Chronic hepatitis B is a dynamic process with an early replicative phase and active liver disease and a late low replicative phase with remission of liver disease [1-5]. A proportion of patients (about 20 to 30% of cases) continue to have or redevelop high levels of hepatitis B virus deoxyribonucleic acid (HBV DNA) and active hepatitis despite hepatitis B e antigen (HBeAg) seroconversion; these patients usually have HBV variants (with mutations in the pre-core and the basal-core promoter regions) unable to express HBeAg (HBeAg-negative chronic hepatitis B) [6-8]. HBeAg-negative chronic hepatitis B represents a late phase in the natural history of chronic hepatitis B and is associated with a very low rate of spontaneous disease remission [6,8,9].The proportion of patients with this form of chronic hepatitis B has been increasing in recent decades and represents the majority of cases in Mediterranean countries [10].
The decision to treat or not to treat patients with HBeAg-negative chronic hepatitis B is mainly based on the results of liver histology [5]. In patients with mild liver disease, treatment is not recommended, unless liver fibrosis deteriorates.
The first objective of treatment is to decrease HBV replication in order to decrease necroinflammation in the liver and therefore prevent the progression of fibrosis. Thus, the interruption of the fibrogenesis process prevents progression to cirrhosis and its complications, including hepatocellular carcinoma (HCC), and therefore improves survival. If HBV replication is completely interrupted (as reflected by the absence of detectable HBV DNA in the serum by sensitive assays), loss of detectable hepatitis B surface antigen (HBsAg; with or without HBsAg seroconversion) may occur, and this is associated with complete disappearance of liver necroinflammation with no risk of reactivation.
This review, after a brief summary on available drugs, focuses on new treatments of chronic hepatitis B.
STANDARD INTERFERON ALPHA
Interferon (IFN) has been used in the treatment of chronic hepatitis B for many years. IFN exerts an antiviral effect on infection with HBV [11]. Many controlled studies of IFN in patients with chronic hepatitis B have been reported [12-15]. In HBeAg-positive chronic hepatitis B, with various schedules, the mean virological response rate was 37 versus 17%, mean HBeAg loss rate was 33 versus 12%, and HBsAg loss rate was 8 versus 2% in the IFN-treated groups versus the placebo groups [12].
In HBeAg-negative chronic hepatitis B, mean biochemical and virological response rate was approximately of 25% [13-15].
PEGYLATED INTERFERON ALPHA-2A
A first proof-of-concept, randomized controlled study of pegylated interferon alpha-2a (PEG IFNα-2a) has been performed in patients with HBeAg-positive chronic hepatitis B [16]. This study strongly suggests that PEG IFNα-2a is more effective than standard IFN 2a for the treatment of chronic hepatitis B.
Three large, randomized controlled trials have confirmed the efficacy of PEG IFNs in HBeAg-positive chronic hepatitis B (two trials with PEG IFNα-2b and one with PEG IFNα-2a) but only one large randomized controlled trial has been performed in HBeAg-negative chronic hepatitis B with PEG IFNα-2a [17-20].
Studies show that, first, the efficacy, as assessed at 24 weeks posttreatment, of PEG IFNα-2a monotherapy is superior to lamivudine monotherapy and, second, the combination of PEG IFNα-2a with lamivudine (with the simultaneous regimen used) is not superior to PEG IFNα-2a used in monotherapy.
LAMIVUDINE
Lamivudine, a nucleoside analogue that directly inhibits HBV-DNA polymerase, was first developed as a reverse transcriptase inhibitor for use in human immunodeficiency virus (HIV) infection. It also has activity against HBV at lower concentrations. Lamivudine (2′,3′-dideoxy-3′-thiacytidine) is a minus enantiomer, and it is thought that this may help to explain the very low rate of side effects noted with this agent. Randomized controlled trials have shown the efficacy of lamivudine in the treatment of HBeAg-positive and HBeAg-negative chronic hepatitis B.
In patients with HBeAg-negative chronic hepatitis B, one randomized controlled study [21] showed an efficacy similar to that observed in patients with HBeAg-positive chronic hepatitis B with the same rate of resistance. HBV DNA was undetectable (non-polymerase chain reaction [PCR]-based assays) after 12 months of therapy in 90% of patients (70% with PCR-based assays). Serum alanine aminotransferase (ALT) normalized in 75% of patients. A fall in HBV DNA and normalization of ALT occurred only in 5% of patients on placebo. Histological response was observed in 60% of lamivudine-treated patients. Predictors of response to lamivudine have not been established in this population. In patients with a virological response at the end of a 12-month course of lamivudine, the sustained response rate 6 months posttreatment was less than 5%. In studies with prolonged therapy, response rates peak at 12 months and decrease thereafter [22]. At 30 months, rates of virological and biochemical responses were 30 and 60%, respectively.
The rate of resistance observed in patients with HBeAg-negative chronic hepatitis was similar to that observed in HBeAg-positive chronic hepatitis. Lamivudine-resistant mutants appeared in 10 to 40% of patients after 1 year of therapy, and in 50 to 60% of those treated continuously for 3 years [23-25]. Likewise in HBeAg-positive patients, the emergence of resistant mutant HBV was accompanied by an increase of HBV DNA and, after a few months, by elevation in ALT. Flares occurred in 30% of patients and were symptomatic or severe in some cases. As in HBeAg-positive patients, treatment with adefovir dipivoxil is generally effective in patients who develop lamivudine resistance.
The tolerability and safety of lamivudine are excellent; the incidence of adverse events is similar to that of placebo. Lamivudine therapy seems to be well tolerated for up to 5 years.
The major inconvenience of lamivudine is the high rate of occurrence of viral resistance related to mutations in the YMDD motif. The most important mutation is a substitution of valine or isoleucine for methionine in the YMDD motif of the HBV polymerase gene (rtM204V/I). In many patients this is accompanied by a second mutation substituting methionine for leucine in an upstream region (rtL180M). Lamivudine resistance is more likely to occur in patients with high baseline serum HBV-DNA levels. The emergence of lamivudine-resistant mutants is usually associated with a breakthrough, with a moderate increase in serum HBV-DNA and ALT levels, which may remain lower than at baseline (ie, before starting therapy) for several months. However, severe cases have been reported in patients with cirrhosis. In patients who develop the lamivudine-resistant mutant, adefovir dipivoxil is effective and should be initiated rapidly if an increase in ALT is observed, especially in patients with cirrhosis who have a risk of hepatic decompensation. In order to diagnose the emergence of resistance earlier during therapy (ie, before the appearance of detectable serum HBV DNA by standard assays and before the increase in ALT), monitoring of serum HBV-DNA levels by a sensitive assay is useful. Indeed, an increase in serum HBV DNA of >1 log generally reflects the appearance of a resistant mutant, and this sign permits switching to another antiviral several months before the increase in ALT.
ADEFOVIR DIPIVOXIL
Adefovir dipivoxil has been recently registered for the treatment of chronic hepatitis B. Adefovir dipivoxil is the oral prodrug of adefovir. Adefovir is a nucleotide analogue of adenosine monophosphate. In vivo, adefovir dipivoxil is converted to the parent compound, adefovir, and through two phosphorylation reactions to adefovir diphosphate, the active intracellular metabolite that interacts with HBV polymerase. Adefovir diphosphate acts as a competitive inhibitor and chain terminator of viral replication.
Adefovir was registered for the treatment of chronic hepatitis B in the United States in September 2002 and in Europe in March 2003. Two large randomized controlled trials have shown that adefovir is effective in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B [26-27]. Adefovir administration for 48 weeks induced a mean reduction of HBV DNA of 3.5 and 3.9 log10 copies/mL, with normalization of ALT in 48 and 72% of patients and improvement of liver histology in 53 and 64% of patients in the two studies, respectively. The results of long-term administration for up to 3 years showed that the benefits of treatment were maintained, and virological, biochemical, and histological response rates were stable [28].
Resistance to adefovir occurs relatively late.There was no case of resistance described during 48 weeks of adefovir administration in the two pivotal studies performed in HBeAg-positive and HBeAg-negative chronic hepatitis B [26-27]. To determine the incidence of resistance to adefovir more precisely, an extensive genotyping study was performed in patients who received adefovir for up to 192 weeks in several clinical studies, including 293 patients with HBeAg-negative compensated chronic hepatitis B, pre- and post-transplantation patients, and HIV-HBV co-infected patients [29]. Two adefovir-resistant mutations (N236T and A181V) were identified in 22 patients. Interestingly, all 22 patients who developed adefovir-resistant mutations were receiving adefovir monotherapy. These observations suggest that the combination of adefovir with lamivudine prevents (or delays) adefovir resistance. Predictors of the risk of developing resistant HBV must be well identified.The probability of developing mutations with adefovir, as with lamivudine, depends on the ability of the drug to suppress viral replication. An analysis of predictors of resistance was performed in 124 HBeAg-negative patients who received 144 weeks of adefovir [29]. HBV-DNA levels at 48 weeks of treatment were associated with the risk of resistance: the risk of resistance was more than 25% in patients with HBV-DNA levels above 3 log10 copies/mL, while it was 4% in those with HBV-DNA levels below 3 log10 copies/mL.
These results show that patients with HBV-DNA levels above 1000 copies/mL after 1 year of treatment with adefovir should be closely monitored, and initiation of lamivudine therapy should be considered. The development of resistance should be diagnosed early [30]. Although reliable assays are available for the detection of specific mutations associated with resistance, they are not always available to clinicians, so regular measurements of HBV-DNA levels are useful for diagnosing resistance: an increase of 1 log or more (if compliance is good) is an early indication of resistance before ALT increases. Therapy can be adjusted and another antiviral drug initiated based on the results of monitoring. Lamivudine is currently the best option, since its efficacy has been reported. However, other drugs (entecavir, telbivudine, or pegylated interferon) might be more effective and must be evaluated so that the best therapeutic strategy in patients developing resistance to adefovir can be determined.
ENTECAVIR
Entecavir, a cyclopentyl guanosine analogue, is a potent inhibitor of HBV-DNA polymerase, inhibiting both the priming and elongation steps of viral DNA replication. Entecavir is phosphorylated to its triphosphate, the active compound, by cellular kinases. It is a selective inhibitor of HBV DNA and is less effective against lamivudine-resistant mutants than it is against wild-type HBV [31-33].
In a 24-week, double-blind, randomized trial, the safety and efficacy of three different doses of entecavir (0.01 mg/day, 0.1 mg/day, and 0.5 mg/day) were compared to lamivudine (100 mg daily). In total, 169 patients were included [34]. Compared with lamivudine, entecavir reduced HBV DNA by an additional 0.97 log at the 0.1 mg dose and 1.28 at the 0.5 mg dose (p <.0001). At 22 weeks of therapy, 83.7% of patients treated with entecavir 0.5 mg had an HBV-DNA level below the lower limit of detection of the assay (0.7 ME/mL) compared to 57.5% treated with lamivudine (p = .008). However, very few patients achieved HBeAg loss (0 and 6% in both groups, respectively). A dose-response relationship was observed. Entecavir was well tolerated at all doses; most adverse events were mild-to-moderate and transient with no significant differences observed between the different doses of entecavir and lamivudine. This study indicates that the 0.5 mg dose of entecavir could be the optimal dose.
Entecavir also showed activity in patients with lamivudine-resistant HBV. A recent randomized, dose-ranging, phase II study compared the efficacy and safety of entecavir with lamivudine in lamivudine-refractory patients [35]. HBeAg-positive and HBeAg-negative patients (n = 182), viremic despite lamivudine treatment for at least 24 weeks or having documented lamivudine-resistance substitutions, were switched directly to entecavir (1.0, 0.5, or 0.1 mg daily) or continued on lamivudine (100 mg daily) for up to 76 weeks. At week 24, significantly more patients receiving entecavir 1.0 mg (79%) or 0.5 mg (51%) had undetectable HBV-DNA levels by branched chain DNA assay compared with lamivudine (13%; p <.0001). Entecavir 1.0 mg was superior to entecavir 0.5 mg for this end point (p <.01). After 48 weeks, mean reductions in HBV-DNA levels were 5.06, 4.46, and 2.85 log10 copies/mL on entecavir 1.0, 0.5, and 0.1 mg, respectively, significantly higher than 1.37 log10 copies/mL on lamivudine. Significantly higher proportions of patients achieved normalization of ALT levels on entecavir 1.0, 0.5, and 0.1 mg (68%, 59%, and 47%, respectively) than on lamivudine (6%). One virological rebound due to resistance occurred (in the 0.5-mg group). In HBeAg-positive and HBeAg-negative lamivudine-refractory patients, treatment with entecavir 1.0 and 0.5 mg daily was well tolerated and resulted in significant reductions in HBV-DNA levels and normalization of ALT levels. In this population, 1 mg of entecavir was more effective than 0.5 mg.
Two phase III studies demonstrate the efficacy and safety of entecavir given for 48 weeks as compared with lamivudine in HBeAg-positive and HBeAg-negative patients [36-37].
In a double-blind trial phase III, 715 patients with HBeAg-positive chronic hepatitis B who had not previously received a nucleoside analogue were randomly assigned to receive either 0.5 mg of entecavir or 100 mg of lamivudine once daily for a minimum of 52 weeks [36]. Histological improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, p = .009; Figure 1A). More patients in the entecavir group than in the lamivudine group had undetectable serum HBV-DNA levels according to a PCR assay (67 vs 36%, p <.001) and normalization of ALT levels (68% vs. 60%, p = .02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs 5.4 log10 copies/mL, p <.001). HBeAg seroconversion occurred in 21% of entecavir-treated patients and 18% of those treated with lamivudine (p = .33). No viral resistance to entecavir was detected. Safety was similar in the two groups.
 | Figure 1A. Entecavir in hepatitis B e antigen (HBeAg)-positive chronic hepatitis B. Histological improvement after 48 weeks occurred in 226 of 314 patients in the entecavir group (72%) and 195 of 314 patients in the lamivudine group (62%, p = .009). More patients in the entecavir group than in the lamivudine group had undetectable serum hepatitis B virus-deoxyribonucleic acid (HBV-DNA) levels according to a polymerase chain reaction (PCR) assay (67 vs 36%, p <.001) and normalization of alanine aminotransferase levels (68 vs. 60%, p = .02). The mean reduction in serum HBV DNA from baseline to week 48 was greater with entecavir than with lamivudine (6.9 vs. 5.4 log10 copies/mL, p<.001).
(From Chang TT, Gish RG, de Man R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006;354(10):1001-1010) |
In HBeAg-negative patients on entecavir, mean reductions in HBV-DNA levels were 5.2 log10 copies/mL, significantly higher than 4.66 log10 copies/mL on lamivudine (Figure 1B) [37]. Significantly higher proportions of patients on entecavir achieved normalization of ALT levels and obtained histological amelioration in comparison with lamivudine. The safety of the two drugs was similar. Accordingly, entecavir dosages of 0.5 mg/day are recommended for treatment-naïve patients and 1.0 mg/day for lamivudine-refractory patients. The response rates tended to be slightly lower in patients with lamivudine¬resistant HBV.
 | Figure 1B. Entecavir in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. In HBeAg-negative patients on entecavir, mean reductions in hepatitis B virus-deoxyribonucleic acid (HBV-DNA) levels were 5.2 log10 copies/mL, significantly higher than 4.66 log10 copies/mL on lamivudine. Significantly higher proportions of patients on entecavir achieved normalization of alanine aminotransferase levels and obtained histological amelioration, in comparison with lamivudine.
(From Lai CL, Shouval D, Lok AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2006;354(10):1011-1020 [Erratum in: N Engl J Med 2006;354(17):1863]) |
Furthermore, a phase III double-blind trial was conducted in HBeAg-positive patients who were refractory to lamivudine therapy (persistent viremia or documented YMDD mutations while receiving lamivudine). Patients were randomized to switch to entecavir 1 mg daily (n = 141) or continue lamivudine 100 mg daily (n = 145) for a minimum of 52 weeks [38]. Histological improvement occurred in 55% (68/124) of entecavir-treated versus 28% (32/116) of lamivudine-treated patients (p < .0001). Mean change from baseline in HBV DNA was -5.11 log10 copies/mL for entecavir-treated patients and -0.48 log10 copies/mL for lamivudine-treated patients (p < .0001). Virological rebound because of entecavir-resistance substitutions occurred in 2 of 141 entecavir-treated patients, and genotypic evidence of resistance was detected in 10 patients. The safety profile of entecavir was comparable to lamivudine with fewer ALT flares on treatment.
EMTRICITABINE
Emtricitabine (FTC) is a cytosine nucleoside analogue approved for treatment of human immunodeficiency virus 1 with clinical activity against HBV [31]. It differs from lamivudine by a fluorine at the 5-position of the nucleic acid.
In a randomized, double-blind study, 98 Asian patients (77 HBeAg-positive and 21 HBeAg-negative) were randomized to receive 25, 100, or 200 mg of emtricitabine daily for 48 weeks [39]. At 48 weeks, the median decreases in viral load were 2.6 log10, 3.1 log10, and 2.9 log10 (copies/mL) for the 3 doses, respectively. The proportions of patients with undetectable HBV DNA (below 4700 copies/mL) were 38, 42, and 61% for the 3 doses, respectively. HBeAg loss was observed in a high proportion (40%) of the HBeAg-positive patients (ranging from 32 to 50%, depending on the dose). Emtricitabine has a comparable efficacy in HBeAg-negative chronic hepatitis B [40].The results of this study suggest that the optimal dose of emtricitabine is 200 mg once daily. Genotypic analysis performed at week 48 showed that 12% of patients treated with 100 mg of emtricitabine and 6% of those treated with 200 mg developed drug-resistant HBV.
To compare the safety and efficacy of emtricitabine with placebo in patients with HBV, a randomized (2:1) double-blind study has been conducted at 34 sites in North America, Asia, and Europe. Between November 2000 and July 2002, the study enrolled adults who had chronic HBV infection but who had never been exposed to nucleoside or nucleotide treatment [41]. Each patient received either 200 mg of emtricitabine (n = 167) or placebo (n = 81) once daily for 48 weeks and underwent a pretreatment and end-of-treatment liver biopsy. At the end of treatment, 103 of 167 (62%) patients receiving active treatment had improved liver histological findings (a 2-point reduction in Knodell necroinflammatory score) versus 20 of 81 (25%) receiving placebo (p <.001), with significance demonstrated in subgroups positive (p <.001) and negative (p = .002) for HBeAg. Serum HBV-DNA readings showed less than 400 copies/mL in 91 of 167 (54%) patients in the emtricitabine group versus 2 of 81 (2%) in the placebo group (p <.001); ALT levels were normal in 65% (109/167) versus 25% (20/81), respectively (p <.001). At week 48, 20 of 159 (13%) patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8-18%). The rate of seroconversion to anti-HBe (12%) and HBeAg loss were no different between arms. The safety profile of emtricitabine during treatment was similar to that of placebo. The rate of emtricitabine-resistant mutations was 13% at 48 weeks. Post-treatment exacerbation of HBV infection developed in 23% of emtricitabine-treated patients. In patients with chronic HBV, both positive and negative for HBeAg, 48 weeks of emtricitabine treatment resulted in significant histological, virological, and biochemical improvement. Results for HBeAg-negative patients are presented in Figure 2.
 | Figure 2. Emtricitabine in chronic hepatitis B. At the end of treatment, 103 of 167 (62%) patients receiving active treatment had improved liver histological findings (2-point reduction in Knodell necroinflammatory score) versus 20 of 81 (25%) receiving placebo (p <.001), with significance demonstrated in subgroups positive (p <.001) and negative (p = .002) for hepatitis B e antigen (HBeAG). Serum hepatitis B virus-deoxyribonucleic acid (HBVDNA) readings showed less than 400 copies/mL in 91 of 167 (54%) patients in the emtricitabine group versus 2 of 81 (2%) in the placebo group (p <.001); alanine aminotransferase (ALT) levels were normal in 65% (109/167) versus 25% (20/81), respectively (p <.001). At week 48, 20 of 159 (13%) patients in the emtricitabine group with HBV DNA measured at the end of treatment had detectable virus with resistance mutations (95% confidence interval, 8-18%).The rate of seroconversion to anti-HBe (12%) and HBe antigen loss were not different between arms.
(From Lim SG, Ng TM, Kung N, et al.Emtricitabine FTCB-301 Study Group. A double-blind placebo-controlled study of emtricitabine in chronic hepatitis B. Arch Intern Med 2006;166:49-56) |
Emtricitabine selects for resistance mutations in the YMDD motif, which also confer resistance to lamivudine and other L-nucleosides, and discontinuation of therapy results in post-treatment exacerbation of hepatitis.Whether the combination of emtricitabine and tenofovir is superior to other approved treatments for chronic hepatitis B remains to be determined. Phase III clinical trials are under way to determine the long-term safety and efficacy of emtricitabine. However, the role of emtricitabine as a monotherapy may be limited by its structural similarity to lamivudine and the attendant risk of developing drug resistance.
TELBIVUDINE
The natural nucleosides in the β-L-configuration (β-L-thymidine [LdT], β-L-2-deoxycytidine [L-dC], and β-L-2-deoxyadenosine [L-dA]) represent a newly discovered class of compounds with potent, selective, and specific activity against hepadnavirus [42]. In vitro studies have shown that these compounds have marked effects on HBV replication [31]. Telbivudine (LdT) is at the most developed stage of clinical investigation. A phase I study showed a safe preclinical toxicology profile with no mitochondrial toxicity and no mutagenic effect [43,44].
A randomized, double-blind, multicenter trial evaluated the efficacy and safety of telbivudine 400 or 600 mg/day and telbivudine 400 or 600 mg/day plus lamivudine 100 mg/day (Comb400 and Comb600) compared with lamivudine 100 mg/day in HBeAg-positive adults with compensated chronic hepatitis B [45]. A total of 104 patients were randomized 1:1:1:1:1 among the 5 groups. Median reductions in serum HBV-DNA levels at week 52 (log10 copies/mL) were as follows: lamivudine, 4.66; telbivudine 400 mg, 6.43; telbivudine 600 mg, 6.09; Comb400, 6.40; and Comb600, 6.05. At week 52, telbivudine monotherapy showed a significantly greater mean reduction in HBV-DNA levels (6.01 vs 4.57 log10 copies/mL; p <.05), clearance of PCR-detectable HBV DNA (61 vs 32%; p <.05), and normalization of ALT levels (86 vs 63%; p <.05), compared with lamivudine monotherapy, with proportionally greater HBeAg seroconversion (31 vs 22%) and less viral breakthrough (4.5 vs 15.8%; p = NS for both). Combination treatment was not better than telbivudine alone. All treatments were well tolerated. In exploratory scientific analyses, clinical efficacy at 1 year appeared related to reduction in HBV-DNA levels in the first 6 months of treatment. Patients with chronic hepatitis B treated with telbivudine exhibited significantly greater virological and biochemical responses compared with lamivudine. Results with the combination regimens were similar to those obtained with telbivudine alone. These data support the ongoing phase III evaluation of telbivudine for treatment of patients with chronic hepatitis B.
CLEVUDINE
Clevudine [L-FMAU; 1-(2'-deoxy-2'-fluoro-β-l-arabinofuranosyl)-5-methyluracil] is a pyrimidine analogue with marked in vitro activity against HBV but not HIV [46]. The active triphosphate inhibits HBV-DNA polymerase but is not an obligate chain terminator. In vitro studies suggest that it may also be effective against lamivudine-resistant HBV mutants. In the woodchuck model, a daily dose of 10 mg/kg of clevudine resulted in a 9 log10 decrease in viral load. Interestingly, a delayed reincrease of viral load after cessation of drug administration in a dose-dependent manner was observed [47]. No evidence of drug-related toxicity was observed in treated animals.
An open label phase I/II, nonrandomized, dose-escalation study was performed in 35 patients who received clevudine for 28 days at the daily dose of 10 mg (n = 10), 50 mg (n = 10), 100 mg (n = 10), or 200 mg (n = 5) followed by a 20-week post-treatment period [48]. At the end of the dosing period, the median reduction in serum HBV DNA was 2.48 log10, 2.74 log10, and 2.95 log10 in the 10-mg, 50-mg, and 100-mg groups, respectively. Interestingly, as in the woodchuck model, there was a slow and delayed reincrease of serum HBV-DNA levels with, at the end of the post-treatment follow-up, lower median HBV-DNA levels as compared to baseline. Clevudine was well tolerated without serious adverse events.
Two phase III studies are ongoing. In a multicenter phase III trial, HBeAg-positive patients were randomized to receive either a 24-week course of clevudine at the dose of 30 mg/day (n = 243) or to receive placebo (n = 61) [49]. The results were presented with a follow-up of 24 weeks. In the clevudine arm, at the end of treatment, the median reduction in serum HBV DNA was 5.10 log10 (copies/mL), in comparison with 0.27 log10 for the placebo (p <.0001). At the end of treatment, HBV DNA was undetectable in 59% of patients under clevudine, in comparison with none given placebo (p < .0001). At the end of follow-up, the median reduction in serum HBV DNA was 2.02 log10 in comparison with 0.68 log10 (p <.0001). HBeAg seroconversion at the end of follow-up was not different in the two groups (10% for clevudine and 12% for placebo).
In a multicenter, phase III trial, HBeAg-negative chronic hepatitis B patients were randomized to receive either 24 weeks of clevudine at the dose of 30 mg/day (n = 63) or placebo (n = 23) [50]. The follow-up period was 24 weeks. In the clevudine arm, at the end of treatment, the median reduction in serum HBV DNA was 4.25 log10 (copies/mL), in comparison with 0.48 log10 for the placebo (p <.0001). At the end of treatment, HBV DNA was undetectable in 92% of patients given clevudine, in comparison with none having received placebo (p < .0001). At the end of follow-up, the median reduction in serum HBV DNA was 3.11 log10, in comparison with 0.66 log10 (p <.0001), and HBV DNA was undetectable in 16% of patients given clevudine, in comparison with none given placebo (p <.0001).
These preliminary results show that clevudine might be one of the most potent antivirals available for the treatment of HBV. Further studies are needed to assess the long-term efficacy and safety of this drug.
TENOFOVIR
Tenofovir disoproxil fumarate, a congender of adefovir that is used in the treatment of HIV-infected patients, has recently been shown to also be effective in patients with lamivudine-resistant HBV infection. The two substances were compared in a study of 53 patients defined by high HBV-DNA (>6 log10 copies/mL) levels and genotypic evidence of lamivudine resistance [51]. The majority of these patients had HBeAg-positive chronic hepatitis B. Thirty-five patients received tenofovir for 72 to 130 weeks, and 18 received adefovir for 60 to 80 weeks. Changes in HBV-DNA levels were followed for the complete period of 48 weeks. Early viral kinetics were compared on matched subgroups of 5 patients each. Individually, all tenofovir-treated patients showed a strong and early suppression of HBV DNA within a few weeks, whether they were coinfected with HIV or were without comorbidity. In contrast, considerable individual variation in HBV-DNA decline were observed in the adefovir group. Thus, at week 48, only 44% of these patients had HBV-DNA levels below 10(5) copies/mL, in contrast to 100% of the tenofovir-treated patients (p = .001). No severe side effects were noticed in either group. No evidence of phenotypic viral resistance could be demonstrated in the tenofovir-treated patients in the long term (up to 130 weeks). In conclusion, tenofovir may become an effective alternative for the treatment of patients with lamivudine-resistant HBV infection. Little is known about its resistance profile in treating HBV.
PRADEFOVIR
Pradefovir is a liver-targeting prodrug of adefovir that is being developed to better suppress HBV in that organ while reducing renal exposure to the drug [52]. Preliminary data suggest that it achieves both goals, but it is unclear yet whether viral suppression is important in comparison with other available drugs.
A phase II randomized open-label multicenter trial of adefovir-naïve patients (n = 244) with pradefovir or adefovir is ongoing [53]. Patients received adefovir 10 mg/day (n = 50) or pradefovir 5, 10, 20, or 30 mg/day (n = 47, 49, 48, and 48 patients, respectively, for each dose) for 48 weeks (Figure 3). The trial enrolled an Asian population, with genotype C being the most frequent genotype (67%) and 70% infected with HBeAg-positive chronic hepatitis B. At week 48, HBV DNA was undetectable (<400 copies/mL) in 36% of patients in the adefovir group (n = 50) and in 45, 63, 56, and 71%, respectively, for pradefovir 5, 10, 20, or 30 mg/day.
 | Figure 3. Pradefovir in chronic hepatitis B. Patients received adefovir 10 mg/day (n = 50) or pradefovir 5, 10, 20, or 30 mg/day (47, 49, 48, 48 patients, respectively, for each dose) for 48 weeks. The cohort was an Asian population, with infection with genotype C being most frequent (67%); 70% had HBeAg-positive chronic hepatitis B. At week 48, hepatitis B virus deoxyribonucleic acid (HBV DNA) was undetectable (<400 copies/mL) in 36% of patients in the adefovir group (n = 50), and in 45, 63, 56, and 71% for the pradefovir 5, 10, 20, or 30 mg/day, respectively .
(From Lee KS, Lim SG, Chuang WL, et al. Safety, tolerability and antiviral activity of pradefovir mesylate in patients with chronic hepatitis B virus infection: 48-week analysis of a phase 2 study. 41st EASL 2006; Abstract 741) |
VALTORCITABINE
Valtorcitabine is a β-L-deoxynucleoside (like telbivudine) and has potential in the treatment of HBV infection. Telbivudine and valtorcitabine are synergistic in the woodchuck model [54] and have potentially complementary mechanisms of action on first- and second-strand HBV-DNA synthesis. The combination has potent synergistic antiviral activity in vitro and in the woodchuck HBV model. Both compounds have excellent safety profiles.
CONCLUSION
Who to treat and when to start treatment?
The decision to treat or not to treat patients with HBeAg-negative chronic hepatitis B is mainly based on the results of liver histology. In patients with mild liver disease, treatment is not recommended, unless liver fibrosis deteriorates. It should be remembered that the best way to reduce the number of patients with resistance is to select the right patients for treatment: those with active liver disease who usually have relatively moderate levels of viral replication, a good chance of responding well to therapy, and a low risk of developing resistance. For patients with mild disease, treatment can be delayed with regular follow-up.
How to treat?
PEG-IFN monotherapy should be considered in patients without contraindications, since this treatment is not associated with resistance and gives the best sustained response rate (about one third) with a definite duration (48 weeks) of therapy. However, most patients (about two thirds) with chronic hepatitis B do not develop a sustained response and therefore need prolonged therapy with an analogue. During treatment with an analogue, the importance of good compliance and careful monitoring (measurement of HBV-DNA levels at least every 3 months) should be emphasized, especially after 1 year of therapy. Indeed, patients with HBV-DNA levels higher than 1000 copies/mL after 1 year of therapy are at high risk for development of resistance. Early diagnosis of resistance allows adjustment of therapy by introducing the drug to prevent a flare of hepatitis. At present no combination has been shown to have a better antiviral effect or a reduced risk of resistance compared to monotherapy. However, experimental studies and preliminary clinical data suggest that combinations may decrease the incidence of resistance. Therefore, this strategy should probably be considered in patients with cirrhosis to minimize the risk of liver failure, which may be associated with resistance.
Obviously, predictors of the risk of resistance need to be clearly identified and new therapeutic strategies including combinations need to be evaluated. Because the virus can escape new antivirals by developing resistant mutants, new drugs must be developed and therapeutic management of chronic hepatitis B must be improved to meet this new challenge.
So far, the combination of PEG IFN with lamivudine, used simultaneously, is disappointing in terms of short-term efficacy. However, long-term efficacy needs to be assessed and different schedules of combination (for example, sequential) need to be evaluated. Long-term efficacy needs to be confirmed in the ongoing long-term follow-up study. In patients who have contraindications to PEG IFN or who do not respond to PEG IFN, response can be assessed after 12 to 24 weeks of therapy with an analogue. Adefovir is generally preferred to lamivudine because of the lower incidence of resistance associated with it. Entecavir is a promising drug; however, its long-term efficacy and resistance profile are not known.
Future directions
The future of chronic hepatitis B therapy seems to lie in the combination of different drugs. Ideally, the optimal drugs to combine would meet the following criteria: they should have different sites of action on HBV-DNA replication, a potent antiviral effect, an excellent safety profile, and they should induce a sustained response with a limited duration of therapy. Indeed, only the combination of PEG IFNα-2a with lamivudine has shown a superior antiviral effect (during therapy) as compared with monotherapy.The combination of PEG IFNα-2a with more potent analogues such as entecavir or tenofovir needs to be further investigated.
More effective drug combinations together with an understanding of the mechanisms of resistance to therapy are important challenges in improving the efficacy of treatment and decreasing the global burden related to chronic hepatitis B infection.
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