Overview of Treatment of Hepatitis B: Key Approaches and Clinical Challenges Robert P. Perrillo, M.D.1
ABSTRACT
The development of nucleoside analogues has been a major advance in the treatment of hepatitis B; however, prolonged monotherapy is associated with drug resistance. Currently, no data in humans indicate that a combination of nucleoside analogues leads to enhanced efficacy. New nucleoside analogues with greater inhibitory effects on hepatitis B virus (HBV) replication being developed could prove to be more effective or less likely to be associated with viral resistance. Interferon still has a role to play in the management of chronic HBV infection. Recent data indicate that the response to interferon may be determined in part by differences in genotype. From a theoretical perspective, a combination of pegylated interferon with one or more nucleosides could induce a higher rate of virological response. Additional studies are needed to further address these issues. KEYWORDS: Hepatitis B, nucleoside analogues, interferon, antiviral therapy
M
ajor advances have been made in the treatment of chronic HBV infection during the past several years.1 As reflected in the practice guidelines recently issued by three scientific organizations, however, several important issues remain to be addressed.2–4 This article presents the pros and cons of the available drugs used for managing HBV infection and describes strategies for using current and future drugs more effectively. This discussion provides an evidence-based perspective on the important recent developments and where the field may be heading. Articles elsewhere in this supplement explore the individual nucleoside analogues and pegylated interferon alfa-2a in more detail. At the present time, three drugs are licensed for the treatment of HBV infection: interferon alfa, lamivudine, and the nucleotide analogue adefovir dipivoxil. Several newer nucleoside analogues, such as entecavir, emtricitabine, and telbivudine, are in various phases of
study. Tenofovir and emtricitabine are currently licensed for the treatment of human immunodeficiency virus (HIV). Adefovir, tenofovir, and entecavir have been shown to have antiviral activity against lamivudineresistant as well as wild-type HBV both in vitro and in vivo.5–7
NUCLEOSIDE ANALOGUE THERAPY Nucleoside analogues have excellent oral bioavailability, a good safety record, and antiviral efficacy comparable to that observed with interferon alfa-2b (Table 1). They are also considerably less expensive than interferon when given for 48 to 52 weeks, as recommended in the prescribing information. These drugs have proved to be particularly useful in the management of decompensated cirrhosis, a clinical situation in which even small doses of interferon alfa-2b can lead to worsening liver failure and severe infections.8
HBV Viral Kinetics and Clinical Management: Key Issues and Current Perspectives; Editor in Chief, Paul D. Berk, M.D.; Guest Editors, Emmet B. Keeffe, M.D., and Jules L. Dienstag, M.D. Seminars in Liver Disease, volume 24, supplement 1, 2004. Address for correspondence and reprint requests: Robert P. Perrillo, M.D., Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, 1514 Jefferson Highway, New Orleans, LA 70121. E-mail:
[email protected]. 1Director, Academic Affairs, Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, Louisiana. Copyright # 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662. 0272-8087,p;2004,24,s1,023,029,ftx,en;sld00261x.
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Table 1
2004
Nucleoside Analogues
Pros
Cons
Orally available
Long duration of treatment (> year) ‘‘virustatic’’
Minimal side effects
Drug-resistant mutants
Useful in decompensated cirrhosis and after liver transplantation
Type of response differs from interferon (HBsAg loss rare)
Much less expensive than interferon*
Postwithdrawal ALT flares (20–25%)
*Based on calculated cost of 1 year of treatment.
Nucleoside analogues replace natural nucleosides during the synthesis of the first or second strand (or both) of HBV DNA. They thus serve as competitive inhibitors of the viral reverse transcriptase and DNA polymerase (Fig. 1A).9 Because nucleoside analogues partially and reversibly suppress viral replication, they have to be given for more than 1 year in most cases to achieve maximal efficacy. Unfortunately, drug resistance occurs with prolonged monotherapy. Nucleoside analogues have several other limitations as well. With these agents, demonstrating the clearance of the covalently closed circular form of HBV DNA (cccDNA) has been difficult, and clearance of hepatitis B surface antigen (HBsAg) rarely occurs after 1 year of treatment. These problems may, in part, be due to the fact that nucleoside analogues, in contrast with interferon, are not considered to have a direct, enhancing effect on the immunologic response to HBV.10 Also, after discontinuation of lamivudine and other nucleoside analogues, postwithdrawal flares of alanine transferase (ALT) are noted in approximately 25% of patients, which may result in serious consequences, particularly in individuals with advanced liver disease.11
The Problem of Viral Resistance The rate of lamivudine resistance increases as a function of the time on therapy. After 4 years of treatment, resistance is observed in approximately 70% of patients (see also Wright12 and Locarnini13). HBV resistance to lamivudine is much more commonly encountered in patients who are coinfected with HIV and HBV because lamivudine is included in highly active antiretroviral treatment regimens. Given the high level of frequency of resistance in this population, lamivudine monotherapy is not a good choice for first-line treatment of chronic HBV infection in HIV-infected patients who have been previously treated with antiretroviral therapy. Early reports indicated that patients who developed lamivudine resistance generally tended to maintain lower levels of serum ALT and HBV DNA than they had before treatment. However, several subsequent studies demonstrated that continued persistence of lamivudine-resistant (YMDD-mutant) HBV is ultimately associated with loss of histological remission and progressive increase in ALT.14 Moreover, rapid clinical
progression of liver disease has been observed after liver transplantation in allograft recipients who are infected with lamivudine-resistant HBV.15 In a recent clinical trial involving 130 patients with genotypically characterized lamividune resistance, improvement in ALT levels and a median decline in serum HBV DNA level of 4.5 log10 were observed when adefovir was added to lamivudine for 52 weeks.16 The differences were statistically significant when compared with continued treatment with lamivudine alone. In a second study, in which patients with lamivudine resistance were switched to adefovir monotherapy, 37% of the patients experienced grade 3 ALT elevation (3.1 to 10 times baseline levels), which may have been caused by a transient re-emergence of wild-type virus.17 The optimal duration of continued lamivudine to avoid ALT flares when patients are switched to adefovir is currently unknown. Resistance is not unique to lamivudine. Resistance, which develops in approximately 2% of patients treated with adefovir for 2 years and 4% treated for 4 years, is attributed to a rtN236R mutation in domain D of the HBV DNA polymerase gene.18 Adefovirresistant HBV remains sensitive to lamivudine, which suggests that combined therapy with lamivudine may be beneficial when long-term use of adefovir is anticipated for the treatment of YMDD-mutant HBV infection. More potent nucleosides, such as entecavir and telbivudine, are currently being evaluated in clinical trials. Resistance to entecavir has been observed in 2 of 181 lamivudine-resistant patients after 80 and 100 weeks of treatment, respectively.19 Resistance to telbivudine was reported in 4% of patients treated for 48 weeks.20 Preliminary studies indicate that it is unlikely that lamivudine-resistant virus is treatable with telbivudine because of the presence of a shared mutation at the rt204 site (domain C of the HBV polymerase gene).
COMBINATION NUCLEOSIDE ANALOGUE TREATMENT The proposal that combination nucleoside-analogue therapy might be more effective against HBV than any one agent used singly is based on the efficacy of combination antiretroviral therapy in HIV infection. Similarly, in vitro data and studies in the woodchuck model of
HEPATITIS B TREATMENT OVERVIEW/PERRILLO
Figure 1 (A) Nucleoside analogues inhibit the synthesis of the first or second HBV DNA strand, or both, during the replication cycle. The reasons for lack of additive benefit in early clinical trials when two nucleosides are used in combination are not yet understood. The term ‘‘saturable’’ refers to the possibility that this could be due to competition for activating phosphorylating enzymes or by competitive binding to the same region of the HBV DNA polymerase. (B) Schematic of interferon’s proposed mechanisms of action (circled numbers). Interferon suppression of viral replication involves mechanisms that are theoretically complementary to those of nucleoside analogues.
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Table 2 Combination Therapy With More Than One Nucleoside Analogue Potential Benefits
Potential Concems
Additive or synergistic
Added costs
Prevent or delay drug (lamivudine) resistance
Potential for increased toxicity Facilitation of multidrug
More rapid stabilization
resistance (?) Clinical necessity not defined
hepatitis B support the value of combination antiviral therapy for hepatitis B in humans. Combination treatment might also prevent or delay the emergence of drug resistance and lead to more rapid clinical stabilization (Table 2). Such improvements would be of considerable importance in individuals with decompensated cirrhosis. Weighing against combination therapy are the added cost and the potential for increased toxicity. In addition, there is a theoretical concern that certain combinations could lead to accelerated multidrug resistance. Evaluation of combination nucleoside analogue treatment requires that several potentially important questions be considered. Do the drugs have additive or synergistic effects (as determined in vitro and, more importantly, in animal models such as the woodchuck)? Do the drugs have different uptake and activation pathways? Are the drugs analogues of different natural substrates (and if not, do they compete with each other and limit efficacy)? Do they have different resistance profiles? From a practical standpoint, the clinician will have to judge whether the added expense is justified by enhanced efficacy and, if so, in which patients this treatment would apply. Somewhat surprisingly, the results of early clinical trials of combination therapy in treatment-naı¨ve patients with chronic HBV infection suggest that additive antiviral effects do not result from the combination of two nucleosides, at least not during the first year of treatment. In one study of 104 patients with chronic hepatitis B e antigen (HBeAg)–positive hepatitis B, two different doses of telbivudine were compared with combinations of lamivudine and the identical doses of telbivudine or with lamivudine monotherapy. Although both combinations were significantly more effective in lowering serum HBV DNA levels than lamivudine monotherapy was, neither was more effective than telbivudine alone.20 In a second study involving 112 HBeAg-positive patients, a 52-week course of lamivudine plus adefovir combination therapy was compared with lamivudine alone.21 Median reductions in HBV DNA levels at week 52 were not statistically significantly different in the two treatment groups. A small increase in serum HBV DNA appeared after week 40 in the monotherapy group and was attributable to the emergence of lamivudine-resistant HBV. The reasons for the lack of apparent additive
effect in these studies remain unexplained. The possibility exists that telbivudine competes with lamivudine in the binding pocket on the HBV DNA polymerase molecule or that nucleoside analogues compete for phosphorylation enzymes needed for drug activation.
Perspective on Nucleoside Analogues The development of nucleoside analogues has been a major advance in our therapeutic armamentarium against HBV infection. However, when used alone, these drugs have to be given for several years or more, and the potential benefit of extended treatment has to be gauged against the chance of resistance. Drug resistance will probably be shown to occur with all nucleoside analogues to some degree, and continued viral suppression will require adding or switching to a different nucleoside analogue once resistance occurs. Some nucleoside analogues demonstrate cross-resistance, requiring that clinicians know which drugs are appropriate for rescue. The results of early studies with combination nucleoside analogue therapy in treatment-naı¨ve patients have been disappointing, and the reasons for these observations are as yet unexplained.
INTERFERON THERAPY The limitations of nucleoside analogues have led to a resurgence of interest in the use of interferon to treat chronic HBV infection. Interferon is effective after a relatively short course of treatment (6 months to 1 year) and, unlike the nucleoside analogues, has not been associated with drug resistance (Table 3). Also in contrast to nucleoside analogues, interferon has direct immunomodulatory properties (Fig. 1B).9 Interferon enhances human leukocyte antigen (HLA) class I antigen expression on the surface of infected hepatocytes and augments CD8þ cytotoxic T-lymphocyte activity. This could be operatively important in reducing the amount of HBV DNA (the genomic template for viral transcription) during the second phase of viral clearance. More sustained reduction of HBV DNA, perhaps even clearance of cccDNA, may explain the loss of HBsAg that occurs in approximately 5 to 8% of interferon-treated patients.22 The major disadvantages of interferon are its Table 3
Interferon Alfa
Pros
Cons
Short course (16–48 wk)
Expensive
30–40% HBeAg loss
Many ‘‘problem’’ patients
HBsAg clearance (5–10%)
Significant side effects
Drug-resistant mutants have
Dangerous in
not been described Immunomodulatory
decompensated cirrhosis
HEPATITIS B TREATMENT OVERVIEW/PERRILLO
tolerability in comparison with nucleoside analogues, its lower level of HBV DNA suppression, and its greater cost. Flares of ALT have been described during therapy with interferon alfa and, although these flares are potentially important in achieving a virological response, their unpredictability leads to inconsistent antiviral efficacy. The magnitude of an ALT flare has been shown to predict the likelihood of sustained virologic response in patients with high-level viremia,23 suggesting that robust cell-mediated immune responses are required to overcome relatively high levels of viral replication. Pegylated interferon has been found to be more effective than standard interferon in the treatment of HBV infection24 (see also Cooksley25). Doses of 1.0 mg per kg of body weight of pegylated interferon alfa-2b and of 180 mg of pegylated interferon alfa-2a given once weekly have been studied in clinical trials.26,27 No data are yet available for judging whether the increased effectiveness of pegylated interferon is primarily a function of a more pronounced effect on viral replication or of greater immunomodulatory action.
Role of Genotype in Response The genotype of HBV does not appear to influence the antiviral efficacy of nucleoside analogues,28 but this may not be the case for interferon. In a report from Taiwan, patients with genotype B, HBeAg-positive, chronic hepatitis B were found to respond more frequently to standard interferon than did those with genotype C.29 A relationship between virological response and genotype was recently reaffirmed in a large multicenter study of pegylated interferon alfa-2b. In this study, HBeAgpositive patients with genotype A responded more frequently than did patients with genotypes B, C, and D.27 These results confirm and extend the findings of earlier studies in HBeAg-positive and HBeAg-negative patients, suggesting that patients with genotype A respond more frequently than patients with genotype D. The impact that genotype exerts on the response to interferon could be particularly relevant in the treatment of North American patients with chronic HBV infection, in light of the recent influx of Asian HBsAg carriers with genotypes B and C.30
COMBINATION INTERFERON AND NUCLEOSIDE ANALOGUE THERAPY Conceptually, a combination of interferon and nucleoside-analogue therapy might prove to be more effective than either drug alone because each of these drugs has a different mechanism of action. Combining drugs in this way might also allow for a shorter course of nucleoside analogue therapy, and thereby reduce the chance for viral resistance. Several studies in the woodchuck model, in
addition to clinical trials in humans, have provided support for these concepts.31–33 Two large multicenter studies have addressed the use of pegylated interferon in combination with lamivudine. In one study, 307 HBeAg-positive patients received either pegylated interferon alfa-2b with 100 mg of lamivudine daily or pegylated interferon plus placebo, both regimens given for 48 weeks.27 At the end of treatment, 44% of the patients in the combined therapy group demonstrated loss of HBeAg versus 29% in the lamivudine alone group; however, response rates in the two groups were not significantly different 6 months after the end of treatment (35 and 36%, respectively). In the second study, 537 patients with HBeAg-negative hepatitis B were treated with 180 mg of pegylated interferon alfa-2a given once weekly for 48 weeks combined with either placebo or lamivudine, and the results from these two treatment groups were compared results with lamivudine monotherapy.26 Virological response was defined as a sustained reduction in serum HBV DNA concentration to a level of
