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HIV and Hepatitis C Co-infection: Current Standards and New Paradigms

HIV and Hepatitis C Co-infection: Current Standards and New Paradigms. Todd S. Wills, MD Associate Professor of Internal Medicine Division of Infectious Disease and International Medicine USF Health Faculty, Florida/Caribbean AIDS Education and Training Center.

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HIV and Hepatitis C Co-infection: Current Standards and New Paradigms

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  1. HIV and Hepatitis C Co-infection: Current Standards and New Paradigms Todd S. Wills, MD Associate Professor of Internal Medicine Division of Infectious Disease and International Medicine USF Health Faculty, Florida/Caribbean AIDS Education and Training Center

  2. Disclosure of Financial Relationships This speaker has significant financial relationships with the following commercial entities to disclose: • Grants/Research Support: Gilead Sciences This speaker will not discuss any off-label use or investigational product during the program. This slide set has been peer-reviewed to ensure that there are no conflicts of interest represented in the presentation.

  3. Objectives • Review current HCV standard of care • Discuss the current use of HCV protease inhibitors in dually infected patients • Identify agents in the HCV therapeutic pipeline and implications for HIV care

  4. Hepatitis C Treatment Guideline Resource Card Available online at www.fcaetc.org/treatment

  5. HCV/HIV Co-infection • Higher rates of progressive liver disease in HIV/HCV co-infection • Unclear whether HCV increases HIV progression • Poor prognosis; unclear whether HIV treatment improves morbidity and mortality for untreated HCV • Higher rates of ARV-associated hepatotoxicity Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 20, 2012

  6. To Treat or Not to Treat: A Constellation of Considerations Genotype: virus, patient (IL28B) Histologic stage 20%+ lifetime risk of cirrhosis Duration of infection Personal plans (marriage, pregnancy) Family and other support Age Patient mindset ALT Occupation Extrahepatic features (fatigue, EMC, PCT) HIV co-infection Contraindications & comorbidities; insulin resistance from Clinical Care Options

  7. In which clinical situation is treatment of HCV absolutely contraindicated? • Renal Failure • Cyroglobulinemic vasculitis • Uncontrolled Major Depression • Current alcohol or drug use

  8. HCV/HIV Co-infection • Higher rates of progressive liver disease in HIV/HCV co-infection • Unclear whether HCV increases HIV progression • Poor prognosis; unclear whether HIV treatment improves morbidity and mortality for untreated HCV • Higher rates of ARV-associated hepatotoxicity Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 20, 2012

  9. HCV/HIV Co-infection: When to Treat • Strongly recommended for detectable plasma HCV RNA and bridging or portal fibrosis on liver biopsy • Consider other factors: • Stage and stability of HIV disease • Other comorbidities • Probability of adherence • Possible contraindications to HCV medications • Prognosis for favorable response Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed February 20, 2012

  10. Assessment of Alcohol and Substance Abuse • Ongoing Alcohol use? Amount? • Ongoing Substance Abuse? Amount? • How much use is acceptable?

  11. Indicators of Decompensated Cirrhosis • Development of ascites • Variceal hemorrhage • Hepatic encephalopathy* • Jaundice • Hepatocellular carcinoma* • Screen via ultrasound every 6 months for patients with cirrhosis or bridging fibrosis * can occur even in incomplete cirrhosis Morgan T, Hepatitis Annual Update 2009. clinicaloptions.com – accessed March 12, 2011

  12. Evaluation of Liver Status and Transplantation Referral • Prognosis via MELD (Model for end stage liver disease) score should be assessed periodically • Calculator available at: http://www.mayoclinic.org/mel/mayomodel6.html • Score greater than 10 indicates need for possible liver transplantation referral

  13. Mental Health Assessment • Mental Health Referral • CES-D or PHQ-9 questionnaires

  14. Factor Predicting Favorable Response • HCV Genotype 2, 3 • HCV RNA level <400,000 • IL-28B genotype CC • Non-African American race • Absence of bridging fibrosis or cirrhosis • Body weight <75 kg • Age <40 • Baseline ALT > 3x ULN May be less predictive of response with use of direct acting antivirals Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

  15. Factors Favoring Initiation of Therapy • Patient motivation • Biopsy with chronic hepatitis and greater than portal fibrosis • Cryoglobulinemic vasculitis or Cryoglobulinemic kidney disease • Stable HIV disease • Compensated liver disease • Acceptable hematologic parameters • Serum creatinine <1.5

  16. Overcoming Barriers to Treatment Initiation • Substance Abuse Counselors • Opioid Dependence Treatment • Patient Education • Peer-Based Counseling • Group Counseling • Clinic-Based Injections

  17. Selecting Patients for Treatment • Need to differentiate between nonsignificant fibrosis and significant fibrosis • International Association for the Study of the Liver scoring system for staging liver fibrosis • Assess liver fibrosis; options include • Liver biopsy • Noninvasive markers of hepatic fibrosis • Transient elastography Ghany M, et al. Hepatol. 2009;49:1335-1374. Soriano V, et al. AIDS. 2007;21:1073-1089.

  18. Absolute Contraindications to Therapy • Uncontrolled active major psychiatric illness • Hepatic decompensation (hepatic encephalopathy, coagulopathy, or ascites) • Uncontrolled HIV with advanced immunosuppression (CD4 < 100 cells/mm3) • Known allergy or severe adverse reaction to interferon and/or ribavirin Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

  19. Absolute Contraindications to Therapy • Women who are pregnant, nursing, or are of childbearing potential and not able to practice contraception • Men who have pregnant partners or partners of childbearing potential and unwilling to practice contraception during treatment and for 6 months after treatment ends • Active, untreated autoimmune disease (e.g., systemic lupus erythematosus) known to be exacerbated by peginterferon and ribavirin • Uncontrolled thyroid disease Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

  20. Relative Contraindications to Treatment • Significant hematologic abnormality: hemoglobin < 10.0 g/dl, absolute neutrophil count < 1,000/μl, or platelet count < 50,000/μl • CD4 <200 cells/mm3 • Patients concurrently receiving zidovudine • Renal dysfunction – (consider specialist referral) Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

  21. Relative Contraindications to Treatment • Autoimmune disorders (systemic lupus erythematosus, rheumatoid arthritis) • Active substance use or ongoing alcohol use if interference with adherence is anticipated • Untreated mental health disorder • Hemoglobinopathies (e.g., thalassemia major and sickle cell anemia) • Sarcoidosis • Solid organ transplantation patients Sulkowski, M, et al. A Guide for Evaluation and Treatment of Hepatitis C in Adults Coinfected with HIV http://hab.hrsa.gov/deliverhivaidscare/files/hepccoinfectguide2011.pdf. Accessed February 21,2012

  22. PegIFN/RBV: Current Standard-of-Care Treatment for HCV/HIV Co-infected Patients

  23. Ribavirin Dose Adjustments in Renal Impairment Specialty referral recommended for HCV treatment in the setting of renal impairment Labeling change for Pegasys and Copegus re: dosing patients with renal impairment. http://www.fda.gov/ForConsumers/ByAudience/ForPatientAdvocates/ucm267594.htm Accessed March 6, 2012

  24. Areas of Advancement in HIV/HCV Therapy • Specific HCV antiviral therapy trials • Limitations of Predictive Biomarkers • Implications of HCV drug resistance

  25. HCV Response Rates in HIV+ and HIV- Patients Treated with PegIFN/RBV APRICOT HIV-Positive Overall SVR: 40% PRESCO HIV-Positive Overall SVR: 50% FRIED HIV-Negative Overall SVR: 56% 100 76 80 72 62 60 46 Patients With SVR (%) 36 40 29 20 n = 176 95 191 152 298 140 0 GT1/4 GT2/3 GT1/4 GT2/3 GT1/4 GT2/3 48 Wks of Therapy,600 mg RBV 24, 48, or 72 Wks of Therapy,Weight-Based RBV 48 Wks of Therapy,Weight-Based RBV Soriano V, et al. Care of patients coinfected with HIV and hepatitis C virus: 2007 updated recommendations from the HCV–HIV International Panel AIDS. 2007;21:1073-1089.

  26. Potential HCV Antiviral Targets C E1 E2/NS1 NS2 NS3 NS4A NS4B NS5A NS5B 5’ 3’ Internal ribosomal entry site RNA binding site Envelope glyco- proteins Signal peptide Serine protease/ helicase RNA dependent RNA polymerase telaprevir, boceprevir

  27. An HCV viral load below the quantitative limit of detection 4 weeks after initiating HCV treatment is called: • Early virologic response (EVR) • End-of-treatment response (EOT) • Rapid virologic response (RVR) • Sustained virologic response (SVR)

  28. Response Terminology

  29. Adherence Triple therapy presents challenges with already busy schedules[143] TID dosing Food requirements Data show pegIFN/RBV adherence decreases over time[5] Addition of PIs may exacerbate this trend 1. Telaprevir [package insert]. May 2011. 2. Boceprevir [package insert]. May 2011. 3. EMA. Boceprevir [package insert] 2011.4. EMA. Telaprevir [package insert] 2011. 5. Lo Re V 3rd, et al. Ann Intern Med. 2011;155:353-360. from Clinical Care Options

  30. Study 110: High Rates of Early Response With TVR + PR in Co-infected Patients • Similar efficacy results observed with or without concurrent ART • Nausea, pruritus, dizziness, fever more common with TVR vs placebo • Pharmacokinetic interactions with ATV or EFV not clinically significant Undetectable HCV RNA, Week 4 (ITT) Undetectable HCV RNA, Week 12 (ITT) No ART ATV/RTV-based ART EFV-based ART Total 100 100 75 75 71 71 80 80 70 68 64 57 60 60 Undetectable HCV RNA (%) Undetectable HCV RNA (%) 40 40 17 14 12 20 12 12 20 5 0 0 0 0 12/16 9/14 26/37 5/7 0/6 1/8 0/8 1/22 12/16 8/14 25/37 n/N = 5/7 1/6 1/8 1/8 3/22 n/N = Telaprevir + PR PR Telaprevir + PR PR Sulkowski M, et al. CROI 2011. Abstract 146LB.

  31. Study 110 – SVR 12 Data Dieterich D, et al. CROI 2012 Abstract 46

  32. Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects *no cases of severe rash Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8

  33. Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs Sulkowski, M. CROI 2012 Abstract 47

  34. Boceprevir Interactions with HIV Medications • No clinically relevant changes in boceprevir exposure when co-administered with ethinyl estradiol or tenofovir. • Boceprevir AUC and Cmax decreased, minimum concentration (Cmin) fell by about 40% when administered with efavirenz. • Boceprevir co-administered with ritonavir-booster HIV protease inhibitors may reduce the levels of both drugs. CROI 2011 Abstract 118: Merck & Co, Inc, Kenilworth, NJ. Merck & Co. Inc. Results of pharmacokinetic study in healthy volunteers given VICTRELIS™ (boceprevir) and ritonavir-boosted HIV protease inhibitors may indicate clinically significant drug interactions for patients coinfected with chronic hepatitis C and HIV. Feb 6 , 2012. (http://www.merck.com/newsroom/pdf/FINAL_DHCP_2_6_2012.pdf)

  35. Telaprevir Interactions with HIV PIs • Telaprevir AUC and Cmin decreased by only about 15% when administered 750 mg 3-times-daily with boosted atazanavir. • Telaprevir levels fell by about 50% when administered at the same dose with lopinavir/ritonavir. • Telaprevir levels decreased by about 30% when taken with darunavir/ritonavir or fosamprenavir/ritonavir. • Conversely, darunavir and fosamprenavir levels fell by more than half when co-administered with telaprevir. • Atazanavir Cmin nearly doubled when taken with 750 mg telaprevir. CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA

  36. Telaprevir Dosing Recommendations • Based on these findings, researchers chose 750 mg 3-times-daily telaprevir plus atazanavir/ritonavir, or telaprevir 1125 mg 3-times-daily with efavirenz as regimens to evaluate in clinical trials of HIV/HCV coinfected patients. CROI 2011 Abstract 119: Tibotec BVBA, Beerse, Belgium; Vertex Pharmaceuticals Inc, Cambridge, MA

  37. Telaprevir Interactions with Raltegravir • Co-administration of raltegravir did not influence telaprevir exposure or pharmacokinetics. • Co-administration of telaprevir increased exposure to raltegravir by 31%. • The least square means ratios for raltegravirCmin, Cmax, and AUC12h were 1.78, 1.26, and 1.31, respectively. • The 2 drugs were generally well-tolerated. • All adverse events were mild-to-moderate (grade 1-2) and no participants discontinued early due to adverse events. R van Heeswijk et al. The Pharmacokinetic Interaction Between Telaprevir & Raltegravir in Healthy Volunteers ICAAC Chicago Sept 17-20 2011

  38. Investigational Agents

  39. PSI-7977 – Phase II Trial Data HCV uridine nucleotide analogue Genotype 1 Genotype 2/3 Lawritz, E. et al. J of Hepatology 54 (s1) 2012

  40. TMC-435 – Phase IIb Trial Data • HCV NS3/4A Protease Inhibitor (Once-Daily) • Prior Treatment Failures 100 mg 150 mg P<0.001 vs placebo Zeuzem S., et al. J of Hepatology 54 (s1) 2012

  41. Interferon Sparing Strategies • ABT 450/r – ritonovir boosted HCV PI + • ABT 072 – HCV polymerase inhibitor + • Weight-based ribavirin • Open label 12 week treatment trial 11 patients • Interferon sparing • 91% SVR24 • One patient relapsed 8 weeks post Rx • All patients were IL28B CC Lawritz, E. et al. J of Hepatology 56 (s1) 2012

  42. Interferon AND Ribavirin Sparing Strategies • Daclatasvir (NS5A replication complex inhibitor) + • Asunaprevir (HCV NS3 PI) • Open label trial of both drugs in 43 prior null responders or with IFN/R intolerance Suzuki, F. et al. J of Hepatology 56 (s1) 2012

  43. Predictive Biomarkers

  44. Which of the following is more likely if a patient is IL28B genotype CC? • Spontaneous clearance of HCV • HCV treatment failure with interferon based therapy • Slower progression to cirrhosis if HIV/HCV co-infected

  45. Percentage of SVR by Genotypes for IL-28B Region DL Ge et al. Nature 461, 399-401 (2009)

  46. Rate of SVR and IL-28 Region C-allele Frequency in Diverse Ethnic Groups DL Ge et al. Nature 461, 399-401 (2009)

  47. SVR to Telaprevir by Response Category and IL28B Genotype Pol S, et al. EASL 2011. Abstract O-13.

  48. Effect of Unfavorable IL28b Genotype is Less in Caucasian Genotype 2/3 HCV Infection P=0.45 P=0.34 P=0.0002 Genotype 2, N=213; Genotype 3, N=55 Mangia A, et al. Gastroenterology 139 (3) 821-827 (2010)

  49. Proportion of HIV/HCV Co-infected Patients with Liver Cirrhosis, According to IL28B Variants and HCV Genotypes Barreiro P et al. J Infect Dis. 2011;203:1629-1636

  50. Risk for Developing HCV–related Liver Cirrhosis Over Time in HIV/HCV Co-infected Patients, According IL28B Variant Barreiro P et al. J Infect Dis. 2011;203:1629-1636

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