Gary DAVIS. Legal Gary L. Davis, M.D. Baylor University Medical Center Dallas, Texas USA Alcohol in Chronic Hepatitis C: or Prohibited ?

Gary DAVISGary DAVIS

LegalLegal

Gary L. Davis, M.D.Gary L. Davis, M.D.

Baylor University Medical CenterBaylor University Medical Center

Dallas, Texas USADallas, Texas USA

Alcohol in Chronic Hepatitis C:Alcohol in Chronic Hepatitis C:or Prohibited ?or Prohibited ?

QuestionsQuestions

• Is this really an issue?Is this really an issue?

• How many chronic hepatitis C patients used, How many chronic hepatitis C patients used, use or abuse alcohol? use or abuse alcohol?

• Does alcohol impact the liver disease?Does alcohol impact the liver disease?

• Does alcohol impair treatment outcome?Does alcohol impair treatment outcome?

• If alcohol is really a problem, then how If alcohol is really a problem, then how much is too much?much is too much?

BackgroundBackground

• 1.5-2% of US and Western Europeans are 1.5-2% of US and Western Europeans are chronically infected with HCVchronically infected with HCV

• ~60% of the population use alcohol regularly~60% of the population use alcohol regularly11

• 5-7% in US are heavy or dependent alcohol 5-7% in US are heavy or dependent alcohol usersusers11 (>2 drinks/day for men, >1 drink/day for women)(>2 drinks/day for men, >1 drink/day for women)

1Alcohol Epid Data System, NIAAA.

BackgroundBackground

• Of patients with chronic hepatitis C:Of patients with chronic hepatitis C:• 60% have a history of prior heavy alcohol use60% have a history of prior heavy alcohol use11

• 28-37% continue use after diagnosis28-37% continue use after diagnosis22

• Of patients with alcoholic liver disease:Of patients with alcoholic liver disease:• 14-50% have HCV infection14-50% have HCV infection33

?

Jamal MM, et al. Dig Dis 2005; 23:285.Cambell JV, et al. Drug Alcohol Depend 2006; 81:259.Safdar K, Schiff ER. Sem Liver Dis 2004; 24:305.

Impact of Alcohol on Liver DiseaseImpact of Alcohol on Liver Disease

• 30-70% of deaths in patients with chronic 30-70% of deaths in patients with chronic hepatitis C have a history of heavy alcohol usehepatitis C have a history of heavy alcohol use11

• Alcohol is an independent risk factor of hepatic Alcohol is an independent risk factor of hepatic death in HCV patients (OR 1.4)death in HCV patients (OR 1.4)22

• Rise in alcohol-related cirrhosis deaths in UK in Rise in alcohol-related cirrhosis deaths in UK in 1990s was attributed to HCV1990s was attributed to HCV33

• In advanced alcoholic liver disease, anti-HCV+ In advanced alcoholic liver disease, anti-HCV+ has less influence on survival than continued has less influence on survival than continued alcohol use, CTP score, or alcoholic hepatitisalcohol use, CTP score, or alcoholic hepatitis44

Harris H, et al. Epidemiol Infect 2006; 134:472.; Kobayashi M, et al. J Med Virol 2006; 78:459.; Henry J, et al. J Clin Pathol 2002; 55:704.; Pessione F, et al. Liver Int 2003; 23:45.

If HCV infection results in higher If HCV infection results in higher liver-related mortality, then it liver-related mortality, then it mustmust result in more progressive liver injuryresult in more progressive liver injury


• Heavy alcohol intake in patients with chronic Heavy alcohol intake in patients with chronic hepatitis C is associated with:hepatitis C is associated with:

• more severe periportal inflammationmore severe periportal inflammation11

• more rapid progression of fibrosismore rapid progression of fibrosis22

• higher incidence of cirrhosishigher incidence of cirrhosis22

• greater risk of decompensationgreater risk of decompensation3,43,4

Hezode C, et al. Aliment Pharmacol Ther 2003; 17:1031. Wiley TE, et al. Hepatology 1998; 28:805. Delarocque-Astagneau E, Ann Epidemiol 2005; 15:551.Niederau C, et al. Hepatology 1998; 28:1687.

Association of Alcohol with Association of Alcohol with Fibrosis Progression in HCV PtsFibrosis Progression in HCV Pts

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

0 <20 20-50 50-80 >80

Daily Alcohol Intake

Fib

rosi

s R

ate

(F/y

r)

MontoA, et al. Hepatology 2004; 39:826.

Association of Alcohol with Association of Alcohol with Fibrosis Progression in HCV PtsFibrosis Progression in HCV Pts

0%

20%

40%

60%

80%

100%

0 <20 20-50 >50

Daily Alcohol Intake

Sta

ge (

%)

Stage 0Stage 1Stage 2Stage 3Stage 4

MontoA, et al. Hepatology2004; 39:826.


• Heavy alcohol intake in patients with chronic Heavy alcohol intake in patients with chronic hepatitis C is associated with:hepatitis C is associated with:

• more severe periportal inflammationmore severe periportal inflammation11

• more rapid progression of fibrosismore rapid progression of fibrosis22

• higher incidence of cirrhosishigher incidence of cirrhosis22

• greater risk of decompensationgreater risk of decompensation3,43,4

Hezode C, et al. Aliment Pharmacol Ther 2003; 17:1031. Wiley TE, et al. Hepatology 1998; 28:805. Delarocque-Astagneau E, Ann Epidemiol 2005; 15:551.Niederau C, et al. Hepatology 1998; 28:1687.


• Heavy alcohol use increases risk of cirrhosis 2 Heavy alcohol use increases risk of cirrhosis 2 to 150 foldto 150 fold1-31-3

Roudot-Thoraval F, et al. Hepatology 1997; 26:485.; Corrao G, et al. Hepatology 1998; 27:914.; Stroffllini T,et al. J Viral Hepat 2006; 13:351.

Impact of Alcohol and HCV Impact of Alcohol and HCV on Risk of Cirrhosison Risk of Cirrhosis

0

20

40

60

80

100

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0 25/50 75/100 125/150 175>

Lifetime Daily Alcohol Intake

Odd

's R

atio

HCV negativeHCV positive

Corrao G, Arico S. Hepatology 1998; 27:914


• Heavy alcohol use increases risk of cirrhosis 2 Heavy alcohol use increases risk of cirrhosis 2 to 150 foldto 150 fold1-31-3

• Only duration of HCV infection has a greater Only duration of HCV infection has a greater influence on progressioninfluence on progression44

• Concurrent or past alcohol use explains most of Concurrent or past alcohol use explains most of the increased mortality in HIV-HCV the increased mortality in HIV-HCV coinfectioncoinfection5 5 and perhaps fibrosis in the obeseand perhaps fibrosis in the obese66

Roudot-Thoraval F, et al. Hepatology 1997; 26:485.; Corrao G, et al. Hepatology 1998; 27:914.; Stroffllini T,et al. J Viral Hepat 2006; 13:351. Poynard T, et al. J Hepatol 2001; 34:730.; Salmon-Ceron D, et al. J Hepatol 2005; 42:799.; Ruhl CE, et al. Clin Gastroenterol Hepatol 2005; 3:1260.

Impact of Alcohol on HCC RiskImpact of Alcohol on HCC Risk

• HCV infection is the most common cause of HCV infection is the most common cause of hepatocellular carcinoma in the US – Europehepatocellular carcinoma in the US – Europe

• Risk of HCC is higher with concurrent HCV Risk of HCC is higher with concurrent HCV infection and alcohol useinfection and alcohol use1-21-2

• Donato: Relative risk for HCCDonato: Relative risk for HCC33

• Alcohol = 5; HCV = 30; HCV + alcohol = 66 Alcohol = 5; HCV = 30; HCV + alcohol = 66

Simonetti RG, et al. Ann Intern Med 1992; 116:97.Ikeda K, et al. J Hepatol 1998; 28:930.Donato F, et al. Cancer Causes Control 1999; 10:417.


0

10

20

30

40

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60

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0-80 g/d >80 g/d 0-80 g/d >80 g/d

HCV negative HCV positive

Rel

ativ

e R

isk

Donato F, et al. Hepatology 1997; 26:579.

Reference


• HCC occurs earlier in heavy drinkersHCC occurs earlier in heavy drinkers11

• Niederau: HCV duration and cirrhosis, not Niederau: HCV duration and cirrhosis, not alcohol, are the major risk factors for HCCalcohol, are the major risk factors for HCC22

Whether alcohol has a direct carcinogenic Whether alcohol has a direct carcinogenic effect or contributes by simply enhancing effect or contributes by simply enhancing progression to cirrhosis is not knownprogression to cirrhosis is not known

Noda K, et al. Alcohol Clin Exp Res 1996; 20(1 Suppl):95A.Niederau C, et al. Hepatology 1998; 28:1687.

Alcohol and Interferon ResponseAlcohol and Interferon Response

• Difficult to assess since most studies have Difficult to assess since most studies have excluded significant alcohol and it is a excluded significant alcohol and it is a common reason not to treatcommon reason not to treat11

• Most studies find that alcohol decreases Most studies find that alcohol decreases response to interferon-based therapyresponse to interferon-based therapy2-4 2-4 and and this effect is alcohol dose-dependentthis effect is alcohol dose-dependent2-32-3

Nguyen HA, et al. Am J Gastroenterol 2002; 97:1813.; Chang A, et al. Pharmacol Ther 2005; 22:701.; Tabone M, et al. J Viral Hepat 2002; 9:288.; Okazaki T, et al. Scand J Gastroenterol 1994; 29:1039-1043.


• Odd’s ratio of sustained viral response:Odd’s ratio of sustained viral response:

OROR TreatmentTreatment ComparisonComparison

• AnandAnand 1.5 1.5 IFN/Riba 0 vs any IFN/Riba 0 vs any alcohol alcohol

• ChangChang 3.0 3.0 Peg/Riba 0-29 vs Peg/Riba 0-29 vs >>30 g/d30 g/d

• TaboneTabone 1.7, 3.7 IFN 0 vs mild vs 1.7, 3.7 IFN 0 vs mild vs heavyheavy

(all w/ >6m (all w/ >6m abstinence)abstinence)


• Poor treatment response largely related to Poor treatment response largely related to early treatment discontinuation (~40%)early treatment discontinuation (~40%)1-21-2

• When full course is completed, SVR is When full course is completed, SVR is similar regardless of alcohol intakesimilar regardless of alcohol intake11

Anand BS, et al. Gastroenterology 2006;130:1607.Cheung RC, et al. Am J Gastroenterol 2005; 100:2186.

Mechanism of Interaction Mechanism of Interaction Between Alcohol and HCVBetween Alcohol and HCV

• Effects of immune functionEffects of immune function

• Oxidative stress and lipid peroxidationOxidative stress and lipid peroxidation


• Alcohol effects on immune functionAlcohol effects on immune function

• Global effects on innate and adaptive responsesGlobal effects on innate and adaptive responses

• Depresses dendritic cell functionDepresses dendritic cell function

• Increased IL-10 expression Increased IL-10 expression

• Impaired proliferation of CD4 and CD8 cellsImpaired proliferation of CD4 and CD8 cells

• Reduced production of endogenous interferons Reduced production of endogenous interferons and interferon-stimulated genes (ISGs)and interferon-stimulated genes (ISGs)

Alcohol Impairs AdaptiveAlcohol Impairs Adaptive Immune Function Immune Function

Hepatocyte

+ -

Cellular Immune Response

IL-10

HCV Replicationand Inflammation

Type 1 IFN

NFκβ-dependentinhibition

Alcohol Inhibits EndogenousAlcohol Inhibits Endogenous IFN and ISG Production IFN and ISG Production

NFκβ-dependentinhibition


• Additive induction of lipid peroxidation in mice by chronic ethanol and HCV core expression

0

20

40

60

80

100

120

ControlWater

ControlEthanol

Core Water CoreEthanol

Eth

ane

exha

lati

on (

pmol

/g B

W)

02468

1012141618

ControlWater

ControlEthanol

Core Water CoreEthanol

Hep

atic

TB

AR

(nm

al/g

live

r)

Perlemuter G, et al. J Hepatol 2003; 39:1020.


• Oxidative stress and liver injury increases Oxidative stress and liver injury increases proportional to alcohol intake in HCV patientsproportional to alcohol intake in HCV patients

0

0.1

0.2

0.3

0.4

AAHP-HSA Ox-Cl

Eth

ane

exha

lati

on (

pmol

/g B

W)

NormalHCV/No EtOHHCV/mod EtOHHCV /heavy EtOHHeavy EtOH

AAHP-HAS = Ig aby to HAS-bound arachadonic acid hydroperoxideOx-Cl = oxidized cardiolipin; Moderate EtOH <50 g/d, heavy EtOH >50 g/d* = p<0.01 vs controls, ** = p<0.05 vs controls, # = p<0.01 vs HCV/no EtOH;

**, #

*, #** * # #

0

1

2

3

4

5

6

7

8

Steatosis Periportal Grade StageH

isto

logi

c sc

ore

(Ish

ak)

<0.01

<0.05

<0.05

Rigaminti C, et al. Hepatology 2003; 38:42.

Summary Summary

Regarding the effect of alcohol in patients withRegarding the effect of alcohol in patients withchronic hepatitis C:chronic hepatitis C: • 10/10 studies show a detrimental effect on 10/10 studies show a detrimental effect on

inflammation, fibrosis progression, cirrhosis, and inflammation, fibrosis progression, cirrhosis, and decompensation decompensation

• 9/10 articles suggest alcohol facilitates 9/10 articles suggest alcohol facilitates development of hepatocellular carcinomadevelopment of hepatocellular carcinoma

• 2/3 studies demonstrate increased HCV RNA2/3 studies demonstrate increased HCV RNA

• 4/4 articles show impaired response to interferon-4/4 articles show impaired response to interferon-based antiviral therapybased antiviral therapy

Conclusions Conclusions

• Alcohol abuse should be discouraged on its Alcohol abuse should be discouraged on its own merits, regardless of whether liver own merits, regardless of whether liver disease is presentdisease is present

• Studies are variable in design, definitions of Studies are variable in design, definitions of alcohol use and abuse, and poweralcohol use and abuse, and power

• Detrimental effects of alcohol are dose-Detrimental effects of alcohol are dose-dependent with greatest impact at >20-50 g/ddependent with greatest impact at >20-50 g/d

• However, deleterious effects are even present However, deleterious effects are even present at daily intake less than 20 gm/dayat daily intake less than 20 gm/day

Clinical Recommendations:Clinical Recommendations:How Much is Too Much?How Much is Too Much?

• The data, limited as it is, does not support any The data, limited as it is, does not support any safe level of daily alcohol consumption in safe level of daily alcohol consumption in patients with chronic hepatitis Cpatients with chronic hepatitis C

• The effects of sporadic and limited alcohol The effects of sporadic and limited alcohol use have not been carefully studieduse have not been carefully studied

• The prudent recommendation to patients is to The prudent recommendation to patients is to avoid alcohol consumption altogetheravoid alcohol consumption altogether

Documents

Gary DAVIS. Legal Gary L. Davis, M.D. Baylor University Medical Center Dallas, Texas USA Alcohol in Chronic Hepatitis C: or Prohibited ?