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Stephanos J. Hadziyannis, George V. Papatheodoridis *
Department of Medicine & Hepatology, Henry Dunant Hospital, Athens, Greece
* Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
New antiviral agents currently evaluated for the treatment of HBeAg–negative chronic hepatitis B include adefovir, entecavir and some other newer nucleoside analogues. Adefovir, a nucleotide analogue of adenosine, is expected to be soon available in clinical practice. The recommended 10 mg daily dose is safe and well tolerated. In a phase III clinical trial, a 48-week course of adefovir was recently shown to achieve histologic improvement, inhibition of HBV replication and biochemical remission in the majority of HBeAg–negative chronic hepatitis B patients. Adefovir is also effective against lamivudine resistant HBV strains, while no evidence of resistance to adefovir has been detected to date. Entecavir, a guanosine analogue, has initially been shown to suppress HBV replication given even in a low dose of 0.1 mg daily. In a recent phase III trial including lamivudine resistant HBV patients, a 24-week course of entecavir at daily doses of 0.5 mg or 1.0 mg achieved significantly greater reduction of serum HBV-DNA levels than the low 0.1 mg entecavir dose or continuation of lamivudine. Entecavir was safe and well tolerated and is currently under evaluation within several phase III trials. Preliminary data for emtricitabine, clevudine, and L-deoxythymidine suggest that all these agents are probably effective against both HBeAg-positive and HBeAg–negative chronic hepatitis B. However, whether any of these new agents as monotherapy or in combination therapies can induce sustained off-therapy responses in the patients with long-standing HBeAg–negative chronic hepatitis B is currently unknown.
Currently approved therapeutic options for chronic hepatitis B are interferon-alfa (IFN-a) and lamivudine (1,2). Their efficacy, safety profile, advantages and disadvantages in HBeAg-negative chronic hepatitis B have already been commented in detail in the previous two articles (3,4). The relative poor efficacy of these agents in achieving sustained response highlights the need for better therapies in both HBeAg–positive and HBeAg–negative hepatitis B virus (HBV) related liver disease (5).
Therapeutic approaches beyond IFN-a and lamivudine under evaluation against HBV include other antiviral agents, mainly nucleos(t)ide analogues, immunomodulation, molecular approaches, or combinations (Table 1). Of the antiviral agents, famciclovir and ganciclovir have been evaluated within phase III and phase II trials respectively and found to be rather ineffective (6,7), adefovir is expected to be soon available in clinical practice and newer agents are under phase II or III clinical trials (Table 1). This review focuses on the efficacy of adefovir, entecavir and some newer antiviral agents in the treatment of HBeAg–negative chronic HBV liver disease. Immunomodulatory, molecular and combination therapies are commented in separate articles of this issue (8,9).
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Adefovir is a very promising new anti-HBV agent that has recently been filed for regulatory approval for the treatment of chronic hepatitis B in both Europe and USA. It is a nucleotide analogue of adenosine and is administered orally as a prodrug, adefovir dipivoxil (ADV), which is adefovir esterified with two pivalic acid molecules and has good oral availability (10). ADV is rapidly converted to adefovir in plasma and tissues, which has a plasma haf-life of 5-7 hours and is excreted in urine (90% of the drug within 24 hours) (10). After being transported intracellularly by a receptor-based mechanism, adefovir is phosphorylated to its diphosphate form, which is an analogue of deoxyadenosine-5’-triphosphate but without a 3’-hydroxylic root and therefore results in competitive inhibition of DNA synthesis by DNA polymerases and reverse transcriptases (10).
The 48-weeks results of a large phase III clinical trial of ADV therapy in patients with HBeAg–negative chronic hepatitis B (11) were recently reported. In total, 184 patients were randomised to initially receive 10 mg of ADV daily (n=123) or placebo (n=61). At 48-weeks, histologic improvement (defined as ³2 point reduction in the Knodell necroinflammatory score with no worsening in fibrosis) was observed in 64% of ADV treated and 33% of placebo treated patients (P<0.001), ALT normalised in 72% and 29% (P<0.001) and serum HBV-DNA was undetectable by a polymerase chain reaction (PCR) assay in 51% and 0% of patients respectively (P<0.001). ). Median serum HBV-DNA levels dropped at 48-weeks compared to baseline by 3.9 logs in the ADV and 1.35 logs in the placebo treated patients (P<0.001).
The 10 mg ADV daily dose was found to be very well tolerated and to have a safety profile similar to placebo in the HBeAg–negative chronic hepatitis B trial (11) as well as in another larger clinical trial including patients with HBeAg–positive chronic hepatitis B (12). In the latter clinical trial, a high ADV daily dose of 30 mg was also used and found to be associated with a higher incidence of mild and reversible renal impairment compared to both placebo and the 10 mg ADV dose (12). Relatively higher ADV doses (60 or 120 mg daily) have also been reported to be associated with an increased risk of nephrotoxicity after 20 or more weeks of therapy (13). Based on these findings and the similar efficacy between the 10 mg and the 30 mg ADV dose in the HBeAg–positive chronic hepatitis B (12), the 10 mg ADV dose has been selected to be the dose of choice for the treatment of both HBeAg–positive and –negative chronic hepatitis B. The 10 mg ADV dose can be safely administered even in patients with hepatic or mild renal impairment and dosing interval adjustments are recommended only for patients with creatinine clearance of less than 50 mL/min and patients requiring hemodialysis (14). ADV has also been shown to have no significant interaction with other drugs (15).
A very interesting finding of the two large ADV trials is that no evidence of resistance to ADV was detected throughout the 48-week treatment period (11,12). In fact, viral resistance to ADV has not been detected to date even in patients taking the drug for up to 136 weeks (16).
ADV has also been evaluated for the treatment of resistant to lamivudine YMDD mutant HBV strains, as initial in vitro data were very promising (17,18). In recent clinical trials including both HBeAg–positive and –negative HBV decompensated cirrhotics or transplant patients with resistance to lamivudine, ADV was shown to be well tolerated and to achieve significant reduction in serum HBV-DNA levels and improvement in liver function tests and Child-Pugh score (19-22). ADV was found to have similar antiviral efficacy against all types of lamivudine resistant YMDD mutant HBV strains (23). Preliminary recent data also suggested that ADV monotherapy may achieve the same inhibition of YMDD mutant HBV replication as that achieved by the combination of ADV plus lamivudine. In a randomised trial including patients with HBeAg–positive chronic hepatitis B and confirmed resistance to lamivudine, the reduction of serum HBV-DNA levels and the proportion of patients with ALT normalization did not significantly differ after 16 weeks of ADV monotherapy (10 mg daily) or of combination of ADV (10 mg daily) and lamivudine (100 mg daily) (24). In addition, maintaining lamivudine therapy seemed to delay or prevent the reversion of YMDD mutant to YMDD wild HBV strains, which was often observed in patients treated with ADV alone (25). Whether ADV monotherapy has similar efficacy with the combination of ADV and lamivudine for the treatment of HBeAg–negative patients with resistance to lamivudine remains to be evaluated.
Although ADV is superior than placebo in the treatment of HBeAg–negative chronic hepatitis B patients, still approximately 30% of them maintain increased biochemical activity after 48 weeks (11). Moreover, there are no data on the frequency of virologic and biochemical relapses after stop of 1, 2 or more years of ADV therapy in patients with HBeAg–negative chronic hepatitis B and, similarly to lamivudine, there is no evidence that sustained off-therapy responses and HBsAg clearance can be achieved with ADV monotherapy of whatever duration. Thus, long-term therapy will probably be needed in order to maintain on-therapy remission in the HBeAg negative chronic hepatitis B patients. Data on the efficacy of long-term ADV therapy are available from only one phase II extension study including 39 patients with HBeAg–positive (n=28) and HBeAg–negative (n=11) chronic hepatitis B (26). In this study, long-term (median: 24 months, maximum: 32 months) of ADV therapy was found to have sustained antiviral activity in both HBeAg–positive and –negative chronic hepatitis B without significant toxicity and without evidence of viral resistance (26). Recently, a program of expanded access of ADV for lamivudine resistant chronic hepatitis B patients has become available in many countries.
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Entecavir is a carboxylic analogue of guanosine with potent and selective inhibition on all HBV polymerase functions, i.e. priming and formation of both negative and positive strand (27). Preliminary data suggested that entecavir given even in a low dose of 0.1 mg daily suppresses satisfactorily HBV replication in treatment-naïve or lamivudine resistant chronic hepatitis B patients (28,29). In a phase II dose defining study, the entecavir daily administration of 0.1 mg and 0.5 mg was found to achieve greater inhibition on HBV replication compared to 100 mg of lamivudine, while the entecavir dose of 0.01 mg was found to be suboptimal (30).
The results of a large clinical trial of entecavir therapy in patients with HBeAg–positive (n=121) or –negative (n=60) chronic hepatitis B and resistance to lamivudine were recently presented (31). In this double-blind, randomised trial, 3 doses of entecavir (0.1 mg, 0.5 mg and 1.0 mg daily) were compared with continued lamivudine therapy in the usual daily dose of 100 mg. At 24-weeks, the primary end-point of the study [serum HBV-DNA undetectable by the Chiron branched DNA (bDNA) assay] was achieved in approximately 75% of patients treated with the high 1.0 mg entecavir dose and in 50% of those treated with the 0.5 mg entecavir dose (P=0.012). Both doses were significantly superior than the low 0.1 mg entecavir dose or continuation of lamivudine, which achieved undetectable by bDNA serum HBV-DNA only in about 15% of cases (P<0.001 for the comparison between the 1.0 mg or 0.5 mg doses of entecavir with lamivudine).The median serum HBV-DNA decrease at 24-weeks compared to baseline levels was 4.4 logs, 3.9 logs and 2.0 logs for the 1.0 mg, 0.5 mg and 0.1 mg entecavir dose respectively and 0.9 logs for continuation of lamivudine, but HBV-DNA clearance by PCR was observed in only 17% in the 1.0 mg and 9% in the 0.5 mg entecavir dose group and in 2% in the lamivudine group (31).
The antiviral efficacy of entecavir appeared to be associated with the type of baseline YMDD mutations (31). In particular, the reduction in HBV-DNA levels was greater in patients with HBV mutant strains with isoleucine at position 552 (M552I), or with valine at position 552 (M552V) and concomitant methionine at position 528 (L528M) compared with those with only M552V mutation, while highly variable virologic responses were observed in cases with both M552I and L528M mutations. Biochemical remission at 24-weeks was observed in approximately 60% of the patients treated with the 0.5 mg entecavir dose, 40% of those treated with the 1.0 mg and 0.1 mg entecavir doses and in only 20% of those treated with lamivudine (31).
Entecavir in all daily doses from 0.1 to 1.0 mg was found to be well tolerated and with a good safety profile similar to that of lamivudine (31). The results of entecavir efficacy at 48 weeks in this study are now awaited.
On the basis of these promising results in terms of entecavir efficacy and safety, the drug is currently under evaluation in phase III trials comprising both HBeAg–positive and HBeAg–negative chronic hepatitis B patients either treatment-naïve or lamivudine resistant. In the case of HBeAg–negative chronic hepatitis B, it has been claimed that the target of entecavir therapy is to induce sustained remission after stopping a course of defined duration.
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Emtricitabine (FTC) is the 5-fluorinated derivative of lamivudine (32). It requires activation by intracellular phosphorylation and results in potent inhibition of HBV replication (32). A probable disadvantage of this agent is that it may be inactive against lamivudine resistant YMDD mutant HBV strains and its use may be associated with development of similar resistant HBV strains (33).
Data of a 48-week course of emtricitabine therapy in 21 patients with HBeAg–negative chronic hepatitis B were recently reported (34). Emtricitabine was given at a daily dose of 25 mg (n=10), 100 mg (n=4) or 200 mg (n=7) and achieved a median HBV-DNA drop of 2.5-2.7 logs irrespective of the drug dose. In this preliminary small study, 95% (20/21) of patients had normal ALT and 76% (16/21) undectable serum HBV-DNA by Digene II assay (sensitivity: 4,700 cp/mL) (34). Emtricitabine is currently evaluated within phase III clinical trials for the treatment of patients with HBeAg–negative chronic hepatitis B.
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Clevudine is a pyrimidine analogue that acts through its triphosphate form inhibiting HBV-DNA polymerase (35). Initial results from a phase I/II dose escalation 4-week study of clevudine therapy in patients with HBeAg–positive or –negative chronic hepatitis B were reported recently (36). Clevudine was given at a daily dose of 10 mg (n=5), 50 mg (n=10) and 100 mg (n=10). At the end of the 4-week study period, ³2 logs reduction in serum HBV-DNA levels was observed in more than 70% of patients irrespective of the drug dose, while ³3 logs HBV-DNA drop was observed relatively more frequently in the 100 mg clevudine dose group. Moreover, there was some degree of sustained antiviral effect, since median serum HBV-DNA remained below baseline levels during the 6-month period following the end of the 4-week clevudine course (36).
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L-Nucleosides, which are the natural nucleosides in their b-L-configuration, represent a new class of agents evaluated in the treatment of chronic hepatitis B. They include L-deoxythymidine (L-dT), L-deoxycytidine (L-dC), and L-deoxyadenosine (L-dA). All L-nucleosides have been shown to have potent, selective and specific inhibitory activity against hepadnaviruses (37). A recent in vitro study, however, suggested that L-dT and L-dC may be inactive against lamivudine resistant YMDD mutant HBV strains (38).
Initial results of a 4-week dose escalation study of L-dT in 30 HBeAg–positive chronic hepatitis B patients were reported recently (39). L-dT was given at a daily dose of 25 mg, 50 mg, 100 mg, 200 mg, and 400 mg and found to achieve a 2.4 to 3.6 logs median decrease in serum HBV-DNA levels without significant or dose related toxicities (39). There was a trend for association between the L-dT dose and the overall reduction in serum HBV-DNA levels (the 800 mg L-dT dose was shown later to achieve 4 logs HBV-DNA drop) and a strong dose related antiviral effect on the second phase of HBV clearance (between weeks 1 and 4) that was suggested to reflect the absolute decrease of infected hepatocytes (40). Phase III clinical trials of L-dT therapy for HBeAg–positive and –negative chronic hepatitis B are in progress.
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The main mechanism of action of all nucleos(t)ide analogues is the competition with natural nucleoside triphosphates for incorporation into viral DNA by the HBV polymerase and thus the termination of the elongation of HBV-DNA chain and the cessation of HBV replication (41). All these agents have little, if any, effect on covalently closed circular DNA (cccDNA) (42) and therefore clearance of cccDNA can be accomplished only indirectly by the death of infected hepatocytes (43). The combination of the high HBV replication rate and the slow death rate of infected hepatocytes (44) suggests that prolonged antiviral therapy is required in order to eradicate HBV (45), particularly in HBeAg-negative chronic hepatitis B patients with long-standing disease and a great percentage of hepatocytes infected by the virus (46).
As shown with lamivudine therapy, the effectiveness of long-term treatment with nucleoside analogues may be progressively decreasing due to emergence of resistant mutant HBV strains with changes in the structure of HBV polymerase resulting in reduced affinity with the drug (45). All retroviruses including HBV exhibit increased rate of emergence of mutations due to both high viral turnover and high error rate of viral polymerase and therefore resistant HBV mutant strains are expected to emerge and be selected in patients with chronic HBV infection treated with nucleoside analogues, similarly to what has been previously observed in patients with HIV infection (47). If the promising findings of absence of viral resistance after ADV therapy are confirmed (16), this would be a great advantage of this agent, which may become the treatment of choice for long-term maintenance of at least on-therapy remission in patients with HBeAg-negative chronic hepatitis B.
The recent development of all these new and potent anti-HBV agents may soon offer to the hepatologists many therapeutic options against HBV. The wide use of lamivudine in chronic hepatitis B during the last 3-4 years, however, has resulted in constant increase of patients with YMDD mutant HBV strains, whose treatment may be the most pressing task for the current anti-HBV clinical practice (45). Both adefovir and entecavir appear to be effective against such YMDD mutant HBV strains and open access programs with adefovir have already started in many liver centers worldwide. Data from phase III clinical trials showed that adefovir, which is probably the first of these agents to be available in the market worldwide, is also effective against YMDD wild HBV strains, while entecavir and other newer agents are currently evaluated and will be probably found to be effective against such HBV strains. However, whether long-term treatment with any of these new nucleos(t)ide analogues can induce sustained on- or off-therapy response at least in a proportion of HBeAg-negative chronic hepatitis B patients or whether combinations of these agents or of drugs with complementary mechanisms of antiviral activity are needed for prevention of HBV resistance and/or induction of sustained responses are currently unknown.
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