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Precore Mutant Chronic Hepatitis B -- Approach to Management
MedGenMed Gastroenterology
Stephanos J. Hadziyannis, MD, George V. Papatheodoridis, MD, Dimitrios Vassilopoulos, MD
Overview and Introduction
Overview
The diagnosis of precore mutant chronic hepatitis B (CHB) can be made with safety only by sequencing the precore region of the hepatitis B virus (HBV) genome, a method not widely available. However, in clinical practice, hepatitis B e antigen (HBeAg)-negative CHB is frequently arbitrarily referred to as precore mutant CHB, although the 2 terms are not synonymous. Because no therapeutic trial has specifically addressed the treatment of precore mutant CHB, all patients with HBeAg-negative CHB are currently treated in the same way. The aim of therapy in this setting is to induce a sustained suppression of liver disease activity before cirrhosis or hepatocellular carcinoma (HCC) develops. This goal may be achieved by efficient suppression of HBV replication, which represents the main determinant of underlying liver necroinflammation and fibrosis. Currently available agents include interferon-alfa, lamivudine, and adefovir dipivoxil. A 12-month or longer course of interferon-alfa treatment or re-treatment achieves sustained biochemical responses in 20% to 25% of patients, with eventual hepatitis B surface antigen (HBsAg) loss and antibody to HBsAg (anti-HBs) development in a proportion of this population. Lamivudine induces initial virologic and biochemical responses in 70% to 90% of patients, but breakthroughs due to lamivudine-resistant mutants accumulate with continuation of therapy and thus, only one third of patients may remain in remission after the third year of therapy. Adefovir dipivoxil also achieves on-therapy responses in the majority of cases. It is effective against lamivudine-resistant HBV strains and is associated with little, if any, drug resistance during the first 2 years of therapy -- highlighting its applicability for long-term treatment of HBeAg-negative CHB. Many other antiviral agents and immunomodulatory approaches are currently being evaluated for HBeAg-negative CHB, but, with the exception of interferon-alfa, none have as yet been shown convincingly to induce sustained off-therapy responses.
Introduction
Chronic infection with HBV is one of the most common causes of chronic liver disease worldwide[1] and is associated with high morbidity and mortality.[2,3] Although the majority of chronic HBV infections may remain with low viral replication and in biochemical and histologic remission, a proportion of them exhibit high HBV replication and active histologic lesions.[3,4] It is estimated that about 15% to 20% of patients with CHB develop cirrhosis within 5 years[5,6] and only 55% to 85% of patients with active HBV-related cirrhosis survive 5 years later.[7-9] Moreover, all patients with chronic HBV infection are at higher risk for HCC when compared with the general population, but the risk is extremely high when cirrhosis is present.[10] Thus, it is estimated that over 250,000 patients die annually from HBV-related liver disease.[1,11]
The first phase of chronic HBV infection is positive for HBeAg and is characterized by high HBV replication, low aminotransferase levels, and mild histologic activity. However, during the course of chronic HBV infection, HBeAg seroconversion and development of the corresponding antibody (anti-HBe) may occur, an event usually associated with transition from the phase of high HBV replication to an inactive phase of the infection, with little residual viral replication and essentially normal liver histology (the so-called "inactive HBsAg carrier state").[12,13] However, not all patients who lose HBeAg and seroconvert to anti-HBe antibody go into sustained remission of HBV replication and liver disease activity. A variable proportion of the HBeAg-negative and anti-HBe-positive patients, depending on HBV genotype as well as other factors, retains or redevelops high serum HBV-DNA levels and persistent or intermittent elevations in alanine aminotransferase (ALT) activity.[12,13] Such patients harbor replication-competent HBV variants that are unable to produce HBeAg due to some mutations either in the precore or the basic core promoter region of the HBV genome.[14] This form of CHB is also referred to as HBeAg-negative, or anti-HBe-positive, CHB[12,13]; it represents a potentially severe and progressive form of liver disease, with frequent development of cirrhosis and HCC.[15-19]
Because mutations in the precore region of the HBV genome were detected[20] some years before the detection of the mutations in the basic core promoter region,[21] HBeAg-negative CHB was initially considered to be identical to precore mutant CHB. The most common precore mutation is a guanosine (G) to adenine (A) change at nucleotide 1896 (G1896A), which leads to premature termination of the translation of the precore region at codon 28, thus preventing the production of HBeAg.[20] In many cases, a second precore G to A mutation at nucleotide 1899 is also found, but its significance remains unknown.[20] HBV variants harboring the 1896 precore stop codon mutation are mainly responsible for "HBeAg-negative CHB" in the Mediterranean basin and Far East, and generally in geographical areas where HBV infection is transmitted vertically or even horizontally in very early life and where the B and D genotypes of HBV prevail.[13,22] In such areas, HBeAg-negative CHB is the predominant type of CHB.[13,22]
This review focuses on the practical approach to the management of patients with HBeAg-negative, precore mutant CHB.
Diagnosis of Precore Mutant CHB
Confirmation of the presence of precore mutant HBV strains can be reliably made only by sequencing the precore region of the HBV genome, a method not widely available. Thus, most frequently, the diagnosis of precore mutant CHB is made in clinical practice on the basis of established HBeAg-negative CHB, although the 2 terms, as explained earlier, are not synonymous. HBeAg-negative CHB is usually associated with precore mutant HBV,[16,20,22-25] but it may also develop in patients with precore wild-type HBV strains,[26-28] particularly in infections with HBV genotype A and C, and be associated with mutations in the basic core promoter (especially with a double mutation at nucleotides 1762 and 1764).[21,29] Whether these 2 subgroups of HBeAg-negative CHB differ with respect to their clinical features, natural course, and response to therapy is not known at present. However, the identification of precore mutations alone is of no clinical value, because both inactive HBsAg carriers and patients with active HBeAg-negative infection may carry precore mutant strains[19,24,25,30]; therefore, the differentiation between these 2 phases of chronic HBV infection is much more crucial than just the detection of precore mutations.
The serologic profile of patients with HBeAg-negative chronic HBV infection includes (1) positive serum HBsAg for at least 6 months, to establish chronic HBV infection; and (2) negative serum HBeAg and usually positive anti-HBe antibody for at least 6, or preferably 12, months, to exclude patients who are still in the unstable phase of HBeAg seroconversion and thus who may revert to the HBeAg-positive CHB phase.[31] In such patients, the diagnosis of HBeAg-negative CHB can be made when the following criteria are fulfilled (Table):
Increased serum ALT level (ie, ALT levels > 2 x upper limit of normal [ULN] on 1 occasion, or ALT > 1.5 x ULN on at least 2 monthly determinations), as a biochemical marker of ongoing hepatocellular damage;
Detectable serum HBV DNA levels, to establish active HBV replication and, presumably, HBV-induced hepatocellular damage;
Exclusion of other concomitant or superimposed causes of liver disease; and
Moderate-to-severe necroinflammation on liver histology, compatible with CHB.[32,33]
Common non-HBV causes of liver damage in this setting include superinfections with other hepatitis viruses (D or C), alcohol abuse, hepatotoxic drug use, or more rare liver diseases (autoimmune, metabolic, etc.). Moreover, increased ALT levels may be due to just fatty liver or steatohepatitis, or due to severe conditions that complicate chronic HBV infection, such as HCC.
The majority of patients with HBeAg-negative CHB fulfill all of the above criteria and therefore can be safely differentiated from individuals in the inactive chronic HBsAg carrier state, who have an identical serologic profile.[32] However, not all patients with HBeAg-negative CHB fulfill all of the above diagnostic criteria because the pattern of virologic and biochemical activity may be intermittent instead of continuous, and the intervening periods of biochemical and virologic remission may be quite long-lasting (Figure). In studies with frequent assessments of ALT and serum HBV DNA levels, major fluctuations in viremia and serum aminotransferase levels were observed in more than 40% of cases.[34] According to our data, 20% to 30% of patients with histologically documented HBeAg-negative CHB first presented with normal ALT levels and low HBV DNA levels (below the cut-off value of 105 -- and even 104 -- copies/mL), and were thus initially misclassified as inactive HBsAg carriers.[35] These findings demonstrate that the diagnosis of HBeAg-negative CHB and its differential diagnosis from the inactive state of chronic HBV infection cannot be reliably made on the basis of cross-sectional (single time-point) determinations, and that therefore, lengthy follow-up assessments of several months' duration may be required in many patients.[32,34]
Figure. Patterns of ALT activity in patients with HBeAg-negative chronic HBV infection. Pattern A: Persistently increased ALT activity; Pattern B: ALT flares without ALT normalization in the intervening period; Pattern C: ALT flares with intervening long periods of normal ALT activity; Pattern D: Persistently normal ALT activity. Patterns A-C represent patients with HBeAg-negative CHB; pattern D represents inactive chronic HBsAg carriers.
Because both the high cost and the lack of an accurate established cut-off level preclude very frequent estimations of serum HBV DNA levels, sequential ALT/aspartate aminotransferase (AST) determinations remain, in clinical practice, the basis for a reliable differentiation between HBeAg-negative CHB and the inactive HBsAg carrier state of chronic HBV infection.[32] ALT/AST determinations are also useful in the follow-up of clear-cut asymptomatic HBsAg carriers, as a percentage of these patients may eventually develop HBV reactivation and thus progress to the HBeAg-negative CHB phase[16,22,36] (Figure).
Management of Precore Mutant CHB
All patients with precore mutant CHB are candidates for therapy; however, no therapeutic trial conducted in patients with HBeAg-negative and/or anti-HBe-positive CHB has ever applied the detection of a precore stop codon mutation as an entry criterion. Therefore, the management of HBeAg-negative CHB will be reviewed here, keeping in mind that this form of CHB is presumed to be related to precore mutant HBV, which is not always the case.[26-29]
Goals/Endpoints of Treatment
It is now becoming clear that complete viral eradication cannot be a realistic therapeutic endpoint, either in HBeAg-positive or HBeAg-negative CHB. Sensitive virologic assays have documented that residual amounts of replicating HBV are detectable in many patients with a sustained virologic and biochemical response, even in those who lose HBsAg and develop its antibody (anti-HBs).[37] Thus, sustained seroconversion of HBeAg to anti-HBe or sustained biochemical and virologic remission are considered to be the most realistic therapeutic goals in HBeAg-positive and HBeAg-negative CHB, respectively.[32,33] In fact, in the subset of patients with HBeAg-positive CHB, HBeAg loss and seroconversion to anti-HBe is usually associated with a decrease in serum HBV-DNA levels to nondetectability by the branched DNA (bDNA) assay (<\= 0.7x106 viral equivalents/mL), biochemical remission, and improved long-term outcome.[37,38] Moreover, for the subset of HBeAg-negative CHB, we have recently shown that a sustained biochemical remission after therapy with interferon-alfa, usually accompanied with low residual viremia levels, is associated with reduced risk of development of liver decompensation and/or HCC and with improved survival.[39] Therefore, induction of sustained normalization of liver enzymes irrespective of the presence of low viremia levels should probably be the main therapeutic goal in this setting.
Definitions of Response to Treatment
In both HBeAg-positive and -negative CHB, virologic and biochemical responses (VRs; BRs) may be evaluated during therapy (on-therapy responses) or after discontinuation of therapy (off-therapy or sustained responses [SR]).[33,40] Specifically, on-therapy responses may be subdivided into initial (achieved at any time within the first 12 months of therapy), maintained (persisting throughout the course of therapy), and end-of-therapy (EOT; evaluated at the end of a course of therapy with defined duration) responses.[40] Currently, VRs are preferably evaluated by qualitative polymerase chain reaction (PCR) assays and are arbitrarily considered to be achieved when serum HBV-DNA levels fall below 100,000 copies/mL.[12,33] However, an effective HBV suppression is probably achieved when serum HBV-DNA levels drop below 400 or even 200 copies/mL, which represents the cut-off levels of most in-house real-time PCR assays.[41,42] When VR and BR are maintained for several months, histologic improvement can also be demonstrated, usually defined as a reduction in the necroinflammatory (histology activity index [HAI]/Knodell) score by >/= 2 points without worsening in fibrosis.[12,33] Because on-therapy responses in patients with HBeAg-negative CHB are not usually durable after termination of treatment, the efficacy of any drug or combination of drugs should be evaluated both at the end of the therapeutic course and 12 or more months after the end of therapy.[32,33]
Indications for Treatment
Ideally, all patients with HBeAg-negative CHB should be treated. Untreated HBeAg-negative CHB follows an indolent, progressive course frequently terminating in cirrhosis, portal hypertension, and liver decompensation.[43] However, patients with minimal or mild histologic liver disease, and usually minimal increases in ALT level, run a very slowly progressive course or do not worsen at all -- thus they never reach the cirrhotic stage. In view of the frequent interferon-alfa-related side effects and the need for very long-term maintenance therapy with nucleoside/nucleotide analogues, which often results in viral resistance and relapse of CHB (particularly in the setting of lamivudine therapy), it is reasonable not to recommend initiation of therapy in such mild cases, at least for the time being. However, frequent follow-up is mandatory, and treatment can be administered if there is deterioration in the biochemical and liver disease profile.
Treatment Strategies
A. Primary treatment of HBeAg-negative CHB:
Currently, there are 3 drugs that are approved for the treatment of both HBeAg-positive and HBeAg-negative CHB: interferon-alfa, lamivudine, and adefovir dipivoxil (recently approved for the treatment of CHB both in the United States and Europe).[40]
Interferon-alfa. Interferon-alfa, an agent with both antiviral and immunomodulatory activity, was the only available therapeutic option for CHB until a few years ago. Despite so many years of interferon-alfa availability, no large randomized, controlled trial has ever been conducted with this agent in HBeAg-negative CHB. In several relatively small controlled or uncontrolled studies, interferon-alfa therapy of up to 6 months' duration was found to be associated with high (60% to 90%) EOT biochemical and virologic response (evaluated by insensitive hybridization assays) rates but low SR rates due to frequent relapses after termination of therapy.[40] Longer courses of interferon-alfa therapy were reported to improve SR rates, reaching 20% to 25%. In a large cohort of 216 treatment-naive patients recently reported on by Manesis and Hadziyannis,[44] the SR was approximately 11% after 6 months and 22% after 12 months of interferon-alfa therapy; it was not affected by the interferon-alfa dose (3 or 5 million units [MU]). In a previous small study, a 24-month course of interferon-alfa given at a dose of 6 MU thrice weekly was found to achieve biochemical and virologic (by a dot-blot assay) SR in 38% of 21 treated patients compared with 10% of 21 untreated controls.[45] In a larger study conducted by the same group, the same 24-month course of interferon-alfa achieved a SR in 30% of 101 patients.[46] Taken together, these findings indicate that at least 12 months of interferon-alfa given at a dose of 3-6 MU thrice weekly appears to be the most appropriate interferon-alfa regimen for patients with HBeAg-negative CHB.[33,40]
All patients treated with interferon-alfa should be followed closely for at least 2 years after discontinuation of therapy. Only half of relapses occur within the first 6 months, whereas more than 20% may occur between the 12th and 24th month after discontinuation of interferon-alfa.[47] Relapses may sometimes be associated with quite severe, usually transient hepatitis flares, with ALT levels exceeding those associated with acute hepatitis and occasionally with even development of liver decompensation.[48,49]
Interferon-alfa therapy is costly, and is associated with several side effects.[50] Its most common side effects include flu-like symptoms, fatigue, bone marrow suppression, irritability, and depression.[50] Because behavioral disturbances and particularly depression as well as bone marrow suppression (expressed as anemia, neutropenia, and/or thrombocytopenia) may be potentially severe, interferon-alfa-treated patients should be closely monitored with monthly clinical examinations, with specific emphasis on behavior and psychiatric symptoms and monthly full blood counts.[33] Moreover, patients should be followed-up with regular ALT/AST determinations in order to monitor the response to therapy. Interferon-alfa therapy is contraindicated in certain subgroups of patients with HBV-related chronic liver disease. The most frequent contraindications include decompensated cirrhosis, anemia (usually hemoglobin < 13 g/dL for men and < 12 g/dL for women), neutropenia (neutrophils < 1.5 x 109/L), thrombocytopenia (platelets < 80 x 109/L), major psychiatric diseases (mainly depression), thyroid diseases, autoimmune diseases, and organ transplantation.[43] Most of the contraindications are linked to the side effects and the immunologic activities of interferon-alfa.
The efficacy, safety, and tolerability of the more potent pegylated forms of interferon-alfa in HBeAg-negative CHB are currently undergoing evaluation in clinical trials.
Although there are no trials using the detection of a precore mutation as an inclusion criterion, the effect of the presence of precore mutant or wild-type HBV strains on the probability of response to interferon-alfa therapy has been retrospectively evaluated in a few small studies, without conclusive results. Precore stop-codon mutant strains compared with wild-type or mixed HBV strains have been associated with worse or similar response rates, irrespective of HBeAg status,[26,51] and with better response rates in HBeAg-positive CHB patients.[52] Consequently, the presence of precore mutant HBV strains has not been definitively associated with increased or decreased probability of response to interferon-alfa therapy; the role of additional mutations in the core or core promoter region has not been studied.[53]
Lamivudine. Lamivudine was introduced in the treatment of chronic HBV infection in the late 1990s, and has been widely applied in almost any subset of chronic HBV-related liver disease because of its potent inhibition of HBV replication, ease of oral administration, rather low associated cost, and excellent safety and tolerance profile. Moreover, lamivudine offered a therapeutic option for subgroups of patients with CHB with high risk of side effects or contraindications to interferon-alfa therapy.
In the HBeAg-negative CHB setting, a 12-month course of lamivudine administered as a daily dose of 100-150 mg has been shown to achieve on-therapy BR and VR, even by sensitive PCR assays, in the vast majority (70% to 90%) of patients, as well as EOT responses in about two thirds of cases.[54-56] Unfortunately, SRs are rare and both biochemical and virologic relapses are observed in most patients after discontinuation of a 12-month lamivudine course.[57]
Long-term lamivudine therapy may be an acceptable alternative therapeutic option given as maintenance therapy in patients with histologically advanced CHB. However, only one third of patients with HBeAg-negative CHB may have long-term benefit from such an approach, because viral resistance due to YMDD mutations develop in approximately two thirds of patients within 3 years of such long-term lamivudine monotherapy.[56] Such virologic breakthroughs are almost invariably followed by increasing viremia levels culminating in biochemical breakthroughs, which ultimately have an adverse effect on liver histology.[56] The optimal duration of lamivudine therapy has not been defined and most patients are currently kept on lamivudine for at least 3-5 years. Moreover, the course of HBeAg-negative CHB after discontinuation of lamivudine in patients who have remained in very prolonged complete on-therapy remission is currently unknown. Virologic and biochemical relapses have occurred in the majority of a series of Greek patients after discontinuation of a 3-year course of effective lamivudine therapy (SJ Hadziyannis 2003, unpublished data.
Whether there is a difference in the sensitivity or resistance to lamivudine therapy between HBeAg-negative CHB patients with and without precore mutant HBV strains is currently unclear.[32] Precore mutant strains have been found to be replaced by precore wild-type strains when YMDD mutants are selected under lamivudine therapy.[58,59] Such observations might suggest that precore wild-type HBV compared with mutant HBV strains are more resistant to lamivudine and therefore "escape" during therapy. However, this hypothesis does not seem to be valid, because reappearance of precore mutant strains after their initial replacement, as well as reversion of precore wild-type strains to mutant strains, have also been reported.[59,60] Thus, no clear relationship between the presence of precore or even core promoter mutant strains and the efficacy of lamivudine therapy can be supported.[32]
Finally, it is noteworthy to point out that when precore HBV mutant strains of genotype D become YMDD-resistant, their replicative efficacy increases, whereas the contrary appears to be true for YMDD mutants with a wild-type precore region.[61] This observation may explain the frequent occurrence of severe virologic and biochemical breakthroughs in patients with HBeAg-negative CHB under lamivudine treatment that have been reported in studies from Greece, where there is a 95% predominance of HBV genotype D.[55,56,62]
Because lamivudine is a safe drug[33,54-56] with a safety profile similar to placebo,[54] specific follow-up for prompt detection of possible adverse events has not been decided. In many clinical trials,[54-56] lamivudine-treated patients were followed up with amylase, creatine phosphokinase, and lactate dehydrogenase determinations at least every 3 months (in order to monitor potential pancreatic reactions and mitochondrial toxicity) without any evidence of toxicity. The most disturbing event seen on lamivudine therapy is the occurrence of exacerbations of hepatitis, as expressed by significant elevations in ALT/AST levels.[33] Such exacerbations may develop during therapy due to emergence of lamivudine-resistant HBV strains[55,56] or after discontinuation of lamivudine therapy due to relapse of wild-type HBV.[33] When hepatitis exacerbations occur in patients with advanced liver disease, they may be associated with development of hepatic decompensation.[33] Thus, lamivudine-treated patients should be closely monitored (at least every 3 months) with ALT/AST determinations during therapy and for at least 1 year after discontinuation of therapy. Monitoring patients on lamivudine with frequent serum HBV-DNA determinations by sensitive PCR assays is useful, because it permits early recognition of virologic and subsequent biochemical breakthroughs.[56] However, the cost-benefit of such a monitoring approach has not been clarified as yet.
Adefovir dipivoxil. Adefovir, a nucleotide analogue of adenosine, is a new anti-HBV agent that is administered orally as adefovir dipivoxil. The prodrug, adefovir dipivoxil, is adefovir esterified with 2 pivalic acid molecules and has good oral availability.[63] The "48-week results" from 2 large phase 3, randomized, placebo-controlled, clinical trials of adefovir dipivoxil therapy in patients with HBeAg-positive and -negative CHB were published recently.[64,65] In both trials, the 10-mg adefovir dipivoxil daily dose was found to be very well tolerated and to have a safety profile similar to placebo,[64,65] whereas a higher daily dose of 30 mg was found to be associated with an increased risk of renal damage without a significant benefit in efficacy.[64] Thus, the recommended dose of adefovir dipivoxil for CHB is 10 mg daily, irrespective of HBeAg status. Adefovir dipivoxil can be safely administered at the daily dose of 10 mg in patients with hepatic or mild renal impairment, but dosing interval adjustments are recommended for patients with creatinine clearance of < 50 mL/min and patients requiring hemodialysis.[66]
In the HBeAg-negative CHB setting, adefovir dipivoxil was found to effectively suppress biochemical activity and HBV replication during the first 48 weeks of therapy.[65] Most specifically, ALT levels normalized in 72% and 29% (P < .001), and serum HBV-DNA was undetectable by PCR in 51% and 0%, of the 123 adefovir dipivoxil- and the 61 placebo-treated patients, respectively (P < .001). Median serum HBV-DNA levels dropped at 48 weeks compared with baseline by 3.9 log10 copies/mL in the adefovir dipivoxil group and by 1.35 log10 copies/mL in the placebo group (P < .001) . Moreover, at 48 weeks, histologic improvement was observed in 64% of adefovir dipivoxil-treated and in 33% of placebo-treated patients (P < .001).[65]
Whether a defined course of adefovir dipivoxil may achieve SR maintained after drug discontinuation in a sizeable proportion of patients with HBeAg-negative CHB is currently not known. However, the majority of on-therapy responders are expected to relapse soon after discontinuation of a 48-week course of adefovir dipivoxil therapy, and therefore, long-term adefovir dipivoxil treatment will likely be needed to maintain on-therapy responses. Data on the efficacy of long-term adefovir dipivoxil therapy are available from a single phase 2 extension study including 39 patients with HBeAg-positive (n = 28) and HBeAg-negative (n = 11) CHB,[67] and from the second year of the study by Hadziyannis and colleagues.[68] Two-year adefovir dipivoxil therapy was found to maintain on-therapy biochemical and virologic remission activity in both patients with HBeAg-positive and -negative CHB without significant toxicity and without evidence of significant viral resistance (< 2%),[67,68] likely signaling the start of a new era in the treatment of CHB. Studies with long-term adefovir dipivoxil therapy are under way. However, similar to lamivudine therapy, the optimal duration of adefovir dipivoxil therapy in patients with HBeAg-negative CHB is currently unknown.
Adefovir dipivoxil given at the recommended dose of 10 mg daily is a safe drug with a safety profile similar to placebo.[64,65] However, careful monitoring is required during its use in clinical practice. Renal toxicity appears to be a potential hazard, at least in patients taking more than 10 mg daily, or in those with impaired renal function,[64] and therefore patients treated with adefovir dipivoxil should be closely monitored with frequent determinations of serum creatinine and phosphorus levels. Moreover, patients should be monitored with ALT/AST determinations, while surveillance for viral resistance should continue -- particularly with long-term use of the drug.
B. Re-treatment of HBeAg-negative CHB:
Patients with HBeAg-negative CHB who fail to achieve SR after 1 course of interferon-alfa therapy may be re-treated with a second interferon-alfa course, with lamivudine, or with adefovir dipivoxil. Re-treatment with interferon-alfa has been shown to have the same efficacy as that of interferon-alfa therapy in treatment-naive patients.[44] The on-drug or on-treatment efficacy of lamivudine or adefovir dipivoxil does not differ between treatment-naive and previously interferon-alfa-treated patients with HBeAg-negative CHB, but the rate of SR is negligible.
Patients who do not initially respond to lamivudine may be treated with interferon-alfa or adefovir dipivoxil or referred for treatment in clinical trials with other antiviral agents. Patients who relapse after discontinuation of lamivudine without having developed YMDD mutants may be re-treated with lamivudine[69] or even with a course of interferon-alfa or adefovir dipivoxil. In contrast, lamivudine re-treatment is ineffective in patients who have developed YMDD mutant HBV strains during a previous course of lamivudine therapy because rapid reemergence of the lamivudine-resistant strains will inevitably occur.[70]
C. Treatment of HBeAg-negative CHB with resistance to lamivudine:
Although adefovir dipivoxil is the only approved agent for the treatment of patients who have developed resistance to lamivudine, entecavir is a potential candidate in this setting.[40,71] Moreover, interferon-alfa given as monotherapy or in combination with lamivudine may be used against lamivudine-resistant HBV mutant strains.[40] However, the efficacy of interferon-alfa has not yet been evaluated in any well-designed study in this setting, therefore no conclusion can de drawn.
In recent clinical trials, the addition of adefovir dipivoxil was shown to achieve significant reduction in serum HBV-DNA levels and improvement in liver function tests and Child-Pugh score in patients with decompensated cirrhosis or in post-liver transplant patients with resistance to lamivudine, irrespective of HBeAg status.[72-75] Adefovir dipivoxil was also found to have similar antiviral efficacy against all types of lamivudine-resistant YMDD mutant HBV strains.[76] Moreover, in a small randomized study including patients with HBeAg-positive CHB and lamivudine resistance, adefovir dipivoxil monotherapy was reported to demonstrate similar efficacy as the combination of adefovir dipivoxil and lamivudine.[77]
Entecavir, a carboxylic analogue of guanosine, has potent and selective inhibitory activity against all HBV polymerase functions.[78] Entecavir has demonstrated efficacy against lamivudine-resistant YMDD mutant HBV strains.[79] In a recent large randomized clinical trial of entecavir treatment, at 24 weeks serum HBV-DNA levels were undetectable by the bDNA assay in approximately 50% to 75% of patients given 0.5 or 1.0 mg entecavir daily. The median serum HBV-DNA log10 drop at 24 weeks was 3.9 and 4.4 for the 0.5- and 1.0-mg entecavir doses respectively, whereas a biochemical response was observed in approximately 60% of patients at 24 weeks.[80]
New Drugs -- Combination Therapies and Concluding Remarks
The development of lamivudine (and recently adefovir dipivoxil) has offered the hepatologist new therapeutic options against HBV infection besides interferon-alfa. Several newer antiviral agents, mainly nucleoside analogues, immunomodulatory agents, or combinations thereof, are currently undergoing evaluation for the treatment of CHB. Newer antiviral agents, such as emtricitabine (the 5-fluorinated derivative of lamivudine), clevudine (a pyrimidine analogue), and L-nucleosides (natural nucleosides in beta-L-configuration), particularly L-deoxythymidine, have yielded promising results in preliminary phase 1/2 trials. In contrast, initial data regarding the efficacy of immunomodulatory approaches, such as interleukin-2 or -12, interferon-gamma, or vaccine-based therapies, have been relatively disappointing.[40]
Besides interferon-alfa therapy, which may achieve SRs in a small proportion (15% to 25%) of HBeAg-negative CHB patients,[32] monotherapy with nucleoside/nucleotide analogues is unlikely to result in clearance of HBV from infected hepatocytes and thus SR, despite a strong initial antiviral effect.[71] Therefore, the use of combinations of therapeutic agents seems to be the next reasonable step in the treatment of such difficult-to-manage patients.[81] However, the efficacy of such regimens cannot be easily extrapolated from in vitro or small preliminary clinical studies and must be documented in well-designed clinical trials. Combination regimens involving lamivudine with pegylated interferon-alfa or immunomodulatory agents, including a therapeutic vaccine, are currently undergoing evaluation in phase 3 clinical trials.
Thus, the development of more effective combination antiviral regimens appears to be a challenging task. Ideally, drugs with complementary mechanisms of antiviral activity should be used concurrently and/or sequentially, and drug resistance should be avoided. It should be kept in mind, however, that patients with CHB do not represent a homogeneous population for global evaluation of new antiviral therapies; response rates may differ between patients with HBeAg-positive and HBeAg-negative CHB, or between treatment-naive patients and those who have failed to respond to different antiviral agents in the past. Therefore, the new therapeutic approach may need to tailor treatment to different patient characteristics.