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2013 Asilomar HIV Medical Update

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1 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 2013 Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;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/mm3. 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
“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.” Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:

7 Raltegravir (Isentress) 400 mg twice daily
2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral Regimens Recommended Antiretroviral Regimens for Occupational PEP (28-Day Duration) Preferred Regimen INSTI NNRTI Pill Burden Raltegravir (Isentress) 400 mg twice daily Tenofovir-Emtricitabine (Truvada) 1 pill daily Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;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
“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.” Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:

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

11 Delayed exposure report (eg. longer than 72 hours)
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 ;34:

12 Post-Exposure Prophylaxis Line (PEPline) 888-448-4911
Sou

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 4th 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 *4th generation combination assay = HIV p24 antigen-HIV antibody test Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:

14 Occupational HIV Postexposure Prophylaxis
Suggestions for Training Incorporate Occupational PEP into Larger Trainings 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)
1

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

17 Dolutegravir Recommended Dolutegravir Dosing Adult Population
Recommended 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 Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations Source: Dolutegravir Prescribing Information

18 Organic Cation Transporter 2 (OCT2)
Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine Bowman’s Capsule Proximal Tubule Distal Tubule Organic Cation Transporter 2 (OCT2) Dolutegravir Collecting Tubule Inhibits tubular secretion of creatinine via inhibition of OCT2 Loop of Henle Excretion Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.

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

20 Dolutegravir Phase 3 Studies
Study ARV History Comparison Results 1 SPRING-2 ARV-Naïve Dolutegravir QD vs. Raltegravir Non-inferior (88% vs. 85%) 2 SINGLE Dolutegravir QD vs. Efavirenz ✔ Dolutegravir superior (88% vs. 81%) 3 FLAMINGO Dolutegravir QD vs. Darunavir-RTV ✔ Dolutegravir superior (90% vs. 81%) 4 SAILING >2-class ARV resistance ✔ Dolutegravir superior (71% vs. 64%) 5 VIKING-3 Integrase resistance Single-arm, Dolutegravir BID Virological suppression (64%) (1) Raffi F, et al. Lancet 2013;381: (2) Walmsley S. 52nd ICAAC Abstract H556b. (3) Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a. (4) Cahn P, et al. Lancet 2013;382:700–8. (5) Nichols G, et al. 7th Conference IAS 2013: Abstract TULBPE19. .

21 Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIs FLAMINGO: Design
Study Design Protocol - Open-label, randomized study - Phase 3 trial - Antiretroviral-naïve patients - Treatment Arms Dolutegravir* (QD) + 2NRTIs Darunavir* + RTV (QD) + 2NRTIs - NRTIs Tenofovir-emtricitabine Abacavir-lamivudine Dolutegravir + 2NRTIs (n = 242) Darunavir + 2NRTIs (n = 242) *Dolutegravir dose = 50 mg once daily; Darunavir dose = 800 mg once daily Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.

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

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

24 Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIs FLAMINGO: Result
Week 48 Virologic Response: Background Dual NRTI Therapy Source: Feinberg J, et al. 53nd 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. 52nd 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. 7th 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. 7th 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. 7th IAS Abstract TuLBPE17.

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

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

31 Functional monotherapy
Dolutegravir in Treatment-Experienced with Integrase Resistance VIKING-3 Study Design Protocol HIV-infected adults with VL >500 copies Resistance to raltegravir or elvitegravir, plus resistance to at least 2 additional ARV classes Dolutegravir 50 mg BID + Failing Regimen Dolutegravir 50 mg BID + OBT Functional monotherapy phase (7 days) Day 8  -activity of OBR was not correlated with response; increased fold-change to dolutegravir did correlate Sources: 1) ViiV Healthcare Press release. Nov ) Nichols G et al. IAS )

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

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 1

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

37 Age-Adjusted Mortality Rates
Age-Adjusted Mortality Rates* from HBV, HCV, & HIV United States, 7 HIV n = 15,106 6 5 4 Hepatitis C Rate per 100,000 PY 3 2 Hepatitis B 1 1999 2000 2001 2002 2003 2004 2005 2006 2007 Year *Mortality Rates = HBV, HCV, HIV listed as cause of death Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.

38 Forecasted Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005 Number Year 2010 Deaths 2014 2018 2022 2026 2030 2034 2038 2042 2046 2050 2054 2058 40,000 35,000 30,000 25,000 20,000 15,000 10,000 5,000 45,000 Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.

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

40 HIV-Infected Persons in United States
HCV-HIV Coinfection HIV-Infected Persons in United States HIV Monoinfection HIV-HCV Coinfection Source: Sulkowski M, et al. Ann Intern Med. 2003;138: 1

41 Cause of Death (Incidence) in the D:A:D Study
N = 1,246 deaths This graph summarizes the death rate, by cause, among subjects who died in the Data Collection on Adverse Events on HIV Drugs (D:A:D) study. The D:A:D study was conducted in in Europe, the United States, and Australia. The investigators prospectively followed 23,441 HIV-infected persons for a median of 3.5 years. In total, 1,246 (5.3%) persons died during the study and among those who died, 5.2% had never received antiretroviral therapy. Overall, 22.5% of the subjects enrolled were hepatitis C positive and 6.8% had active HBV infection. Source: Weber R, et al. Arch Intern Med ;166: 1

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/mm3. 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
“On entry into HIV care, all HIV-infected patients should undergo routine HCV screening.” Source: 2013 Opportunistic Infections Guidelines. AIDS Info. (www.aidsinfo.nih.gov)

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

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

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

47 Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs)
Timeline 1986 1998 2001 2002

48 Therapy for Hepatitis C Projected SVR Rates with Multiple DAAs
Timeline 2011 2014 2015

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

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

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

52 Hepatitis C Virus Protein Processing
HCV Genome Translation Polyprotein Precursor C E1 E2 p7 NS2 NS3 A NS4 B A B NS5 Protein Processing Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B

53 Hepatitis C Virus Structural and Nonstructural Proteins
Hepatitis C Proteins Structural Proteins Nonstructural (NS) Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B Nucleocapsid Envelope Glycoprotein Cysteine Protease Protease Cofactors RNA binding and assembly recognition complex Envelope Glycoprotein Vioporin Protease RNA Helicase Membranous Web Induction RNA-Dependent RNA Polymerase

54 Hepatitis C Virus Direct Acting Agents (DAAs)
Hepatitis C Proteins Structural Proteins Nonstructural (NS) Proteins C E1 E2 p7 NS2 NS3 NS4A NS4B NS5A NS5B RNA binding and assembly recognition complex Protease Protease Cofactors RNA-Dependent RNA Polymerase

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

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

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 Sofosbuvir: Summary of Key Studies
HCV Monoinfection 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

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

60 Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO
Week 12 24 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 Source: Lawitz E, et al. N Engl J Med ;368:

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

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

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

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

65 Sofosbuvir and Ribavirin for Chronic Untreated HCV FISSION Trial
Week 12 24 36 Sofosbuvir + RBV (weight-based) N =256 SVR12 Peginterferon + RBV (fixed dose) N =243 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 Source: Lawitz E, et al. N Engl J Med ;368:

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

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
Week 12 24 48 Randomized 2:1, stratified on IL28B and HCV subtype 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. Simeprevir + PEG + RBV PEG + RBV N = 264 PEG + RBV Placebo + PEG + RBV PEG + RBV N =130 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 Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.

71 Proportion of Patients with SVR12
Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Results Proportion of Patients with SVR12 P < 0.001 Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.

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 1


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