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Successful Medical Management in HIV-HCV Co-Infected Patients

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

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Successful Medical Management in HIV-HCV Co-Infected Patients

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  1. 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

  2. Objectives • Background • Interventions • HAART • HCV Drug Therapy • Algorithm for Optimal Management

  3. HIV-HCV andTime to Liver Cirrhosis Time to Cirrhosis • Multiviric Group • HIV/HCV (n=122) • HCV infected (n=122) • Matched for • Age, sex, daily alcohol intake, age at HCV infection, duration and route of HCV infection • Higher fibrosis progression rates in HIV/HCV-coinfected patients were associated with: • Alcohol consumption >50 g/day • CD4 <200 cells/µL • Age at HCV infection <25 years Alcohol Consumption >50 g/day <50 g/day 40 36 35 Time (years) 21 21 16 HIV- >200 <200 HIV+ CD4 (cells/mm3) Benhamou Y, et al. Hepatology. 1999;30:1054-1058.

  4. 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 50 40 30 20 10 0 50 Deaths due to ESLD (%) 14 11 1991 1996 1998/9 Bica I, et al. Clin Infect Dis 2001;32: 492-7

  5. Therapeutic Interventions in HIV-HCV Co-Infection

  6. 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 Therapeutic Interventions

  7. 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 Rational for HAART Therapy

  8. Antiretroviral Therapy Slows FibrosisBenhamou et al. Hepatology 2001;34:283-287. n=119 n=63

  9. Change in HCV RNA following HAART as a Function of Alcohol Consumption 3 2  HCV RNA (log10) 1 P=0.003 P=0.009 P=0.24 0 -1 0 3 6 12 Months Since Initiation of HAART •  50 grams alcohol per day • < 50 grams alcohol per day Cooper et al. Clin Infect Dis 2005.

  10. Impact of ART on Overall Liver Mortalityin HIV/HCV-Coinfected Patients Overall Mortality • Bonn cohort (1990-2002) • 285 HIV/HCV coinfected patients • Liver-related mortality rates per 100 person-years • HAART: 0.45 • ART: 0.69 • No therapy: 1.70 • Predictors for liver-related mortality • No HAART • Low CD4 cell count • Increasing age HAART* Cumulative Survival ART No therapy *P<0.001 0 1000 2000 3000 4000 5000 6000 Days Liver-Related Mortality HAART* ART No therapy Cumulative Survival *P=0.018 0 1000 2000 3000 4000 5000 6000 Days Qurishi N, et al. Lancet. 2003;362:1708-1713.

  11. HAART, Co-Infection and Toxicity

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

  13. HAART Toxicity in Co-Infection • Definition • Liver Enzyme Elevation • Clinically Relevant Liver Toxicity • Differential • Immune reconstitution • Viral Co-Infection • Concurrent medications • Alcohol

  14. 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

  15. Pathogenesis: What is going on? DRUGMETABOLITE Immune Response Mitochondria DNA Covalent binding (lipid, protein, NA) Reactive O2 (Lipid Peroxidation) GSH depletion TOXICITY Inflammatory / Toxic Mediators Repair OVERT LIVER DISEASE

  16. Specific Antiretrovirals • NNRTI • Nevirapine • NRTI • DDI • D4T • Protease Inhibitors • Ritonavir • Atazanavir (UGT)

  17. Comments • ‘Hepatotoxicity’ definition is faulty • ART safe for most • Antiretroviral Class / Drug • Science or Marketing? • Don’t compromise potency and durability of HAART regimen

  18. HCV Therapy in HIV-HCV Co-Infection

  19. Rational for HCV Drug Therapy in HIV-HCV Co-Infection • CD4 response to HAART • Drug interactions and additive toxicities • Reduce hepatotoxicity with HAART Greub et al. Lancet 2000;356:1800-5.

  20. Diminished Efficacy: APRICOT Virologic response – EOT and SVR 70 64% 62% End of treatment End of follow-up 57% 60 50 38% 40 36% 29% 27% 30 21% 20% 20 14% 8% 7% 10 0 GT1 GT1 GT1 GT2/3 GT2/3 GT2/3 IFN α-2a +RBV peg-IFN α-2a + placebo peg-IFN α-2a +RBV

  21. 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

  22. What’s the biggest bang for your buck? EtOH Opportunistic Infections Other Medications Viral Hepatitis HCV Treatment Antiretrovirals ImmuneReconstitution Herbal Remedies Transplantation

  23. Intervention #1: Alcohol • Alcohol Cessation • Diminished Injury to Liver • Immune Restoration with HAART • HCV RNA Reduction SVR with Interferon

  24. Intervention #2: HAART • HIV • Obvious Benefits • HCV • Slows Fibrosis • Reduced Liver-Specific Mortality • More likely to ‘work’ and for patients to stay on treatment

  25. Intervention #3: HCV Therapy • Potentially Liver and Life Saving • Reduced Efficacy in HIV-HCV Co-Infection • Side Effects

  26. Acknowledgement • Louise Balfour • BMS • WAC Organizing Committee • Ottawa Hospital Division of Infectious Diseases • Immunodeficiency Clinic • Viral Hepatitis Program

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