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. Author manuscript; available in PMC: 2018 Jun 1.
Published in final edited form as: Expert Opin Drug Saf. 2017 May 19;16(6):651–672. doi: 10.1080/14740338.2017.1325869

Table 4.

Summary of the United States Food and Drug Administration Adverse Event Reporting System (FAERS) reported cases of hepatitis B virus (HBV) reactivation during direct-acting antiviral (DAA) therapy and cases of HBV reactivation published in the literature that are not covered by the FAERS report.

Case Study Age Sex HCV genotype Past HCV treatment DAA regimen HBV characteristics pre DAA Timing of HBV reactivation from start of DAAs HBV characteristics during DAA therapy Type of HBV reactivation
Cases of HBV reactivation notified to the FDA
1 FAERS 59 Male 1a Not reported Paritaorevir/r + ombitasvir + dasabuvir + RBV HBsAg(+)
HBeAg(−)
HBV DNA 2,700 IU/mL (Inactive carrier)		 Week 4 ALT 497
Bilirubin 1.3 mg/dL
HBV DNA 1,700,000 IU/mL (treated with TDF)		 HBV flare with acute hepatitis and jaundice
Week 6 ALT 2264
Bilirubin 6.8 mg/dL
2 † Ende et al. 59 Female 1b IFN+RBV Sofosbuvir + Simeprevir + RBV HBsAg(−)
Anti-HBc(+)
HBV DNA not detected (Past infection) 		Week 11 HBV DNA 29,000,000 IU/mL
HBsAg(+)
ALT 2,263
Bili 9.1mg/dL
INR 1.9 (required liver transplantation) 		Fulminant hepatic failure requiring liver transplantation
3 FAERS 69 Male 1 Not reported Daclatasvir + Asunaprevir HBsAg not reported
HBeAg(−)
HBV DNA 2.5 log copies/mL (Inactive carrier)		 Week 4
Week 8		 Increased ALT
ALT 237
HBV DNA 6.7 log copies/mL		 Mild hepatitis
4 De Monte et al. 53 Male 4d IFN+RBV Sofosbuvir + Ledipasvir HBsAg(−)
Anti-HBc(+)
HBV DNA not detected (Past infection)		 Week 6 HBV DNA 8.9 log IU/mL
ALT 1026		 Moderate hepatitis without jaundice
5 * Kimura et al. 65 Female 1 Naïve IFN + RBV + Simeprevir HBsAg(+)
HBeAg(−)
HBV DNA 3.3 log IU/mL (Inactive carrier)		 Week 5 post-treatment (ceased treatment week 3 due to occular bleeding) ALT 32
HBV DNA 4.3 log copies/mL (treated with ETV)		 Isolated increase in HBV DNA - Regimen included IFN + RBV
6 Collins et al. 57 Male 1a IFN+RBV Sofosbuvir + Simeprevir HBsAg(−)
Anti-HBc(+)
HBV DNA <20 IU/mL (+)(Occult HBV)		 Week 2 HBV DNA peaked 11,255 IU/mL at week 4 (treated with TDF) Isolated increase in HBV DNA
7 Collins et al. 55 Male 1a IFN+RBV Sofosbuvir + Simeprevir HBsAg(+)
HBeAg(−)
HBV DNA 2,300IU/mL (Inactive carrier)		 Week 8 HBV DNA 22,000,000 IU/mL (treated with TDF) Isolated increase in HBV DNA
8 FAERS 44 Female 3a Sofosbuvir + RBV HBsAg(+)
HBV DNA 244 IU/mL (Inactive carrier)		 Week 7 ALT 64
HBV DNA 26,194 IU/mL		 Isolated increase in HBV DNA
Week 11 HBV DNA 132,712 IU/mL (treated with ETV)
9 Balagopal et al. 48 Female Not reported Not reported Sofosbuvir + Ledipasvir HBsAg(+)
HBV DNA not detected (Inactive carrier)		 Week 4
Week 8
Week 12		 HBV DNA 96 IU/mL
HBV DNA 303 IU/mL (peaked at week 8)
HBV DNA undetectable by week 12 (no treatment required)		 Isolated increase in HBV DNA
10 FAERS 58 Male 1a Not reported Daclatasvir + Sofosbuvir + RBV HBsAg(+)
HBeAg(−)
HBV DNA 92 IU/mL (Inactive carrier)		 ~Week 6–8 ALT 57
HBV DNA 10,900 IU/mL (treated with TDF)		 Isolated increase in HBV DNA
11 FAERS 79 Female 1b Not reported Daclatasvir + Asunaprevir HBsAg(+)
HBeAg(−)
HBV DNA <2.1 log copies/mL (Inactive carrier)		 Not reported HBV DNA 3.0 log copies/mL
ALT normal		 Isolated increase in HBV DNA
12 FAERS 57 Female 1b IFN+RBV Daclatasvir + Asunaprevir HBsAg(+)
HBeAg(−)
HBV DNA not detected (Inactive carrier)		 Not reported HBV DNA 2.4 log copies/mL Isolated increase in HBV DNA
13 FAERS 52 Female 1 Not reported Daclatasvir + Asunaprevir HBsAg(+)
HBeAg(−)
HBV DNA <2log copies/mL (Inactive carrier)		 Week 4 HBV DNA 3.9 log copies/mL Isolated increase in HBV DNA
14 † FAERS 57 Female Not reported Not reported Daclatasvir + Asunaprevir HBsAg (+)
HBeAg(−)
HBV DNA 3.9 log IU/mL (Inactive carrier) 		Week 8 ALT 2114
Bilirubin 13.2 mg/dL
Prothrombin 24%
HBV DNA 7.4 log copies/mL (Fulminant hepatic failure) (treated with ETV) 		Fulminant hepatic failure and death

  • Initially thought to be DILI -commenced Ursodeoxycholic acid, methylprednisolone pulse with weaning high dose prednisolone

  • Complicated by multiorgan failure and sepsis leading to death
15 FAERS 71 Female 1 IFN+RBV Daclatasvir + Asunaprevir HBsAg(+)
HBeAg not reported
HBV DNA <2.1 log copies/mL (Inactive carrier)		 Week 12 HBV DNA 4.1 log copies/mL Isolated increase in HBV DNA
16 † FAERS 73 Female Not reported Naïve Daclatasvir + Asunaprevir HBsAg(+)
HBeAg not reported
HBV DNA not detected on ETV (Treated HBV) 		Week 7 ALT 462
Bilirubin 2.5 mg/dL (DAAs ceased) 		Fulminant hepatic failure and death - Patient elected to ceased ETV prior to commencing DAA therapy against the advice of the treating physician
Week 7–8 ALT 2461
Bilirubin 19.5 mg/dL
HBV DNA 8.4 log copies/mL (HBV DNA
undetectable 17 days prior)
Died from multiorgan failure
17 FAERS 36 Male Not reported Not reported Sofosbuvir + Ledipasvir HBsAg(−)
Anti-HBc(+)
HBV DNA <LLD (Inactive carrier)		 Week 3 ALT 381
Fever 38°C with lung infiltrates on CT scan
Diagnosed with influenza
Ceased DAAs at week 4
Restarted DAAs 1 week later		 Moderate HBV flare without jaundice
Week 6 HBV DNA 2.4 log copies/mL
ALT normal
18 FAERS 44 Female Not reported IFN Sofosbuvir + Ledipasvir HBsAg(+)
HNeAg not reported
HBV DNA 3.6 log copies/mL (Inactive carrier)		 Week 8
Week 9		 ALT 84
ALT 552
HBV DNA 9.0 log copies/mL
ALT 1417		 Moderate HBV flare without jaundice
19 FAERS 53 Female 1 Not reported Sofosbuvir + RBV HBsAg(+)
HBeAg(−)
HBV DNA <2.1 log copies/mL (Inactive carrier)		 Week 10 HBV DNA 3.2 log copies/mL Isolated increase in HBV DNA
20 FAERS 49 Female 1b Not reported Daclatasvir + Asunaprevir HBsAg(+)
HBeAg(−)
HBV DNA 2.7 log copies/mL (Inactive carrier)		 Week 2
Week 4
Week 8
Week 9–10		 HBV DNA 4.1 log copies/mL
HBV DNA 5.4 log copies/mL
HBV DNA 7.9 log copies/mL
HBV DNA 8.5 log copies/mL
ALT 523 (treated with ETV)		 Mild HBV flare
21 FAERS 78 Female Not reported Not reported Sofosbuvir + Ledipasvir HBsAg(+)
HBeAg(−)
HBV DNA 2.1 log copies/mL (Inactive carrier)		 Week 9 ALT 61
HBV DNA 3.5 log copies/mL (peak)		 Mild HBV flare
22 FAERS 78 Male Not reported Not reported Sofosbuvir + Ledipasvir HBsAg(+)
HBV DNA Not reported (Unable to characterize)		 Week 4
Week 8		 HBV DNA 3.3 log copies/mL
HBV DNA 5.2 log copies/mL (peak)		 Isolated increase in HBV DNA
23 FAERS 69 Male Not reported IFN+RBV Daclatasvir + Asunaprevir HBsAg(+)
HBeAg not reported
HBV DNA not detected (Inactive carrier)		 Week 6 HBV DNA 5.0 log copies/mL (peak) Isolated increase in HBV DNA
24 FAERS 63 Male Not reported Not reported Daclatasvir + Asunaprevir HBsAg not reported
HBeAg(−)
HBV DNA 3.3 log copies/mL (Inactive carrier)		 Week 4–8 HBV DNA 4.7 log copies/mL Isolated increase in HBV DNA
Additional cases of HBV reactivation published in the literature
1 Takayama et al. 69 Male 1b Not reported Daclatasvir + Asunaprevir HBsAg(+)
HBeAg(−)
HBV DNA 2.5 log copies/mL (Inactive carrier)		 Week 6 HBV DNA 7 log copies/mL (treated with ETV) Isolated increase in HBV DNA
2 Ou et al. 53 Male 1b IFN+RBV Sofosbuvir + Ledipasvir HBsAg(+)
HBeAg not reported
HBV DNA not detected (Inactive carrier) 		Week 12 HBV DNA 82,600,000 IU/mL
ALT 779
Bilirubin 90.8 μmol/L (treated with ETV)		 HBV flare with jaundice
3–5 Wang et al. Cohort of 327 patients with HCV treated with DAAs in highly endemic HBV region. A total of 10 patients were coinfected with HBV (HBsAg(+)) and a further 124 patients had occult HBV (HBsAg(−) with detectable HBV DNA). 30% of the HBsAg(+) patients were found to have reactivation of HBV (not defined in the manuscript). No patient with occult HBV was noted to have HBV reactivation.
*

= This regimen includes interferon and ribavirin

†

= Significant outcome from HBV reactivation

IFN = Interferon

RBV = Ribavirin

TDF = Tenofovir

ETV = Entecavir

ALT = Alanine aminotransferase

IU = International units