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N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 2013 Asilomar HIV Medical Update David Spach, MD Clinical Director, Northwest AETC Professor of Medicine,

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Presentation on theme: "N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 2013 Asilomar HIV Medical Update David Spach, MD Clinical Director, Northwest AETC Professor of Medicine,"— Presentation transcript:

1 N ORTHWEST A IDS E DUCATION AND T RAINING C ENTER 2013 Asilomar HIV Medical Update David Spach, MD Clinical Director, Northwest AETC Professor of Medicine, Division of Infectious Diseases University of Washington Last Updated: October 21, 2013

2 2013 Asilomar Update  New Occupational PEP Guidelines  Dolutegravir (Tivicay)  Hepatitis C Update

3 Occupational PEP 2013 Guidelines

4 Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:

5 Case History HIV Exposure in a Health Care Worker A 41-year-old male nurse has a needlestick injury on his left thumb. The site bled for about 2 minutes after the injury. The source patient has documented HIV infection, has never taken antiretroviral medications, and most lab studies showed HIV RNA level of 2,350 copies/ml and CD4 count of 658 cells/mm 3. Based on USPHS 2013 Guidelines, what is recommended? A. 2 drugs: Zidovudine-lamivudine B. 2 drugs: Tenofovir-emtricitabine C. 3 drugs: Tenofovir-emtricitabine + Raltegravir D. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir

6 2013 USPHS Occupational PEP Guidelines Number of Antiretroviral Medications to Use Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34: “As less toxic and better-tolerated medications for the treatment of HIV infection are now available… the PHS working group recommends prescribing 3 (or more) tolerable drugs as PEP for all occupational exposures to HIV.”

7 2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:

8 Case History HIV Exposure in a Health Care Worker A 32-year-old physician has a needlestick injury on her hand that involves an HIV-infected patient. The source patient is taking tenofovir-emtricitabine-efavirenz (Atripla) and had an undetectable HIV RNA level 3 months prior. Based on USPHS 2013 Guidelines, would you recommend antiretroviral PEP for this physician?

9 2013 USPHS Occupational PEP Guidelines PEP when Source Patient has Undetectable HIV RNA Level Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34: “Exposure to a source patient with an undetectable serum viral load does not eliminate the possibility of HIV transmission or the need for PEP and follow-up testing. While the risk of transmission from an occupational exposure to a source patient with an undetectable serum viral load is thought to be very low, PEP should still be offered.”

10 HIV Occupational Postexposure Prophylaxis What are situations in which expert consultation is advised?

11 2013 USPHS Occupational PEP Guidelines Situations for Which Expert Consultation Advised Delayed exposure report (eg. longer than 72 hours) Unknown source (eg. needle in sharps disposal) Known or suspected pregnancy in exposed person Exposed person breast-feeding Known or suspected ARV drug resistance in source patient Serious medical illness in exposed persons Toxicity occurring in exposed person taking PEP regimen Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:

12 Sou Post-Exposure Prophylaxis Line (PEPline)

13 2013 USPHS Occupational PEP Guidelines Baseline and Follow-Up for Occupational PEP Early Reevaluation after Exposure (within 72 hours) Baseline and Follow-up HIV Testing - Baseline HIV testing - Follow-up HIV testing 6, 12, and 24 weeks after exposure - Follow-up HIV testing at 6 and 16 weeks if 4 th generation assay* used Baseline and Follow-up Laboratory Testing - Baseline renal and hepatic function tests - Follow-up renal and hepatic function tests at 2 weeks Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34: *4 th generation combination assay = HIV p24 antigen-HIV antibody test

14 Occupational HIV Postexposure Prophylaxis Suggestions for Training A.Incorporate Occupational PEP into Larger Trainings B.Provide 3 Point Takeaway Training (1) When PEP given, use 3 or more ARV drugs (2) Use Tenofovir-emtricitabine + Raltegravir (3) Know when and how to get expert consultations C. Give trainees PEPLine information/pamphlet

15 Dolutegravir (Tivicay)

16 Source: Slide courtesy of Brian Wood, MD. Raltegravir (Isentress) & Dolutegravir (Tivicay) Tablet Size DolutegravirRaltegravir

17 Source: Dolutegravir Prescribing Information Dolutegravir Recommended Dolutegravir Dosing Adult PopulationRecommended Dose Treatment-naïve or Treatment-experienced INSTI-naïve 50 mg once daily Coadministered with potent UGT1A/CYP3A inducer: Efavirenz Fosamprenavir/ritonavir Tipranavir/ritonavir Rifampin 50 mg twice daily INSTI-experienced with certain INSTI mutations* or Clinically suspected INSTI resistance 50 mg twice daily Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations

18 Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75: Proximal TubuleDistal Tubule Loop of Henle Collecting Tubule Dolutegravir Excretion Inhibits tubular secretion of creatinine via inhibition of OCT2 Organic Cation Transporter 2 (OCT2) Bowman’s Capsule

19 Dolutegravir (Tivicay) Should dolutegravir replace raltegravir in clinical practice?

20 . Dolutegravir Phase 3 Studies (1) Raffi F, et al. Lancet 2013;381: (2) Walmsley S. 52 nd ICAAC Abstract H556b. (3) Feinberg J, et al. 53 nd ICAAC. 2013: Abstract H-146-a. (4) Cahn P, et al. Lancet 2013;382:700–8. (5) Nichols G, et al. 7 th Conference IAS 2013: Abstract TULBPE19.

21 Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIs FLAMINGO: Design Source: Feinberg J, et al. 53 nd ICAAC. 2013: Abstract H-146-a. Dolutegravir + 2NRTIs (n = 242) Darunavir + 2NRTIs (n = 242) *Dolutegravir dose = 50 mg once daily; Darunavir dose = 800 mg once daily

22 Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIs FLAMINGO: Result Week 48 Virologic Response Source: Feinberg J, et al. 53 nd ICAAC. 2013: Abstract H-146-a.

23 Dolutegravir Does the NRTI backbone with dolutegravir matter? Tenofovir-emtricitabineAbacavir-lamivudine

24 Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIs FLAMINGO: Result Week 48 Virologic Response: Background Dual NRTI Therapy Source: Feinberg J, et al. 53 nd ICAAC. 2013: Abstract H-146-a.

25 Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTC SINGLE: Result Week 48 Virologic Response Source: Walmsley S, et al. 52 nd ICAAC. 2012: Abstract H-556-b.

26 Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96 Virologic Response: Background Dual NRTI Therapy Source: Raffi F, et al. 7 th IAS Abstract TuLBPE17.

27 Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96 Virologic Response: Background Dual NRTI Therapy Source: Raffi F, et al. 7 th IAS Abstract TuLBPE17.

28 Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result Week 96: Background Dual NRTI Therapy in Patients on Dolutegravir Source: Raffi F, et al. 7 th IAS Abstract TuLBPE17.

29 Source: Fransen S, et al. J Virol. 2009;83: Major Pathways of Resistance with Raltegravir Raltegravir N155H Q148H/K/R Secondary Mutations (L74M, E92Q, T97A, V151I, G163R) Secondary Mutations (L74M, G140A/S, E138K) Early Delayed

30 Integrase Resistance Testing Integrase Genotype ✔ - Quest Diagnostics - Lab Corp (Monogram Biosciences) - Virco Integrase Phenotype - Lab Corp (Monogram Biosciences) - Virco

31 Dolutegravir in Treatment-Experienced with Integrase Resistance VIKING-3 Sources: 1) ViiV Healthcare Press release. Nov ) Nichols G et al. IAS ) Dolutegravir 50 mg BID + Failing Regimen Dolutegravir 50 mg BID + OBT Functional monotherapy phase (7 days) Day 8 

32 Dolutegravir in Patients with Raltegravir Resistance VIKING-3: Results Source: Dolutegravir Product Information. *without additional INSTI mutations

33 Dolutegravir Discussion How should we use dolutegravir in clinical practice? - In treatment naïve? - In treatment experienced (intregrase naïve)? - In treatment experience and integrase resistant?

34 Use of Dolutegravir Treatment naïve - Excellent first line agent - Likely will become a preferred agent in DHHS Guidelines Treatment experienced (Integrase-naïve) - Attractive as component of salvage regimen Treatment experience (Integrase resistant or experienced) - Parameters for once or twice daily dosing poorly defined - Avoid use with Q148 + ≥ 2 secondary mutations

35 Hepatitis C Update

36 . Hepatitis C Epidemiology in United States Annual Deaths from HCV?

37 Source: Ly KN, et al. Ann Intern Med. 2012:156: Age-Adjusted Mortality Rates* from HBV, HCV, & HIV United States, *Mortality Rates = HBV, HCV, HIV listed as cause of death Rate per 100,000 PY Year HIV Hepatitis C Hepatitis B n = 15,106

38 Forecasted Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005 Source: Rein DR, et al. Dig Liver Dis. 2011:43: Number Year 2010 Deaths ,000 35,000 30,000 25,000 20,000 15,000 10,000 5, ,000

39 Source: Holmberg SD, et al. N Engl J Med. 2013;368: Hepatitis C Cascade of Care in United States 100% 50% 35% 9% 6%

40 Source: Sulkowski M, et al. Ann Intern Med. 2003;138: HCV-HIV Coinfection HIV Monoinfection HIV-HCV Coinfection HIV-Infected Persons in United States

41 Source: Weber R, et al. Arch Intern Med. 2006;166: Cause of Death (Incidence) in the D:A:D Study N = 1,246 deaths

42 Testing for Hepatitis C A 34-year-old man is diagnosed with HIV infection. His risk factor for acquiring HIV is having sex with other men. He has about 8-10 male sexual partners per year.He has never injected drugs. His CD4 count is 684 cells/mm 3. He is referred for routine HIV care. At his initial evaluation, should you test this patient for hepatitis C infection? If the HCV antibody test is negative, should he have repeat testing?

43 Entry into Care Recommendations for HCV Testing Source: 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov) “On entry into HIV care, all HIV-infected patients should undergo routine HCV screening.”

44 Recommendations for Repeat Testing for Hepatitis C in HIV-Infected Persons Source: Page R Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov) “For at risk HCV-seronegative persons, HCV antibody testing is recommended annually or as indicated by risk exposure.”

45 Hepatitis C and Cure Why can antiviral cure hepatitis C but not HIV? Sustained Virologic Response (SVR) with HCV Treatment = Cure

46 Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65: Comparative Treatment Goals with Antiviral Therapy HBV (latent reservoir) HIV (latent reservoir) HCV (no latent reservoir) Host Cell Host DNA ccDNA Proviral DNA HCV RNA Definitive Viral Clearance Lifelong suppression of viral replication Long-term reduction of viral replication

47 Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs) Timeline

48 Therapy for Hepatitis C Projected SVR Rates with Multiple DAAs Timeline

49 Simeprevir: October 24, 2013 Sofosbuvir: October 25, 2013

50 Hepatitis C Virus Genome 5’3’ HCV Genome StructuralNon-Structural

51 Hepatitis C Virus Translation C C A A NS2 NS3 E1 p7 E2 B NS5 A A B NS4 Polyprotein Precursor: ≈ 3,000 amino acids Translation HCV Genome 5’3’ StructuralNon-Structural

52 Hepatitis C Virus Protein Processing HCV Genome C C A A NS2 NS3 E1 p7 E2 B NS5 A A B NS4 Polyprotein Precursor Protein Processing Translation C C NS4B NS5A NS2 NS3 E1 NS4 A p7 E2 NS5B Proteins

53 Hepatitis C Virus Structural and Nonstructural Proteins Hepatitis C Proteins Nucleocapsid Envelope Glycoprotein Vioporin Cysteine Protease ProteaseRNA Helicase Protease Cofactors Membranous Web Induction RNA-Dependent RNA Polymerase C C NS4B NS5A NS2 NS3 E1 NS4 A p7 E2 NS5B Structural ProteinsNonstructural (NS) Proteins Envelope Glycoprotein RNA binding and assembly recognition complex

54 Hepatitis C Virus Direct Acting Agents (DAAs) Hepatitis C Proteins Protease Protease Cofactors RNA-Dependent RNA Polymerase CNS4B NS5A NS2 NS3 E1 NS4 A p7E2 NS5B Structural ProteinsNonstructural (NS) Proteins RNA binding and assembly recognition complex

55 Hepatitis C Virus Direct Acting Agents (DAAs) Hepatitis C Proteins as Antiviral Targets for DAAs NS3/4A Protease Inhibitors NS5B Polymerase Inhibitors NS5A NS3 NS4A NS5B NS5A Inhibitors NRTIsNNRTIs

56 Future HCV Direct Acting Agents (DAAs) Faldaprevir Daclatasvir Danoprevir Asunaprevir Mericitabine Vaniprevir Ledipasvir Simeprevir Sofosbuvir ABT-267 ABT-333 ABT-450/r NS5A NS3 NS4A NS5B IDX-719 BMS Protease InhibitorsPolymerase InhibitorsNS5A Inhibitors BI

57 Sofosbuvir Investigational - FDA Advisory Panel meeting October 25, 2013 Class & Mechanism - NS5B nucleotide analogue polymerase inhibitor - Pan genotypic Sofosbuvir Dosing mg PO once daily Clinical Use - GT 2 (?3): In combination with ribavirin alone (dual therapy) - GT 1,4,5,6: in combination with peginterferon + ribavirin (triple therapy) Drug Interactions and Adverse Effects (AE) - Minimal drug interaction - Well-tolerated

58 Phase 3 Trials in Treatment Naive - NEUTRINO: Sofosbuvir + PEG + RBV; GT 1,4,5,6 - FISSION: Sofosbuvir + RBV vs. PEG + RBV; GT 2,3 - POSITRON: Sofosbuvir + RBV; GT 2,3; Interferon intolerant Phase 3 Trials in Treatment Experienced - FUSION: Sofosbuvir + RBV for 12 vs. 16 weeks; prior Rx failure; GT 2,3 Phase 2 Trials in Treatment Naïve - NIAID: Sofosbuvir + RBV; GT 1; Unfavorable baseline characteristics Phase 3 Trials in Treatment Naive - NEUTRINO: Sofosbuvir + PEG + RBV; GT 1,4,5,6 - FISSION: Sofosbuvir + RBV vs. PEG + RBV; GT 2,3 - POSITRON: Sofosbuvir + RBV; GT 2,3; Interferon intolerant Phase 3 Trials in Treatment Experienced - FUSION: Sofosbuvir + RBV for 12 vs. 16 weeks; prior Rx failure; GT 2,3 Phase 2 Trials in Treatment Naïve - NIAID: Sofosbuvir + RBV; GT 1; Unfavorable baseline characteristics Sofosbuvir: Summary of Key Studies HCV Monoinfection

59 Sofosbuvir in Treatment-Naïve Genotypes 1,4,5,6 NEUTRINO Trial* *Note: Published in tandem with FISSION Trial (Genotypes 2,3) HCV Monoinfection

60 Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO Source: Lawitz E, et al. N Engl J Med. 2013;368: Week 012 Sofosbuvir + PEG + RBV N =327 SVR12 Drug Dosing Sofosbuvir 400 mg once daily Peginterferon alfa-2a = 180 µg once weekly Ribavirin (weight-based): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg

61 Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by Genotype Source: Lawitz E, et al. N Engl J Med. 2013;368: Percentage of Patients with SVR GT = genotype

62 Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by Race Source: Lawitz E, et al. N Engl J Med. 2013;368: Percentage of Patients with SVR

63 Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by Presence of Cirrhosis Source: Lawitz E, et al. N Engl J Med. 2013;368: Percentage of Patients with SVR

64 Sofosbuvir in Treatment-Naïve Genotypes 2,3 FISSION Trial* *Note: Published in tandem with NEUTRINO Trial (Genotypes 1,4,5,6) HCV Monoinfection

65 Sofosbuvir and Ribavirin for Chronic Untreated HCV FISSION Trial Source: Lawitz E, et al. N Engl J Med. 2013;368: Week 012 N =243 N =256 SVR12 Drug Dosing Sofosbuvir 400 mg once daily Peginterferon alfa-2a = 180 µg once weekly Ribavirin (weight-based): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg Ribavirin (fixed dose): 800 mg/day divided BID Peginterferon + RBV (fixed dose) Sofosbuvir + RBV (weight-based)

66 Sofosbuvir for Chronic Untreated HCV Infection GT 2,3 FISSION Study: Results SVR12 (by Genotype) Source: Lawitz E, et al. N Engl J Med. 2013;368: RBV = Ribavirin; PegIFN = Peginterferon

67 Sofosbuvir in HIV-Infected

68 Sofosbuvir Key Summary Points Major impact drug for hepatitis C treatment Active against all HCV genotypes Option for interferon-free treatment of GT2 (?GT3) Excellent results with most difficult to treat GT-1 patients Safe, convenient, potent, and minimal drug interactions Optimal approach with sofosbuvir and genotype 3 uncertain Likely will be very safe and effective in HIV-infected patients Payment/reimbursement with HIV-infected unknown

69 Simeprevir Investigational - FDA application submitted March FDA Advisory Committee meeting on October 24, 2013 Class & Mechanism - NS3/4A protease inhibitor - Multi-genotypic activity against genotypes 1,2,4,5 and 6. Simeprevir Dosing mg PO once daily - In combination with peginterferon + ribavirin (triple therapy) Adverse Effects (AE) attributable to Simeprevir - Reversible hyperbilirubinemia (due to interference with OATP1B1/MRP2 transporters)

70 Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Trial Source: Jacobson I, et al. 48 th Annual Meeting of EASL. Abstract N =130 Placebo + PEG + RBV Simeprevir + PEG + RBV Simeprevir + PEG + RBV N = Week PEG + RBV Response-guided therapy: Patients with extended RVR (HCV RNA <25 IU/ml at weeks 4 and 12) were allowed to stop treatment after 24 weeks. Randomized 2:1, stratified on IL28B and HCV subtype Drug Dosing Simeprevir 150 mg once daily Peginterferon alfa-2a (PEG): 180 mcg/week Ribavirin (RBV) weight-based: 1000 mg if < 75 kg or 1200 mg/day if ≥ 75kg

71 Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Results Proportion of Patients with SVR12 Source: Jacobson I, et al. 48 th Annual Meeting of EASL. Abstract Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin P < 0.001

72 Simeprevir Key Summary Points Modest impact drug for hepatitis C treatment Similar to boceprevir and telaprevir but ONCE DAILY Future use likely as component of multi-DAA therapy Payment/reimbursement with HIV-infected unknown

73 Hepatitis C: Key Points Revolution in Treatment - Cure ≈ 90% of GT1 with 12-week therapy - Cure ≈ 90% GT2 with all 12-weeks all-oral therapy - Future all-oral therapy will have cure > 90% for all GTs Dramatic improvements needed in HCV cascade of care Unknown how quickly new meds available for HIV

74 End


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