Predictors of Serum HBsAg Decline in Chronic Hepatitis B Patients Undergoing Entecavir Therapy

(1)

Predictors of Serum qHBsAg Decline in Chronic Hepatitis B Patients Undergoing Entecavir Therapy

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

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

INTRODUCTION

 Genotype A, high HBV DNA, high ALT, high qHBsAg, and older age were significantly associated with more HBsAg decline in HBeAg-positive CHB patients receiving Entecavir or Tenofovir therapy (JID 2011;204:415-418).

 Patients who cleared HBsAg had a greater median change from baseline in plasma qHBsAg levels at week 24 compared to patients who did not clear HBsAg (2.41 log₁₀ IU/mL vs 0.20 log₁₀ IU/mL) during Tenofovir therapy (GASTROENTEROLOGY 2011: 140:132–143).

 The decline in qHBsAg level and its predictors in CHB patients undergoing long-term ETV therapy remain unclear.

AIM

PATIENTS AND METHODS

 361 CHB patients (321 compensated and 40 acutely decompensated) 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. Acute decompensation was defined as total bilirubin >2 mg/dL and PT>3 seconds prolonged over control. Serum qHBsAg 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.

 Multivariable logistic regression was used to identify factors associated with the decline of serum qHBsAg

.

Statistical analyses were performed using the SAS 9.3 software.

RESULTS

Table 1 Baseline characteristics of CHB patients (N=361)

DISCUSSION AND CONCLUSIONS

 Patients were categorized in three subgroups according to the pattern of qHBsAg decline from baseline:≧50% at 3M, ≧50% at 12M, and <50% at 12M. Among HBeAg-positive patients, the subgroup with qHBsAg decline from baseline of ≧50% at 3M of therapy had significantly lower qHBsAg levels than the other two subgroups up to 2 years of treatment. Among HBeAg-negative patients, the qHBsAg levels between the subgroups with qHBsAg decline from baseline of ≧50% at 3 or 12M of therapy were similar except at baseline

 For HBeAg-positive patients, genotype B, ALT ≧120 IU/L and baseline qHBsAg ≧5000 IU/mL as predictors of qHBsAg decline from baseline of ≧50% at 3M of therapy

 For HBeAg-negative patients, ALT ≧120 IU/L and baseline qHBsAg ≧5000 IU/mL as predictors of qHBsAg decline from baseline of ≧50% at 12M of therapy

The authors have no financial relationship to disclose relevant to this poster presentation

 To examine the predictors of serum qHBsAg decline in CHB patients undergoing ETV therapy Variable Median±IQR or N (%) Total (N=361) HBeAg(-) (N=224) HBeAg(+) (N=137) P value Age: year 49.0±17.0 53.0±15.0 42±16.5 <0.0001 Gender 0.8452 Female 89(24.7) 56(25.0) 33(24.1) Male 272(75.3) 168(75.0) 104(75.9) Genotype 0.0160 B 206(59.2) 138(64.2) 68(51.1) C 142(40.8) 77(35.8) 65(48.9) Cirrhosis 0.0032 No 246(68.1) 140(62.5) 106(77.4) Yes 115(31.9) 84(37.5) 31(22.6) Platelet: x103/μL _154.0±72.5_146.0±69.0 _169.0±69.0_0.0008 ALT: IU/L 87.0±219.0 72±151 116±449 0.0001 METAVIR A 0.1406 0-1 141(62.4) 95(66.0) 46(56.1) 2-3 85(37.6) 49(34.0) 36(43.9) METAVIR F 0.4113 0-2 121(52.4) 74(50.3) 47(56.0) 3-4 110(47.6) 73(49.7) 37(44.0) Albumin: g/dL 4.10±0.60 4.00±0.70 4.10±0.50 0.0467 Total bilirubin: mg/dL 1.06±0.72 1.06±0.60 1.09±0.84 0.5082 PT: seconds prolonged 1.20±2.01 1.20±2.04 1.20±1.97 0.9734 AFP: ng/mL 5.76±12.6 5.09±12.5 7.10±13.0 0.0361 Cr: mg/dL 0.88±0.27 0.90±0.27 0.86±0.25 0.0233

HBVDNA: log₁₀copies/mL 6.56±2.86 6.03±2.23 8.02±2.26 <0.0001 qHBsAg: log₁₀IU/mL 3.30±0.82 3.13±0.77 3.60±0.90 <0.0001

Table 2 Factors associated with serum qHBsAg decline from baseline of ≥ 50% at 3M of therapy in HBeAg-positive CHB patients(N=137)

Table 3 Factors associated with serum qHBsAg decline from baseline at 12 months of therapy in HBeAg-negative CHB patients(N=224)

Variables

Univariable analysis Multivariable analysis

Odds Ratio(95% CI) P value Odds Ratio(95% CI) P value

Age: year 0.950(0.917-0.984) 0.0045

Gender (male vs female) 1.180(0.507-2.745) 0.7004

Genotype (B vs C) 3.244(1.490-7.065) 0.0030 2.572(1.017-6.504) 0.0460 Cirrhosis(no vs yes) NA Platelet: x103/μL _{1.003(0.996-1.010)} _0.3449 ALT: IU/L(≥120 vs <120) 10.833(4.505-26.050) <0.0001 9.295(3.610-23.932) <0.0001 METAVIR A (2-3 vs 0-1) 3.579(1.294-9.901) 0.0141 METAVIR F(0-2 vs 3-4) 5.383(1.623-17.852) 0.0059 Albumin: g/dL 0.812(0.390-1.692) 0.5779 Total bilirubin: mg/dL 1.219(1.001-1.484) 0.0483 PT: seconds prolonged 1.119(0.940-1.330) 0.2058 AFP: ng/mL (≥8 vs <8) 2.704(1.275-5.734) 0.0095 Cr: mg/dL 0.792(0.241-2.608) 0.7014

HBVDNA: log₁₀ copies/mL 1.781(1.290-2.458) 0.0004

qHBsAg: IU/mL (≥5000 vs <5000) 4.315(1.995-9.336) 0.0002 3.795(1.513-6.504) 0.0045

Figure 2. Serial median serum qHBsAg levels during therapy stratified by the qHBsAg decline patterns during the first year

NA: odds ratio cannot be estimated because of empty cell (qHBsAg declines from baseline in all

cirrhosis patients <50% at 3M of therapy For HBeAg-positive patients, the subgroup 1 had significantly lower qHBsAg levels than the

other two subgroups up to 2 years of treatment (All P value <0.05).

For HBeAg-negative patients, the subgroups 1 and 2 were similar except at baseline. The subgroup 1 had significantly lower qHBsAg levels than the subgroup 3 at all on-treatment time points (All P value <0.05)

This analysis included patients receiving treatment for at least 2 years. Variables

Univariable analysis Multivariable analysis

Odds Ratio(95% CI) P value Odds Ratio(95% CI) P value

Age: year 0.972(0.944-1.001) 0.0545

Gender (male vs female) 2.210(0.965-5.062) 0.0608

Genotype (B vs C) 2.132(1.010-4.497) 0.0469

Cirrhosis (no vs yes) 2.011(0.994-4.066) 0.0519

Platelet: x103/μL _{1.002(0.997-1.007)} _0.4846 ALT: IU/L (≥120 vs <120) 8.922(4.386-18.147) <0.0001 8.255(3.866-17.631) <0.0001 METAVIR A (2-3 vs 0-1) 3.889(1.637-9.236) 0.0021 METAVIR F(0-2 vs 3-4) 2.571(1.076-6.145) 0.0337 Albumin: g/dL 0.994(0.506-1.952) 0.9859 Total bilirubin: mg/dL 1.135(0.993-1.298) 0.0627 PT: seconds prolonged 1.317(1.112-1.558) 0.0014 AFP: ng/mL (≥8 vs <8) 1.744(0.912-3.332) 0.0925 Cr: mg/dL 1.523(0.756-3.068) 0.2396

HBVDNA: log₁₀ copies/mL 2.015(1.568-2.589) <0.0001

qHBsAg: IU/mL (≥5000 vs <5000) 7.059(3.361-14.825) <0.0001 6.311(2.724-14.624) <0.0001

Figure 1. Serial median serum qHBsAg levels during therapy (N=186)

The median serum qHBsAg levels in HBeAg-positive patients were significantly higher than in HBeAg-negative patients at each time point (P value <0.001).

For HBeAg-positive patients, there were significant declines in qHBsAg levels between baseline and 3M, 12 and 24M (P value= 0.0281), 36 and 48M(P value= 0.0116)

For HBeAg-negative patients, there were significant declines in qHBsAg levels between baseline and 3M, 6 and 12M,12 and 24M, 24 and 36M, and 36 and 48M (all P value <0.05). This analysis included patients receiving treatment for at least 4 years.

3.66 3.30 3.33 3.34 3.30 3.24 _3.20 3.11 3.02 3.03 2.96 2.86 2.77 2.62 2.30 2.50 2.70 2.90 3.10 3.30 3.50 3.70 3.90 BA 3M 6M 12M 24M 36M 48M HB s A g (L og 10 IU/m L) HBeAg(+) (N=68) HBeAg(-) (N=118) 2.50 2.70 2.90 3.10 3.30 3.50 3.70 BA 3M 6M 12M 24M HB s A g (L og 10 IU/m L 2.70 2.90 3.10 3.30 3.50 3.70 3.90 4.10 4.30 4.50 4.70 BA 3M 6M 12M 24M HB s A g (L og 10 IU/m L

(a) HBeAg(+) patients (b) HBeAg(-) patients