Cases: Initial Hepatitis C Treatment, Including Coinfection

Transcription

1 Cases: Initial Hepatitis C Treatment, Including Coinfection Ricardo Franco MD Assistant Professor of Medicine University of Alabama at Birmingham Birmingham, Alabama Learning Objectives After attending this presentation, learners will be able to: Apply guidance-based strategies for hepatitis C treatment initiation Describe specific nuances of hepatitis C treatment in people with HIV infection Case 1 A 33-year-old caucasian female presents to primary care clinic for routine follow up. She was recently diagnosed with hepatitis C (treatment-naïve). Risk factors include hx of IVDU, in remission for many years. She takes no medications and is otherwise healthy. She is engaged in care and motivated to take DAAs. HCV GT1b, VL 4,000,000 copies/ml Basic labs wnl F0-1

2 ARS Question #1: You realize that the patient is a candidate for 8 weeks of glecaprevir/pibrentasvir or ledipasvir/sofosbuvir. Otherwise, current 8 week-regimens should not be considered for: 1. INF-exp patients 2. patients with GT1a HCV 3. patients with non-gt1 HCV 4. patients with compensated cirrhosis 5. 1 and 4 ENDURANCE-1: GLE/PIB GT1 HCV in non-cirrhotic patients Patient characteristics 85% F0-1 7% F2 (46 pts) 8% F3 (59 pts) 62% treatment-naïve 43% GT1a HCV Failures: - Breakthrough = 1 pt - Relapse = none - Lost to FU = 3 pts Zeuzem et al. N Engl J Med 2018; 378: Side effects: - Headache = 19% - Fatigue = 11% - Nausea = 6% Ion-3: LDV/SOF in TN, non-cirrhotic patients, with GT1 HCV Patient characteristics 59% F0-2 per Bx 13% F3 per Bx (29 pts) 62% treatment-naïve 80% GT1a HCV Side effects: - Headache = 30% - Fatigue = 21% - Nausea = 7% Kowdley et al. N Engl J Med. 2014;370(20):

3 ION-3: Relapse Rates by Baseline Viral Load after 8 and 12 Weeks Uncontrolled post hoc analysis of the RBV-free arms LDV/SOF 8 weeks (N = 215) LDV/SOF 12 weeks (N = 216) Number of Responders at the End of Treatment Baseline HCV RNA* HCV RNA < 6M IU/mL 2% (2/123) HCV RNA 6M IU/mL 10% (9/92) *A subject s HCV RNA may vary from visit to visit 2% (2/131) 1% (1/85) Adapted from package insert LDV/SOF in Black Patients: Retrospective Analysis of Phase 3 Data Wilder et al. Hepatology (Baltimore, Md). 2016;63(2): Recommended for GT1 Tx-Naive or IFN- Exp d Pts Without Cirrhosis HCV GT Regimens Duration 1 EBR/GZR* elbasvir/grazoprevir GLE/PIB** glecaprevir/pibrentasvir LDV/SOF*** ledipasvir/sofosbuvir SOF/VEL sofosbuvir/velpatasvir 12 weeks 8 weeks 12 weeks 12 weeks *Only if no baseline NS5A elbasvir RASs detected in HCV GT1a. ** This is a 3-tablet co-formulation. *** 8 weeks OK for patients who are non-black, HIV-uninfected, and whose HCV RNA level is <6 million IU/mL. AASLD/IDSA. HCV guidance. 2018

4 Recommended for GT1 Tx-Naive or IFN- Exp d Pts With Compensated Cirrhosis HCV GT 1 Recommended Regimens (All 12 Wks) Treatment Naive EBR/GZR* elbasvir/grazoprevir GLE/PIB**glecaprevir/pibrentasvir LDV/SOF ledipasvir/sofosbuvir SOF/VEL sofosbuvir/velpatasvir *Only if no baseline NS5A elbasvir RAVs detected in HCV GT1a. ** This is a 3-tablet co-formulation. IFN/RBV Experienced EBR/GZR* elbasvir/grazoprevir GLE/PIB glecaprevir/pibrentasvir SOF/VEL sofosbuvir/velpatasvir AASLD/IDSA. HCV guidance. September Case 1 cont d A Prior Authorization was subsequently submitted to insurance for 8 weeks of glecaprevir/pibrentasvir. The following week, the patient calls the office to report new-onset nausea and vomiting. Upon further questioning, the patient missed her last period. You bring her back to clinic and her pregnancy test is positive. ARS Question #2: The patient is happy with the news, but concerned about HCV infection. You: 1. Let the PA proceed - this is a ribavirin-free regimen 2. Cancel the application - DAAs are overall highly teratogenic 3. Remain open to treat her and prevent vertical transmission 4. Refer to high-risk prenatal care upfront 5. Wonder about universally testing pregnant patients for HCV

5 Women in Child Bearing Age and Pregnancy Ribavirin (RBV) X (teratogenic) DAAs B (animal studies only) Use not recommended in pregnancy DAA is recommended before pregnancy, whenever practical and feasible, to reduce the risk of vertical transmission Counselling and serum pregnancy testing: recommended prior to RBV-based rx should be offered prior to use DAAs Vertical Transmission of Hepatitis C Virus: Systematic Review and Meta-analysis Clinical Infectious Diseases, Volume 59, Issue 6, 15 September 2014, Pages Trends in acute HCV incidence among young persons by Urbanicity, Among young PWIDs, ~50% are women in reproductive age Clin Infect Dis. 2014;59:1411-9

6 HCV detection rate (females aged years) and testing rate (children aged = 2 years) US and KY Source: Quest Diagnostics reporting to CDC 151% 213% 14% 22% MMWR Morb Mortal Wkly Rep 2016;65: Proportion of infants born to hepatitis C virus (HCV)-infected women US and KY, Source: Birth Certificate data 124% 68% MMWR Morb Mortal Wkly Rep 2016;65: CDC Analysis of the National Notifiable Diseases Surveillance System and the Quest Diagnostics Health Trends Number of reported cases of HCV infection among women aged years and years in the United States, Estimated Number of HCV-Infected Women Who Gave Birth and of HCV-Infected Infants 2011 to million live births occurred/year 0.73% of pregnant women tested for HCV infection were found to have the infection women (0.73%) with HCV infection gave birth during that period 1700 infants (5.8% vertical transmission rate) were born with HCV infection/year Ann Intern Med. 2017;166(11):

7 Current CDC recommendations for HCV Testing Test once (no risk assessment): Adults born Uncertain Long term sexual partner of HCV+ STIs or multiple sex partners Intranasal drug use Tattooing/bodypiercing Not recommended Health-care, emergency medical, and public safety workers Pregnant women Household (nonsexual) contacts of HCV-positive persons General population Test based on risk for exposure: Currently injecting drugs Ever injected drugs Have certain medical conditions, including : received clotting factor pre 1987 long-term hemodialysis with persistently abnormal alanine aminotransferase levels (ALT) who have HIV infection Were prior recipients of transfusions or organ transplants, including persons who: were notified that they received blood from a donor who later tested positive for HCV infection Pre July 1992 Test based on a recognized exposure: Healthcare, emergency medical, and public safety workers after needle sticks, sharps, or mucosal exposures to HCV-positive blood Children born to HCV-positive women Case 1 cont d Our patient returns for follow up after a long hiatus. She brings her 2 year old baby boy. Pregnancy was uneventful, her child tested negative for HCV at 18 months. Since pregnancy, she was started on atorvastatin 40mg and combined oral contraception and is doing well on it. She wants to get back on track with treatment.

8 ARS Question #3: Which of the following is the most reasonable approach: 1. GLE/PIB x 8 weeks and routine follow up 2. GLE/PIB and monitor closely 3. GLE/PIB and decrease atorvastatin to 20mg 4. GLE/PIB and change to progestin-based contraception 5. Avoid protease inhibitors all together 6. Consider other options that may or may not include PIs DDIs: ledipasvir/sofosbuvir FDC PPIs: no more than 20mg; take LDV/SOF at the same time Ranitidine: no more than 150mg po bid; take LDV/SOF at the same time of AM or PM dose Amiodarone: do not co-administer (black box warning) Digoxin: use lowest dose possible; monitor during therapy AEDs: phenytoin, CBZ, barbiturates not OK; levetiracetam, lamotrigine, valproic acid OK Rifampin: do not co-administer Herbals: avoid (St John s wort, milk thistle) Adapted from DAA Package Inserts DDIs: sofosbuvir/velpatasvir FDC PPIs: co-administration not recommended Ranitidine: no more than 150mg po bid; take SOF/VEL at the same time of AM or PM dose Amiodarone: do not co-administer (black box warning) Digoxin: use lowest dose possible; monitor during therapy AEDs: phenytoin, CBZ, barbiturates not OK; levetiracetam, lamotrigine, valproic acid OK Rifampin: do not co-administer Herbals: avoid (St John s wort, milk thistle) Adapted from DAA Package Inserts

9 DDIs: elbasvir/grazoprevir FDC PPIs: no interaction expected Ranitidine: no interaction expected Amiodarone: potential interaction ( amiodarone levels) Digoxin: no interaction expected AEDs: phenytoin, CBZ, barbiturates not OK; levetiracetam, lamotrigine, valproic acid OK Rifampin: do not co-administer Herbals: avoid (St John s wort, milk thistle) Adapted from DAA Package Inserts DDIs: glecaprevir/pibrentasvir FDC PPIs: no interaction expected Ranitidine: no interaction expected Amiodarone: potential interaction ( amiodarone levels) Digoxin: use lowest dose possible; monitor during therapy AEDs: phenytoin, CBZ, barbiturates not OK; levetiracetam, lamotrigine, valproic acid OK Rifampin: do not co-administer Birth control pills: do not co-administer Herbals: avoid (St John s wort, milk thistle) Adapted from DAA Package Inserts DAAs and Statins LDV SOF SOF VEL EBV GZR GLE PIB Simvastatin Monitor Monitor Lowest dose Not recommended Lovastatin Monitor Monitor Lowest dose Not recommended Pravastatin Monitor Monitor Monitor Reduce by 50% Fluvastatin Monitor Monitor Lowest dose Lowest dose Pitavastatin Monitor Monitor Monitor Lowest dose Atorvastatin Monitor Monitor Avoid > 20mg Not recommended Rosuvastatin Not recommended Avoid > 10mg Avoid > 10mg Avoid > 10mg Adapted from DAA Package Inserts

10 First-line HCV Therapy: Distinguishing Among Recommended Options EBR/GZR - QD single tablet 12 wks, GT 1 or 4 Requires RAS testing for GT1a Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: glucocorticoids, statins, PDE inhibitors, rifampin DDIs are drug specific and there are many more to consider than are listed here. AASLD/IDSA. HCV Always check! guidance. September Slide credit: clinicaloptions.com First-line HCV Therapy: Distinguishing Among Recommended Options EBR/GZR - QD single tablet 12 wks, GT 1 or 4 Requires RAS testing for GT1a Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: glucocorticoids, statins, PDE inhibitors, rifampin GLE/PIB - QD 3 tablets with food 8 wks no cirrhosis, 12 wks if cirrhosis, GT 1-6 No RAS testing Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: statins, rifampin DDIs are drug specific and there are many more to consider than are listed here. AASLD/IDSA. HCV Always check! guidance. September Slide credit: clinicaloptions.com

11 First-line HCV Therapy: Distinguishing Among Recommended Options EBR/GZR - QD single tablet 12 wks, GT 1 or 4 Requires RAS testing for GT1a Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: glucocorticoids, statins, PDE inhibitors, rifampin GLE/PIB - QD 3 tablets with food 8 wks no cirrhosis, 12 wks if cirrhosis, GT 1-6 No RAS testing Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: statins, rifampin LDV/SOF - QD single tablet 8-12 wks, GT 1, 4, 5, or 6 No RAS testing Safe in decompensation Not recommended for stage 4/5 CKD DDI highlights: acid-reducing agents, statins, rifampin AASLD/IDSA. HCV DDIs are drug specific and there are many more to consider than are listed here. guidance. September Always check! Slide credit: clinicaloptions.com First-line HCV Therapy: Distinguishing Among Recommended Options EBR/GZR - QD single tablet 12 wks, GT 1 or 4 Requires RAS testing for GT1a Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: glucocorticoids, statins, PDE inhibitors, rifampin LDV/SOF - QD single tablet 8-12 wks, GT 1, 4, 5, or 6 No RAS testing Safe in decompensation Not recommended for stage 4/5 CKD DDI highlights: acid-reducing agents, statins, rifampin GLE/PIB - QD 3 tablets with food 8 wks no cirrhosis, 12 wks if cirrhosis, GT 1-6; No RAS testing Contains PI: do not use if decompensated Can be used in stage 4/5 CKD DDI highlights: statins, rifampin SOF/VEL - QD single tablet 12 wks, GT 1-6 Requires RAS testing for some GT 3 Safe in decompensation Not recommended for stage 4/5 CKD DDI highlights: acid-reducing agents, rifampin AASLD/IDSA. HCV DDIs are drug specific and there are many more to consider than are listed here. guidance. September Always check! Slide credit: clinicaloptions.com HIV/HCV Co-infection

12 ARS Question #4: What is the appropriate approach for initiating treatment in a person with newly diagnosed HCV genotype 1a infection and HIV coinfection with CD4+ cell count of 300 cells/mm 3 and who is hepatitis B surface antigen (HBsAg) negative? 1. The sequencing of HCV therapy and antiretroviral therapy should be individualized 2. Antiretroviral therapy should begin before HCV therapy 3. HCV therapy should begin before antiretroviral therapy 4. HCV therapy and antiretroviral therapy should begin simultaneously 5. Unsure Cotreatment of HIV and HCV coinfection ART initiation should prioritized for many patients HIV treatment and VL suppression are not required before DAAs Treatment readiness for 8-12 wks of DAAs different than for lifelong ART HCV cure may serve to facilitate HIV care engagement SVR may reduce the risk of drug-induced liver injury If ART is initiated first, consider delaying HCV DAAs for 4-6 wks to confirm tolerability and HIV-1 RNA response HIV Co-infection Shortens Survival in HCV-related Decompensated Cirrhosis Pineda JA, Romero-Gómez M, Díaz-García F, et al. HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis. Hepatology. 2005;41:

13 HIV Control does not Completely Overturn Risk of ESLD ART decreases hepatic decompensation events: 0.72 ( ) Prior Experience in HIV/HCV INF Era 1. Chung RT, Andersen J, Volberding P, et al. N Engl J Med. 2004;351: Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. N Engl J Med. 2004;351: Laguno M, Murillas J, Blanco JL, et al. AIDS. 2004;18:F Carrat F, Bani-Sadr F, Pol S, et al. JAMA. 2004;292: Núñez M, Miralles C, Berdún MA, et al. AIDS Res Hum Retroviruses. 2007;23: Núñez M, Miralles C, Berdún MA, et al.. AIDS Res Hum Retroviruses. 2007;23: Poor Rates of HCV Treatment Uptake and Cure Mehta; Sulkowski et al. Limited effectiveness of antiviral treatment for hepatitis C in an urban HIV clinic. AIDS. 20(18): , November 28, 2006.

14 AASLD/IDSA Recommendations for First-line HCV Treatment in HCV/HIV Coinfection Regimen by HCV GT 1, 4 2, 3 5, 6 Duration, Wks No Cirrhosis Compensated Cirrhosis egfr < 30 ml/min 8 GLE/PIB GLE/PIB 12 GZR/EBR,* SOF/LDV, SOF/VEL GLE/PIB, GZR/EBR,* SOF/LDV, SOF/VEL GZR/EBR 8 GLE/PIB GLE/PIB 12 SOF/VEL GLE/PIB, SOF/VEL 8 GLE/PIB GLE/PIB 12 SOF/LDV, SOF/VEL GLE/PIB, SOF/LDV, SOF/VEL *If GT1a with BL NS5A RASs for EBR, 12 wks not recommended; can increase duration to 16 wks with RBV (alternative). Some data to support 8 wks in GT1, but 8 wks not recommended in HCV/HIV coinfection. If decompensated cirrhosis, do not use HCV protease inhibitors. If BL Y93H RAS present in GT3, add RBV or consider SOF/VEL/VOX. If also cirrhotic, increase duration to 12 wks. DHHS Guidelines: Recommended Regimens for First-line ART Class INSTI Bold text identifies single-tablet regimens. Regimen BIC/TAF/FTC DTG/ABC/3TC DTG + (TAF or TDF)/FTC EVG/COBI/(TAF or TDF)/FTC RAL + (TAF or TDF)/FTC Recommendations may differ based on BL HIV-1 RNA, CD4+ cell count, CrCl, egfr, HLA-B*5701 status, HBsAg status, osteoporosis status, and pregnancy status All options available QD [2] (except in pregnancy) 1. DHHS Guidelines Raltegravir [package insert] Slide credit: clinicaloptions.com Drug interactions with antiretrovirals Doravirine (NNRTI): not anticipated to have significant interactions with DAAs

15 1.8/100 P-Y 0.7/100 P-Y 9.4/100 P-Y IngilizP. J Hepatol IngilizP. #612 CROI Case 2 58-year-old man with HCV/HIV coinfection. He is tolerating atazanavir/ritonavir plus lamivudine and tenofovir well with HIV-1 RNA suppression < 20 copies/ml and a CD4+ cell count of 800 cells/mm3. He is HBsAg negative with an egfr of 65 ml/min. He has genotype 1a HCV infection and is HCV treatment naive. His HCV RNA is 1.43 million IU/mL, he has stage 2 fibrosis. His insurance approves 12 weeks of elbasvir/grazoprevir for HCV treatment. ARS Question #5: If starting grazoprevir/elbasvir, what would you recommend to avoid drug drug interactions? 1. Continue atazanavir/ritonavir plus lamivudine and tenofovir 2. Switch to darunavir/ritonavir plus either emtricitabine/tenofovir 3. Switch to elvitegravir/cobicistat/emtricitabine/tenofovir 4. Switch to emtricitabine/tenofovir plus either bictegravir, dolutegravir, or raltegravir 5. Interrupt ART for the 12-week course of grazoprevir/elbasvir 6. Unsure HCV RE-INFECTION: The Achilles Heel for HCV elimination in HIV/HCV 16 GECCO Cohort: 2239 P-Y follow-up Persons With Reinfection, % % MSM, 37% IDU 87% of reinfections: MSM 83% of reinfection: HIV P-Y follow-up Overall IDU MSM Transmission mode

16 1.8/100 P-Y 0.7/100 P-Y 9.4/100 P-Y IngilizP. J Hepatol IngilizP. #612 CROI HCV RE-INFECTION: The Achilles Heel for HCV elimination in HIV/HCV 16 GECCO Cohort: 2239 P-Y follow-up NEAT Network 7.3/100 py 27/64 second re-infection (18.8/100 py) Persons With Reinfection, % % MSM, 37% IDU 87% of reinfections: MSM 83% of reinfection: HIV P-Y follow-up Overall IDU MSM Transmission mode Take home points HIV accelerates the natural history of HCV Treatment of HIV does not completely reverse the adverse impact HCV treatment indicated for all HIV co-infected Plentiful treatment options exist and work just as well in HIV Drug interactions are generally manageable Effective HCV treatment can avert complications More data are needed with long-term follow-up after DAA therapy Re-infection is an issue Enhanced/better prevention efforts are needed Question-and-Answer Remember to raise your hand and wait until you have the microphone before you ask your question we are recording!