Transplant Articles 2003
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Treatment of HCV Patients
Awaiting Liver Transplantation Helps to Prevent HCV Recurrence Following
Surgery
After liver transplantation (LT) infection of the graft with the hepatitis C virus (HCV) is almost universal and chronic hepatitis and cirrhosis develop in a significant proportion of patients. One possible strategy to prevent HCV infection recurrence is to eradicate HCV before LT. Researchers at four liver transplant units in Spain evaluated the efficacy and safety of antiviral therapy to prevent HCV recurrence in 30 HCV-cirrhotic patients awaiting LT. At the time of inclusion 15 patients were Child-Pugh A and 15 Child-Pugh B/C. The infecting genotype was 1b in 25 patients. Treatment with interferon alfa-2b (Intron A) 3 MU/day and ribavirin 800 mg/day was initiated when the expected time for LT was less than 4 months and continued until LT. The median duration of treatment was 12 weeks. Study Results Nine patients (30%) achieved a virological response and 21 did not respond to therapy. In nine (43%) of the 21 non-responders viral load decreased \ge 2 log10 during treatment. A viral load decrease \ge 2 log10 at week 4 of treatment was the strongest predictor of virological response. All nine virological responders have already undergone LT; six patients remain free of infection after a median follow-up of 46 weeks and HCV infection recurred in three patients after LT. In one of these patients HCV-RNA was still detectable in the explanted liver. Side effects were frequent and dose reduction was necessary in 19 (63%) of the 30 patients; no patient died while on therapy. The authors conclude, “Our data support the utilization of antiviral therapy in HCV-infected patients awaiting LT as one of the strategies to prevent hepatitis C recurrence after transplantation.” 08/20/03
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Reversal of cirrhosis: evidence-based medicine?
The term “reversal” (like “regression”) is intrinsically ambiguous. Reversal (and regression) can be minimal, partial, substantial, or complete; all variants are covered by the term reversal (or regression). Poynard et al.1 define reversal of cirrhosis as “a change in fibrosis score based on the biopsy sample” (pg. 1304 and 1312). This is a questionable definition of reversal of cirrhosis. Cirrhosis implies more than just fibrosis, but in addition nodular parenchymal regeneration and development of intrahepatic porto-hepatic and arteriovenous vascular shunts in fibrous septa.2 Furthermore, cirrhosis appears in a broad spectrum of variants: early cirrhosis, fully developed cirrhosis, active and inactive cirrhosis, and as morphological types: micronodular, macronodular, mixed micro-macronudular, and incomplete septal cirrhosis.3,4 It thus is clear that the study by Poynard et al.1 does not concern reversal of cirrhosis (i.e., reversal of all key features of cirrhosis), but concerns reversal of fibrosis in cirrhosis. Such interchangeable use of the terms fibrosis and cirrhosis catapults this topic back into the early previous century when confusion between fibrosis and cirrhosis necessitated consensus meetings, the best known being held in Havana in 1956,5 stating explicitly (pg. 216, lines 1-2) : “Fibrosis should not be used synonymously for cirrhosis.” This is very old stuff, but remains important! Concern is raised by the fact that Poynard et al.1 warn the reader only once about their special definition of “reversal” by using inverted commas (pg. 1309, last paragraph). In the remaining text, they even use reversal interchangeably with disappearance of cirrhosis (pg. 1311). They omit to warn the reader about their special definition of the term “reversal” in the abstract. Any reader scanning the literature by reading abstracts gets incorrect information. “Half of the patients with baseline cirrhosis treated with the reinforced regimen had a disappearance of cirrhosis at the time of the subsequent follow-up biopsy” (pg. 1311). This conclusion represents inadequate interpretation of results, obtained in histological semiquantitative scoring of liver fibrosis in needle biopsies. The Metavir6 scores F3, F2, F1, and even F0 do not exclude cirrhosis; they do not prove a disappearance or absence of cirrhosis! More than one study has documented the conversion of micronodular into macronodular cirrhosis, especially if the causative agent could be eliminated and the necro-inflammatory parenchymal damage reduced.7,8 The repair process of cirrhosis may possibly even evolve into the stage of incomplete septal cirrhosis,9,10 the variant of macronodular cirrhosis which is particularly difficult to diagnose on liver needle specimens.3 Although we fully agree that cirrhosis is not totally irreversible, we also maintain with others9,10 that complete regression of cirrhosis has never been clearly demonstrated. It is our contention that the reinforced regimen used by Poynard et al.1 has converted an originally readily recognizable cirrhosis (Metavir stage F4) into less active macronodular forms of cirrhosis, less easily identifiable in even adequate needle biopsy specimens and correctly staged in the Metavir scoring system as F3, F2, F1, and even F0. Poynard et al.1 might perhaps invoke the definition of the Metavir score F3, which reads: “numerous septa without cirrhosis.”6 Regrettably this definition is somewhat unfortunate; it obviously intends to mean numerous septa without ‘obvious’ cirrhosis.” It cannot be that 10 distinguished French hepatopathologists (the Metavir group) would agree that clinicians, statisticians, or other nonpathologists conclude from a F4-to-F3 conversion that cirrhosis has disappeared! Semiquantitative scoring of liver biopsies and interpretation of the results requires collaboration between pathologists and preferably informed clinicians.11,12 On page 1312, Poynard et al.1 consider the limitations of their study, and mention the “possibility of sampling error especially between stage 3 (extensive fibrosis) and stage 4 (cirrhosis), particularly with biopsies of small size.” This is correct. They then go on apparently minimizing the possibility of sampling error in their study by mentioning three considerations about mean biopsy size, activity improvement, and virologic response. However, none of these remarks excludes the possibility of a micro-to-macronodular conversion of those patients’ cirrhosis, and hence does not justify to conclude to disappearance of cirrhosis. Since patients with cirrhosis reversal were younger, Poynard et al.1 consider the possibility that early cirrhosis is easier to reverse than more established cirrhosis, and conclude: “These large prospective studies with repeated biopsies have finally identified a new category of extensive fibrosis that could be named a “reversible cirrhotic stage.” This allegedly new category is relatively old! Other workers deserve the credit for this concept. It is known since 1936 from experimental work,13 and has been indicated as precirrhotic liver,13,14 as the stage preceding the comitted precursor stage15 and as early minimal cirrhosis by Galambos who insisted on staging of cirrhosis.16 The Ishak scoring system,17 although imperfect like any scoring system, may be more appropriate in this respect than the Metavir system used by Poynard et al.1 The highest score F6 is defined as: “Cirrhosis, probable or definite.” In this way, this scoring system at least recognizes that there is problematic grey zone between cirrhosis and something-that-looks-like-cirrhosis-but-is-not-yet-definite cirrhosis. Admittedly, the Ishak score does not solve the basic problem that indeed today the need persists of defining the borderline between authentic cirrhosis and its more readily reversible precursor stages.18 We insist that our disappointment with the paper by Poynard et al.1 is nowhere due to an obsession by the dogma of irreversibility of liver cirrhosis.19 We agree that cirrhosis can regress to variable extent, but correspondingly maintain that true cirrhosis remains irreversible to variable extent. Convincing proof of complete regression of established cirrhosis has not yet been produced. Reply We thank Drs. Desmet and Roskams for their comments on this optimistic subject, and we recognize their important publications in this field. This subject was also well discussed recently by Bonis et al.1 commenting on a nice description of improvement of cirrhosis (disappearance?) in secondary biliary cirrhosis.2 We agree that there is no single perfect term to define the improvement of cirrhosis. As a matter of fact we were very prudent and never emphatically stated that treatment can result in a “complete cirrhosis regression.” The proposal of Desmet and Roskams remains ambiguous: “cirrhosis can regress to variable extent, ... but true cirrhosis remains irreversible to variable extent.” The pathologist of the study, Zach Goodman, applied the METAVIR criteria. From this methodology and as we discussed in the article we used a simple histological end point with its limitations as discussed. It has its limits like another scoring system but was validated for interobserver variation. Of course skilled pathologists as Dr Desmet or Dr Goodman are used to presuming or suspecting cirrhosis in a fragmented small biopsy with many septa. Because of the limitations of intercostal liver biopsy, sampling error and discordance between pathologists, the recent development of biochemical markers may also be useful for the observation of cirrhosis improvement.3 Among one multicenter study of patients treated 48 weeks with PEG-Interferon and Ribavirin versus Interferon and Ribavirin4 we measured the FibroTest and ActiTest in 352 patients, before treatment at baseline and 24 weeks after the end of the treatment.5 Among these patients 32 had cirrhosis at baseline. For 15 patients stage remains F4 and the Fibrotest did not significantly changed (0.67 ± 0.05 vs. 0.64 ± 0.05). For 17 patients there was at least one fibrosis stage improvement. These patients had a very significant Fibrotest improvement (Wilcoxon signed-rank test Z value = 3.58; P < 0.0001) from 0.68 to 0.44 for 3 stages improvement, 0.60 to 0.47 for 2 stages improvement and from 0.61 to 0.56 for one stage improvement. One clinical proof of cirrhosis improvement, unexpected years ago, is the reversal (disappearance) of cirrhosis and its clinical complications by medical treatment. In hepatitis B nucleoside treatment are associated both with cirrhosis improvement6 and with disappearance of encephalopathy, jaundice, and ascites.7 As such, whilst there are discrepancies and disagreements over nomenclature and terminology as pointed out by Dr. Desmet and colleagues, we believe that our findings are important, real and require further confirmation in subsequent treatment studies in hepatitis C infection and other liver diseases. Copyright © 2003 by American Gastroenterological Association Copyright © 2003 by American Gastroenterological Association
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Immunosuppressive Drugs and the Use of Generic Immunosuppressants
American Journal of Transplantation OnlineEarly doi:10.1046/j.1600-6143.2003.00212.x Meeting Report Report of the American Society of Transplantation Conference on Immunosuppressive Drugs and the Use of Generic Immunosuppressants Rita R. Allowaya, Ross Isaacsb, Kathleen Lakec, Peter Hoyerd, Roy Firste, Harold Heldermanf, Suphamai Bunnapradistg,j, Alan Leichtmanc, M. William Bennetth, Amir Tejanii and Steven K. Takemotoj,* Considerable economic and health-related costs are associated with the life-long maintenance immunosuppressive therapy required to prevent transplant rejection. Generic medications have the potential of providing equivalent therapeutic efficacy at a lower economic cost. In 2001, the American Society of Transplantation invited experts to review the data and issues associated with the approval and use of generic immunosuppressants. A summary of that meeting is reported here. The generic medication approval process has been in effect for more than 30 years. All marketed generic cyclosporin formulations have met FDA criteria demonstrating bioequivalence in healthy subjects, and some were also tested in transplant recipients. Most participants agreed that generic narrow therapeutic index immunosuppressive agents provide adequate de novo immunosuppression in low-risk transplant recipients. However, some participants expressed concern regarding the currently unquantified risk that may be associated with switching immunosuppressive agents under uncontrolled circumstances. There was broad agreement among the participants that generic medications should be clearly labeled and distinguishable from innovator drugs, and that patients should be educated to inform their physicians of any switch to or among generic alternatives. There was also strong support in favor of requiring studies to demonstrate bioequivalence in potentially at-risk patient populations, specifically African-Americans and pediatric patients.
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