Current clinical evidence for nucleos(t)ide analogues in patients with HBV-related hepatocellular carcinoma

Figures & data

Figure 1. Current steps in the management of HBV-related HCC.

Table 1. Studies of pre-transplant anti-HBV treatment.

Study	Study type	Patient population	Treatment	N	Follow-up duration	Clinical improvement measure	Clinical improvement results	Virologic breakthrough	Survival
Schiff [23]	Prospective open-label	LAM-resistant HBV waitlisted for LT	ADV monotherapy	N: 226 (pre-LT)	39 weeks (median follow-up duration)	Mean change in HBV DNA from baseline at 48 weeks Undetectable HBV DNA levels at 48 weeks	–3.5 (log10 copies/ml) in ADV pts 59% in those with detectable HBV DNA at baseline	Not applicable	82.3% of pre-LT pts survived at end of study
Hou [24]	Double-blind RCT	Compensated HBeAg +ve or –ve CHB pts	LdT vs LAM	N: 332 HBeAg ±ve LdT: 147 LAM:143 HBeAg – ve LdT: 20 LAM: 22	52 weeks	Mean change in HBV DNA from baseline at 52 weeks Undetectable HBV DNA levels at 52 weeks	HBeAg ±ve –6.3 LdT vs – 5.5 LAM (P < 0.001) HBeAg -ve –5.5 LdT vs – 4.8 LAM (P = NS) HBeAg ±ve 67% LdT vs 38% LAM (P < 0.001) HBeAg -ve 85% LdT vs 77% LAM (P = NS)	HBeAg ±ve 7.5% LdT vs 17.5% LAM (P = 0.009) HBeAg -ve 0% LdT vs 4.5% LAM (P = NS)	Not applicable
Lai [25]	Double-blind RCT	HBeAg +ve or –ve CHB pts	LdT vs LAM	N: 1367 LdT: 680 LAM: 687	52 weeks	Mean change in HBV DNA from baseline at 52 weeks Undetectable HBV DNA levels at 52 weeks	HBeAg ±ve –6.5 LdT vs – 5.5 LAM (P < 0.001) HBeAg -ve –5.2 LdT vs – 4.4 LAM (P < 0.001) HBeAg ±ve 60% LdT vs 40% LAM (P < 0.001) HBeAg -ve 88% LdT vs 71% LAM (P < 0.001)	HBeAg ±ve 5.9% LdT vs 15.3% LAM (P < 0.001) HBeAg -ve 2.3% LdT vs 12.5% LAM (P < 0.001)	Not applicable
Chan [26]	Double-blind RCT	Tx naïvedecompensated CHB pts	LdT vs LAM	N: 232 LdT: 116 LAM: 116	52 weeks	Composite of serum HBV DNA <10 000 copies/mL, normal serum ALT level and improvement in or stabilization of CTP	56.2% LdT vs 54.0% LAM (P = 0.74) at wk 52 39.1% LdT vs 36.4% LAM (P = 0.67) at wk 104	Not available	94% LdT vs 88% LAM at wk 52 87% LdT vs 79% LAM at wk 104
Chang [15]	Double-blind RCT	NA-naïveHBeAg +ve compensated CHB pts	ETV vs LAM	N: 709 ETV: 354 LAM: 355	48 weeks	2pt improvement in Knodell necroinflammatory score with no worsening in Knodell fibrosis score Mean change in HBV DNA from baseline at 48 weeks Undetectable HBV DNA levels at 48 weeks	72% ETV vs 62% LAM (P = 0.009) –6.9 ETV vs – 5.4 LAM (P < 0.001) 67% ETV vs 36% LAM (P < 0.001)	Not applicable	100% ETV vs 99.4% LAM (P = 0.5)
Lai [27]	Double-blind RCT	NA-naïve HBeAg -ve compensated CHB pts	ETV vs LAM	N: 638 ETV: 325 LAM: 313	48 weeks	2pt improvement in Knodell necroinflammatory score with no worsening in Knodell fibrosis score Mean change in HBV DNA from baseline at 48 weeks Undetectable HBV DNA levels at 48 weeks and ALT< 1.25xULN	70% ETV vs 61% LAM (P < 0.001) –5.1 ETV vs – 0.5 LAM (P < 0.001) 55% ETV vs 4% LAM (P < 0.001)	2% ETV vs 8% LAM	99.4% ETV vs 100% LAM (P = 0.5)
Sherman [28]	Double-blind RCT	LAM-refractory HBeAg +ve pts	ETV vs LAM	N: 286 ETV: 141 LAM: 145	48 weeks	2pt improvement in Knodell necroinflammatory score with no worsening in Knodell fibrosis score Mean change in HBV DNA from baseline at 48 weeks Undetectable HBV DNA levels at 48 weeks	68% ETV vs 32% LAM (P = 0.01) –5.0 ETV vs – 4.5 LAM (P < 0.001) 90% ETV vs 72% LAM (P < 0.001)	Not applicable	99.3% ETV vs 98.6% LAM

Table 2. Studies of post-transplant anti-HBV treatment.

Study	Study type	Treatment	N	Follow-up duration	Virologic breakthrough	HBV recurrence	Survival
Ahn [43]	Retrospective chart review	NA + HBIg vs NA mono	N: 28 NA +HBIg16 NA mono: 12	16.8 months (median follow-up duration post-LT in group 1)	Not applicable	HBV recurrence in 14% of pts(all noncompliant, 3 in HBIG+NA, 1 in NA mono)	No differences in survival
Fung [44]	Prospectiveobservational	HBsAg +ve pts treated with ETV as primary prophylaxis for prevention of HBV recurrence	N: 80 (all HBsAg positive)	26 months (median follow-up duration post-transplant)	10 pts had reappearance of HBsAg; 0 pts had evidence of virologic breakthrough	94% had undetectable levels of HBV DNA (<35 copies/mL) at the last follow-up	No HBV-related mortality in the total cohort
Cholongitas [45]	Prospective observational	Withdrawal of HBIg in stable pts who had been under HBIg+NA (at least 12 months) therapy after LT	N: 47 LAM+ADV: 23 LAM+TDF: 5 TDF: 10 ETV: 9	24 months (median follow-up duration post-HBIg withdrawal)	All pts had undetectable HBV DNA levels	No reported HBV recurrence	No HBV-related mortality was reported
Perrillo [46]	Prospective Open-label trial	ETV combined with various HBIg regimens after CHB-related LT	N: 65 Evaluated: 61 (received at least 4 weeks of ETV treatment) Completed treatment: 55	Follow-up duration was 72 weeks	100% evaluated pts had undetectable HBV DNA 3% of pts had nonviremic HBsAg recurrence	0% reported virologic recurrence	1/61 pts died due to HCC recurrence with metastasis
Tanaka [47]	Retrospective chart review	TDF (± LAM) and one year of HBIg	N: 24 TDF + HBIg: 15 TDF+LAM+HBIg: 9	29.1 months (median post-LT follow-up duration)	Undetectable HBsAg and HBV DNA levels during follow-up period	No recurrent HBV infection reported in median follow-up period	Three deaths (12.5%) during follow-up period Over all patient survival post-LT: Year 1: 100%; Year 5: 84.1%
Ueda [48]	Retrospective chart review	Tx group: ETV + HBIg Control: LAM + HBIg	N: 89 Tx group: 26 Control: 63	Median follow-up: Tx group: 25.1 months Control: 70.6 months	Not applicable	No HBV recurrence with ETV during median follow-up HBV recurrence rates in control pts: Year 1: 2%; Year 3: 4%; Year 5: 6%	Survival rates of ETV pts were 73% at both 1 and 3 years Survival rates of control: Year 1: 81%; Year 3: 78%
Gao [49]	Retrospective chart review	Low-dose HBIg plus LAM or ETV	N: 253 LAM + HBIg: 169 ETV + HBIg: 84	Mean txduration: LAM group: 61.8 ± 18.3 months ETV group: 57.1 ± 15.9 months	Not available	No HBV recurrence reported in the ETV group HBV recurrence rate of 9.46% in the LAM group	There was no significant difference in the survival rate between the two groups
Kim [50]	Retrospective chart review	ETV + HBIg post-LT	N: 154	28.0 months (median follow-up duration)	Not available	3.2% Post-LT HBV recurrence post-LT pts 0% ETV resistant mutants Overall rates of HBV recurrence: Year 1: 0.6%; Year 2: 1.6%; Year 4: 6.2%	Not available
Lee [51]	Retrospective chart review	HBIg ± ETV	N: 667	51.0 months (median follow-up duration)	Median time to HBV recurrence was 22 months	11.4% HBV recurrence at 51 months	54.2% survival at 10 years in pts with HBV recurrence

Figure 2. Post-transplant treatment options for the prevention of HBV recurrence.

X: negative impact; ?: unclear impact; ✓: positive impact; HBV: hepatits B virus; HBIg: hepatitis B immune globulin; NA: nucleos(t)ide analogue; LAM: lamivudine; ETV: entecavir; TDF: tenofovir disoproxilfumarate; IM: intramuscular.

Table 3. Recurrence of HCC. Risk factors and survival rates.

Study	Patient population	Treatment	N	Identified risk factor(s) for HCC recurrence	Follow-up duration	HCC recurrence	Survival
Hung [6]	Liver resection for HBV-related HCC	Not applicable	N: 72 Tumor recurrence: 30 No tumor recurrence: 42	HBV viral load >2,000 IU/mL (4 log10 copies/mL) (P = 0.001) α-fetoprotein (AFP) level >1,000 ng/mL (P = 0.02) Tumor size >5 cm (P = 0.02) Age >60 yrs (P = 0.01)	18.9 months (median)	42% recurrence Median time to recurrence: 7.3 months	7 deaths due to HCC recurrence (23.2%) 100% of patients in the non-recurrence (n = 42) group survived (P = 0.001)
Kuzuya [70]	Resection or radiofrequency ablation for HBV-related HCC	Tx group: LAM therapy Control: No LAM therapy	N: 49 LAM group: 16 Control: 33	Not available	Not available	Cumulative HCC recurrence rates did not differ significantly between the two groups (P = 0.622)	Cumulative survival rates of LAM patients were higher than those in the control group (P = 0.063)
Someya [71]	Cirrhotic patients receiving ablation for HBV-related HCC		N: 80 Abnormal AST: 38 (6 received IFN) Normal AST: 42 (5 received IFN)	Not available	Not available	Tumor recurrence rates in treated and untreated patients with abnormal AST, respectively: Year 1: 16.7% and 37.9%; Year 2: 16.7% and 60.1%; Year 3: 16.7% and 83.4 (P = 0.0139)	Not available
Chan [72]	Hepatectomy for HBV-related HCC	Tx group: NA therapy Control: No NA therapy	N: 136 Tx group: 42 (LAM: 38; ETV: 4) Control: 94	Not available	1 month after hepatectomy to confirm complete tumor clearance and then every 3 months for surveillance	Tumor recurrence developed in 48% of tx patients and 65% of control patients (P = 0.28)	Overall survival rates in in the tx group: Year 1: 88.1%; Year 3: 79.1%; Year 5: 71.2% Overall survival rates in in the tx group: Year 1: 66.5%; Year 3: 51.4%; Year 5: 51.4%
Wu [73]	Curative liver resection for HBV-related HCC	Tx group: NA therapy Control: No NA therapy	N: 4569 Tx group: 518 (LAM, ETV, LdT) Control: 4051	Liver cirrhosis was an independent risk factor for HCC recurrence (P < 0.001)	Median follow-up durations: Control group: 1.57 years Tx group: 2.18 years	HCC recurrence occurred in 43.6% of untreated patients and 20.5% of treated patients (P < 0.001)	Six year overall mortalities for tx patients were 29.0% and for untreated 42.4% (P < 0.001)
Lee [74]	NA-naïve and NA-experienced receiving radiofrequency ablation for HBV-related HCC.	Tx group: NA therapy Control: No NA therapy	N: 399 NA-treated: 133 Control: 266	Not available	Not available	2-year HCC recurrence rate of NA-treated vs control group: 41.8% vs 54.3%; P < 0.05)	Not available
Hann [75]	Local tumor ablation forNA-naïve HBV-related HCC	Tx group: NA therapy Control: No NA therapy	N: 25 Tx group: 16 Control: 9	Not available	Up to 12 years	HCC recurrence occurred in 100% of untreated patients and 18.8% (including residual tumor activity) of treated patients	Median survival: 80 months in Tx group vs 16 months in Control group (P = 0.001)
Piao [76]	Local tumor ablation or surgery for HBV-related HCC	Tx group: LAM therapy Control: No NA therapy	N: 70 Tx group: 30 Control: 40	Not available	Median follow-up: Tx group: 24 months Control group: 31 months	HCC recurrence: At 12 months: Tx group: 25% Control group: 42% At 24 months: Tx group: 54% Control group: 59%	Mortality rate: At 12 months: Tx group: 0% Control group: 8% At 24 months: Tx group: 9% Control group: 13%
Wu [69]	Liver resection for HBV-related HCC	Not applicable	N: 193 Tumor recurrence: 134 No tumor recurrence: 59	Early recurrence (<2 years) AFP >20ng/mL Cut margin ≤1cm Macroscopic venous invasion Multinodularity Late recurrence (≥2 years) HBV DNA >10^6 ICG-15 > 10% Ishak activity >6 Multinodularity	58.2 months (median)	49% early recurrence (<2 years) 69% total recurrence Median time to recurrence: 10 months	Risk factors associated with poor survival: Age > 60 years Microscopic venous invasion Performance status ≥1 AFP >20ng/mL Creatinine >1.5mg/dL Multinodularity
Kim [77]	Curative liver resection for HBV-related HCC	Not applicable	N: 157	Persistent detectable serum HBV DNA (P = 0.041)	35 months (median)	5-year cumulative recurrence: Persistent HBV DNA group: 72.9% No persistent HBV DNA group: 54.7% (P = 0.043)	Not available

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