Precore/core mutation relatedness to viral reactivation in patients undergoing targeted therapy for hepatitis B virus-related hepatocellular carcinoma

Table 1 Hepatitis B serologic testing involves measurement of several hepatitis B virus-specific antigens and antibodies. Different serologic markers or combinations of markers are used to identify different phases of hepatitis B virus infection and to determine whether a patient has acute or chronic hepatitis B virus infection, is immune to hepatitis B virus as a result of prior infection or vaccination, or is susceptible to infection

Test profile	HbsAg	Anti-HBs	Anti-HBc (total)	Anti-HBc (IgM only)	HBeAg	Anti- HBe	Interpretation
Acute, non-enteric or type unknown	-			-			Acute hepatitis A
	+			+			Acute hepatitis B1
	-			-			Acute or chronic hepatitis C with co-existing acute illness of other etiology2
	-			-			Consider early hepatitis C or hepatitis E, CMV, or EBV2
Chronic, type B screen	+		+		+	-	Chronic hepatitis B, active replicating virus1,3
	+		+		-	+	Chronic hepatitis B, non-replicating virus1,3
Chronic, type unknown	+	-	+	-			Chronic hepatitis B1,3
	-	-	-	NT			Chronic hepatitis C4
	-	-	-	NT			Consider non-viral causes of chronic hepatitis
	+	-	+	-			Chronic HBV and HCV co-infection1,3,4
	-	+	+	+	-		Chronic hepatitis C4 and exposure to HBV with recovery/immunity
HBV immunity screen		+					Immune to HBV
HAV immunity screen							Immune to HAV
Previous hepatitis exposure screen	-	-	-				Exposure to HAV with recovery/immunity
	-	-	-				Recent hepatitis A
	-	-	-				Exposure to HCV with recovery or chronicity
	+	-	-				Exposure to HBV, early infection, asymptomatic
	+	-	+	-			Hepatitis B, chronic or carrier state
	+	-	+	+			Acute hepatitis B1
	-	+/-	+	-			Exposure to HBV with recovery/immunity
	-	-	+	+			Early acute hepatitis B (core window)
	-	-	-				Consider non-viral causes of previous hepatitis

¹Consider hepatitis delta virus (delta) co-infection.

²Consider hepatitis E immunoglobulin M Ab test.

³Consider hepatitis B virus DNA test.

⁴Consider hepatitis C virus RNA test.

The presence of hepatitis B surface antigen (HBsAg) indicates that the person is infectious. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make hepatitis B vaccine. The presence of hepatitis B surface antibody is generally indicating recovery and immunity from hepatitis B virus (HBV) infection. Anti-hepatitis B surface also develops in a person who has been successfully vaccinated against hepatitis B. Total hepatitis B core antibody (anti-HBc): Appears at the onset of symptoms in acute hepatitis B and persists for life. The presence of anti-HBc indicates previous or ongoing infection with HBV in an undefined time frame. Immunoglobulin M antibody to hepatitis B core antigen (immunoglobulin M anti-HBc): Positivity indicates recent infection with HBV (< 6 months). Its presence indicates acute infection. HBsAg: Hepatitis B surface antigen, it can be detected in high levels in serum during acute or chronic hepatitis B virus infections; Anti-HBs: Hepatitis B surface antibody; Anti-HBc: Hepatitis B core antibody; IgM: Immunoglobulin M; HBeAg: Hepatitis B e antigen; Anti HBe: Hepatitis B e antibody; CMV: Cytomegalovirus; EBV: Epstein-Barr virus; NT: Not tested; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HAV: Hepatitis A virus.

Table 2 A summary of the identified and published hepatitis B virus mutations

Mutation	Effect	Mechanism
G1896A in precore	Affects early prognosis and severity of HCC	The study compared results between ultra-deep pyrosequencing and cloning based sequencing using HBeAg-positive and negative sera infected, with either genotype D or E
A1762T/G1764A double mutation	HBcAg mutations might increase the risk for HCC; affect early prognosis and severity of HCC; a factor that independently predicts worse survival rates after surgery	When combined with HBx mutants, they upregulate SKP2, which then down-regulates the cyclin kinase inhibitor p21 via ubiquitin-mediated proteasomal degradation. Eventually mRNA precore inhibition; upregulation of pgRNA transcription, and ultimately HCC
A1762T; 1753-1757 jointly with A1762T/G1764A; 1766T jointly with 1768A	HBeAg seroconversion, liver inflammation; FH, HCC, ALT; FH	-
1766T and 1768A; jointly with A1762T/G1764A	Recurrent hepatitis B post liver transplantation	-
T127P, P153 L, and F170S	In hemodialysis patients with occult HBV	Mutation in the precore/core and s regions results in undetectable s region
1915, 2134, 2221, 2245, 2288 in precore/core	Independent predictors of HCC survival	-
S87 and P156	Cancer recurrence	-
E77, P79, E83, L84, and S87 in core	Shorter survival times and increased viral activity. The S87 mutation could interfere with the assembly of the core	-
x/precore of HBV genotype D1, T1673/G1679, G1727, C1741, C1761, A1757/T1764/G1766, T1773, T1773/G1775 and C1909	A marker of HCC	-
G1896A; G1899A, T1846A, G1862C, G1888A, T1821C, C1826T, A1827C, A1850T precore start codon Kozak and G1951T, G1957A, genotype A1 and D	HBeAg-negative chronic; HBV infection and a more severe outcome	-
A2051C	Associated with increased viral replication both in vivo and in vitro	-
P5H/L/T, E83D, I97F/L, L100I, and Q182K/stop	More prevalent in chronic HBV and cirrhotic patients	Evading the host-immune system
The stop codon of W28*(G1896A), precore; S21, E40 and 1105; the epitope substitutions (117-131)	Identified to correlate with the development of the inactive carrier state. Higher in the cirrhotic/HCC group than in the inactive and the chronic active HBV groups	Evading the host-immune system
T1938C (V13A) with A2051C (N51H) in core	Those substitutions in the core correlated with HBV-related HCC and disease progression in Alaskan natives	-
YMDD mutation at codons 203-206 of the HBV RT	It targets the catalytic site of the HBV polymerase, specially at rtM204V/I	-
M204S substitution in the YMDD motif	HBV DNA accumulates, and relapse occurs	-

HCC: Hepatocellular carcinoma; HBeAg: Hepatitis B e antigen; HBcAg: Hepatitis B core antigen; FH: Fulminant hepatitis; ALT: Alanine aminotransferase; HBx: Hepatitis B virus X protein; SKP2: S-phase kinase-associated protein 2; pgRNA: Pregenomic RNA; HBV: Hepatitis B virus; RT: Reverse transcriptase.