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. 2017 May 12;11(5):590–603. doi: 10.5009/gnl16215

Table 3.

Summary of Add-on Therapies for Chronic Hepatitis B

Treatment arm Control arm No., HBeAg Setting/genotype Results of study Reference
NUC-based, add-on IFN
 1 LAM 8 wk+LAM/IFN-α2b 16 wk IFN-α2b 16 wk
LAM 52 wk		 230, pos 63% Caucasian, RCT

  1. HBeAg seroconversion (52 wk): 29% vs 19% vs 18% (all p>0.05)

 Schalm et al. (2000)30
 2 PegIFN-α2b 1–32 wk+LAM 9–60 wk LAM 52 wk 100, pos Gt B : 31%, C : 64% RCT

  1. HBeAg seroconversion+HBV DNA <500,000 cps/mL (VR) (EOT 24 wk): 36% vs 14%, p=0.011

  2. LAM-resistance (EOT): 21% vs 40%

  3. Long-term VR (EOT 76 wk): 29% vs 9%, log rank test, p=0.0015

 Chan et al. (2005)31
Chan et al. (2005)32
 3 ADV/PegIFN-α2b 48 wk+ADV 96 wk - 24, pos/neg

  1. HBeAg loss (EOT): 80%

  2. ALT normalization (EOT): 96%

 Lutgehetmann et al. (2008)33
 4 ETV 24 wk+ETV/PegIFN-α2a 24 wk +response-guided ETV 24 wk or 48 wk ETV 24 wk+ETV 24 wk +response-guided ETV 24 wk or 48 wk 175, pos 61% Asian (ARES study), RCT

  1. HBeAg loss and HBV DNA <200 IU/mL (after ETV discontinuation): 11% vs 2%, p=0.023

  2. HBeAg seroconversion (96 wk): 26% vs 13%, p=0.036

  3. Add-on group: greater decline HBsAg, HBeAg and HBV DNA (all p<0.001)

 Brouwer et al. (2015)34
 5 ETV>2 yr+ETV/PegIFN-α2a 48 wk ETV>2 yr+ETV 48w 100*, pos China

  1. HBeAg seroconversion (48 wk): 44% vs 6%, p<0.0001

 Li et al. (2015)35
 6 NUC>1 yr+NUC/PegIFN-α2a 48 wk NUC>1 yr+NUC 48 wk 183, neg France, RCT

  1. HBsAg loss (48 wk): 8% vs 1% (p=0.032); (96 wk): 8% vs 3% (p>0.05)

 Bourliere et al. (2015)36
 7 ETV/PegIFN-α2a 24 wk+ETV 120 wk ETV 144 wk 168, pos Taiwan, RCT

  1. HBeAg seroconversion (EOT): 40% vs 39% (n=53, interim report)

 Liu et al. (2013)37
IFN-based, add-on NUC
 8 PegIFN-α2a 52 wk+LAM 13–24 wk† PegIFN-α2a 52 wk 32, pos China Overall: HBV DNA <500 copies/mL, HBeAg seroconversion, HBsAg loss and ALT normalization rate (EOT 24 wk): 56%, 44%, 3%, 69% Huang et al. (2013)38
 9 PegIFN-α2a 6 mo‡+PegIFN-α2a/ADV 6 mo PegIFN-α2a 6 mo‡+ PegIFN-α2a 6 mo 85, pos China

  1. HBV DNA<1,000 cps/mL, ALT normalization (EOT 6 mo): 73.5% vs 31.4% (p<0.001); 85.3% vs 39.2% (p<0.001)

  2. HBeAg loss and HBeAg seroconversion (EOT 6 mo): 55.9% vs 19.6% (p=0.001); 41.2% vs 13.7% (p=0.004)

 Wang et al. (2013)39
 10 (A) PegIFN-α2a 48 wk+ETV 13–36 wk (ETV add-on) (B) PegIFN-α2a 48 wk
(C) ETV 24w+PegIFN-α2a 21–68 wk (ETV lead-in)		 218, pos China, RCT

  1. HBeAg decline (48 wk): greater in (A) vs (B), p=0.04

  2. HBeAg seroconversion (EOT 24 wk): (A) 25% vs (B) 31% vs (C) 26% (p>0.05)

 Xie et al. (2014)40
 11 PegIFN-α2a 24 wk (if early responder)§+ (A) PegIFN-α2a 24 wk PegIFN-α2a 24 wk+
(B) PegIFN-α2a 24 wk
(C) PegIFN-α2a 72 wk
(D) PegIFN-α2a 72 wk+ ADV (29–64 wk)		 264, pos China, RCT

  1. HBsAg decline (EOT 24 wk): (A) 1.15 vs (B) 0.67 vs (C) 0.71 vs (D) 0.64 log IU/mL

  2. No significant difference in reduction of HBV DNA, HBeAg, HBeAg seroconversion, HBsAg loss, ALT normalization among arm B, C, D

 Hou et al. (2014)41
 12 (A) PegIFN-α2a/LAM 48 wk+ PegIFN-α2a (135μg) 48 wk (B) PegIFN-α2a 48 wk
(C) PegIFN-α2a 48 wk+ PegIFN-α2a (135 μg) 48 wk		 128, neg Gt D, RCT

  1. HBV DNA<3,400 IU/mL+ALT normalization (EOT 48 wk): (A) 20% vs (B) 12% vs (C) 25%, p=0.08

  2. HBV DNA <2,000 IU/mL (EOT 48 wk): (B) 12% vs (C) 29%, p=0.03

 Lampertico et al. (2013)42

HBeAg, hepatitis B e antigen; NUC, nucleos(t)ide analogue; IFN, interferon; LAM, lamivudine; pos, positive; RCT, randomized controlled trial; PegIFN, pegylated IFN; Gt, genotype; HBV, hepatitis B virus; VR, virologic response; EOT 24 wk, 24 weeks after the end of therapy; ADV, adefovir; neg, negative; ALT, alanine aminotransferase; ETV, entecavir; HBsAg, hepatitis B surface antigen; EOT 6 mo, 6 months after the EOT.

*

By 1:1 matching in both groups;

†

If HBV DNA ≥10,000 copies/mL and HBeAg-positive;

‡

In patients with HBV DNA >1,000 copies/mL;

§

Early responder: HBsAg <1,500 IU/mL+HBV DNA <105 cps/mL.