Figure 1. Algorithm for study participants enrollment and the risk of hepatitis B reactivation in various conditions. CTx, chemotherapy; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; NUC, nuceos(t)ide analogues; TKI, tyrosine kinase inhibitor.

Figure 1. Algorithm for study participants enrollment and the risk of hepatitis B reactivation in various conditions. CTx, chemotherapy; HBV, hepatitis B virus; ICI, immune checkpoint inhibitor; NUC, nuceos(t)ide analogues; TKI, tyrosine kinase inhibitor.

Figure 2. (A) Cumulative incidence of HBV reactivation in HBsAg-positive patients without prophylactic NUC who received chemotherapy or tyrosine kinase inhibitor (TKI). (B) Comparison of cumulative HBV-related hepatitis incidence between HBsAg-positive patients without prophylactic NUC receiving chemotherapy and TKI. (C) Comparison of cumulative HBV reactivation incidence in patients receiving first-line TKI without prophylactic NUC between HBsAg-positive and HBsAg-negative groups. TKI, tyrosine kinase inhibitor.

Table 1. Clinical characteristics of the included patients. N/A, not available; TKI, tyrosine kinase inhibitor.

Table 1. Clinical characteristics of the included patients. N/A, not available; TKI, tyrosine kinase inhibitor.

N = 1960Age, years (range)63.0 (55.0–71.0)Gender, n (%)  Male1176 (60.0%) Female784 (40.0%)Smoking, n (%)  No955 (48.7%) Yes847 (43.2%) N/A158 (8.1%)Stage, n (%)  I165 (8.4%) II85 (4.3%) III349 (17.8%) IV1361 (69.4%)Histology, n (%)  Squamous cell carcinoma245 (12.5%) Adenocarcinoma1423 (72.6%) Small cell carcinoma133 (6.8%) Others159 (8.1%)First-line treatment, n (%)  Chemotherapy1284 (65.5%) Tyrosine kinase inhibitor (TKI)
  EGFR-TKI
   Gefitinib
   Erlotinib
   Afatinib
   Osimertinib
  ALK-inhibitor
   Crizotinib
   Ceritinib
   Alectinib
   Brigatinib658 (33.6%)
 630 (32.1%)
  182 (9.3%)
  269 (13.7%)
  145 (7.4%)
  34 (1.7%)
 28 (1.4%)
  14 (0.7%)
  3 (0.1%)
  8 (0.4%)
  3 (0.1%) Immune checkpoint inhibitor18 (1.0%) HBV serology, n (%)  Positive HBsAg366 (18.7%) Negative HBsAg and negative anti-HBs314 (16.0%) Negative HBsAg and positive anti-HBs1280 (65.3%)

Table 2. Clinical data of patients developing HBV reactivation after systemic anticancer treatment. 3TC, lamivudine; ALT, alanine aminotransferase; ASP8273, an EGFR TKI; ETV, entecavir; LdT, telbivudine; TAF, tenofovir alafenamide; TKI, tyrosine kinase inhibitor. # The treatment duration in patients receiving first-line TKI only was counted since the initiation of TKI, while those receiving chemotherapy with previous TKI treatment was counted since the initiation of chemotherapy. $ HBV reactivation without HBV-related hepatitis. @ HBV prophylaxis before chemotherapy.

Table 2. Clinical data of patients developing HBV reactivation after systemic anticancer treatment. 3TC, lamivudine; ALT, alanine aminotransferase; ASP8273, an EGFR TKI; ETV, entecavir; LdT, telbivudine; TAF, tenofovir alafenamide; TKI, tyrosine kinase inhibitor. # The treatment duration in patients receiving first-line TKI only was counted since the initiation of TKI, while those receiving chemotherapy with previous TKI treatment was counted since the initiation of chemotherapy. $ HBV reactivation without HBV-related hepatitis. @ HBV prophylaxis before chemotherapy.

Patient No.Baseline CharacteristicsAntineoplastic TreatmentHBV ReactivationAge/SexHBsAgALT (U/L)Medication CoursesDuration #
(Month)Peak ALT
(U/L)HBV Viral Load (IU/mL)Rescue NUC TherapyClinical Outcome158/FPositive48TKI then chemotherapy5.1277>1.70 × 108ETVliver failure267/FPositive51TKI then chemotherapy0.9169 1.05 × 105ETVALT decreased360/FPositive15TKI then chemotherapy15.61074>1.70 × 108ETVliver failure445/FPositive63Erlotinib25.019 $ 2.25 × 104ETV @ 562/FPositive30Gefitinib1.9140 7.03 × 103ETVALT decreased648/FPositive20Gefitinib then osimertinib19.6161 8.00 × 104ETVALT decreased750/MPositive27Erlotinib then osimertinib24.416 $>1.70 × 108TAF @ 857/MPositive20Gefitinib9.365 $ 6.44 × 107ETVALT decreased970/MPositive19Gefitinib1.6125 2.82 × 105ETVALT decreased1057/FPositive30Gefitinib14.531 $ 4.51 × 104ETV @ 1170/MPositive21Erlotinib4.0355 1.03 × 105LdTALT decreased1249/FPositive12Erlotinib13.352 $ 5.51 × 104nil 1366/FPositive20Afatinib0.51293>1.70 × 108ETVALT decreased1467/FPositive32ASP8273 then gefitinib5.11227 1.11 × 105ETVALT decreased1567/MPositive40Afatinib31.958 $ 2.47 × 106nil 1660/MPositive104Erlotinib2.5191 5.93 × 106ETVALT decreased1759/FPositive21Erlotinib then osimertinib13.1552 7.93 × 106ETVALT decreased1859/MPositive44Erlotinib8.426 $ 3.87 × 106ETV @ 1967/MNegative16Afatinib then osimertinib25.9529 2.45 × 105ETV + 3TCALT decreased

Table 3. Univariate and multivariable analysis for HBV reactivation in lung cancer patients receiving tyrosine kinase inhibitor treatment only.

Table 3. Univariate and multivariable analysis for HBV reactivation in lung cancer patients receiving tyrosine kinase inhibitor treatment only.

VariableTotalUnivariate AnalysisMultivariable Analysis n = 349Hazard Ratio (95% CI)p ValueHazard Ratio (95% CI)p ValueAge 0.96 (0.92–1.00)0.0670.97 (0.93–1.01)0.164Gender  Female204Reference Reference  Male1451.63 (0.61–4.35)0.3271.18 (0.35–3.97)0.792Smoking habit  Never smoker244Reference Reference  Ever smoker752.04 (0.74–5.62)0.1672.73 (0.72–10.32)0.140Tyrosine kinase inhibitor  Gefitinib85Reference Reference  Erlotinib1410.52 (0.17–1.62)0.2620.32 (0.10–1.04)0.059 Afatinib770.43 (0.11–1.74)0.2390.33 (0.08–1.42)0.135 Osimertinib230.56 (0.07–4.70)0.5960.35 (0.04–3.42)0.365HBV serology  Negative HBsAg276Reference Reference  Positive HBsAg7362.20 (8.21–471.08)<0.00153.77 (7.00–412.90)<0.001