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HIV and HCV Update for the Pharmacist – June 2014 John J. Faragon , PharmD , BCPS, AAHIV-P Regional Pharmacy Director, NY/NJ AETC Pharmacist, Albany Medical Center. Objectives. Discuss recent guidelines changes for HIV infection

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Objectives

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  1. HIV and HCV Update for the Pharmacist – June 2014John J. Faragon, PharmD, BCPS, AAHIV-PRegional Pharmacy Director, NY/NJ AETCPharmacist, Albany Medical Center

  2. Objectives • Discuss recent guidelines changes for HIV infection • Using patient cases, discuss the role of sofosbuvir and simeprevir in HIV/HCV co-infection • Review consensus guidelines for managing HIV/HCV coinfection

  3. DHHS Guidelines Update 2014: Recommended Regimens in ARV Naives Regardless of Baseline CD4 and Viral Load Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

  4. DHHS Guidelines Initial Recommended Regimens - 2014 Atripla 1/day Reyataz/Norvir/Truvada 3/day Prezista/Norvir/Truvada 3/day Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.

  5. DHHS Guidelines Initial Recommended Regimens - 2014 Isentress (BID)/Truvada 3/day Tivicay/Truvada OR Epzicom 2/day OR Stribild 1/day Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14.

  6. DHHS Guidelines Update 2014: Recommended Regimens, ARV Naives, ONLY if Pre ART Viral Load <100,000 copies/ml Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

  7. DHHS Guidelines Update 2014Alternative Regimens in ARV Naives Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed 5/2/14

  8. Preferred NRTI Backbones in Pregnancy – DHHS Perinatal Guidelines, March 2014 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14

  9. Preferred PI, NNRTI Regimens in Pregnancy – DHHS Perinatal Guidelines, March 2014 Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for Use of Antiretroviral Drugs in Pregnant HIV-1-Infected Women for Maternal Health and Interventions to Reduce Perinatal HIV Transmission in the United States. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed 5/2/14

  10. Current Medications for HCV • Older Medications • Pegylated Interferon – PegIntron or Pegasys • Ribavirin • Older Direct Acting Antivirals • Boceprevir (Victrelis) • Telaprevir (Incivek) • New Direct Acting Antivirals • Simeprevir (Olysio) • Sofosbuvir (Sovaldi)

  11. Challenges with Older DAA • Telaprevir (Incivek) • Rash – Black Box Warning • Anemia – Worse than Pegylated interferon + Ribavirin alone • Needs interferon and ribavirin – brings all ADRs with it too • Anorectal adverse events challenging • Only for Genotype 1 – ie not pangenotypic • Response guided therapy/stopping rules • Drug Interactions complex, especially when treating co-infection • Large pull burden (6/day), TID, now BID frequency

  12. Challenges with Older DAA • Boceprevir (Victrelis) • Dygeusia –Anemia – Worse than Pegylated interferon + Ribavirin alone • Needs interferon and ribavirin – brings all ADRs with it too • 4 week lead in period • Only for Genotype 1 – ie not pangenotypic • Response guided therapy/stopping rules • Drug Interactions complex, especially when treating co-infection • Large pull burden (12/day), TID frequency

  13. Contraindicated medications with boceprevir and telaprevir 1. Boceprevir [package insert]. 2013. 2. Telaprevir [package insert]. 2013., 3. www.hep-druginteractions.org

  14. Daclatasvir Ledipasvir ABT- 267 Telaprevir Boceprevir Simeprevir Faldapravir ABT-450 Sofosbuvir ABT-333

  15. Simeprevir FDA Approved November 22, 2013 • FDA Panel recommended approval October 24, 2013, formal approval November 22, 2013 • Recommend approval of simeprevir, an HCV NS3/4A protease inhibitor, in combination with pegylated interferon/ribavirin • 150 mg once-daily for use by genotype 1 hepatitis C patients, either treatment-naive or prior non-responders, with food • No dosage recommendations for East Asian ancestry subjects Janssen Research and Development. FDA Advisory Committee Recommends Approval of Simeprevir for Combination Treatment of Genotype 1 Chronic Hepatitis C in Adult Patients. Press release. October 24, 2013. www.olysio.com. Accessed June 4, 2014.

  16. Simeprevir Key Points • Q80K mutation screening will be important • GT1a polymorphism • Substantial reduction in SVR rates if present at baseline • Pre-treatment screening recommended • Serious photosensitivity reactions have been observed during combination therapy • Use sun protection measures and limit sun exposure. Consider discontinuation if a photosensitivity reaction occurs. • Rash has been observed during combination therapy Discontinue OLYSIO if severe rash occurs. • Caution in Sulfa allergic, simeprevir is a sulfonamide • Hyperbilirubinemia also reported Janssen Research and Development. FDA Advisory Committee Recommends Approval of SimeQ*)previr for Combination Treatment of Genotype 1 Chronic Hepatitis C in Adult Patients. Press release. October 24, 2013. www.olysio.com. Accessed June 4, 2014.

  17. Simeprevir Key Points Janssen Research and Development. FDA Advisory Committee Recommends Approval of SimeQ*)previr for Combination Treatment of Genotype 1 Chronic Hepatitis C in Adult Patients. Press release. October 24, 2013. www.olysio.com. Accessed June 4, 2014.

  18. Simeprevir with PEG/RBV, GT 1 HIV/HCV CoInfection Design SMV + PR PR Follow-up Treatment naïve or Prior relapser Primary Analysis SMV + PR PR Follow-up RGT Prior partial or Null responder SMV + PR PR Follow-up 12 24 36 48 60 72 Dieterich D et al. CROI 2014; Abst 24

  19. Simeprevir + PEG/R,GT1 HIV/HCV CoInfection: SVR 12 Results, ITT p<0.001 p<0.001 Dieterich D et al. CROI 2014; Abst 24

  20. Drug Interactions Considerations • Simeprevir • Mild inhibitor of CYP1A2 activity and intestinal CYP3A4 • Does not affect hepatic CYP3A4 activity • Inhibits OATP1B1/3 and P-glycoprotein • Multiple drug interactions expected www.hcvguidelines.org

  21. Medications to Avoid with Simeprevir www.nynjaetc.org

  22. Medications to Avoid with Simeprevir www.nynjaetc.org

  23. Simeprevir and HIV Medications www.nynjaetc.org

  24. Simeprevir and HIV Medications www.nynjaetc.org

  25. Sofosbuvir FDA Approved, December 6, 2013 • FDA Panel recommended approval October 25, 2013 • Recommendation covers both use with interferon-based therapy for treatment-naive people with HCV genotypes 1 or 4 • Also use in dual therapy with ribavirin for people with easier-to-treat HCV genotypes 2 or 3 - the first approved interferon-free regimen Gilead Sciences. FDA Advisory Committee Supports Approval of Gilead’s Sofosbuvir for Chronic Hepatitis C Infection. Press release. October 25, 2013.www.solvadi.com. Accessed June 4, 2014.

  26. Sofosbuvir Key Points • Indication • NS5B nucleotide polymerase inhibitor for the treatment of chronic HCV as a component of combination anitiviral treatment regimen • 400 mg tablet, once daily dosing, with no food restrictions www.solvadi.com. Accessed June 4, 2014.

  27. Sofosbuvir Key Points • Sofosbuvir + ribavirin ALONE for 24 weeks can be considered for GT1 if intolerant to interferon • No dosage recommendation can be made in patients with severe renal impairment or ESRD – up to 20 fold increase in SOF metabolite • Contraindications – Monotherapy, also ribavirin birth defects www.solvadi.com. Accessed June 4, 2014.

  28. Sofosbuvir Key Points • Adverse Events • Headache and fatigue most common • Anemia and insomnia, nausea when adding peginterferon + ribavirin • Additional info • HIV/HCV coinfection studied, also data on patients with HCC awaiting liver transplantation studied • Drug Interactions • Intestinal PGP inducers likely to reduce levels –ie rifampin, St Johns Wort www.solvadi.com. Accessed June 4, 2014

  29. PHOTON-1 Trial in HIV/HCV Co-infection • Open-label, phase 3 study of sofosbuvir plus weight- • based ribavirin in coinfection, genotypes 1, 2 or 3. Week 0 12 24 36 48 SOF + RBV, n=114 GT1, Naive GT2/3, Naive SOF + RBV, n=68 SOF + RBV, n=41 GT2/3, Experienced SVR 12 SVR 24 NaggieS et al. CROI 2014; Abst 26.

  30. PHOTON-1: Results Naggie S et al. CROI 2014; Abst 26

  31. PHOTON-1: Results • Allowable ARVs: NRTIs, atazanavir/r, darunavir/r, rilpivirine & raltegravir • Most virologic failures had relapse • No sofosbuvir resistance seen Naggie S et al. CROI 2014; Abst 26

  32. PHOTON-1 Adverse Events Naggie S et al. CROI 2014; Abst 26

  33. Drug Interactions Considerations • Sofosbuvir • Substrate for P-glycoprotein and breast cancer resistance protein • Intracellular metabolism mediated by hydrolase and nucleotide phosphorylation pathways • Minimal drug interactions expected www.hcvguidelines.org

  34. Medications to Avoid with Sofosbuvir www.nynjaetc.org

  35. Sofosbuvir and HIV Medications www.nynjaetc.org

  36. Sofosbuvir and HIV Medications www.nynjaetc.org

  37. COSMOS Study Design SMV+SOF+RBV Post-treatment follow-up Arm1 SMV+SOF Post-treatment follow-up Arm2 Randomized 2:1:2:1 SMV+SOF + RBV Post-treatment follow-up Arm 3 SMV+SOF Post-treatment follow-up Arm 4 12 24 36 48 Cohort 1 – Metavir F0-F2, prior null responders Cohort 2 – Metavir F3-F4, prior null responders or naives Primary Endpoint: SVR12 Secondary Endpoints: RVR, Tx failure, relapse rate, safety Lawitz, etal. 49th EASL, April 9-13, 2014.

  38. COSMOS, Baseline Characteristics Lawitz, etal. 49th EASL, April 9-13, 2014.

  39. COSMOS, SVR 12 (ITT) Results 28/30 16/16 25/27 82/87 13/14 24 weeks 12 weeks Overall Lawitz, etal. 49th EASL, April 9-13, 2014.

  40. www.hcvguidelines.orgReleased 1/29/14!

  41. HIV/HCV Co-Infection, GT1 www.hcvguidelines.org

  42. HIV/HCV Co-Infection, GT2 www.hcvguidelines.org

  43. HIV/HCV Co-Infection, GT3 www.hcvguidelines.org

  44. HIV/HCV Coinfection, GT4 www.hcvguidelines.org

  45. HIV/HCV Coinfection, GT 5,6 www.hcvguidelines.org

  46. Standard Dosing • Sofosbuvir – 400mg once daily • Simeprevir – 150mg once daily • Peg Interferon – 180mcg once weekly • Ribavirin – weight based dosing • <75kg – 1000mg daily in divided doses • ≥75 kg – 1200mg daily in divided doses www.hcvguidelines.org

  47. IFN Ineligible Definitions • Intolerance to IFN • Autoimmune hepatitis and other autoimmune disorders • Hypersensitivity to PEG or any of its components • Decompensated hepatic disease • History of depression, or clinical features consistent with depression • A baseline neutrophil count below 1500/μL, a baseline platelet count below 90,000/μL or baseline hemoglobin below 10 g/dL • A history of preexisting cardiac disease www.hcvguidelines.org

  48. Investigational HCV Medications

  49. Select Investigational Medications • All oral, interferon free likely in October 2014 • Ledipasvir (FDC with sofosbuvir) • ABT-450/ritonavir+ABT-267 (ombitasvir) (FDC) plus ABT-333 (dasabuvir) BID • Other meds moving forward (not all inclusive) • Daclatasvir + asunaprevir + BMS-791325 • Faldaprevir • MK-5172, MK-8742 • GS-9669, GS-9451, GS-5816

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