Future prospectives for the management of chronic hepatitis B

Table 1 Baseline factors influencing likelihood of response to antiviral therapy

Treatment	Increased likelihood of response	Decreased likelihood of response
(PEG) interferon	Baseline ALT > 2 ULN[28,145,146]	Baseline ALAT < 2 ULN[28,145,146]
	Baseline HBV DNA < 109 c/mL[4,28]	Baseline HBV DNA > 109 c/mL[4,28]
	Genotype A or B	Genotype C or D
	Longer treatment duration[33-35,147]
Nucleoside/nucleotide analogues	Baseline serum aminotransferases > 2 ULN[148,149]	Baseline serum aminotransferases < 2[148,149]
	Baseline HBV DNA < 109 c/mL[148]	Baseline HBV DNA > 109 c/mL[148]

ULN: Upper limit of normal; c/p = copies/mL.

Table 2 Treatment outcomes after 1 year of treatment for different antiviral drugs for the management of chronic hepatitis B

	Author; Journal; Year	HBeAgloss (%)	HBeAg seroconversion(%)	HBsAgloss (%)	Decline viral load (log10 copies/mL)	HBV DNAnegativity(%)	ALT normalisation (%)	Histological improvement (%)	Resistance (%)
HBeAg pos
PEG-IFN-α 2a	Cooksley; J. Viral Hepatitis; 2003[18]	35	33			399	35
PEG-IFN-α 2a	Lau: NEJM; 2005[4]	34	32	312	2.4	144	41	49
PEG-IFN-α 2b	Janssen; Lancet; 2005[3]	36	29	7	2.3	74	32	5310
Lamivudine	Chang; NEJM; 2006[13]	20	18	1	5.4	362	60	62	13
Lamivudine	Alexander; BMC Gastroenter; 2005[150]	42	28				56		10
Lamivudine	Chan; Ann Intern Med; 2005[151]	28	28	0	2.74	101	78	5911	40
Lamivudine	Yao; Hepatobil Pancr Dis Int; 2004[152]	10	8			36	72		12
Lamivudine	Jonas; NEJM; 2002[153]	26		2		616	55		19
Lamivudine	Mazur; Med Sci Monit; 2002[154]	49	44	5		378	56
Lamivudine	Barbaro; J Hepatol: 2001[155]		19	0			23	2710	16
Lamivudine	Dienstag; NEJM 1999[47]	32	17	2		447	41	5210	32
Lamivudine	Gane; J Hepatol; 2006[63]	23	21		5.5	402	75	56	8
Adefovir	Marcelin; NEJM; 2003[16]	24	12		3.6	214	48	53	0
Adefovir	Lee; Hepatology; 2006[102]	14			4.0	295	79		0
Adefovir15	Zheng; Hepatology; 2006[124]	13	8	0	4.5	282	79		0
Adefovir	Bzowej; Hepatology; 2006[65]	20	18		5.7	392	81		2
Entecavir	Chang; NEJM; 2006[13]	22	21	2	6.9	672	68	72	0
Telbivudine	Gane; J Hepatol; 2006[63]	26	22		6.5	602	77	65	3
Telbivudine	Bzowej; Hepatology; 2006[65]	31	27		6.6	582	77		4
HBeAg neg
PEG-IFN-α 2a	Marcellin; NEJM; 2004[5]			4	2.3	194	59	59
Lamivudine	Marcellin; NEJM; 2004[5]			0	4.2	734	73	5814	41
Lamivudine	Lai; NEJM; 2006[15]			0	4.5	722	71	61	6
Lamivudine	Lai; NEJM; 1999		16	0			72	5610	14
Adefovir	Hadzyannis; NEJM; 2003[14]				3.9	514	72	64	0
Entecavir	Lai; NEJM; 2006[15]			0	5.0	902	78	70	0
Mixed
Lamivudine	Ooga; J Gastroenterology; 2004[156]					785	78		16
Lamivudine	Suzuki; Intervirology; 2003[108]	42	28	0		886	86
Lamivudine	Yao; J Hepatology; 2006[64]		18		4.3	432	78
Entecavir	Yao; J Hepatology; 2006[64]		15		5.9	762	90

Although conventional interferon-α is widely used for the treatment of HBV it is not listed as this treatment will be replaced by PEG-interferon-α in the near future. Efficacy measures for PEG-interferon presented are off-treatment responses after 24 wk of follow-up. Studies are organised by HBeAg status and the mixed studies included both HBeAg positive as HBeAg negative patients.

¹LLD 200 copies/mL;

²LLD 300 copies/mL; ³LLD 366 copies/mL;

⁴400 copies/mL;

⁵5.0 × 10³ copies/mL;

⁶7.0 × 10⁵ copies/mL;

⁷1.0 × 10⁶ copies/mL;

⁸1.4 × 10⁶ copies/mL;

⁹5.0 × 10⁶ copies/mL;

¹⁰only improvement of ≥ 2 points in necroinflammation according to Ishak,

¹¹only improvement of ≥ 2 points in necroinflammation according to Knodell,

¹²HBsAg seroconversion, ¹³treatment duration 24 wk,

¹⁴After 24 wk of follow-up, Lamivudine study performed in children,

¹⁵Includes some lamivudine resistant patients.

Table 3 Response to interferon-α or PEG-interferon-α after having failed a prior course of interferon or response to interferon-α or PEG-interferon-α after having failed a prior course of lamivudine

Author; Journal; Year	Treatment regimen	Pretreatment HBeAg status (n)	HBeAg loss	HBeAg seroconversion (%)	HBV DNA loss (%)	ALT normalisation (%)
Janssen; J Hepatology; 1993[157]	IFN 1.5 MU daily for 4 wk followed by 3 MU daily for 8 wk and then 5 MU daily for 4 wk	Positive (18)		11	17
Carreno; Hepatology; 1999[158]	IFN 9 MU thrice weekly for 24 wk	Positive (27)	41	22	445	22
Munoz; J Hepatology; 2002[159]	IFN 6 MU 5 times weekly for 24 wk	Positive (11)		18	181	18
Munoz; J Hepatology; 2002[159]	IFN 6 MU 5 times weekly for 24 wk	Negative (18)			221	44
Ballauff; Eur J Pediatr;[160]	IFN 5-9 MU/m2 thrice weekly for 16-24 wk	Positive (15)		33	334
Teuber; Z Gastroenterol; 1995[161]		Positive (27)		30	59
Flink; Hepatology; 2004[162]	PEG-IFN-α 2b 100 μg/wk for 32 wk followed by 50 μg/wk for 20 wk	Positive (18)	28		02	22
Lau; J Hepatology; 2005[163]	PEG-IFN-α 2a for 48 wk	Positive (30)		43
Prev lamivudine
Flink; Hepatology; 2004[162]	PEG-IFN-α 2b 100 μg/wk for 32 wk followed by 50 μg/wk for 20 wk	Positive (8)	50		02	47
Lau; J Hepatology; 2005[163]	PEG-IFN-α 2a 180 μg/wk for 48 wk	Positive (31)		32
Marcellin; J Hepatology; 2006[164]	PEG-IFN-α 2a 90-180 μg/wk for median 48 wk	Positive (71)	376	326	4736	51
Marcellin; J Hepatology; 2006[164]	PEG-IFN-α 2a 90-180 μg/wk for median 48 wk	Negative (36)			6736	52

¹LLD 200 copies/mL;

²LLD 400 copies/mL;

³LLD 1.0 × 10⁴ copies/mL;

⁴LLD 4.25 × 10⁵ copies/mL;

⁵LLD 4.81 × 10⁵ copies/mL;

⁶on-treatment responses.

Table 4 Treatment outcomes after 1 year of treatment for different antiviral drugs for the management of lamivudine resistant chronic hepatitis B for both HBeAg positive and HBeAg negative patients

	n	Author; Journal; Yr	HbeAg loss (%)	HBeAg serocon-version(%)	HbsAg loss (%)	Decline viralload (log10 copies/mL)	HBV DNA negativity (%)	ALT normalisation (%)	Histological improvement(%)	Resistance (%)
HBeAg pos
PEG-IFN-α 2b	16	Leemans; J Hepatology; 2006[38]	13	13	6	0.6	64	19
Adefovir	45	Buti; Hepatology; 2004[165]		13	0		337	51
Adefovir	19	Peters; Gastroenterology; 2004[118]	16	11		4.0	265	47		0
HBeAg neg
PEG-IFN-α 2b	20	Vassiliadis; WJG; 2006[39]					54	10
Adefovir	75	Buti; Hepatology; 2004[165]			0		517	63
Adefovir	20	Manilakopoulos; Hepatology; 2005[119]				3.3		72		5
Adefovir + lamivudine	44	Manilakopoulos; Hepatol; 2005[119]				3.3		87		0
Adefovir	26	Koskinas; J Hepatology; 2005[166]				2.5		92		4
Adefovir + lamivudine	74	Lampertico; Hepatology; 2005[167]					786	82		0
Adefovir + lamivudine	23	Koskinas; J Hepatology; 2006[166]				2.8		87		0
Adefovir + lamivudine	49	Vassiliadis; AP&T; 2005[168]			0	6.5	574	75
Mixed
Adefovir	18	van Bömmel; Hepatology; 2004[17]	19		0	2.8	444
Adefovir + lamivudine	20	Peters; Gastroenterology; 2004[118]	17	6		3.6	355	53		0
Adefovir	57	Lee; Hepatology; 2006[102]	20			2.4	193	60		18
Adefovir + lamivudine	46	Perrillo; Gastroenterology; 2004[61]	15	8	0	4.6	201	30
Adefovir ± lamivudine11	126	Schiff; Hepatology; 2003[59]				4.1	814	76		0
Adefovir + lamivudine	34	Moriconi; J Hepatology; 2006[169]					681
Adefovir ± lamivudine	65	Hann; J Hepatology; 2006[132]	710			2.4	215
Entecavir	42	Chang; Gastroenterology; 2005[170]	11	4		5.6	264	68		0
Entecavir	141	Sherman; Gastroenterology; 2006[129]	10	11		5.1	272	61	55	7
Entecavir	42	Karino; J Hepatology; 2006[171]		15		3.8	604	78	60	0
Entecavir	116	Yao; J Hepatology; 2006[172]	8	6		5.8	272	85
Tenofovir ± lamivudine9	35	van Bömmel; Hepatology; 2004[17]				5.5	1004			0
Tenofovir ± lamivudine	44	Hann; J Hepatology; 2006[132]	410			5.0	865
Tenofovir + lamivudine9	11	Van der Eijk; J Viral Hepatitis; 2005[173]	10	0	0	5.0		91
Tenofovir9	10	Dore; J Infect Dis; 2004[174]	20	10		4.9		25
Tenofovir9	12	Núñez; Aids; 2002[175]		11	8	3.8	581
Tenofovir9	20	Nelson; Aids; 2003[176]		25		4.0
Tenofovir9	12	Benhamou; NEJM; 2003[177]	0	0	0	3.8

Efficacy measures presented are off-treatment responses for PEG-interferon and on-treatment responses for nucleos(t)ide analogues.

¹LLD 200 copies/mL;

²LLD 300 copies/mL;

³LLD 366 copies/mL;

⁴LLD 400 copies/mL;

⁵LLD 1.0 × 10³ copies/mL;

⁶LLD 2.0 × 10³ copies/mL ;

⁷LLD 1.0 × 10⁵ copies/mL; ⁸results after 24 wk of treatment;

⁹including HIV/HBV co-infected patients ± some patients with, some patients without combination therapy;

¹⁰after 24 mo of treatment;

¹¹patients with decompensated cirrhosis.