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
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