplant waiting list has informed the recent debate on how best to allocate donor organs. The same concern about preventing avoidable deaths has fueled the search for ways to expand the donor pool, such as "splitting" cadaveric organs for use in two recipients or transplanting partial liver grafts from living donors.

Is it Dangerous to Wait a Long Time for a Liver? Freeman and colleagues conducted an analysis of the UNOS database to determine whether duration of waiting time correlates with transplant outcome.[1] These investigators took all new registrations for 24 months starting from January 1, 1996, and calculated the relative risk (RR) of dying before receiving a transplant within 2 years. This timeframe antedates recent changes in classifying priority status and the introduction of minimal listing criteria. The cohort consisted of 16,414 patients. The endpoints were liver transplantation or death while on the list. Removal from the list due to the patient becoming too ill for transplant was considered waiting-related mortality. The median duration of follow-up was 18 months. Among the factors associated with a greater risk of dying while awaiting transplant, UNOS status was the most significant. Patients who were placed on the list in UNOS status 1 (ie, the most urgent patients) had a relative risk of death in 2 years of 12.8; P < .001. The next most urgent group at entry, UNOS status 2, was also highly at risk of death in 2 years: RR 5.28; P < .001. Compared with these variables, all other parameters had minor or no impact, although previous transplant, black race, age > 60 years, or a primary diagnosis of alcoholic cirrhosis, acute liver failure, or malignant disease were associated with a small, albeit significant, increased risk of death. The size of the transplant program also had a small effect, such that programs with small numbers of registrations were associated with an increased risk of dying. By contrast, patients with blood group A and cholestatic liver disease had a lesser risk of dying. An analysis was performed of mortality at individual centers using a multivariate proportional hazards model while controlling for the previously identified variables. There was no association found between outcome for any of the 4 UNOS priority statuses with average duration of waiting time for patients who enter the list at that status in individual centers. In other words, the clinical status at entry to the list determined risk of death, rather than differences in waiting times incurred between the transplant centers. Novel Approaches to Expanding the Donor Pool The availability of liver transplantation has been constrained by the reliance on a cadaveric source for organs. The use of living donors was pioneered in Japan, where societal mores have been antipathetic to cadaveric donation. Initially, living donation was confined to left lobectomy in adults for transplantation into children. More recently, extensive resections of the right hepatic lobe have provided functional grafts for adult recipients. The regenerative capacity of the liver is such that the donor liver is restored to its ideal mass in about 6 weeks. Ichida[2] reported on the world's largest experience of living related donor liver transplantation (LRDLT) wherein the recipient is an adult. Data were gathered from 37 centers in Japan. Between 1989 and 1999, 200 LRDLTs were carried out with adult recipients. The overall patient survival at 5 years was 71%. Survival was reduced in patients undergoing LRDLT for acute liver failure: 66.7% at 3 years. The majority (120) of grafts were left lobe resections, of which 27 grafts failed. The outcome for the recipient was the same for right or left lobe grafts. No detailed account of donor safety was provided, although it was stated that there have been no donor deaths in any Japanese center. One speaker from a center contributing data to the combined report spoke from the floor and said that their program had experienced two major donor complications: a pulmonary embolus and portal vein thrombosis. The greatest single center experience of living donor liver transplantation between adults in the United States was reported by Marcos and associates.[3] They expanded on data reported in their abstract by discussing the outcome in 40 transplants in which right lobectomy was used exclusively for providing the graft. In their protocol, donor evaluation included liver biopsy, magnetic resonance scanning with volumetric estimation of the right lobe, and angiography. They calculated graft to recipient body weight (GRBW) after correcting for donor liver fat. A GRBW of at least 0.8 was required. Nineteen percent of potential donors were ruled ineligible on account of liver fat rendering the GRBW inadequate. The average resected right lobe mass was 865 +/- 159 grams. The average GRBW was 1.1 +/- 0.21. The average length of hospital stay for the donor in their last 20 transplants was 4.8 days, with no readmissions. There were no donor deaths, although there was some donor morbidity, including pressure sores in 3. There were 5 recipient deaths, and 15% of recipients had biliary complications. No recipient of a living right lobe graft required retransplantation with a cadaveric organ. Managing the Immune Response to the Allograft Two trends regarding immunosuppression after liver transplantation were evident from the proceedings at this meeting. On the one hand, emphasis was placed on the newer, more powerful, or more targeted immunosuppressive agents that are being introduced into the armamentarium. At the same time, because it has become clear that many liver graft recipients require less immunosuppression than previously thought, there was recognition that reducing or eliminating immunosuppressive agents from the management protocol could improve the side effects without threatening the allograft. Mycophenolate Mofetil: An Exciting New Immunosuppressive Agent Wiesner presented the results of a large multicenter study comparing mycophenolate mofetil (MMF) with azathioprine (AZA) as an adjunctive agent in liver transplant recipients managed using microemulsion cyclosporine and corticosteroids.[4] The primary endpoints were patient and graft survival, with secondary endpoints regarding incidence of acute cellular rejection. Subjects were well matched for etiology of liver disease, age, sex, HLA DR mismatching, and cold ischemia time. Two hundred eighty-seven patients were randomized to receive AZA and 278 to receive MMF; all were followed for at least 1 year. There were no differences in primary endpoints: patient survival at 1 year was 85% in the AZA group and 86% in the MMF group. However, acute cellular rejection rates were higher in the AZA group compared with the MMF group (47.7% versus 38.1%), as were the steroid-resistant rejection rates (8.0% versus 4.0%). The rates of withdrawal from the study were high but equal in each treatment group (47% in both groups). Similarly, there were no significant differences in the rates of adverse effects among the groups. In the course of 1 year's observation, 33% of each group withdrew prematurely on account of unwanted effects. These data suggest that MMF is a more potent suppressant of the immune response than AZA. This effect translates into lower rates of rejection, but not greater graft or patient survival.

This study indicates that MMF is a powerful addition to our clinical arsenal, but leaves unanswered the outstanding questions regarding our defining of the optimal immunosuppressant regimens for individual patients. Corticosteroids: Too Much of a Good Thing? Corticosteroids are a mainstay of immunosuppressive regimens for management of liver transplant recipients, both as initial therapy and as bolus therapy for newly diagnosed acute cellular rejection. Lately, corticosteroids have fallen into disrepute because of their many side effects, which become increasingly troublesome to the patient over time following transplantation. Of particular concern has been the incidence of bone loss leading to pathologic fractures and vertebral collapse, hyperlipidemia, diabetes mellitus, and hypertension. For these reasons, many programs have instituted protocols to reduce or withdraw corticosteroids at some point after the first few weeks, that is, once the period of greatest immunogenicity has passed. However, few programs have attempted orthotopic liver transplantation in the absence of corticosteroids. Two important papers, one basic science, and one a clinical study, considered the role of corticosteroids in the early postoperative period. Olthoff and her colleagues from the University of Pennsylvania used liver transplantation between genetically identical (syngeneic) rats to investigate the effect of corticosteroids on tissue recovery after transplantation.[5] Their syngeneic model removes acute cellular rejection from consideration. They found that dexamethasone inhibited DNA replication and binding of NF kappa B, STAT 3, and AP-1, which are important steps in the early phases of hepatocyte recovery and regeneration. These data suggest that the administration of corticosteroids in the operating room may retard recovery of the reperfused allograft. This hypothesis will need to be tested in allogeneic models and in a clinical environment. The Liver Transplant Group from Leuven, Belgium, provided a clinical correlate to Olthoff's paper.[6] They conducted a prospective study of liver transplantation using tacrolimus and azathioprine as immunosuppressives, without corticosteroids. Patients with viral disease, alcoholic cirrhosis, cholestatic liver failure, and acute liver failure were considered eligible, whereas patients with autoimmune liver disease were excluded. Thirty-six patients were screened and 21 met eligibility for inclusion. (The reasons for noninclusion were not stated.) Among the 21 patients, there was no incidence of primary graft nonfunction. At follow-up of 3 to 14 months, graft survival was 95%. One graft was lost to hepatic artery thrombosis. Steroids were introduced in 9 patients. Five patients developed acute cellular rejection, all of whom responded to steroids. In 4 patients, steroids were started for indications other than acute cellular rejection: ie, tacrolimus neurotoxicity or nephrotoxicity, anaphylaxis, or leukopenia. These data suggest that there may be a population in whom no steroids are required to control the early immune response. However, more work is warranted to identify those patients in whom steroids can be safely withheld.

References

Freeman RB, Edwards EB, Turcotte JG, and the UNOS liver subcommittee. Waiting list mortality and liver allocation policy. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 251. Ichida T, Omata M. Clinical outcome of living related donor liver transplantation for adult recipients in Japan. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 241. Marcos A, Fisher RA, Ham JM, et al. Single center analysis of the first 30 adult to adult living donor liver transplants utilizing the right lobe. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 240. Mamelok RD, Kalayoglu M, Klintmalm G, et al. A randomized, double blind, comparative study of mycophenolate mofetil (MMF), and azathioprine (AZA) in combination with cyclosporine and corticosteroids in liver transplant recipients. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 246. Olthoff KM, Dobonera F, Aldeguer X, et al. Dexamethasone inhibits hepatocellular recovery following ischemia/reperfusion injury in liver transplantation. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 248. Liver Transplant Group, Leuven, Belgium. Liver transplantation without steroids. Program and abstracts of the American Association for the Study of Liver Diseases 50th Annual Meeting; November 5-9, 1999; Dallas, Tex. Abstract 247.