Newer treatments of chronic hepatitis B virus infection

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Newer treatments of chronic hepatitis B virus infection

  ANTIVIRAL AGENTS
    • Adefovir
    • Emtricitabine
    • Entecavir
    • Famciclovir
    • Ganciclovir
    • Clevudine
    • Val-d-cytosine and L-deoxythymidine
    • Tenofovir

  NOVEL ANTIVIRAL APPROACHES
    • Selective targeting of antiviral agents to the liver
    • Antisense approaches
    • Non-HBV-specific immunomodulatory therapy
      - Thymosin
    • HBV-specific immunomodulatory therapy
      - S and pre-S antigen vaccines
      - DNA vaccination
      - T cell vaccines
      - Adoptive immunity transfer
    • Alpha-glucosidase inhibitor derivatives
    • Monoclonal antibodies

Anna SF Lok, MD
  Professor of Medicine
  University of Michigan Medical School


UpToDate performs a continuous review of over 270 journals and other resources. Updates are added as important new information is published. The literature review for UpToDate version 10.3 is current through August 2002; this topic was last changed on September 3, 2002.

The main aim of treatment for chronic hepatitis B is to suppress HBV replication before there is irreversible liver damage. Interferon alfa was the first treatment approved in most countries. It leads to a beneficial response in 30 to 40 percent of patients, but is expensive, and may be accompanied by unpleasant side effects. (See "Interferon therapy for chronic hepatitis B virus infection";). Lamivudine has also been approved for the treatment of chronic hepatitis B in most countries. (See "Lamivudine monotherapy for chronic hepatitis B virus infection-I";). Many new antiviral and immunomodulatory therapies have shown promise, and may play a key role in the treatment of chronic hepatitis B.

This topic review will discuss new and experimental treatments of chronic hepatitis B. A general approach to patients with hepatitis B (including other treatment options) is presented separately. This topic is also discussed in an official guideline issued by the American Association for the Study of Liver Diseases.

ANTIVIRAL AGENTS — A number of promising new antiviral agents for the treatment of chronic hepatitis B are being evaluated in clinical trials. These include adefovir dipivoxil, emtricitabine (FTC), entecavir, beta-L-thymidine, and clevudine.

Adefovir — Adefovir dipivoxil (bis-POM PMEA) is a nucleotide analog of adenosine monophosphate that can inhibit reverse transcriptase and DNA polymerase activity levels [1, 2, 3]. Adefovir has been evaluated as primary monotherapy for chronic hepatitis B, and in patients who developed resistance to lamivudine. It has also been evaluated as combination therapy with lamivudine.

Emtricitabine — The efficacy of emtricitabine (FTC), a nucleoside analogue structurally similar to lamivudine, was evaluated in a preliminary study that included 30 patients with chronic HBV infection who were treated with varying doses for 56 days [4]. HBV DNA levels decreased in all patients and the drug appeared to be well tolerated.

A subsequent preliminary report included 98 patients with chronic hepatitis B who had previously participated in a trial of FTC or were treatment naive [5]. Patients were randomly assigned to varying doses of FTC or placebo. After 48 weeks of treatment a decrease in HBV DNA level was observed in all groups receiving active treatment. The proportion of patients with undetectable HBV DNA was 61 percent in patients receiving the 200 mg dose, which appeared to be optimal. HBeAg loss was observed in 40 percent of patients. Resistant mutants developed in 6 percent of patients. These data suggest that FTC may be more potent than lamivudine. However, studies that compare the two drugs have not been performed and FTC is also associated with the selection of YMDD mutations.

Entecavir — Entecavir (BMS 200,475) is an orally administered nucleoside analogue that had potent antiviral activities in animal and in vitro models of HBV infection and initial human trials [6, 7, 8, 9] including patients with lamivudine-resistant HBV mutants [8]. The preliminary report of a controlled trial in humans included 181 patients who had failed therapy with lamivudine and were randomly assigned to three different doses of entecavir or continued treatment with lamivudine [10]. At the end of 52 weeks of treatment, significantly more patients receiving the two higher doses of entecavir (0.5 and 1 mg) experienced a decline in HBV DNA to undetectable levels (53 to 79 versus 13 percent). Similarly, normalization of serum ALT levels was also observed more frequently with entecavir (36 to 60 versus 21 percent). Nine patients discontinued entecavir due to adverse events including hypoglycemia (one patient), an increase in amylase/lipase (two patients), an increase in serum aminotransferases (five patients), and the development of hepatocellular carcinoma (one patient). These data confirm the in vivo efficacy of entecavir against lamivudine-resistant HBV mutants. Phase III clinical trials of entecavir as initial therapy of chronic hepatitis B are ongoing.

Famciclovir — Famciclovir is the oral prodrug of penciclovir, an acyclic deoxyguanosine analog. Penciclovir is phosphorylated to its triphosphate (PCV-TP), which competes with dGTP for incorporation into the nascent HBV DNA chains. Incorporation of PCV-TP may lead to premature chain termination or destabilization of the HBV DNA chains. In addition, PCV-TP may compete with dGTP for the priming of reverse transcription (synthesis of the first DNA strand) [11].

Famciclovir (given in doses of 500 mg three times daily) is well tolerated and can inhibit HBV replication, although the effect is usually transient [12, 13, 14]. In one report, for example, 417 patients with HBeAg positive chronic hepatitis were randomly assigned to famciclovir 500 mg three times daily or 1500 mg daily or placebo for 12 months [14]. At the end of therapy, the median decline in HBV DNA was significantly greater in patients receiving famciclovir (76 and 60 percent versus 37 percent, respectively) while the median decreases in the histologic activity index were 1.5, 1, and 0, respectively. At the end of six months' post-treatment follow-up, significantly more patients who had received famciclovir 500 mg three times daily had anti-HBe seroconversion (9 versus 3 percent).

Although famciclovir was effective in decreasing serum HBV DNA levels, the antiviral effects are weak when compared with other antiviral agents such as lamivudine [15] and adefovir dipivoxil. Furthermore, drug-resistant mutants have been reported, some of which appear to also be resistant to lamivudine [16]. Another disadvantage is that famciclovir needs to be administered three times a day for maximum effects, compared with once a day administration with lamivudine or adefovir dipivoxil. Thus, it is unlikely that famciclovir monotherapy will have a major role in the treatment of chronic hepatitis B. The possible role of combining famciclovir with other agents such as lamivudine is discussed separately.

Ganciclovir — Ganciclovir can decrease serum HBV DNA levels and stabilize or improve liver disease in patients with recurrent hepatitis B post-liver transplantation [17, 18]. However, the lack of sustained antiviral effect, the need for intravenous infusion, and the frequent and potentially serious adverse effects limit the role of ganciclovir in the treatment of chronic HBV infection. Pilot studies suggest that oral ganciclovir may be effective in decreasing serum HBV DNA levels in patients with chronic hepatitis B [19, 20] but these data need to be confirmed.

Clevudine — Clevudine (LFMAU, 2'-fluoro-5-methyl -beta-L-arabinofuranosyl uracil) is a pyrimidine nucleoside analogue that is a potent inhibitor of HBV replication in vitro. Preliminary results of a phase I/II study in humans suggested that treatment was associated with approximately a 2 to 3-log reduction in HBV DNA and a decrease in the serum ALT [21].

Val-d-cytosine and L-deoxythymidine — Val-d-cytosine and L-deoxythymidine are nucleoside analogues with potent activity against HBV replication. The preliminary report of two phase I/II randomized dose escalation trials found consistent and dose-related reductions in HBV DNA for both agents [22, 23]. Both appeared to be safe.

Tenofovir — Tenofovir disoproxil fumarate is a nucleotide analogue used for the treatment of HIV infection. Activity against HBV has been demonstrated in vitro [24]. In a pilot study involving five HIV/HBV coinfected patients with lamivudine-resistant HBV infection, tenofovir was associated with a decline in HBV viremia in all patients and normalization of the serum ALT in the one patient in whom ALT was elevated [25].

NOVEL ANTIVIRAL APPROACHES — Several innovative antiviral approaches have been evaluated in in vitro and in animal models of chronic hepatitis [26]. It is at present unknown if these approaches will have clinical utility.

Selective targeting of antiviral agents to the liver — Conjugation of antiviral agents to ligands that are selectively taken up by the liver may permit these drugs to be used in lower doses with decreased systemic adverse effects [27, 28].

Antisense approaches — Transcription and translation of HBV DNA and HBV RNA can be prevented by antisense molecules or ribozymes that are complementary to the DNA or RNA templates [29]. These molecules can be delivered by the administration of preformed molecules or vector DNA. The advantage of this approach is that specific targets can be selected. In addition, the risk of drug-resistant mutants can be reduced by targeting multiple sites in the viral DNA or RNA or by targeting regulatory sequences that would not tolerate mutations.

In vitro studies have confirmed that this approach is feasible. The major impediments to the clinical use of antisense treatment include rapid degradation of the antisense molecules by nucleases in vivo, lack of an efficient delivery system into the target cells, and hindrance of access to target DNA or RNA sequences by secondary structure. Several pilot studies have demonstrated the feasibility of delivery of antisense molecules to DHBV-infected ducks and the efficacy of these molecules in inhibiting DHBV replication and viral protein expression [30]. Pilot studies in mice showed that ribozymes can be delivered to the liver in sufficient concentrations for antiviral effect [29]. Phase I/II clinical studies are ongoing to evaluate the safety and efficacy of ribozymes in the treatment of chronic hepatitis C. Similar strategies are being planned for hepatitis B. A preliminary in vitro study suggested that an anti-HBV ribozyme (HepBzyme) which cleaved HBV RNA in the S region decreased HBV replication as well as HBsAg expression [31]. In addition, combination of HepBzyme and interferon or lamivudine appeared to have additive antiviral effect.

Non-HBV-specific immunomodulatory therapy — Non-HBV specific immunomodulation with thymosin or levamisole has been studied in patients with chronic HBV infection.

Thymosin — Thymic-derived peptides can stimulate T cell function. Treatment is usually well tolerated but data on efficacy are conflicting [32, 33, 34, 35, 36, 37]. A meta-analysis that included five controlled trials with a total of 353 patients concluded that patients treated with thymosin were significantly more likely than controls to have a virologic response [37]. The maximal rate of response was not seen until 12 months after discontinuing therapy (odds ratio 1.67, 95 percent CI 0.83 to 3.37). In one of the largest and most recent controlled trials, for example, 98 patients were randomly assigned to thymosin alpha 1 (1.6 mg subcutaneously twice per week) for 26 or 52 weeks or no specific treatment [34]. Clearance of HBV DNA and HBeAg at 18 months were observed significantly more often in the two groups that received active treatment (41 and 27 versus 9 percent, respectively). Ongoing studies are evaluating combination therapy with other antiviral agents [38, 39].

HBV-specific immunomodulatory therapy — In the past few years, several HBV-specific immunomodulatory therapies have been developed, some of which have shown promise.

S and pre-S antigen vaccines — In a prospective, non-randomized, pilot study, 3 of 14 patients with chronic hepatitis B who received three standard doses of hepatitis B vaccine were reported to clear serum HBV DNA [40]. More recently, it was suggested that incorporation of pre-S (pre-surface) antigens into hepatitis B vaccines increases the immunogenicity of the vaccine. In one study, 170 patients were randomized to receive GenHevac (preS2/S antigen containing vaccine), Recombivax (S antigen containing vaccine), or no treatment [41]. Available data in 40 patients showed that clearance of HBV DNA occurred in 5 of 17 patients who received GenHevac B, 2 of 10 patients who received Recombivax, and in 1 of 13 controls. Although GenHevac appeared to be associated with a higher rate of antiviral response, the high drop out rate and the subsequent use of interferon therapy at the end of the vaccination schedule make it difficult to interpret the results of this study. (See "Characteristics of the hepatitis B virus and pathogenesis of infection";, section on Characteristics of the virus). Another study reported that 11 of 13 patients with chronic hepatitis B developed an anti-HBs response to a new hepatitis B vaccine (HBV/MF59) that included a potent adjuvant [42]. Controlled trials are in progress to determine if this vaccine is effective in viral clearance.

DNA vaccination — Vaccination with plasmid DNA can stimulate both B and T cell responses [43]. Studies in mice have shown that vaccination with plasmids that contain HBV surface gene can induce an anti-HBs response. DNA vaccination can also decrease the production of HBsAg in transgenic mice that express the HBV surface gene [44]. It remains to be determined whether DNA vaccination can induce anti-HBs production and viral clearance in patients with chronic HBV infection.

T cell vaccines — Patients with chronic HBV infection have an impaired cytotoxic T lymphocyte (CTL) response to HBV antigens, resulting in ineffective virus clearance [45]. Preliminary results of a phase II study showed that the CTL response can be stimulated in patients with chronic HBV infection by inoculation with a vaccine that contained an HLA-restricted HBcAg CTL epitope; however, the antiviral effect was weak [46].

Adoptive immunity transfer — Immunization of bone marrow transplant donors with hepatitis B vaccine can induce anti-HBs antibody production in recipients through adoptive immune transfer. In addition, bone marrow transplantation from donors who are anti-HBs and anti-HBc positive has been associated with clearance of HBV in recipients with chronic HBV infection [47]. This occurrence appears to be related to the transfer of hepatitis B core antigen-reactive T cells [48].

On the other hand, reactivation of HBV replication has also been reported in patients who have anti-HBs and anti-HBc prior to bone marrow transplantation [49]. Bone marrow transplantation is associated with significant morbidity and mortality, and is therefore not a viable option for the treatment of chronic hepatitis.

Alpha-glucosidase inhibitor derivatives — Glucosidases are important cellular enzymes in glycoprotein biosynthesis. They mediate the proper folding of cellular as well as viral structural proteins. As a result, inhibitors of glucosidases have become targets for antiviral therapy. Two derivatives (N-nonyl-DNJ and N-nonyl-DGJ) of N-butyl-DNJ, a glucosidase inhibitor, were associated with a 9- and 15-fold drop in secreted HBV DNA in an in vitro model [50]. These compounds did not interfere with glucosidase activity and had no evidence of cytotoxicity. Whether these agents will be safe and effective in vivo remains to be determined.

Monoclonal antibodies — A phase I trial demonstrated that monoclonal antibodies directed against different epitopes of hepatitis B surface antigen could decrease HBsAg and HBV DNA levels [51]. The long-term benefit of such therapy given alone or in combination with other antiviral approaches remains to be determined.


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