2013 Asilomar HIV Medical Update
description
Transcript of 2013 Asilomar HIV Medical Update
![Page 1: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/1.jpg)
NORTHWEST AIDS EDUCATION AND TRAINING CENTER2013 Asilomar HIV Medical Update
David Spach, MDClinical Director, Northwest AETCProfessor of Medicine, Division of Infectious DiseasesUniversity of Washington
Last Updated: October 21, 2013
![Page 2: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/2.jpg)
2013 Asilomar Update
New Occupational PEP Guidelines
Dolutegravir (Tivicay)
Hepatitis C Update
![Page 3: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/3.jpg)
Occupational PEP 2013 Guidelines
![Page 4: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/4.jpg)
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
2013
![Page 5: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/5.jpg)
Case HistoryHIV 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-lamivudineB. 2 drugs: Tenofovir-emtricitabineC. 3 drugs: Tenofovir-emtricitabine + RaltegravirD. 3 drugs: Tenofovir-emtricitabine + Darunavir + ritonavir
![Page 6: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/6.jpg)
2013 USPHS Occupational PEP GuidelinesNumber of Antiretroviral Medications to Use
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
“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.”
![Page 7: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/7.jpg)
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
2013 USPHS Occupational PEP GuidelinesRecommendations for Antiretroviral Regimens
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
![Page 8: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/8.jpg)
Case HistoryHIV 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?
![Page 9: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/9.jpg)
2013 USPHS Occupational PEP GuidelinesPEP when Source Patient has Undetectable HIV RNA Level
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
“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.”
![Page 10: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/10.jpg)
HIV Occupational Postexposure Prophylaxis
What are situations in which expert consultation is advised?
![Page 11: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/11.jpg)
2013 USPHS Occupational PEP GuidelinesSituations 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;34:875-92.
![Page 12: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/12.jpg)
Sou
Post-Exposure Prophylaxis Line (PEPline)888-448-4911
![Page 13: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/13.jpg)
2013 USPHS Occupational PEP GuidelinesBaseline 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
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
*4th generation combination assay = HIV p24 antigen-HIV antibody test
![Page 14: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/14.jpg)
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
![Page 15: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/15.jpg)
Dolutegravir (Tivicay)
![Page 16: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/16.jpg)
Source: Slide courtesy of Brian Wood, MD.
Raltegravir (Isentress) & Dolutegravir (Tivicay)Tablet Size
DolutegravirRaltegravir
![Page 17: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/17.jpg)
Source: Dolutegravir Prescribing Information
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
50 mg twice daily
Poor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutations
![Page 18: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/18.jpg)
Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of Creatinine
Source: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.
Proximal Tubule Distal Tubule
Loop of Henle
CollectingTubule
Dolutegravir
Excretion
Inhibits tubular secretion of creatinine via inhibition of OCT2
Organic Cation Transporter 2 (OCT2)
Bowman’s Capsule
![Page 19: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/19.jpg)
Dolutegravir (Tivicay)
Should dolutegravir replace raltegravir in clinical practice?
![Page 20: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/20.jpg)
.
Dolutegravir Phase 3 Studies
(1) Raffi F, et al. Lancet 2013;381:735-43. (2) Walmsley S. 52nd ICAAC 2012. 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.
Study ARV History Comparison Results
1 SPRING-2 ARV-Naïve Dolutegravir QD vs. Raltegravir
• Non-inferior (88% vs. 85%)
2 SINGLE ARV-Naïve Dolutegravir QD vs. Efavirenz
✔ Dolutegravir superior (88% vs. 81%)
3 FLAMINGO ARV-Naïve Dolutegravir QD vs. Darunavir-RTV
✔ Dolutegravir superior(90% vs. 81%)
4 SAILING >2-class ARV resistance
Dolutegravir QD vs. Raltegravir
✔ Dolutegravir superior (71% vs. 64%)
5 VIKING-3 Integrase resistance
Single-arm, Dolutegravir BID
• Virological suppression(64%)
![Page 21: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/21.jpg)
Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Design
Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.
Dolutegravir + 2NRTIs (n = 242)
Darunavir + 2NRTIs(n = 242)
Study DesignProtocol - 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 dose = 50 mg once daily; Darunavir dose = 800 mg once daily
![Page 22: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/22.jpg)
Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result
Week 48 Virologic Response
Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.
![Page 23: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/23.jpg)
Dolutegravir
Does the NRTI backbone with dolutegravir matter?
Tenofovir-emtricitabine Abacavir-lamivudine
![Page 24: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/24.jpg)
Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result
Week 48 Virologic Response: Background Dual NRTI Therapy
Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.
![Page 25: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/25.jpg)
Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTCSINGLE: Result
Week 48 Virologic Response
Source: Walmsley S, et al. 52nd ICAAC. 2012: Abstract H-556-b.
![Page 26: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/26.jpg)
Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result
Week 96 Virologic Response: Background Dual NRTI Therapy
Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.
![Page 27: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/27.jpg)
Dolutegravir + 2NRTIs versus Raltegravir + 2NRTIs SPRING-2: Result
Week 96 Virologic Response: Background Dual NRTI Therapy
Source: Raffi F, et al. 7th IAS. 2013. Abstract TuLBPE17.
![Page 28: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/28.jpg)
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. 2013. Abstract TuLBPE17.
![Page 29: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/29.jpg)
Source: Fransen S, et al. J Virol. 2009;83:11440-6.
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
![Page 30: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/30.jpg)
Integrase Resistance Testing
• Integrase Genotype ✔- Quest Diagnostics- Lab Corp (Monogram Biosciences)- Virco
• Integrase Phenotype- Lab Corp (Monogram Biosciences)- Virco
![Page 31: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/31.jpg)
Dolutegravir in Treatment-Experienced with Integrase ResistanceVIKING-3
Sources: 1) ViiV Healthcare Press release. Nov 2012. 2) Nichols G et al. IAS 2013. 3) http://www.viivhealthcare.com/media/58599/us_tivicay.pdf
Dolutegravir 50 mg BID
+ Failing Regimen
Dolutegravir 50 mg BID
+ OBT
Study Design
Protocol- HIV-infected adults with
VL >500 copies- Resistance to raltegravir
or elvitegravir, plus resistance to at least 2 additional ARV classes
Functional monotherapyphase (7 days) Day 8
![Page 32: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/32.jpg)
Dolutegravir in Patients with Raltegravir ResistanceVIKING-3: Results
Source: Dolutegravir Product Information.
*without additional INSTI mutations
![Page 33: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/33.jpg)
Dolutegravir Discussion
How should we use dolutegravir in clinical practice?
- In treatment naïve?
- In treatment experienced (intregrase naïve)?
- In treatment experience and integrase resistant?
![Page 34: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/34.jpg)
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
![Page 35: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/35.jpg)
Hepatitis C Update
![Page 36: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/36.jpg)
.
Hepatitis C Epidemiology in United States
Annual Deaths from HCV?
![Page 37: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/37.jpg)
Source: Ly KN, et al. Ann Intern Med. 2012:156:271-8.
Age-Adjusted Mortality Rates* from HBV, HCV, & HIV United States, 1999-2007
*Mortality Rates = HBV, HCV, HIV listed as cause of death
Rate
per
100
,000
PY
Year
HIV
1999 2000 2001 2002 2003 2004 2006 20072005
5
4
3
2
1
0
7
6
Hepatitis C
Hepatitis B
n = 15,106
![Page 38: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/38.jpg)
Forecasted 2010-2060 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. 2011:43:66-72.
Num
ber
Year2010
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
0
45,000
![Page 39: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/39.jpg)
Source: Holmberg SD, et al. N Engl J Med. 2013;368:1859-61.
Hepatitis C Cascade of Care in United States
100%
50%
35%
9% 6%
![Page 40: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/40.jpg)
Source: Sulkowski M, et al. Ann Intern Med. 2003;138:197-207.
HCV-HIV Coinfection
HIV Monoinfection
HIV-HCV Coinfection
HIV-Infected Persons in United States
![Page 41: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/41.jpg)
Source: Weber R, et al. Arch Intern Med. 2006;166:1632-41.
Cause of Death (Incidence) in the D:A:D Study
N = 1,246 deaths
![Page 42: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/42.jpg)
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?
![Page 43: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/43.jpg)
Entry into CareRecommendations 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.”
![Page 44: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/44.jpg)
Recommendations for Repeat Testing for Hepatitis C in HIV-Infected Persons
Source: Page R-2. 2013 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.”
![Page 45: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/45.jpg)
Hepatitis C and Cure
Why can antiviral cure hepatitis C but not HIV?
Sustained Virologic Response (SVR) with HCV Treatment = Cure
![Page 46: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/46.jpg)
Source: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:2012-12
Comparative Treatment Goals with Antiviral Therapy
HBV(latent reservoir)
HIV(latent reservoir)
HCV(no latent reservoir)
Host CellHost Cell Host Cell
Host DNAHost DNA Host DNA
ccDNAProviral DNA
HCV RNA
Definitive Viral Clearance
Lifelong suppression of viral replication
Long-term reductionof viral replication
![Page 47: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/47.jpg)
Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs)
1986 1998 2001 2002
Timeline
![Page 48: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/48.jpg)
Therapy for Hepatitis CProjected SVR Rates with Multiple DAAs
Timeline2011 2014 2015
![Page 49: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/49.jpg)
Simeprevir: October 24, 2013
Sofosbuvir: October 25, 2013
![Page 50: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/50.jpg)
Hepatitis C VirusGenome
5’ 3’
HCV Genome
Structural Non-Structural
![Page 51: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/51.jpg)
Hepatitis C VirusTranslation
C ANS2 NS3E1 p7E2 B NS5A B NS4
Polyprotein Precursor: ≈ 3,000 amino acids
Translation
HCV Genome
5’ 3’
Structural Non-Structural
![Page 52: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/52.jpg)
Hepatitis C VirusProtein Processing
HCV Genome
C ANS2 NS3E1 p7E2 B NS5A B NS4
Polyprotein Precursor
Protein Processing
Translation
C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B
Proteins
![Page 53: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/53.jpg)
Hepatitis C VirusStructural and Nonstructural Proteins
Hepatitis C Proteins
Nucleocapsid
Envelope Glycoprotein
Vioporin
CysteineProtease
Protease RNAHelicase
Protease Cofactors
Membranous Web Induction
RNA-Dependent RNA Polymerase
C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B
Structural Proteins Nonstructural (NS) Proteins
Envelope Glycoprotein
RNA binding and assembly recognition complex
![Page 54: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/54.jpg)
Hepatitis C VirusDirect Acting Agents (DAAs)
Hepatitis C Proteins
Protease Protease Cofactors
RNA-Dependent RNA Polymerase
C NS4B NS5ANS2 NS3E1 NS4Ap7E2 NS5B
Structural Proteins Nonstructural (NS) Proteins
RNA binding and assembly recognition complex
![Page 55: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/55.jpg)
Hepatitis C VirusDirect Acting Agents (DAAs)
Hepatitis C Proteins as Antiviral Targets for DAAs
NS3/4AProtease Inhibitors
NS5B Polymerase Inhibitors
NS5ANS3 NS4A NS5B
NS5A Inhibitors
NRTIs NNRTIs
![Page 56: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/56.jpg)
Future HCV Direct Acting Agents (DAAs)
Faldaprevir
Daclatasvir
Danoprevir
Asunaprevir Mericitabine
Vaniprevir
Ledipasvir
Simeprevir
Sofosbuvir
ABT-267 ABT-333
ABT-450/r
NS5ANS3 NS4A NS5B
IDX-719 BMS-791325
Protease Inhibitors Polymerase InhibitorsNS5A Inhibitors
BI-207127
![Page 57: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/57.jpg)
Sofosbuvir
• Investigational- FDA Advisory Panel meeting October 25, 2013
• Class & Mechanism- NS5B nucleotide analogue polymerase inhibitor- Pan genotypic
• Sofosbuvir Dosing- 400 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
![Page 58: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/58.jpg)
• 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
![Page 59: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/59.jpg)
Sofosbuvir in Treatment-Naïve Genotypes 1,4,5,6NEUTRINO Trial*
*Note: Published in tandem with FISSION Trial (Genotypes 2,3)
HCV Monoinfection
![Page 60: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/60.jpg)
Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6)NEUTRINO
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
24Week 0 12
Sofosbuvir + PEG + RBVN =327 SVR12
Drug DosingSofosbuvir 400 mg once dailyPeginterferon alfa-2a = 180 µg once weeklyRibavirin (weight-based): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kg
![Page 61: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/61.jpg)
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;368:1878-87.
• Percentage of Patients with SVR
GT = genotype
![Page 62: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/62.jpg)
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;368:1878-87.
• Percentage of Patients with SVR
![Page 63: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/63.jpg)
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;368:1878-87.
• Percentage of Patients with SVR
![Page 64: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/64.jpg)
Sofosbuvir in Treatment-Naïve Genotypes 2,3FISSION Trial*
*Note: Published in tandem with NEUTRINO Trial (Genotypes 1,4,5,6)
HCV Monoinfection
![Page 65: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/65.jpg)
Sofosbuvir and Ribavirin for Chronic Untreated HCVFISSION Trial
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
24 36Week 0 12
N =243
N =256 SVR12
SVR12
Drug DosingSofosbuvir 400 mg once dailyPeginterferon alfa-2a = 180 µg once weeklyRibavirin (weight-based): 1000 mg if < 75kg or 1200 mg/day if ≥ 75kgRibavirin (fixed dose): 800 mg/day divided BID
Peginterferon + RBV (fixed dose)
Sofosbuvir + RBV (weight-based)
![Page 66: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/66.jpg)
Sofosbuvir for Chronic Untreated HCV Infection GT 2,3FISSION Study: Results
SVR12 (by Genotype)
Source: Lawitz E, et al. N Engl J Med. 2013;368:1878-87.
RBV = Ribavirin; PegIFN = Peginterferon
![Page 67: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/67.jpg)
Sofosbuvir in HIV-Infected
![Page 68: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/68.jpg)
SofosbuvirKey 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
![Page 69: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/69.jpg)
Simeprevir
• Investigational- FDA application submitted March 2013- 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- 150 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)
![Page 70: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/70.jpg)
Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Trial
Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.
N =130 Placebo+ PEG + RBV
Simeprevir + PEG + RBV
N = 264
48Week 0 12 24
PEG + RBVPEG + RBV
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 DosingSimeprevir 150 mg once dailyPeginterferon alfa-2a (PEG): 180 mcg/weekRibavirin (RBV) weight-based: 1000 mg if < 75 kg or 1200 mg/day if ≥ 75kg
![Page 71: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/71.jpg)
Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Results
Proportion of Patients with SVR12
Source: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.
Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirin
P < 0.001
![Page 72: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/72.jpg)
SimeprevirKey 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
![Page 73: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/73.jpg)
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
![Page 74: 2013 Asilomar HIV Medical Update](https://reader036.fdocuments.us/reader036/viewer/2022081514/5681677a550346895ddc7b53/html5/thumbnails/74.jpg)
End