Hepatitis B virus treatment: Which patients should be treated with interferon?

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Abbreviations.

ALT

alanine aminotransferase

CHB

chronic hepatitis B

HBeAg

hepatitis B e antigen

HBsAg

hepatitis B surface antigen

HBV

hepatitis B virus

NA

nucleos(t)ide analogue

PEG‐IFN

pegylated interferon

Although safe and effective vaccines have been available for several decades, chronic hepatitis B (CHB) remains one of the most prevalent infectious diseases. Therefore, many patients require antiviral therapy to prevent progression to cirrhosis, liver failure, hepatocellular carcinoma, and liver‐related death.1

The potential of antiviral therapy for CHB has increased enormously in recent years as a result of the introduction of pegylated interferon (PEG‐IFN), which renewed the interest for this immunomodulating drug, as well as the introduction of better nucleos(t)ide analogues (NAs). Even though NAs are very effective, increasing evidence suggests that after hepatitis B e antigen (HBeAg) seroconversion, stopping NA therapy results in a relapse of hepatitis B virus (HBV) infection in the majority of patients.2 We therefore have to anticipate that NA should be given indefinitely. Thus, the long‐term side effects and costs of NA should be taken into account when initiating such therapy.

Both treatment modalities (NA and PEG‐IFN) have proven to be effective, but current guidelines are lacking clear recommendations as to which treatment strategy should be used as first‐line therapy.1 In HBeAg‐positive patients, PEG‐IFN results in a response (sustained HBeAg seroconversion 24 weeks posttreatment) in approximately 25% to 30% of patients. In HBeAg‐negative patients, a sustained response (HBV DNA <2,000 IU/mL and normal alanine aminotransferase [ALT] 24 weeks posttreatment) occurs in approximately 25% of patients after a finite treatment with PEG‐IFN. However, clinical use of PEG‐IFN is compromised by suboptimal tolerability and costs.1 Selection of patients with the highest probability of achieving a response to PEG‐IFN is therefore essential for optimal use of this agent in clinical practice and to guide physicians in deciding whether to start with PEG‐IFN.

It has been demonstrated among 721 HBeAg‐positive patients that older age, female sex, higher serum ALT levels, lower serum HBV DNA levels, and HBV genotypes A and B were associated with an increased likelihood of sustained response defined as HBeAg loss with HBV DNA <2,000 IU/mL.3 Subsequently, a multivariable prediction model was developed that can guide clinicians in decisions on whether to consider patients for PEG‐IFN–based treatment.4 Furthermore, presence of only wild‐type virus at baseline has recently been shown to be a strong predictor of a sustained virological response to PEG‐IFN5 (Table 1).

Table 1.

Baseline Predictors Associated with Higher Likelihood of Response to PEG‐IFN for HBeAg‐Positive and HBeAg‐Negative CHB

	Baseline Factor
HBeAg‐positive	HBV genotypes A and B
	Lower serum HBV DNA (<2 × 108 IU/mL)
	Higher serum ALT (2‐5× ULN)
	Female sex
	Older age
	Wild‐type virus
	rs12979860 CC near IL28B *
HBeAg‐negative	Lower serum HBV DNA
	Higher serum ALT (2‐5× ULN)
	Female sex
	Younger age
	rs12979860 CC near IL28B *

Abbreviation: ULN, upper limit of normal.

^*Controversial data have been reported.

For HBeAg‐negative patients, data on baseline predictors of response to PEG‐IFN are limited. Using a multivariable logistic regression model in a cohort of 518 HBeAg‐negative patients, younger age, female sex, higher serum ALT levels, and lower serum HBV DNA levels were found to be associated with a higher probability of achieving a sustained response defined as HBV DNA <2,000 IU/mL and normal alanine aminotransferase [ALT] 24 weeks posttreatment6 (Table 1).

In addition to these variables, recent studies suggested an influence of host genetic factors on response to PEG‐IFN treatment (Table 2). Large genome‐wide association studies of patients infected with hepatitis C virus revealed an association between sustained virological response to PEG‐IFN and ribavirin and several single nucleotide polymorphisms on chromosome 19, located near the IL28B gene. IL28B encodes for IFN‐λ3, which has similarities in the signaling pathway (JAK‐STAT) with the IFN‐α preparations used for antiviral treatment.

Table 2.

PEG‐IFN Response Rates for HBeAg‐Positive and HBeAg‐Negative CHB Patients

	Response Rate
HBeAg‐positive
HBeAg seroconversion	29%‐32%
HBV DNA <60‐80 IU/Ml	7%‐14%
ALT normalization	32%‐41%
HBsAg loss*	3%‐7%
HBeAg‐negative
HBV DNA <60‐80 IU/mL	19%
ALT normalization	59%
HBsAg loss	4%‐9%

^*After long‐term follow‐up.

Studies in CHB with respect to the association of polymorphisms near IL28B genotype and response to PEG‐IFN have yielded contradictory results. In a cohort of 205 HBeAg‐positive patients treated with PEG‐IFN, rs12980275 AA and rs12979860 CC genotype were associated with HBeAg seroconversion and a higher probability of hepatitis B surface antigen (HBsAg) clearance.7 This association was also found in HBeAg‐negative patients infected with HBV genotype D; rs12979860 CC genotype was a positive predictor of HBsAg clearance.8 Host IL28B genotype may therefore be a valuable baseline predictor of response to PEG‐IFN therapy. However, a Chinese study of HBeAg‐positive patients infected with HBV genotypes B and C showed an opposite effect; the minor IL28B‐related G allele of rs8099917 was associated with a good response to IFN.9 The contradictory findings may be explained by the heterogeneity with respect to study populations, treatment regimens, and outcomes studied. Furthermore, there appears to be a strong association between IL28B genotype and patient ethnicity. Consequently, patients with favorable IL28B genotypes are often infected with unfavorable HBV genotypes.10 This interplay requires further elucidation in well‐defined cohorts treated with PEG‐IFN according to currently licensed protocols before routinely performing IL28B genotyping is indicated for CHB patients.

In addition to baseline predictors of response, other aspects should be taken into account when initiating PEG‐IFN therapy. Patients with a history of decompensated liver disease or known neuropsychiatric medical history should preferably not be treated with PEG‐IFN.

Considering the absence of clear guidelines regarding which patients should initially be considered for PEG‐IFN, and the risk of nonresponse even in those with the highest baseline probabilities of success, on‐treatment monitoring of viral replication using HBV DNA is currently recommended.1 However, even patients with late HBV DNA decline during treatment may achieve a sustained response, thereby limiting the use of HBV DNA quantification as a predictor of the outcome after PEG‐INF therapy.

Fortunately, it has recently been observed that the on‐treatment decline of serum HBsAg may reflect the efficacy of PEG‐IFN in decreasing intrahepatic transcriptionally active covalently closed circular DNA (ccc DNA) levels and may consequently predict a sustained response to PEG‐IFN therapy. These guidelines have also been adopted by the recent European Association for the Study of the Liver guidelines.11 In a cohort of 221 HBeAg‐positive patients, it was shown that patients without HBsAg decline at week 12 of PEG‐IFN therapy had little chance of achieving a response and no chance of HBsAg loss.12 In addition, Piratvisuth et al.13 showed that patients with HBsAg levels of >20,000 IU/mL after 12 weeks of treatment have a low probability of response. However, these prediction rules have shown suboptimal external validity, possibly due to the influence of HBV genotype on HBsAg kinetics.14 The optimal choice of stopping rule for HBeAg‐positive patients therefore remains to be determined.

Decision‐making during treatment of HBeAg‐negative CHB has also been established. Patients without any HBsAg decline and less than 2 log HBV DNA decline at week 12 of treatment had no chance of achieving a sustained virological response in a European study.15 This stopping rule was recently confirmed in a cohort of 262 HBeAg‐negative patients harboring genotypes A‐D (negative predictive value, 95% [100% for genotype D]). This stopping rule can therefore be used in the management of PEG‐IFN treatment in HBeAg‐negative CHB.16 (Table 3).

Table 3.

Stopping Rules at Week 12 for HBeAg‐Positive CHB Patients Treated with PEG‐IFN18

	NPV	n	Most Common Genotypes
No HBsAg decline	97%	202	A, D
No HBsAg decline	71%‐82%	526	B, C
HBsAg >20,000	100%	114	B, C
HBsAg >20,000	84%	399	B, C

In addition to HBV DNA and HBsAg monitoring, other factors may contribute to the decision of whether to continue PEG‐IFN–based therapy. Treatment with PEG‐IFN can be associated with considerable side effects, such as flu‐like symptoms, headache, myalgia, fatigue, depression, thrombocytopenia, and neutropenia, which may result in the necessity of stopping PEG‐IFN treatment in a subset of patients.17 Frequent monitoring every 4 to 8 weeks is therefore necessary to asses the severity of these side effects.

In conclusion, recent data on the influence of HBV genotype and host genetics on response to PEG‐IFN may help select patients for PEG‐IFN therapy, but their interplay needs to be elucidated further in well‐defined cohorts. Monitoring of HBsAg levels and side effects may help in decision making during treatment; nevertheless, the advantages and disadvantages should always be considered on an individual basis. 1

Figure 1.

Negative predictive values (NPV) and positive predictive values (PPV) at week 12 of PEG‐IFN treatment for HBeAg‐negative CHB using HBV DNA and HBsAg levels as predictive parameters of a sustained response (SR) defined as HBV DNA <2,000 IU/mL and normal alanine aminotransferase [ALT] 24 weeks posttreatment.16