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Management of Hepatitis B Infection

Stefan Zeuzem, MD
Program Director
Harry L. A. Janssen, MD, PhD
Milan J. Sonneveld, MD, PhD, MSc
Released: June 17, 2019

Choosing the Appropriate First-line Therapy

In all major guidelines, including those from the AASLD,[3] EASL,[4] and APASL,[9] 3-4 first-line HBV agents are currently indicated as “preferred”: peginterferon, entecavir, tenofovir DF, and tenofovir AF. Both nucleos(t)ide analogues and peginterferon have substantial advantages and important limitations (Table 6).[115] In addition, each of the 4 recommended first-line agents may be preferred in certain clinical circumstances (Table 7).

Table 6. Advantages and Disadvantages of Peginterferon vs Nucleos(t)ide Analogues


Table 7. Circumstances Where a Certain First-line Anti-HBV Agent May Be Preferred Over Others


Nucleos(t)ide analogues are the most frequently used first-line treatment options in HBV, specifically entecavir, tenofovir DF, and tenofovir AF, because they are preferred by all major guidelines due to the considerable risk of antiviral resistance in patients treated with lamivudine, adefovir, and telbivudine.[3,4,9] Peginterferon therapy should also be considered, especially in HBeAg-positive patients, because of the relatively high sustainability of response, as well as the higher rates of HBsAg clearance.[102,109,116] Current guidelines from the Asian Pacific Association for the Study of the Liver also note that interferon-based therapy is preferred for younger patients.[9] Patients should ideally be selected for peginterferon therapy on the basis of their individual probability of response, as discussed below. In case of a low baseline probability of response to peginterferon, nucleos(t)ide analogue therapy should be advised. In addition, nucleos(t)ide analogues are the treatment regimen of choice for patients with hepatic decompensation, those receiving chemotherapy, immunocompromised patients, pregnant patients that require therapy, and patients with contraindications to peginterferon (such as psychiatric disorders, cardiovascular disease, or thyroid disorders).[117]

Baseline Predictors of Response to Peginterferon Therapy

Because peginterferon is effective in only a subset of patients, only those with the highest probability of response should be offered this therapy option.

HBeAg-Positive Patients. HBV genotype is a major predictor of response to peginterferon.[118-120] Other baseline factors associated with an increased likelihood of a sustained off-treatment response include older age, female sex, higher serum ALT levels, and lower serum HBV DNA levels (Table 8).[118-120] Other factors that are currently under investigation but not ready for clinical application include host IL28B genotype,[121,122] presence of precore and core promoter mutants,[123,124] and pretreatment level of IP-10.[125]

Table 8. Baseline Predictors of Response to Peginterferon*


HBeAg-Negative Patients. Although there are fewer studies in HBeAg-negative patients vs HBeAg-positive patients, several baseline predictors of response to peginterferon in HBeAg-negative patients have been discovered (Table 8). Data suggest female sex, HBV genotype, higher baseline ALT level, and lower baseline HBV DNA levels may be associated with a higher probability of achieving a sustained off-treatment response (defined as HBV DNA levels < 20,000 copies/mL combined with normal ALT level at 6 months after treatment).[126] Of note, Marcellin and colleagues[90] demonstrated that treatment with peginterferon alfa-2a and a high baseline ALT level were independent predictors of long-term virologic response in HBeAg-negative patients. Baseline HBsAg levels do not differentiate responders from nonresponders to peginterferon therapy.[127-129]

Since HBeAg-negative patients show limited response to peginterferon, nucleos(t)ide analogue–based treatment is the best choice for the majority of these patients. For a small subset, such as the young, peginterferon may be an option, but the individualized probabilities of a response cannot be determined, and the option of an extended treatment duration (2 years) in patients with HBV genotype D should be considered.[111]

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