A number of factors should be weighed when choosing a first-line agent in the initial treatment of a patient with chronic hepatitis B virus (HBV) infection: efficacy of the treatment, patient tolerance of the therapy, safety of the regimen, risk of developing drug resistance, durability of treatment response, cost of therapy, and whether the patient is co-infected with hepatitis C virus or HIV. Treatment decisions also need to take patient preferences into account. The primary decision point when choosing initial therapy in a patient with chronic hepatitis B is whether to use an interferon-based preparation or an oral antiviral agent (nucleoside or nucleotide analogue). The following discussion will compare the use of interferon-based preparations versus oral antiviral agents for initial therapy in patients with chronic hepatitis B. In addition, we will also address the choice of which specific oral antiviral agent to use, and whether to use monotherapy or combination therapy. A more detailed discussion of the individual agents used to treat hepatitis B, including efficacy, dosing, and safety, is addressed in the case Antiviral Agents used to Treat Hepatitis B Virus Infection.
Goals and Outcome of Therapy Related to Choice of Agent
In evaluating the optimal choice for therapy, it is important to consider the goals and outcomes desired as a result of treatment. The ultimate long-term goals of therapy are to prevent cirrhosis, hepatic failure, and hepatocellular cancer. Shorter-term goals include normalization of serum alanine aminotransferase levels (ALT) levels, a decrease in serum HBV DNA to an undetectable level, loss of HBeAg (in patients HBeAg-positive at baseline), and loss of HBsAg (in patients HBeAg-negative at baseline). In patients with HBeAg-positive status at baseline, HBeAg loss and anti-HBe seroconversion, when accompanied by HBV viral suppression, represent immune-mediated control of HBV by the host. Multiple studies have shown sustained clearance of HBeAg with therapy corresponds with reduced incidence of cirrhosis, decreased risk for hepatocellular carcinoma, and improved survival[2,3,4,5,6]. This immune-mediated control represents an important milestone in chronic HBV infection and is associated with greater likelihood of clearing hepatitis B surface antigen (HBsAg). Clearance of HBsAg with or without seroconversion to HBV surface antibody (anti-HBs) represents a major positive treatment outcome and the closest marker to a clinical cure we can achieve with HBV therapy. An overall comparison of the treatment responses is shown for the different agents used to treat HBeAg-positive patients (Figure 1 and Figure 2) and those used to treat HBeAg-negative patients (Figure 3 and Figure 4).[1,7] The monitoring to evaluate treatment responses is discussed in detail in the case Monitoring and Management of Patients on Therapy for Chronic Hepatitis B.
Advantages and Disadvantages of Interferon-Based Therapy
Several factors favor the use of interferon (or peginterferon) over an oral nucleos(t)ide analogue: fixed duration of therapy, superior durable serologic responses off-treatment, absence of risk of developing drug-resistant HBV, and activity against hepatitis C virus. The alpha interferons have both antiviral and immunomodulatory properties against HBV. The latter property, the immune-enhancing activity of interferon-based therapies, is thought to confer the slight serologic advantage over oral nucleos(t)ide analogues. In particular, patients with HBeAg-positive status at baseline have a slightly higher HBe seroconversion rate when treated with peginterferon than with an oral antiviral agent (Figure 5). HBeAg seroconversion occurs in 30-35% of HBeAg-positive patients within 6 months of completing 48 weeks of peginterferon-based treatment[8,9,10]. This HBeAg seroconversion was sustained in 81% of initial based on a 3-year follow-up study of 172 participants. Peginterferon may also have a role in HBeAg-negative patients. One randomized controlled trial demonstrated that patients who received 48 weeks of peginterferon alfa-2a (with or without lamivudine) were more likely than recipients of lamivudine alone to have biochemical (normal ALT values, 59% versus 44%) and virologic (HBV DNA level less than 20,000 copies/mL, 43% versus 29%) responses 6 months after stopping therapy. In addition, loss of HBsAg appears to occur earlier in patients treated with standard or peginterferon than with the oral antiviral agents. HBsAg seroconversion has been observed in 3 to 5% of HBeAg-positive patients[8,10] and in 3% of HBeAg-negative patients treated with peginterferon 6 months after treatment, with long-term follow-up studies reporting rates as high as 11% (HBeAg-negative) and 30% (HBeAg-positive) among initial responders[11,13].
From the negative perspective, interferon-based therapy can be poorly tolerated, mainly because of the high incidence of flu-like symptoms and the need to give the medication as a subcutaneous injection. In addition, interferon-based therapy is often complicated by a number of more serious adverse effects, including myelosuppresion, endocrine abnormalities, and psychiatric disturbances. Although interferon-based therapy has been used safely in patients with compensated cirrhosis, it is contraindicated in patients with advanced cirrhosis (Child Class B or C) because of the risk of hepatic decompensation with immune-mediated hepatitis flares; such flares can occur in up to 20 to 40% patients on interferon-based therapy[15,16]. Additional contraindications for the use of interferon-based preparations include autoimmune hepatitis (and other autoimmune conditions), severe psychiatric comorbidity (depression with suicidal ideation), and severe cardiopulmonary conditions. Available data suggest interferon-based therapies have reduced efficacy in patients with normal ALT levels at baseline or high baseline HBV DNA levels[7,17]. Among HBeAg-positive patients, those with HBV genotype A appear to have better response to interferon-based therapy than genotype C or D[8,11,18,19].
Choice of Standard Interferon versus Peginterferon
If an interferon preparation is used, most expert recommendations and clinicians favor the use of peginterferon over standard interferon[7,20,21,22]. Peginterferon is better tolerated than standard interferon and studies in HBeAg-positive patients have shown peginterferon to be more effective than standard interferon with respect to serologic and virologic outcomes Figure 6[9,23]. Furthermore, the weekly injection of peginterferon is more convenient than the three times weekly injections required with standard interferon.
Advantages and Disadvantages of Oral Antiviral Therapy
Nucleos(t)ide analogues have several important advantages over interferon-based preparations: oral formulations, convenient once-daily dosing, excellent tolerance, and low rate of adverse effects. Although interferon-based treatment may have a seroconversion advantage over oral antiviral therapy, the newer oral antiviral agents--entecavir (Baraclude), telbivudine (Tyzeka), and tenofovir (Viread)--are superior to interferon-based therapy in achieving other clinical endpoints, including HBV viral suppression, normalization of ALT, and histologic improvement on liver biopsy. In general, the response to oral antiviral agents is not affected by HBV genotype. The major disadvantages of oral antiviral are the often prolonged and indeterminate duration of therapy and the potential emergence of drug resistance.
Choice of Oral Antiviral Agent
Five nucleos(t)ide analogue agents are currently approved for use in patients with chronic hepatitis B: lamivudine (Epivir-HBV), adefovir (Hepsera), entecavir, telbivudine, and tenofovir. Comparative estimates of efficacy with respect to a variety of surrogate end-points are included in Figure 1 and Figure 2 for hepatitis B eAg-positive patients and in Figure 3 and Figure 4 for HBeAg-negative patients. Overall, there are minimal differences among the oral antiviral agents with respect to serologic, biochemical, or histologic outcomes. Antiviral potency is notably lower for adefovir compared with the other agents and intermediate for lamivudine compared with the newer antiviral agents (entecavir, telbivudine, and tenofovir). For patients with high HBV viral levels, neither adefovir nor lamivudine would be an ideal choice compared with the newer agents. The genetic barrier for drug resistance serves as the major distinguishing feature among the nucleos(t)ide analogue agents and resistance is of extreme importance considering the frequent need for prolonged therapy. The rates of HBV resistance observed over time with these different agents varies markedly, with high rates of resistance observed with lamivudine, moderate with adeofovir and telbivudine, and low rates with entecavir and tenofovir (Figure 7). Lamivudine is no longer recommended as initial therapy because of the high cumulative rate of resistance over time and although telbivudine is potent, the moderate rate of resistance with this agent argue against its use as first-line therapy. Advantages and disadvantages of these oral antiviral agents for the treatment of hepatitis B are highlighted in Figure 8. Tenofovir and entecavir are currently the preferred oral antiviral agents for both HBeAg-negative and HBeAg-positive patients for initial therapy due to their greater potency and lower rate of HBV resistance[1,7].
Single Agent or Combination Oral Antiviral Therapy
An interest in combination therapy for HBV has emerged as clinicians face challenges similar to those encountered with HIV antiretroviral therapy: the selection of drug-resistant virus with monotherapy or sequential add-on therapy. Combination therapy could, by additive or synergistic antiviral efficacy, theoretically improve the durability of viral suppression and diminish rates of HBV resistance, or better yet, permit cessation of therapy without viral relapse. Unfortunately, for initial therapy in patients with HBV, current evidence falls short of establishing a clear benefit of combination therapy. Multiple studies have examined different nucleoside analogue dual combinations and aside from offering a slight advantage with respect to initial viral decay and decreased rates of lamivudine resistance when adefovir is combined with lamivudine, combination therapy does not clearly offer an advantage from the standpoint of HBeAg seroconversion or histologic improvement. Some experts, however, support the use of dual nucleoside analogue therapy for the following situations: (1) patients with cirrhosis who may experience hepatic decompensation from viral breakthrough and therefore cannot afford to lose antiviral activity, (2) patients who have had suboptimal responses to initial monotherapy with a drug, such as lamivudine, that has a low genetic barrier for resistance, (3) patients coinfected with HIV and HBV, and (4) patients who have undergone liver transplantation[28,29]. If two oral agents are used, it is important that these drugs have complementary cross-resistance profiles (see the case Management of Patients with Chronic Hepatitis B and Antiviral Resistance for further discussion).
Combining Interferon-Based Preparations with Oral Antiviral Agents
Several studies have also addressed combination therapy that involved the use of peginterferon and lamivudine in both HBeAg-positive and HBeAg-negative patients. These studies failed to demonstrate superiority of these combinations over monotherapy with respect to HBeAg seroconversion, histologic improvement, or sustained virologic response. Thus, the use of peginterferon combined with a nucleoside analogue is not recommended at this time.