October 2, 2012

Efficacy and Tolerability of Pegylated Interferon-α-2a in Chronic Hepatitis B: A Multicenter Clinical Experience

From Journal of Gastroenterology and Hepatology

Dilip Ratnam; Anouk Dev; Tin Nguyen; Vijaya Sundararajan; Hugh Harley; Wendy Cheng; Alice Lee; Ferry Rusli; Robert Chen; Sally Bell; Stephen Pianko; William Sievert

Posted: 10/01/2012; J Gastroenterol Hepatol. 2012;27(9):1447-1453. © 2012 Blackwell Publishing

Abstract and Introduction
Abstract

Background and Aim: Pegylated interferon-α (PEG-IFN) provides potential advantages over nucleos(t)ide analogues in the treatment of chronic hepatitis B (CHB) given its finite course, durability and lack of drug resistance. Much of the evidence is derived from controlled studies and it is unclear whether these results can be replicated in an everyday, non-controlled setting. The aim of this study was to examine the efficacy and tolerability of PEG-IFN-α2A in CHB patients in a clinical setting.
Methods: Chronic hepatitis B patients treated with PEG-IFN-α2A (180 μg/week, 48 weeks) at five tertiary hospitals were retrospectively identified. Baseline demographic and clinical data, on-treatment virological and serological responses and adverse events (AE) were recorded. Treatment outcomes were defined as alanine aminotransferase (ALT) normalization, hepatitis B virus DNA < 351 IU/mL and hepatitis B e antigen (HBeAg) seroconversion.
Results: Sixty three HBeAg positive patients were identified (65% male, 80% born in Asia, 84% with viral loads > 6log IU/mL, 9.5% advanced fibrosis). Six months after therapy 46% achieved normalization of ALT, 16% had viral loads < 351 IU/mL and 32% achieved HBeAg seroconversion. 29 HBeAg negative patients were treated (75% male, 86% born in Asia, 48% had viral loads > 6log IU/mL, 24% advanced fibrosis). Six months post-treatment, 55% and 36% maintained a normalized ALT and HBV DNA < 351 IU/mL, respectively. Optimal viral suppression was maintained in 50–75% of patients over 2 years of follow up. 6.5% of all patients discontinued therapy due to AEs.
Conclusion: In everyday clinical practice PEG-IFN therapy in CHB is well tolerated and can achieve a similar efficacy to that seen in large controlled trials.

Introduction

Chronic infection with the hepatitis B virus (CHB) is a global health concern, affecting up to 400 million people worldwide. Between 20% to 40% of affected individuals will develop the most serious consequences of cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC), resulting in approximately 500 000 to 1.2 million deaths per year worldwide.[1] Treatment can reduce mortality from end stage liver disease.[2–6] Two classes of antiviral therapy are available—nucleoside or nucleotide analogues, and interferon-α (INF-α) (standard or pegylated forms). The choice of a particular therapy for a given individual can be complex, influenced by factors including age, serum alanine transasminase (ALT), histological findings, hepatitis B e-antigen (HBeAg) status, hepatitis B virus (HBV) viral load and genotype, previous therapy and tolerability of potential adverse effects. Globally, nucleos(t)ide analogues are the more commonly used option, often favored due to their combination of high antiviral potency, ease of use and high tolerability. However, this class has limitations such as the potential development of viral resistance, as well the need for long term therapy in many individuals.

Interferon-α acts against HBV by both immunomodulatory and direct antiviral mechanisms. Compared with the nucleoside analogues it is associated with higher rates of HBeAg to anti-HBe seroconversion, greater durability of response and lack of antiviral resistance.[7] However, it is not as potent at achieving viral suppression, is less convenient to use and is associated with a number of side effects. Pegylated interferon-α (PEG-IFN) was introduced approximately a decade ago with a view to improving efficacy, convenience and tolerability through its improved pharmacodynamic profile compared with standard interferon. While the evidence suggests that PEG-IFN is both effective and safe in the treatment of CHB, this data has been derived almost exclusively from a handful of controlled trials. Whether these results can be replicated in a day to day, non-controlled setting is unclear, particularly given concerns that tolerability of the drug may adversely affect adherence. In this study we performed a retrospective evaluation of the outcomes of PEG-IFN-α therapy for both HBeAg positive (HBeAg[+]) and HBeAg negative (HBeAg[−]) CHB patients treated in Australian tertiary hospitals, with the aim of determining effectiveness and tolerability in an everyday clinical setting.

Methods

Five tertiary medical centres in Australia participated in this study. Institutional databases were used to identify individuals with CHB commenced on a 48 week course of Pegylated Interferon-α2a (Pegasys, Roche Products, Dee Why, Australia) at a dose of 180 μg weekly by subcutaneous injection between 2005 and 2009.

Baseline data included patient demographics, previous antiviral therapy and hepatic fibrosis scores (METAVIR scoring system).[8] Serum ALT (U/L) was recorded at baseline, at 4-weekly intervals during therapy and at 12 and 24 weeks post-therapy. HBeAg, anti-HBe, and HBV DNA viral load (IU/mL) were recorded at 3-monthly intervals until 24 weeks post-treatment. HBV viral load was measured using either the Bayer Versant bDNA HBV 3.0 test (range 351–1.8 × 107 IU/mL), Roche Cobas Taqman assay (55–1.1 × 108 IU/mL) or Abbott M2000 test (15–1 × 109 IU/mL). HBV genotyping was tested at only two institutions while hepatitis B surface antigen (HBsAg) and anti-HBs were not routinely measured after the completion of therapy.

Treatment outcomes were defined as normalization of serum ALT, HBV viral suppression, loss of HBeAg and development of anti-HBe and measured at the end of therapy and after 6 months of follow up. The upper limit of the normal (ULN) range for ALT at one hospital was 45 U/L for males and 35 U/L for females, and 55 U/L for all patients at the remaining hospitals. Optimal viral suppression was considered to be a viral load ≤ 351 IU/mL, which was the lower limit of detection of the Bayer Versant test used by most centres. Sustained virological suppression (SVS) was defined as the achievement of optimal viral suppression 6 months after completing therapy. Suppression of HBV DNA levels to below 2000 IU/mL was used as a secondary measure of efficacy in line with the threshold used in numerous guidelines to differentiate between active and inactive CHB.[9–11] Early relapse was defined as a rebound in viral load to ≥ 351 IU/mL within 6 months of having achieved optimal suppression at the end of therapy. Patients achieving either level of viral suppression were followed for 2 years to assess the durability of the response. Tolerability and safety were assessed by the ability to complete 48 weeks of treatment, incidence of adverse events (AE) and deaths.

Statistical Analysis

Statistical comparisons were performed using Stata Statistical software Version 11 (StataCorp, College Station, TX, USA). Continuous variables with normal distribution were expressed as mean and standard deviation, and variables with skewed distribution as median and range. Baseline categorical variables were compared by Pearson's χ2 test, and continuous variables were compared by the Mann–Whitney U-test. The relation between characteristics at baseline and during therapy and post-treatment response was examined by logistic regression analyses. All statistical tests were two-sided. Statistical significance was taken as P < 0.05.

HBeAg[+] Patients

A total of 63 HBeAg[+] patients were commenced on PEG-IFN, of which 58 (92%) completed the 48 week course. Four patients ceased treatment prematurely due to AEs and one was lost to follow up before completion of therapy. A further two were lost to follow up after treatment. Patient demographics and baseline investigations are outlined in Table 1. The majority were male (65%), born in North or South East Asia (80%) and the median age was 32.5 years. Of the eight (13%) patients previously exposed to antiviral therapy (six Lamividine[LAM] monotherapy two combination LAM and Adefovir), four had confirmed LAM resistance mutations (M204V/I + L180M). Of the 23 patients who were genotyped (Gt), three were Gt A, eight Gt B, 10 Gt C and two Gt D, reflecting the ethnic origins of the cohort. Serum ALT > 2×ULN occurred in 75% of patients, 84% had a viral load > 6 log IU/mL and 9.5% had advanced fibrosis on pretreatment liver biopsy.

Biochemical, serological and virological responses are shown in Table 2. By the end of 48 weeks of therapy 52% of patients had normalized serum ALT and this was sustained in the majority of patients over the 6 month follow up period. A total of 20 (32%) individuals lost HBeAg and seroconverted to anti-HBe over the study period. In three patients this response was delayed, occurring in the 6-month post-treatment follow-up period. Despite not being routinely measured, two (3.5%) patients (both genotype A) achieved loss of HBsAg.

The proportion of patients with optimal viral suppression at the end of treatment and sustained viral suppression at the end of 6 months follow up was 25% and 16%, respectively. Viral load dynamics during the 48 weeks of treatment were similar in the SVS and early relapser groups, with a progressive decline in mean viral load over the first 36 weeks that was most marked during the initial 12 weeks of therapy (Fig. 1a). This was in contrast to those who did not respond to treatment who after an initial modest decline in viral load demonstrated little change thereafter.

770298-fig1

Figure 1. Virological responses to pegylated interferon-α (PEG-IFN). (a) Viral dynamics of hepatitis B e antigen (HBeAg) [+] patients. Those patients displaying sustained virological suppression (SVS) (solid light grey line) and early relapse (black line) displayed a similar progressive decline in mean viral load during therapy, with the latter group subsequently experiencing a rapid rebound soon after completing PEG-IFN. In contrast, those who were virological non-responders (dark grey broken line) showed little change in mean viral load after an early modest decline so that significant differences were apparent by 12 weeks compared to the other two groups. (b) Viral dynamics of HBeAg [−] patients. These patients who achieved SVS had a significantly lower median viral load at baseline compared with the non-responders (5.1 log vs 6.3, P = 0.02) but not the early relapsers (5.1 vs 6.0, P = 0.12). The viral load dynamics on treatment followed a similar trend to the HBeAg[+] cohort, though the time taken by the early relapsers and SVS patients to achieve optimal suppression was shorter. Despite experiencing a modest fall over the 48 weeks, the median viral load of the non-responders remained significantly higher than the responders and early relapsers at all timepoints during therapy. Non-responders; , Early relapsers; , Sustained viral suppression.

HBeAg[−] Patients

Twenty-seven of 29 patients completed the 48 week course, with two ceasing treatment prematurely due to AEs (one of whom was subsequently lost to follow up). Compared with the HBeAg[+] group, these patients were older (42 vs 33 years, P < 0.005), had a greater proportion of advanced fibrosis (24 vs 9.5%, P = 0.03), lower baseline ALT (median 68 vs 123 IU/L, P = 0.003) and fewer individuals with a viral load > 6 logIU/mL (48% vs 84%, P = 0.001) (Table 1). These differences are consistent with the natural history of CHB, where the HBeAg[−] phase usually represents a later and often more advanced stage of disease. Of the four patients who had previously received antiviral therapy, none had documented resistance mutations.

Treatment outcomes are shown in Table 3. Six months after treatment, 55% of patients had an ALT within normal range and 37% achieved sustained viral suppression. Patients who achieved SVS had a significantly lower median viral load at baseline compared with the non-responders (5.1 log vs 6.3, P = 0.02) but not the early relapsers (5.1 vs 6.0, P = 0.12) (Fig. 1b). The viral load dynamics on treatment followed a similar trend to the HBeAg[+] cohort, although the time taken by the early relapsers and SVS patients to achieve optimal suppression was shorter. Despite experiencing a modest fall over the 48 weeks, the median viral load of the non-responders remained significantly higher than the responders and early relapsers at all timepoints during therapy. Two patients (both genotype C) lost HBsAg without seroconverting to anti-HBs.

In order to determine factors that might allow for individualization of therapy, we analyzed a number of baseline factors that might predict virological response. These included age, gender, genotype, previous treatment, serum ALT (stratified into < 2×ULN, 2 − 5×ULN and > 5×ULN), advanced fibrosis and HBV DNA levels greater or less than 4 or 6 log IU/mL (Table 4). Of these, only viral load > 6 log IU/mL in HBeAg[−] patients had significant predictive value, with these patients far less likely to achieve SVS (OR 0.12, P = 0.017). We then analyzed the on-treatment variables of ALT and viral load at 12 and 24 weeks of treatment. Similar to baseline, the only significant predictor was a week 12 viral load > 6 log IU/mL in HBeAg[−] patients, which was also associated with a reduced chance of achieving SVS (OR 0.57, P = 0.009)(Table 5).

Long Term Durability of Viral Suppression

HBeAg[+] Long term follow up data was available on 8 of 11 (72%) HBeAg[+] patients who achieved both SVS and HBeAg seroconversion. The durability of this response decreased from 100% at 1 year to 75% at 2 years; one patient was commenced on Entecavir for an increasing viral load and one was lost to follow up. For patients with viral suppression < 2000 IU/mL, 60% maintained this response 2 years after treatment.

HBeAg[−] Long term follow-up data was available for 8 of 10 patients who achieved SVS and normalized ALT. After 2 years, four patients (50%) maintained this response while three had detectable viremia between 2 to 4 log IU/mL and one patient with a viral load < 351 IU/mL was commenced on Entecavir due to advanced fibrosis. Two-year follow up data were available for 10 of 15 patients who achieved a HBV DNA < 2000 IU/mL and demonstrated a durable response in 60%.

Tolerability

Four HBeAg[+] and two HBeAg[−] patients ceased therapy prematurely due to AEs. In four patients this was a consequence of non-specific symptoms such as fever, headaches and fatigue, while two had more serious disease including pneumonitis and thrombocytopenia leading to GI hemorrhage. Two other patients developed symptomatic hyperthyroidism that required treatment with carbimazole but were able to complete a full course of therapy. There were no deaths.

Discussion

To date, most of the evidence pertaining to PEG-IFN efficacy has been derived from large controlled trials.[7,12–15] Outcomes from such studies are often better than what can be achieved in routine clinical practice as a consequence of the increased monitoring, support and improved compliance. Given the relatively low rates of viral suppression following PEG-IFN, even in these controlled circumstances, and the expectation of poor tolerability, the level of response that can be expected in a non-trial setting is unclear. Therefore, we studied a cohort of patients treated in the setting of routine clinical care in order to address these concerns. This multicentre study provides a number of valuable insights relating to the use of PEG-IFN for CHB in an everyday clinical setting.

In HBeAg[+] disease, we identified a PEG-IFN induced HBeAg seroconversion rate of 32% that compared well with the rates of 21% to 32% in controlled studies. ALT normalization occurred in 46%, which was also consistent with the published rates of 35–48%.[7,12,14,15] The definition of optimal viral suppression has evolved with increasingly sensitive assays to measure viral load, the degree of suppression now achievable with oral antivirals and evidence suggesting viral load as an independent predictor of adverse outcomes.[16] We evaluated viral load suppression below 351 IU/mL (lower limit of detection of our assay) and 2000 IU/mL, which is a widely accepted cutoff for inactive disease.[9–11] Six months after completing treatment, 16% and 22% of HBeAg [+] patients remained below these respective thresholds. The combined response of viral load suppression plus HBeAg seroconversion was seen in 13% and 19% of patients, an even more desirable result as the combined outcome is more likely to decrease the risk of long term complications.[17,18]

PEG-IFN has typically been used less frequently in HBeAg[−] disease, largely due to low response rates, the absence of an endpoint such as HBeAg seroconversion and the high rates of relapse previously seen following conventional interferon.[10] The sustained viral suppression rate (< 351 IU/mL) of 36% that we observed in this group appears encouraging, though difficult to compare to other controlled studies, which used a lower cutoff of 400 copies/mL (approximately 50 IU/mL) and achieved suppression rates of 9–19%.[19,20] In relation to the threshold of < 2000 IU/mL, our viral suppression rate of 50% compared favorably with a rate of 20% for a comparable cutoff in a recent controlled trial and a rate of 43% below 4000 IU/mL observed in a large phase 3 registration study.[19,20]

Another advantage of IFN based therapy is the durability of the response. Three-year follow-up data from the large registration studies revealed PEG-IFN induced HBeAg seroconversion was sustained in over 80% of responders, with 60% also maintaining a viral load less than 2000 IU/mL. Similarly, in HBeAg negative patients the initial rates of viral suppression were also effectively well maintained over the 3 years.[21,22] Though not part of the initial study design, we were able to follow the majority of viral responders for up to 2 years post-treatment. In both HBeAg positive and negative patients with initial viral suppression below 2000 IU/mL (and HBeAg seroconversion in the HBeAg[+] group) the response was maintained in approximately 60% over the 2 years. For those with initial suppression below 351 IU/mL the durability ranged from 50% in the HBeAg [−] group to 75% in the HBeAg[+] group. Given the small number of patients involved, further studies are required to definitively assess durability of response in a non-controlled setting. The potential benefit of such long term IFN induced viral suppression is shown in studies involving standard IFN-α in which HBsAg clearance rates in both HBeAg positive and negative patients displaying an initial response to IFN-α exceeded 60% over 15 years.[3,4,6,23–25] Most importantly, these studies also show that successful IFN-α therapy reduces the risk of developing cirrhosis, hepatic decompensation and HCC.[3,25–27]

Concerns relating to AEs and poor tolerability are often cited as a barrier to the use of PEG-IFN. However, observational studies demonstrate that when used in CHB, PEG-IFN is associated with significantly less AEs, treatment withdrawals and impact on health related quality of life compared with when used as monotherapy in chronic hepatitis C.[28] Although our cohort included a significant proportion with advanced fibrosis, we found PEG-IFN to be well tolerated, with 94% of all patients able to complete 48 weeks of therapy. Nevertheless, given the potential AEs and lower antiviral potency compared with the nucleos(t)ide analogues, identifying and treating patients that are more likely to respond to PEG-IFN is important in defining its optimal use in CHB therapy. Multiple studies have demonstrated that female sex, high serum ALT, low HBV viral load and genotype A are among these factors.[29–31] Apart from the negative predictive value of a high viral load in HBeAg negative patients, our study was unable to confirm the predictive value of the other baseline variables, which may be related to our sample size. The predictive value of "on treatment" markers such as the week 12 HBV viral load has also been studied.[32] We found that the failure to suppress viral load to below 6log IU/mL by week 12 of therapy was an indicator of poor outcome in HBeAg[−] patients. Recently, the emergence of quantitative HBsAg and HBeAg measurements as both pre- and on-treatment predictors of outcome has been another encouraging development that is likely to improve results.[33–37] Not only can these measurements contribute to better patient selection but in future may also form the basis of on-treatment stopping rules similar to that used in HCV therapy.

There are some limitations to our study due to retrospective data collection that restrict its comparability to data from prospective controlled studies. HBV genotype, a factor shown to influence PEG-IFN induced HBeAg seroconversion rates was only tested in 41% of the cohort. Nevertheless it is unlikely that our outcomes were skewed by genotype given that over 80% of our patients were from East Asia where genotypes B and C predominate. These two have a modest influence on outcome compared with genotypes A and D, which are the most and least favorable genotypes, respectively.[31] The upper limit of normal range of 55 U/L for ALT was also higher than that used in the majority of controlled trials as well as current guidelines. We elected to use this limit in assessing biochemical response given it formed part of the range used by the majority of the centers in clinical decision making. This may, however, have led to an overestimation of ALT normalization rates in our study when compared with the existing literature. Similarly, differences in the viral load detection limits of assays used in our study (< 351 IU/mL) and previous trials (50 IU/mL) made direct comparisons difficult.

In conclusion, our study provides a "real world" perspective to data obtained from controlled studies. Evaluating over 90 patients, we found that both HBeAg positive and negative patients treated in a clinical setting can expect efficacy and safety outcomes equivalent to those seen in those large trials. In addition, our cohort was principally of Asian ethnicity, in which genotypes B and C, typically associated with poorer outcomes than genotype A, predominated. Combined with the existing literature these results should engender a greater sense of confidence regarding the use of PEG-IFN. It is also likely that the availability of well characterized pretreatment and on treatment predictors will allow greater individualization of therapy in future to maximize beneficial patient outcomes.

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