Predictive value of baseline and on-treatment quantitative serum HBsAg levels in therapeutic outcome to entecavir in patients with chronic hepatitis B.

Predictive Value of Baseline and On-Treatment Quantitative Serum HBsAg Levels in

Therapeutic Outcome to Entecavir in Patients with Chronic Hepatitis B

Cheng-Yuan Peng, Hsueh-Chou Lai, Wen-Pang Su, Chia-Hsin Lin, Po-Heng Chuang, Sheng-Hung Chen

Division of Hepatogastroenterology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan

INTRODUCTION

 Baseline and on-treatment serum qHBeAg levels are associated with VR (HBV DNA <60 copies/mL) and HBeAg seroconversion in CHB patients receiving ETV (HEPATOLOGY 2011;53:1486-1493), but the associations between qHBsAg levels and the therapeutic outcomes remain unclear.

 Baseline serum qHBsAg level is a predictor of VR (HBV DNA <60 copies/mL) in HBeAg-positive CHB patients receiving ETV (HEPATOLOGY 2011;53:1486-1493).

AIM

 To identify baseline and on-treatment factors predictive of the therapeutic outcome in CHB patients receiving ETV therapy

PATIENTS AND METHODS

 321 CHB patients (120 HBeAg-positive and 201 HBeAg-negative) receiving ETV therapy for at least 1 year were recruited from the China Medical University Hospital from JUN 2006 to May 2013.

 Baseline clinical data included age, gender, cirrhosis, inflammatory activity, fibrosis stage, platelet, alanine aminotransferase (ALT), albumin, total bilirubin, PT, AFP, Cr, genotype, HBV DNA, and qHBsAg. Serum ALT and HBeAg/anti-HBe (for HBeAg-positive CHB) were measured at least every 3 months during therapy. Serum HBsAg levels were quantified using the Abbott Architect HBsAg QT assay (dynamic range, 0.05-250 IU/mL) at baseline (BL), 12, 24 and 52 weeks, and yearly thereafter during therapy. Serum HBV DNA levels were measured with the Cobas Amplicor HBV Monitor Test (Roche Diagnostics, lower limit of detection, 312 copies/mL) at baseline, 12, 24 and 52 weeks, and every 6 months thereafter during therapy.

 Three therapeutic endpoints were defined: 1) virological response (VR), defined as undetectable serum HBV DNA (<312 copies/mL); 2) HBeAg loss and HBeAg seroconversion (SC); 3) achievement of serum qHBsAg level ≦2 log₁₀ IU/mL during treatment.

 Statistical analyses were performed using the SAS 9.3 software.

RESULTS

Table 1 Baseline characteristics of CHB patients (N=321)

Variables Median or N (%) Total (N=321) HBeAg(-) (N=201) HBeAg(+) (N=120) P value Age: year 49.0±17.0 53.0±15.0 41.0±16.0 <0.0001 Gender 0.8090 Female 80(24.9) 51(25.4) 29(24.2) Male 241(75.1) 150(74.6) 91(75.8) Genotype 0.0027 B 182(59.1) 126(65.6) 56(48.3) C 126(40.9) 66(34.4) 60(51.7) Cirrhosis 0.0124 No 222(69.2) 129(64.2) 93(77.5) Yes 99(30.8) 72(35.8) 27(22.5) Platelet: x103/μL _{160.0±72.0 149.0±67.0 175.0±73.0 0.0002} ALT: IU/L 79.0±173.0 71.0±126.0 102.0±318.0 0.0002 METAVIR A 0.2420 0-1 138(63.6) 93(66.4) 45(58.4) 2-3 79(36.4) 47(33.6) 32(41.6) METAVIR F 0.3537 0-2 120(54.1) 74(51.7) 46(58.2) 3-4 102(45.9) 69(48.3) 33(41.8) Albumin: g/dL 4.10±0.50 4.10±0.50 4.20±0.50 0.0093 Total bilirubin: mg/dL 1.00±0.55 1.01±0.49 0.98±0.68 0.8266 PT: seconds prolonged 0.94±1.67 0.94±1.75 0.96±1.54 0.7938 AFP: ng/mL 5.11±9.27 4.90±8.97 6.09±9.37 0.0769 Cr: mg/dL 0.89±0.27 0.90±0.27 0.84±0.24 0.0058 HBVDNA: log₁₀ copies/mL 6.56±2.86 5.99±2.17 8.20±1.99 <0.0001 qHBsAg: log₁₀ IU/mL 3.29±0.80 3.12±0.66 3.64±1.00 <0.0001

Table 2 Factors associated with VR during the first year of therapy in CHB patients

Variables Univariable analysis Multivariable analysis Median ± IQR or N(%) VR(-) VR(+) P value Odds Ratio(95%CI) P value

Total patients HBeAg - + 6(19.4) 25(80.6) 195(67.2) 95(37.8) <0.0001 4.956(1.634-15.032) 1.000 0.0047

BL HBV DNA: log₁₀ copies/mL <8 ≥8 9(33.3) 18(66.7) 217(76.7) 66(23.3) <0.0001 7.113(2.451-20.644) 1.000 0.0003 BL-3M qHBsAg decline <50% ≥50% 20(76.9) 6(23.1) 203(76.3) 63(23.7) 0.9445 1.000 4.295(1.418-13.015) 0.0100 HBeAg(+)

BL HBV DNA: log₁₀ copies/mL <8 ≥8 6(27.3) 16(72.7) 48(52.7) 43(47.3) 0.0318 5.746(1.726-14.180) 1.000 0.0044 BL-3M qHBsAg decline <50% ≥50% 16(76.2) 5(23.8) 52(59.8) 35(40.2) 0.1619 1.000 4.202(1.245-14.180) 0.0207

Table 3 Cox regression analyses of factors for HBeAg loss in HBeAg-positive CHB patients

Variables

Univariable analysis Multivariable analysis Hazard Ratio(95%CI) P value Hazard Ratio(95%CI) P value

Cirrhosis 0.0807 No 1.000 Yes 1.735(0.935-3.221) ALT: IU/L 0.0695 0.0369 <120 1.000 1.000 ≥120 1.670(0.96-2.906) 1.881(1.039-3.405) AFP: ng/mL 0.0100 <8 1.000 ≥8 2.100(1.194-3.694) qHBsAg: IU/mL <5000 2.047(0.914-4.584) 0.0816 2.410(1.061-5.471) 0.0355 5000-15999 4.279(1.794-10.209) 0.0010 4.421(1.854-10.452) 0.0008 ≥16000 1.000 1.000

Table 4 Cox regression analyses of factors for HBeAg SC in HBeAg-positive CHB patients

Variables

Univariable analysis Multivariable analysis Hazard Ratio(95%CI) P value Hazard Ratio(95%CI) P value

HBeAg(-) CHB

qHBsAg: log₁₀ IU/mL 0.0059 <2.5 15.347(6.382-36.907) <0.0001 3.965(1.486-1.583) ≥2.5 1.000 1.000 BL-12M qHBsAg decline 0.0167 <0.0001 <50% 1.000 1.000 ≥50% 2.565(1.186-5.549) 22.355(8.528-58.599) HBeAg(+) CHB

qHBsAg: log₁₀ IU/mL 0.0472 0.0210 <3.5 3.478(1.106-11.909) 4.784(1.266-18.073) ≥3.5 1.000 1.000 BL-3M qHBsAg decline 0.0272 0.0368 <50% 1.000 1.000 ≥50% 4.000(1.169-13.682) 4.115(1.091-15.523) Therapeutic outcomes

Baseline qHBsAg: IU/mL

P value <5000 5000-15999 ≥16000 VR (1 year) 0.0038 - 8(14.0) 2(8.0) 12(40.0) + 49(86.0) 23(92.0) 18(60.0) HBeAg SC (3 years) 0.0339 - 27(73.0) 10(47.6) 19(82.6) + 10(27.0) 11(52.4) 4(17.4)

HBeAg loss (3 years) 0.0178 - 19(50.0) 5(27.8) 6(72.7)

+ 19(50.0) 13(72.2) 6(27.3)

HBeAg loss (4 years) 0.0046 - 15(42.9) 2(11.8) 13(65.0)

+ 20(57.1) 15(88.2) 7(35.0)

HBeAg loss (5 years) 0.0050 - 6(22.2) 0(0.0) 7(50.0)

+ 32(77.8) 16(100) 7(50.0)

Variables

Univariable analysis Multivariable analysis Hazard Ratio(95%CI) P value Hazard Ratio(95%CI) P value

Genotype 0.0702 B 1.000 C 2.114(0.940-4.753) ALT: IU/L 0.0383 0.0258 <120 1.000 1.000 ≥120 2.284(1.046-4.989) 2.578(1.121-5.928) AFP: ng/mL 0.0597 <8 1.000 ≥8 2.100(0.97-4.545) qHBsAg: IU/mL <5000 1.573(0.493-5.020) 0.4446 1.461(0.418-5.109) 0.5527 5000-15999 4.330(1.376-13.62) 0.0122 5.488(1.733-17.381) 0.0038 ≥16000 1.000 1.000

Table 6 Cox regression analyses of factors for achieving qHBsAg <2 log₁₀ IU/mL during therapy

Table 5 Therapeutic outcomes among three baseline qHBsAg Groups

DISCUSSION AND CONCLUSIONS

 Baseline HBV DNA <8 log₁₀ copies/mL and qHBsAg decline from baseline ≥50% at 3 months of therapy are predictors of VR at one year for the whole group and the HBeAg-positive subgroup

 Baseline serum qHBsAg between 5000-15999 IU/mL and ALT _{≥120 IU/mL are predictors of HBeAg} loss or seroconversion during ETV therapy in HBeAg-positive patients

 Patients with baseline qHBsAg between 5000 to 15999 IU/mL have the highest VR rate at 1 year, cumulative rate of HBeAg seroconversion at 3 years, and cumulative rates of HBeAg loss up to 5 years

 Baseline qHBsAg level <3.5 log₁₀ IU/mL and qHBsAg decline from baseline ≧50% at 3 months of therapy were predictors of achieving qHBsAg level ≦2 log₁₀IU/mL during treatment in HBeAg-positive patients; baseline qHBsAg level <2.5 log₁₀ IU/mL and qHBsAg decline from baseline ≧50% at 12 months of therapy were predictors of achieving qHBsAg level ≦2 log₁₀IU/mL during treatment in HBeAg-negative patients

Cumulative HBeAg loss and seroconversion rates