successful medical management in hiv-hcv co-infected patients
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Successful Medical Management in HIV-HCV Co-Infected Patients. World AIDS Conference Symposium August 16, 2006 Curtis Cooper, MD, FRCPC Associate Professor of Medicine University of Ottawa Division of Infectious Diseases. Objectives. Background Interventions HAART HCV Drug Therapy - PowerPoint PPT PresentationTRANSCRIPT
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