Yun-Fan Liaw and Fabien Zoulim (eds.)Hepatitis B Virus in Human DiseasesMolecular and Translational Medicine10.1007/978-3-319-22330-8_15

15. IFN-Based Therapy and Management of Patients

Victor C. K. Lo¹ and Harry L. A. Janssen^{2, 1}

(1)

Toronto Centre for Liver Diseases, University Health Network, 399 Bathurst Street, 6B Fell Pavilion, Toronto, ON, Canada, M5T 2S8

(2)

Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

Victor C. K. Lo

Email: victor.lo@uhn.ca

Harry L. A. Janssen (Corresponding author)

Email: Harry.Janssen@uhn.ca

Keywords

Hepatitis B virus pegylated interferonNucleoside analoguesNucleotide analoguesTenofovirEntecavirLamivudineAdefovirTelbivudineResponse prediction

Introduction

Interferon alfa (IFN) is an endogenously produced 128-amino acid cytokine that acts as an immunomodulator, enhancing cell-mediated immunity against viruses. Specifically, they are named because of their ability to interfere with viral replication. They also activate natural killer cells and macrophages, and upregulate antigen-presenting cells. Recombinant IFN alfa was approved in the 90s as the first agent for the treatment of chronic HBV. It is administered parenterally.

A study in 2014 investigated the mechanism by which IFN alfa induces a direct antiviral effect . It was found that interferon alfa and lymphotoxin-β receptor activation may induce non-cytolytic degradation of covalently closed circular DNA (cccDNA) via upregulation of proteins of the APOBEC3 family [1]. The degradation of intrahepatic cccDNA would prevent HBV reactivation. Since the genomic DNA was not affected, the authors suggest that the induction of nuclear deaminases, such as those induced by lymphotoxin-β receptor activation, may have potential as a new therapeutic for hepatitis B.

The pegylation of interferon (pegIFN), in which a polyethylene glycol is attached to the interferon protein, extends the half-life of IFN, stabilizes serum concentrations, and reduces the frequency of dosing and side effects, thereby improving patient compliance with treatment. Additionally, it was demonstrated that the use of pegIFN alfa leads to comparable or higher rates of HBeAg loss, HBV DNA suppression, and ALT normalization as conventional IFN [2]. Thus conventional (standard) IFN has largely been replaced with the use of pegIFN alfa. The treatment of chronic hepatitis B (CHB ) uses recombinant pegIFN alfa-2a or 2b. PegIFN alfa-2a has a 40 kDa branched peg that is attached to IFN, whereas pegIFN-alfa-2b has a 12 kDa straight chain peg.

Interferon Monotherapy

The advantage of using IFN over oral nucleos(t)ide analogue (NUC) therapies is that treatment duration is finite, usually 48 weeks as recommended by current guidelines for treatment-naive patients, and there is no evidence for drug resistance. However, the frequency of adverse events is higher and is dose-dependent, and patient compliance may be lower due to the need for injection in contrast to the convenience of an oral agent. With the introduction of pegIFN alfa, injection schedules can be reduced from thrice weekly with conventional IFN to only once weekly.

While pegIFN alfa does not result in HBV suppression rates as great as NUCs, it has been shown that there exists post-treatment antiviral benefits which are more durable—a “delayed” effect. In patients with HBeAg-positive CHB, pegIFN alfa induces an early reduction of HBV replication, sometimes with a subsequent hepatitis flare. Using pegIFN alfa for a finite 1-year in HBeAg-positive patients resulted in HBeAg seroconversion rates of 32 % and 29 % respectively, found at 6 months post-treatment follow-up [3, 4]. These HBeAg seroconversion rates are significantly higher and more durable than what has been found with 1 year of NUCs such as LAM, ETV, or TDF. PegIFN alfa has also been shown to induce HBV DNA suppression , HBsAg clearance, normalization of ALT, and histological improvement [5]. Patients who achieve an IFN-induced HBeAg seroconversion also have a reduced risk of developing cirrhosis and HCC, leading to better clinical outcomes for patients.

PegIFN alfa has been used in the treatment of HBeAg-negative patients in whom HBV DNA continues to replicate despite the presence of anti-HBe immunity [6]. Treatment in HBeAg-negative patients with pegIFN alfa has shown a response (defined as HBV DNA below 400 copies/mL for up to 24 weeks after cessation of therapy according to the Peginterferon Alfa-2a Negative Chronic Hepatitis B Study Group) rate of approximately 20 % [5, 7], which is also durable and leads to better clinical outcomes [8]. Thus, a 48 week course of treatment with pegIFN alfa is currently recommended for HBeAg-negative CHB patients who have no contraindications to pegIFN alfa, as treatment is finite and virological response is durable.

A study in 2012 compared the treatment response between HBeAg-negative patients who received pegIFN alfa for 48 weeks with those who received pegIFN alfa for 96 weeks (with a dose reduction from 180 to 135 μg in the latter 48 weeks) [9]. This study examined a group of 128 patients with mostly HBV genotype D. It was observed that more than twice the number of patients who received pegIFN alfa for 96 weeks had a combined response of HBV DNA <3400 IU/mL and ALT normalization at 48 weeks post-treatment. Thus they concluded that extending treatment duration to 96 weeks improves sustained virological responses. However, it is important to consider side effects, as 12 % of patients withdrew from the extension group due to adverse events (AEs). The extended use of pegIFN alfa incurs a higher cost and risk of patient non-adherence, as well, so careful consideration is required before extending pegIFN alfa therapy. Nonetheless, pegIFN alfa is currently only therapeutic option that offers a reasonable chance of sustained off-treatment response.

Several studies examined the long-term effects of interferon use in CHB patients, particularly on survival and hepatocellular carcinoma (HCC). A placebo-controlled study analyzed 101 patients with a follow-up period of 1.1–11.5 years [10]. It was found that the cumulative incidence of HCC development was significantly higher, and the cumulative survival rate was lower in the placebo group compared to the treatment group. These findings were replicated in another study of 165 HBeAg-positive patients treated with IFN with a median follow-up period of 8.8 years [11]. Thus, the authors concluded that IFN results in long-term beneficial effects in terms of reduction of HCC and prolongation of survival.

Interferon Safety and Adverse Event Management

The most frequently reported side-effects associated with the use of conventional IFN were flu-like symptoms including: fever, fatigue, irritability, chills, headache, muscle aches, and local reaction at the injection site [12, 13]. Less common are: anorexia, nausea, insomnia, neutropenia, thrombocytopenia, alopecia, weight loss, and depression. A study in 2005 investigated the safety of pegIFN alfa for the treatment of CHB in 300 patients [13]. They found that all patients reported one or more of the adverse effects known to conventional IFN treatment with no reports of new adverse effects. The rate of dose reduction in the study was 22 % and therapy discontinuation was 9 %. The higher frequency of dose reduction using pegIFN alfa-2a compared to conventional IFN (rate of 10 %) was attributed to increased occurrence of neutropenia. However, while pegIFN alfa induced thrombocytopenia and neutropenia , it was found that the number of infections was low and relatively mild and that bleeding complications were also mild (epistaxis). Patients with liver cirrhosis should have more frequent monitoring, as they are at an increased risk of thrombocytopenia and bleeding complications.

Informing patients about adverse events and adequate treatment of symptoms, such as specific serotonin reuptake inhibitors (SSRIs) for depression, may lead to an increased proportion of patients capable of completing treatment without dose reduction. The use of anti-pyretics and analgesia may also help to relieve other side effects associated with the use of pegIFN alfa, such as flu-like symptoms .

Predicting Response to pegIFN Alfa

Since pegIFN alfa treatment is expensive and associated with considerable side effects, it is of clinical interest and significance to be able to predict which patients will have a high probability of response. Much investigation has been done on serum HBV DNA, ALT and HBsAg levels, HBV genotype and IL28B polymorphisms [14].

Pretreatment Response Prediction

Pretreatment virological, serological, and biochemical parameters such as viral load, HBsAg, HBeAg, and ALT levels as well as host and virus genetic factors have been investigated for their role in predicting response to pegIFN alfa. Being able to reliably predict and identify which patients will likely and unlikely benefit from pegIFN alfa or continuation of pegIFN will serve to increase cost-effectiveness and reduce patient side effects. Pretreatment ALT and HBV DNA levels have been demonstrated to be a reliable factor in helping clinicians form treatment plans [15]. Specifically, high pretreatment ALT levels and low HBV DNA were associated with a higher rate of sustained response to pegIFN alfa.

However, as viral load and ALT levels fluctuate throughout the natural course of disease, they are somewhat unreliable as predictive variables to treatment response. Thus, both host and viral genetic factors, like HBV genotype, have been investigated as a predictor of response to pegIFN alfa treatment. It has been found that CHB patients with HBV genotype A have the best response and that HBV genotype D is associated with poorer responses to treatment compared to other genotypes. Genotype A and D are more common among the Caucasian population, whereas genotypes B and C are more common among Asian populations [3, 16].

A 2012 study demonstrated that the presence of precore (PC) and basal core promoter (BCP) mutations in the viral genome affect the serological and virological response to pegIFN alfa [17] in HBeAg positive disease. Specifically, those with detectable mutant PC/BCP have a lower probability of response (HBeAg loss and suppressed HBV DNA) compared to those with wild-type, irrespective of HBV genotype. Thus, the authors conclude that the presence of wild-type virus is a strong predictor of response and HBsAg clearance. However, another failed to confirm these findings [18], suggesting that further investigation is needed to fully understand the effect of PC and BCP mutations and their predictive value to pegIFN alfa response.

Another study investigated the effects of host genetic polymorphisms on the interleukin 28B gene (IL28B, also known as IFN-λ-3 ) [19] on pegIFN alfa treatment response in 208 HBeAg-positive CHB patients. While the exact mechanism by which these genetic polymorphisms affect treatment response remain unclear, it was shown that there exists favorable IL28B genotypes (AA for rs12980275 and CC for rs12979860) which increase the probability of achieving a sustained HBeAg seroconversion with pegIFN alfa. However, some patients maintain detectable HBV DNA and elevated ALT level despite HBeAg seroconversion [20]. While favorable IL28B polymorphisms were a strong predictor for serological response to pegIFN alfa in terms of HBeAg seroconversion, it was found that they are poor predictors for combined responses of HBeAg seroconversion and HBV DNA suppression (HBV DNA <2000 IU/mL). Thus, the authors recommend that genotypic variations in IL28B can be used in combination with other predictors of response such as HBV genotype and pretreatment HBV DNA and ALT levels, but not as a replacement. Another study in 2011 looked at other host genetic polymorphisms such as HLA-DPA1 and HLA-DPB1 as predictors to response to pegIFN therapy in HBeAg-positive patients [21]. Their findings suggest that genetic variations in HLA-DP regions may influence spontaneous and/or treatment-induced HBV clearance, but that further research is required to fully characterize the effects. Altogether, these studies provide evidence that host genetic factors are also important in the response to pegIFN alfa therapy, in addition to viral genotypic factors.

With regard to HBeAg-negative disease, a 2013 retrospective study also examined the effects of IL28B on pegIFN alfa response in CHB patients with mostly HBV genotype D [22]. They similarly found that particular IL28B genotypes are more favorable towards a positive response. Specifically, HBeAg-negative patients with HBV genotype D who carry the CC genotype of rs12979860 IL28B had an increased rate of sustained virological response and HBsAg clearance (3.9-fold higher) than those with the CT or TT genotype.

In contrast to the above two studies, other studies on CHB patients treated with pegIFN alfa demonstrated evidence that polymorphisms near IL28B gene were not associated with on- and post-treatment kinetics of HBV DNA and HBsAg levels [23, 24]. In light of conflicting results, further investigation is needed to fully characterize the effect of IL28B polymorphisms on pegIFN alfa response, particularly for HBeAg-negative patients, and its clinical relevance as a treatment predictor.

In a 2013 study, it was found that baseline HBsAg was the only independent predictor of loss of HBsAg at week 144, after combination pegIFN + ADV treatment for 48 weeks [25]. Specifically, the authors noted that a low baseline HBsAg was a strong predictor for HBsAg loss for HBeAg-negative CHB patients. However, two large multinational studies of patients treated with pegIFN alfa-2a found that baseline serum HBsAg levels did not correlate with antiviral response, regardless of HBeAg status [26, 27]. These conflicting results suggest that further studies are required to validate the predictive value of baseline HBsAg levels for pegIFN alfa response.

Response-Guided Therapy

Strategies to evaluate the effectiveness of pegIFN alfa during the course of therapy is important as well, as stopping treatment early for patients whom it will be ineffective serves to improve cost-efficiency and reduce side-effects. A number of studies have examined on-treatment parameters for their predictive value in determining treatment-response.

A study in 2013 analyzed the HBsAg levels of 803 HBeAg-positive patients treated with pegIFN [28]. The authors found that on-treatment levels of HBsAg could predict off-treatment response. Specifically, for patients who had serum levels of HBsAg <1500 IU/mL by week 12 of therapy, 45 % achieved response (defined as HBV DNA <2000 IU/mL and HBeAg loss). In contrast, only 14 % achieved a response in those who did not experience HBsAg decline, and only 6 % of patients responded if they had serum HBsAg levels >20,000 IU/mL by week 12. This effect was found to be HBV genotype-dependent, as response rates were low in patients with genotype A or D if there was no HBsAg decline, and B and C if HBsAg levels were >20,000 IU/mL by week 12. By week 24, nearly all patients with serum HBsAg >20,000 IU/mL failed to respond regardless of HBV genotype. This study demonstrates that on-treatment serum HBsAg can be used to guide treatment decisions, particularly with regard to discontinuing pegIFN when HBsAg levels remain >20,000 IU/mL after 24 weeks of therapy.

For HBeAg-negative patients, a study in 2009 observed that an on-treatment HBsAg decline of greater than 1 log₁₀ IU/mL and <10 IU/mL at week 48 was significantly associated with sustained HBsAg clearance 3 years after pegIFN alfa treatment [29].

A 2010 study investigated early on-treatment kinetics of HBV DNA and HBsAg and their predictive power on pegIFN alfa treatment response in HBeAg negative patients [26]. It was found that patients with HBV genotype D who do not experience a decline in HBsAg levels and achieve <2 log₁₀ copies/mL change in HBV DNA by week 12 of treatment do not achieve HBV DNA suppression or ALT normalization 6 months post-treatment. Follow-up studies were conducted to validate this finding, and thus the stopping rule for this study was incorporated into current treatment recommendations for patients with HBV genotype D [30].

Combination of IFN with NUCs for the Treatment of Chronic Hepatitis B

Combination therapy of IFN with NUCs has been investigated as an approach to treating chronic hepatitis B. Theoretically, the antiviral effects of NUCs would strongly suppress HBV DNA replication, and the immunomodulating effects of pegIFN alfa would enhance the host response to eliminate infected hepatocytes. However, the following sections on pegIFN alfa combination with specific NUCs demonstrate that the superiority of combination therapy to monotherapy is not well established. Thus current international guidelines do not support the use of pegIFN alfa in combination with NUCs for the treatment of CHB. However, studies investigating the use of more recently approved NUCs and their combination with pegIFN alfa are currently underway in both HBeAg-positive and HBeAg-negative CHB patients. Additionally, other strategies such as add-on or switch-over to pegIFN alfa from NUC have been explored as alternatives to concurrent pegIFN + NUC therapy.

Combination IFN and Nucleoside Analogues

Lamivudine (LAM)

Many studies have been conducted on the use of pegIFN alfa combined with LAM for the treatment of chronic hepatitis B, as LAM is the first approved NUC for the treatment of chronic hepatitis B. A number of pivotal studies on both HBeAg-positive and HBeAg-negative disease have been described in this section in chronological order respectively.

Only gold members can continue reading. Log In or Register to continue