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Alimentary Pharmacology and Therapeutics

Meta-analysis: reduction in hepatic events following interferon-alfa therapy of chronic hepatitis B G. L.-H. Wong, K. K.-L. Yiu, V. W.-S. Wong, K. K.-F. Tsoi & H. L.-Y. Chan

Institute of Digestive Disease and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong.

Correspondence to: Dr H. L.-Y. Chan, Department of Medicine and Therapeutics, 9 ⁄ F Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong. E-mail: [email protected]

Publication data Submitted 10 July 2010 First decision 3 August 2010 Resubmitted 11 August 2010 Accepted 13 August 2010 EV Pub Online 29 August 2010 As part of AP&T’s peer-review process, a technical check of this meta-analysis was performed by Dr. P. Collins.

SUMMARY Background The long-term benefit of interferon-alfa (IFN-a) treatment in preventing various hepatic complications is not certain. Aim To study the effects of IFN-a on reducing the risk of developing overall hepatic events (hepatocellular carcinoma, cirrhotic complications and liverrelated mortality) in chronic hepatitis B patients. Methods Randomized controlled trials, case–control studies and cohort studies were retrieved from electronic databases and conference abstracts. Relative risks (RRs) of different hepatic complications among patients treated by IFN-a vs. no treatment or placebo were studied. Results Eleven studies were identified totalling 975 patients treated by IFN-a vs. 1147 untreated controls for analysis. Patients were treated by IFN-a for 1– 24 months with a post-treatment follow-up of 1–13 years. Treatment by IFN-a reduced the risk of overall hepatic events (RR 0.55, 95% confident interval or CI 0.43–0.70, P < 0.001) and cirrhotic complications (RR 0.46, 95% CI 0.32–0.67, P < 0.001) by 45% and 54% respectively. Patients who responded to IFN-a had more profound reduction in overall hepatic events (RR 0.20, 95% CI 0.05–0.87, P = 0.03) and cirrhotic complications (RR 0.19, 95% CI 0.09–0.38, P < 0.001) vs. the untreated controls. Conclusion Interferon-alfa treatment reduces the risk of hepatic events particularly among responders to treatment. Aliment Pharmacol Ther 2010; 32: 1059–1068

ª 2010 Blackwell Publishing Ltd doi:10.1111/j.1365-2036.2010.04447.x

1059

G. L.-H. Wong et al. INTRODUCTION Chronic hepatitis B virus (HBV) infection is one of the major global healthcare problems affecting around 350 million people worldwide. It can cause various complications including liver failure, hepatic decompensation and hepatocellular carcinoma (HCC), which lead to significant morbidity and mortality with more than 1 million deaths annually.1 Liver cirrhosis is the major risk factor for the development of HCC, as more than 80% of HCC developed in the presence of cirrhosis.2 Approximately 75% of HCC patients die within 2 years after diagnosis of the tumour.3 One of the short-term goals of anti-viral treatment is persistent viral suppression, which can retard the progression of liver disease, reduce hepatic complications and ultimately prolong patient survival. Interferon-alfa (IFN-a) was the first agent approved by the Food and Drug Administration for CHB in 1980s.4 Unlike oral anti-viral agents, IFN-a is given for finite treatment duration and administrated subcutaneously. Around 33% of CHB patients respond to IFN-a treatment with beneficial effects including normalization of alanine aminotransferase (ALT), clearance of hepatitis B virus e antigen (HBeAg) and suppression of HBV DNA.5, 6 A small proportion of patients can even lose hepatitis B surface antigen after a course of IFN-a therapy.6 Peginterferon is produced by the addition of a polyethylene glycol moiety to interferon, thus prolonging the half-life of the drug and the average drug concentration in the body. It is currently widely used due to the convenient weekly dosing. This therapy gives good short-term effect, as 30–40% of the recipients develop HBeAg seroconversion after a course of treatment.7 Some data suggested that the virological response of peginterferon was sustained up to 5 years after cessation of therapy.8–10 Whether virological response can be extrapolated to improvement in long-term clinical outcome remains uncertain.11 In a study in Hong Kong, surrogate endpoints such as biochemical and histological responses at the end of anti-viral therapy were found associated with decreased hepatic complications in a follow-up of 7 years.12 With the limited efficacy of IFN-a therapy, its long-term benefit in preventing hepatic complications has been controversial.13–17 These conflicting findings might be partly related to the relatively small sample sizes, lack of adequate controls, differences in treatment regimes, as well as different study designs and patient populations in these clinical trials. A few meta-analyses have suggested a reduced risk of HCC 1060

after IFN-a treatment.18, 19 However, the analysis of other cirrhotic complications, which may cause 30–40% of death in cirrhotic patients,20 and patient mortality was lacking. Therefore, we conducted a meta-analysis to compare the effect of IFN-a vs. no treatment or placebo on the incidence of various hepatic complications and patient mortality. The different outcomes of the responders and the nonresponders to IFN-a in the risk of hepatic complications were also investigated.

METHODS A structured search using keywords ‘interferon’, ‘hepatitis B’, ‘cirrhosis’, ‘complication’, ‘liver failure’, ‘ascites’, ‘hepatic decompensation’, ‘hepatic encephalopathy’, ‘hepatorenal syndrome’, ‘portal hypertension’, ‘spontaneous bacterial peritonitis’, ‘variceal bleeding’, ‘hepatocellular carcinoma’, and ‘death’ to identify abstracts of literatures from seven computerized databases: MEDLINE (1950 to week 1 February 2009), EMBASE (1980 to February 2009), the Cochrane Central Register of Controlled Trials (1st Quarter of 2009), Database of Abstracts of Reviews of Effects (1st Quarter of 2009) and International Pharmaceutical Abstracts (1970 to February 2009). All randomized controlled trials (RCTs) and cohort studies were included if they met the following criteria: (i) confirmed HBV infection, (ii) IFN-a used for treatment, (iii) no treatment, or placebo used for control, (iv) reported cases of hepatic complications developed during the follow-up period, (v) RCTs, cohort studies or case–control studies and (vi) human subjects involved. Studies that recruited patients co-infected with hepatitis C virus, hepatitis D virus and ⁄ or human immunodeficiency virus, and clinical trials that used oral anti-viral agents were excluded. Studies with duplicated publications on the same group of patients or those which failed to indicate the numbers of the hepatic complications in the treatment or no therapy group were also excluded. The primary outcome of this study was the number of overall hepatic events that occurred during the study period in both treatment and control groups. The overall hepatic events were defined as cirrhotic complications, HCC and ⁄ or liver-related mortality. Cirrhotic complications (excluding HCC) included ascites, hepatic decompensation, hepatic encephalopathy, hepatorenal syndrome, portal hypertension, spontaneous bacterial peritonitis and ⁄ or variceal bleeding. HCC was diagnosed based on liver tumour feature detected by imaging methods and confirmed by histology and ⁄ or high alpha-fetoprotein level Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

Meta-analysis: IFN and risk of hepatitis B complications (above 400 ng ⁄ mL), or other diagnostic criteria generally accepted for HCC. Liver-related mortality was defined as any death related to cirrhotic complications and ⁄ or HCC. The secondary outcomes were the number of cirrhotic complications and liver-related mortality. Subgroup analysis was conducted to investigate the different outcomes of responders and nonresponders to IFN-a. Responders were defined as normalization of ALT and HBeAg seroconversion (among HBeAg positive patients) at least 6 months after stopping treatment. As HBV DNA was not widely available in the earlier studies, it was not included as a criterion for treatment response. Studies lacking data for clear definitions of responder were not included in this subgroup analysis. Two investigators (KKY, KKT) independently assessed the generated abstracts for relevance. Articles would be rejected if they had no English abstract, did not involve human subjects and did not report the number of hepatic complications that occurred during the study in both treatment and control groups. Two investigators (GLW, KKY) independently extracted data into the standardized data extraction form. In case of discrepancies between the investigators during the process of abstract selection and data extraction, a third investigator (HLC) would make the definitive decision. Quality of each study was assessed based on seven criteria: (i) prospective design, (ii) recruitment settings mentioned, (iii) inclusion and exclusion criteria reported, (iv) clear definitions of exposures and outcomes, (v) potential bias or confounders described, (vi) adequate study size over 100 patient-years and (vii) adequate number of follow-up over 80%. Statistics A meta-analysis of outcomes by combining various studies was performed, and Mantel-Haenszel method (REVMAN, version 5; The Cochrane Collaboration, Copenhagen, Denmark) was used. Statistical heterogeneity was assessed with I2, which indicated the percentage of the total variation across studies. Chi-square test was used to test the heterogeneity and P < 0.1 was considered statistically significant. A fixed-effects model was selected for significant homogeneous studies; otherwise a random-effects model was applied. All outcomes were summarized as relative risks (RR) and 95% confidence intervals (CI). RR < 1 represented a lower rate of outcome among the interferon-treated group. Subgroup analysis was also conducted to investigate the different outcomes of the responders vs. the nonresponders. Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

RESULTS Characteristics of the studies Nine hundred and nineteen abstracts were found through the literature search and 52 abstracts fulfilled the inclusion criteria. Among these 52 publications, the following studies were excluded: 28 systematic reviews, six studies comparing IFN-a vs. other anti-viral treatment, and three studies comparing IFN-a monotherapy vs. combination therapy of IFN-a and ⁄ or oral nucleos(t)ide analogues. In the remaining 15 studies, four studies were repeated publications that reported the same cohort at different time points.21–24 Hence, the most updated and complete dataset was selected. Three studies including patients coinfected with hepatitis C virus, hepatitis D virus and ⁄ or human immunodeficiency virus were also excluded.25–27 Three additional studies from the bibliographies of retrieved studies were added to the analysis.28–30 The 11 studies included in the final meta-analysis were published from 1990 to 2007 (Figure 1).14–17, 28–34 Among these 11 studies, three of them were RCTs32–34 and the remaining were cohort studies.14–17, 28–31 A total of 2122 patients with a mean age of 41 years were included: 975 patients in the treatment group and 1147 patients in the control group (received no treatment or received placebo) (Table 1). Most of the studies included mainly HBeAg-positive patients. IFN treatment and overall hepatic events By pooling the data from these 11 studies, there were fewer overall hepatic events (i.e. cirrhotic complications, HCC and ⁄ or liver-related mortality) among the IFN-a treated (133 of 975, 14%) vs. the untreated (253 of 1147, 22%) patients. The risk of overall hepatic events was reduced by 45% (RR 0.55, 95% CI 0.43–0.70, P < 0.001) (Figure 2a). Statistical heterogeneity was found (I2 = 66%, P = 0.001) and hence random-effects model was used. Treatment response and overall hepatic events. Seven studies reported the outcome of patients with and without response to IFN-a.14, 15, 17, 29, 31, 32, 34 There were fewer overall hepatic events among the IFN-a responders (12 of 352, 3%) vs. the untreated (180 of 804, 22%) patients. The risk of overall hepatic events was reduced by 80% (RR 0.20, 95% CI 0.05–0.87, P = 0.03) (Figure 2b). Statistical heterogeneity was found (I2 = 75%, P < 0.001) and hence random-effects model was used. There was a trend of fewer overall hepatic events in the nonresponders (83 of 458 patients, 18%) than the no treatment group (180 of 804 patients, 22%). The risk 1061

G. L.-H. Wong et al. 919 abstracts collected under search criteria 867 abstracts rejected 52 abstracts accepted 28 case-control studies, system reviews

6 studies compared antiviral treatment with IFN

24 RCTs or cohort studies included

15 studies compared IFN vs placebo/no treatment

Patients from 4 studies were duplicated*

3 studies compared IFN vs IFN + antiviral treatment

3 studies included HCV, HDV and/or HIV co-infection 8 studies were accepted

3 extra studies from bibliographies of eligible study

11 studies were included: IFN vs placebo/no treatment

reduction just fell short of statistical significance (RR: 0.77, 95% CI: 0.57–1.06, P = 0.11) (Figure 2c). Statistical heterogeneity was found (I2 = 63%, P = 0.01) and hence random-effects model was used. IFN treatment and cirrhotic complications By pooling the data from 7 of the 11 studies,14–17, 29, 31, 34 significantly fewer non-HCC cirrhotic complications occurred after patients received IFN-a treatment (49 of 804 patients, 6%) as compared with no treatment or placebo (100 of 808 patients, 12%). The risk of cirrhotic complications was reduced by 54% (RR: 0.46, 95% CI: 0.32– 0.67, P < 0.001) (Figure 3a). No significant statistical heterogeneity was found (I2 = 53%, P = 0.05), and hence fixed-effects model was used in the analysis. Treatment response and cirrhotic complications. Six studies reported the outcome of patients with and without treatment response and cirrhotic complications.14, 15, 17, 29, 31, 34 Fewer cirrhotic complications occurred among the IFN-a responders (7 of 330, 2%) vs. the untreated (95 of 773, 12%) patients. The risk of cirrhotic complications was reduced by 81% (RR: 0.19, 95% CI: 0.09–0.38, P < 0.001) with IFN-a treatment (Figure 3b). Statistical heterogeneity was found among these four studies (I2 = 75%, P = 0.003) and hence randomeffects model was used in the analysis. There were also fewer cirrhotic complications among the IFN-a nonresponders (38 of 447, 9%) vs. untreated (95 of 773, 12%) patients, although the difference was not as big as that for the IFN-a responders and just fell 1062

Figure 1 | Flowchart of literature search.

short of statistical significance. The risk of hepatic complications was reduced by 30% (RR: 0.70, 95% CI: 0.47–1.05, P = 0.09) with IFN-a treatment (Figure 3c). Statistical heterogeneity was found (I2 = 64%, P = 0.002) and hence random-effects model was used. IFN treatment and liver-related mortality The data from eight studies that reported liver-related mortality were pooled for analysis.14–17, 29, 31, 32, 34 The difference in liver-related mortality in the IFN-a treatment group (30 of 837 patients, 4%) and the no treatment group (50 of 839 patients, 6%), which was statistically significant (RR: 0.63, 95% CI: 0.42–0.96; P = 0.03) (Figure 4a). No statistical heterogeneity was found among these studies (I2 = 7%, P = 0.37) and hence fixed-effects model was used. Treatment response and liver-related mortality. Seven studies reported the outcome of patients with and without treatment response and liver-related mortality.14, 15, 17, 29, 31, 32, 34 There was significantly less liverrelated mortality in the IFN-a responders (2 of 342 patients, 0.6%) than in the no treatment group (50 of 804 patients, 6%). The risk of liver-related mortality was reduced by 80% in the responders (RR: 0.20, 95% CI: 0.08–0.52; P = 0.001) as compared with the untreated control (Figure 4b). No statistical heterogeneity was found among these studies (I2 = 18%, P = 0.30) and hence fixed-effects model was used. The liver-related mortality among the IFN-a nonresponders (26 of 468 patients, 6%) was similar to that Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

ª 2010 Blackwell Publishing Ltd

Aliment Pharmacol Ther 2010; 32: 1059–1068

15

29

411 (208 vs. 203) 2122 (975 vs. 1147)

N

3 ⁄ 11 RCT

Yuen et al.17

Total or median (range)

RCT, randomized controlled trial; Y, yes; N, no; NA, not available.

40 (20 vs. 20)

Y

Waked et al.34

62 (27 vs. 35)

404 (209 vs. 195)

139 (67 vs. 72)

N

N

N

64 (33 vs. 31)

91 (23 vs. 68)

466 (233 vs. 233)

42 (21 vs. 21)

313 (94 vs. 219)

90 (40 vs. 50)

Truong et al.16

Papatheodoridis et al.

Tangkijvanich et al.

Y

N

Mahmood et al.30

Mazzella et al.

N

Lin et al.31

32

Y

N

Lampertico et al.33

Ikeda et al.

N

Fattovich et al.14

28

RCT

Study

No. of patients (treatment vs. control)

39 (27.5–48.9)

27.5

35

35.1

47.8

38.4

38.45

48.9

31.5

45.5

43.1

45.9

Age (mean)

100.0 (0–100.0)

100.0

100.0

59.7

0.0

100.0

100.0

36.3

100.0

0.0

36.0

100.0

HBeAg positive (%)

131 (42–184)

42

72

184

91

137

125

NA

181

157

NA

92

ALT (mean)

20.0 (0–100)

6.5

0.0

1.6

30.9

20.0

0.0

100

9.4

16.0

100.0

100.0

Cirrhosis (%)

5.5 (1–24)

3-6

4.0

1–6

6 or 12

5–6

6.0

1

3–7

24.0

10.0

1–13

Treatment Duration (month)

Table 1 | Characteristics and quality of studies comparing anti-viral treatment against no treatment in hepatocellular carcinoma recurrence

6 (1–13)

2.0

1.0

7.0

6.0

5.0

13.0

7

6.8

1

7.0

7.2

Treatment follow-up (years)

4 (3–5)

4

4

4

3

3

4

4

4

5

3

3

Quality score (1–7)

Meta-analysis: IFN and risk of hepatitis B complications

1063

G. L.-H. Wong et al. (a) Study or subgroup Fattovich et al. 1997 Ikeda et al. 1998 Lampertico et al. 1997 Lin et al. 2007 Mahmood et al. 2005 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Troung et al. 2005 Waked et al. 1990 Yuen et al. 2001

Placebo/no treatment IFN Events Total Events Total 40 94 21 233 23 33 209 67 27 20 208

20 10 1 14 5 4 46 9 5 4 15

Total (95% CI)

34 51 2 50 18 8 57 25 2 4 2

975

Weight

Odds ratio M-H, fixed, 95% CI

50 219 21 233 68 31 195 72 35 20 203

8.4% 15.3% 1.1% 26.2% 4.0% 4.0% 25.7% 11.6% 0.8% 1.8% 1.0%

0.47 [0.20, 1.11] 0.39 [0.19, 0.81] 0.47 [0.04, 5.68] 0.23 [0.13, 0.44] 0.77 [0.25, 2.38] 0.40 [0.11, 1.48] 0.68 [0.44, 1.07] 0.29 [0.12, 0.68] 3.75 [0.67, 21.07] 1.00 [0.21, 4.71] 7.81 [1.76, 34.61]

1147

100.0%

0.55 [0.43, 0.70]

Total events 133 253 Heterogeneity: Chi2 = 29.31, df = 10 (P = 0.001); I 2 = 66% Test for overall effect: Z = 4.78 (P < 0.00001)

(b) Study or subgroup

0.01 0.1 1 Favours experimental

IFN responder Placebo/no Tx Total Weight Total Events Events

Risk ratio M-H, random, 95% Cl

11.8% 11.8% 14.7% 18.7% 15.0% 11.6% 16.4%

0.03 [0.00, 0.41] 0.02 [0.00, 0.32] 0.18 [0.02, 1.31] 0.24 [0.09, 0.63] 0.12 [0.02, 0.84] 0.21 [0.01, 3.59] 6.28 [1.29, 30.54]

804 100.0% 352 Total (95% CI) 180 12 Total events Heterogeneity: Tau2 = 2.74; Chi2 = 24.32, df = 6 (P = 0.0005); I 2 = 75% Test for overall effect: Z = 2.15 (P = 0.03)

0.20 [0.05, 0.87]

Fattovich et al. 1997 Lin et al 2007 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001

(c) Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001 Total (95% CI)

34 50 8 57 25 4 2

27 115 22 57 24 10 97

0 0 1 4 1 0 6

50 233 31 195 72 20 203

IFN non-responder Placebo/no Tx Events Total Total Events 12 14 0 42 8 1 6

13 118 11 152 43 10 111

34 50 8 57 25 4 2

458

Total events 83 Heterogeneity: Chi2 = 15.09, df = 6 (P = 0.02); I 2 = 60% Test for overall effect: Z = 1.60 (P = 0.11)


10 100 Favours control

Risk ratio M-H, random, 95% Cl

0.001 0.1 1 10 1000 Favours IFN responder Favours placebo/no Tx

Weight

Odds ratio M-H, fixed, 95% Cl

50 233 31 195 72 20 203

1.2% 32.8% 4.9% 40.0% 16.9% 2.7% 1.5%

5.65 [0.67, 47.27] 0.49 [0.26, 0.93] 0.12 [0.01, 2.27] 0.92 [0.58, 1.48] 0.43 [0.17, 1.07] 0.44 [0.04, 4.61] 5.74 [1.14, 28.95]

804

100.0%

0.77 [0.57, 1.06]

Odds ratio M-H, fixed, 95% Cl

180 0.01 0.1 1 Favours experimental


Figure 2 | Forest plot to compare the effect of interferon vs. no treatment or placebo in the overall hepatic events for (a) all patients, (b) sustained responders and (c) nonresponders.

of the no treatment group (50 of 804 patients, 6%) (RR: 1.00, 95% CI: 0.60–1.66; P = 0.99) (Figure 4c). No statistical heterogeneity was found among these studies (I2 = 45%, P = 0.10) and hence fixed-effects model was used.

DISCUSSION This meta-analysis showed that IFN-a treatment could significantly reduce the risk of developing hepatic events including cirrhotic complications and possibly liverrelated mortality in HBV-infected patients. Patients who 1064

responded to IFN-a treatment had the most benefits in all clinical outcomes. To our knowledge, this was the first study that provided a comprehensive assessment of all the hepatic events including mortality after IFN-a treatment. It completed the information provided from previous meta-analyses that focused only on the development of HCC.18, 19 The beneficial effect of IFN-a treatment on cirrhotic complications and liver-related mortality has been controversial. While two cohort studies demonstrated clear benefits of IFN-a treatment on reducing cirrhotic Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

Meta-analysis: IFN and risk of hepatitis B complications (a) Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Papatheodoridis 2001 Tangkijvanich et al. 2001 Troung et al. 2005 Waked et al. 1990 Yuen et al. 2001

IFN Events Total 8 9 13 7 3 2 7

Placebo/no treatment Events Total

40 233 209 67 27 20 208

Total (95% CI)

14 34 29 16 2 3 2

804

Weight

50 233 195 72 35 20 203

11.0% 36.0% 31.0% 15.2% 1.7% 3.0% 2.2%

0.64 [0.24, 1.73] 0.24 [0.11, 0.50] 0.38 [0.19, 0.75] 0.41 [0.16, 1.07] 2.06 [0.32, 13.31] 0.63 [0.09, 4.24] 3.50 [0.72, 17.05]

808

100.0%

0.46 [0.32, 0.67]

Total events 49 100 Heterogeneity: Chi 2 = 12.70, df = 6 (P = 0.05); I 2 = 53% Test for overall effect: Z = 4.17 (P < 0.0001)

(b) Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001

IFN responder Events Total 0 0 2 1 0 4

Total (95% CI)

1 0.1 0.01 Favours experimental

Placebo/no Tx Events Total

27 115 57 24 10 97

14 34 29 16 0 2

330

Weight

50 233 195 72 20 203

18.5% 41.8% 23.3% 14.1%

773

100.0%

2.3%

Total events 7 95 Heterogeneity: Chi 2 = 15.84, df = 4 (P = 0.003); I 2 = 75% Test for overall effect: Z = 4.56 (P < 0.00001)

(c) Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001

IFN non-responder Total Events 8 9 11 6 1 3

Total (95% CI)

13 118 152 43 10 111


Placebo/no Tx Total Events 14 34 29 16 0 2

Weight



0.05 [0.00, 0.80] 0.03 [0.00, 0.41] 0.21 [0.05, 0.90] 0.15 [0.02, 1.22] Not estimable 4.32 [0.78, 24.02] 0.19 [0.09, 0.38]

1 0.01 0.1 Favours experimental

447

38 Total events Heterogeneity: Chi 2 = 13.91, df = 5 (P = 0.02); I 2 = 64% Test for overall effect: Z = 1.71 (P = 0.09)




50 233 195 72 20 203

3.8% 35.9% 40.0% 17.5% 0.5% 2.3%

4.11 [1.15, 14.75] 0.48 [0.22, 1.04] 0.45 [0.22, 0.93] 0.57 [0.20, 1.58] 6.47 [0.24, 174.08] 2.79 [0.46, 16.96]

773

100.0%

0.70 [0.47, 1.05]



95 0.1 1 0.01 Favours experimental


Figure 3 | Forest plot to compare the effect of interferon vs. no treatment or placebo in the hepatic complications for (a) all patients, (b) sustained responders and (c) nonresponders.

complications,29, 31 two other cohort studies showed that there were even more cirrhotic complications in patients who received IFN-a treatment.16, 17 This discrepancy may be explained by the small numbers of events17 as well as the small sample sizes of the study groups.16 Another possible explanation would be the bias of selecting patients in the control groups, which were usually concurrent patients in the same clinic, but did not receive IFN-a in these cohort studies. Patients suffering from more severe liver disease were inevitably more likely to have received IFN-a. In the two studies showing more cirrhotic complications in IFN-a treated patients, the ALT levels were higher in the treatment group than in the control group in one study,16 whereas there were Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

more male patients in the treatment group in the other study.17 As it is almost impossible to conduct a randomized trial with cirrhotic complications or mortality as an endpoint, this meta-analysis is important to pool the existing data and demonstrate the true effect of IFN-a treatment on cirrhotic complications. Subgroup analysis revealed that the beneficial effects on all the outcomes were more profound on responders. The response rates of these studies ranged from 27.3% to 67.5%.14, 15, 17, 29, 31, 32, 34 One reason for the high response rate was the unavailability of HBV DNA levels. Some patients with normal ALT but elevated HBV DNA might be regarded as responders on analysis. This would minimize the real benefit of the true responders who 1065

G. L.-H. Wong et al. (a) Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Troung et al. 2005 Waked et al. 1990 Yuen et al. 2001

IFN Events Total 8 2 0 16 0 1 2 1

Placebo/no treatment Events Total

40 233 33 209 67 27 20 208

14 12 2 20 0 0 2 0

837

Total (95% CI)

30 Total events Heterogeneity: Chi2 = 6.46, df = 6 (P = 0.37); I 2 = 7% Test for overall effect: Z = 2.15 (P = 0.03)

(b) Study or subgroup Fattovich et al. 1997 Fattovich et al. 1997 Lin et al. 2007 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001

IFN responder Events Total 0 0 0 27 0 115 0 12 1 57 0 24 0 10 1 97

Study or subgroup Fattovich et al. 1997 Lin et al. 2007 Mazzella et al. 1999 Papatheodoridis 2001 Tangkijvanich et al. 2001 Waked et al. 1990 Yuen et al. 2001 Total (95% CI)

8 2 0 15 0 0 1

50 233 31 195 72 35 20 203

24.6% 23.7% 5.1% 40.8% 0.9% 3.9% 1.0%

0.71 [0.33, 1.53] 0.17 [0.04, 0.74] 0.19 [0.01, 3.77] 0.75 [0.40, 1.40] Not estimable 3.86 [0.16, 91.12] 1.00 [0.16, 6.42] 2.93 [0.12, 71.46]

839

100.0%

0.63 [0.42, 0.96]

0.01

Placebo/no Tx Events Total Weight 0 0 14 50 33.1% 12 233 26.6% 2 31 4.6% 20 195 29.1% 0 72 2 20 5.5% 0 203 1.0%

IFN non-responder Total Events 13 118 21 152 43 10 111

804

100.0%

Risk ratio M-H, fixed, 95% CI Not estimable 0.06 [0.00, 1.01] 0.08 [0.00, 1.35] 0.49 [0.03, 9.57] 0.17 [0.02, 1.25] Not estimable 0.38 [0.02, 7.28] 6.24 [0.26, 151.91]

0.1 Favours IFN

Placebo/no Tx Events Total 14 12 2 20 0 2 0

1 10 100 Favours placebo/no

Risk ratio M-H, fixed, 95% CI

0.20 [0.08, 0.52] 0.005 0.1 Favours IFN responder

468

26 Total events Heterogeneity: Chi2 = 9.13, df = 5 (P = 0.10); I 2 = 45% Test for overall effect: Z = 0.01 (P = 0.99)



50

Total (95% CI) 342 Total events 2 50 Heterogeneity: Chi2 = 6.08, df = 5 (P = 0.30); I 2 = 18% Test for overall effect: Z = 3.30 (P = 0.0010)

(c)

Weight

Weight


50 233 31 195 72 20 203

7.4% 26.5% 6.7% 52.8% 5.5% 1.2%

4.11 [1.15, 14.75] 0.32 [0.07, 1.44] 0.27 [0.01, 6.01] 0.96 [0.47, 1.94] Not estimable 0.35 [0.02, 8.06] 5.52 [0.22, 136.76]

804

100.0%

1.00 [0.60, 1.66]

1 10 200 Favours placebo/no Tx


50 0.1 1 0.01 Favours experimental


Figure 4 | Forest plot to compare the effect of interferon vs. no treatment or placebo in liver-related mortality for (a) all patients, (b) sustained responders and (c) nonresponders.

have good suppression of HBV DNA in addition to ALT normalization. The results of the subgroup analyses therefore reinforced the importance and need to improve the treatment response rate, which can to lead to a better long-term clinical outcome. Longer duration of IFN-a treatment, 24 months vs. 6–12 months, may increase the rate of sustained response in HBeAg-negative patients.35 Utilization of different response predictors may help select patients who are likely to have better response to IFN-a treatment. The strongest predictor of HBeAg seroconversion to IFN-a is the pre-treatment ALT level.10 Other predictors to good response include high 1066

histological activity index, low HBV DNA level and HBV genotypes A.10, 36, 37 Baseline and on-treatment quantitative HBsAg levels could provide a reasonable prediction of sustained virological response.38 Previous studies have shown strong association between the HBV DNA and the cirrhosis, as high viral load is the most important risk factor of cirrhosis and HCC.39, 40 It is interesting to note that even the IFN-a nonresponders had reduced risk of hepatic complications as compared with patients who received no treatment or placebo. It might be related to the antifibrotic effect of IFN-a in addition to its effect on viral clearance.41, 42 Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

Meta-analysis: IFN and risk of hepatitis B complications Previous studies have shown that IFN-a has inhibitory activities on hepatic stellate cells (HSCs) activation by suppressing the effects of interleukin-1b and tumour necrosis factor-a, which can stimulate hepatocyte matrix metalloprotease-9 production and leading to activation of human HSCs.43 IFN-a was also able to induce apoptosis of HSC.44 As HSCs play a central role in fibrogenesis, the long-term benefit of the antifibrogenic effect of IFNa deserves further investigation. There are several limitations in this meta-analysis. First, cohort studies were included in this meta-analysis and they might suffer from a bias in the recruitment of control subjects. This was because most of the originally conducted RCTs had small sample size and short followup duration and there was no planned follow-up for surveillance of clinical outcome. Second, different studies of different follow-up durations were included in this metaanalysis. We could not analyse the effects of IFN-a in relation to temporal sequence. Based on survival analysis of a large-scaled study, the development of HCC and other complications diverged with the duration of follow-up. The longer the follow-up or treatment period, the more remarkable was the difference seen in HCC incidence.16 Finally, these 11 studies identified in the

literature represent different qualities of study design and documentation. Some studies with negative results might not be published and were omitted from our analysis. Nonetheless, all the included studies scored 3–5 out of 7 in the quality assessment and were of satisfactory quality. In conclusion, this meta-analysis confirmed the beneficial effect of IFN-a treatment on reducing the overall hepatic events, hepatic complications and possibly liverrelated mortality in chronic HBV-infected patients. The benefit was most obvious among treatment responders. Although long-term data from peginterferon were not available, it is reasonable to believe the same benefit could be obtained with peginterferon treatment. Future effort should focus on the improvement of response rate to interferon-based therapy, which can possibly be translated into a better clinical outcome.

ACKNOWLEDGEMENTS Declaration of personal interests: Vincent WS Wong has served as a speaker for Roche and Bristol-Myers Squibb. Henry LY Chan has served as an advisory board member for Bristol-Myers Squibb, F Hoffmann La Roche and Novartis Pharmaceutical. Declaration of funding interests: None.

REFERENCES 1. Chan HLY, Sung JJY. Hepatocellular carcinoma and hepatitis B virus. Semin Liver Dis 2006; 26: 153–61. 2. Liaw YF, Tai DI, Chu CM, et al. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study. Hepatology 1988; 8: 493–6. 3. Wong GLH, Wong VWS, Tan GM, et al. Surveillance programme for hepatocellular carcinoma improves the survival of patients with chronic viral hepatitis. Liver Int 2008; 28: 79–87. 4. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007; 45: 507–39. 5. Korenman J, Baker B, Waggoner J, et al. Long-term remission of chronic hepatitis B after alpha-interferon therapy. Ann Intern Med 1991; 114: 629–34. 6. Wong DKH, Cheung AM, O’Rourke K, et al. Effect of alpha-interferon treatment in patients with hepatitis B e antigenpositive chronic hepatitis B. A meta-analysis. Ann Intern Med 1993; 119: 312–23. 7. Hui AY, Chan HL, Cheung AY, et al. Systematic review: treatment of chronic hepatitis B virus infection by pegylated interferon. Aliment Pharmacol Ther 2005; 22: 519–28.

Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd

8. Wong VW, Wong GL, Yan KK, et al. Durability of peginterferon alfa-2b treatment at 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2010; 51: 1945–53. 9. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med 2004; 351: 1206–17. 10. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet 2005; 365: 123–9. 11. Shamliyan TA, MacDonald R, Shaukat A, et al. Antiviral therapy for adults with chronic hepatitis B: a systematic review for a National Institutes of Health Consensus Development Conference. Ann Intern Med 2009; 150: 111–24. 12. Wong VW, Wong GL, Chim AM, et al. Surrogate end points and long-term outcome in patients with chronic hepatitis B. Clin Gastroenterol Hepatol 2009; 7: 1113–20.

13. Lin SM, Sheen IS, Chien RN, et al. Long-term beneficial effect of interferon therapy in patient with chronic hepatitis B virus infection. Hepatology 1999; 29: 971–5. 14. Fattovich G, Giustina G, Realdi G, et al. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alpha. Hepatology 1997; 26: 1338–42. 15. Tangkijvanich P, Thong-ngam D, Mahachai V, et al. Long-term effect of interferon therapy on incidence of cirrhosis and hepatocellular carcinoma in Thai patient with chronic hepatitis B. Southeast Asia J Trop Med Public Health 2001; 32: 52–8. 16. Truong BX, Seo Y, Kato M, et al. Longterm follow-up of Japanese patients with chronic hepatitis B treated with interferon-alfa. Int J Mol Med 2005; 16: 279–84. 17. Yuen MF, Hui CK, Cheng CC, et al. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on effect on hepatitis B e antigen seroconversion and the development of

1067

G. L.-H. Wong et al.

18.

19.

20.

21.

22.

23.

24.

25.

26.

cirrhosis-related complications. Hepatology 2001; 34: 139–45. Yang YF, Zhao W, Zhong YD, et al. Interferon therapy in chronic hepatitis B reduces progression to cirrhosis and hepatocellular carcinoma: a meta-analysis. J Viral Hepat 2009; 16: 265–71. Sung JJY, Tsoi KKF, Wong VWS, et al. Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma. Aliment Pharmacol Ther 2009; 28: 1067–77. Chu CM, Liaw YF. Hepatitis B virusrelated cirrhosis: natural history and treatment. Semin Liver Dis 2006; 26: 142–52. Lin SM, Tai DI, Chien RN, et al. Comparison of long-term effects of lymphoblastoid interferon alpha and recombinant interferon alpha-2a therapy in patients with chronic hepatitis B. J Viral Hep 2004; 11: 349–57. Liaw YF, Lin SM, Chen TJ, et al. Beneficial effect of prednisolone withdrawal followed by human lymphoblastoid interferon on the treatment of chronic type B hepatitis in Asians: a randomized controlled trial. J Hepatol 1994; 20: 175– 80. Chien RN, Sheen IS, Chu CM, et al. Beneficial effect of prednisolone priming and the need of maintenance interferon therapy in patients with chronic hepatitis B. J Hepatol 1993; 18(S1): S24–30. Krogsgaard K. The long-term effect of treatment with interferon-alpha 2a in chronic hepatitis B. The long-term follow-up investigator group. The European Study Group on Viral Hepatitis (EUROHEP). Executive team on anti-viral treatment. J Viral Hepatitis 1998; 5: 389–97. Mazzella G, Accogli E, Sottili S, et al. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J Hepatol 1996; 24: 141–7. Benvegnu L, Chemello L, Noventa F, et al. Retrospective analysis of the effect

1068

27.

28.

29.

30.

31.

32.

33.

34.

35.

of interferon therapy on the clinical outcome of patients with viral cirrhosis. Cancer 1998; 83: 901–9. Brunetto MR, Oliveri F, Koehler M, et al. Effect of interferon-alpha on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study. Lancet 1998; 351: 1535–9. Ikeda K, Saitoh S, Suzuki Y, et al. Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study. Cancer 1998; 82: 827–35. Papatheodoridis GV, Manesis E, Hadziyannis SJ. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B. J Hepatol 2001; 34: 306–13. Mahmood S, Niiyama G, Kamei A, et al. Influence of viral load and genotype in the progression of hepatitis B-associated liver cirrhosis to hepatocellular carcinoma. Liver Int 2005; 25: 220–5. Lin SM, Yu ML, Lee CM, et al. Interferon therapy in HBeAg positive chronic hepatitis reduces progression to cirrhosis and hepatocellular carcinoma. J Hepatol 2007; 46: 45–52. Mazzella G, Saracco G, Festi D, et al. Long-term results with interferon therapy in chronic type B hepatitis: a prospective randomized trial. Am J Gastroenterol 1999; 94: 2246–50. Lampertico P, Ninno ED, Manzin A, et al. A randomized, controlled trial of a 24 month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum. Hepatology 1997; 26: 1621–5. Waked I, Amin M, Abd el Fattah S, et al. Experience with Interferon in chronic hepatitis B in Egypt. J Chemother 1990; 2: 310–8. Lampertico P, Del Ninno E, Vigano M, et al. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B

36.

37.

38.

39.

40.

41.

42.

43.

44.

by 24-month interferon therapy. Hepatology 2003; 37: 756–63. Chan HLY, Wong VWS, Chim AML, et al. Virological response to different combination regimes of peginterferon alpha-2b and lamivudine in hepatitis B e antigen positive chronic hepatitis B. Antivir Ther 2007; 12: 815–23. Chan HLY, Wong VWS, Chim AML, et al. Treatment of patients with chronic hepatitis B who have failed previous antiviral treatment with pegylated interferon alpha2a (40 kda; PEGASYS). Antivir Ther 2008; 13: 555–62. Wong GLH, Chan HLY. Predictors of treatment response in chronic hepatitis B. Drugs 2009; 69: 2167–77. Yu MW, Yeh SH, Chen PJ, et al. Hepatitis B virus genotype and DNA levels and hepatocellular carcinoma: a prospective study in men. J Natl Cancer Inst 2005; 97: 265–72. Chen CJ, Yang HI, Su J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 2006; 295: 65–73. Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during longterm lamivudine therapy. Gastroenterology 2003; 124: 105–17. van Zonneveld M, Zondervan PE, Cakaloglu Y, et al. Peg-interferon improves liver histology in patients with HBeAg positive hepatitis B: no additional benefit of combination with lamivudine. Liver Int 2006; 26: 399–405. Giannelli G, Bergamini C, Marinosci F, et al. Antifibrogenic effect of IFNalpha2b on hepatic stellate cell activation by human hepatocytes. J Interferon Cytokine Res 2006; 26: 301–8. Tasci I, Mas MR, Vural SA, et al. Rat liver fibrosis regresses better with pegylated interferon alpha-2b and ursodeoxycholic acid treatment than spontaneously recovery. Liver Int 2006; 26: 261–8.

Aliment Pharmacol Ther 2010; 32: 1059–1068 ª 2010 Blackwell Publishing Ltd