New York State HCV Provider Webinar Series. Treatment of HCV/HIV Co-Infection

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2 New York State HCV Provider Webinar Series Treatment of HCV/HIV Co-Infection

3 Objectives Review the epidemiology of HCV and HIV/HCV co-infection Discuss the burden of HIV/HCV co-infection Discuss the treatment considerations for coinfected population Understand drug drug interactions that are unique to the HIV/HCV co-infected population

4 Epidemiology of HCV and HCV/HIV Co-Infection

5 HCV Prevalence in the U.S million Reported (NHANES) 5-7 million Sarpel, et al. Expert Review of Anti-Infective Therapy

6 HCV Prevalence in the U.S million Reported (NHANES) 5-7 million True Sarpel, et al. Expert Review of Anti-Infective Therapy

7 HCV Prevalence in the U.S % unaware of HCV status million Reported (NHANES) 5-7 million True Sarpel, et al. Expert Review of Anti-Infective Therapy

8 What is the Gap Between Reported and True Prevalence Attributable to? A failure to count the following persons: Homeless Incarcerated Immigrant Nursing Home Residents Hospitalized Patients Military Personnel

9 Worldwide Burden HCV 115 Million HIV 40 Million Liver disease (largely due to HCV) is 2nd leading cause of death in HIV+ Sarpel, et al. Expert of Therapy Review Anti-Infective.

10 Best Estimates of Prevalence of Hepatitis C Virus (HCV) Co-Infection in Four Population Samples 2.4% 4% 6.4% 82.4% Risk of HCV infection 5-8 times higher across all patient groups in HIV+ compared to HIV- individuals Platt L, et al. Lancett Infect Dis Feb 24.

11 % Prevalence HCV The Longer the Duration of IVDU, the Higher the Risk of HCV Infection Pre-1995 Post Years Hagan, et al. Am J Epidemiol

12 No. of Cases per 100,000 Population Increases in Hepatitis C Virus Infection Related to Injection Drug Use Among Persons Age 30 Years Kentucky, Tennessee, Virginia, and West Virginia, Nonurban Urban Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. Vol. 64, No May 8.

13 HCV/HIV Co-Infection Outbreak in Indiana

14 HCV/HIV Co-Infection Outbreak in Indiana 92.3% Co-infected with HCV

15 Co-factors for a Perfect Storm Multigenerational injection drug use (IDU) No access to prevention (PEP, PrEP), drug treatment services, support groups, or needle exchange services Limited access to testing and treatment for HIV and HCV Limited knowledge among PWID regarding HIV and HCV transmission routes and efficacious treatment available for HIV and HCV (ART and DAAs)

16 HCV Co-Infection in HIV+ MSM Prevalence of HCV co-infection 6.4% Highest in North America 8 fold higher risk of coinfection vs. HIV- MSM Increased risk of sexual transmission HCV isolated in semen as well as rectum Platt L, et al. Lancet Infect Dis Feb 24; Foster AL, et al. Clin Infect Dis Feb 1.

17 Burden of HIV Co-Infection

18 Rate per 100,000 Population Age-Adjusted Mortality Rates from Hepatitis B and Hepatitis C Virus and HIV Infections Listed as Underlying Causes of Death in the United States Year Hepatitis B Hepatitis C HIV Extended from: KN Ly, et al. Ann Intern Med. 2012;156:271-8.

19 Rate per 100,000 Population Age-Adjusted Mortality Rates from Hepatitis B and Hepatitis C Virus and HIV Infections Listed as Underlying Causes of Death in the United States Hepatitis B Hepatitis C HIV HCV mortality increasing HIV mortality stable Year Extended from: KN Ly, et al. Ann Intern Med. 2012;156:271-8.

20 Number of Deaths Annual Number of Deaths from HCV Exceeds All Other Nationally Notifiable Infectious Conditions Combined 30,000 25,000 Other nationally notifiable infectious conditions 20,000 15,000 Hepatitis C 10,000 5,000 Ly KN. Clin Infect Dis Years 60 infectious conditions other than HCV, as reported to CDC

21 HIV Adds a Decade to Fibrosis Scores Persons with HIV found to have liver fibrosis measurements equal to HIV patients who were 9.2 years older on average On average fibrosis scores kpa greater in HIV+ patients Low CD4 counts associated with higher liver fibrosis scores Kirk, et al. Ann Intern Med

22 Mechanisms of Accelerated Fibrosis in HIV/HCV Co-Infection Chen. Nat Rev Gastroenterol Hepatol

Survival Rate HIV-HCC Cooperative Italian-Spanish Group: HCC and HCV/HIV Coinfection Retrospective cohort (1986-2002) HCC in HIV cohort (n=41) Most had stable HIV disease (30/31 deaths due to liver

23 Survival Rate HIV-HCC Cooperative Italian-Spanish Group: HCC and HCV/HIV Coinfection Retrospective cohort ( ) HCC in HIV cohort (n=41) Most had stable HIV disease (30/31 deaths due to liver disease) HCV positive (88%) HCC in HIV-negative controls (n=701) CLIP database, HCV positive (75%) HCC diagnosis occurred at a younger age in HIV cohort 42 versus 64 years of age (P=0.002) HCC had a more aggressive course in the mostly HCV/HIV coinfected cohort Puoti M, et al. AIDS. 2004;18: HCC and Survival HIV Negative HIV Positive Time from HCC Diagnosis (Days)

24 HIV Treatment Does Not Completely Abrogate the Negative Effect ART decreases hepatic decompensation events: 0.72 ( ). Lo Re V. Ann Intern Med Anderson JP. CID 2004.

25 HIV/HCV Co-infection: Natural History Considerations Accelerated rates of fibrosis progression Possible weak cellular immune response to HCV antigens HIV-associated immune activation may influence liver disease progression Activation of hepatic stellate cells HCV-associated proinflammatory cytokines may impact HIV disease HCV coinfection is associated with higher rates of morbidity and mortality related to end-stage liver disease Lower rates of spontaneous HCV clearance in HIV patients Faster progression to cirrhosis and decompensated liver disease HCC occurs at a younger age and associated with shorter survival Lin W, et al. J Infect Dis. 2013;207(suppl 1):S13-S18; Weber R, et al. HIV Med. 2013;14: ; Ioannou GN, et al. Hepatology. 2013;57: ; Weber R, et al. Arch Intern Med. 2006;166: ; Chen TY, et al. Clin Infect Dis. 2009;49: ; Curry MP. J Infect Dis. 2013(suppl 1):S40-S44; Macias J, et al. Clin Infect Dis. 2013;57: d

26 Screening and Linkage to Care

27 HIV/HCV Co-infection: Natural History Considerations Screening Test Individuals at High Risk that should be Screened Screening Guidelines (CDC) Anti-HCV antibody test followed by confirmatory HCV RNA One time screening of persons born between 1945 and 1965 without assessment of risk factors One time testing should be performed for any individual at high risk for HCV infection Any history of injection drug use Long term hemodialysis Recipient of blood or blood components or underwent organ transplant prior to July 1992 Recipient of clotting factor concentrates prior to 1987 *HIV infected individuals Children born to HCV infected mothers Unexplained liver disease including persistently elevated ALT Inmates of correctional facilities (AASLD) Receiving tattoo in an unregulated setting (AASLD) *Consider HCV RNA in immunocompromised individuals * Annual HCV testing is recommended for HIV-seropositive men who have unprotected sex with men.

28 HCV Testing Algorithm Immunocompromised

29 HCV Treatment Cascade in HIV/HCV Co-infected Patients

30 Treatment of HIV/HCV Co-Infection

31 Potential Therapeutic Targets in the HCV Replication Cycle Transport and release Translation HCV RNA Fusion and uncoating RNA replication Viral assembly NS2 NS4B Polyprotein processing CypA NS3 NS5B NS4B NS5A NS2 medicalgrapevineasia.com NS3 NS5A NS5B HCV NS proteins

32 Potential Therapeutic Targets in the HCV Replication Cycle Transport and release Translation HCV RNA Fusion and uncoating NS2 NS4B Polyprotein processing NS3 NS5A NS5B HCV NS proteins Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Voxilaprevir Glecaprevir NS3/4A protease inhibitors RNA replication Viral assembly CypA NS3 NS5B NS4B NS5A NS2 medicalgrapevineasia.com

33 Potential Therapeutic Targets in the HCV Replication Cycle Transport and release Translation medicalgrapevineasia.com HCV RNA Fusion and uncoating NS2 NS4B Polyprotein processing NS3 NS5A NS5B HCV NS proteins Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Voxilaprevir Glecaprevir NS3/4A protease inhibitors Dasubuvir Sofosbuvir RNA replication NS5B polymerase inhibitors Viral assembly CypA NS3 NS5B NS4B NS5A NS2

34 Potential Therapeutic Targets in the HCV Replication Cycle Transport and release Translation medicalgrapevineasia.com HCV RNA Fusion and uncoating NS2 NS4B Polyprotein processing NS3 NS5A NS5B HCV NS proteins Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Voxilaprevir Glecaprevir NS3/4A protease inhibitors Dasubuvir Sofosbuvir RNA replication NS5B polymerase inhibitors NS5A inhibitors Viral assembly CypA NS3 NS5B NS4B NS5A NS2 Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir Pibrentasvir NS5A inhibitors Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir Pibrentasvir

Voxilaprevir Glecaprevir NS3/4A protease inhibitors Ribavirin (RBV) Dasubuvir Sofosbuvir RNA replication NS5B polymerase inhibitors NS5A inhibitors

35 Potential Therapeutic Targets in the HCV Replication Cycle Transport and release Translation medicalgrapevineasia.com HCV RNA Fusion and uncoating NS2 NS4B Polyprotein processing NS3 NS5A NS5B HCV NS proteins Telaprevir Boceprevir Simeprevir Paritaprevir Grazoprevir Voxilaprevir Glecaprevir NS3/4A protease inhibitors Ribavirin (RBV) Dasubuvir Sofosbuvir RNA replication NS5B polymerase inhibitors NS5A inhibitors Viral assembly CypA NS3 NS5B NS4B NS5A NS2 Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir Pibrentasvir NS5A inhibitors Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir Pibrentasvir

36 Evolution of Direct Acting Antivirals (DAAs)

37 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV

38 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV Curability of HCV without IFN

39 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV telaprevir boceprevir + IFN/RBV Curability of HCV without IFN

40 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV telaprevir boceprevir + IFN/RBV Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV

41 Evolution of Direct Acting Antivirals (DAAs) ledipasvir + sofosbuvir IFN + RBV telaprevir boceprevir + IFN/RBV simeprevir + sofosbuvir paritaprevir/rombitasvir/ dasabuvir ± RBV Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV

42 Evolution of Direct Acting Antivirals (DAAs) ledipasvir + sofosbuvir IFN + RBV telaprevir boceprevir + IFN/RBV simeprevir + sofosbuvir paritaprevir/rombitasvir/ dasabuvir ± RBV Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV Daclatasvir+ Sofosbuvir Paritaprevir/r ombitasvir

43 Evolution of Direct Acting Antivirals (DAAs) ledipasvir + sofosbuvir simeprevir + sofosbuvir IFN + RBV telaprevir boceprevir + IFN/RBV paritaprevir/rombitasvir/ dasabuvir ± RBV elbasvir+ grazoprevir Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV Daclatasvir+ Sofosbuvir Paritaprevir/r ombitasvir

44 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV telaprevir boceprevir + IFN/RBV ledipasvir + sofosbuvir simeprevir + sofosbuvir paritaprevir/rombitasvir/ dasabuvir ± RBV QDay Paritaprevir/r/ ombitasvir/dasabuvir elbasvir+ grazoprevir Sofosbuvir+ velpatasvir Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV Daclatasvir+ Sofosbuvir Paritaprevir/r ombitasvir

45 Evolution of Direct Acting Antivirals (DAAs) IFN + RBV telaprevir boceprevir + IFN/RBV ledipasvir + sofosbuvir simeprevir + sofosbuvir paritaprevir/rombitasvir/ dasabuvir ± RBV QDay Paritaprevir/r/ ombitasvir/dasabuvir elbasvir+ grazoprevir Sofosbuvir+ velpatasvir Curability of HCV without IFN Simeprevir+ IFN/RBV First approved IFN-free therapy: sofosbuvir + RBV Daclatasvir+ Sofosbuvir Paritaprevir/r ombitasvir Sofosbuvir/velpatasvir/vox ilaprevir Gelcaprevir/pibrentasvir

46 Direct Acting Antivirals (DAAs) NS3/4A Protease inhibitors (PREVIR) 1 st gen: telaprevir, boceprevir 2 nd gen: simeprevir, paritaprevir, grazoprevir 3 rd gen: glecaprevir* and voxilaprevir* NS5A inhibitors (ASVIR) 1 st gen: ledipasvir, ombitasvir, daclatasvir, elbasvir 2 nd gen: velpatasvir, pibrentasvir* and MK-8408*

47 Direct Acting Antivirals (DAAs) NS3/4A Protease inhibitors (PREVIR) 1 st gen: telaprevir, boceprevir 2 nd gen: simeprevir, paritaprevir, grazoprevir 3 rd gen: glecaprevir* and voxilaprevir* NS5A inhibitors (ASVIR) 1 st gen: ledipasvir, ombitasvir, daclatasvir, elbasvir 2 nd gen: velpatasvir, pibrentasvir* and MK-8408*

48 Direct Acting Antivirals (DAAs) NS5B polymerase inhibitors (BUVIR) Nucleoside/tide polymerase inhibitors (NPI) Sofosbuvir Non-nucleoside polymerase inhibitors (NNPI) Dasabuvir Oral prodrug HCV nucleotide analogue NS5B polymerase inhibitor MK-3682* Novel Drug Targets mir-1222*: mir inhibitor (works at the level of the ribosome) RG-101*: a GalNAc-conjugated anti-mir targeting mir-122 (SC injection)

49 DAA Combination Pills

50 DAA Combination Pills Ledipasvir/sofosbuvir (Harvoni) GT 1, 4, 5, 6

51 DAA Combination Pills Ledipasvir/sofosbuvir (Harvoni) GT 1, 4, 5, 6 Paritaprevir/r/ombitasvir+dasabuvir (Viekira) (XR) GT 1 Paritaprevir/r/Ombitasvir (Technivie) GT 4

52 DAA Combination Pills Ledipasvir/sofosbuvir (Harvoni) GT 1, 4, 5, 6 Paritaprevir/r/ombitasvir+dasabuvir (Viekira) (XR) GT 1 Paritaprevir/r/Ombitasvir (Technivie) GT 4 Elibasvir/Grazoprevir (Zepatier) GT 1 or 4

53 DAA Combination Pills Ledipasvir/sofosbuvir (Harvoni) GT 1, 4, 5, 6 Paritaprevir/r/ombitasvir+dasabuvir (Viekira) (XR) GT 1 Paritaprevir/r/Ombitasvir (Technivie) GT 4 Elibasvir/Grazoprevir (Zepatier) GT 1 or 4 Sofosbuvir/Velpatasvir (Epclusa) Pangenotypic (1-6)

54 Integrated Overall SVR12 Analysis of HCV/HIV Co-infected Patients: 12 Weeks of Treatment % 95% 94% 93% % 100% Naggie, et al. NEJM Wyles D, et al. NEJM Wyles D, et al. EASL Barcelona Sulkowski M, et al. JAMA. March Rockstroh JK, et al. Lancet HIV Zuezem S, et al. AASLD Boston. 2016

55 Wyles D, et al. NEJM Dieterich. EASL Zuezem S, et al. AASLD Boston Integrated SVR12 Analysis 8 vs 12 Weeks of Treatment in GT1 HCV/HIV Co-Infected Patients 8 weeks % 100% 98% 99% 100% 100% 12 weeks % / SOF/DCV: ALLY-2 LDV/SOF: TRIO G/P: ENDURANCE

56 Wyles D, et al. NEJM Dieterich. EASL Zuezem S, et al. AASLD Boston Integrated SVR12 Analysis 8 vs 12 Weeks of Treatment in GT1 HCV/HIV Co-Infected Patients 8 weeks % 100% 98% 99% 100% 100% 12 weeks % / SOF/DCV: ALLY-2 LDV/SOF: TRIO G/P: ENDURANCE

57 Wyles D, et al. NEJM Dieterich. EASL Zuezem S, et al. AASLD Boston Integrated SVR12 Analysis 8 vs 12 Weeks of Treatment in GT1 HCV/HIV Co-Infected Patients 8 weeks % 100% 98% 99% 100% 100% 12 weeks % / SOF/DCV: ALLY-2 LDV/SOF: TRIO G/P: ENDURANCE

58 Wyles D, et al. NEJM Dieterich. EASL Zuezem S, et al. AASLD Boston Integrated SVR12 Analysis 8 vs 12 Weeks of Treatment in GT1 HCV/HIV Co-Infected Patients 8 weeks % 100% 98% 99% 100% 100% 12 weeks % / SOF/DCV: ALLY-2 LDV/SOF: TRIO G/P: ENDURANCE

59 HCV Guidelines: Treatment Recommendations in HIV/HCV Co-infection Regimens Not Recommended for Patients with HIV/HCV Coinfection Treatment courses shorter than 12 weeks, such as the use of 8 weeks of ledipasvir/sofosbuvir. Rating: Class IIb, Level C

60 GECCO-01:LDV/SOF for 8 Weeks in Mono and HIV/HCV Co-Infected Patients Week 0 Week 8 Week 12 Week SVR 12 Rates 94% 93% 96% n=29 HIV/HCV Co-Infected SVR n=199 HCV Mono-infected SVR / /166 27/28 Treatment naïve, non-cirrhotic, HCVgenotype 1 women or men with low viral load (<6 million IU/mL) All HIV patients were on ART Median CD4 cell count 601 cells/ml Co-infected patients had significantly higher ALT, AST and GGT levels Ingiliz, et al. Clin Infect Dis Overall HCV HIV/HCV 10 patients lost to follow up 2 patients with virologic relapse

61 HCV/HIV Treatment Summary HIV co-infection no longer adversely affects HCV treatment SVR rates are now equivalent compared to mono-infected 8 week regimens Too short?? ART stable for 8 weeks: Is it necessary?

62 What About Drug-Drug Interactions?

63 Special Considerations in Co-Infection When treatment for both HIV and HCV is indicated, the regimen should be selected with special consideration for potential drug-drug interactions (DDI) and overlapping toxicities Increased pill burden, increased toxicities (cirrhosis, CKD) CD4<200 cells/mm 3 initiate ARV and HCV therapy may be delayed until patient is stable on HIV treatment (CIII) ARV naïve patients with CD4>500 cells/mm 3 some clinicians may choose to defer ARV until HCV treatment is completed (CIII) Always check potential interactions! aidsinfo: AASLD/IDSA hcvguidelines: Liverpool:

Special Considerations in Co-Infection When treatment for both HIV and HCV is indicated, the regimen should be selected with special consideration for potential drug-drug interactions (DDI) and

64 Special Considerations in Co-Infection When treatment for both HIV and HCV is indicated, the regimen should be selected with special consideration for potential drug-drug interactions (DDI) and overlapping toxicities Increased pill burden, increased toxicities (cirrhosis, CKD) CD4<200 cells/mm 3 initiate ARV and HCV therapy may be delayed until patient is stable on HIV treatment (CIII) ARV naïve patients with CD4>500 cells/mm 3 some clinicians may choose to defer ARV until HCV treatment is completed (CIII) Always check potential interactions! aidsinfo: AASLD/IDSA hcvguidelines: Liverpool:

65 Up to 70% May Have DAA-ARV Interactions Retrospective analysis of 125 coinfected patients prior to initiation of DAA 100% 90% DAA regimens included SMV/SOF, SOF/LDV, SOF/DCV and P/r/O/D ARVs included 81% TDF, 35% RAL, 16% EFV, 40% PI/r 80% 70% 60% 50% 40% 30% 20% 7% 64% 54% 20% 47% 41% None Moderate Severe 10% 0% 10% SOF/SMV SOF/LDV SOF/DCV P/r/O/D Langness J. 16th HIV and Hep Clin Pharm Workshop

66 DAA-ARV Interactions 35 patients started LDV/SOF 2 on ARVs with direct contraindications 17 could have moderate interactions 10 switched ARV regimen 7/35 had resistance patterns that did not allow for change in ARVs Langness J. 16th HIV and Hep Clin Pharm Workshop

67 DAA-ARV Interactions Selected HIV ARVs SOF SOF/ LDV SOF/ VEL HCV DAA Drugs DCV P/r/O/D GRZ/EBV SMV Protease Inhibitors ATV/r or ATV/c DRV/r or DRV/c If used with TDF, TDF expected. Avoid in CrCl <60 DCV 30mg ATV 300mg in AM, d/c booster FPV/r or LPV/r Integrase Inhibitors RAL DTG If used with TDF, may TDF. Monitor toxicity EVG/c/FTC/TDF DCV 30mg EVG/c/FTC/TAF DCV 30mg

68 DAA-ARV Interactions Selected HIV ARVs NRTI s TDF TAF FTC ABC 3TC SOF SOF/LDV SOF/ VEL If used with PI booster, TDF expected. Avoid in CrCl <60. Monitor if used with DTG HCV DAA Drugs DCV P/r/O/D GRZ/EBV SMV NNRTI s EFR RPV ETR NVP If used with TDF, TDF expected. Avoid in CrCl <60 DCV 90mg DCV 90mg DCV 90mg

69 Summary Screen all populations at risk for HIV/HCV co-infection Co-infected patients have accelerated rates of fibrosis progression HIV/HCV co-infection is associated with higher rates of morbidity and mortality related to end-stage liver disease HIV/HCV co-infected persons should be treated and retreated the same as persons without HIV infection, after recognizing and managing interactions with antiretroviral medications Treatment courses shorter than 12 weeks not currently recommended

New York State HCV Provider Webinar Series

New York State HCV Provider Webinar Series Treatment of HCV/HIV Co-Infection Dost Sarpel, MD Division of Infectious Disease Viral Hepatology Milford Regional Medical Center Objectives Review the epidemiology