W5 HIV, HCV, and HBV Co-Infection Jayaweera

1

HIV, HCV and HBV COINFECTION

Dushyantha Jayaweera, M.D., M.R.C.O.G., F.A.C.P.

Professor in Clinical Medicine

Division of Infectious Diseases

University of Miami Miller School of Medicine

● Epidemiology

● Hepatitis C Virus natural History

● HCV/HIV Co-infection

● Novel drug therapies

● HBV infection

● HBV vaccinations

Outline

clinicaloptions.com/hepatitisAASLD Practice Guidelines: An Update


HCV Prevalence by Selected Groups in the United States

Hemophilia

Injecting Drug Users

Surgeons

Hemodialysis

Average Proportion Anti-HCV Positive (%)

General Population Adults

Military Personnel

STD Clients

Pregnant Women

Centers for Disease Control and Prevention, 2003.

87

79

10

6

3.5

2

1

0.3

0 10 20 30 40 50 60 70 80 90 100


Infectious Disease Burden Among Released Inmates: United States 1997

Infection/Disease Infected Inmates Released[1]

Total Infected in US Population

% of Total Infected

Population[1] HCV (anti-HCV+) 1,321,781-1,943,796 4,500,000*[2] 29.4-43.2

HIV 150,950–196,555 750,000† 20.1-26.2

TB 12,531 31,660† 39.6

1. Hammett TM, et al. Am J Public Health. 2002;92:1789-1794. 2. McQuillan GM, et al. In: Rizzetto M, et al, editors. Viral hepatitis and liver disease. Turin, Italy: Edizioni Minerva Medica; 1997. p. 267-270.

*Data based on prevalence estimate.†Centers for Disease Control and Prevention estimate.

● Epidemiology


● Pathogenesis of HCV



● HBV infection


Outline





clinicaloptions.com/hepatitisHighlights from AASLD 2009

Worldwide Distribution of HCV Genotypes

Zein N. Clin Microbiol Rev. 2000;13:223-235. Reproduced with permission. http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999.

1a1b234567-8-9Others

http://cmr.asm.org/cgi/content/full/13/2/223?view=long&pmid=10755999





● Epidemiology




● HBV infection


Outline

Liver-related Mortality UK Hemophiliac Cohort

• Liver deaths– HIV - 16.7-fold– HIV + 94.4-fold

• Risk after 10 years

Darby et al. Lancet. 1997;350:1425-1431.

0

20

40

60

80

100

HIV+ HIV- Generalpopulation

Liv

er

de

ath

s (

O/E

)

O/E, observed to expected ratio; UK, United Kingdom.

Increased Risk of Cirrhosis and ESLD in HIV/HCV Coinfected

Patients

Graham et al. Clin Infect Dis. 2001;33:562-569.

Histological Cirrhosis Decompensated Liver Disease

Combined

Benhamou

Pol

Soto

Makris

Makris

Telfer

Eyster

Lesens

Combined

10.832.071.0.76

Relative Risk (95% CI)

.61 1.0 6.14 10 175.32

CI, confidence interval; ESLD, end stage liver disease; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

HIV/HCV Coinfection TrialsPEG IFN/RBV

PEG IFN alfa-2a 180 µg + RBV 600 mg 1 g/dIFN alfa-2a 6 MIU 3 MIU + RBV 600 mg 1 g/d

ACTG 5071USA(N = 133)

PEG IFN alfa-2a 180 µg + RBV 800 mgIFN alfa-2a 3 MIU + RBV 800 mgPEG IFN alfa-2a 180 µg + RBV placebo 800 mg

APRICOTInternational(N = 868)

PEG IFN alfa-2b 1.5 μg/kg + RBV 800 mg

IFN alfa-2b 3 MIU + RBV 800 mg

RIBAVICFrance(N = 412)

Treatment RegimenStudy


APRICOTVirologic Response*–End of Treatment vs End of Follow-

up (Genotype 1)

*Defined as <50 IU/mL HCV RNA.Torriani et al. 11th CROI; February 8-11, 2004; San Francisco, Calif. Abstract 112.

8

21

38

7

14

29

0

10

20

30

40

50

60

Res

po

nse

(%

)

IFN alfa-2a/RBV PEG IFN alfa-2a/Placebo

PEG IFN alfa-2a/RBV

EOT EOTSVR SVR SVREOT

APRICOTVirologic Response*–End of

Treatment vs End of Follow-up (Genotype 2 and 3)

*Defined as <50 IU/mL HCV RNA.

Torriani et al. 11th CROI; February 8-11, 2004; San Francisco, Calif. Abstract 112.

57

27

64

36

20

62

0

10

20

30

40

50

60

70

Res

po

nse

(%

)

IFN alfa-2a/RBV PEG IFN alfa-2a/Placebo

PEG IFN alfa-2a/RBV

EOT SVR EOT SVR EOT SVR

● Epidemiology



● Novel drug therapies (in mono infection with HCV)

● HBV infection


Outline

clinicaloptions.com/hepatitisSmoother Waters Ahead? New Directions in the Management of HCV

HCV Lifecycle and STAT-C Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation and

polyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

*Role in HCV lifecycle not well defined

NS5A* inhibitors


On-Treatment Viral Kinetics

STAT-C drugs may improve both first and second phase kinetics

Second phase

First phase

HC

V R

NA

0 12 24 36 484

HCV RNA negative in blood

Wks

30

Resistant Variants occurs Naturally










40

Maximize Response and Minimize Resistance



● Epidemiology



● Novel drug therapies (in mono infection with HCV)

● HBV infection


Outline

Geographic Prevalence of Chronic Hepatitis B May Geographic Prevalence of Chronic Hepatitis B May Be Impacted by MigrationBe Impacted by Migration

World Health Organization. Geographic Prevalence of HBsAg. Data from 1996 (unpublished). http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm. Accessed: June 14, 2007

2002 Yearbook of Immigration Statistics. http://uscis.gov/graphics/shared/aboutus/statistics/IMM02yrbk/IMM2002list.htm. Accessed: June 14, 2007.

Mahoney FJ. Clin Microbiol Rev. 1999;12:351-366.

HBsAg Prevalence

8% - High

2-7% - Intermediate

<2% - Low

Immigration numbers summed by continent from 1996-2002

~2 million Asians

~400,000South Americans

~350,000 Africans

~930, 000 Europeans

http://www.who.int/vaccines-surveillance/graphics/htmls/hepbprev.htm

http://uscis.gov/graphics/shared/aboutus/statistics/IMM02yrbk/IMM2002list.htm

Clinical Liver Disease and HBV Clinical Liver Disease and HBV GenotypeGenotype

Duong TN, et al. Journal of Medical Virology. 2004;72:551–557.

Diagnosis, n (%)

Genotypes N Asymptomatic carrier

Chronic hepatitis

Liver cirrhosis

HCC

Genotype A 11 8 (72.7) 3 (27.3) 0 0

Genotype B 14 10 (71.4) 3 (21.4) 0 1 (7.2)

Genotype C 350 129 (36.8) 126 (36.0) 50 (14.3) 45 (12.9)

Genotype D 38 32 (84.2)b 6 (15.8)a 0 0a

a P<0.05 vs genotype C.b P<0.001 vs genotype C.

Is HBsAg present?Is HBsAg present?

Is IgM anti-HBc present?Is IgM anti-HBc present?

Is HBeAg or HBV DNA present?Is HBeAg or HBV DNA present? Is anti-HBs present?Is anti-HBs present?

Chronic Chronic HepatitisHepatitis

Acute Acute HepatitisHepatitis

Replicative HBV Replicative HBV infectioninfection

Non-replicative HBV Non-replicative HBV infectioninfection

Recovered or Recovered or vaccinated vaccinated

+/- anti-HBc+/- anti-HBc

No HBV No HBV infectioninfection

NoNo

YesYes

YesYes

YesYes

YesYes

NoNo

NoNoNoNo

Anti-HBc Anti-HBc +/-+/-

nonoyesyes

To reduce the risk for transmission, HBsAg-To reduce the risk for transmission, HBsAg-positive persons should:positive persons should:

• Use condoms to protect nonimmune sex partners. • Refrain from donating blood, plasma, tissue, or semen. • HBsAg-positive pregnant women should be advised

their newborns to receive hepatitis B vaccine and hepatitis B immune globulin

• To protect the liver HBsAg-positive persons should be advised to avoid or limit alcohol consumption, vaccination against hepatitis A.

• 15%--25% of persons with chronic HBV infection are at risk for premature death from cirrhosis and liver cancer,

Treatment of HBV in HIVTreatment of HBV in HIV

• Always start with emtricitabine/tenofovir • If the patient has been on lamivudine add

tenofovir• If the patient is on Epzicom change to

emtricitabine/tenofovir• If the patient has renal failure or low GFR <60

it is safer to use lamivudine or emtricitabine with entecavir than using dose adjusted emtricitabine/tenofovir

Add another drug

without cross resistance

Monitor every 3 months

Addanother drug

orContinue

Monitor every 3 months

Continue Monitor every 6 months

Management Roadmap According to 24 Week Virologic Response

Inadequate response>104 copies/mL

Complete response <300 copies/mL

Partial response 300-104 copies/mL

Week 24: Early predictors of efficacy

Keeffe et al. Clin Gastroenterol Hepatol, 2007

Monitoring for Drug Resistance

All patients • HBV DNA and ALT at baseline and at 3 months

after starting therapy (assess antiviral efficacy)

Mild liver disease• HBV DNA and ALT q 6 mo for first 2 years;

thereafter q 3 mo and at any change in therapy

Advanced liver disease/cirrhosis• HBV DNA and ALT q 3 mo with clinical evaluation

Locarnini S, et al. Antiviral Ther. 2004;9:679-693.

Yang H, et al. Hepatology. 2003;38:705A. Lai CL, et al. Hepatology. 2003;38:262A.

V173L L180M A181V A184G S202I M204I M204V N236T M250V

Lamivudine

Entecavir

Telbivudine

Emtricitabine

Adefovir

YMDD

Cross Resistance with HBV Drugs

Hepatitis B VirusWild Type and Mutants

• Wild type– Usual HBeAg (+) hepatitis

• Precore mutation (27% U.S. patients)1

– Abolishes HBeAg production• Core promoter mutation (44% U.S. patients)1

– Down-regulates HBeAg production• Treatment-induced mutations2

– Lamivudine: L180M +/- M204V/I (YMDD)– Adefovir: N236T and A181V– Entecavir: I169, T184, S202 and M250 (LAMR

patients)– Telbivudine: M204I

1Chu CJ, et al. Gastroenterology. 2003;125:444-451.2Keeffe EB, et al. Clin Gastroenterol Hepatol. 2006;4:936-962.

● Epidemiology




● HBV infection


Outline

HBV Vaccination

● Of persons who did not respond to a primary 3-dose vaccine series with anti-HBs concentrations of >10 mIU/mL, 25%--50% responded to an additional vaccine dose, and 44%--100% responded to a 3-dose revaccination series.

HBV Vaccination

● Better response to revaccination occurs in persons who have measurable but low (<10 mIU/mL) levels of antibody after the initial series

● Increased vaccine doses (e.g., double the standard dose) were demonstrated to enhance revaccination response rates in one study but not in another .

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Thank You

Dushyantha Jayaweera, M.D., M.R.C.O.G., F.A.C.P.

Professor in Clinical Medicine

Division of Infectious Diseases

University of Miami Miller School of Medicine

Documents

W5 HIV, HCV, and HBV Co-Infection Jayaweera