Does treatment with interferon-based therapy improve the natural history of chro

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Journal of Hepatology

Volume 46, Issue 1 , January 2007, Pages 6-8

Editorial

Does treatment with interferon-based therapy improve the natural history of

chronic hepatitis B infection?

K.K. Lau, a,

aDepartment of Medicine, Li Ka Shing Faculty of Medicine, The University of

Hong Kong, Rm 1838, Block K, Queen Hospital, 102 Pokfulam Road, Hong

Kong SAR, China

Available online 7 November 2006.

Worldwide, approximately 400 million people are chronically infected with

hepatitis B virus (HBV). Most of them reside in the Asia-Pacific region,

such as Southern China and Taiwan, where chronic HBV infection is highly

prevalent (>10%). Among them, around 25–40% will eventually die of liver

disease (viz. cirrhosis with or without hepatocellular carcinoma), largely

due to protracted hepatic necroinflammation (chronic active hepatitis). In

greater China, it is estimated that more than half-a-million deaths were due

to HBV-related liver complications annually [1]. For those patients with

chronic active HBV infection, progression to cirrhosis occurs at an annual

rate of 2–6% in hepatitis B e antigen (HBeAg) positive and 8–10% for HBeAg

negative patients [2], [3] and [4]. Once cirrhosis is established, the

yearly incidence of hepatic decompensation is about 3% [5] and the annual

incidence of hepatocellular carcinoma will be markedly increased from close

to zero percent in inactive HBV carriers [6] to over 2%, with a cumulative

5-year incidence of 15–20% [2] and [7].

The diversity of clinical outcome of HBV infection in humans, either

resolution (immunity) or persistence of infection with protracted hepatic

necroinflammation (immunopathogenesis), is dependent on the host immune

response to the virus [8]. For those with an impaired host immune control to

the virus, there will be protracted hepatic necroinflammation. Therefore, it

is not surprising that among the various risk factors identified for the

progression to cirrhosis and hepatocellular carcinoma, a high level of HBV

replication DNA level (a reflection of impaired host immune control on the

virus) has been identified as the most important factor. The adjusted

relative risk of cirrhosis was 2.3 (95% CI, 1.6–3.5) and 9.3 (95% CI,

6.5–13.1) for baseline serum HBV DNA > 104 and 106, respectively [9], and

for hepatocellular carcinoma, the adjusted odds ratio for patients with the

highest quintile (5.91–10.81 log10 copies/mL) versus those with lowest

quantile (2.77–3.61 log10 copies/mL) of serum HBV DNA was 7.26 (95% CI =

3.54–14.89) [10]. Logically, most of the treatment guidelines emphasize the

necessity of reducing hepatitis B viral load levels in those patients with

active hepatic necroinflammation, as a measure of the effectiveness of

therapy with a long-term goal to reduce the development of liver cirrhosis

and hepatocellular carcinoma [8].

By the year 2006, there are seven agents registered for treatment of chronic

HBV infection. Two are immunomodulatory agents, namely conventional

interferon-á2b and pegylated interferon-á2a, which aim to restore host

immune control on HBV and thus lead to sustained off-treatment disease

remission. The other three agents are all nucleos(t)ide analogues

(lamivudine, adefovir, entecavir and telbuvidine) with direct anti-viral

activity. However, direct antiviral agents have little impact on host immune

response, as reflected by a low rate of HBeAg seroconversion and negligible

hepatitis B surface antigen (HBsAg) seroconversion, and thus most patients

treated with these agents need prolonged or even life-long therapy. The

major limitations of immunomodulatory therapy are: [1] lack of efficacy in

40–60% of patients treated and [2] side effect profile. This has limited its

usage, especially in those patients with decompensated liver cirrhosis,

immune incompetent, other immune-mediated diseases, marrow insufficiency and

psychiatric disorders. On the other hand, the risk of development of viral

resistance increases with prolonged therapy with pure anti-viral agents,

running a risk of worsening of liver function [8].

A million-dollar question is whether these agents really transform the

natural history of chronic HBV infection? Most importantly, does the use of

these agents reduce the risk of liver complications, such as liver cirrhosis

and hepatocellular carcinoma, and hence improve the survival of chronic HBV

patients? These questions could only be answered by well-conducted long-term

follow-up studies (Table 1) [11], [12], [13] and [14]. With the continued

use of lamivudine, disease progression has been shown to be significantly

reduced in chronic HBV patients with advanced fibrosis/cirrhosis. However,

this beneficial effect was markedly diminished with the development of

lamivudine resistance, which increased with prolonged therapy [14]. An

alternative to avoid the use of prolonged maintenance therapy in chronic HBV

patients with nucleos(t)ide analogues is to induce disease remission with

the use of interferon-based therapy at an earlier stage. In keeping with

this, sustained disease remission has been shown to be accelerated in

chronic HBV patients with active hepatitis, treated with conventional

interferon. In Caucasians, it has been demonstrated that treatment with a

finite course of conventional interferon not only will hasten disease

remission but those who have responded were shown to have a better long-term

prognosis with a significant reduction of liver-related mortality [11] and

[13]. In Asians, so far, the long-term follow-up data on the use of

interferon-based therapy on chronic HBV patients with active hepatitis are

limited [12].

Table 1.

Long-term follow-up on chronic HBV patients with active hepatitis or advance

fibrosis/cirrhosis treated with finite duration of conventional interferon

or continuous lamivudine

C, Caucasian; A, Asians; IFN, conventional interferon; LAM, lamivudine.

a Treatment arm was lamivudine instead of interferon.

In this important study by Lin et al., the long-term outcome of interferon-á

therapy in HBeAg positive patients was examined [15]. Altogether, 233

Chinese patients with active hepatitis (baseline serum ALT is 175 IU/l)

treated with a finite course of interferon-based therapy were followed up

for a median of 6.8 years (range 1.1–16.8 years). All treated and untreated

controls were followed up at intervals of at least 3–6 months. Compared to

untreated controls (n = 233) with persistent HBeAg positivity, HBeAg

seroconversion in untreated and interferon-treated patients had a

significantly lower incidence of liver cirrhosis and cancer. This supports

the use of HBeAg seroconversion as a measure of treatment efficacy for HBeAg

positive chronic active hepatitis. An added value of HBeAg seroconversion is

that it is a prerequisite for HBsAg seroconversion and it occurs in up to

one-tenth of those patients treated with interferon-based therapy and

experienced HBeAg seroconversion [16]. Serological clearance of HBsAg is of

paramount importance in the natural history of chronic hepatitis B as its

development will be close to a cure, provided the patient has not already

developed liver cirrhosis or hepatocellular carcinoma [8].

As pointed out by Lin et al., the result of this retrospective study is in

contrast with other reports which showed that interferon therapy has a

minimal effect on reducing the risk of cirrhosis, hepatocellular carcinoma

and liver-related mortality. Compared to the other studies, the present

study has the superiority of studying more patients with appropriate disease

characteristics (active hepatitis) and for a long-enough duration. This is

reflected in the expected outcome of the untreated control group, with an

incidence of liver-related mortality of 11% [15]. This supports the validity

of the design and the conduct of this long-term follow-up study. From the

scientific point of view, having a well-matched control group in a

retrospective study is still only second to ideal design with a long-term

prospective follow-up from the original randomised registration study.

However, with the availability of effective agents for controlling the viral

replication, it is perhaps difficult to keep patients untreated.

Nonetheless, in collaboration with the industrial partners, longer term

off-treatment follow-up study comparing patients treated with

interferon-based therapy to those new and recent more potent nucleos(t)ide

analogues will be awaited.

References <CUT>

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