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
2013 Asilomar Update
New Occupational PEP Guidelines
Dolutegravir (Tivicay)
Hepatitis C Update
Occupational PEP 2013 Guidelines
Source: Kuhar DT, et al. Infect Control Hosp Epidemiol. 2013;34:875-92.
2013
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
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.”
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.
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?
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.”
HIV Occupational Postexposure Prophylaxis
What are situations in which expert consultation is advised?
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.
Sou
Post-Exposure Prophylaxis Line (PEPline)888-448-4911
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
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
Dolutegravir (Tivicay)
Source: Slide courtesy of Brian Wood, MD.
Raltegravir (Isentress) & Dolutegravir (Tivicay)Tablet Size
DolutegravirRaltegravir
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
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
Dolutegravir (Tivicay)
Should dolutegravir replace raltegravir in clinical practice?
.
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%)
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
Dolutegravir + 2NRTIs versus Darunavir-RTV + 2NRTIsFLAMINGO: Result
Week 48 Virologic Response
Source: Feinberg J, et al. 53nd ICAAC. 2013: Abstract H-146-a.
Dolutegravir
Does the NRTI backbone with dolutegravir matter?
Tenofovir-emtricitabine Abacavir-lamivudine
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.
Dolutegravir-ABC-3TC versus Efavirenz-TDF-FTCSINGLE: Result
Week 48 Virologic Response
Source: Walmsley S, et al. 52nd ICAAC. 2012: Abstract H-556-b.
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.
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.
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.
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
Integrase Resistance Testing
• Integrase Genotype ✔- Quest Diagnostics- Lab Corp (Monogram Biosciences)- Virco
• Integrase Phenotype- Lab Corp (Monogram Biosciences)- Virco
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
Dolutegravir in Patients with Raltegravir ResistanceVIKING-3: Results
Source: Dolutegravir Product Information.
*without additional INSTI mutations
Dolutegravir Discussion
How should we use dolutegravir in clinical practice?
- In treatment naïve?
- In treatment experienced (intregrase naïve)?
- In treatment experience and integrase resistant?
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
Hepatitis C Update
.
Hepatitis C Epidemiology in United States
Annual Deaths from HCV?
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
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
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%
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
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
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?
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.”
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.”
Hepatitis C and Cure
Why can antiviral cure hepatitis C but not HIV?
Sustained Virologic Response (SVR) with HCV Treatment = Cure
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
Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs)
1986 1998 2001 2002
Timeline
Therapy for Hepatitis CProjected SVR Rates with Multiple DAAs
Timeline2011 2014 2015
Simeprevir: October 24, 2013
Sofosbuvir: October 25, 2013
Hepatitis C VirusGenome
5’ 3’
HCV Genome
Structural Non-Structural
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
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
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
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
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
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
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
• 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
Sofosbuvir in Treatment-Naïve Genotypes 1,4,5,6NEUTRINO Trial*
*Note: Published in tandem with FISSION Trial (Genotypes 2,3)
HCV Monoinfection
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
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
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
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
Sofosbuvir in Treatment-Naïve Genotypes 2,3FISSION Trial*
*Note: Published in tandem with NEUTRINO Trial (Genotypes 1,4,5,6)
HCV Monoinfection
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)
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
Sofosbuvir in HIV-Infected
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
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)
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
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
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
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
End