Options of Antiviral Treatment

SILS 2009 - The 5th Seoul International Liver Symposium -

Symposium Ⅰ Debates on hepatitis B treatment

Options of antiviral treatment

Dong Joon Kim Department of Internal Medicine, Hallym University College of Medicine

Introduction

Since the landmark description of the Australia antigen by Blumberg and coworkers in 1965,1 active and pro- ductive hepatitis B research began and resulted in remarkable advances in our understanding of hepatitis B virus (HBV) infection and in development of means of its prevention. The development of hepatitis B vaccine has been one of the great medical achievements of the 20th Century. Subsequently approaches to treatment of hepatitis B were first attempted in the late 1970s and early 1980s, and by 1991, the first therapeutic agent for hepatitis B, recombinant human alpha interferon, was licensed. In multiple controlled trials, alpha interferon was shown to result in remission of disease in approximately one‐ third of patients. The availability of interferon was an important first step toward effective means of treatment of hepatitis B, but it was far from satisfactory. In 1998, lamivudine, the first effective oral nucleoside analog for hepatitis B, was approved. This important first step was followed by development of other nucleoside analogs with different and/or more potent activities. At present, six nucleoside analogs (including clevudine in Korea) and two forms of interferon are available as therapy for hepatitis B. Although there have been great advances in hepatitis B treatment, questions and controversies still remain. What are the benefits and risks of the current therapeutic options for hepatitis B? Which persons with hepatitis B should be treated? What measures are appropriate to monitor therapy and assess outcomes? And, most importantly, does therapy of hepatitis B alter its natural history and prevent its serious long term outcomes? These controversies and questions were recently addressed and published.2,3 The prevalence of HBV infection is uneven throughout the world, with significant burdens in Asia and the Pacific Islands, sub‐Saharan Africa, the Amazon Basin, and Eastern Europe. The major regional societies for the study of the liver disease including the Asia‐Pacific Association for the Study of the Liver (APASL), American Association for the Study of the Liver (AASLD), and European Association for the Study of the Liver (EASL) have published treatment guidelines for hepatitis B since the late 1990s. As new research data accumulated rapidly, those societies and several expert groups published new or revised guidelines and opinions. But these guidelines and opinions are not consistent in important points such as indications, options, and optimal endpoints of antiviral treatment,4‐8 and controversies and questions are still remain.

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Indications, options, and endpoints of antiviral treatment - an interconnected debates

The increase in more efficacious and safer treatment options, together with new knowledge on the natural history of chronic HBV infection, has expanded the indications for therapy in hepatitis B. The question is no longer “Who should be treated?” but “When should treatment be initiated?” Every person with chronic HBV infection is a potential candidate for treatment. The patient who is not a treatment candidate at the time of this presentation may become one in the future.9

Importance of the initial “watch and wait” policy Because current HBV treatments suppress but do not eradicate the virus, most patients require long term therapy and some may require life‐long therapy, which raise the important issues of drug resistance, adverse events, and costs. For these reasons, the decision to initiate treatment should also take into account the anticipated duration of treatment and the likelihood of achieving sustained virus suppression after a finite course of treatment. Deferring treatment, at least temporarily, in HBeAg‐positive patients who have elevated ALT levels without jaundice and compensated liver disease is important because spontaneous HBeAg seroconversion can occur at a rate of ~10% of patients per year. This ‘watch and wait’ strategy may be preferable to initiating immediate treatment, particularly in young patients who may have many years of therapy ahead of them. All patients who are not initiated on treatment should continue to be monitored so treatment can be started if and when the indication arises. On the other hand, treatment should not be deferred in patients with HBeAg‐negative chronic hepatitis, because the likelihood of sustained spontaneous remission is low.

The goals of antiviral treatment - what we know, what we don’t know The major goals of anti‐HBV therapy are to prevent the development of progressive liver disease, specifically cirrhosis and liver failure, and prevent the development of hepatocellular carcinoma (HCC) and subsequent death. To date, no conclusive evidence from RCTs of anti‐HBV therapy has demonstrated a beneficial impact on any of these primary clinical outcomes because cirrhosis, HCC, and death often do not occur for many years after infection with HBV and would therefore require long‐term evaluation of therapy to demonstrate benefit. As a consequence, most published reports of anti‐HBV therapy use changes in short‐term virologic, biochemical, and histologic parameters to infer the likelihood of longterm benefit. It is important to understand the limitations of this practice when assessing potential benefit. No RCTs of anti‐HBV therapies have demonstrated a beneficial impact on overall mortality, liver‐specific mortality, or development of HCC.2,3 For example, the Taiwan REVEAL‐HBV (Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer‐ HBV) Study found the risk was approximately six times higher for people with viral levels above 104 as compared to those with undetectable viral levels.10 This same study reported a similar association between viral level and risk of cirrhosis.11 But whether treatment‐induced decreases in HBV DNA levels are associated with improved clinical outcomes is less clear. Thus even in the setting of approved drugs, large, multicenter RCTs, including placebo‐controlled trials, of monotherapy and combined therapies with measurement of the effect of treatment on clinical health outcomes are needed.

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HBeAg‐positive vs. HBeAg‐negative chronic hepatitis B ‐ a false dichotomy?

Although several studies have reported a consistently higher rate of dreadful outcomes among individuals who are HBeAg positive compared to HBeAg‐negative,10‐15 it is difficult to assess the effect of the HBeAg independently. One study in Taiwan found that the incidence of HCC was 3.6 times higher in individuals who were HBsAg‐positive and HBeAg‐positive compared to those who were HBsAg‐positive but HBeAg‐negative.15 From the REVEAL‐HBV study in Taiwan, this increased risk of HCC (hazard ratio=2.6; 95% CI=1.6~4.2) and cirrhosis (hazard ratio=1.7; 95% CI=1.3~2.9) for HBeAg‐positive adults persisted following adjustment for age, sex, HBV viral level, and ALT level.10,11 A third large Taiwanese study also reported a twofold to three‐fold increased risk of HCC among adults with HBeAg‐positive chronic hepatitis B.13,14 On the other hand, HBeAg‐ negative chronic hepatitis B is generally associated with a more severe liver disease with a very low rate of spontaneous disease remission and a low sustained response rate to antiviral therapy.16‐18 One U.S. study that classified patients into “inactive carriers,” “chronic hepatitis,”or “cirrhotic” groups found that adults positive for HBeAg at baseline had similar rates of HCC and all‐cause death as adults with anti‐HBe at baseline.19 Thus, it is difficult to interpret the association between HBeAg status and clinical outcomes without adjusting for ALT and HBV DNA levels and classifying patients into immune tolerant, inactive carrier, or HBeAg‐negative but active carrier status. Because it is well known that inactive carriers have lower rates of clinical outcomes than those with chronic active hepatitis regardless of HBeAg status, the interesting research questions may be to determine the impact of HBeAg status in people with active hepatitis and the effect of HBeAg reversion on clinical outcomes. There are few studies that classified people into groups of inactive and active chronic hepatitis and then examined the effect of HBeAg within those groups.20

The current therapeutic options for hepatitis B and the long term outcomes

Our knowledge of the natural history of chronic HBV infection suggest that active HBV replication is key to subsequent clinical outcomes. HBV elimination or permanent HBV suppression by antiviral therapy should ‘theoretically’ be able to reduce the risk of or slow the progression of liver disease. Eight treatments are currently approved for chronic HBV infection: interferon (IFN), pegylated IFN (peg- IFN), lamivudine, adefovir dipivoxil, entecavir, telbivudine, clevudine, and tenofovir disoproxil fumarate. Among these, interferon and lamivudine have been used most extensively. A recent large study comparing 233 IFN‐treated HBeAg‐positive patients with 233 well‐matched untreated patients showed a reduced cumulative incidence of cirrhosis (17.8 vs 33.7%; p=0.041) and HCC (2.7 vs 12.5%; p=0.011) during a median follow‐up period of 6.8 (1.1~15.5) years.21 Studies also showed that sustained elimination of HBeAg was associated with a significant increase in survival.21,22 In HBeAg‐negative European patients treated with IFN for 6~24 months, sustained responders had significantly improved long‐term outcomes, including less severe cirrhosis related complications, reduced incidence of HCC (1.8 vs 10.5% in relapsers; p=

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0.027 and 7.7% in untreated; p=0.048), less need for liver transplantation, and lower mortality, although the sustained response rate in HBeAg‐negative patients was usually <30%.23‐25 A meta‐analysis of seven non- randomized‐controlled trials in cirrhosis patients (1,505 patients with 122 observed HCC cases) suggested that IFN therapy decreased the incidence of HCC. Although the difference was significant in only three trials, the pooled estimate was significantly in favour of the preventive effect of IFN therapy.26 Recently, it has been shown that IFN therapy in compensated cirrhotic patients is safe and even more effective than in noncirrhotic patients.27 A long‐term lamivudine (median, 89.9 months; range, 26.5~128.3 months) therapy involving 142 HBeAg‐positive, noncirrhotic patients from Hong Kong demonstrated a significantly lower cumulative rate of cirrhosis and/or HCC development (p=0.005) compared to 124 untreated controls.28 A double‐blind, randomized‐controlled trial demonstrated that maintenance lamivudine therapy for a median of 32.4 months in 436 patients with cirrhosis or advanced fibrosis significantly reduced overall disease progression compared to 215 untreated controls.29 Long‐term lamivudine therapy in 303 HBeAg‐negative patients with cirrhosis also showed that patients who maintained a virological response were less likely to show worsening of liver disease than those with viral breakthrough.30 The incidence of HCC was also significantly reduced (3.9 vs 7.4% in the placebo group, p=0.048) in the lamivudine‐treated patients with advanced fibrosis or cirrhosis.29 A retrospective multicenter study involving 656 HBeAg negative patients (353 with chronic hepatitis, 303 with liver cirrhosis) treated with lamivudine for 1~66 months (median, 22 months) also showed that HBV suppression reduced HCC development, even in patients with liver cirrhosis.30 However, long‐term lamivudine therapy was associated with a high rate of drug‐resistant mutations.28‐30 These patients were more likely to experience disease progression and to die due to the worsening of liver function.29 These results have proven the concept that suppression of HBV reduces the risk of or slows the progression of liver disease, and that resumption of HBV replication may restore the potential for disease progression. It is anticipated that long‐term therapy with peg-IFN, entecavir, or tenofovir would have similar or even better long‐term outcomes in the future. The establishment of management strategies capable of producing a better sustained or maintained HBV suppression without inducing drug resistance would be the ultimate goal in the management of chronic HBV infection.31

Pegylated interferon vs. nucleos(t)ide analogues - friend or foe?

Each category of treatment, IFNs or nucleos(t)ide analogs, has unique pros and cons. The advantage of IFN is that it is given for a defined course, is not associated with the development of antiviral resistance, and a higher likelihood for hepatitis B surface antigen (HBsAg) clearance. But the use of IFN is associated with more frequent side effects. Approximately 30% of HBeAg positive and 40% of HBeAg‐negative cases have a sustained virological response (when defined as HBeAg seroconversion and/or HBV DNA levels below 20,000 copies/mL, respectively) 6 months after completion of a 48‐week course of peg-IFN alfa‐2a. These responses remain durable in 80% and 50% of cases, respectively, when evaluated several years later. Currently, interferon is infrequently used for hepatitis B, having been replaced by the oral nucleoside analogs maily due to its con-

9 SILS 2009 - The 5th Seoul International Liver Symposium - venience and less side effects. But some authorities still advocate peg-IFN as first line therapy in selected cases, especially for younger patients with modest levels of HBV DNA, substantial ALT elevations, and favorable genotypes (A and B versus C and D [at least for peg-IFN alfa‐2b,32 not statistically for peg-IFN alfa‐2a33]), who have been identified as more likely to benefit from peg-IFN therapy. Nucleos(t)ide analogs are administered orally and are associated with more profound HBV DNA suppression than interferon. However, if prematurely discontinued, these drugs are associated with resurgence of HBV DNA levels or reactivation of hepatitis. In addition, long‐term use of nucleos(t)ide analogs is compromised by the development of resistance, and several of these drugs are associated with renal toxicity, myopathy, and mi- tochondrial toxicity.3 Although a finite 48‐week period of peg-IFN therapy results in a higher frequency of durable HBeAg and HBsAg responses during therapy compared to a year of oral agent therapy, some authorities advocate oral agents since with longer use, oral agents can equal (‘catching up’) and exceed the level of peg-IFN‐associated HBeAg serologic responses. For antiviral resistance which complicates oral agent therapy, they also claim that rescue therapy with a non‐cross resistant oral agent is almost always successful, and the new generation of antivirals (entecavir, tenofovir) has such a favorable resistance profile that IFN‐based therapy no longer has a measurable resistance advantage.34 The evidence available at this time does not permit concrete recommendations regarding selection of a partic- ular therapeutic course. Health care providers should discuss the risks and benefits of treatment options with patients to arrive at the best possible decisions.3

Pegylated interferon

There has been a resurgence of interest in IFN therapy over the past 5 years, largely based on results of large clinical trials demonstrating that peg-IFN has more potent antiviral activity than standard alpha IFN and, in contrast to nucleoside analogs, does not result in antiviral resistance and can be given for a finite period rather than indefinitely.

Clinical trials The efficacy of peg‐IFN alfa‐2a in HBeAg‐positive and ‐negative patients has been established in two large pivotal trials including 814 and 552 patients, respectively.35,36 In both studies, peg‐IFN alfa‐2a monotherapy, the combination of peg‐IFN and lamivudine, and lamivudine monotherapy were compared in a 48‐week treatment course. At the end of 24 weeks post‐treatment follow‐up, HBeAg seroconversion rates were 32, 27, and 19%, respectively, in the HBeAg positive study, and serum HBV DNA was <400 copies/mL in 19, 20, and 7%, respectively, in the HBeAg negative study. Recently, 4‐year follow‐up data were reported for a subgroup of patients of the HBeAg negative trial who agreed to enrollment in a long‐term follow‐up study.37 Interestingly, sustained off‐treatment response (HBV DNA <400 copies/mL) was maintained in 18% of patients treated with peg‐ IFN alfa‐2a. Importantly, HBsAg loss occurred with a high steady rate (more than 10% per year) in these patients. Recent data have demonstrated a better tolerability of peg‐IFN alfa‐2a in chronic hepatitis B compared with hepatitis C patients, with a lower incidence of common IFN‐related adverse events and a significantly lower incidence of depression.38

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In a multinational European study, peg-IFN alfa‐2b was given in a dose of 100 μg weekly for 32 weeks followed by 50 μg weekly until completion of 52 weeks of treatment with or without lamivudine (100 mg daily) to subjects who were HBeAg‐positive.32 Loss of HBeAg by 6 months after treatment occurred in similar proportions of patients receiving monotherapy as combination therapy (36% versus 35%: p=0.91) as did loss of HBsAg (7% versus 7%). These results suggested that a trial of a 1‐year course of peg-IFN might be appropriate in selected patients with chronic hepatitis B, before embarking on long‐term suppressive therapy with a nucleoside analog. Clinical trials of peg-IFN tend to emphasize its antiviral activity.32,35‐37 There are multiple indirect evidence, however, that immune regulation is important to its effectiveness. For example, loss of HBeAg and seroconversion to anti‐HBe with interferon treatment typically occurs weeks to months after the end of treatment, a feature which is consistent with prolonged immunological control over HBV replication. In addition, host‐de- rived flares of disease, characterized by marked increases in serum ALT levels, occur during treatment in 25~40% of HBeAg‐positive patients. These flares often have been associated with HBeAg seroconversion, and their magnitude appears to be important in overcoming high level viremia.39

HBsAg loss and seroconversion Loss of HBsAg was reported to occur in 3~7% of patients in the three large clinical trials of peg-IFN. HBsAg clearance has occured less commonly in HBeAg‐negative hepatitis, reflecting the generally lower rates of sustained virological response with this disorder and perhaps differences in immune features and duration of infection compared to HBeAg‐positive hepatitis. Prolongation of treatment in HBeAg negative hepatitis beyond 48 weeks may be more effective in achieving sustained virological response and HBsAg clearance, but this has not been systematically studied.

Predictors of response Multivariate analysis from the registration trial for peg-IFN alfa‐2a has confirmed that higher baseline ALT levels and lower baseline HBV DNA concentrations (<109 copies/mL) are predictive of HBeAg seroconversion with treatment. In a study using peg-IFN alfa‐2b in combination with lamivudine, patients with lower baseline intrahepatic HBV cccDNA levels and lower serum HBsAg levels, but not necessarily lower serum HBV DNA levels, were more likely to achieve a sustained HBeAg seroconversion.40 Baseline predictors of sustained virological response are less well‐defined for patients with HBeAg‐negative chronic hepatitis B, but younger age, female sex, higher baseline ALT levels, lower baseline HBV DNA concentrations, and HBV genotype are predictive of a combined virological and biochemical response.41

Response according to viral genotype A large study from Taiwan found associations of 3~6 folds increased risk of HCC among people with HBV genotype C compared to people with genotype B.42 In a large study from Hong Kong, HBV genotype C was associated with only a modest increased rate of HCC (1.5 folds; 95% CI=1.2~2.0) compared to genotype B after accounting for age, sex, cirrhosis, viral DNA level, and albumin.43 In patients treated with peg-IFN alfa‐2b, the highest rate of HBeAg clearance at the end of follow‐up occurred in patients infected with genotype A (47%), followed by genotype B (44%), C (28%), and D (25%).32

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The data evaluating the relationship between genotype and virological response in HBeAg‐positive patients treated with peg-IFN alfa‐2a were not as robust (52% HBeAg seroconversion with HBV genotype A vs. 32% as a whole), because 93% of those enrolled had non‐A genotypes.36 The relationship between response to peg-IFN and genotype is less well‐defined in HBeAg‐negative hepatitis B. An analysis of a large patient population treated with peg-IFN alfa‐2a also indicated that individuals infected with genotypes B or C had a higher chance of response than those with genotype D (p< 0.001).35 Taken together, the data provide compelling support for the fact that genotype A is the most treatment‐responsive genotype in HBeAg‐positive hepatitis B. Genotype A is relatively uncommon in patients with HBeAg‐negative cases, but non‐D genotypes, particularly C, appear to have higher rates of sustained virological response in this form of chronic hepatitis B.39 Thus, genotype may play a role in selecting first‐line therapy in areas where genotypes A or D are prevalent but does not influence therapeutic decision where genotypes B and C are common.33 Moreover, genotype itself cannot predict response in individual patients. So genotype should not be the sole factor in making the decision between peg‐IFN and nucleos(t)ide analogs.7,33

On‐treatment HBsAg concentration as an indicator of response One of the more unique and interesting associations has been with serum HBsAg concentration during treatment. Data from several small studies that included serial monitoring of serum HBsAg concentration provide some evidence that a decline in HBsAg concentration can be helpful in predicting response.44‐46 It can be especially helpful in HBeAg‐negative hepatitis, because reliable treatment endpoints that correlate with a durable response have not been established. In a study of 48 patients with HBeAg‐negative hepatitis B, a 1‐log decline in HBsAg concentration at treatment week 24 of peg-IFN alfa‐2a had a 97% negative predictive value for a sustained virological response.44,47 In 356 HBeAg negative patients treated with peg-IFN alfa‐2a, alone or in combination with lamivudine, a reduction in HBsAg concentration was found to also predict HBV DNA levels of fewer than 400 copies/mL 6 months after treatment. End‐of‐treatment HBsAg levels of less than 10

IU/mL or an on‐treatment reduction in HBsAg levels of >1 log10 IU/mL was significantly associated with durable HBsAg clearance for 3 years after treatment. In contrast, HBV DNA levels at the end of treatment were not predictive of a sustained response, and HBsAg levels remained essentially unchanged in the group treated with lamivudine alone.47

Durability of response Long‐term follow‐up studies using standard alpha IFN or peg-IFN have convincingly shown that HBeAg loss and seroconversion is sustained in at least 80% of patients followed for a mean of 3~6 years after the end of treatment.39 But less favorable long‐term responses have been reported in Asian patients who have undergone IFN‐induced HBeAg seroconversion.48 A higher rate of relapse has been associated with HBeAg‐negative hepatitis after standard alpha IFN or peg-IFN treatment. A large cohort of patients treated with peg-IFN alfa‐2a (230/356) has been followed for an average of 4 years after treatment, and sustained virologic response occurred in 43% of patients. However, this response was durable in only 25% up to slightly more than half of the initial responders at the 4‐year interval.37

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A unified treatment management strategy33 A course of peg‐IFN may be the most appropriate first‐line treatment strategy in young patients in order to give them a one in three overall chance of sustained response. If seroconversion is not achieved with peg‐IFN, longer‐term treatment with nucleos(t)ide analogues could be a fall‐back strategy. Considering that there are currently no evidence‐based recommendations regarding when to stop nucleos(t)ide analogue therapy should HBeAg seroconversion occur, although reports suggest that 6~12 months appears prudent, judicious use of nucleos(t)ide anlogs to young patients can not be overemphasized. A basic algorithm to improve clinical outcomes is proposed. In appropriately selected patients, im- munomodulatory therapy of finite duration with (peg‐)IFN should be the firstline treatment of choice. For those who do not achieve sustained remission, treatment of longer duration with nucleos(t)ide analogues should be instigated as a second choice.

Nucles(t)ide analogues

Oral nucleos(t)ide analogs have revolutionaized the management of chronic hepatitis B. Six nucleos(t)ide analogs (including clevudine in Korea) have been approved at present.

Clinical trials In the registration trials, lamivudine, adefovir dipivoxil, and clevudine were compared to placebos while the other approved agents were compared to an active agents―entecavir and telbivudine against lamivudine, and tenofovir disoproxil fumarate against adefovir. In the registration trials for entecavir, telbivudine, and tenofovir, these agents were superior to the active comparator (lamivudine, adefovir) in virological, biochemical, and his- tological, but not serological, endpoints. Interestingly HBeAg loss or seroconversion is relatively uniform (~20%) regardless of drugs used.49‐56

Clinical use in decompensated liver cirrhosis Most importantly, these oral agents can not only retard the progression of fibrosis and reverse both fibrosis and cirrhosis,57,58 but also salvage patients with decompensated chronic hepatitis B,59,60 and prevent hepatic de- compensation in patients with advanced fibrosis and cirrhosis. Since the adoption of widespread nucleoside analog therapy, the number of patients per year registered in the United States as candidates for liver transplantation has fallen by a third.61

HBsAg loss or seroconversion Loss of HBsAg during a year of oral‐agent therapy is limited, but extending therapy for a second year and beyond with the most potent agents can yield frequencies of HBsAg responses close to those reported in trials of interferon based therapy.34,55,62

Resistance rates and preference - idealism vs. realism Current use of lamivudine is limited by the high frequency of lamivudine resistance (up to 30% in year 1

13 SILS 2009 - The 5th Seoul International Liver Symposium - and up to 70% by the end of 5 years).63 In an ideal world, expense is not a consideration when selecting treatments. Unfortunately, not all patients have equivalent access to treatments in terms of cost. Despite the high rate of resistance development, lamivudine is frequently prescribed in many Asian and sub‐Saharan coun- tries as a result of cost savings compared with other nucleos(t)ide analogues. Although resistance to adefovir is slow to emerge, resistant variants increase progressively after the first year, reaching almost 30% by the end of 4 years.64 The advantages of adefovir are the absence of cross‐resistance with lamivudine and other L‐nucleosides. It therefore has value as treatment for lamivudine‐resistant chronic hepatitis B.65,66 The high potency and excellent safety profile of entecavir are complemented by its very high barrier to resistance in treatment‐naïve patients: negligible (≤1%) for up to 4 years.67 At a double dose of 1 mg, entecavir is also active against and approved for use in lamivudine‐resistant HBV;68 however, in patients with pre‐existing lamivudine resistance, entecavir resistance emerged in 7% by the end of year 1 and in 43% by the end of year 4.67 The frequency of antiviral resistance to telbivudine at 1 year was 5% in HBeAg‐positive patients and only 2% in HBeAg‐negative patients.52 By the end of year 2, however, resistance emerged in 25% of HBeAg‐positive patients and in 11% of HBeAg‐negative group.69 Among the six oral agents, based on superiority in efficacy and resistance profile, entecavir and tenofovir have been recognized as the best agents to use as first‐line therapy, eclipsing lamivudine, telbivudine, and adefovir.4‐7

Tenofovir Tenofovir is a nucleotide analogue differing from adefovir in the presence of one methyl group. It was approved for the treatment of HIV in 2002 and HBV in 2008. Recent data from pivotal large randomized comparative trials have shown that 300 mg daily of tenofovir is associated with impressive rates of viral suppression at 48 weeks of therapy in HBV‐monoinfected patients. In these studies, 76% of HBeAg positive patients and 93% of HBeAg‐negative patients had undetectable HBV DNA after 48 weeks of tenofovir therapy, compared to only 13% and 63% of HBeAg‐positive and HBeAg‐negative patients, respectively, for adefovir. An important finding was HBsAg seroconversion in 3% of patients during the first 48 weeks of therapy in the tenofovir group. But tenofovir and adefovir treatment resulted in similar rates of HBeAg seroconversion (21% vs. 18%).55 No genotypic resistance or viral breakthrough related to resistance were seen in either group of patients receiving tenofovir. Recent 96‐week data demonstrated HBV DNA undetectability in 79% and 91% of HBeAg‐positive and HBeAg‐negative patients, respectively, without resistance.70,71 In the HBeAg‐positive group, at the end of year 2 of continuous tenofovir treatment, HBsAg loss increased to 6%.

Clevudine Clevudine was approved for use only in Korea. A distinguishing characteristic of clevudine over other oral agents is the long delay in return of baseline HBV DNA levels after cessation of therapy. On the other hand, HBeAg seroconversion occurred in only 8% of test subjects (vs. 9% in placebo recipients).56, 72 In fact, reductions of cccDNA occur, paralleling declines in serum HBV DNA, during treatment with all antiviral drugs and during spontaneous reductions in HBV replication (e.g., during spontaneous HBeAg responses); to date, no anti-

14 SILS 2009 - The 5th Seoul International Liver Symposium - viral agent has been documented to be superior to others in lowering cccDNA, and none has eradicated cccDNA.34 Resistance to clevudine has not been observed in some trials, whereas in others, resistance has emerged in up to 10% of patients during a year of clevudine therapy. To date, clevudine has not been observed to achieve improvements over already approved antivirals in the traditional clinical endpoints measured during clinical trials. Clinical trials in which clevudine is being compared to adefovir, the least potent of the oral agents, are in progress.34

Durability of response The ‘consolidation’ treatment for 6~12 months after HBeAg seroconversion leads to a durable response in ~80% of western patients,73 but durability of HBeAg responses has been reported to be substantially lower in Asian populations.74 In a recent report, the level of pretreatment baseline HBV DNA was predictive of relapse versus durability after lamivudine treatment.75 In 71 Asian subjects with lamivudine‐associated HBeAg seroconversion, relapse after treatment occurred in only 11% (durability 89%) in patients with a baseline HBV DNA of ≤108 copies/mL but in as many as 44% (durability 56%) in those with baseline HBV DNA levels of >108 copies/mL. Potentially, the difference in baseline HBV DNA could account for the discrepancies in reported durability of HBeAg seroconversion between western and Asian populations. In contrast, in HBeAg‐negative chronic hepatitis B, a year of treatment almost always results in a posttreat- ment relapse after withdrawal of therapy. Thus, durable responses are the exception rather than the rule in the majority of patients treated with oral agents; almost all HBeAg‐negative patients and ~80% of HBeAg‐positive patients who do not achieve HBeAg seroconversion do not sustain their responses when treatment is discontinued.34

Combination therapy - fact or fantasy?

Rationale of combination therapy Combining drugs with different targets and mechanisms of action may achieve synergistic or additive antiviral effects compared with single drug therapy. Additionally, combinations of drugs without cross‐resistance can delay or prevent the emergence of drug resistant mutants, a paradigm well established in other chronic viral infections. The ideal combination therapy would target different aspects of HBV replication using agents that have no cross resistance. Interferon has both antiviral and immune‐modulating effects. Currently, all of the approved oral drugs for hepatitis B target the HBV polymerase and have very similar mechanisms of action. Combining drugs with the same mechanism of action may lead to drug interference rather than synergy, or other adverse effects.76

Current indications for combination therapy The societal treatment guidelines recommend the use of combination therapy in a limited number of patient subgroups, including those with decompensated cirrhosis, those with HIV/HBV coinfection on antiretroviral therapy, and patients after liver transplantation. These recommendations are not based on results of randomized

15 SILS 2009 - The 5th Seoul International Liver Symposium - controlled, prospective trials but rather upon small case series and the recognized risk of rapid disease progression in the absence of controlled HBV replication in these patient populations.77 Combination therapy is also recommended for patients with evidence of drug resistance to minimize the risk of multidrug‐resistant HBV with sequential monotherapy.78

Combination therapy in treatment‐naïve patients There is insufficient evidence to recommend combination therapy as first‐line therapy for all patients with chronic hepatitis B. There have been four randomized controlled trials evaluating combined peg-IFN and lamivudine and one evaluating peg-IFN and adefovir compared to each one of these agents.32,35‐37,79 The studies were consistent in their findings. peg-IFN (with or without lamivudine) was superior to lamivudine monotherapy, but there was no advantage to combination therapy over use of peg-IFN alone. Interestingly, the decline in HBV DNA levels during treatment was greater with combination therapy compared to peg-IFN alone or lamivudine alone, however, these differences did not translate into higher rates of HBeAg seroconversion or HBsAg loss. In terms of preventing lamivudine resistance, the combination of peg-IFN and lamivudine was associated with significantly lower rates of genotypic resistance at the end of 48 weeks of treatment compared to lamivudine alone; nevertheless, lamivudine resistance was not completely prevented.76 Combinations of analogues may decrease the long‐term risk of resistance but did not show increased antiviral efficacy and increased seroconversion rates.80‐82 Nonetheless, these studies revealed little additive or synergistic antiviral effects of combination nucleoside analog therapy over monotherapy. These data are limited in several ways. First, combination therapy has been shown to reduce the rate of drug resistance in chronic hepatitis B, but only when drugs with a low barrier to resistance are used (lamivudine, defovir). Combination therapies may achieve greater degrees of HBV DNA suppression, but this has not been associated with higher rates of seroconversion (HBeAg or HBsAg) compared to single drug therapy. The benefit of combination therapy has yet to be demonstrated with agents that are associated with a high barrier to resistance (tenofovir, entecavir). Additionally, the studies of combination nucleoside analogs were of small sam- ple size, of relatively short duration, and were underpowered to detect small‐to‐moderate treatment differences. Lastly, one treatment strategy has predominated, namely combination therapy starting and ending at the same time. Few studies have examined alternative combination approaches. Evaluation of the possible role of a limited course of peg-IFN in combination with long‐term nucleoside analog therapy, compared to long‐term therapy with the nucleoside analog alone, calls for future research. Fortunately, at least some of these questions will be addressed by clinical trials that are currently planned or underway (see the registry at www.clinicaltrials.gov).76 Despite the lessons drawn from the antiretroviral therapy of HIV infection, the situation in chronic hepatitis B treatment is clearly different. Indeed, the antiretroviral drugs belong to several different classes of compounds that target different steps of the viral life cycle (nucleos(‐t)ide and non‐nucleos(t)ide reverse‐transcriptase inhibitors, protease inhibitors, integrase inhibitors and fusion inhibitors). By contrast, in the setting of chronic hepatitis B, antivirals belong to the same class of nucleos(t)ide analogues and target only the viral polymerase. This might be the reason why the combination of nucleoside analogues did not show any additive effect in terms of viraemia decline compared with the most potent antiviral drug in the combination.83

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The benefit of combination therapy is difficult to demonstrate in short term trials. An urgent priority is to identify the patients who have the highest risk of resistance (e.g. long‐standing infection and high viraemia levels associated with more complex viral populations before therapy, together with high ALT levels that are associated with a more rapid hepatocyte turnover that in turn generates a wider replication space).83 And an important group for preferred use of combination therapy concerns the patients who can least afford to develop antiviral drug resistance from a clinical perspective (e.g. patients with liver cirrhosis and/or with HBV re- currence after liver transplantation). Also, trials comparing combination therapy vs. monotherapy followed by early add‐on therapy in case of a partial response should be evaluated as soon as possible in these patient groups.83

New treatment strategies - 2009 EASL guidelines

The AASLD Practice Guidelines recommend that antiviral therapy initiation depends on the HBeAg status, presence of cirrhosis, elevated level of ALT, and serum HBV DNA levels (>2,000 IU/mL vs. >20,000 IU/mL).4,84 This lower threshold HBV DNA level was ‘chosen’ on the basis of population‐based studies which showed that high levels of HBV DNA is a strong predictor of disease progression.10,11 However, the efficacy of antiviral therapy in preventing clinical outcomes, which depends on serum HBV DNA, has not been established. A threshold ALT level of two times the upper limit of the normal range (ULN) has been recommended, based on the ‘assumption’ that the ALT level is a reliable marker for necrosis and inflammation in the liver. The primary drawback of using serum ALT as a marker of treatment response is its limited predictive value and the fact that serum ALT alone does not suffice as a marker for disease activity. As new data become available, the cutoff for ALT and HBV DNA values for initiating treatment should be revised. These values should be set at a lower level for older patients who may have been infected for a longer period. The AASLD Practice Guidelines recommended different approaches for patients who are HBeAg‐positive and HBeAg‐negative. Although HBeAg status can influence treatment decision in several ways, known natural history of chronic HBV infection shows that HBeAg status is closely related with HBV DNA level, and there is little solid evidence which validated different indication for initiation of treatment based on HBeAg status. The 2009 EASL Guidelines7 differ from other guidelines in several important points (Table 1, 2). These changes are introduced to reach the new therapeutic goal more efficiently. The important changes are: first, HBeAg positive and negative patients have not been divided separately; second, HBV DNA level ＞2,000 IU/mL is uniformly applied to both HBeAg positive and negative patients as an indication of treatment; third, serum ALT level as an indication of treatment is lowered to >ULN; fourth, the primary non‐response is defined at 3 months of therapy; fifth, virologic responses are defined separately depending on the drug; and sixth, the definition of partial virologic response depends on the drug and are introduced separately, as a guide of ‘early adaptation of a treatment strategy’.

Primary non‐response

The failure to achieve a 1 log10 copies/mL decline in viral load after 12 weeks of therapy is considered as a primary non‐response. It indicates that either there is a compliance issue or the medication does not exhibit

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Table 1. Comparison of the indication for treatment

Table 2. Definitions of response7

its antiviral activity in a given patient. When a primary non‐response is identified, antiviral treatment should be modified.

On‐treatment milestones (partial response) and their predictive value Serum HBV DNA level and its decline at various time points during antiviral therapy are likely to play an important role in dictating the course of therapy. Recent studies suggest that early viral kinetics during antiviral therapy may predict the likelihood of sustained virological response in chronic hepatitis B, as it does in chronic hepatitis C. The Globe Study Group evaluated 1370 patients with chronic hepatitis B, randomly assigned to receive telbivudine (600 mg daily) or lamivudine (100 mg daily).52 During therapy, patients with undetectable serum HBV DNA at 24 weeks had an HBeAg seroconversion rate of 41% at 1 year, compared to just 4% in those with

HBV DNA in excess of 4 log10 copies/mL. Resistance rates for the same groups at 1 year were 2% and 15%, respectively.85,86 In multivariate analysis, undetectable HBV DNA at week 24 was the best predictor of clinical and virological efficacy (independent of HBeAg status). These findings have been confirmed by several smaller studies. In 56 patients receiving adefovir therapy after the development of lamivudine resistance, 87% of patients who experienced a decline in serum HBV DNA by more than 3 logs10 at 3 months lost HBeAg, as compared to only 24% of patients who had less than a 3 log10 decline.87 A study evaluating the predictive value of HBV DNA levels at numerous time points during lamivudine therapy found that HBV DNA levels at week 4 (<2,000 IU/mL) and week 16 (<800 IU/mL) were the best predictors of a combined endpoint of anti‐HBe seroconversion.88 In a study of 66 patients receiving peg-IFN and lamivudine (with the majority starting peg-IFN 8 weeks prior to lamivudine), receiver operating characteristic (ROC) curves were used to identify predictors of sustained response. The area under the ROC curve for HBV DNA level was greatest at week 8 and yielded a negative predictive value of 92%, meaning that patients without early virological response were highly unlikely to experience sustained response.89 Of great

18 SILS 2009 - The 5th Seoul International Liver Symposium - concern is the fact that patients who do not experience early and significant HBV DNA suppression are far more likely to develop nucleoside antiviral resistance. In one study, patients with serum HBV DNA levels in excess of 103 copies/mL after 6 months of lamivudine therapy had a 63% chance of developing YMDD‐resistance mutations.90 Although these data do not yet permit definitive decisions regarding treatment duration based on early virological response, they highlight the importance of assessing early predictors of sustained virological response in large prospective clinical trials. A group of expert hepatologists recently proposed a “roadmap” for antiviral therapy based on early on‐treatment response.5 The proposed roadmap applies to patients receiving nucleoside analogs, but an analogous approach may offer a stopping rule for peg-IFN. The applicability of the current roadmap to entecavir and tenofovir, which have excellent suppressive efficacy and little long‐term resistance to date, is unclear.91 The timing of treatment adaptation depends on the drug used and on the kinetics of viral load decay, especially in patients starting from a very high viral load who may need additional weeks of therapy to reach the threshold of 1,000 copies/mL. If viral load is still detectable after 48 weeks of therapy and viral load evolution shows a continuous decline, therapy may be continued until the next check point. By contrast, if the kinetics show a plateau level of viral load, then antiviral treatment should be adapted to prevent the emergence of resistance.83 Adefovir dipivoxil was shown to suppress viraemia levels with a slower effect in comparison with other nucleoside analogues, i.e. lamivudine, entecavir or telbivudine. Therefore, the week 48 time point may be used for predicting resistance to adefovir dipivoxil therapy.87

Early adaptation of a treatment strategy For patients treated with nucleoside analogs, it is recommended that antiviral response to treatment be evaluated at specific intervals and changes in therapy made in those with a ‘suboptimal’ virological response.4‐7 The guidelines indicate that this change in drug therapy can either be ‘add on’ (i.e., adding the second agent result- ing in combination therapy) or a ‘switch’ (i.e., switching to alternative single drug) where the complementary crossresistance profile should be considered (Figure 1, 2).

Adding versus switching nucleoside analogs in therapy for patients with a suboptimal antiviral response There have been no studies addressing the issue of whether add‐on (combination) therapy versus switching to an alternative monotherapy is preferable in patients with a suboptimal initial virological response to a single

figure 1. proposed treatment algorithm of hbv infection. chb, chronic hepatitis b; lc, liver cirrhosis; pegifn, pegylated interferon; nuc, nucleos(t)ide analogue

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Figure 2. Proposed ‘early adaptation’ of treatment strategies and treatment monitoring of HBV infection. PegIFN, pegylated interferon; NUC, nucleos(t)ide analogue; 1°NR, primary non‐response; VR, virological response; PVR, partial virological response; LAM, lamivudine; LdT, telbivudine; ETV, entecavir; TDF, tenofovir. nucleoside analog. In a small study of 79 patients (~60% lamivudine‐experienced) with suboptimal responses to adefovir therapy, patients were randomized to receive tenofovir (switch, N=39) or tenofovir plus emtricitabine (add, n=40). At the end of 48 weeks of treatment, the proportion of patients with undetectable HBV DNA levels was the same in patients receiving combination versus tenofovir monotherapy (81% in both groups).92 In another small study of 69 HBeAg‐positive patients with suboptimal response to adefovir, those who switched to telbivudine was evaluated compared to those continuing adefovir. None of the patients switching therapy developed virologic breakthrough during the study period.93 Finally, in the registration trials for tenofovir, patients initially randomized to adefovir were switched to tenofovir at week 48. Of the 125 patients who were initially treated with adefovir but continued to have HBV DNA levels above 400 copies/mL, suppression of HBV DNA to undetectable levels was achieved in 75% of 90 HBeAg‐positive and 94% of 35 HBeAg‐negative patients 24 weeks after the change to tenofovir monotherapy.94 Thus, based on the current understanding of factors influencing treatment failure, the add‐on strategy may be preferred if the initial drug has a low genetic barrier to resistance and/or if the time from initiation of therapy to change is prolonged, such that resistance mutations are likely to have been selected. However, switching to an agent with a higher genetic barrier to resistance may be more effective than adding a second agent with a low genetic barrier to resistance.76 Regardless of whether an add‐on or switch of therapy is undertaken, the subsequent drug used should be one without cross‐resistance to the first drug.4‐7,76

Conclusions

During the past 45 years, there have been remarkable advances in our understanding of hepatitis B virus infection and in the development of means to prevent and treat HBV infection. Still, many questions and controversies remain. Some of those are: Which persons with hepatitis B should be treated? What are the optimal

20 SILS 2009 - The 5th Seoul International Liver Symposium - therapeutic options for hepatitis B? What measures are appropriate to monitor therapy and assess outcomes? And, most importantly, does therapy of hepatitis B alter its natural history and prevent its serious long term outcomes? To answer these questions and controversies, clearer and widely accepted definitions and evaluation methods of response should be established first. Also, ‘adaptation’ therapy depending on response should be extensively examined and verified. With these developments, we can afford the ‘individualized and tailored’ therapy over the ‘one‐size‐fits‐all’ therapy in the near future.

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through in patients receiving prolonged lamivudine therapy. Hepatology 2001;34:785‐791. 91. Andersson KL,Chung RT. Monitoring During and After Antiviral Therapy for Hepatitis B. Hepatology 2009;49:S166‐ S173. 92. Berg T, Moller B, Trinh H, Chan S, et al. TDF vs TDF _ FTC for treatment of CHB in patients with persistent viral replication receiving ADV [Abstract]. In: Proceedings of the 43rd Annual Meeting of the European Association for the Study of the Liver, Milan, Italy, April 23‐27, 2008. Abstract 76: p. A1219. 93. Chan HL, Heathcote EJ, Marcellin P, Lai CL, Cho M, Moon YM, et al. Treatment of hepatitis B e antigen positive chronic hepatitis with telbivudine or adefovir: a randomized trial. Ann Intern Med 2007;147:745‐754. 94. Marcellin P, Buti M, Krastev Z, Gurel S, Balabanska R, Dusheiko G, et al. Two year tenofovir disoproxil fumarate (TDF) treatment and adefovir dipivoxil (ADV) switch data in HBeAg‐negative patients with chronic hepatitis B (Study 102) [Abstract].