1. ADAP ADVOCACY ASSOCIATION 2013 HIV/HCV CO-INFECTION ADAP SUMMIT ROBERT L. CALDWELL, PH.D. A MEDICAL PERSPECTIVE ON HIV/HCV CO- INFECTION HIV and Hepatitis C Co-Infection

2. GENERAL OVERVIEW OF HEPATITIS C HIV AND HEPATITIS C – DIFFERENCES AND SIMILARITIES HIV AND HEPATITIS C CO-INFECTION TREATMENT OF THE CO-INFECTED PATIENT Agenda

3. HCV STATISTICS THE HCV DIAGNOSIS HCV TRANSMISSION & PREVENTION HCV SYMPTOMS, DISEASE PROGRESSION, MANAGEMENT Hepatitis C Overview

4. U.S. POPULATION (1.6% OVERALL) ~4 MILLION AMERICANS INFECTED 3.2 MILLION CHRONICALLY INFECTED Hepatitis C Statistics

5. Hepatitis C Is A Common Public Health Problem In The U.S. Sulkowski MS et al. Clin Infect Dis. 2000;30 Kim WR et al, Gastro 2009:137; Ly KN et al AnnIntMed 2012: 156; Kanwal F et al Gastro 2011;140 0 1 2 3 4 5 Population Number infected (millions) HCV HIV DEATHS: 8,000 – 15,000/YEAR - 56% INCREASE IN HCV ASSOCIATED MORTALITY (1999 – 2007) HCV IS THE LEADING CAUSE OF  CHRONIC LIVER DISEASE  CIRRHOSIS  LIVER CANCER : 50% OF CASES (HCC FASTEST RISING CAUSE OF CANCER-RELATED DEATH)  LIVER TRANSPLANTATION

6. HCV ELISA IMMUNOASSAY (EIA) MOST COMMON ANTIBODY TEST POSITIVE ANTIBODY TEST INDICATES EXPOSURE DOES NOT INDICATE ACTIVE HEPATITIS C INFECTION HCV Diagnostics: Antibody Tests

7. GOLD STANDARD FOR DETERMINING THE HEALTH OF THE LIVER MEASURE OF INFLAMMATION EXTENT OF SCARRING (IF ANY) NON-INVASIVE METHODS – NOT AS ACCURATE HCV Diagnostics: Liver Biopsy

8. Transmission and Prevention Shared NeedlesAll Drug Paraphernalia Blood Before 1992 - transfused, products, procedures Sexual Transmission (1-3%) Healthcare Workers – needle sticks Shared House-hold items – razors & toothbrushes Mother to Child <5%Tattoos / Piercing <10% of routes can not be identified

9. HCV IS NOT SPREAD BY BREAST FEEDING, SHARING EATING UTENSILS OR DRINKING GLASSES, KISSING, HUGGING DIRECT BLOOD TO BLOOD TRANSMISSION ROUTE Transmission and Prevention

10. HCV Infection Demographics (US) HCV Infection Demographics (US) GeneralPopulation 1.6% 1.6% White: 1.5% African American: 3% African American Males, 50-59 years of age: 13.6% Veterans(esp. Vietnam) : ~20% HIV + people: 25-30% Homeless people: ~40% Current & former IDU: up to 90%

11. Chronic HCV Symptoms LIVER PAIN LOSS OF APPETITE HEADACHES GASTRO PROBLEMS FATIGUE – MILD TO SEVERE FLU-LIKE SYMPTOMS (MUSCLE/JOINT/FEVER) ‘BRAIN FOG’

12. 10-25% OF HCV POSITIVE PEOPLE PROGRESS TO SERIOUS LIVER DAMAGE OVER 10-40 YEARS FIBROSIS LIGHT SCARRING CIRRHOSIS COMPENSATED VS. DECOMPENSATED STEATOSIS FATTY DEPOSITS IN THE LIVER HCV Disease Progression

13. WHAT IS INTERFERON? GENERAL ANTIVIRAL – IMMUNE BOOSTER BY INJECTION WHAT IS RIBAVIRIN? ANTIVIRAL USED ONLY IN COMBINATION WITH INTERFERON PILL OR CAPSULE HCV Treatment

14. AGE > 50 YEARS DURATION OF INFECTION MALE GENDER IRON OVERLOAD STEATOSIS ALCOHOL CO-INFECTION WITH HIV Factors Associated with Disease Progression in HCV Infected Patients NOT ASSOCIATED: HCV “VIRAL LOAD” HCV GENOTYPE SERUM ALT ? SMOKING

15. HIV ~1,000,000 HCV ~4,000,000 HIV ~1,000,000 HCV ~4,000,000 Comparisons – Prevalence in the United States

16. Deaths Associated With Hepatitis C Have Overtaken Deaths Caused By HIV Lk KN et al, Ann of Int Med 2012:156 Holmberg S et al, CDC, AASLD 2011

17. VIROLOGICAL COMPARISONS TRANSMISSION AND DIAGNOSIS CO-INFECTION STATISTICS DISEASE PROGRESSION TREATMENT RESPONSE Hepatitis C and HIV/HCV Co- Infection

18. C0-Infection Statistics IN THE U.S., AN ESTIMATED 1/4 OF THOSE INFECTED WITH HIV ARE ALSO INFECTED WITH HEPATITIS C VIRUS (HCV). ESTIMATES OF HIV/HCV CO-INFECTION RANGE FROM 50- 90% AMONG CERTAIN SUB-POPULATIONS. SUPPORTING EVIDENCE THAT HIV NEGATIVELY IMPACTS HCV DISEASE PROGRESSION AND REDUCES THE EFFECTIVENESS OF AVAILABLE TREATMENTS.

19. HIV Comparisons HCV SINGLE STRANDED RNA RETROVIRUS INTEGRATES INTO DNA SINGLE STRANDED RNA FLAVIVIRUS DOES NOT INTEGRATE INTO DNA

20. HIV Comparisons HCV MAINLY INFECTS CD 4+ CELLS, MACROPHAGES AND DENDRITIC CELLS DAILY – REPLICATES BILLIONS HIGH MUTATION RATE MAINLY INFECTS LIVER CELLS DAILY – REPLICATES TRILLIONS VERY HIGH MUTATION RATE

21. HIV Comparisons www.hcvadvocate.org HCV CHRONIC – 100% US – 1 MAJOR STRAIN HIGH SEXUAL TRANSMISSION RATE HIGH IDU TRANSMISSION RATES (BLOOD) CHRONIC RATES - 55-85% US – 3 MAJOR STRAINS VERY HIGH SEXUAL TRANSMISSION RATE VERY HIGH IDU TRANSMISSION RATES (BLOOD)

22. HIV Comparisons HCV Cure?  No Treatment - lifelong Can become resistant Cure?  Virological Cure Treatment 24 to 48 weeks No resistant issues yet  New direct antivirals will lead to resistance

23. HCV HCV Transmission HIV/HCV Co-Infection SEXUAL TRANSMISSION IS (0-3%) MOTHER-TO-CHILD TRANSMISSION ~5-6%  HCV MEDS CAN CAUSE BIRTH DEFECTS SEXUAL TRANSMISSION IS HIGHER (~ 15-25%) MOTHER-TO-CHILD TRANSMISSION ~25%  HCV MEDS CAN CAUSE BIRTH DEFECTS

24. HEPATITIS C Diagnosing HCV HIV/HCV CO-INFECTION ANTIBODY TEST HCV VIRAL LOAD TO CONFIRM ACTIVE INFECTION ANTIBODY TEST  NOTE: IF LOW CD4+ CELL COUNT, MEASURE HCV RNA HCV RNA TO CONFIRM ACTIVE INFECTION *PEOPLE WITH A COMPRISED IMMUNE SYSTEM MAY NOT DEVELOP HCV ANTIBODIES

25. STILL A CONTROVERSIAL ISSUE BUT MOST EXPERTS DO NOT BELIEVE THAT HCV MAKES HIV WORSE HCV may blunt immune system reconstitution. Does HCV Make HIV Worse?

26. HIV ACCELERATES HCV DISEASE PROGRESSION, DOUBLING THE RISK FOR CIRRHOSIS AND INCREASES THE CHANCE FOR LIVER CANCER. CLINICAL TRIALS SUGGEST THAT WHEN HIV INFECTION IS CONTROLLED, HCV DISEASE PROGRESSION IS CONTROLLED IN PEOPLE CO-INFECTED. Does HIV Make HCV Worse?

27. HCV Co-Infection is Common in HIV Infected Subjects 0 2020 4040 6060 8080 100 Population Percentage IVDU 90% MSM 10% All HIV+ 33% US Pop. 1.9% Sulkowski MS, et al. Clin Infect Dis. 2000;30:

28. HEPATITIS C HCV Disease Progression HIV/HCV Co-Infection SLOW RATE OF DISEASE PROGRESSION – USUALLY OVER 10, 20, 30 YEARS FASTER RATE OF DISEASE PROGRESSION TO CIRRHOSIS – UP TO 2-3 TIMES FASTER & CAN OCCUR IN AS LITTLE AS 10 YEARS HCV CO-INFECTION IS THE LEADING CAUSE OF DEATH AMONG PEOPLE WITH HIV

29. HIV Co-Infection Accelerates Liver Fibrosis Progression Rate HCV - infection duration (years) 0 Fibrosis Grades (METAVR scoring system) HIV positive (n=122) Matched controls (n=122) 4 3 2 1 0 1020 30 40 Terrault et al. HEPATOLOGY 2009 AASLD, Stock P et al: Abstract HIV and Liver Disease 2010

30. Patient Survival Post Liver Transplant: Mono- vs. C0-Infection P=0.01 HCV mono-infected N=135 N=67 N=22 HCV-HIV co-infected N=46 N=28 N=14 P=0.01 Terrault et al. HEPATOLOGY 2009 AASLD, Stock P et al: Abstract HIV and Liver Disease 2010

31. HCV IS COMMON IN HIV PATIENTS (APPROX 25-40% IN U.S.) HCV IS A MORE SERIOUS DISEASE IN CO- INFECTED PATIENTS THAN IN MONOINFECTED. HCV HAS BECOME ONE OF THE LEADING CAUSES OF DEATH IN THE HIV POPULATION. HCV CO-INFECTION CARRIES SIGNIFICANT MORBIDITY, LIMITS ANTI-RETROVIRAL OPTIONS, DECREASES QUALITY OF LIFE. Why Treat HIV/HCV Co-Infected Patients?

32. GENERALLY, HIV SHOULD BE UNDER CONTROL TREAT THE HIV INFECTION FIRST. PEOPLE CO-INFECTED SHOULD BE CONSIDERED FOR HCV TREATMENT UNLESS: CD4+ COUNTS LESS THAN 200, AND/OR ACTIVE OPPORTUNISTIC ILLNESS ARE PRESENT When and Which to Treat?

33. GENERALLY, SOME MEDICATIONS INCLUDING HIV MEDICATIONS CAN BE DIFFICULT FOR A LIVER TO PROCESS. HIV MEDS TEMPORARILY INCREASE LIVER ENZYMES AS WELL AS HCV VIRAL LOAD. THESE USUALLY STABILIZE OVER TIME. IF ALT’S 4 TO 5 TIMES BASELINE, THEN CHANGE TO MORE “LIVER-FRIENDLY” HIV MEDICATIONS. HIV Meds and the Liver

34. HIV SPECIALIST AND LIVER SPECIALIST SHOULD CLOSELY FOLLOW CO-INFECTED PEOPLE MONITOR LIVER FUNCTIONS ESPECIALLY WHEN ON HIV TREATMENT SWITCH TO MORE “LIVER-FRIENDLY” HIV MEDICATIONS Recommendations

35. TWO OR MORE POTENTIALLY LIFE- THREATENING CONDITIONS LACK OF AWARENESS LACK OF SUPPORT FINANCIAL BURDENS Psychological Impact

36. GREGORY PAPPAS, M.D. HIV/AIDS, HEPATITIS, STD, AND TB ADMINISTRATION, D.C. DEPARTMENT OF HEALTH DAWN FISHBEIN, M.D., M.S. WASHINGTON HOSPITAL CENTER, MEDSTAR HEALTH ROHIT TALWANI, M.D. ASSISTANT PROFESSOR AT UNIVERSITY OF MARYLAND - INSTITUTE OF HUMAN VIROLOGY Acknowledgements Contact Information: Robert L. Caldwell, Ph.D. robertcaldwell@icloud.com