Discussion

Introduction

As of January 2010, United States Food and Drug Administration (FDA) had approved seven agents for the treatment of hepatitis B virus (HBV) infection: interferon alpha-2b (Intron A), peginterferon alpha-2a (Pegasys), adefovir dipivoxil (Hepsera), entecavir (Baraclude), lamivudine (Epivir-HBV), telbivudine (Tyzeka), and tenofovir disoproxil fumarate (TDF) (Viread) (Figure 1)[1]. These agents are broadly classified as either interferons (interferon-alpha 2b and peginterferon-alpha 2a) or nucleoside/nucleotide reverse transcriptase inhibitors (adefovir, entecavir, lamivudine, telbivudine, and tenofovir). The generic and trade medication names, along with recommended dosing are listed in Figure 2; common side effects and cautionary notes are outlined in Figure 3. Among these seven FDA-approved agents, most experts now consider peginterferon-alpha 2a, entecavir, or tenofovir as the preferred first-line therapeutic options for treatment-naïve individuals with chronic hepatitis B[2].

This discussion will review key studies for each agent, including a review of the virologic, biochemical, serologic, and histologic responses of each agent. Agents that have activity against HBV, but are not FDA-approved for the treatment of HBV, specifically emtricitabine, will not be discussed. The indications for initiating therapy, the approach to choosing initial therapy, the monitoring patients on therapy, and the approach to treatment-resistant HBV are not discussed in this case, but are addressed in other cases in this section (Hepatitis B: Management).

Interferon alpha-2b (Intron A)

Interferon preparations have dual immunomodulatory and antiviral activity against HBV. Interferon alfa-2b (Intron A) was the first drug approved for the treatment of chronic hepatitis B and remains the only FDA-approved standard interferon for the treatment of hepatitis B. Cohort studies have shown reduction in risk of progression to cirrhosis, hepatocellular carcinoma, and liver-related death in long-term responders of interferon[3,4]. Nevertheless, because of improved response rates and easier dosing schedule of pegylated interferons, interferon alpha-2b is now infrequently used for the treatment of HBV.

Peginterferon alfa-2a (Pegasys)

Similar to interferon alpha-2b (standard IFN), peginterferon preparations have dual immunomodulatory and antiviral activity against HBV. The polyethylene glycol moiety on peginterferon results in a longer serum half-life than standard interferon and maintenance of therapeutic concentrations throughout the dosing interval, allowing for once-weekly administration. Pegylated interferon preparations have replaced the use of standard interferon for the treatment of hepatitis B and C, predominantly because of greater convenience and efficacy[5]. When compared with oral regimens, peginterferon offers several advantages, including a fixed duration of treatment (typically 48 weeks), lack of development of drug resistance, and greater rates of HBeAg seroconversion. On the other hand, overall rates of sustained viral suppression are low when given for a fixed duration and peginterferon causes multiple side effects, such as fatigue, anorexia, influenza-like symptoms, and cytopenias (Figure 4), which discourage its use.

In 2004, investigators randomized 552 patients with HBeAg-negative chronic hepatitis B infection to receive 48 weeks of treatment with one of three regimens: peginterferon alfa-2a monotherapy, peginterferon alfa-2a plus lamivudine, or lamivudine monotherapy (Figure 5)[6]. At the 24 week post-treatment follow-up analysis, patients who received either peginterferon alfa-2a monotherapy or peginterferon alfa-2a plus lamivudine had higher responses than lamivudine monotherapy in terms of normalization of alanine aminotransferase (ALT) levels and HBV DNA levels less than 400 copies/ml. In a subsequent similar clinical trial, but involving HBeAg-positive subjects, 814 patients with chronic hepatitis B infection were randomized to receive 48 weeks of treatment with peginterferon alfa-2a monotherapy, peginterferon alfa-2a plus lamivudine, or lamivudine alone (Figure 6)[7]. Most of these patients were Asian (87%) with either genotype B or C infection (88%). In both the end-of-treatment and 24-week post-treatment analyses, peginterferon (with or without lamivudine) performed better than lamivudine alone with respect to HBeAg seroconversion and sustained HBV viral suppression to less than 400 copies/mL. A follow-up study of patients in this study showed a rate of HBsAg clearance among peginterferon-treated patients of only 3% at 6 months post treatment, but this increased to 11% at year 4[8].

Peginterferon alfa-2b does not have FDA-approval for the treatment of patients with chronic hepatitis B, but data exist in this setting: in a trial involving HBeAg-positive patients, peginterferon alfa-2b alone showed similar response rates as peginterferon alfa-2b plus lamivudine for HBeAg seroconversion (29% for both arms) and HBsAb seroconversion (5% monotherapy versus 7% combination therapy)[9]. No major trial has been performed that compares the efficacy peginterferon alfa-2a versus peginterferon alfa-2b for the treatment of chronic hepatitis B. The best sustained responses to interferon appear to be in patients with HBV genotype A infection, immune-active disease, high baseline serum ALT levels (greater than 100 U/L), and low baseline HBV DNA levels[10,11]. Hepatitis flares in the form of ALT elevations exceeding 10 times the upper limit of normal can occur in up to 12% of patients on peginterferon[10]. Although these flares can indicate a favorable immunologic response to therapy, they can also lead to hepatic decompensation, particularly in patients with cirrhosis.

Oral Antiviral Therapy for HBV

Five oral agents have been approved by the FDA for the treatment of chronic hepatitis B (in chronological order of FDA approval): lamivudine, adefovir, entecavir, telbivudine, and tenofovir. They all inhibit HBV DNA polymerase by competing with natural substrates, thereby causing premature DNA chain termination. These oral agents (Figure 2) are attractive because of their excellent safety profile, tolerability, and once-daily dosing. Unlike interferon, the oral agents also appear to be equally effective across HBV genotypes and ethnic groups, but differences in response across genotypes have not been well studied.

Lamivudine (Epivir-HBV, 3TC)

In 1998, lamivudine was the first oral agent approved for hepatitis B. It has since fallen out of favor as first-line therapy largely because of the high rate of drug resistance associated with longer duration of use (65-70% after 4-5 years of therapy)[12]. A number of landmark studies, however, have used lamivudine to demonstrate the impact of oral antiviral therapy on important clinical outcomes. A double-blind randomized placebo-controlled trial demonstrated slower disease progression and reduced incidence of hepatocellular carcinoma in patients with chronic hepatitis B who were treated with lamivudine compared with placebo for a median of 32 months[13]. Furthermore, a number of studies have shown the benefit of lamivudine in patients with decompensated cirrhosis[14,15,16]. Lamivudine is the only antiviral that has been shown in clinical trials to be a safe and potentially effective adjunct to immunoprophylaxis (vaccine and hepatitis B immune globulin) in reducing rates of vertical transmission in mothers with hepatitis B viremia during late pregnancy[17].

Adefovir dipivoxil (Hepsera, ADV)

Adefovir dipivoxil, a prodrug of an acyclic phosphonate nucleotide analogue of adenosine, has in vitro activity against both HIV and HBV, but at low doses shows relatively greater activity against HBV. Adefovir was initially studied at 30-60 mg/d for the treatment of HIV infection, but caused unacceptably high rates of nephrotoxicity. Investigators subsequently studied adefovir at 10 mg/d for the treatment of HBV, and, in 2002, the FDA approved the 10 mg/d dose for the treatment of hepatitis B. Adefovir at 10 mg is inferior against HBV compared with entecavir, telbivudine, and tenofovir: complete HBV viral suppression to less than 400 copies/mL occurs less reliably on adefovir, with rates of 13-21% in HBeAg-positive and 51-63% in HBeAg-negative patients after 48 weeks[18,19,20,21]. In addition, a substantial proportion (20-50%) of patients receiving adefovir appear to have a primary virologic non-response, defined as less than 2 log copies/mL reduction in HBV DNA levels after at least 24 weeks of therapy[22]. Most adefovir-treated patients who achieved viral suppression by year 1 sustained their response to year 5 and experienced HBeAg seroconversion, ALT decline, and improved liver histology[23]. Sustained HBeAg seroconversion out to a median follow-up of 150 weeks occurred in 41 (91%) of 45 patients after discontinuing adefovir therapy[24]; similar outcomes are yet to be observed with the newer agents. Although resistance occurs at a slower rate with adefovir than with lamivudine, rates of 20-22% have been reported after 2 years of adefovir, with resistance predominantly occurring in patients with a history of lamivudine resistance[22,23,25].

Entecavir (Baraclude, ETV)

Entecavir is a potent cyclopentyl guanosine analogue that inhibits HBV DNA replication at 3 different steps: the priming of HBV polymerase, the reverse transcription of negative-strand HBV DNA, and the synthesis of positive-strand HBV DNA. Entecavir has more than 100-fold greater potency against HBV in culture than either adefovir or lamivudine[26]. Entecavir received FDA approval in 2005. In treatment-naïve HBeAg-positive patients, entecavir was superior to lamivudine at 48 weeks of therapy in reducing HBV DNA levels (-6.9 versus -5.4 log10 copies/mL, P<0.001) and improving liver histology (72% versus 62% demonstrated >=2 point decrease in Knodell necroinflammatory index, P=0.009)[27]. At 2 years of follow-up, entecavir-treated patients were more likely than lamivudine-treated patients to sustain HBV viral suppression to less than 300 copies/mL (80% versus 39%, P<0.001) and have ALT levels normalize (87% versus 79%, P=0.0056) (Figure 7)[28]. Entecavir has also been effective in HBeAg-negative infection[29] (Figure 8), with potency greater than adefovir as demonstrated by earlier and more rapid viral suppression[21]. The HBeAg seroconversion rates tend to be similar with entecavir, lamivudine, and adefovir.

Entecavir has a high genetic barrier for resistance and has performed well in long-term follow-up in treatment-naïve patients. Five-year follow-up data demonstrated a low (1.2%) risk of cumulative resistance[30]. No discontinuations due to adverse events were reported. Loss of HBsAg occurred in 5% of patients on entecavir through 120 weeks. The degree and durability of entecavir's efficacy, however, are diminished in HBeAg-positive patients who are refractory or resistant to lamivudine. The standard recommended once-daily 0.5 mg dose should be increased to 1.0 mg once daily in patients with lamivudine-resistant HBV. In lamivudine-refractory patients, even when using the higher 1 mg dose of entecavir, only 21% and 34% of patients achieved HBV DNA suppression to less than 300 copies/mL by weeks 48 and week 96, respectively[31]. Resistance to entecavir requires the prior selection of the rtM204V/I mutation, a characteristic lamivudine resistance mutation. Viral breakthrough emerged in 43% patients with a history of lamivudine resistance during 4 years of entecavir therapy[31,32]. For these reasons, entecavir monotherapy, even at the higher 1 mg dose, is not a first-line agent in patients with lamivudine-resistant HBV.

Investigators have shown monotherapy with entecavir has anti-HIV activity and can select for lamivudine resistance among HIV variants[33,34]. Accordingly, in patients co-infected with HIV and HBV, entecavir should only be used if concomitant combination antiretroviral therapy is given.

Telbivudine (Tyzeka, LdT)

Telbivudine is an L-nucleoside analogue of thymidine that was approved for treatment of HBV in 2006. It demonstrates no activity against HIV in vitro[35] but has been associated with HIV-1 viral suppression in one case report[36]. Telbivudine has superior efficacy against HBV compared with lamivudine. In the GLOBE Study, a randomized trial involving patients with HBeAg-positive or HBeAg-negative chronic hepatitis B, 1367 treatment-naïve subjects received either telbivudine or lamivudine (Figure 9)[37]. At 52 weeks, a higher proportion of the telbivudine-treated patients (HBeAg-positive and HBeAg-negative) had HBV DNA less than 300 copies/ml; improved histologic response was observed in a higher proportion of HBeAg-positive telbivudine-treated patients, whereas no difference in histologic response was observed in HBeAg-negative patients. During 2-year follow-up of patients in the GLOBE trial, a higher proportion of patients treated with telbivudine than lamivudine had HBV DNA less than 300 copies/ml (HBeAg-positive: 56% versus 39%; HBeAg-negative: 82% versus 57%) and ALT normalization (HBeAg-positive: 70% versus 62%, HBeAg-negative: 78% versus 70%)[38]. Viral resistance occurred less frequently with telbivudine than lamivudine (HBeAg-positive: 25% versus 40%, HBeAg-negative: 11% versus 26%), but at higher rates than seen in others studies with either tenofovir or entecavir. Because lamivudine and telbivudine are both L-nucleosides that are cross-resistant, telbivudine should not be used in patients with lamivudine-resistant HBV. Telbivudine also demonstrated greater and more consistent HBV DNA suppression than adefovir[39].

The initial viral decay to undetectable levels at 24 weeks is a strong predictor of favorable outcomes in patients on telbivudine: 41% of HBeAg-positive patients who were undetectable by week 24 achieved HBeAg seroconversion by year 1 compared with only 4% of those who had HBV DNA greater than 4 log10 copies/mL at week 24[37]. Nevertheless, the variable responses seen at this 24-week benchmark make telbivudine a less compelling option for first-line therapy compared with less resistance-prone agents, such as tenofovir or entecavir. Telbivudine is well-tolerated but has been associated with creatine kinase elevations exceeding 7 times the upper limit of normal (12.9% versus 4.1% with lamivudine), with 2 cases of symptomatic myopathy that resulted in discontinuation of therapy in clinical trial[38].

Tenofovir disoproxil fumarate (Viread, TDF)

Tenofovir is an acyclic nucleotide analogue of adenosine, a molecular congener of adefovir, with potent in vivo and in vitro activity against both HIV and HBV. It was initially licensed for use against HIV infection in 2001 and received FDA approval for HBV treatment in 2008. In two double-blind, phase III studies involving HBeAg-positive and negative subjects, a higher proportion of patients in the tenofovir than adefovir arm achieved HBV viral suppression to less than 400 copies/mL after 48 weeks (HBeAg-positive: 76% versus 13%, HBeAg-negative: 93% versus 63%, P<0.001 for both) (Figure 10). Histologic improvement and HBeAg seroconversion occurred at similar rates. Loss of HBsAg occurred in 3% of tenofovir-treated patients during follow-up compared with none among adefovir-treated patients. The presence of lamivudine-resistant mutants does not appear to influence the antiviral efficacy of tenofovir in treating HBV[40]. Suppression of HBV DNA with tenofovir appears to be durable (up to 96-130 weeks of therapy) and viral breakthrough due to resistance is rare[41,42,43]. Tenofovir has also shown high rates of HBV viral suppression to less than 1000 copies/mL in HIV and HBV co-infected patients. Among 23 patients on tenofovir-containing antiretroviral regimens, after 48 weeks of therapy, loss of HBeAg occurred in 33% and HBsAg loss occurred in 8%[44].

Renal impairment, including acute renal failure and Fanconi's syndrome (characterized by renal tubular injury with severe phosphate wasting) has been reported with tenofovir use. Although the incidence of clinically significant renal disease appears to be infrequent, monitoring of serum creatinine and phosphate is recommended, particularly in high-risk populations such as the elderly, patients with medical comorbidities, and patients taking multiple concomitant medications. Tenofovir has also been associated with decreased bone mineral density[46], and thus some experts recommend obtaining Dual Energy X-ray Absorptiometry (DEXA) scans with long-term tenofovir use.

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    Figure 1. Timeline for FDA-Approved Agents used to Treat HBV
    Figure 1
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    Figure 2. Dosing of Agents FDA-Approved for Treatment of Chronic HBV.
    Figure 2
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    Figure 3. Cautionary Notes for Agents used to Treat HBV
    Figure 3
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    Figure 4. Adverse Effects of Interferon and Peginterferon Preparations
    Figure 4
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    Figure 5. Image 1. Peginterferon alpha-2a versus Lamivudine alone or in Combination in HBeAg-Negative Patients: Study Features

    From: Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-17.


    Figure 5

    From: Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206-17.

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    Figure 6. Image 1. Peginterferon alfa-2a versus Lamivudine Alone or in Combination in HBeAg-Positive Patients: Study Features

    From: Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-95.


    Figure 6

    From: Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon Alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005;352:2682-95.

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    Figure 7. Image 1. Entecavir versus Lamivudine in HBeAg-Positive Patients: Study Features

    From: Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437-44.


    Figure 7

    From: Gish RG, Lok AS, Chang TT, et al. Entecavir therapy for up to 96 weeks in patients with HBeAg-positive chronic hepatitis B. Gastroenterology 2007;133:1437-44.

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    Figure 8. Image 1. Entecavir versus Lamivudine in HBeAg-Negative Patients: Study Features

    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;354:1011-20.


    Figure 8

    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;354:1011-20.

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    Figure 9. Image 1. Telbivudine versus Lamivudine in HBeAg-Negative and HBeAg-Positive Patients (Globe Study): Study Features

    From: Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576-88.


    Figure 9

    From: Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med. 2007;357:2576-88.

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    Figure 10. Image 1. Tenofovir versus Adefovir in HBeAg-Negative and HBeAg-Positive Patients: Study 102 Design

    From: Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-55.


    Figure 10

    From: Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-55.

    From: Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-55.

    From: Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B. N Engl J Med. 2008;359:2442-55.