Journal of Hepatology
Volume 48, Supplement 1 , Pages S2-S19, 2008

Hepatitis B: Reflections on the current approach to antiviral therapy☆

  • Fabien Zoulim

      Affiliations

    • INSERM, U871, 69003 Lyon, France
    • Université Lyon 1, IFR62 Lyon-Est, 69008 Lyon, France
    • Hospices Civils de Lyon, Hôtel Dieu, Liver Unit, 69002 Lyon, France
    • ,
  • Robert Perrillo

      Affiliations

    • Hepatology Division, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75206, USA
    • Corresponding Author InformationCorresponding author.

published online 13 February 2008.

Article Outline

This article summarizes the current state of antiviral therapy of hepatitis B with special attention given to areas that remain controversial or poorly defined. Strict adherence to liver association practice guidelines may result in missed opportunities to treat patients with significant underlying liver disease. In particular, recommended ALT thresholds may not appropriately reflect disease activity or degree of fibrosis. There is growing evidence that an alternative treatment paradigm for preventing late-stage disease complications may be indicated in highly viremic patients with early life exposure to hepatitis B. Pegylated interferon therapy is often a better choice for young to middle-aged patients with genotype A and B because of the higher rate of HBeAg seroconversion and a greater chance for HBsAg seroconversion in both HBeAg-positive and -negative patients as compared to nucleoside analogs. Nucleoside analog monotherapy is the current standard of care for many patients. However, long-term monotherapy results in resistance to a variable degree and sequential monotherapy may result in multi-drug resistant virus. Which patients would specifically benefit from early combination therapy also remains poorly defined. The rapidity and robustness of the suppression of HBV DNA while on a nucleoside analog should be monitored relatively early during treatment because it affects treatment outcome and the rate of resistance. While great progress has been made in treating hepatitis B, many important issues require further study.

Keywords: Hepatitis B, Antiviral therapy combination therapy, Rescue therapy, Monotherapy

Abbreviations: HBV, hepatitis B virus, PCR, polymerase chain reaction, ALT, alanine aminotransferase, AST, aspartate aminotransferase, HIV, human immunodeficiency virus

 

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1. Introduction 

Hepatitis B is a major global health problem. The World Health Organization reports that there are more than 400 million carriers in the world, approximately 75% of whom reside in Asia and the Western Pacific [1]. However, this disorder is not uncommon in Europe and in the United States where changing immigration patterns have led to substantial expansion of the numbers of cases of chronic hepatitis B in geographic regions formerly considered to be of low prevalence.

Hepatitis B is the leading cause of liver cancer in the world today and frequently leads to cirrhosis and liver failure, particularly in individuals with early life acquisition. Although significant progress has been made in the area of vaccination, universal vaccination of children and young adults has not yet been realized [2]. This places tremendous importance on the development of more effective antiviral therapies.

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2. Goals of hepatitis B therapy 

Current antiviral therapies are inadequate to eradicate HBV infection. Thus, practitioners must settle on achieving incomplete virologic responses in the vast majority of cases. There are both short-term and long-term goals of treatment. Short-term goals include achieving the virologic endpoints of HBeAg seroconversion and reduction in HBV DNA levels to below those associated with liver disease as well as restoration of serum aminotransferase levels to the normal range. Ideally, patients should become HBV DNA undetectable by PCR on therapy because persistent viremia has been associated with a higher rate of failed response later on as well as a greater chance of viral resistance. Long-term goals such as improved survival, prevention of cirrhosis and disease complications are even more important and are achievable if treatment results in a durable virologic response with the lowest level of HBV DNA possible. HBsAg seroconversion occurs infrequently with current antiviral therapy, but this is an important virologic endpoint since it is associated with a lower rate of relapse, less chance for complications, and improved survival in cirrhotic patients [3].

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3. Hepatitis B as an immune-based disorder 

Hepatitis B is an immune-based disorder in which the extent of disease as well as the frequency and quality of virologic response are profoundly influenced by the depth of the host immunologic response [4]. Following acute infection, innate and adaptive immune responses are insufficient to achieve immunologic recovery in individuals destined to become HBV carriers [5]. Partial preservation of this immune response, however, is essential to hepatocyte injury, progression of liver disease, and response to therapy. The often repeated observation that both interferon and nucleoside analogs are more likely to be effective in patients with moderate to severe elevation of pre-therapy ALT reflects this dynamic interaction [6]. Unfortunately, the immunologic interface between the host and the replicating virus also determines the extent to which liver disease becomes evident. At any given stage of hepatitis B, there is a balance between immunologic control and viral replication. The triggering events for spontaneous reactivation and clinical relapse of hepatitis B are poorly understood, but are likely to be due to viral or host events that change this balance [4].

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4. Treatment paradigms 

The AASLD, EASL, and APASL associations have each published guidelines for the management of hepatitis B in an attempt to provide objectivity and clarity to treatment [7], [8], [9]. Because the guidelines are evidence-based documents, recommendations are similar about who to treat and how to administer antiviral therapy. Each has similar thresholds for serum HBV DNA and ALT beyond which treatment is recommended and below which continued observation is suggested. HBV DNA levels in excess of 100,000 copies or approximately 20,000IU/mL have been proposed as thresholds for treatment in both HBeAg-positive and HBeAg-negative hepatitis B. Despite these seeming consistencies in the treatment guidelines, there is mounting evidence that strict adherence to arbitrary HBV DNA and ALT cut-offs would exclude many patients with significant underlying liver disease from treatment (Table 1). For example, the suggested HBV DNA threshold (20,000IU/L) identifies the majority of patients, but not all, with active liver disease. When HBV DNA was measured by polymerase chain reaction (PCR) in 165 Chinese patients, 89% of 27 persistently HBeAg-positive individuals had serum HBV DNA levels above 20,000IU/mL in all available samples [10]. In the same study, 45% of patients with HBeAg-negative CHB had values lower than 20,000IU/mL when testing was only performed at the time of presentation. Greek investigators also found that a level of 30,000 copies of HBV DNA (approximately 6000IU/mL) accurately distinguished patients with HBeAg-negative CHB from inactive HBsAg carriers in 93% of cases [11]. Serum HBV DNA levels less than 30,000 copies were detected in 10.5% of 134 patients with HBeAg-negative CHB, and values below 100,000 copies were found in 12.9%. Finally, a large study also from Greece has recently demonstrated that more than 10% of HBeAg-negative hepatitis B patients with persistently or transiently increased serum aminotransferase levels have serum HBV DNA values <2000IU/mL [12]. Taken together, the data indicate that some patients have active liver disease, even to the point of end-stage cirrhosis, and yet fall below the HBV DNA thresholds suggested in the current guidelines. This is particularly important in HBeAg-negative hepatitis B where multiple determinations of serum HBV DNA may be required to ensure detection of spontaneous fluctuations in viremia levels.

Table 1. Reasons to consider less stringent indications for the treatment of hepatitis B when compared to current practice guidelines
If patient has ALT <2×ULNIf patient has HBV DNA <20,000IU/mL

•May be associated with significant underlying liver disease

•Does not predict a lower risk of long-term complications

•Although a lower rate of HBeAg seroconversion, can still respond following a finite course of therapy

•Lower rate of clinical progression in cases with advanced fibrosis when maintenance nucleoside analog therapy is provided


•May follow a flare of ALT in patients with HBeAg-positive hepatitis B

•Serum HBV DNA fluctuations are frequent in HBeAg-negative hepatitis B

•Poor correlation of HBV DNA level with liver histology in HBeAg-negative hepatitis B

•Values of 104 copies (2000IU/mL) may be associated with a higher risk for long-term complication such as cirrhosis and hepatocellular carcinoma

An even greater degree of concern has been raised about the ALT cut-offs that have been suggested in the practice guidelines. The recommendation to consider therapy in patients with ALT values at least twice the upper limit of normal is primarily based on the observation of poor response rates to antiviral therapy in patients with lower levels of ALT [6]. There are several lines of evidence, however, that adherence to this threshold would exclude a substantial number of patients from therapy who might otherwise benefit. For example, serum aminotransferase elevations frequently fluctuate in HBeAg-negative hepatitis. In an Italian observational study involving monthly monitoring of 164 untreated patients, 45% had ALT flares with periods of normalization, and 20% had flares superimposed upon persistent ALT abnormalities [13]. There are also data to suggest that serum aminotransferase level is not a good surrogate for underlying liver disease. As both ALT and AST vary according to body mass index, gender, and a number of other factors, it has been proposed that the upper range of normal for ALT may be set too high and values in the higher side of the normal range may be abnormal for someone of lean body mass [14]. Indirect evidence for this comes from a Korean study in which liver-related mortality was evaluated against ALT and AST testing in more than 140,000 persons. Mean BMI for men was 23.4 and for women was 22.2. Compared with values <20IU/mL, the adjusted relative mortality risks for an ALT of 30–39 were 9.5 in men and 6.6 in women [15]. The results of a recent Chinese study also emphasize how normal ALT levels may not accurately reflect underlying histologic severity [16]. Investigators biopsied 183 HBeAg-positive and 144 HBeAg-negative patients with persistently normal ALT. Approximately 40 percent of the patients in each group had ⩾grade 2 inflammation and 35% had ⩾stage 2 fibrosis. Nor do these findings appear to be linked to Asian ethnicity. Recently, Iranian investigators found that ALT level accurately predicted inflammation in HBeAg-positive, but not HBeAg-negative patients [17]. In both groups, ALT was an inaccurate marker of fibrosis.

The potential fallibility in using the suggested HBV DNA and ALT thresholds has also been underscored by a longitudinal follow-up study of 3233 untreated HBV carriers from Hong Kong [18]. When the risk of disease complications such as liver failure and hepatocellular carcinoma was stratified according to ALT levels on presentation, the cumulative risk was seen to be highest in patients with ALT values >1 to 2× the ULN. Moreover, more than 70% of the patients were already anti-HBe-positive and 44% had HBV DNA levels equal to or less than 142,000copies/mL, (approximately 28,000IU/mL) at the time complications developed. These data led the senior author to conclude that treatment according to the suggested ALT thresholds in the practice guidelines would exclude patients with the highest risks for the development of complications. The study provides support for the hypothesis that prolonged viremia at a relatively low level is the most likely pathway leading to these complications in HBeAg-negative patients [19].

In consideration of the above findings, a modified treatment algorithm has been proposed by a panel of expert hepatologists that endorses the treatment of patients according to less stringent treatment thresholds for HBV DNA and ALT [20]. The major areas of difference from the practice guidelines of the liver associations are in the proposal to use a lower HBV DNA threshold (2000IU/mL) for HBeAg-negative chronic hepatitis B and to treat patients with any degree of ALT abnormality. The authors also suggest that the normal range for ALT should be considered to be 19IU/mL for women and 30IU/mL for men.

A recent survey of the international and national membership of the American Association for the Study of Liver Diseases also suggests that a substantial percentage of hepatologists are concerned that the ALT and HBV DNA treatment thresholds in the practice guidelines are too restrictive. When asked if they would treat a patient with HBeAg-positive chronic hepatitis B only if serum HBV DNA exceeded 20,000IU/mL, 11% of 241 members of the organization rejected this completely and 34% rejected it with some degree of reservation. When the same group was asked if they would treat patients with high level viremia only if serum ALT was greater than twice the ULN, 4% rejected this completely and 13% rejected it with some degree of reservation [21]. Important to this study is that the responses were unlikely to have been affected by a lack of clinical experience with hepatitis B.

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5. Predicting long-term complications of chronic hepatitis B by HBV DNA level: is a new paradigm indicated? 

The predominant goal of antiviral therapy is to extend life expectancy and prevent long-term complications. The therapeutic endpoints of phase III antiviral therapy studies have been HBeAg seroconversion, sustained reduction in HBV DNA, ALT improvement, and improvement in histologic activity. For these endpoints to be most meaningful in clinical practice, however, one must assume that the response is durable and there has been clear identification of a level of HBV DNA and ALT below which disease does not progress and complications do not occur. Unfortunately, as a surrogate marker of liver disease, there is substantial variation in values for any given patient and no precise levels have been identified below which serious disease may not be found.

Large Asian cohort studies which depict the natural history of hepatitis B over a 10–12 year period of follow-up have recently shed new light on the relationship of HBV DNA, HBeAg and ALT status to the risk of developing late disease complications [22], [23], [24], [25], [26], [27], [28], [29] (Table 2). These studies have clearly shown that HBV DNA level at diagnosis is the best independent predictor of future complications such as cirrhosis and hepatocellular carcinoma. More important, even values of 10,000 copies (2000IU/mL) have been associated with an increased risk of complications.

Table 2. Representative natural history studies in which serum HBV DNA is shown to predict late complications or mortality in chronic hepatitis B
Population under study (reference number)Findings

•3582 untreated Taiwanese HBV carriers recruited in 1991–1992, [23]


•Cumulative incidence of cirrhosis increases with HBV DNA level

•HBV DNA, rather than HBeAg status or ALT, is the strongest predictor of cirrhosis

•Increased relative risk of cirrhosis starting with HBV DNA⩾104−<105copies/mL

•4841 Taiwanese HBV carriers recruited in 1988–1992, [24]


•Progressive increase in HCC incidence starting with HBV DNA level of 104 copies or greater

•HBV carriers with >4.2 log 10 copies had 2- to 7-fold greater risk of HCC than those with <3.6 log10

•Genotype C independently and additively associated with increased risk of HCC

•Nested case control analysis of 37 HCC cases and 61 controls derived from population of 3754 Asian Americans, [27]


•HBV DNA is a strongly correlated with risk of HCC

•Nearly 20% of HCC cases occurred in group with baseline HBV DNA level <105 copies

•2354 Taiwanese HBV carriers recruited in 1992–1993, [28]


•Progressive increase in HCC-related mortality and liver disease mortality according to HBV DNA status (non-detectable, >1.6×103−<105 copies; >105 copies)

•1520 mainland Chinese HBV carriers recruited in 1992–1993, [25]


•High viral load strongly associated with increased risk of liver disease 10 years later

•17% of patients with undetectable (<3×104) or >3×104−<105copies/mL had cirrhosis at 10 years

•3653 Taiwanese carriers recruited in 1991–1992, [29]


•Serum HBV DNA⩾10,000copies/mL is strong independent predictor of HCC independent of HBeAg, ALT, and cirrhosis

As multiple fluctuations in HBV DNA levels occur during longstanding infection, confining the analysis to one time screening levels does not properly address the duration of active viremia as an important modifier of disease progression and complication frequency [30]. Further analysis in one of the large Asian cohort studies, however, included serum HBV DNA values at the last study visit or at the follow-up visit that preceded the clinical detection of hepatocellular carcinoma [29]. This study demonstrated that individuals who maintained values equal to or greater than 100,000 copies (20,000IU/mL) during the 11-year follow-up had the highest rate of hepatocellular carcinoma. Perhaps, more important is that patients whose entry HBV DNA level was greater than 100,000 copies but at last follow-up had declined to less than 10,000 copies had an intermediate risk of hepatocellular carcinoma compared to those who were persistently less than 10,000 copies and individuals persistently greater than 100,000 copies. These data reaffirm that incidence rates for hepatocellular carcinoma occur along a biological gradient of HBV DNA and suggest that inhibition of viral replication, whether spontaneous or drug-induced, reduces the rate of hepatocellular carcinoma. The findings also are consistent with observations from a multicenter, randomized, controlled study in Asian HBV carriers which demonstrated that long-term treatment with lamivudine reduces the rate of disease progression and hepatocellular carcinoma in patients with advanced fibrosis [31].

The large size and long-term follow-up in these natural history studies make the relationship between HBV DNA level and the risk of liver disease complications compelling. This also points to a need for a different approach to treatment in patients infected during early life. On the basis of these data, it has been suggested that long-term nucleoside analog treatment be administered to patients with prolonged detectable viremia and mildly elevated ALT [18], [19], [20], [32]. This may even apply to lean patients with high normal ALT (<.5×ULN-1×ULN) since this group of patients has higher viral load than those with low normal ALT values and appear to more frequently enter into the immune clearance phase [33], [34], [35]. The intent of this new therapeutic paradigm would be to reduce the rate of long-term complications by continuous viral suppression to the lowest possible HBV DNA level. Such a strategy would be at odds with practice guideline recommendations as to when to initiate therapy. Furthermore, stopping rules based upon achievement of endpoints like HBeAg seroconversion or prolonged non-detectability of HBV DNA by PCR would no longer apply. Instead, maintained suppression of HBV replication during treatment would assume overriding importance.

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6. Interferon therapy 

6.1. Mechanisms of action 

Treatment with alpha interferon results in an antiviral state due to induction and expression of intracellular genes and the functional activation of a variety of cellular proteins [36]. Interferon alfa also stimulates cell mediated immune responses against HBV which in turn results in the destruction of infected hepatocytes. Early clinical studies with standard interferon emphasized the immunoregulatory properties of this drug [37], [38]. With the advent of the more potent pegylated forms of interferon, clinical trials have tended to emphasize the antiviral activity of interferon [39], [40], [41], [42]. The heavy emphasis placed on the ability of interferon to suppress HBV replication, rather than its immune enhancing activity, is attributable to poor understanding of immunologic events occurring during treatment and a lack of standardized and readily available means of immunologic testing. It has been demonstrated that ALT flares occurring during treatment with standard interferon are predictive of HBeAg loss and sustained reduction of HBV DNA, and the magnitude of these flares also has been shown to predict virologic response in the presence of relatively high levels of HBV viremia [43]. Not surprisingly, then, the rate of HBeAg and HBsAg seroconversion has been shown to be highest in patients having ALT flares during treatment with pegylated interferon [41], [44].

HBsAg clearance, implying greater loss of covalently closed circular (cccDNA), occurs in 3–5% of patients within the first year of follow-up in interferon-treated patients and has been demonstrated to increase with time in sustained virologic responders [45], [46]. By contrast, HBsAg seroconversion is rare with nucleoside analog therapy despite the greater antiviral potency of these agents. These observations underscore the need for future development of more effective immunomodulatory therapy and provide a rationale for the use of interferon in combination with one or more nucleoside analogs.

6.2. Standard vs pegylated interferon 

Standard interferon alfa-2b was first made commercially available as treatment for hepatitis B in 1992. Phase III trials demonstrated that it was significantly more likely to result in HBeAg loss when compared to untreated controls. Achieving this virologic endpoint was associated with major improvement or normalization in ALT and sustained loss of HBV DNA as measured by direct hybridization assay. In addition, early studies indicated that HBsAg loss occurred in approximately one third of those losing HBeAg, and the rate of HBsAg disappearance in virologic responders increased with prolonged follow-up [38], [45], [46]. Interferon remained the only licensed treatment for hepatitis B until lamivudine became available in 1998. Since then, the use of nucleoside analog therapy has been preferred. The reasons for this are multifactorial, but a driving force has been the adverse events associated with the use of interferon as well as the need for administration by injection. In sharp contrast, nucleoside analogs are orally delivered and generally free of adverse events.

There has been a resurrection of interest in the use of interferon over the past several years because large multicenter and multinational studies have demonstrated an enhanced antiviral potency for pegylated interferon alfa and administration of first generation nucleoside analogs has been associated with the development of drug resistance. When compared to standard interferon alfa-2a administered in a dose of 4.5 million units three times weekly, a 180μg dose of pegylated interferon alfa-2a resulted in a steeper decline in HBV DNA levels and a higher rate of HBeAg seroconversion (33% vs 25%) [39]. Less benefit was observed with the 270μg dose of peginterferon, providing impetus for the incorporation of 180μg in phase III trials.

6.3. Pegylated interferon in combination with nucleoside analog therapy for HBeAg-positive and HBeAg-negative chronic hepatitis B 

6.3.1. Review of clinical trial data 

Three large phase III trials of pegylated interferon have been published [40], [41], [42]. Two included only HBeAg-positive patients, and the third enrolled only HBeAg-negative subjects. Each incorporated a treatment arm of pegylated interferon combined with lamivudine. In one study, pegylated interferon alfa-2b was given in a dose of 100μg weekly for 32 weeks followed by 50μg weekly until completion of 52 weeks of treatment [40]. This treatment arm was compared to the identical dose and duration of pegylated interferon given simultaneously with 52 weeks of lamivudine. Whereas there was a greater decline in HBV DNA in the combined group (approximately −5 log vs −2 log) as well as a higher rate of HBeAg loss (44% vs 29%) at the end of treatment, these differences were not sustained during a 26-week follow-up period. The reasons for this discrepancy are unclear but the modification in dosage at the 32-week treatment interval could have been a contributing element.

Of note, HBsAg loss occurred in 5% of the pegylated interferon monotherapy group and 7% of the combined therapy patients. One of the major findings of this study was the relationship of HBeAg loss to HBV genotype. Genotype A patients had the highest rate of HBeAg loss (47%), followed by genotype B (44%), genotype C (28%), and genotype D (25%). Further analyses of the data demonstrated that the rate of HBeAg clearance was highest (58%, P=0.008) in patients who had host induced ALT flares [44] and the rate of HBsAg clearance was closely linked to viral genotype (14%, 9%, 3%, and 2% for genotypes A, B, C and D, respectively) [47].

In the other 2 phase III trials, pegylated interferon alfa-2a was given in a dose of 180μg once weekly for 48 weeks in HBeAg-positive and HBeAg-negative patients, respectively [41], [42]. In both studies, peginterferon monotherapy was compared to 48 weeks of lamivudine monotherapy or the combination of lamivudine and peginterferon. As with the pegylated interferon alfa-2b study above, end of treatment decline in HBV DNA was more robust in patients treated with the combination therapy (HBeAg-positive: −7.2 log, −4.5 log, and −5.8 log, respectively, for combination therapy, peginterferon alone, and lamivudine monotherapy; HBeAg-negative: −5.0 log, −4.1 log, and −4.2 log, respectively). However, in both studies combination therapy was not more effective in achieving sustained virologic response at the end of a 24-week follow-up period. A potentially important finding was that HBeAg seroconversion occurred more frequently in patients with on treatment ALT flares (defined as ALT levels 5×the baseline value) [45]. The rate of HBeAg in this subgroup treated with peginterferon monotherapy group was 43% vs 32% for the group as a whole, and the magnitude of ALT flares was seen to be closely correlated with the rate of HBeAg seroconversion [48].

The phase III trials with peginterferon alfa-2a also demonstrated that HBsAg seroconversion was limited to patients who received peginterferon. While the rates of HBsAg seroconversion were modest, occurring in 3% of all peginterferon-treated patients, this information should be viewed in the context that 87% of the HBeAg-positive and 61% of the HBeAg-negative subjects were of Asian ethnicity which could have limited the rate of HBsAg seroconversion. Furthermore, most patients (60% of the HBeAg-positive and 67% of the HBeAg-negative) had unfavorable genotypes (C and D) for HBsAg clearance. Finally, multivariate analysis confirmed that baseline ALT, baseline HBV DNA (⩽109copies/mL), and low concentrations of pre-treatment HBeAg were predictive of HBeAg seroconversion [49]. In the HBeAg-negative study, predictors of sustained virologic included baseline and end of treatment HBV DNA, age and HBV genotype. When evaluated at the one year post-treatment interval, patients with genotype B or C had a significantly greater chance for combined biochemical and virologic response than did patients with genotype D, and the latter group appeared to do best with combined therapy [50].

6.3.2. Extended follow-up and durability of response 

Prolonged follow-up has been achieved with a subset of HBeAg-negative patients treated with peginterferon alfa-2a in the phase III trial [51]. Only 230 of the original peginterferon treated 354 patients were enrolled in this extended follow-up study providing a potential selection bias. Nonetheless, the data indicate that a substantial proportion of patients who achieve a virological response maintain this for at least 3 years. Due to the high rate of relapse in HBeAg-negative chronic hepatitis B, future studies need to include all patients on an intent-to-treat basis in an extension of post-treatment follow-up for at least 5 years.

6.3.3. Additional studies 

Criticism has been directed to the phase III trials that compared peginterferon alfa-2a to lamivudine monotherapy because the latter group of patients were only treated for one year, which is not the way the drug is used in clinical practice. Additionally, a number of smaller studies have been published which give the suggestion of enhanced therapeutic efficacy when pegylated interferon is used with lamivudine or adefovir as compared to nucleoside analog or peginterferon monotherapy [52], [53], [54], [55]. A small pilot study has been reported in which adefovir was combined with pegylated interferon alfa-2b, both administered for 48 weeks; not only was the rate of HBeAg seroconversion higher (53%) when compared to historical cohorts, but also the rate of HBsAg seroconversion (15%) [55]. These data suggest that the two drugs may work synergisitically to promote greater elimination of cccDNA. Finally, the results from a recent study from India suggest that therapeutic efficacy is enhanced when a nucleoside analog, in this case, lamivudine, is used to lower HBV DNA levels before commencing pegylated interferon [56].

6.3.4. Need for further studies 

The current recommended duration of treatment with pegylated interferon alfa-2a is 48 weeks. Because the frequency of HBeAg seroconversion with 24 weeks of pegylated alfa-2a interferon (33%) was not different from that achieved with a 48-week course (32%), an appropriately powered trial comparing 24 vs 48 weeks of therapy is warranted in HBeAg-positive disease [39], [41]. This is important because a shorter course of peginterferon is likely to be better tolerated. By contrast, prolongation of standard interferon therapy beyond 24 weeks has achieved a higher rate of sustained response in HBeAg-negative hepatitis B [57], [58]. The best virologic endpoint that permits treatment discontinuation with the lowest rate of relapse remains unclear. Early studies that have incorporated serial measurement of HBsAg concentration suggest this to be helpful [59], [60]. Future studies should, therefore, monitor HBsAg concentration at fixed time points during treatment which may allow one to determine the length of therapy that is needed in this difficult to treat disorder.

The consistent demonstration of greater viral suppression when peginterferon and lamivudine are taken together as compared to either agent alone; the lower rate of lamivudine resistance (and one may presume resistance to other nucleoside analogs) with combination therapy; and a surprisingly high rate of HBsAg clearance when adefovir is used with peginterferon warrant further combination therapy studies. These studies should include more potent nucleos(t)ides with a favorable resistance profile and/or a high genetic barrier to resistance such as tenofovir or entecavir. Because nucleoside analogs work slowly in promoting HBeAg seroconversion, the results of combination therapy should be compared to the nucleoside analog alone given for a suitably long period of time (for example, 2–4 years). Also, it remains unresolved as to whether staggered treatment rather than simultaneous therapy might be more effective, and this needs more careful assessment.

6.3.5. Importance of patient selection 

All of the major practice guidelines have advocated interferon as potential first-line therapy for both HBeAg-positive and HBeAg-negative hepatitis B. Nonetheless, the use of interferon currently accounts for no more than 10% of all prescriptions for hepatitis B treatment in the US and Europe, and the usage is apt to be even less in Asia. This low usage pattern may be explained by the unpleasant side effects, lower antiviral potency, and need for administration by injection. However, another contributing element may be that the practice guidelines do not specifically advocate its use as being preferred in specific subsets of patients who are most likely to have a sustained virologic response and HBsAg seroconversion. Recently, advisements about when to use peginterferon as first-line therapy have been proposed [61], [62]. For HBeAg-positive patients, this includes selection of patients with ALT at least twice the ULN and HBV DNA levels less than or equal to 109 copies per mL at baseline. Other factors that have not been specifically addressed in analyses of the phase III clinical trial data but seem prudent nonetheless include age less than 60 years of age and lack of cormorbid illnesses that might decrease tolerability. The need for genotyping patients who meet these criteria cannot be overemphasized since genotype A and B patients have much higher rates of HBsAg seroconversion as well as HBeAg seroconversion. HBeAg-negative patients with genotype D have the poorest response to interferon. The favorable results with a combination of peginterferon and a nucleoside analog in this most difficult to treat subset of patients requires further confirmation [50].

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7. Nucleoside analogs 

7.1. Mechanisms of action of nucleoside analogs 

Nucleoside analogs inhibit the viral polymerase activity. Depending on the drug, this inhibitory activity can affect the priming of reverse transcription, viral minus strand DNA synthesis (i.e., RNA dependent DNA polymerase activity or reverse transcription), or plus strand DNA synthesis (i.e., the DNA dependent DNA polymerase activity of the viral enzyme) [63]. None of these drugs targets the RNAseH activity of the viral enzyme. Lamivudine is mainly an inhibitor of the reverse transcriptase activity, while clevudine has been shown to affect both minus- and plus-strand DNA synthesis [64], [65]. Adefovir and tenofovir are active on the priming of reverse transcription as well as on elongation of viral minus strand DNA [66], [67]. Entecavir inhibits both minus and plus strand DNA synthesis [68]. Telbivudine is also supposed to inhibit all three enzymatic activities [69]. It is unknown if antiviral potency is affected by more than one site of inhibition. Results of in vitro studies suggest an additive antiviral effect for some combinations of nucleoside analogs [70], [71], but this has not been demonstrated by clinical trials in which the antiviral efficacy was driven by the most potent drug in the combination [72], [73].

All nucleoside analogs are competitive inhibitors of the viral polymerase as they compete with the incorporation of the natural endogenous intracellular nucleotides in nascent viral DNA. Furthermore, once incorporated they can also terminate DNA synthesis by preventing the incorporation of the next nucleotide in the viral DNA strand. The effect of nucleoside analogs on viral polymerase activity results in a decreased production of infectious viral particles and, therefore, limits the spread of virus to uninfected hepatocytes.

7.2. Effects of antiviral therapy on intrahepatic cccDNA 

One of the major questions concerning antiviral therapy of chronic hepatitis B is whether treatment might be able to deplete the pool of intrahepatic cccDNA to levels below which the adaptive and innate anti-HBV immune responses might control the infection, and eventually clear cccDNA. Experimental data obtained in tissue culture systems and in animal models of hepadnavirus infection have shown that none of the currently available nucleoside is able to prevent the de novo formation of cccDNA in infected hepatocytes [74], [75]. This implies that residual viremia during antiviral therapy may lead to the infection of new hepatocytes. Furthermore, in chronically infected cells, the effect of nucleoside analog administration does not completely block the recycling of nucleocapsids towards the nucleus. Because of the long half life of cccDNA and that of infected hepatocytes, the decrease in cccDNA levels during nucleoside administration has been shown to be primarily associated with hepatocyte turn-over [76], [77], [78]. What seems critical is that, cccDNA is lost during cell division and by drug-induced inhibition of viral replication not transmitted to progeny cells leading to a dilution of infected cells.

There are only few well performed studies on the quantification of cccDNA in the liver of patients undergoing antiviral therapy. These relatively short-term studies have demonstrated that cccDNA persists in the liver of the majority of the patients during treatment [79], [80]. Curiously, it has been shown that administration of adefovir, one of the less potent nucleoside analogs, may decrease the levels of intrahepatic cccDNA [81]. Furthermore, the combination of pegylated interferon with adefovir has been reported to enhance the clearance of cccDNA [55]. Studies with appropriate treatment control arms are needed, however, to confirm these observations. It is very important that established and future therapies be properly analyzed for their effect on the clearance of cccDNA because a progressive decrease of this genomic template, whether induced by nucleoside analogs and/or by interferon, can lead to HBsAg clearance. Several small scale studies have shown that the decline of intrahepatic cccDNA paralleled that of serum HBsAg [55], [81], [82].

7.3. Licensed nucleoside analogs 

7.3.1. Lamivudine 

This nucleoside analog is a potent inhibitor of the viral polymerase activity, has an excellent safety profile, and is the least expensive of the licensed nucleoside analogs. Despite these features, it is no longer recommended as first-line therapy because it induces a high rate of drug resistance, especially during long-term administration [83], [84]. However, several studies have shown its potential usefulness when used short-term. It was shown that lamivudine administration during the third trimester of pregnancy in highly viremic mothers may decrease viral load and enhance the prophylactic efficacy of HBV vaccination in neonates [85]. Another indication might be the treatment of acute severe hepatitis, as some studies have demonstrated an improved clinical outcome in patients who received lamivudine [86]. Moreover, several studies have shown lamivudine to be effective in the prevention of HBV reactivation and ALT flares in chronic carriers who receive immunosuppressive therapy or chemotherapy [87], [88]. In fact, the efficacy of nucleoside analogs such as lamivudine in this setting has led to a suggestion that all potential recipients of chemotherapy be screened for HBsAg and/or anti-HBc before chemotherapy.

It is also noteworthy that approximately 20% of patients maintain viral suppression during 5 years of lamivudine treatment. Although several factors have been identified as predictors of lamivudine resistance, i.e., high viral load, high HAI, and high BMI [83], [89], it is still difficult to predict before treatment initiation which patients will maintain viral suppression during lamivudine therapy.

7.3.2. Adefovir dipivoxil 

Adefovir dipivoxil has an interesting antiviral activity profile. It is as active on wild-type virus as on lamivudine-resistant mutants, both in vitro in tissue culture models and in vivo in patients. Therefore, it was approved as a first-line therapy, but also as a rescue therapy for patients with lamivudine resistance [90], [91]. Its clinical interest is limited by its moderate antiviral potency as compared to other nucleoside analogs. For instance, it was shown that approximately 25% of patients have a viral load decline lower than 2.2 log10copies/mL after one year of administration [92], [93], [94]. This is particularly true for HBeAg-positive patients with high viral load. On the other hand, most HBeAg-negative patients may benefit from long-term adefovir administration because of lower baseline viremia levels, and a relatively low rate of selection of drug-resistant mutants. Adefovir-resistant mutants are detected by population sequencing in approximately 29% of patients after 5 years of therapy [95]. Interestingly, the adefovir-resistant strains are usually susceptible to lamivudine and vice versa.

Currently, adefovir dipivoxil should be used primarily for the treatment of HBeAg-negative chronic hepatitis. Another indication is the rescue of lamivudine resistance with the best results occurring when initiated as soon as viremia levels start to rise [96]. Several studies have shown that the addition of adefovir to lamivudine, rather than switchover to adefovir monotherapy, results in a lower rate of adefovir resistance [97]. It might be replaced in the near future by tenofovir which shows a similar antiviral activity spectrum but a much better antiviral potency.

7.3.3. Entecavir 

This nucleoside analog is a very potent anti-HBV agent which induces dramatic decline in viral load in both HBeAg-positive and -negative patients [98], [99]. Despite this strong antiviral potency, the rate of HBeAg seroconversion is relatively low and comparable to that observed with other nucleoside analogues. In naïve patients, the rate of emergence of entecavir-resistant strains seems to be very low even after four years of therapy [100]. By contrast, entecavir administration in patients with lamivudine resistance give rise to entecavir-resistant mutants in more than 35% of patients after 4 years of therapy [101], [102]. This is due to a particular mode of selection of entecavir strains which follows a two-step process with the selection of primary resistance mutations [at position rt204 which are also resistant to lamivudine], followed by the addition of secondary resistance mutations on the same viral genomes [103], [104]. Once these secondary substitutions occur, high level resistance to entecavir occurs.

While entecavir was believed not to be active against HIV reverse transcriptase, recent reports have shown that entecavir administration in HIV–HBV co-infected patients may select for HIV mutants that are resistant to lamivudine [105]. The best indication for entecavir therapy is represented by HBeAg-positive or -negative, nucleoside naïve, patients. Entecavir should be used cautiously in patients with lamivudine resistance and those who are co-infected with HIV.

7.3.4. Telbivudine 

This is a nucleoside analog with strong antiviral potency, found to be comparable to that of entecavir in phase III clinical trials in both HBeAg-positive and -negative patients [72], [106], [107]. In HBeAg-positive patients, the rate of HBe seroconversion at 52 and 104 weeks is comparable to that of entecavir and lamivudine. Unfortunately, its administration is associated with a resistance rate of approximately 10% per year. Phase III clinical studies have helped to identify on-treatment predictive factors for virologic response and drug resistance, with primary importance given to persisting viremia at 24 weeks of treatment. Telbivudine mainly selects for rtM204I mutation which is also resistant to lamivudine and entecavir, but sensitive to adefovir and tenofovir.

While the drug can be used for nucleoside naïve patients, the low rates of resistance with tenofovir and entecavir have led to a more restricted pattern of use. Importantly, it can be used against adefovir-resistant mutants. Telbivudine is priced higher than lamivudine, but is considerably less expensive than adefovir, tenofovir, and entecavir. Correspondingly, it may find more use when economic considerations are of major importance. Its use in combination regimen should also be evaluated in clinical trials.

7.3.5. Tenofovir 

Tenofovir belongs to the same family of nucleotide analogs as adefovir. It exhibits a potent inhibitory activity against the wild-type and drug-resistant mutants (i.e., lamivudine and entecavir-resistant strains) [108], [109]. Clinical experience has been mainly in HIV–HBV co-infected patients as tenofovir is also active against the HIV reverse transcriptase [110], [111], [112], [113]. In this setting, it has been shown that tenofovir can control HBV replication in the majority of patients and can rescue HBV lamivudine failure. Moreover, clinical studies have demonstrated it to be effective when there is primary non-response to adefovir in non-HIV infected patients. In HIV co-infected patients, it has been mainly prescribed as an add-on therapy with lamivudine, and more recently as a combination with emtricitabine, another nucleoside analog with an antiviral activity profile that is similar to lamivudine for both HBV and HIV. This may be the reason why until now, there has been no definite observation of HBV resistance to tenofovir. It will be interesting to see whether this holds true when tenofovir is prescribed as monotherapy.

Recent results of ongoing phase III studies in chronic hepatitis B patients, negative for HIV, have shown that tenofovir has a better antiviral efficacy compared to that of adefovir [114], [115]. Approximately 75% and 90% of HBeAg-positive and -negative patients, respectively, achieved undetectable HBV DNA by quantitative PCR after one year of therapy. In HBeAg-positive patients, the rate of HBe seroconversion was the same as that observed with other nucleoside analogs. Follow-up of patients undergoing long-term tenofovir administration is ongoing.

Because of its spectrum of antiviral activity, it can be recommended for use in both naïve patients and those with first-line treatment failure. Indeed, there is in vitro and in vivo evidence suggesting that it is active against lamivudine, entecavir, telbivudine and even adefovir-resistant mutants. In this setting, an add-on strategy or a switch to a combination of tenofovir plus emtricitabine might be recommended; clinical studies are warranted in this setting.

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8. Failed response and viral resistance to nucleoside analogs 

8.1. Definitions 

8.1.1. Response 

Virologic response is defined by the decline in HBV DNA below 100,000 or 10,000copies/mL, the biochemical response by the normalization of ALT levels, and the histological response by the improvement in the inflammatory activity or fibrosis indices [7]. Most studies have used a 2 point or greater change in necroinflammatory score without any negative change in fibrosis as a defining element for histologic response. The combined response is defined by the improvement in ALT levels and decrease in viral load while the complete response is characterized by the combination of the decrease in viral load, the normalization of ALT levels, the occurrence of an HBe or HBs seroconversion, and an improvement in the histologic appearance.

The treatment response is also defined depending on the timing during therapy [116]. The initial response is characterized by a decrease in viral load, at week 12 of therapy, by at least one log10copies/mL compared to the baseline value. The maintained response is defined by a continuing low viral load during therapy. Depending on the use of nucleoside analog or interferon, there is no universally agreed upon threshold to define the maintained response. Usually, a decrease of viral load below 10,000copies/mL is associated with an improvement of liver histology. However, with nucleoside analogs, the lower the viral load, the less the risk of developing drug resistance. The end of treatment response is defined by the response observed at the end of therapy, if it was decided to stop treatment. A relapse is defined by the increase in viral load after treatment cessation. The sustained response is conventionally defined by the maintenance of the response 6 months after drug withdrawal. A durable response has been used to suggest prolonged viral suppression long after the end of therapy.

8.1.2. Primary non-response 

The failure to achieve a one log10copies/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 that the medication does not exhibit its antiviral activity in a given patient; one large study demonstrated that a suboptimal response may be due to a host pharmacological effect or to patient compliance but not a reduced susceptibility to adefovir as measured in vitro [94]. When a sub-optimal response is identified, antiviral treatment should be modified. Many experts would choose to switch to a more potent nucleoside analog at this interval. The week 12 time point is therefore important to determine the antiviral activity of the treatment regimen. Partial response after 6–12 months depending on the drugs and the kinetics of viral load decline should lead to treatment adaptation.

8.1.3. Partial response 

A partial response corresponds to the failure to achieve a viral load decline to a threshold that translates to an improvement in liver histology and/or to a minimum risk of resistance. When considering liver histology as an endpoint, antiviral therapy should lead to a decrease in HBV DNA levels to below 100,000copies/mL. Due to lower baseline HBV DNA levels, some experts would suggest a lower level is necessary for histological improvement in HBeAg-negative chronic hepatitis B (i.e., 10,000copies/mL). The risk of drug resistance, however, is associated with much lower viral loads than 100,000copies/mL.

The antiviral response at week 24 of therapy was also found to be a predictor of resistance in patients treated with telbivudine or lamivudine in the Globe trial [117]. Higher rate of resistance at 2 years was observed when week 24 viral load was >1000copies/mL compared to patients with a lower viral load at the same time point, whatever their initial HBeAg status. The rate of HBeAg seroconversion at year 2 was 46% in patients with undetectable viral DNA at week 24 vs 6% for those having viral DNA levels higher than 6 log10copies/mL at week 24. The rate of resistance to telbivudine at year 2 was 4% in HBeAg-positive and 2% in HBeAg-negative patients with undetectable HBV DNA levels at week 24, vs 30% and 60% for patients with viremia levels higher than 10,000copies/mL at week 24.

Adefovir dipivoxil was shown to suppress viremia levels with a slower effect by comparison with other nucleoside analogs, i.e., lamivudine, entecavir or telbivudine. Therefore, the week 48 time point may be used for predicting resistance to ADV therapy [95]. Interestingly, it was demonstrated in HBe-negative patients treated with adefovir dipivoxil for 192 weeks, that patients with HBV DNA levels 1000copies/mL after 48 weeks of therapy had a higher risk of developing adefovir resistance at week 192. 17/35 patients (49%) developed ADV-resistant mutants, as compared to 6% (5/89) of patients with a viral load <1000copies/mL at week 48. From these different studies, the current definition of partial response is the failure to achieve viral suppression below 1000copies/mL after 6–12 months of therapy. This should lead to treatment adaptation to maximize viral suppression and minimize the subsequent risk of resistance [118]. The timing of treatment adaptation depends on the drug used and on the kinetics of viral load decay, especially in patients starting from very high viral load who may need additional weeks of therapy to reach the threshold of 1000copies/mL.

8.1.4. Virologic breakthrough 

Virologic breakthrough is defined by an increase of at least one log10copies/mL compared to the lower value during treatment, confirmed by a second test, in a treatment compliant patient. It is usually associated with the presence of resistance mutations and follows genotypic resistance (detection of resistance mutations) [116], [119], [120]. The confirmation by a second HBV DNA test is not necessary when patients present also with ALT elevation.

In the absence of treatment adaptation, the rise in viremia levels may be followed in the following weeks or months by an increase in ALT levels (biochemical breakthrough) and subsequently progression of liver disease (clinical breakthrough).

8.2. Treatment adaptation 

8.2.1. Cross-resistance 

Cross-resistance refers to the situation in which a decreased susceptibility to more than one antiviral drug is conferred by the same amino acid substitution or combination of amino acid substitutions. Results of in vitro cross-resistance data are summarized in Table 3.

Table 3. Cross-resistance profile of nucleoside analogs for hepatitis B as measured in vitroa
LamivudineTelbivudineEntecavirAdefovirTenofovir
Wild-typeSSSSS
M204lRRRSS
L180M+M204VRRISS
A181T/VISSRS
N236TSSSRI
I169T+V173L+M250VbRRRSS
T184G+S202I/GbRRRSS

R, resistant; S, susceptible; I, decreased in vitro activity.

aResults were obtained in vitro in tissue culture experiments using transient transfection experiments or cell lines permanently expressing the different drug resistant mutants as described in references: [66], [102], [103], [104], [122], [125], [126], [131], [139].

bThese mutations are observed on a genetic background of mutations at position rtM204.

Results of in vitro cross-resistance testing have shown that lamivudine-resistant mutants (rtM204V or rtM204I mutants) are not sensitive to other l-pyrimidine analogs such as emtricitabine, clevudine, and telbivudine while they remain susceptible to purine analogs such as adefovir and tenofovir [64], [66], [121], [122]; these mutants also have an intermediate susceptibility to entecavir [103], [104]. In vitro studies demonstrated that rtN236T adefovir-resistant mutant is susceptible to lamivudine, emtricitabine, telbivudine and entecavir, while the rtA181V mutant has a reduced susceptibility to lamivudine [123], [124], [125]. Although some level of cross-resistance has been observed in vitro, rtN236T adefovir-resistant strains remain sensitive to tenofovir in vivo at least initially, most likely because of the greater exposure to active drug. The A181V mutant-resistant to adefovir was shown to be as sensitive to tenofovir in vitro as wild-type HBV [126]. Further trials of longer duration are needed to see if tenofovir may maintain a sustained response in patients with adefovir-resistant strains. Two mutants are subject to a controversy, the rtI233V mutation was shown to confer primary to resistance to adefovir in one study but not in another one [127], [128]; the rtA194T has been associated with the emergence of HBV resistance to tenofovir in one study but this was not confirmed by another [66], [129].

Current data suggest that the development of entecavir resistance follows a “two hits” model with the first selection of primary resistance mutations at position rt204, followed by the addition of secondary resistance mutations (at position rt184, rt202, or rt250) conferring higher resistance to entecavir [103], [104]. This may explain why the development of entecavir resistance is more rapid in patients with lamivudine failure who already have selected the primary resistance mutations, by comparison with the nucleoside naïve patients in whom the whole process of selection of primary and secondary mutations needs to take place. Although strains harboring classic lamivudine resistance mutations exhibit an intermediate susceptibility to entecavir, they remain sensitive initially to entecavir in vivo, when this latter is administered at a higher dose (1.0mg daily). If additional secondary mutations occur, resistance to entecavir is observed and is followed by viral breakthrough. This suggests that entecavir may not be considered as an optimal treatment for patients infected with lamivudine-resistant HBV, but a good treatment option in nucleoside naïve patients. If entecavir has to be prescribed in patients with lamivudine failure, lamivudine should be discontinued, and entecavir prescribed at double dose (1mg daily).

Telbivudine is ineffective in vitro against the rtM204I mutant as well as the rtL180M+M204V mutant, but remains active against the rtM204V single mutant. This may explain why the single rtM204I mutant has been the only resistant mutant detected during the phase III trials of telbivudine.

8.2.2. Problems with sequential monotherapy: multi-drug resistance 

Based on clinical experience, the knowledge of cross-resistance, and viral quasi-species evolution during therapy, it was clearly shown that sequential therapy may expose the patients to the risk of selection of multi-drug resistant strains. One example is the use of sequential treatment with cross-resistance drugs like lamivudine followed by entecavir [104], [130], and another being the development of dual resistance to both lamivudine and adefovir [125], [131]. It was shown by clonal analyses that multi-drug resistance may occur by the sequential addition of resistance mutations on the same viral genome leading to resistance to both drugs. Results of phenotypic analysis of the mutants during the selection process demonstrated that the cumulative addition of these mutations conferred full resistance to both drugs.

Another situation is the use of an add-on strategy with drugs having a complementary cross-resistance profile which may lead to the selection of multi-drug resistant strains if the add-on strategy does not induce a complete viral suppression, especially if there is a large replication space available for the mutants to spread. This was demonstrated by the longitudinal clonal analysis and phenotypic analysis of the main variants in a patient who selected a multi-drug resistant strain, after liver transplantation, harboring mutations in the overlapping polymerase and surface that conferred resistance to both lamivudine and adefovir as well as a decreased recognition by anti-HBs antibodies [125].

Because of the risk of development of multi-drug resistance which may not be rescued by currently available drugs, treatment decision and the choice of first-line treatment should be made with caution. Furthermore, in specific patient populations with a high risk of resistance development and in whom drug resistance may not be tolerated, de novo combination therapy should be considered to minimize the risk of resistance development.

8.2.3. Add-on therapy with drugs lacking cross-resistance 

In the past, salvage therapy was proposed to patients with lamivudine resistance and clinical breakthrough (high viral load and ALT elevation). There was a debate on whether adefovir dipivoxil switch or add-on to ongoing lamivudine was the best strategy. The knowledge of cross-resistance data and the results of long-term studies advocate for an add-on therapy at an early stage, i.e., viral breakthrough, to control rapidly viral replication and prevent clinical deterioration. Several studies have shown that switching from lamivudine to adefovir monotherapy was associated with a high incidence of adefovir resistance. A large multicenter Italian cohort study showed that rescue therapy with the addition of adefovir after development of virological breakthrough in HBeAg-negative patients treated with lamivudine led to viral suppression for three years in most patients [132]. None of the patients receiving the add-on strategy developed genotypic resistance to adefovir by contrast to those who received adefovir monotherapy. Another Italian study compared two groups of patients with known resistance to lamivudine: in one group, adefovir was added at the time of clinical breakthrough with high viremia levels, while in the other group, adefovir was introduced earlier, at the time of viral breakthrough [96]. The results clearly showed that treatment efficacy was improved when adefovir was started earlier, at the time of virologic escape.

8.3. Importance of virologic monitoring 

The objective of viral load levels measurement is twofold, firstly to monitor magnitude of viral load suppression, and secondly to detect viral breakthrough as early as possible [116], [119], [133].

Early during therapy, at week 12, viral load assessment allows to confirm the initial antiviral response. A primary treatment failure is an indication to change treatment regimen at an early stage. The next monitoring time point should be at week 24 of therapy. This measurement is considered essential in the management of both HBeAg-positive and HBeAg-negative patients, because it was found to be the main predictor of subsequent treatment efficacy in terms of HBeAg seroconversion in HBeAg-positive patients, and of subsequent resistance [118], [134].

Altogether a precise monitoring of viral load during antiviral therapy allows the diagnoses of primary treatment failure, insufficient viral suppression predicting a high likelihood of drug-resistance development, or virologic breakthrough. In all these situations, an early intervention is mandatory to adjust antiviral therapy and control viral replication to prevent clinical deterioration (Fig. 1).

The use of genotypic assays to define the resistance pattern and adapt antiviral treatment accordingly is critically important (Table 3). Indeed, since more and more patients have received several courses of drug therapy, the pattern of resistance mutations is becoming more and more complex. Its knowledge is becoming important to make informed treatment decisions. There are still many issues to be addressed. One is the fact that the currently available assays can detect only the major variants in the viral quasi-species, and it will be even more difficult to detect mutants that are archived in intrahepatic cccDNA and will emerge only in the presence of a specific antiviral pressure [125], [135]. Another issue is the cost of the assays and the reimbursement policy from country to country. In any case, genotypic assays for the detection of drug-resistant mutants would be recommended in patients who experience a virologic breakthrough. Currently, we still do not know if these assays are sensitive enough to detect resistant mutants in case of partial virologic response. Also, the commercially available assays are limited by the inclusion of oligonucleotide probes only for the most commonly defined mutations.

8.4. Combination nucleoside analog therapy 

With the availability of new antivirals, the concept of combination therapy for chronic hepatitis B has been debated over the past several years. Despite the lessons drawn from the antiretroviral therapy of HIV infection, the situation is clearly different. Indeed, the antiretroviral drugs belong to several different classes of compounds which target different steps of the viral life cycle. It was therefore easier to demonstrate in relatively short-term clinical trials that the combination of antiretrovirals can achieve an additive effect on viral load suppression. Furthermore, HIV drug resistance emerges rapidly during monotherapy. The beneficial effect of combinations was, therefore, assessed in short-term trials showing the added value of combination in terms of viral load decline, prevention of drug resistance and decrease in mortality rate [136].

By contrast, in the setting of chronic hepatitis B, antivirals belong to the same class of nucleos(t)ide analogs and target the viral polymerase and no other key step of the HBV life cycle [63]. This might be the reason why the combination of nucleoside analogs did not show any additive effect in terms of viremia decline compared to the most potent antiviral drug in the combination [72], [73], [137].

The issue of prevention of drug resistance by combination therapy is critical. Several drugs with different cross-resistance profiles are now approved. Clinical experience has shown that the combination of nucleoside analogs with complementary cross-resistance profile is an effective strategy to manage resistance [96]. The new generation of inhibitors has also an improved resistance profile with very low rates of resistance in nucleoside naïve patients during the first five years of therapy. The benefit of combination therapy will therefore be difficult to demonstrate in short-term trials.

It will, therefore, become an urgent priority in the future to identify the patients who have the highest risk of resistance (for example, long standing infection and high viremia levels associated with more complex viral populations prior to therapy, together with high ALT levels which are associated with a more rapid hepatocyte turnover that in turn generates a wider replication space) [83], [138], [78]. An equally important group for preferred use of combination therapy exists in those patients who can least afford to develop antiviral drug resistance from a clinical perspective (for example, patients with liver cirrhosis and/or with HBV recurrence after liver transplantation) (Fig. 1). Strategy trials comparing combination therapy vs early add-on therapy in case of partial response should be designed and evaluated as soon as possible in these patient groups.

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9. Conclusions 

Major breakthroughs in the treatment of chronic hepatitis B have occurred in the last ten years. However, much remains to be done. Strict adherence to the practice guidelines of the major liver associations can result in missed opportunities for treatment, particularly when using the suggested ALT thresholds. It can be argued that the use of the current ALT threshold of twice the upper limit of normal is an indictment of the inadequacy of our current drug therapy. Peginterferon is more potent than standard interferon, yet its use has been relegated to a few patients only. This is unfortunate since genotype A and B patients respond well and may lose HBsAg. The loss of hepatitis B surface antigen in response to peginterferon therapy, while infrequent in the short term, increases with time; this effect provides proof for a higher level of viral clearance when compared to nucleoside analogs. In the authors’ opinion, more study needs to be given to a combination of peginterferon and newer nucleosides with lower rates of viral resistance and greater antiviral potency.

While the newer nucleoside analog agents have been associated with much lower rates of drug resistance, this continues to be a concern when monotherapy is used. Part of this concern rests on the knowledge that drug resistant mutants exist in nature and if there is not a rapid and robust decline in HBV DNA, this may allow for selection pressures for drug-resistant virus. Thus, drugs with high antiviral potency are preferable over those in which responses occur more slowly, and patients need to be monitored early on and at regular intervals to document that an appropriate antiviral response is occurring. The common practice of using sequential monotherapy raises concerns because multi-drug resistant virus has been detected in both non-immunosuppressed and immunosuppressed patients. For this reason, most experts recommend adding on therapy rather than switchover to a nucleoside lacking evidence for cross-resistance (Fig. 1). There is still a debate by clinical virologists and infectious disease specialists as to whether we ought to be following the model with HIV of multi-drug therapy as a first-line approach. It is quite clear that this would greatly diminish the rate of drug resistance, but this approach has considerable cost implications and uncertain effects on enhancing antiviral potency. The real question may be in which subpopulation of patients is combination therapy preferential? For example, it would be useful to have appropriately designed studies in which patients judged to be at highest risk for resistance, for example, cirrhotic patients with high level viremia, in whom the complexity of the viral quasi-species may predispose to the presence of pre-existing resistant mutants in higher proportion in the viral population, are treated with either combination therapy or monotherapy with a high potency, low resistance nucleoside.

In summary, the number of therapeutic choices facing the clinician has expanded greatly, but hepatitis B is not a disorder best treated with a “one-size fits all strategy.” The best choice is often based on the knowledge of host variables as well as virologic and clinical features of disease (Fig. 2). As with many other things in medicine, careful selection and individualized treatment decisions may ultimately prove best.

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☆ F. Zoulim declares that he is a consultant for: Gilead Sciences, Bristol Myers Squibb and Novartis. R.P. Perrillo declares that he receives funding from Novartis and Bristol Myers Squibb for clinical research in hepatitis B. This study was not funded by any of the above.

PII: S0168-8278(08)00057-3

doi:10.1016/j.jhep.2008.01.011

Journal of Hepatology
Volume 48, Supplement 1 , Pages S2-S19, 2008

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