WORLD LITERATURE REVIEWEditor: David Johnson, M.D., F.A.C.G.REVIEW PANELLuis BalartJamie BarkinDavid BjorkmanCedric BremnerWilliam CareyHarold ConnJack DiPalmaMark Fendrick
M. Brian FennertyMark FlemmerChristopher GostoutRobert HawesJorge HerreraBrenda HoffmanPerry HookmanJohn Johanson
Philip KatzTimothy KochMark LawsonAnil MinochaEdward C. Oldfield IIIDavid OttC. S. PitchumoniK. Rajender Reddy
Douglas RexArvey RogersRichard SamplinerPaul SouneyChristina SurawiczNimish VakilHarlan Vingan
A Toast to PentoxifyllineAkriviadis E, Botla D, Briggs W, et al.Pentoxifylline Improves Short-Term Survival in Severe AcuteAlcoholic Hepatitis: A Double-Blind, Placebo-Controlled TrialGastroenterology 2000;119:163540
ABSTRACTThe aim of this study was to evaluate the efficacy of pen-toxifylline in patients with severe acute alcoholic hepatitis.Pentoxifylline is a nonselective phosphodiesterase inhibitorthat decreases tumor necrosis factor (TNF) gene transcrip-tion. Elevated TNF levels have been found in the sera ofpatients with alcoholic hepatitis, and hence the rationale forthis large scale study was to definitively address the thera-peutic role of pentoxifylline in this disease. The study wasconducted in the liver unit at the University of SouthernCalifornia in patients with a history of heavy alcohol abuseand a clinical diagnosis of acute alcoholic hepatitis. Inclu-sion criteria for patients in the study were jaundice; Mad-drey discriminant factor (DF) of $32 and one or more of theclinical or laboratory parameters of fever, palpable tenderhepatomegaly, white blood cell count of .12,000/ml3 withpredominantly neutrophilic differentiation, hepatic enceph-alopathy, and hepatic systolic bruit. Enrollment into thestudy 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. Ahistological diagnosis was not required for inclusion in thestudy, as the investigators feared that severely ill, coagulo-pathic patients might not be able to undergo a percutaneousliver biopsy. The study was a prospective, double blind,randomized, placebo-controlled study. The two primaryendpoints were the effect of pentoxifylline on 1) the shortterm survival (during the index hospitalization or over the28-day study period) and 2) progression to hepatorenalsyndrome (HRS). Secondary endpoints were the effect ofpentoxifylline on 1) the course of laboratory parameters,including serum TNF levels, and 2) development of clinicalcomplications of liver disease.
One hundred two patients were enrolled and randomizedto receive either pentoxifylline 400 mg t.i.d. for 4 wk or aplacebo. Patients with previous hepatic decompensation(n 5 22), hepatic encephalopathy (n 5 10), and renalimpairement (serum creatinine of .2.4 mg/dl, n 5 9 pa-tients) were also included. There were no significant differ-ences between the two groups for any of the demographic orclinical variables. Among the pentoxifylline group, 78%received medication until the completion of 28 days or untildeath, whereas in the control group 92% received placebocapsules for 28 days or until death. The mean period oftreatment was 21 (21.5 6 9.5) days for both groups, therebyproviding active treatment for a sufficient period. Reasonsfor discontinuation in the pentoxifylline group includedheadache, GI symptoms, and generalized skin rash.
Plasma TNF levels were available for 60 patients (29 inthe pentoxifylline group and 31 in the control group). Base-line TNF levels were above the normal range in all patientsfrom both groups. There were no differences between thetwo groups at randomization or at any time during thetreatment period in absolute values or in changes frombaseline when all patients or only survivors of the twogroups were compared. When only the nonsurvivors werecompared, control patients had higher TNF values thanpentoxifylline-treated patients at wk 1, 2, and 4.
In this study, 25% and 46% in the pentoxifylline andcontrol arms died (p 5 0.037, reluctant risk [RR] 5 0.59,95% CI 5 0.350.97) after a range of 554 days and 7139days, respectively. In the patients who died, hepatic failurewith HRS had developed in 50% in the pentoxifylline groupand 92% in the control group. New onset renal failureoccurred in 11% and 43% in the pentoxifylline and controlgroups, respectively (p 5 0.001, RR 5 0.35, 95% CI 50.150.77), and progressed to HRS in 80% and 90% ofpatients, respectively, in the two groups (p 5 0.0015, RR 50.32, 95% CI 5 0.130.79). In multiple logistic regressionanalysis, two variables (DF and age) were independentlyassociated with survival in the control group, and one vari-able (creatinine) in the pentoxifylline group. Three variables(creatinine, age, and treatment with pentoxifylline) wereindependently associated with survival in the two groups
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 96, No. 5, 2001 2001 by Am. Coll. of Gastroenterology ISSN 0002-9270/01/$20.00Published by Elsevier Science Inc. PII S0002-9270(01)02373-5
combined. (Am J Gastroenterol 2001;96:16351637. 2001 by Am. Coll. of Gastroenterology)
About two-thirds of the US population drinks alcohol, butonly about 2 million develop alcoholic liver disease (1).Patients with cirrhosis and superimposed alcoholic hepatitishave a .60% mortality over a 4-yr period. More sobering isthe fact that patients with severe alcoholic hepatitis as de-fined by Maddreys discriminant function of $32 have up to40% mortality within 6 months. Abstinence is the key inprevention of progression of alcoholic liver disease in pa-tients who survive an index episode of alcoholic hepatitis.
The pathogenesis of alcoholic hepatitis is complex, withTNF emerging as one of the prominent cytokines involvedin the necroinflammatory reaction that characterizes theprocess. Cultured peripheral blood monocytes in patientswith alcoholic hepatitis spontaneously produce more TNFand significantly more in response to lipopolysaccaridestimulussuggestive of dysregulated TNF metabolism inalcoholic hepatitis (2). Serum TNF values have also beencorrelated with disease severity and mortality (3). Mostimpressive is the fact that TNF receptor knockout mice areresistant to alcohol-induced liver injury (4). Further, TNFhas a host of effects including inhibition of cytokine/che-moattractant synthesis, decreased expression of adhesionmolecules on endothelial cells, inhibition of proliferationand chemotaxis of leucocytes, and decreased secretion ofcollagen and other interstitial matrix proteins (57).
Histologically, acute alcoholic hepatitis is characterizedby neutrophilic infiltration of zone 3, perivenular fibrosis,and intrasinusoidal collagen deposition, all of which couldpotentially be decreased by pentoxifylline, making it anattractive treatment modality in acute alcoholic hepatitis.Where does this study fit in the current literature of therapyfor acute alcoholic hepatitis? Colchicine, propylthiouracil(PTU), and corticosteroids have been studied in acute alco-holic hepatitis. Two studies with colchicine and one withPTU did not show any effect on short term survival. Of the13 randomized clinical trials evaluating corticosteroids inpatients with alcoholic hepatitis, five observed a survivalbenefit. A meta-analysis of the 13 randomized clinical trialsshowed a significant short term survival effect of cortico-steroids, with a mean difference of 15% (CI 5 624%, p ,0.01) (8). The effect was higher in the subgroup of patientswith encephalopathy, with a mean difference of 27% (CI 51144%, p , 0.0001). These translate to number of patientsneeded to be treated (NNT) of seven and four in alcoholichepatitis with and without encephalopathy, respectively, toachieve a benefit from therapy. Based on these data, thecurrent American College of Gastroenterology treatmentguidelines recommend a regimen of prednisolone, 40 mg/day for 28 days, followed by taper for patients with severealcoholic hepatitis (8).
The trial and results of the study by Akriviadis et al. are
commendable for several reasons. It is a large randomized,double blind, placebo-controlled study, the first of its kind inpatients with severe alcoholic hepatitis. Medicine consump-tion was sufficient in both groups, and survival data wereavailable for all patients. There was no statistically signifi-cant increase in infections in the pentoxifylline group rela-tive to the control group. The statistical design and largesample size enable several important and valid conclusionsto be drawn. The NNT in this study, to achieve a therapeuticbenefit, is close to four. This is comparable to severalaccepted treatment options such as b blockers for preven-tion of recurrent variceal bleeding (NNT of five). Most ofthe decrease in mortality was secondary to decrease in HRS.
Skeptics might suggest that a third group of patientstreated with prednisolone should have been included in thetrial. Such a trial would have taken much longer, and basedon historical data on survival after corticosteroids, thereprobably would still be a greater benefit from pentoxifylline.Though the results show an impressive reduction in newonset HRS and subsequent mortality from it, this study doesnot address the possible mechanisms involved in such afavorable outcome while on pentoxifylline.
In summary, this study gives us a reasonable basis forconsideration of pentoxifylline therapy in patients with se-vere alcoholic hepatitis. Therapy is safe, well tolerated, andinexpensive. Further studies should also be done to assessthe efficacy of pentoxifylline in decreasing the incidence ofHRS in patients with other forms of liver disease. Therapywith pentoxifylline should go hand in hand with reinforcingthe need for strict abstinence from alcohol, as recidivismwould set back any gains made. Its time to raise our glassesfor 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 MedicineMiami, Florida
1. Dufour MC, Stinson FS, Caces MF. Trends in cirrhosis mor-bidity and mortality: United States, 19791988. Semin LiverDis 1993;13:10925.
2. McClain C, Cohen D. Increased tumor necrosis factor produc-tion by monocytes in alcoholic hepatitis. Hepatology 1989;9:34951.
3. Felver M, Mezey E, McGuire M, et al. Plasma tumor necrosisfactor alpha predicts decreased long-term survival in severealcoholic hepatitis. Alcohol Clin Exp Res 1990;14:2559.
4. Yin M, Wheeler M, Kono H, et al. Essential role of tumornecrosis factor alpha in alcohol-induced liver injury in mice.Gastroenterology 1999;117:94252.
5. Krakauer T. Pentoxifylline inhibits ICAM-1 expression andcytokine production induced by proinflammatory cytokines inhuman pulmonary epithelial cells. Immunopharmacology 2000;46:25362.
6. Neuner P, Kloser G, Pourmojib M, et al. Pentoxifylline in vivoand in vitro down-regulates the expression of the intercellular
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adhesion molecule-1 in monocytes. Immunology 1997;90:4359.
7. Balazs C, Kiss L, Farid N. Inhibitory effect of pentoxifylline onHLA-DR expression and glycosaminoglycan synthesis by ret-robulbar fibroblasts. Horm Metab Res 1998;30:4969.
8. McCullough A, OConnor J. Alcoholic liver disease: Proposedrecommendations for the American College of Gastroenterol-ogy. Am J Gastroenterol 1998;93:202236.
Peginterferon Is Here to StayZeuzem S, Feinman SV, Rasenack J, et al.Peginterferon Alfa-2a in Patients With Chronic Hepatitis CN Engl J Med 2000;343:166672
Heathcote EJ, Shiffman ML, Cooksley WGE, et al.Peginterferon Alfa-2a in Patients With Chronic Hepatitis C andCirrhosisN Engl J Med 2000;343:167380
ABSTRACTThe purpose of the first study was to compare the efficacyand safety of peginterferon alfa-2a (PEG IFN) administeredonce per wk for 48 wk s.c., with IFN alfa-2a administeredthree times/wk. The primary efficacy endpoints were a sus-tained virologic response (indicated by ,100 copies/ml ofhepatitis C virus [HCV]) at wk 72 and a sustained biochem-ical response (normalization of serum ALT to a value at orbelow the upper limit of normal) at wk 72. A subgroup ofpatients had liver biopsies done both pretreatment and 24 wkafter cessation of treatment, and a histologic response (de-fined as a decrease of $2 points in the total HistologicalActivity Index score) was also assessed. In this study, 531patients were randomly assigned to receive either 180 mgs.c. of PEG IFN once a wk for 48 wk (267 patients) or IFNalfa-2a 6 million U s.c. three times a wk for 12 wk followedby 3 million U s.c. three times/wk for 36 wk. In the PEGIFN group 223 of 267 patients (82.5%) completed treatmentand 206 completed follow-up. In the IFN group 161 of 264patients (61%) completed treatment and 154 completed fol-low-up. The baseline characteristics of the patients in thetwo treatment groups were similar. In an intent-to-treatanalysis in which patients who missed the examination atthe end of follow-up were considered as not having had aresponse, PEG IFN was associated with a higher rate ofvirologic response at wk 48 (69% vs 28%, p 5 0.001) andat wk 72 (39% vs 19%, p 5 0.001). The rate of sustainedbiochemical response at week 72 was also greater in thePEG IFN group (45% vs 25%, p 5 0.001). In addition, theproportion of patients with both a sustained virologic and abiochemical response was higher in the PEG IFN group(38% vs 17%, p 5 0.001). PEG IFN was associated with a28% rate of sustained virologic response in patients infectedwith HCV genotype 1, whereas IFN alone resulted in ,10%sustained virologic response in this subgroup. Sixty-six per-cent of the 531 patients had paired pre- and posttreatmentliver biopsies. Histological improvement was observed in
63% of patients in the PEG IFN group and 55% of those inthe IFN group. Independent factors associated with a sus-tained virologic response were identified as age of #40 yr,absence of cirrhosis or bridging fibrosis, body surface areaof #2.0 m2, treatment with PEG IFN, HCV RNA level of#2 million copies/ml, pretreatment ALT quotient of .3(ALT quotient being the average of the serum ALT valuesbefore treatment divided by the upper limit of normal), andHCV genotype other than 1. The frequency and severity ofadverse effects were similar in the two groups. Psychiatricdisorders were the most frequent serious adverse events, andsignificant anemia or thrombocytopenia was rare in bothtreatment groups.
In the second study the efficacy and safety of PEG IFNalfa-2a in patients with HCV-related cirrhosis (7679%) orbridging fibrosis (2024%) were studied. In this multi-center, open label, randomized, parallel dose study, 271patients with cirrhosis or bridging fibrosis were randomlyassigned to receive treatment with 3 million U of IFNalfa-2a three times weekly (n 5 88 patients), 90 mg of PEGIFN alfa-2a once weekly (n 5 96), or 180 mg of PEG IFNalfa-2a once weekly (n 5 87). Treatment was given for 48wk and patients were observed thereafter for 24 more wk.Patients with decompensated cirrhosis, HIV infection, can-cer, neutrophil count of ,1,500/ml3, a platelet count of,75,000/ml3, and an alpha-fetoprotein of .100 ng/ml wereexcluded from the study. The primary endpoints and theirdefinitions were similar to those in the study by Zeuzem etal. The secondary endpoints included virological and bio-chemical responses at the end of the 48-wk treatment period.Histological changes were also accessed on a 22-point His-tological Activity Index (inflammation graded from 0 to 18and fibrosis graded from 0 to 4) and defined as a positiveresponse based on a $2 point decrease in the total score.Treatment was completed by 64, 78, and 67 patients, respec-tively, 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 IFNalfa-2a, 90 mg of PEG IFN alfa-2a, and 180 mg of PEG IFNalfa-2a, respectively (p 5 0.001 for comparison between thefirst and third groups). However, among patients infectedwith genotype 1, the response rates were 2%, 5%, and 13%in the three groups (genotype 1b had a 2-fold better responserate than 1a). It is also of note that a response at wk 12predicted a sustained response. The rates of sustained bio-chemical response were 15%, 20%, and 34% in the threegroups (p 5 0.004 for comparison between the first andthird groups). Among the patients who had paired liverbiopsies, the histological responses were 31%, 44%, and54% in patients assigned to unmodified interferon alfa-2a,90 mg of PEG IFN alfa-2a, and 180 mg of PEG IFN alfa-2a,respectively (p 5 0.02 for comparison between the first andthird groups). A histological response correlated with asustained virologic response (80100%). The virologicalresponse was similar among patients with either bridging
1637AJG May, 2001 World Literature Review