Successful Medical Management in HIV-HCV Co-Infected Patients

World AIDS ConferenceSymposium

August 16, 2006

Curtis Cooper, MD, FRCPCAssociate Professor of Medicine

University of OttawaDivision of Infectious Diseases

Objectives

• Background

• Interventions– HAART

– HCV Drug Therapy

• Algorithm for Optimal Management

•

4

HIV-HCV andHIV-HCV andTime to Liver CirrhosisTime to Liver Cirrhosis

• Multiviric GroupMultiviric Group- HIV/HCV (n=122)HIV/HCV (n=122)

- HCV infected (n=122)HCV infected (n=122)

- Matched forMatched for

• Age, sex, daily alcohol intake, Age, sex, daily alcohol intake, age at HCV infection, duration age at HCV infection, duration and route of HCV infectionand route of HCV infection

• Higher fibrosis progression Higher fibrosis progression rates in HIV/HCV-coinfected rates in HIV/HCV-coinfected patients were associated with:patients were associated with:

- Alcohol consumption >50 g/dayAlcohol consumption >50 g/day

- CD4 CD4 <<200 cells/200 cells/µLµL

- Age at HCV infection <25 yearsAge at HCV infection <25 years 0

10

20

30

40

50

Tim

e (y

ears

)T

ime

(yea

rs)

HIV- >200 HIV- >200 <<200200

3535

Benhamou Y, et al. Hepatology. 1999;30:1054-1058.

Time to CirrhosisTime to CirrhosisAlcohol ConsumptionAlcohol Consumption

>50 g/day>50 g/day <50 g/day<50 g/day

HIV+HIV+CD4 (cells/mmCD4 (cells/mm33))

4040

2121

3636

1616

2121

Increasing Mortality From ESLD in Patients With HIV Infection(Lemuel Shattuck Hospital, Jamaica Plain, MA)

• 55% who died with ESLD had either NDVL or CD4 >200/mm3 within 1 year prior to death

Bica I, et al. Clin Infect Dis 2001;32: 492-7

Death

s d

ue t

o E

SLD

(%

)

50

40

30

20

10

0

1114

50

1991 1996 1998/9

Therapeutic Interventions in HIV-HCV Co-Infection

Therapeutic Interventions

• HIV– HAART

– Life long commitment

– 60-80% virologic suppression at 1 yr

– Immune Restoration

– Improved Quantity and Quality of Life

• HCV– Pegylated Interferon

and Ribavirin

– Difficult therapy but finite duration

– SVR is possible

– Presumably prolongs life

Rational for HAART Therapy

• HIV– CD4 <200: Morbidity

and Mortality reduced

– CD4 <350: Avoid AIDS-defining illness when initiating HAART at higher CD4

• HCV– Slows fibrosis

– Reduced liver specific mortality

Antiretroviral Therapy Slows FibrosisBenhamou et al. Hepatology 2001;34:283-287.

n=119n=119

n=63n=63

0 3 6 12-1

0

1

2

3

Months Since Initiation of HAART

HCV RNA(log10)

Change in HCV RNA following HAART as a Function of Alcohol Consumption

• 50 grams alcohol per day• < 50 grams alcohol per day

P=0.24 P=0.003 P=0.009

Cooper et al. Clin Infect Dis 2005.Cooper et al. Clin Infect Dis 2005.

11

Impact of ART on Overall Liver MortalityImpact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patientsin HIV/HCV-Coinfected Patients

• Bonn cohort (1990-2002)Bonn cohort (1990-2002)

- 285 HIV/HCV coinfected 285 HIV/HCV coinfected patientspatients

• Liver-related mortality rates Liver-related mortality rates per 100 person-yearsper 100 person-years

- HAART: 0.45HAART: 0.45

- ART: 0.69ART: 0.69

- No therapy: 1.70No therapy: 1.70

• Predictors for liver-related Predictors for liver-related mortalitymortality

- No HAARTNo HAART

- Low CD4 cell countLow CD4 cell count

- Increasing ageIncreasing ageQurishi N, et al. Lancet. 2003;362:1708-1713.

0.2

0.4

0.6

0.8

1

DaysDays

Overall MortalityOverall Mortality

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000

ARTART

HAART*HAART*

0.2

0.4

0.6

0.8

1

DaysDays

Liver-Related MortalityLiver-Related Mortality

Cu

mu

lati

ve S

urv

ival

Cu

mu

lati

ve S

urv

ival

0 1000 2000 3000 4000 5000 60000 1000 2000 3000 4000 5000 6000

HAART*HAART*

No therapyNo therapy

ARTART

No therapyNo therapy

**PP=0.018=0.018

**PP<0.001<0.001

HAART, Co-Infection and Toxicity

Keep things in Perspective…. Cooper et al. HIV Medicine 2006.

0%

5%

10%

15%

20%

25%

Reason for HAART

Interruption

GI

Adherence

Neurocognitive

ImprovedRegimen

SubstanceAbuse

Liver

HAART Toxicity in Co-Infection

• Definition– Liver Enzyme Elevation– Clinically Relevant Liver Toxicity

• Differential– Immune reconstitution– Viral Co-Infection– Concurrent medications– Alcohol

Why is there More Liver Complications in HIV?

• Decrease in Defense Mechanisms • Glutathione levels

• Viral-Infected cells more sensitive to drug and metabolites

• Cytokine milieu may down regulate acetylation and oxidative enzyme production

• Antiretroviral Drug Levels

Pathogenesis: What is going on?

DRUG METABOLITE Immune Response

TOXICITY

Covalent binding (lipid, protein, NA) Reactive O2 (Lipid Peroxidation) GSH depletion

Mitochondria DNA

Inflammatory / Toxic Mediators

Repair

OVERT LIVER DISEASE

Specific Antiretrovirals

• NNRTI– Nevirapine

• NRTI– DDI– D4T

• Protease Inhibitors– Ritonavir– Atazanavir (UGT)

Comments

• ‘Hepatotoxicity’ definition is faulty

• ART safe for most

• Antiretroviral Class / Drug– Science or Marketing?

• Don’t compromise potency and durability of HAART regimen

HCV Therapy in HIV-HCV Co-Infection

Rational for HCV Drug Therapy in HIV-HCV Co-Infection

• CD4 response to HAART

• Drug interactions and additive toxicities

• Reduce hepatotoxicity with HAART

0

50

100

150

200

250

Mean Increase CD4 Count

6 12 24 36

Months of Antiretroviral Therapy

HCV -HCV+

Greub et al. Lancet 2000;356:1800-5.Greub et al. Lancet 2000;356:1800-5.

Diminished Efficacy: APRICOT

27%

20%

8% 7%

End of treatment

End of follow-up

21%

14%

38%

29%

57%

36%

64% 62%

0

10

20

30

40

50

60

70

GT1 GT1 GT1

Virologic response – EOT and SVR

IFN α-2a+RBV

peg-IFNα-2a

+ placebo

peg-IFNα-2a

+RBV

GT2/3 GT2/3 GT2/3

Should Therapy for HCV be Initiated?

• Decision to Treat– Biopsy Results / Duration of Infection

– Predicted adherence and tolerance of therapy• Substance abuse

• Psychiatric health

• Age

• Co-morbid disease

What’s the biggest bang for your buck?

Opportunistic Infections

Viral Hepatitis

Transplantation

ImmuneReconstitution

Herbal Remedies

EtOH

HCV Treatment

Antiretrovirals

Other Medications

Intervention #1: Alcohol

• Alcohol Cessation– Diminished Injury to Liver– Immune Restoration with HAART– HCV RNA Reduction SVR with Interferon

Intervention #2: HAART

• HIV– Obvious Benefits

• HCV– Slows Fibrosis– Reduced Liver-Specific Mortality – More likely to ‘work’ and for patients to stay

on treatment

Intervention #3: HCV Therapy

• Potentially Liver and Life Saving

• Reduced Efficacy in HIV-HCV Co-Infection

• Side Effects

Acknowledgement

• Louise Balfour• BMS• WAC Organizing Committee

• Ottawa Hospital Division of Infectious Diseases– Immunodeficiency Clinic – Viral Hepatitis Program