Table 1.
Select Studies of Immune Checkpoint Inhibitor Therapy in Patients with HBV Infection and Advanced Cancer
| Reference | Year | Sample Size | Tumor Type | Number of HBV Infection | ICIs Therapy | Viral Load* | Antiviral Prophylaxis | Antiviral Therapy | HBV Reactivation Number of Events | Adverse Events | ORR (%) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Prospective clinical trails (n=2) | ||||||||||||
| El-Khoueiry AB | 2017 | 226(66HBV) | HCCs | 15 in escalation phase/51 in expansion phase | Nivolumab | Undetectable (66) | Yes (All patients were required to be receiving effective antiviral therapy) | Nil (0/66) | (0/66) No patient had reactivation of HBV, no anti- HBs sero conversion | in the dose-expansion phase, HBV infected group Diarrhoea(G3/4):1(2%) | CR(1) PR(8) SD(39) PD(17) NR(1) 13.6% | |
| Zhu AX | 2018 | 104(22HBV) | HCCs | Hepatitis B positive (22) | Pembrolizumab | Undetectable (22) | Yes (All patients were required to be receiving effective antiviral therapy) | Nil (0/22) | (0/22) No cases of flares of hepatitis B virus occurred. | Not specifically reported for HBV positive patients. | PR(5) SD+PD(16) NR(1) 23.8% | |
| Retrospective case series (n=10) | ||||||||||||
| Ravi S | 2014 | 9(5HBV) | Melanoma (9) | 5 HBV positive (active/inactive 3/2) | Ipilimumab (9) | Undetectable/Detected (2/3) | Entecavir (2) Tenofovir(2) Nil (1) | Nil (0) | (0/5) No patient had reactivation of HBV, (3/5) HBV-DNA levels remained undetectable | Only ALT elevation reported. ALT elevation G1: 2 | SD(1) PD(4) | |
| Wen X | 2016 | 23(11HBV) | Melanoma (11) | 11 pre-existing hepatitis B virus (HBV) infection | Ipilimumab (3) Pembrolizumab (5) Concurrent Ipilimumab -pembrolizumab (3) | Undetectable/Detected (10/1) | Entecavir (3) Nil (8) | Nil (0) | (0/11) No patient had reactivation of HBV, (6/11) HBV-DNA levels remained undetectable | Any G: (8/11)73%, ALT/AST increaseG3:(1/11) | NR | |
| Kothapalli A | 2018 | 7(5HBV/2HCV) | NSCLC(4) Melanoma(1) | Chronic HBV (1), Possible Past HBV (1), Past HBV (3, 1 of these had HCV co-infection) | Nivolumab(4) Pembrolizumab(1) | Unknown(5) | Unknown(5) | Nil (0/5) | (0/14) No patient had reactivation of HBV | ALT rise G1:(3), Nil(2) | PR(1) SD(2) PD(2) | |
| Tio M | 2018 | 46(14HBV/14HCV/12HIV/6Organ transplant) | Melanoma (9) Mesothelioma (1)Glioblastoma (1) HCC (1)Gastric (1)Urothelial (1) | hepatitis B infection(14) | Pembrolizumab (9)Nivolumab (4)Sequentialpembrolizumab + Ipilimumab (1) | Undetectable/Detected (4/4) Unknown (6) | Tenofovir (3) Entecavir (5) Nil (6) | Nil (0/14) | (0/14) No patient had reactivation of HBV | hypothyroidism G2:(1), rashG1:(1) G2:(1) pneumonitis G2:(1) vitiligo G1:(1) | CR(1)/PR(2) /SD(8) (21.4%). | |
| Zhang X | 2019 | 114 | NSCLC (13) HCC (28) Melanoma (14) Nasopharyngeal carcinoma (35) Lymohoma(8) Others(16) | HBsAg positive (114) | Anti-PD-1/PDL-1 monotherapy (83) Combination therapy (31) Immunotherapy monotherapy(83): pembrolizumab, nivolumab, toripalimab, camrelizumab, sintilimab, atezolizumab. Combinations of immunotherapy and chemotherapy (22), targeted agent ((osimertinib [n = 1], bevacizumab [n = 1],regorafenib [n = 1], apatinib[n = 1], sunitinib [n = 1], nimotuzumab [n = 2], cetuximab [n = 1]) and ipilimumab (n = 2) | Undetectable/Detectable (79/35) | Tenofovir (5) Entecavir (68) Lamivudine (10) Telbivudine (1)Adefovir (1) Nil (29) | Entecavir (4) Entecavir + Tenofovir (1)Nil (1) | (6/114)These 6 patients had baseline HBV- DNA negative, only 1 patients receiving prophylactic entecavir | hepatitis G1-2: (35) G3-4: (10) | NR | |
| Shah NJ | 2019 | 34 (16 HBV/ 18 HCV | HCC (16) NSCLC (10) RCC (3)Gastric (1) SCLC (1)H&N (1)Anal SCC (2) | 16 HBV chronic viral infections (1 of these had HCV and 1 of these had HIV co-infection. 8 patients had positive HBsAg, 4 patients were HBsAg (-), HBsAb (-), and HBcAb (+), and 3 patients were HBsAg (-), HBsAb (+), and HBcAb (+). One patient's HBV status was unknown.) | Anti-PD-(L)1 monotherapy (30) Anti-PD-(L)1 plus chemotherapy (3)Concurrent Ipilimumab -Nivolumab (1) | Undetectable/Detectable (8/5) Unknown (3) | Tenofovir (6) Entecavir (3) Nil (7) | Nil(0) | No patient had reactivation of HBV | Any grade 15 (44%)Grade≥ 3: 10 (29%) | 6 PR (18%) | |
| Pertejo-Fernandez A | 2020 | 19(16HBV/3HCV) | NSCLC | HBV (16, 2 of these had HCV co-infection) | Anti-PD-1/PDL-1 monotherapy(14) Combination therapy(2)Immunotherapy monotherapy(14):nivolumab(3), pembrolizumab(7), atezolizumab(3), durvalumab(1)Combinations of immunotherapy and chemotherapy(2):pembrolizumab+chemotherapy(1), ipilimumab+nivolumab(1) | Undetectable/Detectable (11/4), one is N/A | Tenofovir (2) Entecavir (1) Nil(13) | Nil(0) | No patient (0) | Neutropenia G4:(1) Colitis G3:(1) Diabetes mellitus G3:(1) | SD(7) PD(4) PR(5) 31% | |
| Byeon S | 2020 | 61(32HBV) | NSCLC | HBV (32, 16 past HBV infections and 16 chronic HBV infections) | Nivolumab(15) Pembrolizumab (17) | Undetectable/Detectable (23/4), N/A(5) | Entecavir(10), Tenofovir(1), Lamivudine(3) Nil(18) | Entecavir(2), Tenofovir(1) | (3/32) 2 patients had baseline HBV- DNA undetectable, 1 patient had an HBV DNA level of 1553 IU/mL before treatment, then rose to 11 317 IU/mL after 1 month of pembrolizumab treatment | Fatigue G2:(1) DNA seroconversion:(1)Pneumonitis G2:(1),G4:(1)Hyperglycemia G3:(1),G2(1)AST elevation G3:(6),G2:(1),G1(2) ALT elevation G4(2), G3(3),G2(1),G1(3) | SD(9) PD(11) PR(6) Not evaluate(6) 18.8% | |
| He MK | 2021 | 202 (202 HBV) | HCC | HBsAg positive and HBV-DNA positive (202) | Nivolumab (50) Pembrolizumab (45) Toripalimab (59) Sintilimab (35) Camrelizumab (13) Combinations of immunotherapy and HAIC (84) | HBV-DNA Low group ( ≤ 500 IU/ml N = 94) High group ( > 500 IU/ml N = 108) | Entecavir (148) Tenofovir (51) Other (3) | Entecavir(5), Tenofovir(2) | 7 patients had HBV reactivation, 5 patients in the HBV-DNA low group and 2 patients in the HBV-DNA high group. | Hepatitis All grades (49), Grade 3/4 (14) | Not reported | |
| Zhong L | 2021 | 120(43HBV) | HCC (32) Lung cancer (2) Esophgeal cancer (1) Melanoma (4) Others (4) | HBsAg positive (43) | Anti-PD-1 monotherapy(13) Combinations of immunotherapy and chemotherapy/targeted agent (30) | Undetectable/Detectable (20/14), N/A(9) | All patients (n=43) with HBV received regular antiviral therapy | All patients (n=43) with HBV received regular antiviral therapy | No patient (0) | Not reported | CR (0) PR (5) SD(9) PD (12) 11.63% | |
| Case reports (n=8) | ||||||||||||
| Sharma A | 2013 | 2(1HBV/1HCV) | Melanoma | 1 HBeAb(+) | Ipilimumab | Undetectable | tenofovir | tenofovir | 0 | Not reported | PD | |
| Koksal AS | 2017 | 1 | Melanoma | 1 HBsAg(+) | Ipilimumab+Nivolumab | Unknown | No | tenofovir disoproxil fumarate | 1 | hepatitis (G3-4) | Not reported | |
| Pandey A | 2018 | 1 | NSCLC (ADC) | 1 HBsAg(+) | Pembrolizumab | Unknown | No | tenofovir disoproxil fumarate | 1 | hepatitis (G3-4) | Not reported | |
| Ragunathan K | 2017 | 1 | NSCLC (ADC) | 1 HBsAg(+) | Pembrolizumab | Unknown | No | Unknown | 1 | hepatitis (G3-4) | Not reported | |
| Lake AC | 2017 | 1 | NSCLC (ADC) | 1 HBsAg(+) HBeAg (+) /HIV | Nivolumab | Undetectable | No | tenofovir disoproxil fumarate | 1 | hepatitis (G3-4) | CR | |
| Liu Z | 2019 | 1 | HCC | Chronic HBV infection | Pembrolizumab | Detectable | Entecavir | Entecavir | 0 | Diarrhea G3, Thrombocytopenia G4 occurred after the administration of Lenvatinib | CR | |
| Akar E | 2019 | 1 | RCC(clear cell) | HBsAg(+), also HDV-DNA(+) | Nivolumab | Detectable | Entecavir | Entecavir | 0 | Nil | SD | |
| Duan X | 2020 | 1 | HCC | Chronic HBV infection | Sintilimab | Detectable | Entecavir | Entecavir | 0 | fatigue G1, thrombocytopenia G1, AST elevation G1, ALT elevation G2 | CR | |
| ASCO meeting abstract&Poster (n=2) | ||||||||||||
| Kennedy Ng | 2020 | 114(62HBV/13HCV/) | HCCs | 62 HBV positive | Most received ICI as monotherapy (62%),most commonly a PD-1(58.8%) | Undetectable/Detectable (15/40) | Unknown (Most HBV patients (57, 91.9%) were on antiviral therapy) | Unknown | 6 /62 (1 patient were on baseline anti-virals before ICI initiation, 5 were not. 1 required treatment discontinuation. ) | Any Grades(79 69.3%), Grade3 or 4(17, 14.9%) | PR(21, 18.4%) SD(37, 32.5%) PD(46, 40.4%) ORR(21, 18.4%) | |
| Chongrui Xu | 2020 | 17 | NSCLC | 17 HBsAg(+) | Nivolumab(4) Pembrolizumab(5) Nivolumab+chemo(2) Pembrolizumab+chemo(5) | Unknown | 8 patients received anti-virus therapy including entecavir and adfovir during the treatment | Nil | 0 | Transaminase or bilirubin elevation(G1):6, Transaminase elevation(G3):1, bilirubin elevation(G4):1 | NR | |
HBV=Hepatitis B virus, HCV=Hepatitis C virus, HIV=Human immunodeficiency virus; HCC=Hepatocellular Carcinoma; NSCLC=Non-Small cell lung cancer; ADC=adenocarcinoma; SCLC=Small cell lung cancer; H&N=Head and neck squamous cell carcinoma,RCC=Renal cell carcinoma; CR= complete response, PR=partial response, SD=stable disease, PD=progressive diseas; NR=Not Report;Nil=Zero; ALT=Alanine transaminase; AST=Aspartate aminotransferase; HBsAg=Hepatitis B surface antigen, HBsAb=Hepatitis B surface antibody, HBcAb=Hepatitis B core antibody, HBeAg=Hepatitis B e antigen, HBeAb=Hepatitis B e antibody HAIC=Hepatic arterial infusion chemotherapy.
*Viral Load (IU/ml) Detectable HBV-DNA≥100 IU/ml;Undetectable<100.