Table 2.
The results of combination therapy of low-dose hepatitis B immunoglobulin and nucleos(t)ide analogues and the effects of withdrawal of hepatitis B immunoglobulin from combination therapy
| Ref. | NA | HBIG protocol | Median follow-up (mo) | HBV recurrence |
| Angus et al[119], 2000 | 32 LAM | 400 IU or 800 IU/d for 1 wk from LT followed by 400 IU or 800 IU/monthly thereafter | 18.4 | 3.1% HBsAg + and 0% HBV DNA+ |
| Gane et al[121], 2007 | 147 LAM | 400 IU or 800 IU/d for 1 wk followed by 400 IU or 800 IU/monthly thereafter | 62 | 1% at 1 yr and 4% at 5 yr. Baseline HBV DNA was associated with HBV recurrence |
| Karademir et al[125], 2006 | 33 LAM, 2 LAM + ADV | All patients received 4000 IU of intramuscular HBIG during surgery, 2000 IU intramuscular daily thereafter, until the HBsAb titer > 200 IU/mL and the HBsAg was seronegative, followed by lifelong 1200 to 2000 IU HBIG on-demand if HBsAb titer fell below 100 IU/mL | 16 | 5.7% (2 of 35 patients) had HBV DNA recurrence. They were LAM resistant |
| Iacob et al[126], 2008 | 42 LAM | 10000 IU within anhepatic phase and daily within the first postoperative week, followed by 2500 IU on demand | 21.6 | HBV recurrence rate was 4.8% after a median of 1.8 yr |
| Jiang et al[127], 2010 | 254 LAM | 2000 IU in anhepatic phase, followed by 800 IU/d for first day then weekly for the rest of 3 wk in the first post-operative month, then 800 IU monthly | 41.2 | 1-, 3- and 5-yr HBV recurrence rates were 2.3%, 6.2% and 8.2%, respectively 5 cases have YVDD mutations |
| Nath et al[128] , 2006 | 14 LAM + ADV | 1000 IU HBIG in anhepatic phase 1000 IU/daily for week 1, then HBIG withdrawn, replaced with oral ADV | 14.1 | 7.1% |
| Saab et al[129], 2011 | 18 LAM + HBIG, 16 LAM to LAM + ADV | Randomized trial Patients treated with low dose HBIG + LAM ≥ 1-yr post LT 18 patients continued HBIG 16 patients discontinued HBIG and ADV added | 21 | 0% in HBIG + LMV 6.1% in LMV + ADV Recurrent case: HBsAg + /HBV DNA (-) |
| Saab et al[129] , 2011 | 19 LAM to LAM + ADV, 41 LAM to LAM + TDF, 1 ETV to ETV + ADV | All patients treated with low dose HBIG + LAM ≥ 1-yr post-LT. All patients discontinued HBIG | 15 | 3.3% recurrent cases: HBsAg (+)/HBV DNA (-) |
| Radhakrishnan et al[130], 2017 | 42 (ETV (12%), TDF (83%), or TDF/FTC (5%) | HBIG 5000 IU given in anhepatic phase and daily for 5 d together with nucleos(t)ide analogues after LT and then continued indefinitely. | 36 | 1- and 3-year cumulative incidences of recurrence, defined by positive serum HBsAg of 2.9% |
| Chen et al[131], 2015 | 50 (ETV before and after LT) | Two doses of HBIG-First dose anhepatic phase (10000 IU) and other dose (10000 IU) during surgery (additional doses as needed to maintain HBIG level > 300 IU/mL from 6 wk to 12 mo) | 36 | 0% recurrence at 3 years defined as reappearance of HBsAg and HBV DNA level |
| Cholangitas et al[132], 2016 | 34 (LAM = 2, AFV = 1, ETV = 9, TDF = 12) | HBIG 1000-10000 IU bolus during anhepatic phase, followed by daily × 7 d, and then monthly 1000-2000 IU intramuscularly for 6-12 mo post-LT and then discontinued NA were continued indefinitely | 28 | 5.8% recurrence defined as reappearance of serum HDV in LT recipients with detectable serum HBsAg and/or HBV DNA |
| Wesdorp et al[133], 2013 | 17 (15 of 17 converted from LAM/ADV to TDF/FTC) | All received HBIG ± (10000 IU given during anhepatic phase followed by a 4-7 d course of 10000 IU of IV HBIG daily, and then monthly intramuscularly for > 6 mo and then switched to TDF/FTC | 24 | No recurrence defined by HBsAg and HBV-DNA positivity. However, 6.7% had isolated HBsAg recurrence |
| Stravitz et al[134], 2012 | 21 (Patients were initially on LAM = 11, ETV = 4, AFV = 2, LAM + ADV = 2, LAM + ADV = 2. All patients were converted to TDF/FTC) | HBIG ± nucleos(t)ide > 6 mo, then substituted with TDF/FTC | 31 | 0% recurrence of HBV DNA after switching to TDF/FTC |
| Taperman et al[135], 2013 | 37 patients were randomized to TDF/FTC plus HBIG (n = 19) or receive (TDF/FTC) alone (n = 18) | HBIG ± nucleos(t)ide for 24 wk, then randomized to TDF/FTC plus HBIG (n = 19) or receive TDF/FTC alone (n = 18) for an additional 72 wk | 72 | 0% recurrence of HBV DNA in both arms |
| Gane et al[136], 2013 | 20 patients with initial HBIG for 7 d and then switched to LAM+ ADV | HBIG 800 intramuscularly given immediately after LT and the daily for 7 d and then switched to LAM/ADV | 57 | 0% recurrence defined as reappearance of HBsAg and HBV DNA |
| McGonigal et al[137,141], 2013 | 4 (ETV = 2, LAM = 1, TDF = 1) | HBIG + NA for more than one year and switched to TDF/FTC | 15 | 0% recurrence of HBsAg and HBV DNA |
| Angus et al[138], 2008 | 34 patients randomized after 12 mo of HBIG +LAM to ADV (n = 16) with and without HIBIG (n = 18) | Low dose HBIG × 12 mo along with LAM | 4.4 yr for the LAM/ADV and 4.6 yr for the HBIG/LAM group | 1 of 15 (6%) in the LAM/ADV and 0 of 15 (0%) in the HBIG/LAM group had HBsAg positive at last follow up |
HBIG: Hepatitis B immunoglobulin; HBV: Hepatitis B virus; HBsAg: Hepatitis B surface antigen; HCC: Hepatocellular carcinoma; HIV: Human immunodeficiency virus; HDV: Hepatitis delta virus; LAM: Lamivudine; LT: Liver transplantation; ETV: Entecavir; TDF: Tenofovir.