Reactivation hepatitis B as a result of chemotherapy induced immunosuppression is well documented in the medical literature. Complications range from anicteric hepatitis to fulminant hepatic failure and death. Although lamivudine has been successfully used to treat hepatitis B reactivation in cancer patients, its role as prophylaxis in these patients is less well defined. We describe successfully lamivudine prophylaxis of a patient with chronic hepatitis B undergoing chemotherapy for acute myelogenous leukemia (AML). We support the position that lamivudine may play a significant role in the successful prevention of reactivation hepatitis B in cancer patients undergoing chemotherapy. The views expressed in this manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. Government

Berenberg, Jeffrey L.

Mills, Shane J

Ramos, Fernando

eVols at University of Hawaii at Manoa

Lamivudine Prophylaxis forChemotherapy Induced ReactivationHepatitis B: A Case Report and Review.............. -..,...0 VS ..“ 1 tni,. Ii ‘-T’AMC HI e’AbstractReact.vator? t?COOi/iS B as a resu:t o ccsrnotheracra ceo r> j”Q ow, . S ILtOe rned,ca ‘terature Corn iicaticns range frornanicteric hepattstc fulrnnant hepatic ta/ore aria deathAlthough iamivudine has been successfully used totreat hepatitis B reactivation in cancer oatients its roleas prophy/axis in these patients is less well defined.We describe successful lamivudine prophylaxis ofa patient with chronic hepatitis B undergoing chemotherapy for acute myelogenous leukemia (A ML). Wesupport the position that lamivudine may playa significant role in the successful prevention of reactivationhepatitis B in cancer patients undergoing chernother.apv.The views espressedin this manuscript are those ofthe authors and do not reflect the official policy orpositIon of the Department of the Army. Department ofDefense. or the LI S. GovernmentIntroductionReactivation hepatiti sB in cancer patients undergoingchemotherapy is well documented in the literature. Inthe setting of chemotherapy-induced immunosuppression, reactivation of hepatitis B can lead to a spectrumof adverse outcomes including fulminant hepatic failure and death. Lamivudine, a reverse transcriptaseinhibitor, has been used to treat reacti\ ation hepatitisin this subset of patients. Although prophvlaxis isotten suggested. reports arc rare. We describe successful lamivudine prophvlaxis of a patient with chronichepatitis B undersoing chemotherapy for acute mvel—ogenous leukemia (Case ReportThe patient is a 25-year-old female with chronichepatitis B who was diagnosed with AML after evaluation for buccal ecchymosis and extremity hematomas. Initial labs were remarkable for hepatitis Bsurface antigen ([IBsAg) reactivity, hepatitis B virusif-lB V) DNA ol .1)3 pg/mI, aspartate arniuotransferasei .-\ST)of69 [IL. and alanine arninotransferase (ALT)of h2 [/L.She began prophv lactic treatment ss ith lamivudineprior to induction chemotherapy with daruhicin andcvtarabine. Proph axis was continued throughout thesubsequent consolidation chemotherap . which included fourc clesofhieh dosec tatabinc. \side fromses erul episodes of neutropenic fes er. she toleratedthe chemotheraps well. Althou 11 the patient hidpersistentl\ I ated li\ er associ t d en/\ mes \l Ttingin om 68 to 7 1 IL and AST ran ‘ing 1mmto ISO [IL) HB\ DN \ 1ev 1 r tn in d undetei.. abland th pan nt had no clint all si nih ant h patiequ lae.Dut im h r ninth month of trcatm nt th pati nt hada Pt olony d p nod of panc top ma v ith hone mat tohiops show in a i elapse of her AvlI . \ftei failedteinduction with mito\antrone and etoposide. the patient was schduled for an al Iogenetc bone mat rowtransplant. At that time, the patient’s li er associateden/i mes included an AST of O [IL and an \1 Tot 6%f-/I . HBV DNA leels were still undetectable. 1 hehighest le els of transaminases occurred during induction and retnduction and were thouuht secondaryto chemotheraps induced hepatoto icit (Figure hDiscussionA spectrum of liver injury is associated with chemotherapy, ranging, from anicteric hepatitis to fulminanthepatic failure and death. Etiologies include viralhepatttts. drug hepatoto\icitv. malignant hepatic tnftl—trat it ‘n. shock, sepsi. and crvptovenic cause.A growing body of’ literature has concentrated on the ad erscoutcomes of chemothet’apv patients with iral ht.’pati -ti s.ua. 400—AlT300 CAST0 ist 2nd 3rd 4th 5th 6th 7th 8th 9thMonth220Reacti ation hepatitis B in cancer patients receivingcvtotoxic chemotherapy is vell reported. Althoughmost cases have involved hematological rnalignan—cies (ie. lvmphomaL occasional cases involving solidtumors ha e been reported as well. In a I 991 retrospective study of Chinese lvmphoma patients. 27%were found to he HBsAg seropositive. Of these patients, 47% developed reactivation hepatitis duringchemotherapy. which resulted in a 5% mortality.2 Ina similar Japanese study. 3.3% of lymphoma patientswere found to have chronic HBV infection .Seerehepatitis occurred in 53% of these patients and mortal—tv rates were as high as 24%. In 2000. Yeo et al.conducted the first prospective assessment of HBVreactivation rates in Chinese cancer patients recei ingc\totoxic chemotherap. In this study. 12% of 626consecutive cancerpatients were HBsAg positive, andreactivation occurred in nearly 20% of these patients.This data clearly supports the need for in depth assessment of this adverse process. Of note, hepatitis Cinjection has also been documented in associationwith chemotherap —induced hepatitis. and mortalit\rates appear to he similar to that seen in patients withHBV reactivation.There are two proposed mechanisms ofreactivationhepatitis B in cancer patients undergoing c totoxicchemotherapy. The first involves immunosuppres—sion, enhanced KBV replication, and direct hepatotoxicity from infection. The second mechanism involves a rebound immune response upon withdrawalofchernotherapv. resulting in hepatocyte destruction.Attempts to identify risk factors for reactivationhepatitis B ha e produced conflicting results. A 190study of 105 lvmphoma patients b Liang et al. con—eluded that age, sex, stage. symptoms. lvmphomasubtype. presence of hepatic lvinphoma. treatment.presence of HBcAg and anti-H13e serologies. andunderlying liver pathology \ere not predictive ofhepatic complications.5However, a prospective studyby Yeo et al. identified several significant associatedfactors. These included male sex, younger age. presence of lymphoma. chernotherapeutic agent (mostcommon being corticosteroids. anthracvclincs. cvclo—phosphamide. and ‘ inca alkaloids), and HBeAg posi—ti\ itv (although %ome virulent precore mutant strainsare unable to produce the eAg and are still highlyassociated v ith fulminant hepatic failurePerhaps the most promising treatment for reactivation hepatitis in cancerpatients is the use of lami udine(3-thiacytidine), areverse transcriptase inhibitor, Thisnucleoside analog, originally used for HJV infection,was found to reduce KBV DNA to undetectable les elsin 86% of I-IlV infected HBV carriers ithin t omonths. Several successful pilot studies and fourlarge multicenter randomized control led trials sho’ edthat lamivudine therapy va’ associated with an in—creased tate of HBeAc serocon\ erion. impro edserunt ALT levels and liver histology, and a decreasein the development of eiThosis.’- In addition to itsefficacy. lamivudine was associated with few if anyside etfects.r The drug was approved as therapy forHBeAg positi e chronic hepatitis B patients in 1998.Lamivudine’s role has subsequently been broadenedto treat chemotherapy-induced reactivation hepatitisB. There are at least 13 documented case reports ofsuccessful lamivudine treatment of reactivation hepatitis. including those patients with fulminant disease.4Lamivudine may also play an important role asproph laxis for chronic HBV cancer patients prior tochemotherap . B’ suppressing HBV DNA replication(as evidenced by histology and HBV DNA levels).lami vudine prevents hepatocvte infection, the reboundimmune response. and subsequent reacti\ ation hepatitis. Several case reports (including our own) and tworecent studies, give direct support to this proposal.8In our patient, HBV DNA levels remained undetectable throughout chemotherapy, and transient elevations in her liver enzymes were secondary to chemotherap —induced hepatotoxieitv. In a retrospective Israeli study. 13 FIBV infected cancer patients wereprophylactically treated with lamivudine prior to andfollo ing immunosuppressive therapy, with a meanfollow—up of 2 1 months. None of the patients hadclinical or serological evidence of HBV reactivationduring or after prophvlaxis. Likewise, in a prospectiveItalian study, 20 consecutive patients with HBV andhematologic malignancies were prophylacticallytreated with 100 mg of lamivudine from the start ofchemotherapy until one month after the end of treatment. Only one patient developed reactivation hepatitis during a median follow—up of six months.Several unresolved issues regarding lamivudineprophvlaxis need to he addressed. Specificaii. optimal dose, duration of therapy, and resistance havebeen investigated in chronic HBV patients, but not inthose patients undergoing chemotherapy. In a oneyear trial of lamivudine. Lai et al. showed that 100mgdaily was more effective than 25 mg in the extent ofhistologic improvement, degree of HBV DNA suppression. and prevention of fihrosi.- Duration oftherapy and resistance have also been studied extensivel . as prolonged lamivudine therap allows forgenot pie mutations in the YMDD locus of HBV thatconfers a reduced sensitivity to lamivudine, Resistance rates at one, two. three, and four years are 17%.40%, 55%, and 67%. respectively. These patientstypically have higher ALT and HBV DNA levels thanthose ithout resistance. but levels on average are stilllower in affected indi iduals than their pretreatmentalues. Continued histologic improvement is alsoseen ith extended therap regardless of YMDDresistance, as evidenced by liver biopsies from patients treated with t o or more years of lamivudine inthe .\%ian 1uiticenter trial.- In addition. a large co—HAWAS MEENCAL. JOURNAL. VOL 62, OCTOBER 200322hon study showed no increased incidence of hepaticinsufficiency or change in adverse events noted withthe YMDD mutant I-IBV. Therefore, while prophylaxis nn ith 100mg of larnivudine for extended periodsof time seems safe and effective in chronic HBVpatients despite YMDD resistance. randomized double-blinded trials will be needed to better assess theseissues in cancer patients undergoing cvtotoxicchemotherapyConclusionThere are 400 million cases of hepatitis B worlcks idewith prevalence rates in chemotherapy patients reported at 12%. Reactivation hepatitis occurs in 20-50% of these patients and is a potentially lethal complication, with mortality rates documented as high as25% in affected individuals. Lamivudine therapy,originally used in HIV patients and then approved forHBeAg chronic HBV, has now been used to successfully treat reactivation hepatitis B in chemotherapypatients. We support the position that lamivudineshould also be used as prophylaxis to prevent reactivation hepatitis in cancer patients, and we provide a casereport of successful lamivudine prophylaxis.References1 Yeo W, Chan P. Zhong S, et al, Frequency of Hepatitis B Virus Reactivation inCancer Patients Undergoing Cytotoxic Chemotherapy: A Prospective Study of626 Patients With ldentificaton of Risk Factors, J Med Virol 2000: 62(3): 299-307.2 Lok A Liao R Cbiu E e a Re1v tio’ c hepa’ 1 Bv’u’epliuatio flrece ving cytotcxic the aov Reoo’t of orcspe’. “..dj aviroe’’erc j,199 120 ‘82 ‘883 Nw::u’a Y Motoku — T F.. ‘a A t a S:ere —p ‘vlatc ‘C C-“at tn B . c. “ - sitS ii CC ‘a _“ — .- u ‘ J0.lxv 1°fll Om’rr’° 6 8u2’_.2 S$ 5if I LiCe R Ha— — J ‘-‘ Pc: ‘ c’ -. —‘t ‘ 9 ‘- -on no nrc” se ‘e’v:’ —“o “c — — — —“ ‘ - A‘CH”-’toOr—’°8Lw A H’--:5_ot’ B H—”r”c e ‘.: - ——c - - 1 S—ic.‘,‘•“ G :‘ ‘ ‘e’co” ‘ -‘L.C C”P Le1,’ct Ac” 0- — r ;ovi ‘0Cct, B-c Lleo n8 ‘9 2 1’ 8A’a’QMo’H,jusc, A ‘ P uen’o otpt1i B pcne’cc’ erspy..-nl —c cn’w ‘port d n woOh 1—r A -He”a’o 1 09 ‘8 5 24’ 0-’Enoo T vaca T Fj: n’c’o H A 01 roi br i mu .n propnvsgvir I “eoa5t- B whc u dero fi hi‘py no utOO flu p pii r hi P‘r’. l: ‘ran p nt ti to on Ilodg in i ph vi Bon M cowTr ii p n27.’ 433-sNkagav-a U Sim u V u mu t, ‘1 u c u Ion ‘m ntr I viii’larriuuo:ne aga n r dv d S p A B mt eon f Icwiro nten iv Stheaojnd utlosou prmph rmbl000t tm lltrrolrhh dl onHodgkn’ly’n ho xp rm n t2 An’JH m tol2 r .01 (60Pc’ G Pc viz A MoSt M t P’ ii’ proohyi my with viiuud nepahte B mnu re ctiv ton vi hron’ Hb Ag c rr r with lymph A n- e’ 5 d wi h h moth rapy B I H m to’ 2001 .5 5 621 bhmboletO II n’s’ Gil: t L mivudin th pfc pr v ntionofmmmuno us’pr ‘iv nduc d h satiti B Iiru re lv tm vi heo Ii B yrt tgC rrier sod 2002 100 I 3°1 63 Liaw V F L ung NWY Ch rig TT t I Eff t or en. nd d lamivudmn ther pyin Asian p 8 nt ‘myth chroni p 8 B G tIn 4 rology 2v00 1 1 1814 LeuraN LaiC Ch noT, t 1 Threy ri n’iuuoin th rpym.’hro’v HBVmabstr J H p 01 199° 301 uppl 5 915 CrangT LaiC Li WV, t i In r m n lincr I HB Ag roconv r ion rdconlmnuedALTnorm tionviAsm nchronicHBVp ti nt tr at dwithl mivudinfor four years at In Antivir T. er 000 Si uppi 5 4416 SA ER Heath or I, Dien t IL ta lmprov ment in liv r hi rology ridci”bosis with extend d i mivudin th r py ( bstrm Hep tology 000, 32 20 A17 AtkinaM WoessnerM L iC t I “linical Sign: i nc ofYMODMut nthep MmB v ran IHBV1 n a Large Cohort of L mmvudin Tr ated hepatiti B P ti fitsHepatology 1°98 28 i4m At tract 625FIVE WAYS I.Hitbyagolf baiL2. Run over by a golf carT.TO DIE ON THE4 Suck by igntrnrigGOLF COURSE: 5 ForgotSurpr:srwiy. one mrlhon r.e’sv cases of skm cancer are detec:ed ever; year. One person an hour IL the U.S.. dies-e aeon o s cancer r c speed a c I cc o n”o setOne oct of five Americans develops sn cancer during their lifetime. Dm0 be one of them. Stay out of the middaysun. Coverun. 5Ieer a nat, Seek shade. d use sunsereen. For more information on how to prolect yourself from5jc cancer, call 1-888-462-DERM or visit wwvsaad.org.<AADzi.xuxAMERICAN ACADEMY OF DERMATOLOGY

Lamivudine prophylaxis for chemotherapy induced reactivation hepatitis B: a case report and review.

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Lamivudine prophylaxis for chemotherapy induced reactivation hepatitis B: a case report and review.

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