HBV Infection NEJM Review.pdf - Free

The new england journal of medicineAAcute Self-Limited HBV InfectionAntigen or Antibody Level0 5 10 15 20 48 2 4 6 8 >10Weeks since ExposureYears since ExposureHBV DNAHBeAgAnti-HBsHBsAgAnti-HBcAnti-HBeALTBChronic HBV InfectionAntigen or Antibody Level0 5 10 15 20 48 2 4 6 8 >10Weeks since ExposureYears since ExposureHBV DNAHBeAgAnti-HBsHBsAgAnti-HBcAnti-HBeALTFigure 4. Patterns of Serologic and Molecular Markers in HBV Infection.Typical levels of alanine aminotransferase (ALT), HBV DNA, hepatitis B s and e antigens (HBsAg and HBeAg), and anti-HBc, anti-HBe, and anti-HBs antibodies are shown in acute self-limited HBV infection (Panel A) and in infections thatbecome chronic (Panel B). The intensity of the responses, as a function of time after infection, is indicated schematically.HBV DNA may persist for many years after the resolution of acute self-limited infection. 42sistently abnormal levels of alanine aminotransferaseand elevated levels of viral DNA may denote asubgroup of HBeAg-negative carriers who shouldreceive active antiviral therapy. 47Hepatocellular CarcinomaAnother feature of the natural history of HBV infectionis its link to primary hepatocellular carcinoma.Chronically infected subjects have a risk of hepatocellularcarcinoma that is 100 times as high as thatfor noncarriers 48 ; within the HBsAg-positive group,HBeAg-positive carriers have the highest risk ofhepatocellular carcinoma, but even carriers withanti-HBe antibodies have a substantial risk of cancer.49 (Although the role of HBV in provoking hepatocellularcarcinoma is undisputed, its cellularand molecular mechanisms remain incompletelyunderstood. 50-54 ) Given these facts, twice-a-yearscreening of chronically infected patients with measurementsof serum alpha fetoprotein or hepaticultrasonography, or both, is warranted. 47 However,there is debate as to when such screening shouldbegin. Furthermore, screening is imperfect — alphafetoprotein screening, for example, has an excellentnegative predictive value, but its positive predictivevalue ranges from 9 to 30 percent. 47implications for therapyThe goals of therapy in patients with HBV infectionare a reduction in the level of viremia and ameliorationof hepatic dysfunction. Most clinical studieshave focused on chronically infected patients withelevated aminotransferase levels and circulatingHBeAg, in whom viral loads can be readily measuredeven with first-generation DNA tests. Thereare clear indications for therapy in HBeAg-positivepatients. They have an increased risk of early progressionto chronic active hepatitis and cirrhosis, 55and they have a risk of hepatocellular carcinomathat is substantially higher than that for other carriers.49 By contrast, asymptomatic HBeAg-negativechronic carriers with viral loads below 10 5 genomesper milliliter and normal alanine aminotransferase1124n engl j med 350;11 www.nejm.org march 11, 2004Downloaded from www.nejm.org at INSERM on June 28, 2008 .Copyright © 2004 Massachusetts Medical Society. All rights reserved.

mechanisms of diseasevalues tend to have a relatively stable course, withlow rates of clinical or pathological progression. 30At present, therapy is usually not offered to suchpersons. As noted above, some HBeAg-negative patientshave liver dysfunction and substantial viremia(>10 5 molecules per milliliter). Discussionsof the treatment of such patients are rare in the publishedliterature, but results of a recent trial suggestthat many of these patients would also benefit fromeffective antiviral therapy. 56 A recent clinical practiceguideline 47 includes this group in its discussionof treatment; clearly, future clinical investigationsshould focus more attention on this group.The usual markers of successful therapy are theloss of HBeAg, seroconversion to anti-HBe antibodies,and reduction of the circulating viral load.These are useful indicators, since patients with stableseroconversion to anti-HBe–positive status typicallyhave improved histologic findings in the liver,and this improvement tends to be maintainedover the long term. 57 True cure of infection (loss ofHBsAg and complete disappearance of viremia, asmeasured by stringent PCR assays) is achieved onlyinfrequently (in 1 to 5 percent of patients) with currentregimens, although the increasing numbers ofactive antiviral drugs might lead to an upward revisionof this figure in the future. In the case of patientswith HBeAg-negative chronic hepatitis, thereis no information about which markers best measurethe response to therapy. Quantitation of viremiaby PCR assays would seem a logical startingplace, but there have been no systematic studies toguide the clinical interpretation of results.interferonFor many years, administration of interferon alfa(5 million to 10 million units subcutaneously threetimes per week, for at least three months) was themainstay of therapy. About 30 percent of patientswho tolerated this regimen had a successful response,defined as a loss of HBeAg, the developmentof anti-HBe antibodies, and a decline in serumalanine aminotransferase levels. 58 With HBeseroconversion and normalization of alanine aminotransferaselevels, improvement is usually sustainedwell after therapy has been discontinued. 58Interferon alfa treatment of chronic HBV infectionsin patients with cirrhosis has even been reported toreduce the risk of hepatocellular carcinoma. 59However, the side effects of therapy with interferonalfa (fever, myalgias, thrombocytopenia, anddepression) make it a difficult treatment for manypatients. Moreover, in many patients a flare of liverinjury occurs during administration of interferonalfa, often just before or during clearance of HBeAg.This phenomenon may reflect the immunomodulatoryactivity of interferon alfa, which, in additionto impairing HBV replication, can also cause up-regulationof MHC class I antigens on hepatocytes andthereby augment the recognition of infected cellsby cytotoxic T lymphocytes. Although sometimesdisquieting to patients and physicians alike, theseflares are intrinsic to the therapy and, as markers ofenhanced antiviral immune responsiveness, oftenpresage a successful outcome. However, treatmentwith interferon alfa is generally contraindicated invery advanced liver disease, since in such cases theflares may precipitate overt liver failure. Moreover,patients with advanced cirrhosis and splenomegalyusually have base-line leukopenia and thrombocytopenia,which can be exacerbated by the drug.antiviral drugsLamivudineIn the past decade, therapy for HBV has been revolutionizedby the advent of drugs that directly blockreplication of the HBV genome. All these drugs (todate) are nucleoside or nucleotide analogues thatselectively target the viral reverse transcriptase. Thefirst successful drug, lamivudine, emerged fromscreening for inhibitors of the HIV reverse transcriptaseand was introduced into clinical practicefor the management of HIV infection. Carriers ofHIV who are also infected with HBV had substantialdeclines in HBV viremia when treated with lamivudine,60 and such declines were also observedin patients with chronic hepatitis B who did nothave HIV infection. 61 In general, treatment with lamivudineresults in a reduction of 3 to 4 log in circulatinglevels of HBV DNA in the first three monthsof therapy; this decline is associated with more rapidloss of HBeAg, seroconversion to anti-HBe–positivestatus, and improvement in serum aminotransferaselevels. The drug is usually well tolerated, afactor that has led to the rapid displacement of interferonalfa from the roster of first-line therapiesfor HBV. Lamivudine is not immunomodulatory andcan be used in patients with decompensated cirrhosis.62 Even polyarteritis nodosa associated withHBV has been shown to respond dramatically totreatment with lamivudine plus plasma exchange. 63Although lamivudine is not an immunomodulator,there is strong evidence that successful treatmentwith lamivudine relies to some extent on ann engl j med 350;11 www.nejm.org march 11, 20041125Downloaded from www.nejm.org at INSERM on June 28, 2008 .Copyright © 2004 Massachusetts Medical Society. All rights reserved.

The new england journal of medicineadequate host immune response. This evidenceemerged from a retrospective examination of subgroupsof patients with optimal responses to therapy,which revealed a strong correlation betweenHBeAg clearance and elevated pretreatment valuesfor alanine aminotransferase. 64 HBeAg seroconversionoccurred in 65 percent of cases in whichpretreatment values for alanine aminotransferasewere more than five times the upper limit of thenormal range, as compared with only 26 percentin patients with elevations in alanine aminotransferasevalues that were two to five times the upperlimit of the normal range. Only 5 percent of patientswith pretreatment alanine aminotransferasevalues that were less than twice the upper limit ofthe normal range had clearance of HBeAg — arate similar to that for the spontaneous loss of thismarker. This finding suggests that by reducing theviral load, lamivudine allows the immune and inflammatoryresponses to deal more effectively withthe remaining infected hepatocytes in the host.The principal limitation of lamivudine monotherapyis the development of drug resistance,which is mediated largely by point mutations atthe YMDD motif at the catalytic center of the viralreverse transcriptase. The resulting mutants areslightly less fit than wild-type HBV in the absenceof the drug, but they are strongly selected for in itspresence. 65 Viral resistance emerges much moreslowly in HBV infection than in HIV infection, forcomplex reasons beyond the scope of this review.By the end of one year of therapy, 15 to 20 percentof patients have resistant variants in the circulation;the figure rises to 40 percent by two years, andto 67 percent by the fourth year. 66The clinical significance of the development ofresistance is still being debated. Clearly, in manypatients, resistance presages a return of higherlevelviremia, and in some of these patients furtherliver injury develops. However, although the levelof viremia rises, in many patients it may still remainbelow pretreatment levels — perhaps as a resultof the reduced fitness of the variants. In addition,some patients continue to undergo conversion fromHBeAg-positive status to HBeAg-negative status,even after the appearance of lamivudine-resistantmutants in the circulation; by the end of four yearsof therapy, 40 to 50 percent of patients treated withlamivudine have undergone such conversion. Therefore,some experts favor the continuation of lamivudinetherapy in patients with resistant variantsbut no evidence of overt clinical failure, especiallysince transient exacerbations of liver injury developin some patients when antiviral therapy is withdrawn.67 (Such postwithdrawal flares are not limitedto lamivudine but have also been observed withother anti-HBV regimens. 56,68 ) Now that neweranti-HBV drugs are available, additional optionsexist for patients with resistant strains of HBV.Other Nucleotide AnaloguesRecently, the Food and Drug Administration (FDA)approved a second antiviral drug, adefovir, to treatHBV infection. Adefovir, a nucleotide (adenosinemonophosphate) analogue, is a prodrug that undergoestwo intracellular phosphorylations to yieldthe active drug, an inhibitor of the viral polymerase.Initially developed as an inhibitor of HIV reversetranscriptase, it proved nephrotoxic in the dosesthat were required for effective inhibition of HIVreplication. However, in lower doses (10 mg per day)it has shown little nephrotoxicity and retains goodefficacy against HBV in HBeAg-positive patients,with a reduction of 3 to 4 log in viremia; the frequencyof HBeAg seroconversion is enhanced, andthere is histologic improvement in the liver. 68 Similarefficacy was documented in HBeAg-negative patientswith abnormal liver function and elevated levelsof viral DNA. 56 Moreover, the drug effectivelyinhibits the replication of lamivudine-resistant HBVmutants, both in vitro and in vivo. 69,70 Clear evidenceof the emergence of adefovir-resistant HBVmutants has not been found in the clinical trialsperformed to date, 56,68,71 although this issue remainsopen now that large numbers of patientswill be using the drug.Tenofovir, another adenine nucleotide analoguethat was approved by the FDA for the treatment ofHIV, also has activity against the HBV polymerase.In recent trials in HIV carriers who were positive forHBeAg, treatment with standard doses of tenofovirled to a reduction of 4 log in circulating HBV DNAlevels, even in patients who had evidence of lamivudine-resistantvirus. 72,73 However, the FDA hasnot yet approved tenofovir for use in patients withHBV infection.Several investigational drugs are now in advancedstages of clinical trials. Entecavir is a guanosineanalogue that, unlike the drugs discussedabove, is highly selective for the HBV polymeraseand has no activity against HIV. It is extremely potenton a molar basis, and doses as low as 0.1 mg per1126n engl j med 350;11 www.nejm.org march 11, 2004Downloaded from www.nejm.org at INSERM on June 28, 2008 .Copyright © 2004 Massachusetts Medical Society. All rights reserved.

mechanisms of diseaseday can cause reductions of 4 log in levels of HBVDNA; a dose of 0.5 mg per day caused a reductionof nearly 5 log in 24 weeks of monotherapy. 74 Thedrug is also active against lamivudine-resistant HBV.l-deoxythymidine is a thymidine analogue that alsoselectively inhibits the HBV polymerase and is advancingthrough clinical trials; it, too, appears to beactive against lamivudine-resistant virus. 75 Twoother nucleoside analogues (emtricitabine and clevudine)have also shown promise in vitro and in vivo,although neither is reliably active against all lamivudine-resistantvariants. 76Thus, the past few years have witnessed the developmentof a plethora of new drugs for the treatmentof HBV infection. It seems likely that combinationtherapy will become the wave of the futurein HBV therapy, but many questions remain to beresolved by clinical investigation. Is combinationtherapy truly superior to monotherapy, clinically aswell as virologically? If, as most expect, it proves tobe superior, which combination of drugs should beused for initial treatment? Will there be an evolutionof cross-resistance among drugs that are effectiveagainst lamivudine-resistant viruses? What shouldbe the duration of therapy? (One recent practiceguideline recommends stopping antiviral therapyat one year in HBeAg-positive patients who haveseroconversion to anti-HBe antibodies but continuingtherapy in those who do not have seroconversionin the first year or in whom breakthrough viremiadevelops. 47 ) More speculatively, could morepotent combination therapy reduce HBV levels toa point where the remaining virus could be clearedby the host’s own immune system, either spontaneouslyor after therapeutic vaccination with HBVantigens?liver transplantationLiver transplantation for HBV disease is attendedby recurrent viral infection in more than 80 percentof patients if no interventions are undertaken to preventreinfection. 77 Recurrent HBV infection in thecontext of the level of immunosuppression neededto prevent graft rejection is typically associated withhigh viral loads and a poor outcome, especiallyfor patients with chronic HBeAg-positive hepatitis.Hepatitis B immune globulin, administered overlong periods, cuts the reinfection rate in half andextends the two-year survival rate from 50 percentto approximately 80 percent. 77,78 Use of lamivudineafter transplantation has resulted in similarimprovement, 79 but without question, the best resultshave been obtained with post-transplantationprophylaxis consisting of both hepatitis B immuneglobulin and lamivudine. 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mechanisms of diseaseAsian patients with chronic hepatitis B. Gastroenterology2000;119:172-80.67. Honkoop P, de Man RA, Niesters HG,Zondervan PE, Schalm SW. Acute exacerbationof chronic hepatitis B virus infection afterwithdrawal of lamivudine therapy. Hepatology2000;32:635-9.68. Marcellin P, Chang T-T, Lim SG, et al.Adefovir dipivoxil for the treatment of hepatitisB e antigen–positive chronic hepatitisB. N Engl J Med 2003;348:808-16.69. Ying C, De Clercq E, Nicholson W, FurmanP, Neyts J. Inhibition of the replication ofthe DNA polymerase M550V mutation variantof human hepatitis B virus by adefovir,tenofovir, L-FMAU, DAPD, penciclovir andlobucavir. J Viral Hepat 2000;7:161-5.70. Perrillo R, Schiff E, Yoshida E, et al. Adefovirdipivoxil for the treatment of lamivudine-resistanthepatitis B mutants. Hepatology2000;32:129-34.71. Yang H, Westland CE, Delaney WE IV, etal. Resistance surveillance in chronic hepatitisB patients treated with adefovir dipivoxilfor up to 60 weeks. Hepatology 2002;36:464-73.72. Nelson M, Portsmouth J, Stebbing J, etal. An open-label study of tenofovir in HIV-1and hepatitis B virus co-infected individuals.AIDS 2003;17:F7-F10.73. Ristig MB, Crippin J, Aberg JA, et al.Tenofovir disoproxil fumarate therapy forchronic hepatitis B in human immunodeficiencyvirus/hepatitis B virus-coinfected individualsfor whom interferon-alpha and lamivudinetherapy have failed. J Infect Dis2002;186:1844-7.74. Lai C-L, Rosmawati M, Lao J, et al. Entecaviris superior to lamivudine in reducinghepatitis B virus DNA in patients with chronichepatitis B infection. Gastroenterology 2002;123:1831-8.75. Standring DN, Bridges EG, Placidi L, etal. Antiviral beta-L-nucleosides specific forhepatitis B virus infection. Antivir ChemChemother 2001;12:Suppl 1:119-29.76. Chin R, Shaw T, Torresi J, et al. In vitrosusceptibilities of wild-type or drug-resistanthepatitis B virus to (-)-beta-D-2,6-diaminopurinedioxolane and 2'-fluoro-5-methylbeta-L-arabinofuranosyluracil.AntimicrobAgents Chemother 2001;45:2495-501.77. Samuel D, Muller R, Alexander G, et al.Liver transplantation in European patientswith the hepatitis B surface antigen. N EnglJ Med 1993;329:1842-7.78. Terrault NA, Zhou S, Combs C, et al. Prophylaxisin liver transplant recipients usinga fixed dosing schedule of hepatitis B immunoglobulin.Hepatology 1996;24:1327-33.79. Perrillo R, Rakela J, Dienstag J, et al. Multicenterstudy of lamivudine therapy for hepatitisB after liver transplantation. Hepatology1999;29:1581-6.80. Anselmo DM, Ghobrial RM, Jung LC,et al. New era of liver transplantation forhepatitis B: 17-year single-center experience.Ann Surg 2002;235:611-20.Copyright © 2004 Massachusetts Medical Society.electronic access to the journal’s cumulative indexAt the Journal’s site on the World Wide Web (www.nejm.org), you can search anindex of all articles published since January 1975 (abstracts 1975–1992, full text1993–present). You can search by author, key word, title, type of article, and date.The results will include the citations for the articles plus links to the abstracts ofarticles published since 1993. For nonsubscribers, time-limited access to singlearticles and 24-hour site access can also be ordered for a fee through the Internet(www.nejm.org).n engl j med 350;11 www.nejm.org march 11, 20041129Downloaded from www.nejm.org at INSERM on June 28, 2008 .Copyright © 2004 Massachusetts Medical Society. All rights reserved.

New England Journal of MedicineCORRECTIONHepatitis B Virus Infection — Natural History andClinical ConsequencesHepatitis B Virus Infection — Natural History and Clinical Consequences. On page 1119, lines 7 through 9 of the first full paragraphshould have read, ``Initiation at the next upstream start codon,´´ ratherthan ``Initiation at the most upstream start codon,´´ as printed. We regretthe error.N Engl J Med 2004;351:1268-aDownloaded from www.nejm.org at INSERM on June 28, 2008 .Copyright © 2004 Massachusetts Medical Society. All rights reserved.