42013Source: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:
5Case 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
62013 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:
7Raltegravir (Isentress) 400 mg twice daily 2013 USPHS Occupational PEP Guidelines Recommendations for Antiretroviral RegimensRecommended Antiretroviral Regimens for Occupational PEP (28-Day Duration)Preferred RegimenINSTINNRTIPill BurdenRaltegravir (Isentress) 400 mg twice dailyTenofovir-Emtricitabine (Truvada) 1 pill dailySource: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:
8Case 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?
92013 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:
10HIV Occupational Postexposure Prophylaxis What are situations in which expert consultation is advised?
11Delayed exposure report (eg. longer than 72 hours) 2013 USPHS Occupational PEP Guidelines Situations for Which Expert Consultation AdvisedDelayed exposure report (eg. longer than 72 hours)Unknown source (eg. needle in sharps disposal)Known or suspected pregnancy in exposed personExposed person breast-feedingKnown or suspected ARV drug resistance in source patientSerious medical illness in exposed personsToxicity occurring in exposed person taking PEP regimenSource: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:
12Post-Exposure Prophylaxis Line (PEPline) 888-448-4911 Sou
132013 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* usedBaseline 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 testSource: Kuhar DT, et al. Infect Control Hosp Epidemiol ;34:
14Occupational HIV Postexposure Prophylaxis Suggestions for TrainingIncorporate Occupational PEP into Larger TrainingsProvide 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 consultationsC. Give trainees PEPLine information/pamphlet
16Raltegravir (Isentress) & Dolutegravir (Tivicay) Tablet Size Source: Slide courtesy of Brian Wood, MD.
17Dolutegravir Recommended Dolutegravir Dosing Adult Population Recommended DoseTreatment-naïve or Treatment-experienced INSTI-naïve50 mg once dailyCoadministered with potent UGT1A/CYP3A inducer: Efavirenz Fosamprenavir/ritonavir Tipranavir/ritonavir Rifampin50 mg twice dailyINSTI-experienced with certain INSTI mutations* or Clinically suspected INSTI resistancePoor virologic response associated with Q148 Substitution plus ≥ 2 more INSTI mutationsSource: Dolutegravir Prescribing Information
18Organic Cation Transporter 2 (OCT2) Dolutegravir Increases Serum Creatinine by Benign Inhibition of Tubular Secretion of CreatinineBowman’s CapsuleProximal TubuleDistal TubuleOrganic Cation Transporter 2 (OCT2)DolutegravirCollecting TubuleInhibits tubular secretion of creatinine via inhibition of OCT2Loop of HenleExcretionSource: Koteff J, et al. Br J Clin Pharmacol. 2013:75:990-6.
19Dolutegravir (Tivicay) Should dolutegravir replace raltegravir in clinical practice?
20Dolutegravir Phase 3 Studies StudyARV HistoryComparisonResults1 SPRING-2ARV-NaïveDolutegravir QD vs. RaltegravirNon-inferior (88% vs. 85%)2 SINGLEDolutegravir QD vs. Efavirenz✔ Dolutegravir superior (88% vs. 81%)3 FLAMINGODolutegravir QD vs. Darunavir-RTV✔ Dolutegravir superior (90% vs. 81%)4 SAILING>2-class ARV resistance✔ Dolutegravir superior (71% vs. 64%)5 VIKING-3Integrase resistanceSingle-arm, Dolutegravir BIDVirological 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..
31Functional monotherapy Dolutegravir in Treatment-Experienced with Integrase Resistance VIKING-3Study DesignProtocolHIV-infected adults with VL >500 copiesResistance to raltegravir or elvitegravir, plus resistance to at least 2 additional ARV classesDolutegravir50 mg BID+ Failing RegimenDolutegravir50 mg BID+ OBTFunctional monotherapyphase (7 days)Day 8 -activity of OBR was not correlated with response; increased fold-change to dolutegravir did correlateSources: 1) ViiV Healthcare Press release. Nov ) Nichols G et al. IAS )
32Dolutegravir in Patients with Raltegravir Resistance VIKING-3: Results *without additional INSTI mutationsSource: Dolutegravir Product Information.
33Dolutegravir Discussion How should we use dolutegravir in clinical practice? In treatment naïve? In treatment experienced (intregrase naïve)?- In treatment experience and integrase resistant?
34Use of DolutegravirTreatment naïve - Excellent first line agent - Likely will become a preferred agent in DHHS GuidelinesTreatment experienced (Integrase-naïve) - Attractive as component of salvage regimenTreatment experience (Integrase resistant or experienced) - Parameters for once or twice daily dosing poorly defined - Avoid use with Q148 + ≥ 2 secondary mutations
36Hepatitis C Epidemiology in United States Annual Deaths from HCV?.
37Age-Adjusted Mortality Rates Age-Adjusted Mortality Rates* from HBV, HCV, & HIV United States,7HIVn = 15,106654Hepatitis CRate per 100,000 PY32Hepatitis B1199920002001200220032004200520062007Year*Mortality Rates = HBV, HCV, HIV listed as cause of deathSource: Ly KN, et al. Ann Intern Med. 2012:156:271-8.
38Forecasted Annual HCV-Related Deaths in the United States Persons with Chronic Hepatitis C and no Cirrhosis in 2005NumberYear2010Deaths20142018202220262030203420382042204620502054205840,00035,00030,00025,00020,00015,00010,0005,00045,000Source: Rein DR, et al. Dig Liver Dis. 2011:43:66-72.
39Hepatitis C Cascade of Care in United States 100%50%35%9%6%Source: Holmberg SD, et al. N Engl J Med. 2013;368:
40HIV-Infected Persons in United States HCV-HIV CoinfectionHIV-Infected Persons in United StatesHIV MonoinfectionHIV-HCV CoinfectionSource: Sulkowski M, et al. Ann Intern Med. 2003;138:1
41Cause of Death (Incidence) in the D:A:D Study N = 1,246 deathsThis 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
42Testing 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?
43Entry 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)
44Recommendations 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)
45Sustained Virologic Response (SVR) with HCV Treatment = Cure Hepatitis C and CureWhy can antiviral cure hepatitis C but not HIV?Sustained Virologic Response (SVR) with HCV Treatment = Cure
46Comparative Treatment Goals with Antiviral Therapy HIV (latent reservoir)HBV (latent reservoir)HCV (no latent reservoir)HCV RNAccDNAProviral DNAHost DNAHost DNAHost DNAHost CellHost CellHost CellLifelong suppression of viral replicationLong-term reduction of viral replicationDefinitive Viral ClearanceSource: Kieffer TA, et al. J Antimicrob Chemother. 2010:65:
47Therapy for Hepatitis C Milestones Prior to Use of Direct Acting Agents ( DAAs) Timeline1986199820012002
48Therapy for Hepatitis C Projected SVR Rates with Multiple DAAs Timeline201120142015
49Simeprevir: October 24, 2013Sofosbuvir: October 25, 2013
50Hepatitis C Virus Genome HCV Genome5’3’StructuralNon-Structural
52Hepatitis C Virus Protein Processing HCV GenomeTranslationPolyprotein PrecursorCE1E2p7NS2NS3ANS4BABNS5Protein ProcessingProteinsCE1E2p7NS2NS3NS4ANS4BNS5ANS5B
53Hepatitis C Virus Structural and Nonstructural Proteins Hepatitis C ProteinsStructural ProteinsNonstructural (NS) ProteinsCE1E2p7NS2NS3NS4ANS4BNS5ANS5BNucleocapsidEnvelope GlycoproteinCysteine ProteaseProtease CofactorsRNA binding and assembly recognition complexEnvelope GlycoproteinVioporinProteaseRNA HelicaseMembranous Web InductionRNA-Dependent RNA Polymerase
54Hepatitis C Virus Direct Acting Agents (DAAs) Hepatitis C ProteinsStructural ProteinsNonstructural (NS) ProteinsCE1E2p7NS2NS3NS4ANS4BNS5ANS5BRNA binding and assembly recognition complexProteaseProtease CofactorsRNA-Dependent RNA Polymerase
55Hepatitis C Virus Direct Acting Agents (DAAs) Hepatitis C Proteins as Antiviral Targets for DAAsNS3NS4ANS5ANS5BNS3/4A Protease InhibitorsNS5B Polymerase InhibitorsNS5A InhibitorsNRTIsNNRTIs
56Future HCV Direct Acting Agents (DAAs) NS3NS4ANS5ANS5BProtease InhibitorsNS5A InhibitorsPolymerase InhibitorsAsunaprevirDaclatasvirMericitabineDanoprevirLedipasvirSofosbuvirFaldaprevirABT-267ABT-333SimeprevirIDX-719BMSVaniprevirBIABT-450/r
57SofosbuvirInvestigational - FDA Advisory Panel meeting October 25, 2013Class & Mechanism - NS5B nucleotide analogue polymerase inhibitor - Pan genotypicSofosbuvir Dosing mg PO once dailyClinical 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
59Sofosbuvir in Treatment-Naïve Genotypes 1,4,5,6 NEUTRINO Trial* HCV MonoinfectionSofosbuvir in Treatment-Naïve Genotypes 1,4,5,6 NEUTRINO Trial**Note: Published in tandem with FISSION Trial (Genotypes 2,3)
60Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO Week1224Sofosbuvir + PEG + RBVN =327SVR12Drug 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 ≥ 75kgSource: Lawitz E, et al. N Engl J Med ;368:
61Percentage of Patients with SVR Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by GenotypePercentage of Patients with SVRGT = genotypeSource: Lawitz E, et al. N Engl J Med ;368:
62Percentage of Patients with SVR Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by RacePercentage of Patients with SVRSource: Lawitz E, et al. N Engl J Med ;368:
63Percentage of Patients with SVR Sofosbuvir for Chronic Untreated HCV Infection (GT 1,4,5,6) NEUTRINO: SVR12 by Presence of CirrhosisPercentage of Patients with SVRSource: Lawitz E, et al. N Engl J Med ;368:
64Sofosbuvir in Treatment-Naïve Genotypes 2,3 FISSION Trial* HCV MonoinfectionSofosbuvir in Treatment-Naïve Genotypes 2,3 FISSION Trial**Note: Published in tandem with NEUTRINO Trial (Genotypes 1,4,5,6)
65Sofosbuvir and Ribavirin for Chronic Untreated HCV FISSION Trial Week122436Sofosbuvir + RBV (weight-based)N =256SVR12Peginterferon + RBV (fixed dose)N =243SVR12Drug 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 BIDSource: Lawitz E, et al. N Engl J Med ;368:
66Sofosbuvir for Chronic Untreated HCV Infection GT 2,3 FISSION Study: Results SVR12 (by Genotype)RBV = Ribavirin; PegIFN = PeginterferonSource: Lawitz E, et al. N Engl J Med ;368:
68Sofosbuvir Key Summary Points Major impact drug for hepatitis C treatmentActive against all HCV genotypesOption for interferon-free treatment of GT2 (?GT3)Excellent results with most difficult to treat GT-1 patientsSafe, convenient, potent, and minimal drug interactionsOptimal approach with sofosbuvir and genotype 3 uncertainLikely will be very safe and effective in HIV-infected patientsPayment/reimbursement with HIV-infected unknown
69SimeprevirInvestigational - FDA application submitted March FDA Advisory Committee meeting on October 24, 2013Class & 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)
70Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 Trial Week122448Randomized 2:1, stratified on IL28B and HCV subtypeResponse-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 + RBVPEG + RBVN = 264PEG + RBVPlacebo + PEG + RBVPEG + RBVN =130Drug 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 ≥ 75kgSource: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.
71Proportion of Patients with SVR12 Simeprevir and Peginterferon plus Ribavirin for Chronic HCV QUEST-1 ResultsProportion of Patients with SVR12P < 0.001Abbreviations: SVR12 = sustained virologic response at 12 weeks; PEG = peginterferon; RBV = ribavirinSource: Jacobson I, et al. 48th Annual Meeting of EASL. Abstract 1425.
72Simeprevir Key Summary Points Modest impact drug for hepatitis C treatmentSimilar to boceprevir and telaprevir but ONCE DAILYFuture use likely as component of multi-DAA therapyPayment/reimbursement with HIV-infected unknown
73Hepatitis 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 GTsDramatic improvements needed in HCV cascade of careUnknown how quickly new meds available for HIV