Potent antiviral therapy improves survival in acute on chronic liver failure due to hepatitis B virus reactivation

Table 1 Risk factors and causes of reactivation of chronic hepatitis B

Causes of HBV reactivation	Risk factors
	Male sex
Cancer chemotherapy	Genotypes B and D
Immunosuppressants	Pre-core and core promoter mutations
Corticosteroid withdrawal	Elevated ALT at presentation
Interferon therapy
Hepatitis A/E virus superinfection
Hepatitis C virus superinfection
Hepatitis delta virus superinfection/co-infection
Interaction with HIV infection
Effect of immune reconstitution therapy

Modified from Jindal et al. Liver International (2011).

Table 2 Factors to differentiate severe acute exacerbation of chronic hepatitis B from acute hepatitis B

Parameters		AVH-B	HBV-R
IgM anti-HBc	> 600 Paul Ehrlich units/mL	Yes	Yes
		(7 s and 8 s forms)	(19 s form)
	> 1:1000 titer	Yes	No
HBV DNA	> 2.25 × 104/mL	No	Yes
	(121 000 copies/mL)
	Liver biopsy: evidence of chronic hepatitis such as lymphocytic portal inflammation with interface hepatitis, spotty lobular inflammation, portal expansion, periportal fibrous strands, bridging fibrosis, and/or cirrhosis			No	Yes
Basal core promoter mutation		No	Yes
Pre-core stop codon mutation		No	Yes

Jindal et al. Management of acute hepatitis B and reactivation of hepatitis B. Liver International 2013. HBV: Hepatitis B virus.

Table 3 Independent prognostic factors for mortality (and liver transplantation) in severe acute exacerbation of chronic hepatitis B[22]

Parameters	Chan et al[40] 2002, J Viral Hepatol	Yuen et al[19] 2003, Clin Infect Dis	Chien et al[49] 2003, J Hepatol	Tsubota et al[45] 2005, J Gastroenterol Hepatol	Kumar et al[38] 2006, Dig Dis Sci
Age	N/A	N/A	N/A	N/A	N/A
Sex	N/A	N/A	N/A	N/A	N/A
Albumin	N/A	N/A	Low	N/A	N/A
Bilirubin	High	High	High	High	High
Prothrombin Time	N/A	Prolonged	Prolonged	Prolonged	Prolonged
ALT	N/A	N/A	N/A	N/A	High
Platelet count	Low	Low	Low	N/A	Not studied
HBeAg	N/A	N/A	N/A	N/A	High
HBV DNA	Not studied	N/A	N/A	N/A	High
Creatinine	N/A	N/A	N/A	Not studied	Not studied
AFP	Not studied	N/A	N/A	N/A	Not studied
Cirrhosis	Not studied	Present	N/A	Present	Not studied
Ascites	Not studied	Not studied	Present	N/A	Not studied
CTP	Not studied	Not studied	High	High	Not studied

AFP: α-fetoprotein; N/A: Not applicable; HBeAg: Hepatitis B e antigen; ALT: Alanine aminotransferase; HBV: Hepatitis B virus; CTP: Child-Turcotte-Pugh.

Table 4 Studies that have provided long-term data on lamivudine treatment for severe acute exacerbation of chronic hepatitis B

Characteristics	Chan et al[40] 2002, J Viral Heapt	Wong et al[25] 2009, J Gastroenterol Hepatol	Tsubota et al[45] 2005, J Gastroenterol Hepatol	Kumar et al[38] 2006, Dig Dis Sci
Location	Hong Kong	Hong Kong	Japan	India
Follow up	2.5	2.8	2.9	1.5
(median, yr)
ALT (median, IU/L)	1758	1325	816	1658
Bilirubin (median, mg/dL)	31.6	19.6	14.4	10.1
PT/INR (median)	1.63	1.60	1.58	2.0
HBeAg +ve (%)	0	100	70	83
HBV DNA (median, log copies/mL)	6.76	8.08	8.69	5.135
SVR	21/26	21/29	18/21	21/31

SVR defined by Chan and Wong as < 10000 copies/mL; Tsubota as undetectable by bDNa assay (Chiron) and by Kumar as < 600 copies/mL. SVR: Sustained virological response.

Table 5 Summary of older studies that dealt with role of entecavir and entacavir vs lamivudine in patients of hepatitis B virus-related acute on chronic liver failure[52-55]

Study	Patient No.	Drug used (no. of patients treated)	Clinical implications	Salient features	Conclusion
Chen et al[53]	55	Entecavir	ALT, albumin, bilirubin, PT; no significant change between groups	No difference in mortality rates below 3 mo and after 3 mo, MELD not affected between groups	Short-term suppression of HBV replication offers no benefit on survival
Wong et al[56]	124	Entecavir	Treatment achieved	Tongji prognostic predictor model is better than MELD in prognostication in HBV-ACLF	Entecavir prevents disease progression and increases the
			< 3 logs HBV DNA; significantly higher survival rate; prevention of liver or renal dysfunction		survival of patients with HBV-ACLF
Shouval et al[61]	36 vs 117	Entecavir (36); Lamivudine (117)	Prolonged jaundice, encephalopathy, ascites in Entecavir group	More liver-related mortality in entecavir group, faster virological response	Short-term mortality high in entecavir group, but faster reduction in viral load
Cui et al[58]	33/34/37	Entecavir (33); lamivudine (34); placebo (37)	Liver function and MELD scores did not improve significantly	No significant difference in 3-mo survival was observed, levels of HBV DNA and rates of recurrence of HBV-associated ACLF were lower	Nucleoside analog treatment did not improve the short-term prognosis of patients with HBV-associated ACLF although it was efficacious and safe in the management of HBV DNA levels
Imamura et al[20]	34	Entecavir and lamivudine consecutively	No reduction of < 1 log IU/mL in HBV DNA after 1 or 3 mo of treatment. Initial virological response, with lamivudine and entecavir, respectively, was 83.3% and 100%	Twelve months after treatment, 41.6% of 24 lamivudine group patients switched to another drug or added adefovir to their treatment due to the emergence of lamivudine-resistant mutants	Entecavir appears to be as effective as lamivudine in the treatment of patients with acute exacerbation of chronic hepatitis B

HBV: Hepatitis B virus; ACLF: Acute on chronic liver failure.

Table 6 Important studies on antiviral therapy in hepatitis-B-related acute on chronic liver failure

Ref.	Country	Study design	Drugs/dose	No of patients treated	End events	Follow up	Remarks
Yang et al[79]	China	RCT	Entecavir (0.5 mg)	55	Liver function, HBV DNA	1 mo	Useful
Sun et al[50]	China	Retrospective cohort	LAM (100 mg)	130	Mortality, DNA, YMDD mutation	3 mo	Not useful
Qiu et al[80]	China	RCT	Telbivudine (600 mg)	30	Liver function, HBV DNA	1 mo	Useful
Cui et al[58]	China	Retrospective cohort	LAM (100 mg) or EVT (0.5 mg)	67 (LAM) vs EVT (37)	Mortality, MELD, HBV DNA, recurrence	12 mo	Similar
Zhang et al[72]	China	Observational study	LAM (100 mg) plus Dexamethasone (10 mg/d, 5 d)	56	Liver function, MELD, Survival	1 mo	Useful
Garg et al[62]	India	RCT	Tenofovir (300 mg) vs placebo	14 vs 27	Mortality, MELD, HBV DNA	3 mo	Useful
Chen et al[60]	China	Retrospective cohort	LAM (100 mg) or EVT (0.5 mg)	72 (LAM) vs 34 (EVT)	Mortality, recurrence, HBV DNA, YMDD mutation	7 mo	Similar
Chen et al[47]	China	RCT	LAM (100 mg) or EVT (0.5 mg)	42(EVT) vs 30(LAM)	HBV DNA, YMDD mutation, MELD Na	7 mo	Evt more useful
Qin et al[81]	China	RCT	Telbivudine (600 mg)	12	Mortality, liver function, HBV DNA	3 mo	Useful in renal dysfunction
Lai et al[54]	China	RCT	LAM (100 mg) or EVT (0.5 mg)	93(EVT) vs 89(LAM)	HBV DNA, MELD, HBeAg -ve	3 mo	Evt useful
Chen et al[82]	China	RCT	Entecavir (0.5 mg) plus Dexamethasone (10 mg/d, 3 d)	31	Liver function, MELD, Mortality	3 mo	Useful

HBV: Hepatitis B virus.