Postgraduate Medicine
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Chronic hepatitis B and C Teresa L. Wright MD To cite this article: Teresa L. Wright MD (1992) Chronic hepatitis B and C, Postgraduate Medicine, 92:4, 75-82, DOI: 10.1080/00325481.1992.11701466 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701466
Published online: 17 May 2016.
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Third of three articles on hepatitis
Chronic hepatitis BandC What is the status of drug therapy?
Preview Chronic hepatitis remains difficult to treat. Use of interferon has been successful against both hepatitis B and C viruses, but the outcome of long-tenn administration has yet to be determined. Not all patients respond to interferon, however, and some have side effects that cause them to discontinue therapy. Dr Wright discusses the results of studies to evaluate therapy with alpha, beta, and gamma interferon as well as with other agents, such as ribavirin, thymosin, and ursodeoxycholic acid.
Teresa L Wright, MD •:•Chronic liver disease plays a role in 40,000 deaths annually in the United States. Although such disease is due to excessive alcohol consumption in the majority of cases, infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis nonA non-B accounts for a large number of cases. Half of these deaths occur in patients younger than 60 years of age. About 5% of the world's pop-
ulation is infected with HBV. In the United States, 300,000 new cases of HBV infection are reported annually. 1 Chronic liver disease occurs in about 5% of patients with acute HBV infection, but it develops in about 50% of patients with acute HCV infection (and cirrhosis occurs in about 20% of these patients). 1 The estimated number ofHCV infections annually in the United States is half that of HBV infections, although the true incidence is probably underestimated be-
cause of underreporting. Among patients with chronic hepatitis C, 95% are infected by routes other than blood transfusion. 2 Hence, screening of donor blood for antibody to HCV {anti-HCV) is unlikely to significandy reduce the prevalence of chronic hepatitis C. Despite rapid advances in understanding of the biology of the hepatitis viruses, the ability to effectively treat chronic infection is limited. Interferon alfa-2b (Intron A) is the only therapy approved by the Food and Drug Administration for chronic nonA non-B hepatitis {the majority of cases of which are caused by HCV). Interferon alfa-2b has recendy been approved for use in the treatment of chronic HBV infection as well. General approaches to the treatment of viral hepatitis (figure I)-notably, the use of diuretics for ascites, beta-blocker therapy, esophageal sclerotherapy, portosystemic shunt placement for portal hypertension, and liver transplantation for hepatic decompensation-are also applicable to other chronic liver diseases. This article focuses on approved and experimental treatment strategies (other than liver transplantation) that apply specifically to patients with chronic hepatitis B,
continued
VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE • HEPATITIS 8 AND C
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Antiviral effects of interferons include reduced entry of viruses, impaired viral uncoating, and inhibition of viral mRNA and protein synthesis.
Chronic viral hepatitis Antiviral agent (ribavirin, alpha interferon)
' ' ' '
Immune response in host lmmunomodulatory agent (alpha, beta, or gamma interferon; thymosin), immunosuppressive agent (eg, corticosteroid)
Fibrosis or cirrhosis Antifibrogenic agent (colchicine, gamma interferon)
Portal hypertension or hepatic decompensation Diuretic, beta blocker, portosystemic shunt
Hepatic failure Liver transplantation
Figure 1. Potential therapeutic interventions for chronic viral hepatitis.
hepatitis C, or non-A non-B hepatitis.
Effects of interferons Interferons are proteins that have both antiviral and immunomodTeresa L. Wright, MD Dr Wright is assistant professor of medicine, division of gastroenterology and hepatology, University of California, San Francisco, School of Medicine and San Francisco Veterans Affairs Medical Center.
76
ulatory effects. 3 The three classes of interferon (ie, alpha, beta, and gamma) have different structures and biochemical properties. Alpha interferon is produced by lymphocytes in response to the presence of viruses and antigens. Alpha interferon is coded by 23 different genes, and commercially available forms of recombinant alpha interferon consist of mixtures of these different types. 4 Beta interferon is produced by fibroblasts in response to viral infection and is coded by a single gene. The alpha and beta interferon genes are quite homologous, and these forms of interferon have similar effects in vivo. In contrast, gamma interferon appears to have more potent immunoregulatory effects than antiviral effects. Both alpha and beta interferon were once thought to bind to a common receptor on a wide variety of human cells, but recent evidence has suggested that the two may bind to different receptors. This may result in a difference in efficacy when they are used to treat chronic viral infection. The antiviral effects of interferons include reduced entry of viruses, impaired viral uncoating, and inhibition of viral mRNA and protein synthesis. The antitumor effects of interferons include inhi-
bition of cell division and direct cytotoxicity to malignant cells. Because of these wide-ranging antiviral and immunomodulatory effects, interferons have been used to treat chronic viral infection as well as malignant tumors (eg, Kaposi's sarcoma, hairy-cell leukemia). Preliminary studies have suggested that treatment with alpha interferon may inhibit collagen production. Thus, interferon therapy may have general application for liver diseases other than chronic viral hepatitis. 5 Side effects with interferon treatment are common and may lead to cessation of therapy. Often encountered are flulike symptoms, fatigue, myalgias, fever, thrombocytopenia, and leukopenia. Less commonly seen are depression, altered mental state, proteinuria, and cardiac abnormalities. Contraindications to alphainterferon therapy in patients with chronic viral hepatitis are summarized in table 1, and an algorithm for selection of patients for treatment is shown in figure 2.
Treatment of chronic hepatitis B Alpha interferon appears to beefficacious in reducing HBV replication and liver inflammation in some patients. However, long-
HEPATITIS B AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
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Predictors of increased response to interferon therapy for hepatitis B include short duration of disease, low levels of HBV DNA, and a high pretreatment level of alanine aminotransferase.
term interferon treatment has not none had experienced reactivabeen evaluated, and the impact tion (ie, reappearance ofHBV of interferon use on the developDNA or HBeAg after cessation ment of hepatocellular carcinoma of treatment) by follow-up. In and on survival rates is unknown. contrast, only 7 (17%) of the 41 Other therapeutic agents have patients treated with 1 million U been tried and continue to unof interferon and 3 (7%) of the dergo study. 43 untreated controls responded. INTERFERONs--Several studies Patients treated with a short of alpha, beta, and gamma intercourse of prednisone before interferon in the treatment of chronic feron therapy had a response rate HBV infection have been undersimilar to that of patients treated taken. However, since many of with 5 million U of interferon the initial studies were unconalone. Comparison of liver bitrolled and the dosing schedules opsy specimens before and after varied, interpretation of results treatment showed improvement has been difficult. 6 The goal of in inflammation among patients most such studies has been loss of who responded to treatment. HBV DNA and seroconversion Loss ofHBeAg and HBV DNA to hepatitis Be antigen (HBeAg) in serum has been associated with negativity. the disappearance of replicative forms ofHBV DNA in the liver. 9 A small, controlled study by Hoofnagle and associates7 in In the study described, 8 only a 1988 showed that 16 weeks of re- small proportion of patients (ie, combinant alpha-interferon treat- 10% of all treated patients and one third of those who respondment resulted in clearance of HBeAg in one third of patients. ed) lost hepatitis B surface antigen (HBsAg) with treatment. In a recent multicenter study, 8 A pilot study of combination 169 patients were randomized to one of four regimens: 5 million therapy with beta and gamma U of interferon alfa for 16 weeks, interferon in 20 patients with chronic hepatitis B suggested that 1 million U of interferon for 16 weeks, prednisone for 6 weeks these interferons may be effective when started within 4 years of followed by 5 million U of interthe onset of infection. 10 Further feron for 16 weeks, or observastudies are needed to validate tion only. Of the 41 patients treated with 5 million U of inter- these results. Given the expense and side efferon, 15 (37%) responded and
VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE • HEPATITIS B AND C
Table 1. Contraindications to alpha-interferon therapy for chronic viral hepatitis Active substance abuse Alcoholic liver disease Chronic active autoimmune hepatitis Decompensated liver disease Hemodialysis Hemophilia Human immunodeficiency virus infection Organ transplantation Psychiatric disease Significant cardiac disease Thrombocytopenia, leukopenia Uncorrected thyroid disease
fects of interferon treatment, factors that predict therapeutic response need to be identified so that the patients most likely to benefit can be selected. 11 The pretreatment level ofHBV DNA seems to be a reliable predictor. Patients with HBV DNA levels less than 200 pg/mL are more likely to respond to therapy than are those with higher levels. Other predictors of an increased response to therapy include short duration of disease, a high pretreatment level of alanine aminotransferase, and the finding of chronic active hepatitis on liver biopsy. 11 Typically, patients whorecontinued
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Certain ethnic groups who commonly acquire hepatitis B infection in the perinatal period may have poor response to interferon therapy.
Figure 2. Algorithm for treatment of chronic viral hepatitis.
spond to interferon therapy have a flare-up of disease with an increase in liver enzyme levels before clearance of the hepatitis virus. Certain ethnic groups (eg, Asians) who commonly acquire
78
infection in the perinatal period and have low alanine aminotransferase levels are less likely to respond to interferon therapy. 12 Recent evidence has suggested that HBeAg-positive Asians with high
pretreatment alanine aminotransferase levels may respond to alpha interferon. 13 Follow-up studies of patients previously treated with a variety of doses of alpha interferon have provided important information. Korenman and associates 14 have shown that remission is maintained in the majority of patients with hepatitis B who respond to therapy and that seroconversion continues after treatment. Of the 23 patients who responded to interferon (with loss ofHBeAg and HBV DNA) followed for a mean of 4 years after completion of therapy, 20 (87%) remained in remission and 13 (56%) lost HBsAg after 3 years (20% of the original treatment group). Viral replication could not be detected in the serum of most HBsAgnegative patients but was present in that of all HBsAg-positive patients.14 Histologic progression of hepatitis B is also slowed in patients in remission. 15 Thus, unlike patients with HCV infection (discussed later), those with chronic HBV infection appear to derive long-term benefit from interferon. As mentioned, use of alphainterferon for HBV infection was recently approved in the United States. The agent is already available in Europe.
HEPATinS 8 AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
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No factors except the dose have consistently been shown to predict response to interferon treatment of chronic hepatitis C.
OIHER AGENTS-Many trials have shown efficacy of the nucleoside analogue adenine arabinoside and the more soluble adenosine monophosphate, but neurotoxicity has made therapy unacceptable. 16 Acyclovir also may be beneficial, but the doses necessary for inhibition ofHBV DNA synthesis are nephrotoxic. 17 Other drugs that have been used to treat chronic hepatitis B include foscarnet sodium, azidothymidine, ribavirin, and extract of the plant Phyllanthus amarns.18-20 No trials have been large enough to demonstrate efficacy of any of these compounds. An exciting preliminary report has suggested that thymus extract (thymosin) is effective against chronic HBV infection. 21 A multicenter, controlled trial of this compound is currently under way in the United States.
Treatment of chronic hepatitis C Interferon alfa-2b is the approved therapy for hepatitis C. Studies of other agents (ie, beta and gamma interferon, ribavirin, and ursodeoxycholic acid) are ongoing. INTERFERONs-Several studies have evaluated the effects of interferon treatment in patients with chronic hepatitis C. The first report was by Hoofnagle and associates, 22 who treated 10 pa-
tients with a variety of doses of alpha interferon daily for up to 12 months. Eight (80%) of them responded with a reduction in liver enzyme levels, although a prompt increase occurred on cessation of treatment. This preliminary report led to two major studies23 ' 24 in which different doses of alpha interferon were evaluated. The first studf3 evaluated administration of 3 million U or 1 million U of interferon three times a week for 24 weeks versus no treatment. Normalization of liver enzyme levels was seen in 46% of patients at the higher dose and 28% at the lower dose, compared with 8% of patients receiving no treatment. When treatment was stopped, however, 50% of patients relapsed within 6 months of follow-up. Similar results were seen in the second study/4 in which 2 million U of interferon was given three times a week for 24 weeks. Alpha interferon has comparable efficacy in the treatment of sporadic non-A non-B hepatitis, the majority of cases of which are caused by HCV: 25 Serum samples from these3' 24 and other studies were tested retrospectively for anti-HCV, which was detectable in 75% to 90% of cases of chronic non-A non-B hepatitis. 26
The biochemical improvement induced by alpha interferon is associated with a loss of detectable HCV genome in serum. 27 When such factors as pretreatment histologic findings, source ofHCV infection, and antiH CV status have been examined, the only factor predictive of response is the dose of interferon given. 23 '26 A recent studf8 suggested that women and younger patients are more likely to respond. Since 90% of patients who respond to treatment do so by 12 weeks, it is reasonable to discontinue therapy at 12 weeks in nonresponders. A preliminary study of gammainterferon therapy for chronic hepatitis C was unable to demonstrate efficacy. 29 The beneficial effect of higher doses remains to be determined. Beta-interferon therapy has shown some efficacy in patients with acute HCV infection, and a pilot study of this compound's effect on chronic hepatitis Cis under way. 30 Further studies are needed to define the role of maintenance therapy and the long-term natural history of chronic hepatitis C. Although relapse occurs in about half of patients who initially respond to interferon, patients usually respond to another course of treatment.
continued
VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE • HI!N.nTJS 8 AND C
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Although the studies discussed support administration of alpha interferon as primary treatment of chronic non-A non-B hepatitis, at least three issues remain to be addressed: optimal dose, optimal duration of treatment, and long-term effects on patient survival (or percentage of patients requiring liver transplantation). Multicenter studies are currendy under way to address the issues of optimal dose and duration of treatment. OIHER AGENTS-As with HBV infection, use of corticosteroids has no proven efficacy in the treatment of chronic hepatitis C. The first study of the orally active agent ribavirin in 10 patients showed a reduction in mean serum alanine aminotransferase
levels31 ; further evaluation of this compound is in progress at the National Institutes of Health. Biochemical improvement has been shown in small studies of patients with chronic active hepatitis (the majority of whom were positive for anti-HCV) treated with ursodeoxycholic acid in a dosage of250 mg/day. 32
Conclusion Interferon therapy for hepatitis B and hepatitis C has been studied extensively, and interferon alf.t-2b (lntron-A) is now approved for both indications. However, interferon therapy can cause significant side effects and is expensive (eg, $2,500 to
$4,000 a year in San Francisco). Relapse after discontinuation of treatment is a fairly common problem, particularly in patients with chronic hepatitis C. Although the long-term impact of treatment on the need for liver transplantation, the development of hepatocellular carcinoma, and survival rates is unknown, interferon offers promise for patients with chronic viral hepatitis. Rill
-®
Earn credit on this article.
See CME Quiz.
Address for correspondence: Teresa L. Wright, MD, Division of Gastroenterology 111 B, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121.
References 1. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991;11:84-92 2. Alter MJ, Hadler SC, Judson FN, et al. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 1990;264:2231-5 3. Peters M. Mechanisms of action of interferons. Semin Liver Dis 1989;9(4):235-9 4. Hoofnagle JH, Di Bisceglie AM. Treatment of chronic type C hepatitis with alpha interferon. Semin Liver Dis 1989;9(4):259-63 5. Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease: effects of interferon alfa therapy. N Eng!J Med 1991;324(14}:933-40
6. Greenberg HB, Pollard RB, Lutwick U, et al. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Eng! J Med 1976; 295(10}:517-22 7. Hoofnagle JH, Peters M, Mullen KD, et a!. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology 1988;95(5}: 1318-25 8. Perrillo RP, SchiffER, Davis GL, et al. A randomized, controlled trial of interferon alfa2b alone and afi:er prednisone withdrawal for the treatment of chronic hepatitis B. N Eng! J Med 1990;323(5}:295-301 9. Lok AS, Ma OC, Lau JY. Interferon alfa
therapy in patients with chronic hepatitis B virus infection: effects on hepatitis B virus DNA in the liver. Gastroenterology 1991;100(3): 756-61 10. Caselmann WH, EisenburgJ, Hofschneider PH, et al. Beta- and gamma-interferon in chronic active hepatitis B: a pilot trial of short-term combination therapy. Gastroenterology 1989;96(2 Pt 1):449-55 11. Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989;10(5}:761-3 12. Lok AS, Lai CL, ~ PC, et al. Long-term follow-up in a randomised controlled trial of re-
continued
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HEPATITIS BAND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
NAPROSYN®
(NAPROXEN) 500 mg tablets
Brief Summary: Conlralndlcatlons: Patients who have had allergic reactions to NAPROSYN, ANAPROX or ANAPROX OS or in whom aspirin or other NSAIDs induce lhe syndrome of asthma, rhinitis, and nasal polyps. Because anaphylactic reactions usually occur in patients with a history of such reactions, question patients for asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs before starting therapy. If such symptoms occur, discontinue the drug. Warnings: Seuous Gl toxicity such as bleeding, ulceration, and perforation can occur at an~ time, with or without warning 1
~Ye~f\~~sul~~r~~~~n~sn~reb~~~~i~gr~~ic;~~h w~~~ie~f: ~v~nR(nmf~~
absence of previous Gl tract symptoms. In clinical trials, symptomatic upper Gl ulcers, gross bleeding or perforation ap~ear to
~c~~oi~t a~?J~:i~a~~le~\; o.'r~;/!dn~~~r~~~~!~~ 31~~o~~n~a~'iea~~
about the signs and/or symptoms of serious Gl toxicity and what steps to take if !hey occur. Studies have not identified any subset
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factors known lo be associated wilh peptic ulcer disease, such as 0
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seem to tolerate ulceration or bleeding less well than others and mosl spontaneous reports of fatal Gl events are in I his population. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of Gl toxicity. Precautions: DO NOT GIVE NAPROSYN® (NAPROXEN~ CONCOMITANTLY WITH ANAPROX® (NAPROXEN SODIUM OR ANAPROX® OS INAPROXEN SODIUM) SINCE THEY BO H CIRCULATE IN PLASMA AS THE NAPROXEN ANION. Acute interstitial nephritis with hematuria, proteinuria, and nephrotic syndrome has been reported. Patients with impaired renal function, heart failure, liver dysfunction, patients taking diuretics, and the elderly areal greater risk of overt renal decompensation. If this occurs, discontinue lhe drug. Use with caution and monitor serum creatinine and/or creatinine clearance in patients wilh significantly impaired renal function. Use caution 1n patients with baseline creatinine clearance less 1
1~a;af;~nTsuw~li~~t~ro~l~ ~~~o g~~sli~!fre~~~v;a~~s~r i~i~~~o~i~:%f~ NSAIDs, borderline elevations of liver lesls may occur in up lo
i~a~si~~f~:i~tZo~n~~e~ath~~~~re~fev~i~~~n o~ng~atf'~i gG8f
occurred in controlled clinical trials in less !han 1% of patients.
~:~:r~e~~p~t~~r\~~c~~~(y il~~1~~:n~J:aus~ddce~e~~~sf~;a/f ~~~~t~ii~
manifestations occur (e.g., eosinophilia or rash), discontinue therapy. If steroid dosage is reduced or eliminated during therapy, do so slowly and observe patients closely for adverse effects, including adrenal insufficiency and exacerbation of arthritis symptoms. Determine hemoglobin values periodically for patients with initial 1
~~~~e:d~~~ ~~~m~e~~ er~~~r~tf~~r~lg~n~~ ~~:hag~"i;~~p~patienls with fluid retention, hypertension or hear! failure. The
~;~~r"a;~ti~X~e~~~~gn,a~\~~i1;~n~a~~;rr ~f~~v~~~~ic~~ru!e~u;;_ duct ophthalmic studies if any change or disturbance in vision occurs. For patients with restricted sodium intake, note that the suseension contains 8 m~/mL of sodium. Information for
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may result in hospitalization and even fatal outcomes. Physicians may wish to discuss wilh patients the potential risks and likely
~~~e~~;ig~sN~:~~i~~~e;~~t~ti/t~;~~~;~rw'Y~eonulh~~~~su~ea~ fg! an acceptable alternative. Patients should use caution for activities requiring alertness if !hey experience drowsiness, diuiness, vertigo or depression during therapy. Laboratory Tests: Because serious Gl tract ulceration and bleeding can occur without warning symptoms, follow chronically treated patients for signs and symptoms of these and inform them of the importance of this follow-up. Drug Interactions: Use caution when ting concomi-
~~~~ w~:h s~~ro~~f~~~tr:pef;r~~~~i~~l;a~whi~~r g~~~~~los~~~~~;-
probenecid; or methotrexate. Drug/Laboratory Tesllnteractlons: The drug may decrease platelet aggregation and prolong bleeding time or Increase urinary values for 17-ketogenic steroids. Temporarily stop therapy for 72 hours before doing adrenal function 5
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genicity. Pregnancy: Category B. Do not use during pregnancy 13
~~~~:r~~eX~~i~e~~~dinA~~~~i~~e ~~~~~~s ~e~\i~~~nfi'se~~i~;~~ ~i~t~~~~/-~;~ ~~;k~n ~~~~r~o~a~v~il~ ~~~is ng/ i~~,~~~~r~~
Reactions: In a study, Gl reactions were more frequent and severe in rheumatoid arthritis patients on 1,500 mgiday than in !hose on
~~~o~~~~a~ 1 ;~~~~dit~~~ns c~~~!e~~~hf~~~~~~r, ~~h;~~sc~tr;~~ ~~~~~sa~~~i~:~~,S&~~Iear"~h~~h~~,~e~~~~~bie1~siu~~1"1\':l~\ib~~~i~n
Gl: The most frequent complaints related to the Gl tract: constipa-
~~~ari;~t~~Ef h~~~~~~~~~ d~~r~esns~u~;~:s~~;~~Fii~ht~~~;~:~: ness, vertigo. Dermatologic: itching (pruritus): skin eruptions:
r;;~i~~;~~n~::~aJ~~~aiP~[ft~rrta~g:~ia~~d~~~~~i~~~~~u;~e~:: ~~~~~~~ g;~~~~~~~iiio~~~T~~~~l~i~1tn~~~i~e~~:r Lf~~scJ~~nte1:\;:, 1 ~~:~~a. ~e~ i~e~~i~~ra~~~~it~e~l~;~\~;an~~~,a~~~~;~~\oi;,u~~~ii:
ing. Renal: glomerular nephritis, hematuria, hyperkalemia, interStitial nephntis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis. Hematologic: agranulocytosis, eosino· philia, qranulocytopenia, leukopenia, thrombocytopenia. CNS: depress1on, dream abnormalities, inability to concentrate, insom1
~i:: ~~~i~~e~lifi 9~a ~~~m~rilf~~ ~:tnknr~~she~er~t~~~~t~e~~~~:-
hearing impairment. Cardiovascular: congestive heart failure.
~~~~~~~~r~e~~t:~~r~~~~rSe~~~~~r~~ii: ~~;~~;r;~~ ~~;~r1Y~i~~~~ ~~~~i~n~ifs:U~s~~~~n~~n~~g~\?i~~~~n~fl~~s~~s~~~~~~nh6~~~~-
combinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection. Lancet 1988;2(8606):298-302 13. Lok AS, Ma OC, Lai CL, et al. Treatment of chronic hepatitis B with interferon: experience in Asian patients. Semin Liver Dis 1989; 9:249-53 14. KorenmanJ, Baker B, Waggoner J, et al. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med 1991; 114(8):629-34 15. Perrillo RP, Brunt EM. Hepatic histologic and immunohistochemical changes in chronic hepatitis B after prolonged clearance of hepatitis B e antigen and hepatitis B surface antigen. Ann Intern Med 1991;115(2):113-5 16. Garcia G, Smith CI, Weissberg ]I, et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B: a randomized, double-blinded, placebo-controlled trial. Ann Intern Med 1987; 107(3):278-85 17. Alexander GJ, Fagan EA, Hegarty JE, et al. Controlled trial of acyclovir in chronic hepatitis B virus infection. J Med Virol 1987;21 :81-7 18. Hess G, Rossol S, Voth R, et al. Treatment of patients with chronic type B hepatitis and concurrent human immunodeficiency virus infection with a combination of interferon alpha and azidothymidine: a pilot study. Digestion 1989;43(1-2):56-9
19. Thyagarajan SP, Subramanian S, Thirunalasundari T, et al. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2(8614):764-6
20. Hedin G, Weiland 0, Ljunggren K, et al. Treatment of fulminant hepatitis B and fulminant hepatitis B and D coinfection with foscarnet. Prog Clin Bioi Res 1987;234:309-20 21. MutchnickMG,Appelman HD, Chung HT, et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 1991; 14(3):409-15 22. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: a preliminary report. N Engl J Med 1986; 315(25):1575-8
23. Davis GL, Balart LA, SchiffER, et al. Treatment of chronic hepatitis C with recombinant interferon alf.t: a multicenter randomized, controlled trial. N EngiJ Med 1989;321(22): 1501-6 24. Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alf.t therapy for chronic hepatitis C: a randomized, doubleblind, placebo-controlled trial. N Eng! J Med 1989;321(22): 1506-10 25. Realdi G, Diodati G, Bonetti P, et al. Recombinant human interferon alfa-2a in community-acquired non-A, non-B chronic active hepatitis: preliminary results of a randomized, controlled trial. J Hepatol1990;ll(Suppll): 568-71 26. Marcellin P, Boyer N, Giostra E, et al. Recombinant human alpha-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology 1991;13(3):393-7
27. Shindo M, Di Bisceglie AM, Cheung L, et al. Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatitis C. Ann Intern Med 1991; 115(9):700-4 28. Causse X, Godinot H, Chevallier M, et al. Comparison of I or 3 MU of interferon alfa2b and placebo in patients with chronic non-A, non-B hepatitis. Gastroenterology 1991;101(2): 497-502 29. Saez-Royuela F, Pones JC, Moreno A, et al. High doses of recombinant alpha-interferon or gamma-interferon for chronic hepatitis C: a randomized, controlled trial. Hepatology 1991; 13(2):327-31 30. Omata M, Yokosuka 0, Takano S, et al. Resolution of acute hepatitis C after therapy with natural beta interferon. Lancet 1991; 338(8772):914-5 31. Reichard 0, Andersson J, Schvara R, et al. Ribavirin treatment for chronic hepatitis C. Lancet 1991;337(8749):1058-61 32. Crosignani A, Battczzati PM, Setchell KD, et al. Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: a dose-response study. Hepatology 1991;13(2):339-44
logic: epidermal necrolysis, erythema mulliforme, photosensitivity reactions resembling porphyria culanea tarda and epidermolysis bullosa, Stevens-Johnson syndrome, urticaria. Gl: non·peptic Gl ulceration, ulcerative stomatitis. Cardiovascular: vasculitis. General: angioneurotic edema, hyperglycemia, hypo-
~~~.e~~~s~a~·~~~~~: ~are!a;;,~~~~~~~;sh:J~~i~~~~sin~:~~-
stomach and use usual supportive measures. In animals 0.5 g/kg of activated charcoal reduced plasma levels of naproxen. cautlon: ~~~~~e~~1o~\~~i~;;s~;fCi~~s:~ro~~?~~ prescuption. see pack-
5vNTEX
" Incidence of reported reaction 3%·9%. 1~ 1 1 Where unmarked, incidence less than 3%. L""=-'-'--·_ _ _ __j_ U.S. patent nos. 3,904,682, 3,998,966 and others. ©1991 Syntex Puerto Rico, Inc. Rev. 39 September 1990
82
HEPATITIS 8 AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
ISSN: 0032-5481 (Print) 1941-9260 (Online) Journal homepage: http://www.tandfonline.com/loi/ipgm20
Chronic hepatitis B and C Teresa L. Wright MD To cite this article: Teresa L. Wright MD (1992) Chronic hepatitis B and C, Postgraduate Medicine, 92:4, 75-82, DOI: 10.1080/00325481.1992.11701466 To link to this article: http://dx.doi.org/10.1080/00325481.1992.11701466
Published online: 17 May 2016.
Submit your article to this journal
View related articles
Citing articles: 1 View citing articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ipgm20 Download by: [University of Saskatchewan Library]
Date: 13 June 2016, At: 13:09
Symposium
Downloaded by [University of Saskatchewan Library] at 13:09 13 June 2016
Third of three articles on hepatitis
Chronic hepatitis BandC What is the status of drug therapy?
Preview Chronic hepatitis remains difficult to treat. Use of interferon has been successful against both hepatitis B and C viruses, but the outcome of long-tenn administration has yet to be determined. Not all patients respond to interferon, however, and some have side effects that cause them to discontinue therapy. Dr Wright discusses the results of studies to evaluate therapy with alpha, beta, and gamma interferon as well as with other agents, such as ribavirin, thymosin, and ursodeoxycholic acid.
Teresa L Wright, MD •:•Chronic liver disease plays a role in 40,000 deaths annually in the United States. Although such disease is due to excessive alcohol consumption in the majority of cases, infection with hepatitis B virus (HBV), hepatitis C virus (HCV), and hepatitis nonA non-B accounts for a large number of cases. Half of these deaths occur in patients younger than 60 years of age. About 5% of the world's pop-
ulation is infected with HBV. In the United States, 300,000 new cases of HBV infection are reported annually. 1 Chronic liver disease occurs in about 5% of patients with acute HBV infection, but it develops in about 50% of patients with acute HCV infection (and cirrhosis occurs in about 20% of these patients). 1 The estimated number ofHCV infections annually in the United States is half that of HBV infections, although the true incidence is probably underestimated be-
cause of underreporting. Among patients with chronic hepatitis C, 95% are infected by routes other than blood transfusion. 2 Hence, screening of donor blood for antibody to HCV {anti-HCV) is unlikely to significandy reduce the prevalence of chronic hepatitis C. Despite rapid advances in understanding of the biology of the hepatitis viruses, the ability to effectively treat chronic infection is limited. Interferon alfa-2b (Intron A) is the only therapy approved by the Food and Drug Administration for chronic nonA non-B hepatitis {the majority of cases of which are caused by HCV). Interferon alfa-2b has recendy been approved for use in the treatment of chronic HBV infection as well. General approaches to the treatment of viral hepatitis (figure I)-notably, the use of diuretics for ascites, beta-blocker therapy, esophageal sclerotherapy, portosystemic shunt placement for portal hypertension, and liver transplantation for hepatic decompensation-are also applicable to other chronic liver diseases. This article focuses on approved and experimental treatment strategies (other than liver transplantation) that apply specifically to patients with chronic hepatitis B,
continued
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Antiviral effects of interferons include reduced entry of viruses, impaired viral uncoating, and inhibition of viral mRNA and protein synthesis.
Chronic viral hepatitis Antiviral agent (ribavirin, alpha interferon)
' ' ' '
Immune response in host lmmunomodulatory agent (alpha, beta, or gamma interferon; thymosin), immunosuppressive agent (eg, corticosteroid)
Fibrosis or cirrhosis Antifibrogenic agent (colchicine, gamma interferon)
Portal hypertension or hepatic decompensation Diuretic, beta blocker, portosystemic shunt
Hepatic failure Liver transplantation
Figure 1. Potential therapeutic interventions for chronic viral hepatitis.
hepatitis C, or non-A non-B hepatitis.
Effects of interferons Interferons are proteins that have both antiviral and immunomodTeresa L. Wright, MD Dr Wright is assistant professor of medicine, division of gastroenterology and hepatology, University of California, San Francisco, School of Medicine and San Francisco Veterans Affairs Medical Center.
76
ulatory effects. 3 The three classes of interferon (ie, alpha, beta, and gamma) have different structures and biochemical properties. Alpha interferon is produced by lymphocytes in response to the presence of viruses and antigens. Alpha interferon is coded by 23 different genes, and commercially available forms of recombinant alpha interferon consist of mixtures of these different types. 4 Beta interferon is produced by fibroblasts in response to viral infection and is coded by a single gene. The alpha and beta interferon genes are quite homologous, and these forms of interferon have similar effects in vivo. In contrast, gamma interferon appears to have more potent immunoregulatory effects than antiviral effects. Both alpha and beta interferon were once thought to bind to a common receptor on a wide variety of human cells, but recent evidence has suggested that the two may bind to different receptors. This may result in a difference in efficacy when they are used to treat chronic viral infection. The antiviral effects of interferons include reduced entry of viruses, impaired viral uncoating, and inhibition of viral mRNA and protein synthesis. The antitumor effects of interferons include inhi-
bition of cell division and direct cytotoxicity to malignant cells. Because of these wide-ranging antiviral and immunomodulatory effects, interferons have been used to treat chronic viral infection as well as malignant tumors (eg, Kaposi's sarcoma, hairy-cell leukemia). Preliminary studies have suggested that treatment with alpha interferon may inhibit collagen production. Thus, interferon therapy may have general application for liver diseases other than chronic viral hepatitis. 5 Side effects with interferon treatment are common and may lead to cessation of therapy. Often encountered are flulike symptoms, fatigue, myalgias, fever, thrombocytopenia, and leukopenia. Less commonly seen are depression, altered mental state, proteinuria, and cardiac abnormalities. Contraindications to alphainterferon therapy in patients with chronic viral hepatitis are summarized in table 1, and an algorithm for selection of patients for treatment is shown in figure 2.
Treatment of chronic hepatitis B Alpha interferon appears to beefficacious in reducing HBV replication and liver inflammation in some patients. However, long-
HEPATITIS B AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
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Predictors of increased response to interferon therapy for hepatitis B include short duration of disease, low levels of HBV DNA, and a high pretreatment level of alanine aminotransferase.
term interferon treatment has not none had experienced reactivabeen evaluated, and the impact tion (ie, reappearance ofHBV of interferon use on the developDNA or HBeAg after cessation ment of hepatocellular carcinoma of treatment) by follow-up. In and on survival rates is unknown. contrast, only 7 (17%) of the 41 Other therapeutic agents have patients treated with 1 million U been tried and continue to unof interferon and 3 (7%) of the dergo study. 43 untreated controls responded. INTERFERONs--Several studies Patients treated with a short of alpha, beta, and gamma intercourse of prednisone before interferon in the treatment of chronic feron therapy had a response rate HBV infection have been undersimilar to that of patients treated taken. However, since many of with 5 million U of interferon the initial studies were unconalone. Comparison of liver bitrolled and the dosing schedules opsy specimens before and after varied, interpretation of results treatment showed improvement has been difficult. 6 The goal of in inflammation among patients most such studies has been loss of who responded to treatment. HBV DNA and seroconversion Loss ofHBeAg and HBV DNA to hepatitis Be antigen (HBeAg) in serum has been associated with negativity. the disappearance of replicative forms ofHBV DNA in the liver. 9 A small, controlled study by Hoofnagle and associates7 in In the study described, 8 only a 1988 showed that 16 weeks of re- small proportion of patients (ie, combinant alpha-interferon treat- 10% of all treated patients and one third of those who respondment resulted in clearance of HBeAg in one third of patients. ed) lost hepatitis B surface antigen (HBsAg) with treatment. In a recent multicenter study, 8 A pilot study of combination 169 patients were randomized to one of four regimens: 5 million therapy with beta and gamma U of interferon alfa for 16 weeks, interferon in 20 patients with chronic hepatitis B suggested that 1 million U of interferon for 16 weeks, prednisone for 6 weeks these interferons may be effective when started within 4 years of followed by 5 million U of interthe onset of infection. 10 Further feron for 16 weeks, or observastudies are needed to validate tion only. Of the 41 patients treated with 5 million U of inter- these results. Given the expense and side efferon, 15 (37%) responded and
VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE • HEPATITIS B AND C
Table 1. Contraindications to alpha-interferon therapy for chronic viral hepatitis Active substance abuse Alcoholic liver disease Chronic active autoimmune hepatitis Decompensated liver disease Hemodialysis Hemophilia Human immunodeficiency virus infection Organ transplantation Psychiatric disease Significant cardiac disease Thrombocytopenia, leukopenia Uncorrected thyroid disease
fects of interferon treatment, factors that predict therapeutic response need to be identified so that the patients most likely to benefit can be selected. 11 The pretreatment level ofHBV DNA seems to be a reliable predictor. Patients with HBV DNA levels less than 200 pg/mL are more likely to respond to therapy than are those with higher levels. Other predictors of an increased response to therapy include short duration of disease, a high pretreatment level of alanine aminotransferase, and the finding of chronic active hepatitis on liver biopsy. 11 Typically, patients whorecontinued
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Certain ethnic groups who commonly acquire hepatitis B infection in the perinatal period may have poor response to interferon therapy.
Figure 2. Algorithm for treatment of chronic viral hepatitis.
spond to interferon therapy have a flare-up of disease with an increase in liver enzyme levels before clearance of the hepatitis virus. Certain ethnic groups (eg, Asians) who commonly acquire
78
infection in the perinatal period and have low alanine aminotransferase levels are less likely to respond to interferon therapy. 12 Recent evidence has suggested that HBeAg-positive Asians with high
pretreatment alanine aminotransferase levels may respond to alpha interferon. 13 Follow-up studies of patients previously treated with a variety of doses of alpha interferon have provided important information. Korenman and associates 14 have shown that remission is maintained in the majority of patients with hepatitis B who respond to therapy and that seroconversion continues after treatment. Of the 23 patients who responded to interferon (with loss ofHBeAg and HBV DNA) followed for a mean of 4 years after completion of therapy, 20 (87%) remained in remission and 13 (56%) lost HBsAg after 3 years (20% of the original treatment group). Viral replication could not be detected in the serum of most HBsAgnegative patients but was present in that of all HBsAg-positive patients.14 Histologic progression of hepatitis B is also slowed in patients in remission. 15 Thus, unlike patients with HCV infection (discussed later), those with chronic HBV infection appear to derive long-term benefit from interferon. As mentioned, use of alphainterferon for HBV infection was recently approved in the United States. The agent is already available in Europe.
HEPATinS 8 AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
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No factors except the dose have consistently been shown to predict response to interferon treatment of chronic hepatitis C.
OIHER AGENTS-Many trials have shown efficacy of the nucleoside analogue adenine arabinoside and the more soluble adenosine monophosphate, but neurotoxicity has made therapy unacceptable. 16 Acyclovir also may be beneficial, but the doses necessary for inhibition ofHBV DNA synthesis are nephrotoxic. 17 Other drugs that have been used to treat chronic hepatitis B include foscarnet sodium, azidothymidine, ribavirin, and extract of the plant Phyllanthus amarns.18-20 No trials have been large enough to demonstrate efficacy of any of these compounds. An exciting preliminary report has suggested that thymus extract (thymosin) is effective against chronic HBV infection. 21 A multicenter, controlled trial of this compound is currently under way in the United States.
Treatment of chronic hepatitis C Interferon alfa-2b is the approved therapy for hepatitis C. Studies of other agents (ie, beta and gamma interferon, ribavirin, and ursodeoxycholic acid) are ongoing. INTERFERONs-Several studies have evaluated the effects of interferon treatment in patients with chronic hepatitis C. The first report was by Hoofnagle and associates, 22 who treated 10 pa-
tients with a variety of doses of alpha interferon daily for up to 12 months. Eight (80%) of them responded with a reduction in liver enzyme levels, although a prompt increase occurred on cessation of treatment. This preliminary report led to two major studies23 ' 24 in which different doses of alpha interferon were evaluated. The first studf3 evaluated administration of 3 million U or 1 million U of interferon three times a week for 24 weeks versus no treatment. Normalization of liver enzyme levels was seen in 46% of patients at the higher dose and 28% at the lower dose, compared with 8% of patients receiving no treatment. When treatment was stopped, however, 50% of patients relapsed within 6 months of follow-up. Similar results were seen in the second study/4 in which 2 million U of interferon was given three times a week for 24 weeks. Alpha interferon has comparable efficacy in the treatment of sporadic non-A non-B hepatitis, the majority of cases of which are caused by HCV: 25 Serum samples from these3' 24 and other studies were tested retrospectively for anti-HCV, which was detectable in 75% to 90% of cases of chronic non-A non-B hepatitis. 26
The biochemical improvement induced by alpha interferon is associated with a loss of detectable HCV genome in serum. 27 When such factors as pretreatment histologic findings, source ofHCV infection, and antiH CV status have been examined, the only factor predictive of response is the dose of interferon given. 23 '26 A recent studf8 suggested that women and younger patients are more likely to respond. Since 90% of patients who respond to treatment do so by 12 weeks, it is reasonable to discontinue therapy at 12 weeks in nonresponders. A preliminary study of gammainterferon therapy for chronic hepatitis C was unable to demonstrate efficacy. 29 The beneficial effect of higher doses remains to be determined. Beta-interferon therapy has shown some efficacy in patients with acute HCV infection, and a pilot study of this compound's effect on chronic hepatitis Cis under way. 30 Further studies are needed to define the role of maintenance therapy and the long-term natural history of chronic hepatitis C. Although relapse occurs in about half of patients who initially respond to interferon, patients usually respond to another course of treatment.
continued
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Although the studies discussed support administration of alpha interferon as primary treatment of chronic non-A non-B hepatitis, at least three issues remain to be addressed: optimal dose, optimal duration of treatment, and long-term effects on patient survival (or percentage of patients requiring liver transplantation). Multicenter studies are currendy under way to address the issues of optimal dose and duration of treatment. OIHER AGENTS-As with HBV infection, use of corticosteroids has no proven efficacy in the treatment of chronic hepatitis C. The first study of the orally active agent ribavirin in 10 patients showed a reduction in mean serum alanine aminotransferase
levels31 ; further evaluation of this compound is in progress at the National Institutes of Health. Biochemical improvement has been shown in small studies of patients with chronic active hepatitis (the majority of whom were positive for anti-HCV) treated with ursodeoxycholic acid in a dosage of250 mg/day. 32
Conclusion Interferon therapy for hepatitis B and hepatitis C has been studied extensively, and interferon alf.t-2b (lntron-A) is now approved for both indications. However, interferon therapy can cause significant side effects and is expensive (eg, $2,500 to
$4,000 a year in San Francisco). Relapse after discontinuation of treatment is a fairly common problem, particularly in patients with chronic hepatitis C. Although the long-term impact of treatment on the need for liver transplantation, the development of hepatocellular carcinoma, and survival rates is unknown, interferon offers promise for patients with chronic viral hepatitis. Rill
-®
Earn credit on this article.
See CME Quiz.
Address for correspondence: Teresa L. Wright, MD, Division of Gastroenterology 111 B, San Francisco Veterans Affairs Medical Center, 4150 Clement St, San Francisco, CA 94121.
References 1. Margolis HS, Alter MJ, Hadler SC. Hepatitis B: evolving epidemiology and implications for control. Semin Liver Dis 1991;11:84-92 2. Alter MJ, Hadler SC, Judson FN, et al. Risk factors for acute non-A, non-B hepatitis in the United States and association with hepatitis C virus infection. JAMA 1990;264:2231-5 3. Peters M. Mechanisms of action of interferons. Semin Liver Dis 1989;9(4):235-9 4. Hoofnagle JH, Di Bisceglie AM. Treatment of chronic type C hepatitis with alpha interferon. Semin Liver Dis 1989;9(4):259-63 5. Castilla A, Prieto J, Fausto N. Transforming growth factors beta 1 and alpha in chronic liver disease: effects of interferon alfa therapy. N Eng!J Med 1991;324(14}:933-40
6. Greenberg HB, Pollard RB, Lutwick U, et al. Effect of human leukocyte interferon on hepatitis B virus infection in patients with chronic active hepatitis. N Eng! J Med 1976; 295(10}:517-22 7. Hoofnagle JH, Peters M, Mullen KD, et a!. Randomized, controlled trial of recombinant human alpha-interferon in patients with chronic hepatitis B. Gastroenterology 1988;95(5}: 1318-25 8. Perrillo RP, SchiffER, Davis GL, et al. A randomized, controlled trial of interferon alfa2b alone and afi:er prednisone withdrawal for the treatment of chronic hepatitis B. N Eng! J Med 1990;323(5}:295-301 9. Lok AS, Ma OC, Lau JY. Interferon alfa
therapy in patients with chronic hepatitis B virus infection: effects on hepatitis B virus DNA in the liver. Gastroenterology 1991;100(3): 756-61 10. Caselmann WH, EisenburgJ, Hofschneider PH, et al. Beta- and gamma-interferon in chronic active hepatitis B: a pilot trial of short-term combination therapy. Gastroenterology 1989;96(2 Pt 1):449-55 11. Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology 1989;10(5}:761-3 12. Lok AS, Lai CL, ~ PC, et al. Long-term follow-up in a randomised controlled trial of re-
continued
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HEPATITIS BAND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
NAPROSYN®
(NAPROXEN) 500 mg tablets
Brief Summary: Conlralndlcatlons: Patients who have had allergic reactions to NAPROSYN, ANAPROX or ANAPROX OS or in whom aspirin or other NSAIDs induce lhe syndrome of asthma, rhinitis, and nasal polyps. Because anaphylactic reactions usually occur in patients with a history of such reactions, question patients for asthma, nasal polyps, urticaria, and hypotension associated with NSAIDs before starting therapy. If such symptoms occur, discontinue the drug. Warnings: Seuous Gl toxicity such as bleeding, ulceration, and perforation can occur at an~ time, with or without warning 1
~Ye~f\~~sul~~r~~~~n~sn~reb~~~~i~gr~~ic;~~h w~~~ie~f: ~v~nR(nmf~~
absence of previous Gl tract symptoms. In clinical trials, symptomatic upper Gl ulcers, gross bleeding or perforation ap~ear to
~c~~oi~t a~?J~:i~a~~le~\; o.'r~;/!dn~~~r~~~~!~~ 31~~o~~n~a~'iea~~
about the signs and/or symptoms of serious Gl toxicity and what steps to take if !hey occur. Studies have not identified any subset
~~g;~\e~b~ n~tparlci~s~i~\~~e~~P~~?ig~ft~l u~~~;t~o~;dndo~~~;d;rs~
factors known lo be associated wilh peptic ulcer disease, such as 0
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~~c~~~~~~cial~ ~i~~·in'i~eas~~ ~:~~ ft~~~~~ J; 9ebiT~~ie~e~l~~~~~
seem to tolerate ulceration or bleeding less well than others and mosl spontaneous reports of fatal Gl events are in I his population. In considering the use of relatively large doses (within the recommended dosage range), sufficient benefit should be anticipated to offset the potential increased risk of Gl toxicity. Precautions: DO NOT GIVE NAPROSYN® (NAPROXEN~ CONCOMITANTLY WITH ANAPROX® (NAPROXEN SODIUM OR ANAPROX® OS INAPROXEN SODIUM) SINCE THEY BO H CIRCULATE IN PLASMA AS THE NAPROXEN ANION. Acute interstitial nephritis with hematuria, proteinuria, and nephrotic syndrome has been reported. Patients with impaired renal function, heart failure, liver dysfunction, patients taking diuretics, and the elderly areal greater risk of overt renal decompensation. If this occurs, discontinue lhe drug. Use with caution and monitor serum creatinine and/or creatinine clearance in patients wilh significantly impaired renal function. Use caution 1n patients with baseline creatinine clearance less 1
1~a;af;~nTsuw~li~~t~ro~l~ ~~~o g~~sli~!fre~~~v;a~~s~r i~i~~~o~i~:%f~ NSAIDs, borderline elevations of liver lesls may occur in up lo
i~a~si~~f~:i~tZo~n~~e~ath~~~~re~fev~i~~~n o~ng~atf'~i gG8f
occurred in controlled clinical trials in less !han 1% of patients.
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manifestations occur (e.g., eosinophilia or rash), discontinue therapy. If steroid dosage is reduced or eliminated during therapy, do so slowly and observe patients closely for adverse effects, including adrenal insufficiency and exacerbation of arthritis symptoms. Determine hemoglobin values periodically for patients with initial 1
~~~~e:d~~~ ~~~m~e~~ er~~~r~tf~~r~lg~n~~ ~~:hag~"i;~~p~patienls with fluid retention, hypertension or hear! failure. The
~;~~r"a;~ti~X~e~~~~gn,a~\~~i1;~n~a~~;rr ~f~~v~~~~ic~~ru!e~u;;_ duct ophthalmic studies if any change or disturbance in vision occurs. For patients with restricted sodium intake, note that the suseension contains 8 m~/mL of sodium. Information for
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may result in hospitalization and even fatal outcomes. Physicians may wish to discuss wilh patients the potential risks and likely
~~~e~~;ig~sN~:~~i~~~e;~~t~ti/t~;~~~;~rw'Y~eonulh~~~~su~ea~ fg! an acceptable alternative. Patients should use caution for activities requiring alertness if !hey experience drowsiness, diuiness, vertigo or depression during therapy. Laboratory Tests: Because serious Gl tract ulceration and bleeding can occur without warning symptoms, follow chronically treated patients for signs and symptoms of these and inform them of the importance of this follow-up. Drug Interactions: Use caution when ting concomi-
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probenecid; or methotrexate. Drug/Laboratory Tesllnteractlons: The drug may decrease platelet aggregation and prolong bleeding time or Increase urinary values for 17-ketogenic steroids. Temporarily stop therapy for 72 hours before doing adrenal function 5
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genicity. Pregnancy: Category B. Do not use during pregnancy 13
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Reactions: In a study, Gl reactions were more frequent and severe in rheumatoid arthritis patients on 1,500 mgiday than in !hose on
~~~o~~~~a~ 1 ;~~~~dit~~~ns c~~~!e~~~hf~~~~~~r, ~~h;~~sc~tr;~~ ~~~~~sa~~~i~:~~,S&~~Iear"~h~~h~~,~e~~~~~bie1~siu~~1"1\':l~\ib~~~i~n
Gl: The most frequent complaints related to the Gl tract: constipa-
~~~ari;~t~~Ef h~~~~~~~~~ d~~r~esns~u~;~:s~~;~~Fii~ht~~~;~:~: ness, vertigo. Dermatologic: itching (pruritus): skin eruptions:
r;;~i~~;~~n~::~aJ~~~aiP~[ft~rrta~g:~ia~~d~~~~~i~~~~~u;~e~:: ~~~~~~~ g;~~~~~~~iiio~~~T~~~~l~i~1tn~~~i~e~~:r Lf~~scJ~~nte1:\;:, 1 ~~:~~a. ~e~ i~e~~i~~ra~~~~it~e~l~;~\~;an~~~,a~~~~;~~\oi;,u~~~ii:
ing. Renal: glomerular nephritis, hematuria, hyperkalemia, interStitial nephntis, nephrotic syndrome, renal disease, renal failure, renal papillary necrosis. Hematologic: agranulocytosis, eosino· philia, qranulocytopenia, leukopenia, thrombocytopenia. CNS: depress1on, dream abnormalities, inability to concentrate, insom1
~i:: ~~~i~~e~lifi 9~a ~~~m~rilf~~ ~:tnknr~~she~er~t~~~~t~e~~~~:-
hearing impairment. Cardiovascular: congestive heart failure.
~~~~~~~~r~e~~t:~~r~~~~rSe~~~~~r~~ii: ~~;~~;r;~~ ~~;~r1Y~i~~~~ ~~~~i~n~ifs:U~s~~~~n~~n~~g~\?i~~~~n~fl~~s~~s~~~~~~nh6~~~~-
combinant alpha 2-interferon in Chinese patients with chronic hepatitis B infection. Lancet 1988;2(8606):298-302 13. Lok AS, Ma OC, Lai CL, et al. Treatment of chronic hepatitis B with interferon: experience in Asian patients. Semin Liver Dis 1989; 9:249-53 14. KorenmanJ, Baker B, Waggoner J, et al. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med 1991; 114(8):629-34 15. Perrillo RP, Brunt EM. Hepatic histologic and immunohistochemical changes in chronic hepatitis B after prolonged clearance of hepatitis B e antigen and hepatitis B surface antigen. Ann Intern Med 1991;115(2):113-5 16. Garcia G, Smith CI, Weissberg ]I, et al. Adenine arabinoside monophosphate (vidarabine phosphate) in combination with human leukocyte interferon in the treatment of chronic hepatitis B: a randomized, double-blinded, placebo-controlled trial. Ann Intern Med 1987; 107(3):278-85 17. Alexander GJ, Fagan EA, Hegarty JE, et al. Controlled trial of acyclovir in chronic hepatitis B virus infection. J Med Virol 1987;21 :81-7 18. Hess G, Rossol S, Voth R, et al. Treatment of patients with chronic type B hepatitis and concurrent human immunodeficiency virus infection with a combination of interferon alpha and azidothymidine: a pilot study. Digestion 1989;43(1-2):56-9
19. Thyagarajan SP, Subramanian S, Thirunalasundari T, et al. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2(8614):764-6
20. Hedin G, Weiland 0, Ljunggren K, et al. Treatment of fulminant hepatitis B and fulminant hepatitis B and D coinfection with foscarnet. Prog Clin Bioi Res 1987;234:309-20 21. MutchnickMG,Appelman HD, Chung HT, et al. Thymosin treatment of chronic hepatitis B: a placebo-controlled pilot trial. Hepatology 1991; 14(3):409-15 22. Hoofnagle JH, Mullen KD, Jones DB, et al. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon: a preliminary report. N Engl J Med 1986; 315(25):1575-8
23. Davis GL, Balart LA, SchiffER, et al. Treatment of chronic hepatitis C with recombinant interferon alf.t: a multicenter randomized, controlled trial. N EngiJ Med 1989;321(22): 1501-6 24. Di Bisceglie AM, Martin P, Kassianides C, et al. Recombinant interferon alf.t therapy for chronic hepatitis C: a randomized, doubleblind, placebo-controlled trial. N Eng! J Med 1989;321(22): 1506-10 25. Realdi G, Diodati G, Bonetti P, et al. Recombinant human interferon alfa-2a in community-acquired non-A, non-B chronic active hepatitis: preliminary results of a randomized, controlled trial. J Hepatol1990;ll(Suppll): 568-71 26. Marcellin P, Boyer N, Giostra E, et al. Recombinant human alpha-interferon in patients with chronic non-A, non-B hepatitis: a multicenter randomized controlled trial from France. Hepatology 1991;13(3):393-7
27. Shindo M, Di Bisceglie AM, Cheung L, et al. Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatitis C. Ann Intern Med 1991; 115(9):700-4 28. Causse X, Godinot H, Chevallier M, et al. Comparison of I or 3 MU of interferon alfa2b and placebo in patients with chronic non-A, non-B hepatitis. Gastroenterology 1991;101(2): 497-502 29. Saez-Royuela F, Pones JC, Moreno A, et al. High doses of recombinant alpha-interferon or gamma-interferon for chronic hepatitis C: a randomized, controlled trial. Hepatology 1991; 13(2):327-31 30. Omata M, Yokosuka 0, Takano S, et al. Resolution of acute hepatitis C after therapy with natural beta interferon. Lancet 1991; 338(8772):914-5 31. Reichard 0, Andersson J, Schvara R, et al. Ribavirin treatment for chronic hepatitis C. Lancet 1991;337(8749):1058-61 32. Crosignani A, Battczzati PM, Setchell KD, et al. Effects of ursodeoxycholic acid on serum liver enzymes and bile acid metabolism in chronic active hepatitis: a dose-response study. Hepatology 1991;13(2):339-44
logic: epidermal necrolysis, erythema mulliforme, photosensitivity reactions resembling porphyria culanea tarda and epidermolysis bullosa, Stevens-Johnson syndrome, urticaria. Gl: non·peptic Gl ulceration, ulcerative stomatitis. Cardiovascular: vasculitis. General: angioneurotic edema, hyperglycemia, hypo-
~~~.e~~~s~a~·~~~~~: ~are!a;;,~~~~~~~;sh:J~~i~~~~sin~:~~-
stomach and use usual supportive measures. In animals 0.5 g/kg of activated charcoal reduced plasma levels of naproxen. cautlon: ~~~~~e~~1o~\~~i~;;s~;fCi~~s:~ro~~?~~ prescuption. see pack-
5vNTEX
" Incidence of reported reaction 3%·9%. 1~ 1 1 Where unmarked, incidence less than 3%. L""=-'-'--·_ _ _ __j_ U.S. patent nos. 3,904,682, 3,998,966 and others. ©1991 Syntex Puerto Rico, Inc. Rev. 39 September 1990
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HEPATITIS 8 AND C • VOL 92/NO 4/SEPTEMBER 15, 1992/POSTGRADUATE MEDICINE
