The Natural History of Delta Hepatitis

Prof. Dr. Cihan YurdaydinUniversity of Ankara Medical SchoolGastroenterology Department

EASL Monothematic Conference onDELTA HEPATITISIstanbul, 24-26 September 2010

Delta Hepatitis

Early chimpanzee experiments disclosed:

Supression of HBV infection- Decline or disappearance of HBcAg in liver tissue- Decrease in HBsAg

Typical patient with delta hepatitis:- HBeAg-negative, HBeAb-positive- HBV DNA low- High HDV RNA

Hepatitis D > Hepatitis B

Hepatitis D = Hepatitis B

Hepatitis D < Hepatitis B

• Both viruses were active in 15 (40.5%) patients and inactive in 4 (10.8%)

• HDV alone was active in 12 (32.4%) and HBV in 6 (16.2%)

• Considerable fluctuating activity of one or both viruses, including alternating predominance

Schaper et al. J Hepatol 2010;

HBeAg-positive chronic delta hepatitis534 patients; 71/534 (13%) HBeAg (+)

Heidrich et al, AALD 2008

p <0.001 p <0.001 p <0.001

HBeAg-positive chronic delta hepatitis534 patients; 71/534 (13%) HBeAg (+)

Heidrich et al, AALD 2008

(%)

HBV-HDV co-infection

Europe 43/111 (39%) 101/532 (19%) <0.000001Smedile et al 1982

USA 24/71 (34%) 5/118 (4%) 0.000016Govindarajan et al 1984

Fulminant AcuteHepatitis B Hepatitis B p value

Proportion of patients with evidence of HDV in acute self limited vs. fulminant hepatitis B

Chronicity infrequent: 5/208 patients (2.4%) Caredda et al 1987

138 acute hepatitis D

23 acute superinfection115 acute co-infection

104 resolution(90%)

10 chronic hepatitis (8%)

Outcome of Acute Delta HepatitisButi et al, J Viral Hepat 2010 (in press)

23 chronichepatitis (100%)

Chronic delta hepatitis

1

4

3

2

55 10 10 15 15 Years Years

FIBR

OSI

SFI

BRO

SIS

NATURAL HISTORYNATURAL HISTORY

1977-1986 1987-1996n= 162 n= 122

Mild hepatitis 9 (6%) 9 (8%)Severe hepatitis 105 (65%) 21 (17%)Histologic cirrhosis 46 (28%) 38 (31%)Clinical cirrhosis 2 (1%) 54 (44%)

Changing pattern of chronic hepatitis D in Southern Europe

Rosina et al, Gastroenterology 1999

CLINICAL PRSENTATION OF CLINICAL PRSENTATION OF DELTA HEPATITIS IN THE 90’sDELTA HEPATITIS IN THE 90’s

0 1 2 3 4 5 6 7 8 9 10

Mild Hepatitis

Severe Hepatitis

Histologic Cirrhosis

Clinical Cirrhosis

Years

Rosina et al, Gastroenterology 1999

40

80

60

100

Surv

ival

(%)

Delta hepatitis and HCC

Early studies: infrequent association due to diminished life expectancy (Rizzetto & Verme, J Hepatol 1985)

A European wide study reported a 3.2 fold increasedrisk compared to mono-infected pts (p<0.05); somerisk for hepatic decompenstaion (2.2 fold, p= NS)(Fattovich et al, Gut 2000)

Romeo et al, Gastro 2009

HCC vs. hepaticdecompensation inHDV cirrhosis: a 28 yearfollow-up study

HCC vs. decompensation in HDV cirrhosis

Romeo et al, Gastroenterology 2009

188 patierts enrolled

106 cirrhosis82 chronic hepatitis

21 cirrhosis61 chronic hepatitis

5 decomp. cirrh.+ 3 HCC

13 comp.cirrhosis

55 comp. cirrh.

37 decomp. cirrh.+ 14 HCC

Follow up

59 Liver major complications

Outcome of CDH in Italy(mean FU: 7.8 ± 4.1 years) Niro et al, J Hepatol 2010 (in press)

158 chronic hepatitis D

114 stabile(72 %)

11 resolution (7 %)

Buti et al, J Hepatol 2010

29 decompensation(18 %)

4 HCC(3 %)

Outcome of CDH in Spain(median FU: 13.2 years)

Decompensation vs HCC in Cirrhotic HDV Patients (n=54)

HCCDec.

p=0,2; HR=1,7 %95 CI(0,7 – 3,9)Decompensation [n=14 (25,9%)]: Median=59 mo(min-max=8,2 – 93,1)HCC [n=8 (14,8%)]: Median = 42,8 mo(min-max=17,5 – 87,8)

Months

Chronic Delta Hepatitis Progression to Cirrhosis (n=97)

Progression to Cirrhosis [n=19 (19,6 %)], Median 58,4 mo (min – max= 3,5 – 174,9)

Months

Mortality in Cirrhotic HDV Cases (n=54)Ex+Tx

event

0 24 48 72 96 120 144 168 192

100

90

80

70

60

50

40

30

20

10

0

Time

Su

rviv

al p

rob

ab

ility

(%

)

Number at risk54 51 46 45 39 34 27 20 13 9 9 8 6 2 1 1 1 1

Survival

Median survival of cirrhotic HDV cases is 70 mo (min – max=15,5 – 99,8) (n=54)Mortality 16 cases (29,6 %); tx in 9 patients (17%)

1. HBsAg clerance2. Extrahepatic Malignancies

in the Course of CDH• HBsAg clearance in 14 patients after a median follow-up of 76 months (16/151- 11%).

• There were 7 (4.3 %) extrahepatic malignancies in the course of disease (4 adeno Ca of GI tract and 3 leukemia)

HDV-3

HDV-2

HDV-4

HDV-1

HDV genotypes- phylogenetic analysis(new classification) (Radjef et al, J Virol 2004)

HDV-6

HDV-5

HDV-7

Effect of genotype on outcome• HDV genotype affects outcome

– Genotype I vs. genotype II12:– Higher incidence of fulminant or subfulminant hepatic failure in acute phase– Greater incidence of adverse outcome (cirrhosis, HCC,

mortality) in chronic phase– Genotype III:– Frequently associated with fulminant hepatic failure

• Coinfecting HBV genotype can affect outcome – It is not always possible to genotype HBV as HBV DNA may be

suppressed to low levels– HBV genotype C is significantly associated with adverse outcome

(cirrhosis, HCC or mortality) in patients with CHD3

1. Wu Lancet 1995; 2. Su et al. Gastroenterol 2006; 3. Wu Curr Top Microbiol Immunol 2006

Affect of HDV genotype on survival

0 5 10 15Follow-up (yrs)

Cum

ulati

ve s

urvi

val r

ate

(%)

P=0.0105

0

20

40

60

80

100

HDV genotype II

HDV genotype I

Patients at riskHDV genotype I: 46 29 25 10HDV genotype II: 72 55 49 27

Su et al. Gastroenterol 2006

Taiwanese study of untreated patients with median median follow-up of 135 months

HBV- HDV genotype connectionHBV- HDV genotype connectionSu et al, Gastroenterology 2006

Variable Risk ratio 95% Confidence p valueInterval

Genotype C HBV 13.43 2.31- 78.16 0.004

Age > 60 11.96 1.83- 78.01 0.009

Genotype I HDV 9.74 1.94- 48.89 0.006

HBV genotypes D and F were associated with higher HDV viral load compared to HBV genotype A

(Kiesslich D et al, JID 2009)

High HDV viral load has been reported to be associated with poor prognosis

(Smedile A et al, Hepatology 1991)

Natural history- open issues

HBeAg (+) CDH Genotype III Other genotypes

Is there change in the natural history of genotype III HDV

Other HDV genotypes

Other HBV genotypes

Reason for different epidemiology of HDV

HBsAg Clearance in Chronic Hepatitis, and Cirrhotics (n=151)

event

0 24 48 72 96 120 144 168 192 216 240 264 288

100

90

80

70

60

50

40

30

20

10

0

Time

Sur

viva

l pro

babi

lity

(%)

HBsAgLoss

HBsAg Clearance was seen in 16 cases (10,6 %), in median 76,4 mo (min – max=11,9 – 248,5)

Mortality in Cirrhotic HDV Cases (n=54)

Mortality [n=8 (14,8 %)]: Median 73,75 mo (min – max = 22,0 – 101,0)

Transplantation in Cirrhotic HDV Cases (n=54)

Transplantation (n=9/54): Median 56,9mo (min – max=15,4 – 99,8)

Decompensation vs HCC in all HDV Patients

p = 0,8, Hazard ratio 1,06 95% CI (0,5128 - 2,1990)

event

0 24 48 72 96 120 144 168 192 216 240 264 288

100

90

80

70

60

50

40

30

20

10

0

Time

Surv

ival pro

bability (

%)

Number at riskGroup: 1

15014413312611296867664544740292013 7 5 5 5 3 3 2 2 1 1 1Group: 2

15114413112211197847464534739292013 7 5 5 5 3 3 2 2 1 1 1

group1 Decompensation (n=15)2 HCC (n=14)

Decompensation vs HCC in all HDV Patients

p = 0,8, Hazard ratio 1,06 95% CI (0,5128 - 2,1990)Decompensation Median: 58, 0 (min – max= 0 – 93,1)HCC Median: 62,6 (min – max=11,3 – 129,2)

HCCDec.

Months

Cumulative Survival (all group)Mortality=16/161 (10%)

Figure 2

Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )

Copyright © 2009 AGA Institute Terms and Conditions

Chronic Delta Hepatitis HBsAg Clearance (n=97)

HBsAg clearance [n=14 (14,4%)]; Median: 81,2 mo (min – max=11,9 – 248,5)

There is no difference between HBV, and D in means of HCC development

HCC among HBV – Cirrhotics: n=4 (6,2 %)HCC among HDV – Cirrhotics: n= 8 (14,8%) p = 0,7570, Hazard ratio = 0,8 95% CI (0,2520 - 2,7248)

Decompensation vs HCC in Cirrhotic HDV Patients (n=54)

p=0,2; HR=1,7 %95 CI(0,7 – 3,9)Decompensation [n=14 (25,9%)]: Median=59 mo(min-max=8,2 – 93,1)HCC [n=8 (14,8%)]: Median = 42,8 mo(min-max=17,5 – 87,8)

HCCDec.

Chronic Delta Hepatitis Progression to Cirrhosis (n=97)

Progression to Cirrhosis [n=19 (19,6 %)], Median 58,4 mo (min – max= 3,5 – 174,9)

Figure 2

Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )

Copyright © 2009 AGA Institute Terms and Conditions

Figure 4

Source: Gastroenterology 2009; 136:1629-1638 (DOI:10.1053/j.gastro.2009.01.052 )

Copyright © 2009 AGA Institute Terms and Conditions