current treatment of hepatitis b 2008

doi:10.1136/gut.2005.077891 2008;57;105-124; originally published online 14 May 2007; Gut G Dusheiko and N Antonakopoulos Current treatment of hepatitis B http://gut.bmj.com/cgi/content/full/57/1/105 Updated information and services can be found at: These include: References http://gut.bmj.com/cgi/content/full/57/1/105#BIBL This article cites 174 articles, 46 of which can be accessed free at: service Email alerting the top right corner of the article Receive free email alerts when new articles cite this article - sign up in the box at Correction http://gut.bmj.com/cgi/content/full/57/6/872-a available online at: been appended to the original article in this reprint. The correction is also have correctionA correction has been published for this article. The contents of the Notes http://journals.bmj.com/cgi/reprintform To order reprints of this article go to: http://journals.bmj.com/subscriptions/ go to: GutTo subscribe to on 11 August 2008 gut.bmj.comDownloaded from Current treatment of hepatitis B G Dusheiko, N Antonakopoulos UCL Centre for Hepatology and Royal Free Hospital, London, UK Correspondence to: Professor Geoff Dusheiko, University Department of Medicine, Royal Free Hospital, Pond Street, London HA5 1DE, UK; g.dusheiko@medsch.ucl.ac. uk Hepatitis B has a complex natural history and causes a wide spectrum of disease. There is a large reservoir of carriers of hepatitis B virus (HBV) in the human population. Low (less than 2% of the population), intermediate (2–8%), and high prevalence regions (more than 8%) are recognised. Population movements and immigration are chan- ging the prevalence of the disease in several non- endemic countries in Europe and elsewhere. Treatment is indicated for chronic, progressive disease, although there is a role for rapidly acting nucleoside analogues in fulminant acute hepatitis or subacute hepatic necrosis. Substantial health care resources will be required for the worldwide burden of disease. In endemic areas the direct costs can total 3.2% of the national health care expenditure. 12 Several difficulties remain in formulating treatments for HBV infection and thus areas of disagreement on the management of chronic hepatitis B exist. Choices of treatment depend on a number of factors predictive of treatment response, clinical circumstances and stage of disease, potency of different agents, the likelihood and consequences of resistance to treatment, as well as the personal choice of the patient and physician. 3 Current guidelines are not always constant or agreed and will require rapid adjust- ment as new treatments become available. 4–6 Thus this review summarises an overall view of treatment and points to areas of controversy. REPLICATION OF HBV AND HOST IMMUNE RESPONSE Key steps in the replication of HBV have been defined. After entry into the cell, the virus is uncoated, and translocated to the nucleus. Relaxed circular HBV DNA is converted into supercoiled, or covalently closed (cccDNA) from which a prege- nomic RNA is transcribed. HBV replicates through transcription of HBV RNA to DNA. The crucial steps include encapsidation, minus strand (2) DNA strand synthesis, plus strand (+) DNA synthesis, and maturation and release of viral particles. cccDNA is shuttled back to the nucleus. Importantly, the stability and replenishment of cccDNA accounts for the difficulty in eradicating hepatitis B, and acts as an archive of antiviral resistant DNA. HBV also integrates within the host genome. HBV is not generally cytopathic but HBV DNA levels correlate with long term progression. Acute hepatitis B is self limited in the majority of immunologically normal adults. 17 After acute hepatitis low levels of virus persist for decades after acute resolution of disease. Recovery from hepatitis B is associated with long term persistence of cytotoxic T lymphocytes (CTL) that actively maintain CTL responses for life. 8–10 An inadequate innate and adaptive host immune response accounts for persistent infection, and immunological tolerance is evident in HBeAg positive patients with high viral loads. Conversely, HBV clearance is associated with a degree of liver damage. The host immune responses that characterise the chronic phase of active disease are not sufficient to control active viral replication (for reasons that are uncertain). High antigen expression in the liver may impair T cell effector functions, 11 and in many patients the immune paresis is irreversible despite a reduction in viral load. HBV specific T cell responses are weak, narrowly focused, or totally undetectable in the peripheral blood of patients with long lasting chronic hepatitis B. 12–14 However, T cell responsive- ness can be partially restored. Treatment with both lamivudine and adefovir has been shown to restore or enhance transiently the HBV specific HLA class II response to HBV antigens. A complex pattern of genomic variability and selection of pre- core mutants and core promoter mutants occurs during prolonged chronic infection, accounting for different serological patterns of disease. CHRONIC HEPATITIS B Chronic hepatitis B is defined as persistence of hepatitis B surface antigen (HBsAg) in the circula- tion for more than six months. The disease may cause liver damage varying from mild chronic hepatitis to severe, active hepatitis, cirrhosis, and primary liver cancer. Chronic hepatitis B is more likely to follow infections acquired in childhood than those acquired in adult life, and is more likely to occur in patients with natural or acquired immune deficiencies, including HIV infection. DIAGNOSIS AND PATHOLOGY Hepatitis B is usually diagnosed by the detection of HBsAg in serum. Detection of viral DNA is the optimal method of establishing hepatitis B viraemia and standardised quantitative assays are valuable for monitoring virus loads during antiviral therapy. 15 16 Quantitative assays for HBV DNA were previously limited by a lack of standardisa- tion but more recently a World Health Organisation (WHO) standard has been developed. 17 18 HBeAg is a marker of viraemia but detection anti-HBe does not indicate clearance of virus replication. Typically the levels of serum aminotransferases are raised in patients with HBeAg, HBV DNA positive active chronic hepatitis, but patients may have normal or near normal values. Many patients go on to develop moderate to severe HBeAg positive chronic hepatitis with RECENT ADVANCES IN CLINICAL PRACTICE Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 105 on 11 August 2008 gut.bmj.comDownloaded from raised serum alanine aminotransferase (ALT) after several decades of infection, which can ultimately progress to cirrhosis. The levels of aminotransferases may fluctuate with time. Usually, the levels of ALT are higher than those of aspartate aminotransferase (AST). However, with progression of the disease to cirrhosis, the AST/ALT ratio may be reversed. An increase in these enzymes may be the only abnormality to be found in individuals with asymptomatic and anicteric infections. A progressive decline in serum albumin concentrations and prolongation of the prothrombin time are characteristically observed after decompensated cirrhosis has developed. Single measures of ALT (and HBV DNA) are not useful in a disease as dynamic as hepatitis B, and there is controversy over the level below which HBV DNA concentrations are indicative of ‘‘inactive’’ disease, or indicate a threshold for initiating treatment. Thus longitudinal mea- fosures, over at least a few months or longer, are required. HBV genotypes have been reported to correlate with spontaneous and interferon induced HBeAg seroconversion, activity of liver disease, and progression to cirrhosis and hepatocellular carcinoma. In China and Japan, where genotypes B and C predominate, there is evidence for increased pathogenicity of genotype C over B, with the likelihood of developing hepatocellular carcinoma. 19–22 In chronic hepatitis B with mild activity, only rare piecemeal necrosis is seen. Characteristic hepatocytes with eosinophilic ‘‘ground glass’’ cells are relatively common in anti-HBe positive patients with low levels of virus replication. Lobular hepatitis is more common in patients with active virus replication and raised serum ALT. HBsAg and HBcAg can be detected by immuno- peroxidase staining in routinely fixed liver biopsy sections. Patients with high levels of viraemia may have minimal hepatitis. 23 MAJOR PATTERNS OF CHRONIC HEPATITIS Three broad groups of chronic hepatitis B are recognised. HBeAg positive chronic hepatitis B HBeAg positive disease is typically associated with high levels of HBV replication for a prolonged period of time. The disease is found in young individuals with chronic hepatitis B, who have high levels of HBV DNA (usually .10 7 copies/ml) in serum. They may have normal ALT in the ‘‘immunotolerant phase’’ of the disease, or have raised ALT in later active disease. Spontaneous seroconversion rates are higher in patients with raised ALT and genotype B (vs C) and genotype D (vs A). Importantly, patients with normal serum ALT and high circulating concentrations of HBV DNA show profound peripheral immunological tolerance. Finite treatment remains difficult, probably for this reason. These individuals are poor responders to interferon treatment, and often poor short term responders to nucleoside or nucleotide antiviral drugs because of resistance. Spon- taneous seroconversion rates remain relatively low in this group at approximately 20% at one year. HBeAg negative disease Anti-HBe positive chronic hepatitis B is characterised by the absence of HBeAg in serum due to genotypic changes preventing expression of HBeAg. Viral replication is detectable, and patients show an active disease course characterised typically by fluctuations in levels of HBV replication and not infrequently, fluctuations in serum ALT. These patients are HBsAg positive and anti-HBe positive. HBV DNA concentrations are typically .10 5 copies/ml, but fewer than 10 8 copies/ml. Liver biopsy shows necroinflammation and varying stages of fibrosis. Sustained antiviral responses are difficult to achieve with this group after both interferon and nucleoside analogue therapy, but viraemia and necroinflammatory change are improved on treatment. 24 25 Inactive carrier state Patients with an inactive carrier state are characterised by a spontaneous remission in disease activity. These patients are HBeAg negative, anti- HBe positive with lower HBV DNA levels (,10 5 or 10 4 copies/ml), and little or no necroinflammation or fibrosis, depending on the timing of seroconversion. The disease may need to be a retrospective- prospective diagnosis as inactive carriers show some propensity to reactivation. The distinction between inactive carriers and anti-HBe positive patients who have progressive disease can be difficult without longitudinal follow up, particularly in endemic areas. Seroconversion to anti-HBe, occurring relatively late in patients who acquire the disease early in life, is not necessarily a marker of remission if accompanied by ongoing HBV replication. In HBeAg positive patients, progression to cirrhosis occurs at an annual rate of 2–5.5%, with a cumulative five year incidence of progression of 8 to 20%. Recurrent exacerbations and bridging fibrosis with severe necroinflammatory change characterise patients who are more likely to progress. The reported yearly incidence of hepatic decompensation is about 3%, with a five year cumulative incidence of 16%. In a European multicentre longitudinal study to assess the survival of 366 cases of HBsAg positive compensated cirrhosis, death occurred in 23% of patients, mainly from liver failure or hepatocellular carcinoma. The cumulative probability of survival in this cohort was 84% and 68% at 5 and 10 years, respectively. The worst survival was in HBeAg and HBV DNA positive subjects. 26 In population based Taiwanese studies, patients remaining HBeAg positive, and with continued HBV replication were more likely to develop cirrhosis and hepatocellular carcinoma. 27–29 RECENT ADVANCES IN CLINICAL PRACTICE 106 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 on 11 August 2008 gut.bmj.comDownloaded from ANTIVIRAL THERAPY FOR HEPATITIS B Treatment of acute hepatitis B Most icteric patients with acute hepatitis B resolve their infection and do not require treatment. Fulminant hepatitis B is a severe form of acute infection complicated by encephalopathy, bleed- ing, and liver failure. Subacute hepatic necrosis is characterised by a more protracted acute course and transition to chronic hepatitis with ongoing HBV replication. Patients with fulminant hepatitis (including acute and subacute forms) should be considered for liver transplantation if appropriate. Interferons are not used for the treatment of acute or fulminant hepatitis. There are no controlled trials of lamivudine, adefovir telbivudine, or entecavir for patients with acute fulminant or subacute fulminant hepatitis. However, uncontrolled reports suggest some efficacy of lamivudine in these patients, and, in the absence of randomised controlled clinical trials, lamivudine (the most studied) or another rapidly acting antiviral drug can be tried if there is evidence of ongoing HBV replication. 30–33 THERAPY OF CHRONIC HEPATITIS B The treatment of hepatitis B remains complex, with somewhat unpredictable responses. Current antiviral agents either inhibit hepatitis B replication, or invoke an immune response, which may be necessary but not sufficient to effect viral control. Indications Patients with mild disease and normal ALT may not require immediate treatment and should be monitored carefully at appropriate intervals. Most clinicians consider that treatment should be considered only if there is evidence of moderate to severe activity. HBeAg positive patients should be followed for a few months to ascertain their status, and antiviral therapy should be considered if there is active HBV replication (HBV DNA above 1610 5 copies/ml, (20 000 iu/ml) and raised ALT after observation, with a biopsy showing active hepatitis—that is, inflammation, necrosis, or accu- mulating fibrosis. HBeAg positive patients with greater disease activity may be more likely to seroconvert to anti-HBe within one year of treatment. HBeAg negative patients should be considered for antiviral therapy when the serum ALT is raised and there is active viral replication (HBV DNA above 1610 4–5 copies/ml (2000–20 000 iu/ml) and active hepatitis (inflammation, necrosis, or accu- mulating fibrosis). The threshold for treatment remains uncertain. Anti-HBe positive patients with normal ALT and low levels of DNA (,10 000 copies/ml, ,2000 iu/ml) should be monitored. No definite consensus criteria have been established for initiating treatment in this group. Indeed both HBeAg positive and HBeAg negative patients require careful and regular monitoring to ascertain a change in the pattern of disease. Many clinicians would consider a liver biopsy helpful for determining the degree of necroinflammation and fibrosis (fig 3). In many centres a Figure 1 Serological markers in the natural history of hepatitis B infection. Box 1 Hepatitis B c Hepatitis B virus causes a wide spectrum of disease c Treatment is indicated for fulminant and particularly chronic progressive disease c Treatment remains difficult to formulate for all patients c Three major forms of disease are recognised: – HBeAg positive chronic hepatitis – Anti-HBe positive chronic hepatitis – Anti-HBe positive inactive carrier state c The distinction between an inactive carrier state and anti-HBe positive disease requires longitudinal assessment. c Liver biopsy may be helpful in ascertaining the degree of inflammation and fibrosis RECENT ADVANCES IN CLINICAL PRACTICE Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 107 on 11 August 2008 gut.bmj.comDownloaded from biopsy would be considered to assess the stage and grade of inflammation, as hepatic morphology can assist the decision to treat. There are several established methods of scoring histology, measur- ing activity (necroinflammation) separately from stage (fibrosis). There are, however, several limita- tions of biopsy, including sampling error, subjec- tivity and reproducibility, and of course costs, risks, and discomfort to the patient. The activity of hepatitis B can vary over time but ultimately determines the prognosis and response to treatment, particular HBeAg seroconversion. Assessment of fibrosis measures how far the disease has progressed. Progression of disease in hepatitis B is not necessarily linear, but is influenced by episodes of activity. 34 Progression of disease is often punctuated by episodes of activity which are injurious to the liver. There is growing interest in the use of non-invasive methods, including serum markers and transient elastogra- phy, to assess hepatic fibrosis. Goals of treatment The major goals of treatment for hepatitis B are to prevent progression of the disease to cirrhosis, end stage liver disease, or hepatocellular carcinoma. If HBV replication can be suppressed, the accompanying reduction in histological chronic active hepatitis lessens the risk of cirrhosis and hepatocellular carcinoma. 35 Patients may request treatment to reduce infectivity. Extrahepatic manifestations of hepatitis B such as glomerulone- phritis or polyarteritis nodosa require treatment. The immediate objectives depend upon the stage of disease. If the disease has not progressed to cirrhosis then prevention of progression to advanced fibrosis or cirrhosis is desirable. If cirrhosis has developed then preventing decompensation or hepatocellular carcinoma or death is important. It may be somewhat more difficult to eliminate the risk of hepatocellular carcinoma in the short term. If decompensated disease is already present, it is important to attempt to rapidly reduce viral loads and to stabilise the disease. Suppression of HBV replication will improve synthetic function and a decrease the Child–Pugh score in patients who present with early decompensation. In some patients this may perhaps obviate the need for liver transplant. Lower viral loads enable liver transplantation, with a reduced risk of recurrence. End points The end points of treatment are not clearly defined, and differ in HBeAg positive versus negative disease (fig 2). It is reasonable to infer improvement in disease outcome if HBV replication is suppressed to fewer than 1610 4 copies/ml (2000 iu/ml), with an accompanying improvement in serum ALT and hepatic necroinflammatory disease. Newer potent agents are capable of suppressing most patients to fewer than 1610 3 copies/ml (200 iu/ml), or even to levels undetectable by current polymerase chain reaction (PCR) assays—that is, ,200 copies/ml (50 iu/ml), which may become the important benchmark. HBeAg positive disease In our current state of knowledge, antiviral treatment for HBeAg positive disease is directed to attaining loss of HBeAg and ideally, durable seroconversion to anti-HBe. In HBeAg positive disease reduction in HBV replication leads to an accompanying reduction in ALT. A reduction of HBV DNA concentrations to fewer than 10 4 copies/ml (2000 iu/ml) or preferably levels undetectable by sensitive PCR to levels of around 200 copies/ml (or 50 iu/ml) or lower within six months may enhance the rate of loss of HBeAg and reduce the rate of resistance. 36 37 Loss of HBeAg and associated suppression of viral leads to biochemical remission, histological improvement, and in a small percentage, loss of HBsAg. Histological improvement follows suppression of necroinflammatory disease. Figure 2 End points of antiviral response in HBeAg positive and negative patients. Figure 3 Active hepatitis B and cirrhosis. RECENT ADVANCES IN CLINICAL PRACTICE 108 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 on 11 August 2008 gut.bmj.comDownloaded from Loss of HBeAg and seroconversion to anti-HBe is a potential stopping point in HBeAg positive patients, although treatment with nucleoside analogues should be prolonged for at least six months after loss of HBeAg. Unfortunately a variable T cell response and antiviral resistance suggests that finite courses with such circum- scribed responses occur in only a minority of HBeAg positive patients, and the majority of patients still require long term maintenance suppressive treatment. Categorical analysis has not clarified what relative or absolute reduction in ALT and DNA predicts histological improvement and HBeAg seroconversion, and will alter the natural history of the disease, although there are some pointers. It not clear whether profound reductions in DNA (for example, 6–7 log 10 ) are critical for long term treatment. However, the rapidity and efficacy of HBV DNA reduction to fewer than 10 3 copies/ml or undetectable by sensitive PCR (,200 to 300 copies/ml) clearly has implications for the development of resistance and loss of HBeAg. HBeAg negative disease In anti-HBe positive disease (as such patients are already HBeAg negative), reduction in ALT and HBV DNA, and the accompanying reduction in cccDNA and histological improvement, are the end points. Stopping points and finite courses of treatment are less commonly achieved, because of higher rates of relapse in these patients, but progression can be halted if HBV DNA remains suppressed and resistance or relapse does not occur. Successful treatment with a nucleoside or nucleotide is characterised by a decline in HBV DNA to fewer than less than 10 4 copies/ml (,2000 iu/ml) or preferably to levels undetectable by sensitive PCR. Maintaining the response is the objective, defined by a low viral load during treatment. As for HBeAg positive disease, rapid lowering of viral load lessens the risk of developing viral drug resistance. ANTIVIRAL TREATMENT Two major groups of antiviral treatment are currently used. These include interferon alpha (IFNa, or PEG-IFNa) and nucleoside or nucleotide analogues. Approaches to treatment of hepatitis B Treatment can theoretically involve a finite course, continuous long term therapy (or indefinite suppressive therapy), or for many patients, a treatment course that is undefined at the start and will be dependent upon the initial response. There are major uncertainties in predicting whether monotherapy will suffice, or whether de novo or add-on combination therapies are necessary or more bene- ficial. Thus there are several treatment options for individual patients, making rational choices for first line and second line treatment somewhat difficult. 38 Several guidelines have been published, but these will require regular and frequent reassessment. 39–41 There are various major areas of dissent which have not been resolved (box 5). LICENSED AGENTS Interferons IFNa binds to cellular receptors and activates secondary messengers to initiate the production of multiple proteins which are pivotal for the defence of the cell against viruses. Their mechan- ism of action is complex. The antiviral effects of IFN include degradation of viral mRNA, inhibition of viral protein synthesis, and prevention of the viral infection of cells. The immunomodulating effects of IFN include enhancement of antigen presentation by HLA I and II to the immune system, activation of natural killer (NK) cells and other immune cells, and increased cytokine production. The main advantages of IFNa with nucleoside analogues are the absence of resistance and the possibility of immune mediated clearance of hepatitis B. 42–44 A meta-analysis of 15 randomised controlled trials in HBeAg positive patients showed a 33% HBeAg seroconversion rate after 16 weeks of IFNa treatment, compared with 12% in untreated control patients. 45 The incidence of HBsAg loss was 7.8% and 1.8%, respectively. The recommended regimen for HBeAg positive adult patients is 5 MU daily or 10 MU thrice weekly for four to six months. 46 Pretreatment factors predictive of response to IFNa are low viral load, high serum ALT, increased activity scores on liver biopsy, and shorter duration of infection. The HBeAg seroconversion rate correlates with baseline ALT values and reaches 30–40% for baseline ALT greater than five times the upper limit of normal. 47 An increase of ALT during the second or third month of treatment can be observed. HBV DNA suppression is the end point sought in HBeAg negative patients, who relapse fre- quently after IFNa treatment. Sustained response rates of 6–24% at 12–18 months after end of treatment have been reported. 48 49 For this reason the recommended duration of treatment is one year for this group of patients. Pegylated a2a interferon Pegylated forms of IFNa (PEG-IFNa) with improved pharmacokinetic profiles and more con- venient once weekly administration are licensed for the treatment of hepatitis C, and PEG-IFNa2a is licensed for the treatment of hepatitis B. The efficacy of PEG-IFNa2a in HBeAg positive and negative chronic hepatitis B has been established in two large pivotal trials; PEG-IFNa2b has also recently been shown to be active against HBeAg positive chronic hepatitis. 50 51 HBeAg positive patients A study in HBeAg positive patients compared treatment for 48 weeks with PEG-IFNa2a, PEG- IFNa2a plus lamivudine in combination, and lamivudine monotherapy. 50 At the end of 24 weeks RECENT ADVANCES IN CLINICAL PRACTICE Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 109 on 11 August 2008 gut.bmj.comDownloaded from of follow up, HBeAg seroconversion rates were 32%, 27%, and 19%, respectively. ALT normalisation occurred in 41%, 39%, and 28% of the same groups. HBeAg values higher than 100 iu/ml at weeks 12 and 24 were highly predictive of failure to achieve seroconversion. Conversely, low HBeAg values at baseline, week 12, and week 24 correlated with improved rates of seroconversion. The addition of lamivudine to PEG-IFNa2a has not improved seroconversion rates compared with PEG-IFNa2a alone. However, in HBeAg positive patients, a 27.2 log additive suppression of HBV DNA at the end of 48 weeks in patients with lamivudine plus PEG-IFNa2a was found, compared to a 24.5 log suppression of HBV DNA in patients treated with PEG-IFNa2a. Resistance to lamivudine was reduced. PEG-IFNa2b has also been shown to be active in HBeAg positive patients, with similar seroconversion rates. 51 There may be an effect of genotype and other baseline factors on response to PEG- IFNa2a in HBeAg positive chronic hepatitis B: patients with genotype A and B tend to respond better than patients with genotype C and D. HBeAg negative patients In a similar study of HBeAg negative patients, at the end of 48 weeks of follow up, HBV DNA fewer than 400 copies/ml was maintained in 17% of an observational subset of PEG-IFNa2a treated patients followed for three years post-treatment. 52 Baseline ALT and HBV DNA, patient age, sex, and infecting HBV genotype significantly influenced response at 24 weeks post-treatment. 53 HBsAg loss occurred in 8% of a longer term cohort after three years. Somewhat higher HBeAg (and HBsAg) seroconversion rates in HBeAg positive patients enhance the possibility of a finite course of treatment. Perhaps combination therapy with prolongation of treatment with an oral agent might consolidate the on-treatment response? 54 It will be interesting to observe patient choices for first line therapy, given the pros and cons of treatment with PEG-IFN vs nucleosides. Relapse rates remain relatively high after stopping 48 weeks of PEG-IFNa2a treatment in anti-HBe positive patients. Frequent side effects and the need to monitor patients closely are the main disadvantages of PEG- IFN treatment. There is no role for alpha interferon in the treatment of acute or fulminant hepatitis B. The role of interferon in patients with decompensated hepatitis B is more problematic, given their effect on platelets and neutrophils and their pro-inflammatory effects. Interferon should be used with caution and with regular monitoring in patients with compensated cirrhosis, as there is a risk of hepatic decompensation with prolonged treatment. 55 Moreover, the occurrence of serious bacterial infections has been reported in this group of patients. 56 NUCLEOSIDE ANALOGUES Nucleoside analogues have similar structures to the natural nucleotides and compete at the HBV polymerase catalytic site during the synthesis of viral DNA. They lack a hydroxyl group, preventing the formation of a covalent bond with the adjoining nucleotide, causing chain termination of the elongation of DNA. Although all nucleotide analogues act on HBV polymerase, their mechan- ism differs; thus adefovir inhibits the priming of reverse transcription, while lamivudine and emtricitabine inhibit the synthesis of the viral (2) strand DNA. 57 Entecavir inhibits three major stages of HBV replication. 58–61 Clevudine inhibits the elongation of the + strand DNA and has a weaker effect on priming, and may have additional effects of cccDNA. Nucleic acids in general are less effective against cccDNA formation after viral entry in the hepatocyte, and thus residual viraemia persists during antiviral treatment. 62–64 There are various new nucleosides and nucleotides in the pipeline. Thus the array of nucleosides may shortly include the licensed drugs (lamivudine, adefovir, entecavir, telbivudine), tenofovir, emtricitabine (licensed for HIV), as well as clevudine, elvucitabine, valtorcitabine, amdoxovir, racivir, MIV 210, b-L-FddC, alamifovir, and hepavir B. The patterns of response observed with nucleosides are broadly similar, although these agents have different structures and inhibit different phases of hepatitis B replication, including priming of reverse transcription, elongation of (2) strand DNA, DNA dependent DNA polymerase activity, and (+) strand synthesis. Nucleosides and nucleotides have variable mechanisms of action, and their pharmacokinetics, inhibitory capacity, onset of action, resistance patterns, and rates of HBeAg seroconversion vary during the first year of treatment. LAMIVUDINE Lamivudine (29,39-dideoxy-39-thiacytidine or 3TC) is a cytidine analogue. It competes with cytosine in the synthesis of the viral DNA. It is a (2) enantiomer, and a phosphorylation step is required for the transformation to active drug. The drug has a strong track and safety record, and reliably reduces HBV DNA concentrations in serum by 2– 4 log 10 . Raised serum ALT levels have likewise been shown to predict a higher likelihood of HBeAg loss in patients with chronic hepatitis B treated with lamivudine. Lamivudine is a relatively inexpensive drug, and the lack of side effects in patients with advanced disease is attractive. As a result it has become a widely used first line drug for the treatment of HBeAg and anti-HBe positive disease. The major disadvantage of lamivudine treatment is the high rate of resistance observed in both HBeAg and anti-HBe positive patients. Lamivudine resistance has been mapped to mutations in the tyrosine-methionine-aspartate-aspartate (YMDD) motif of the reverse transcriptase (rt) domain of HBV DNA polymerase. Lowering viral load may be RECENT ADVANCES IN CLINICAL PRACTICE 110 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 on 11 August 2008 gut.bmj.comDownloaded from associated with some restoration of CTL reactiv- ity. 65 Elimination of lamivudine occurs mainly by renal elimination and dosages should be adapted to creatinine clearance. Lamivudine in acute hepatitis B Although 95% of immune competent adults clear HBsAg spontaneously, lamivudine may play a role in acute HBV infection in preventing progression to fulminant hepatic failure. In small uncontrolled studies of patients with acute severe HBV, with an INR .1.5, raised bilirubin, and raised ALT, treatment with lamivudine 100 mg/day may have prevented death from fulminant hepatic failure. Lamivudine in chronic hepatitis B Lamivudine has been used for a more than a decade for the treatment of chronic hepatitis B with proven efficacy. This agent ushered in a new era of safe and effective oral agents active against hepatitis B. Much information has been gleaned from the early controlled trials of lamivudine and by the use of lamivudine as the control arm in trials of newer agents (tables 1 and 2). Longer term studies have also been informative. In HBeAg positive patients reductions in HBV DNA concentration, HBeAg seroconversion, ALT normalisation, and histological improvement observed after one year of treatment reach 44%, 17%, 41%, and 52%, respectively. 66 Pretreatment factors predictive of response are high baseline serum ALT levels and a high degree of histological necroinflammation. 67 68 Several factors, including genotype and the presence of cirrhosis, may predict the durability of response to lamivudine; higher rates of resistance have been reported in serotype adw (genotype A) than ayw (genotype D) (54% vs (8%). 69 Early viral suppression, in particular HBV DNA levels either below 200 copies/ml or under than 3 log 10 after six months of treatment predict a lower risk of resistance after one year of treatment. 70 71 In HBeAg negative patients after one year of treatment with lamivudine, HBV DNA became ‘‘undetectable’’ with a non-standardised assay in 70% of patients, serum ALT normalised in 75%, and histological improvement was noticed in 60. 72 However, the overwhelming majority of patients relapsed after treatment cessation. Long term lamivudine treatment can prevent complications of HBV related liver disease as long as viral suppression is maintained. 73 Thus liver disease progression can be prevented with a prolonged viral response but this response is attenuated in those with virological breakthrough (that is, resistance). There is wide experience of lamivudine in preventing chemotherapy associated exacerbations of hepatitis B. Lamivudine is effective in preventing reactivation, although this can be unpredictable. The argument for ‘‘deferred’’ or ‘‘pre-emptive therapy’’ is probably weighted in favour of early treatment and prolonged treatment. Resistance to lamivudine Lamivudine resistance is conferred through acquired selection of HBV with mutations of the YMDD motif of the HBV DNA polymerase gene. 74 Resistance to lamivudine emerges in higher rates in HIV-HBV coinfection, 75 and more rapidly in patients with HBV genotype A than genotype D during the first year of infection. 76 Variants emerging during lamivudine treatment show mutations in the viral polymerase within the catalytic domain (C domain), which includes the YMDD motif (for example, M204V or M204I), and within the B domain (such as L180M or V173L). These mutants have a reduced replicative capacity compared with the wild type virus. The common- est mutation is the substitution of methionine to isoleucine or valine (rtM204V/I) at the highly conserved YMDD motif of the reverse transcriptase. Four major patterns have been observed: L18OM + M204V; M204I; L180M + M204I; V173L + L180M + M204V; and occasionally L180M + M204V/I. The L18OM + M204V occurs most often. Although viral ‘‘fitness’’ may be reduced as lower levels of HBV DNA occur, recent studies have suggested that the disease may progress. 77 The incidence of lamivudine resistance is 15–20% per year, with 70% of patients becoming resistant after five years of treatment. Lamivudine resistance is accompanied by a breakthrough of HBV DNA levels and a subsequent rise of ALT, but this is variable. In patients with decompensated cirrhosis treated with lamivudine monotherapy, early detection of viral breakthrough is critical. A 1 log 10 rise of previously undetectable HBV DNA levels is taken as indicative of phenotypic resistance; adding adefovir before waiting for an ALT rise would be helpful for those patients (see below) Box 2 Goals of treatment c The major goal of treatment is to prevent progression to cirrhosis, end stage liver disease, or hepatocellular carcinoma c Extrahepatic complications require treatment c If cirrhosis has developed, then prevention of decompensation or hepatocellular carcinoma is important c If decompensated disease is present then the goal is to stabilise the disease, or lower viral loads before liver transplantation Box 3 End points of treatment c The end points of treatment differ between HBeAg positive and HBeAg negative disease c In HBeAg positive disease treatment is directed toward achieving HBeAg seroconversion – Treatment may be stopped at a point thereafter – Raised ALT levels predict a higher likelihood of HBeAg loss c In HBeAg negative disease, reduction in ALT, and HBV DNA and the accompanying histological improvement are the end points. c Stopping points and finite courses of treatment are difficult to achieve with nucleoside analogues RECENT ADVANCES IN CLINICAL PRACTICE Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 111 on 11 August 2008 gut.bmj.comDownloaded from In summary, the two main clinical concerns during lamivudine monotherapy are the emergence of viral resistance and withdrawal hepatitis flares. Patients who remain HBeAg positive are suscep- tible to flare with the development of resistance. After emerging of resistance, the clinical benefit of continuing lamivudine is doubtful, and resistance can be taken to imply treatment failure. Adefovir and tenofovir (and to a degree, entecavir) are active against lamivudine resistant hepatitis B, but it is advisable to continue lamivudine and adefovir in these patients, rather than replacing lamivudine with adefovir. Nonetheless the clinical course after the development of resistance is complex and variable. Hepatitis is common, but is not always severe. Most patients generally experience worsen- ing of liver disease. 77 The efficacy of lamivudine monotherapy is offset by the development of resistance, restricting its use as first line monotherapy—although monotherapy will suffice for three to five years in about one third of anti-HBe positive patients with low levels of replication. The value of lamivudine monotherapy is being questioned because of the likelihood of subsequent resistance to a lineage of drugs including entecavir, telbivudine, and possibly adefovir. Telbivudine shares cross resistance with lamivudine. 78 79 Clevudine and emtricitabine share also cross resistance with lamivudine, with mutations emerging at the C, B, and B domains, respectively. Lamivudine could form (as will other nucleosides with even lower rates of resistance) the backbone of maintenance combination therapies. Lamivudine resistance has typically been managed by sequential treatment with adefovir (or more recently entecavir), but the advantage of this strategy compared with de novo combination therapy is questionable. ADEFOVIR DIPIVOXIL Adefovir dipivoxil is an orally bioavailable prodrug of adefovir, a phosphonate acyclic nucleotide analogue of adenosine monophosphate. 80 Adefovir diphosphate acts by selectively inhibiting the reverse transcriptase-DNA polymerase of HBV by direct binding in competition with the endogenous substrate deoxyadenosine triphosphate (dATP). 81 Adefovir lacks a 39 hydroxyl group and, after incorporation into the nascent viral DNA, results in premature termination of viral DNA synthesis. Unlike other nucleoside analogues such as lamivudine, adefovir is monophosphorylated and is not dependent on initial phosphorylation by viral nucleoside kinases to exert its antiviral effect. Clearance of adefovir is by renal excretion. Adefovir pharmacokinetics are substantially altered in subjects with moderate and severe renal impair- ment (creatinine clearance ,50 ml/min). 82 83 Nephrotoxicity is the major side effect of higher doses of adefovir. Adefovir causes a proximal con- voluted tubule lesion characterised biochemically by Table 1 One year studies of PEG-IFN, entecavir, and telbivudine in HBeAg positive patients where lamivudine was the control arm Lamivudine 100 mg PEG-IFN Lamivudine 100 mg Entecavir 0.5 mg Lamivudine 100 mg Telbivudine 600 mg Number 272 214 355 354 463 458 Histological response* 38% 34% 62% 72% 56% 64% HBV DNA decline (log 10 ) 25.8 24.5 25.4 26.9 25.5 26.5 DNA negative (PCR){ 40% (5%){ 25% (14%){ 38% 69% 40% 60% ALT normal 39% (41%){ 62% (28%){ 60% 68% 75% 72% HBeAg seroconversion 20% (19%){ 27% (32%){ 18% 21% 22% 21% Resistance1 27% 4% 18% 0–2% 10% 3% Reference 48 83 The same definitions were used in the investigational drug and the lamivudine control arm. *Histological response was measured by varying methods. {PCR negatively was variously measured (typically ,200 to ,400 copies/ml). {Values in brackets are at the end of follow up. 1Resistance defined variously; the PEG-IFN study may have received lamivudine previously. ALT, alanine aminotransferase; HBeAg, hepatitis B ‘‘e’’ antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon. Table 2 One year studies of PEG-IFN, entecavir, and telbivudine in HBeAg negative patients where lamivudine was the control arm Lamivudine 100 mg PEG-IFN Lamivudine 100 mg Entecavir 0.5 mg Lamivudine 100mg Telbivudine 600 mg Number 181 177 286 296 224 222 Histological response* 40% 48% 61% 70% 66% 66% HBV DNA decline (log 10 ) 24.1 24.2 24.5 25.0 24.0 25.2 DNA negative (PCR){ 73% (7%){ 63% (19%){ 72% 90% 71% 88% ALT normal 38% (59%){ 73% (44%){ 71% 78% 79% 74% Resistance1 18% 1% 2% 8% 9% 2% Reference 50 83 The same definitions were used in the investigational drug and lamivudine control arm. *Histological response was measured by varying methods. {PCR negatively was variously measured (typically ,200–,400 copies/ml). {Value in brackets is the end of follow up. 1Resistance defined variously; the PEG-IFN study may have received lamivudine previously. ALT, alanine aminotransferase; HBeAg, hepatitis B ‘‘e’’ antigen; HBV, hepatitis B virus; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon. RECENT ADVANCES IN CLINICAL PRACTICE 112 Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 on 11 August 2008 gut.bmj.comDownloaded from a rise in urea and creatinine. However, in the two largest hepatitis B phase 3 trials involving 695 patients, no renal toxicity was found at the 10 mg dose. Adefovir in HBeAg positive disease The efficacy of adefovir has been assessed in patients with HBeAg positive and negative disease and other settings in the spectrum of chronic hepatitis B infection. Adefovir 10 mg daily resulted in significant improvement when compared with placebo: improvement in liver histology (53% vs 25%), reductions in HBV DNA (3.52 vs 0.55 log copies/ml), normalisation of ALT (48% vs 16%), and HBeAg seroconversion (12% vs 6%). There were no significant side effects and no resistance was found. As a result, adefovir 10 mg daily is the recommended and approved dose. A dose effect of 10 mg vs 30 mg in the pivotal phase III trial was apparent: 10 mg resulted in 3.5 log suppression of HBV DNA vs 4.5 log suppression by 30 mg at 48 weeks. The 10 mg dose was chosen because of the more favourable risk–benefit ratio, but this dose is not optimal for a proportion of patients. An increment in HBeAg loss and ALT normalisation can occur over time: 40% HBeAg seroconversion rates have been reported after three years of treatment. These incremental responses imply that continued treatment of HBeAg positive patients with an antiviral drug with a low rate of resistance leads to satisfactory HBeAg seroconversion rates that improve with time. However, a high proportion of patients in this analysis received a misallocation of drug, with interrupted therapy associated with flares in serum aminotransferases after the first year of treatment, and the data are based on Kaplan–Meier extrapolation of a subset of HBeAg positive patients who continued long term treatment. A variable proportion of patients, particularly HBeAg positive patients with a higher body mass index (BMI) and a high viral load, have slower and poor primary responses. In one analysis 25% of patients had a smaller than 2.2 log 10 reduction; the third quartile had a 2.2–3.5 log 10 reduction. These effects may be seen in routine clinical practice where worse compliance and a higher BMI may affect susceptibility to adefovir, resulting in poor primary responses. Adefovir in HBeAg negative chronic hepatitis B These patients require long term treatment to suppress viraemia. In the pivotal anti-HBe positive adefovir study 84 185 patients were randomised to placebo or adefovir 10 mg daily for 48 weeks. At 48 weeks the adefovir treated group had significant improvement when compared with placebo: improvement in liver histology (64% vs 33%), reduction in HBV DNA (3.91 vs 1.35 log copies per ml), an undetectable HBV DNA (,400 copies/ ml) in 51% vs 0%), and normalisation of ALT (72% vs 29%). No significant side effects compared with placebo were reported, and no genotypic resistance was found. Thus adefovir is an agent that has low rates of resistance and good long term viral suppression, which is of particular benefit in HBeAg negative HBV infection. Longer term results indicate that continued treatment with adefovir resulted in suppression of HBV DNA to levels of ,1000 copies/ml in 79% of patients after 144 weeks of treatment. Resistance mutations were noted in 5.9% of patients after 144 weeks. 85 HBV DNA concentrations were less than 1000 copies/ml in 67% of patients after 240 weeks. The cumulative probability of HBV polymerase mutations was 29%. Creatinine elevations were found in 3%. 86 It is important to identify patients with high levels of replication, or host factors, for whom adefovir monotherapy will not suffice. Many anti- HBe positive patients could be treated with adefovir monotherapy, as first line treatment is effective in this group. Long term therapy is required, and resistance has been reported but at lower rates than with lamivudine therapy. In other groups—such as HBeAg positive patients or anti- HBe positive patients with decompensated cirrhosis or high viral loads—rapid suppression of HBV DNA replication with a low risk of primary non- response or resistance is important, and combination therapies could be advantageous. Adefovir resistant mutations There are various structural differences between lamivudine and adefovir that predict lower rates of resistance with adefovir. 87 First, adefovir diphosphate more closely resembles its natural substrate deoxyadenosine triphosphate (dATP) than lamivudine, which contains an L-sugar ring. 88 In contrast to lamivudine, adefovir diphosphate has a minimal acyclic linker in place of the L-sugar ring that closely matches the D-sugar ring of dATP. This similarity between adefovir diphosphate and dATP means that a mutation in HBV DNA polymerase not binding adefovir diphosphate would also impair dATP binding. It also results in more flexibility, allowing the adefovir to bind lamivudine resistant HBV DNA polymerase without steric hindrance. 12 13 Second, because adefovir is monophosphorylated, it requires only two phosphorylation steps compared with three for lamivudine. Nevertheless, the development of resistant mutations has been reported with adefovir monotherapy in both HBeAg positive and HBeAg Box 4 Antiviral treatments for hepatitis B c There are two major groups of drugs – Interferon alpha (or pegylated interferon alpha) – Nucleoside or nucleotide analogues c Treatment can involve a finite course or indefinite maintenance suppressive treatment c In some with low levels of HBV replication, monotherapy may suffice, but for most, combination treatments could become the norm c Long term treatment with a single nucleoside analogue may lead to drug resistance. In some circumstances newer agents cause relatively low ratesof resistance RECENT ADVANCES IN CLINICAL PRACTICE Gut 2008;57:105–124. doi:10.1136/gut.2005.077891 113 on 11 August 2008 gut.bmj.comDownloaded from [...]... suppressive therapy of HIV and HBV will be required for HBeAg patients who fail to seroconvert, and for anti-HBe positive patients This should be factored in before starting treatment The timing of acquisition of HBV vs HIV will have a bearing on considerations about treatment HIV superinfection may occur in patients with chronic hepatitis B; alternatively, reactivation of hepatitis B may occur in an... the treatment of hepatitis B in HIV coinfected patients where treatment of HIV is not deemed necessary, as the drug has no effect on HIV at a dose of 10 mg/day, or for lamivudine resistant HBV For HIV HBV coinfection where treatment of HIV is necessary, tenofovir is the better option as it is active against both viruses Entecavir may have activity against both HIV and HBV VACCINATION Hepatitis B can be... management of hepatitis B is made more complex with coinfection with HIV HBV has little effect on the natural history or treatment on HIV infection; however, HIV and HIV treatment profoundly affect the natural history of HBV Therefore it is usually important to target treatment of HBV to alter the outcome and take into account the impact of HBV treatment on HIV Reactivation of hepatitis B may occur... Heathcote EJ, Hoofnagle JH Management of hepatitis B: 2000 – summary of a workshop Gastroenterology 2001;120:1828–53 Manesis EK, Hadziyannis SJ Interferon a treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B Gastroenterology 2001;121:101–9 Oliveri F, Santantonio T, Bellati G, et al Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type... 2004;189:1185–92 Lacombe K, Gozlan J, Boelle PY, et al Long-term hepatitis B virus dynamics in HIV -hepatitis B virus-co-infected patients treated with tenofovir disoproxil fumarate AIDS 2005;19:907–15 Nelson M, Portsmouth S, Stebbing J, et al An open-label study of tenofovir in HIV-1 and hepatitis B virus co-infected individuals AIDS 2003;17:F7–10 Benhamou Y, Tubiana R, Thibault V Tenofovir disoproxil... 2005;43:60–6 Korba BE, Schinazi RF, Cote P, et al Effect of oral administration of emtricitabine on woodchuck hepatitis virus replication in chronically infected woodchucks Antimicrob Agents Chemother 2000;44:1757–60 Lim SG, Ng TM, Kung N, et al A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B Arch Intern Med 2006;166:49–56 Kocic I Clevudine University of Georgia/Abbott/Bukwang/... and safety of newer potent agents such as entecavir, telbivudine, and tenofovir in this group, but these could be used Recurrent HBV infection in the transplanted liver has previously been a major problem Lamivudine for pre-transplant prophylaxis, in combination with hepatitis B immunoglobulin (HBIG), reduces the risk of graft infection to less than 10%, as long as the HBV virus is suppressed before transplantation... has not been established, but selection of resistant strains before surgery should be avoided Shorter courses of HBIG and other forms of prophylaxis, including adefovir in combination with lamivudine, are being studied Antiviral therapy for prophylaxis of recurrence post-transplantation probably requires life long continuation of treatment Pregnancy Recent studies suggest that lamivudine therapy of pregnant... vs 48% of those on lamivudine) (table 1) The mean log10 decline was –5.7 log in recipients of telbivudine vs –4.4 log in recipients of lamivudine In particular, HBV DNA was not detectable by PCR in 56% of the HBeAg positive patients receiving telbivudine vs 39% of those on lamivudine HBeAg seroconversion occurred in 30% at year 2; 70% had normal ALT No differences by HBV genotype B or C among HBeAg positive... whose level of HBV DNA at 24 weeks was 4 log10 (45% of HBeAg positive patients and 80% of the HBeAg negative patients treated with telbivudine had undetectable HBV DNA by 24 weeks of treatment) Limited follow up information suggests that patients may discontinue treatment after HBeAg seroconversion Responses are durable in approximately 80%.37 Other studies have been completed.133 Anti-HBe negative . of ongoing HBV replication. 30–33 THERAPY OF CHRONIC HEPATITIS B The treatment of hepatitis B remains complex, with somewhat unpredictable responses. Current antiviral agents either inhibit hepatitis. treatment of hepatitis B. The efficacy of PEG-IFNa2a in HBeAg positive and negative chronic hepatitis B has been established in two large pivotal trials; PEG-IFNa 2b has also recently been shown to be. 70% of patients becoming resistant after five years of treatment. Lamivudine resistance is accompanied by a breakthrough of HBV DNA levels and a subsequent rise of ALT, but this is variable.

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