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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 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. 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 Hepatitis C Treatment Guideline Resource Card Available online at www.fcaetc.org/treatment 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 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) Age Family and other support Patient mindset ALT Occupation HIV co-infection Contraindications & comorbidities; insulin resistance Extrahepatic features (fatigue, EMC, PCT) from Clinical Care Options In which clinical situation is treatment of HCV absolutely contraindicated? A. Renal Failure B. Cyroglobulinemic vasculitis C. Uncontrolled Major Depression D. Current alcohol or drug use 54% 28% 16% 2% A. B. C. D. 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 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 Assessment of Alcohol and Substance Abuse • Ongoing Alcohol use? Amount? • Ongoing Substance Abuse? Amount? • How much use is acceptable? 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 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 Mental Health Assessment • Mental Health Referral • CES-D or PHQ-9 questionnaires Factor Predicting Favorable Response • • • • • • • • HCV Genotype 2, 3 HCV RNA level <400,000 May be less predictive of IL-28B genotype CC response with use of direct acting antivirals Non-African American race Absence of bridging fibrosis or cirrhosis Body weight <75 kg Age <40 Baseline ALT > 3x ULN 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 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 Overcoming Barriers to Treatment Initiation • • • • • • Substance Abuse Counselors Opioid Dependence Treatment Patient Education Peer-Based Counseling Group Counseling Clinic-Based Injections 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 • Stage 0 1 2 3 4 Score None Significance Mild Moderate Nonsignificant Severe Significant • 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. Cirrhosis 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 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 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 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 PegIFN/RBV: Current Standard-of-Care Treatment for HCV/HIV Co-infected Patients Regimens for Genotype 1 and 4 x 48 weeks 180 mcg sc weekly pegylated interferon alfa-2a AND ribavirin* ≤ 75 kg: 1000 mg/day in 2 divided doses >75 kg: 1200 mg/day in 2 divided doses pegylated interferon alfa-2b AND ribavirin 1.5 mcg/kg sc weekly < 65 kg: 800 mg/day in 2 divided doses 66-80 kg: 1,000 mg/day in 2 divided doses 81-105 kg: 1,200 mg/day in 2 divided doses >105 kg: 1,400 mg/day in 2 divided doses Regimens for Genotype 2 and 3 x 48 weeks pegylated interferon alfa-2a* OR 180 mcg sc weekly pegylated interferon alfa-2b 1.5 mcg/kg sc weekly AND ribavirin* 800 mg daily *ribavirin and pegylated interferon alfa-2a doses should be reduced in patients with a creatinine clearance <50 ml/min. No data is available for the use of pegylated interferon alfa-2b/ribavirin in patients with a CrCl <50 mL.min. Ribavirin Dose Adjustments in Renal Impairment Creatinine Clearance pegylated interferon alfa-2a dose Ribavirin dose 30-50 mL/min 180 mcg/week 200 mg alternating with 400 mg every other day < 30 mL/min 135 mcg/week 200 mg daily Hemodialysis 135 mcg/week 200 mg daily 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 Areas of Advancement in HIV/HCV Therapy • Specific HCV antiviral therapy trials • Limitations of Predictive Biomarkers • Implications of HCV drug resistance HCV Response Rates in HIV+ and HIV- Patients Treated with PegIFN/RBV APRICOT HIV-Positive PRESCO HIV-Positive FRIED HIV-Negative Overall SVR: 40% Overall SVR: 50% Overall SVR: 56% Patients With SVR (%) 100 80 76 72 62 60 40 46 36 29 20 0 n = 176 95 191 152 298 140 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. Potential HCV Antiviral Targets 5’ Internal ribosomal entry site C RNA binding site E1 E2/NS1 Envelope glycoproteins NS2 Signal peptide NS3 NS4A NS4B Serine protease/ helicase telaprevir, boceprevir NS5A NS5B RNA dependent RNA polymerase 3’ An HCV viral load below the quantitative limit of detection 4 weeks after initiating HCV treatment is called: A. Early virologic response (EVR) B. End-of-treatment response (EOT) C. Rapid virologic response (RVR) D. Sustained virologic response (SVR) 52% 42% 5% 2% A. B. C. D. Response Terminology Term Time Point HCV RNA Level Rapid virologic response (RVR) Wk 4 of therapy Undetectable Early virologic response (EVR) Wk 12 of therapy ≥ 2 log10 IU decrease from baseline Complete early virologic response (cEVR) Wk 12 of therapy Undetectable Slow to respond Wk 24 of therapy Undetectable (but with detectable HCV RNA at Wk 12) End of therapy Undetectable 6 mos post-therapy Undetectable End of treatment response (EOT or ETR) Sustained virologic response (SVR) 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 Busy Sales Professional Monday Monday 6:00 AM TVR/BOC (with food) + RBV TVR/BOC (with food) + RBV 7:00 AM 8:00 AM 9:00 AM Daily Team Conference Call 11:00 AM English Composition Travel to and Meet With Client Lunch Lunch 1:00 PM Lunch Biology TVR/BOC (with food) Dentist Appt 4:00 PM Work Travel to and Meet With Clients 5:00 PM Dinner RBV Patient Appointments TVR/BOC (with food) Pick up kids, commute home RBV 7:00 PM Running Club Dinner Study Group Researching Trade Articles 9:00 PM 10:00 PM TVR/BOC (with food) Calls to Clients 3:00 PM 8:00 PM TVR/BOC (with food) + RBV Wake, feed, and dress children for school School and daycare drop-off, commute to work Patient Appointments 12:00 PM 2:00 PM Mother With Small Children and Full-time Nurse Monday Chemistry Lab 10:00 AM 6:00 PM 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. Typical Student TVR/BOC (with food) TVR/BOC (with food) from Clinical Care Options Dinner RBV Get children ready for and in to bed Dinner cleanup, make lunches for next day TVR/BOC (with food) 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) No ART EFV-based ART Undetectable HCV RNA, Week 12 (ITT) ATV/RTV-based ART Total 80 100 71 75 64 70 60 40 12 20 0 n/N = 5/7 12/16 9/14 26/37 Telaprevir + PR 0 0 5 0/6 1/8 0/8 1/22 Undetectable HCV RNA (%) Undetectable HCV RNA (%) 100 80 60 71 75 68 57 40 17 12 12 14 20 0 PR Sulkowski M, et al. CROI 2011. Abstract 146LB. n/N = 5/7 12/16 8/14 25/37 Telaprevir + PR 1/6 1/8 1/8 PR 3/22 Study 110 – SVR 12 Data Telaprevir Group N=38 Placebo Group SVR12 28/38 (74) 10/22 (45) On Treatment Virologic Failure 3/38 (8) 8/22 (36) Not Suppressed at End of Treatment 5/37 (14) 9/22 (41) Relapse 1/32 (3) 2/13 (15) Dieterich D, et al. CROI 2012 Abstract 46 Telaprevir plus PegINF and Ribavirin in HIV/HCV Infected Patients – Side Effects Adverse Effect TVR+PR PR Pruritis or Itching 39% 9% Headache 37% 27% Nausea 34% 23% Skin Rash* 34% 23% Fever 21% 9% Anemia 13% 18% Depression 21% 9% Insomnia 13% 23% *no cases of severe rash Sherman, KE et al.. AASLD Conference November 2011 – Late Breaker Abstract 8 Boceprevir in Addition to Pegylated INF alfa 2a in HIV/HCV Patients on ARVs Sulkowski, M. CROI 2012 Abstract 47 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) 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 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 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 raltegravir Cmin, 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 Investigational Agents PSI-7977 – Phase II Trial Data HCV uridine nucleotide analogue 12 WEEK Treatment PSI-7977/P/R n=47 PSI 7977/P/R PSI 7977/R n=54 n=10 PSI-7977 n=10 EOT 43 54 10 10 Week 1-4 Relapse 1 0 0 4 SVR 4 42 54 10 6 > Week 4 Relapse 0 0 0 0 SVR 12 42 54 10 pending SVR 24 42 41 (11 pend) 4 (6 pend) pending Genotype 1 Genotype 2/3 Lawritz, E. et al. J of Hepatology 54 (s1) 2012 TMC-435 – Phase IIb Trial Data • HCV NS3/4A Protease Inhibitor (Once-Daily) • Prior Treatment Failures TMC12/P R48 n=66 TMC24/ PR48 N=65 TMC48/P R48 N=66 TMC12/P R48 n-=66 TMC24/P R48 N=68 TMC48/PR Pbo48/P 48 R48 N=65 N=66 RVR Total 44/66 (67) 38/65 (59) 35/66 (53) 41/66 (62) 46/68 (68) 43/65 (66) 1/66 (2) SVR Total 46/66 (70) 43/65 (66) 40/66 (61) 44/66 (67) 49/68 (72) 52/65 (80) 15/66 (23) SVR Null 6/16 (38) 9/16 (56) 8/18 (44) 9/17 (53) 7/17 (41) 10/17 (59) 3/16 (19) SVR Partial 16/23 (70) 11/23 (48) 12/22 (55) 15/23 (65) 18/24 (75) 19/22 (86) 2/23 (9) SVR Relapse 24/27 ( 89) 23/26 (89) 20/26 (77) 20/26 (77) 24/37 (89) 23/26 (89) 10/27 (37) 100 mg 150 mg P<0.001 vs placebo Zeuzem S., et al. J of Hepatology 54 (s1) 2012 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 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 Null Responders N=21 IFN/R Ineligible or Intolerant N=22 IL28B CC 3/21 (14.3) 16/22 (72.7) RVR 11/21 (52.4) 19/22 (86.4) cEVR 19/21 (90.5) 20/22 (90.9) EOT 18/21 (85.7) 16/22 (72.7) SVR 12 19/21 (90.5) 14/22 (63.6) Suzuki, F. et al. J of Hepatology 56 (s1) 2012 Predictive Biomarkers Which of the following is more likely if a patient is IL28B genotype CC? A. Spontaneous clearance of HCV B. HCV treatment failure with interferon based therapy C. Slower progression to cirrhosis if HIV/HCV co-infected 47% 29% 24% A. B. C. Percentage of SVR by Genotypes for IL-28B Region DL Ge et al. Nature 461, 399-401 (2009) Rate of SVR and IL-28 Region C-allele Frequency in Diverse Ethnic Groups DL Ge et al. Nature 461, 399-401 (2009) SVR to Telaprevir by Response Category and IL28B Genotype Pol S, et al. EASL 2011. Abstract O-13. Effect of Unfavorable IL28b Genotype is Less in Caucasian Genotype 2/3 HCV Infection P=0.45 P=0.34 Genotype 2, N=213; Genotype 3, N=55 Mangia A, et al. Gastroenterology 139 (3) 821-827 (2010) P=0.0002 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 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 Predictors of Liver Cirrhosis in Human Immunodeficiency Virus (HIV)–Hepatitis C Virus (HCV) Co-infected Patients, by Logistic Regression Analysis Variable OR (95% CI) P-value Age (per year) 1.05 (0.99-1.12) 0.08 Male Sex 1.20 (0.42-3.44) 0.72 Prior ETOH >60g/d 1.97 (0.95-4.06) 0.07 ALT (per IU/L) 0.99 (0.94-1.06) 0.93 Nadir CD4 0.98 (0.99-1.01) 0.63 Receipt of ARVs 2.04 (0.42-9.93) 0.38 IL28B CC vs CT/TT 2.32 (1.22-4.41) 0.01 Barreiro P et al. J Infect Dis. 2011;203:1629-1636 Stable Viral Reservoirs Prevent Eradication of HIV Infection Courtesy of RF Siliciano from Clinical Care Options HCV Life Cycle From Clinical Care Options 2011HIV/HCV Annual Symposium; Stuart Ray, MD Reversion of Drug Resistance Mutations Following Telaprevir Failure US DHHS. Advisory committee briefing document for NDA 201-917 telaprevir 375 mg tablets. Primary Mutations Conferring Resistance to NS3/4A Protease Inhibitors Soriano V et al. Clin Infect Dis. 2009;48:313-320 Conclusions • HCV treatment in HIV-infected patients is of increasing importance as proportion of liverrelated morbidity and mortality in HIV increases • A comprehensive clinical approach is helpful in managing the multiple co-morbidities and treatment related complications in HIV/HCV infected patients • Novel HCV antivirals are significantly improving disease outcome in HCV