A toast to pentoxifylline12

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2001 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 96, No. 5, 2001 ISSN 0002-9270/01/$20.00 PII S0002-9270(01)02373-5

WORLD LITERATURE REVIEW Editor: David Johnson, M.D., F.A.C.G. REVIEW PANEL Luis Balart Jamie Barkin David Bjorkman Cedric Bremner William Carey Harold Conn Jack DiPalma Mark Fendrick

M. Brian Fennerty Mark Flemmer Christopher Gostout Robert Hawes Jorge Herrera Brenda Hoffman Perry Hookman John Johanson

A Toast to Pentoxifylline Akriviadis E, Botla D, Briggs W, et al. Pentoxifylline Improves Short-Term Survival in Severe Acute Alcoholic Hepatitis: A Double-Blind, Placebo-Controlled Trial Gastroenterology 2000;119:1635– 40

ABSTRACT The aim of this study was to evaluate the efficacy of pentoxifylline in patients with severe acute alcoholic hepatitis. Pentoxifylline is a nonselective phosphodiesterase inhibitor that decreases tumor necrosis factor (TNF) gene transcription. Elevated TNF levels have been found in the sera of patients with alcoholic hepatitis, and hence the rationale for this large scale study was to definitively address the therapeutic role of pentoxifylline in this disease. The study was conducted in the liver unit at the University of Southern California in patients with a history of heavy alcohol abuse and a clinical diagnosis of acute alcoholic hepatitis. Inclusion criteria for patients in the study were jaundice; Maddrey discriminant factor (DF) of ⱖ32 and one or more of the clinical or laboratory parameters of fever, palpable tender hepatomegaly, white blood cell count of ⬎12,000/ml3 with predominantly neutrophilic differentiation, hepatic encephalopathy, and hepatic systolic bruit. Enrollment into the study was attempted within the first 10 days after admission. Exclusion criteria included concomitant bacterial infections, active GI hemorrhage, or severe cardiopulmonary disease, and clinical evidence of advanced alcoholic cirrhosis. A histological diagnosis was not required for inclusion in the study, as the investigators feared that severely ill, coagulopathic patients might not be able to undergo a percutaneous liver biopsy. The study was a prospective, double blind, randomized, placebo-controlled study. The two primary endpoints were the effect of pentoxifylline on 1) the short term survival (during the index hospitalization or over the 28-day study period) and 2) progression to hepatorenal syndrome (HRS). Secondary endpoints were the effect of pentoxifylline on 1) the course of laboratory parameters, including serum TNF levels, and 2) development of clinical complications of liver disease.

Philip Katz Timothy Koch Mark Lawson Anil Minocha Edward C. Oldfield III David Ott C. S. Pitchumoni K. Rajender Reddy

Douglas Rex Arvey Rogers Richard Sampliner Paul Souney Christina Surawicz Nimish Vakil Harlan Vingan

One hundred two patients were enrolled and randomized to receive either pentoxifylline 400 mg t.i.d. for 4 wk or a placebo. Patients with previous hepatic decompensation (n ⫽ 22), hepatic encephalopathy (n ⫽ 10), and renal impairement (serum creatinine of ⬎2.4 mg/dl, n ⫽ 9 patients) were also included. There were no significant differences between the two groups for any of the demographic or clinical variables. Among the pentoxifylline group, 78% received medication until the completion of 28 days or until death, whereas in the control group 92% received placebo capsules for 28 days or until death. The mean period of treatment was 21 (21.5 ⫾ 9.5) days for both groups, thereby providing active treatment for a sufficient period. Reasons for discontinuation in the pentoxifylline group included headache, GI symptoms, and generalized skin rash. Plasma TNF levels were available for 60 patients (29 in the pentoxifylline group and 31 in the control group). Baseline TNF levels were above the normal range in all patients from both groups. There were no differences between the two groups at randomization or at any time during the treatment period in absolute values or in changes from baseline when all patients or only survivors of the two groups were compared. When only the nonsurvivors were compared, control patients had higher TNF values than pentoxifylline-treated patients at wk 1, 2, and 4. In this study, 25% and 46% in the pentoxifylline and control arms died (p ⫽ 0.037, reluctant risk [RR] ⫽ 0.59, 95% CI ⫽ 0.35– 0.97) after a range of 5–54 days and 7–139 days, respectively. In the patients who died, hepatic failure with HRS had developed in 50% in the pentoxifylline group and 92% in the control group. New onset renal failure occurred in 11% and 43% in the pentoxifylline and control groups, respectively (p ⫽ 0.001, RR ⫽ 0.35, 95% CI ⫽ 0.15– 0.77), and progressed to HRS in 80% and 90% of patients, respectively, in the two groups (p ⫽ 0.0015, RR ⫽ 0.32, 95% CI ⫽ 0.13– 0.79). In multiple logistic regression analysis, two variables (DF and age) were independently associated with survival in the control group, and one variable (creatinine) in the pentoxifylline group. Three variables (creatinine, age, and treatment with pentoxifylline) were independently associated with survival in the two groups

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combined. (Am J Gastroenterol 2001;96:1635–1637. © 2001 by Am. Coll. of Gastroenterology)

COMMENT About two-thirds of the US population drinks alcohol, but only about 2 million develop alcoholic liver disease (1). Patients with cirrhosis and superimposed alcoholic hepatitis have a ⬎60% mortality over a 4-yr period. More sobering is the fact that patients with severe alcoholic hepatitis as defined by Maddrey’s discriminant function of ⱖ32 have up to 40% mortality within 6 months. Abstinence is the key in prevention of progression of alcoholic liver disease in patients who survive an index episode of alcoholic hepatitis. The pathogenesis of alcoholic hepatitis is complex, with TNF emerging as one of the prominent cytokines involved in the necroinflammatory reaction that characterizes the process. Cultured peripheral blood monocytes in patients with alcoholic hepatitis spontaneously produce more TNF and significantly more in response to lipopolysaccaride stimulus—suggestive of dysregulated TNF metabolism in alcoholic hepatitis (2). Serum TNF values have also been correlated with disease severity and mortality (3). Most impressive is the fact that TNF receptor knockout mice are resistant to alcohol-induced liver injury (4). Further, TNF has a host of effects including inhibition of cytokine/chemoattractant synthesis, decreased expression of adhesion molecules on endothelial cells, inhibition of proliferation and chemotaxis of leucocytes, and decreased secretion of collagen and other interstitial matrix proteins (5–7). Histologically, acute alcoholic hepatitis is characterized by neutrophilic infiltration of zone 3, perivenular fibrosis, and intrasinusoidal collagen deposition, all of which could potentially be decreased by pentoxifylline, making it an attractive treatment modality in acute alcoholic hepatitis. Where does this study fit in the current literature of therapy for acute alcoholic hepatitis? Colchicine, propylthiouracil (PTU), and corticosteroids have been studied in acute alcoholic hepatitis. Two studies with colchicine and one with PTU did not show any effect on short term survival. Of the 13 randomized clinical trials evaluating corticosteroids in patients with alcoholic hepatitis, five observed a survival benefit. A meta-analysis of the 13 randomized clinical trials showed a significant short term survival effect of corticosteroids, with a mean difference of 15% (CI ⫽ 6 –24%, p ⬍ 0.01) (8). The effect was higher in the subgroup of patients with encephalopathy, with a mean difference of 27% (CI ⫽ 11– 44%, p ⬍ 0.0001). These translate to number of patients needed to be treated (NNT) of seven and four in alcoholic hepatitis with and without encephalopathy, respectively, to achieve a benefit from therapy. Based on these data, the current American College of Gastroenterology treatment guidelines recommend a regimen of prednisolone, 40 mg/ day for 28 days, followed by taper for patients with severe alcoholic hepatitis (8). The trial and results of the study by Akriviadis et al. are

AJG – Vol. 96, No. 5, 2001

commendable for several reasons. It is a large randomized, double blind, placebo-controlled study, the first of its kind in patients with severe alcoholic hepatitis. Medicine consumption was sufficient in both groups, and survival data were available for all patients. There was no statistically significant increase in infections in the pentoxifylline group relative to the control group. The statistical design and large sample size enable several important and valid conclusions to be drawn. The NNT in this study, to achieve a therapeutic benefit, is close to four. This is comparable to several accepted treatment options such as ␤ blockers for prevention of recurrent variceal bleeding (NNT of five). Most of the decrease in mortality was secondary to decrease in HRS. Skeptics might suggest that a third group of patients treated with prednisolone should have been included in the trial. Such a trial would have taken much longer, and based on historical data on survival after corticosteroids, there probably would still be a greater benefit from pentoxifylline. Though the results show an impressive reduction in new onset HRS and subsequent mortality from it, this study does not address the possible mechanisms involved in such a favorable outcome while on pentoxifylline. In summary, this study gives us a reasonable basis for consideration of pentoxifylline therapy in patients with severe alcoholic hepatitis. Therapy is safe, well tolerated, and inexpensive. Further studies should also be done to assess the efficacy of pentoxifylline in decreasing the incidence of HRS in patients with other forms of liver disease. Therapy with pentoxifylline should go hand in hand with reinforcing the need for strict abstinence from alcohol, as recidivism would set back any gains made. It’s time to raise our glasses for a toast . . . this time to pentoxifylline! Umaprasanna S. Karnam, M.D. K. Rajender Reddy, M.D., F.A.C.G. University of Miami School of Medicine Miami, Florida

REFERENCES 1. Dufour MC, Stinson FS, Caces MF. Trends in cirrhosis morbidity and mortality: United States, 1979 –1988. Semin Liver Dis 1993;13:109 –25. 2. McClain C, Cohen D. Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 1989;9: 349 –51. 3. Felver M, Mezey E, McGuire M, et al. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res 1990;14:255–9. 4. Yin M, Wheeler M, Kono H, et al. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999;117:942–52. 5. Krakauer T. Pentoxifylline inhibits ICAM-1 expression and cytokine production induced by proinflammatory cytokines in human pulmonary epithelial cells. Immunopharmacology 2000; 46:253– 62. 6. Neuner P, Kloser G, Pourmojib M, et al. Pentoxifylline in vivo and in vitro down-regulates the expression of the intercellular

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adhesion molecule-1 in monocytes. Immunology 1997;90: 435–9. 7. Balazs C, Kiss L, Farid N. Inhibitory effect of pentoxifylline on HLA-DR expression and glycosaminoglycan synthesis by retrobulbar fibroblasts. Horm Metab Res 1998;30:496 –9. 8. McCullough A, O’Connor J. Alcoholic liver disease: Proposed recommendations for the American College of Gastroenterology. Am J Gastroenterol 1998;93:2022–36.

Peginterferon Is Here to Stay Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon Alfa-2a in Patients With Chronic Hepatitis C N Engl J Med 2000;343:1666 –72 Heathcote EJ, Shiffman ML, Cooksley WGE, et al. Peginterferon Alfa-2a in Patients With Chronic Hepatitis C and Cirrhosis N Engl J Med 2000;343:1673– 80

ABSTRACT The purpose of the first study was to compare the efficacy and safety of peginterferon alfa-2a (PEG IFN) administered once per wk for 48 wk s.c., with IFN alfa-2a administered three times/wk. The primary efficacy endpoints were a sustained virologic response (indicated by ⬍100 copies/ml of hepatitis C virus [HCV]) at wk 72 and a sustained biochemical response (normalization of serum ALT to a value at or below the upper limit of normal) at wk 72. A subgroup of patients had liver biopsies done both pretreatment and 24 wk after cessation of treatment, and a histologic response (defined as a decrease of ⱖ2 points in the total Histological Activity Index score) was also assessed. In this study, 531 patients were randomly assigned to receive either 180 ␮g s.c. of PEG IFN once a wk for 48 wk (267 patients) or IFN alfa-2a 6 million U s.c. three times a wk for 12 wk followed by 3 million U s.c. three times/wk for 36 wk. In the PEG IFN group 223 of 267 patients (82.5%) completed treatment and 206 completed follow-up. In the IFN group 161 of 264 patients (61%) completed treatment and 154 completed follow-up. The baseline characteristics of the patients in the two treatment groups were similar. In an intent-to-treat analysis in which patients who missed the examination at the end of follow-up were considered as not having had a response, PEG IFN was associated with a higher rate of virologic response at wk 48 (69% vs 28%, p ⫽ 0.001) and at wk 72 (39% vs 19%, p ⫽ 0.001). The rate of sustained biochemical response at week 72 was also greater in the PEG IFN group (45% vs 25%, p ⫽ 0.001). In addition, the proportion of patients with both a sustained virologic and a biochemical response was higher in the PEG IFN group (38% vs 17%, p ⫽ 0.001). PEG IFN was associated with a 28% rate of sustained virologic response in patients infected with HCV genotype 1, whereas IFN alone resulted in ⬍10% sustained virologic response in this subgroup. Sixty-six percent of the 531 patients had paired pre- and posttreatment liver biopsies. Histological improvement was observed in

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63% of patients in the PEG IFN group and 55% of those in the IFN group. Independent factors associated with a sustained virologic response were identified as age of ⱕ40 yr, absence of cirrhosis or bridging fibrosis, body surface area of ⱕ2.0 m2, treatment with PEG IFN, HCV RNA level of ⱕ2 million copies/ml, pretreatment ALT quotient of ⬎3 (ALT quotient being the average of the serum ALT values before treatment divided by the upper limit of normal), and HCV genotype other than 1. The frequency and severity of adverse effects were similar in the two groups. Psychiatric disorders were the most frequent serious adverse events, and significant anemia or thrombocytopenia was rare in both treatment groups. In the second study the efficacy and safety of PEG IFN alfa-2a in patients with HCV-related cirrhosis (76 –79%) or bridging fibrosis (20 –24%) were studied. In this multicenter, open label, randomized, parallel dose study, 271 patients with cirrhosis or bridging fibrosis were randomly assigned to receive treatment with 3 million U of IFN alfa-2a three times weekly (n ⫽ 88 patients), 90 ␮g of PEG IFN alfa-2a once weekly (n ⫽ 96), or 180 ␮g of PEG IFN alfa-2a once weekly (n ⫽ 87). Treatment was given for 48 wk and patients were observed thereafter for 24 more wk. Patients with decompensated cirrhosis, HIV infection, cancer, neutrophil count of ⬍1,500/ml3, a platelet count of ⬍75,000/ml3, and an alpha-fetoprotein of ⬎100 ng/ml were excluded from the study. The primary endpoints and their definitions were similar to those in the study by Zeuzem et al. The secondary endpoints included virological and biochemical responses at the end of the 48-wk treatment period. Histological changes were also accessed on a 22-point Histological Activity Index (inflammation graded from 0 to 18 and fibrosis graded from 0 to 4) and defined as a positive response based on a ⱖ2 point decrease in the total score. Treatment was completed by 64, 78, and 67 patients, respectively, in the three groups, and follow-up was completed by 68, 79, and 74 patients, respectively, in the three groups. The rates of sustained virological response were 8%, 15%, and 30% in patients assigned to unmodified IFN alfa-2a, 90 ␮g of PEG IFN alfa-2a, and 180 ␮g of PEG IFN alfa-2a, respectively (p ⫽ 0.001 for comparison between the first and third groups). However, among patients infected with genotype 1, the response rates were 2%, 5%, and 13% in the three groups (genotype 1b had a 2-fold better response rate than 1a). It is also of note that a response at wk 12 predicted a sustained response. The rates of sustained biochemical response were 15%, 20%, and 34% in the three groups (p ⫽ 0.004 for comparison between the first and third groups). Among the patients who had paired liver biopsies, the histological responses were 31%, 44%, and 54% in patients assigned to unmodified interferon alfa-2a, 90 ␮g of PEG IFN alfa-2a, and 180 ␮g of PEG IFN alfa-2a, respectively (p ⫽ 0.02 for comparison between the first and third groups). A histological response correlated with a sustained virologic response (80 –100%). The virological response was similar among patients with either bridging