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Injectable HIV Treatment

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Injectable HIV Treatment Alexandra Danforth, PharmD, BCACP, AAHIVP Manager, Clinical Pharmacy Trillium Health Rochester, NY 1 Disclosures "This [project/publication/program/website] [is/was] supported by the Health Resources and Services Administration (HRSA) of the U.S. Department of Health and Human Services (HHS) as part of an award totaling $3,879,101 with zero percentage financed with nongovernmental sources. The contents are those of the author(s) and do not necessarily represent the official views of, nor an endorsement, by HRSA, HHS or the U.S. Government." 2 Learning Objectives Describe injectable antiretroviral therapies in clinical trials for HIV treatment and prevention. Review patients who might be good candidates for injectable therapy. Describe challenges that providers might face implementing these new therapies. 3 4 2020 Fostemsavir (AI) 2021 Cabotegravir (INSTI) What to start? 5 https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv https://www.positivelyaware.com/articles/choice-options Do we even need more new drugs? Options for heavily treatment experienced patients More convenience PrEP options 6 New Horizons in Therapy Patient desires Freedom from stigma Decreased pill burden or side effects Ideal long-acting ARV characteristics Potent Extended dosing intervals Low volume injections Patient self-administration 7 IBALIZUMAB 8 HIV Entry Inhibitors 9 *FDA approved Adapted from Moore JP, PNAS 2003; 100: 10598-10602. * Ibalizumab-uiyk (IBA, Trogarzo) Post attachment inhibitor Binds to CD4 and prevents HIV entry into the cell IV infusion every 2 weeks Loading dose of 2000mg; Maintenance dose of 800mg Observe patient for 1 hr post loading dose, if no reaction can be 15 min for maintenance doses Need to re-load if more than 3 days late for maintenance ADRs: diarrhea, dizziness, rash, nausea 10 IBA: Phase 3 Trial Single arm, open-label Phase III study 40 adults with multi-drug resistant HIV, VL>1000 cp/mL IBA with optimized background regimen with at least 1 fully active agent 11 At 24 wks, 43% of patients has VL<50 copies/mL In 48 wk completer analysis, 67% (16/24) were VL<50 copies/mL Emu et al. N Engl J Med; 2018; 379:645-654. Emu et al. Glasgow 2018, #O345 What are nanosuspensions? Drug nanocrystals suspended in liquid Varied size of nanoparticles leads to prolonged dissolution Currently approved drug examples: Invega Sustenna and Trinza (paliperidone) Abilify Maintena (aripiprazole) 12 Question #1 Which of the following does NOT affect the pharmacokinetics of a long acting injectable nanoformulation? Nanoparticle size and shape Injection site (muscle vs fat) Injection route (IM vs SC) Lipophilicity of the drug 13 CABOTEGRAVIR 14 Question #2 Which statement about Cabotegravir (CAB) is TRUE? CAB is a new nucleoside reverse trascriptase inhibitor (NRTI). Patients preferred taking oral CAB to injectable CAB. CAB has been used for both HIV treatment and prevention in clinical trials. CAB is not effective for PrEP in cis-women. 15 Cabotegravir (CAB) INSTI, similar to dolutegravir Active against some INSTI resistant strains Half-life is 21-50 days Nanosuspension, given IM or SC ADRs: mild injection site reactions, nodules with SC 16 CAB/RPV: FLAIR Study Multicenter randomized, open-label, Phase 3 trial Treatment nave adults 17 Orkin et al. CROI 2019, #140LB Slide credit: clinicaloptions.com CAB/RPV: FLAIR Study 18 Orkin et al. CROI 2019, #140LB Slide credit: clinicaloptions.com CAB/RPV: ATLAS Study Multicenter, randomized, open-label Phase 3 switch study 19 Swindells et al. CROI 2019, #139 Slide credit: clinicaloptions.com CAB/RPV: ATLAS Study 20 Swindells et al. CROI 2019, #139 Slide credit: clinicaloptions.com ATLAS Study: Patient Satisfaction Use of patient reported outcome tools to assess patient views on switching to CAB/RPV injections vs continuing baseline oral ART suggested injectable treatment was well tolerated through Week 48 Health status and QoL were similar between LA and oral ART groups Treatment acceptance was significantly higher with LA vs oral ART group 90% of patients receiving LA treatment scored ISRs as totally or very acceptable and 86% scored pain as totally or very acceptable Greater improvement in treatment satisfaction with LA vs oral ART group 97% of patients receiving LA treatment said they preferred LA treatment to daily oral therapy 21 Murray et al. IAS 2019, #MOAB0103 ATLAS 2M Multicenter, randomized, open-label, phase 3 non-inferiority trial 22 Overton et al. CROI 2020, #34 Slide credit: clinicaloptions.com ATLAS 2M 23 Overton et al. CROI 2020, #34 Slide credit: clinicaloptions.com CAB/RPV Treatment Failures Multivariate post hoc analysis of the confirmed virologic failures in ATLAS, FLAIR, ATLAS-2M (n=13/1039) About 1% in each study Four factors were associated with increased odds ratio for CVF 24 Margolis et al. HIV Drug Therapy Glasgow 2020, O442 CAB/RPV Treatment Failures CVF was rare and associated with the presence of at least 2 baseline factors: RPV resistance mutations, BMI>30, HIV-1 subtype A6/A1 25 Margolis et al. HIV Drug Therapy Glasgow 2020, O442 CAB/RPV (Cabenuva)Approved 1/21/21! Approved for switch in stable suppressed patients (VL<50) No history of treatment failure or known/suspected resistance to CAB or RPV 1 month oral lead in phase with 30mg CAB (Vocabria) and 25mg RPV (Edurant) daily Initiation dose: 3mL 600mg CAB; 3mL 900mg RPV Maintenace dose: 2mL 400mg CAB; 2mL 600mg RPV 26 CAB/RPV (Cabenuva)Approved 1/21/21! Contraindicated with Carbamazepine, oxcarbazepine, phenobarbital, phenytoin Rifabutin, rifampin, reiapentine St Johns wort Dexamethasone (more than a single dose treatment) ADRs: injection site reactions, fatigue, fever, headache, nausea, musculoskeletal pain 27 CAB for PrEP: HPTN 083 Phase 2b/3 randomized, double-blind, double-dummy @ 43 sites globally MSM/TGW age 18+ Risk: any nCRAI, >5 partners, stimulant drug use, incident rectal or urethral STI (or incident syphilis) in past 6 months; or SexPro Score 16 (US only) Generally good health No HBV or HCV No contraindication to gluteal injections, seizures, gluteal tattoos/skin conditions Planned enrollment 5000 50% under age 30 10% TGW 50% of US enrollment Black Primary efficacy endpoint: Incident HIV infections during blinded comparison Primary safety endpoint: G2 or higher clinical and laboratory AEs 28 Landovitz et al. AIDS 2020, #OAXLB01 CAB for PrEP: HPTN 083 29 Landovitz et al. AIDS 2020, #OAXLB01 CAB for PrEP: HPTN 083 30 Landovitz et al. AIDS 2020, #OAXLB01 66% reduction in risk of HIV infection in CAB group CAB well tolerated, ISR CAB for PrEP: HPTN 084 Planned enrollment of 3,200 cis-women in sub-Saharan Africa as risk for HIV acquisition 31 https://www.hptn.org/research/studies/hptn084#views-field-field-public-f... 31 CAB for PrEP: HPTN 084 Stopped early in November 2020, was designed to go to 2022 3223 cisgender women enrolled CAB was superior to TDF/FTC at preventing HIV HIV incidence 0.21% in CAB group, n=4 1.79% in TDF/FTC group, n=38 32 https://www.084life.org/study-results/ 32 Question #3 In HPTN 083 and 084, cabotegravir (CAB) was ___________ to TDF/FTC daily oral tablets for PrEP. Non-inferior Inferior Superior 33 New Mechanisms of Action Translocation inhibitor Capsid inhibitor 34 ISLATRAVIR 35 Islatravir (ISL, MK-8591) Nucleoside reverse transcriptase translocation inhibitor (NRTTI) Chain terminator and translocation inhibitor Half-life is 50-60hrs in plasma Daily or once weekly dosing! Low doses orally and parenteral formulations Potent activity with broad coverage for HIV-1 and HIV-2 and NRTI resistant strains Minimal cross resistance with other NRTIs 36 ISL: Activity against NRTI resistant strains 37 Grobler et al. CROI 2019, #481 ISL + DOR: Phase 2B International, randomized, double-blind trial 38 Molina et al. HIV Drug Therapy Glasgow 2020, #O415 Slide credit: clinicaloptions.com ISL + DOR: Phase 2B 39 Molina et al. HIV Drug Therapy Glasgow 2020, #O415 Slide credit: clinicaloptions.com Why implants? Advantages Removable Consistent drug release PK not dependent on injection site Can be in place for years Disadvantages Need implantation device Minor procedure to remove Difficult to bring to market as a generic 40 ISL for PrEP: Long acting implant ISL prototype design based on Nexplanon/Implanon Uses same applicator and polymer Removable Double-blind, placebo-controlled in healthy volunteers Groups had either54mg or 62mg implant Placed in upper arm ofnon-dominant hand Removed after 12 weeks 41 Matthews et al. IAS 2019; # TUAC0401LB ISL for PrEP: Long acting implant 42 Modeling suggests 62mg implant would have protective levels at 52 weeks, approximately 16 mo before under PK threshold Half-life after removal similar to oral ISL Well tolerated with most implantation site reactions self-resolving Matthews et al. IAS 2019; # TUAC0401LB LENACAPAVIR 43 HIV Capsid Inhibitor 44 Sager et al. CROI 2019, #141 Lenacapavir (LEN): Capsid Inhibitor First in-class inhibitor of HIV capsid inhibitor with picomolar potency Given as subcutaneous suspension Also has oral formulation in trials In-vitro: active against HIV-1 variants and resistant strains Low clearance and low solubilityvery long half life In clinical trials, for both treatment and PrEP 45 Sager et al. CROI 2019, #141 LEN: PK Study 46 Begley et al. AIDS 2020, #PEB0265 Slide credit: clinicaloptions.com Phase 1 PK and safety data in healthy volunteers Potential for every 6-mo dosing, will need oral loading dose Most ADEs were mild injection site reactions LEN: HIV Capsid Inhibitor Phase 1b, double-blind, randomized, placebo controlled, dose ranging study Single subcutaneous injection, then started B/F/TAF at day 10 Current trials: treatment nave patients, heavily treatment experienced 47 Daar et al. CROI 2020, #469 Who might benefit? Patients who Have issues with tablet size Have issues with stigma Trouble remembering to take their meds Can commit to attend appointments Drug interactions Have resistance to current options 48 Challenges Insurance coverage Patient factors Pregnancy potential Managing adverse effects Drug drug interactions Body composition 49 Administration Office visits Missed appointments Techniques Injection vs infusion Summary Injectable and implantable ARV therapy have great potential for both HIV treatment and prevention Patients may face challenges with access and administration but also may prefer this to traditional oral therapy 50 HIV - HCV - PrEP - PEP Clinical Consultations For Providers in Upstate NY Call or E-mail for a consultation: 518-262-6864 Monday Friday 8:00 a.m. 4:30 p.m. [email protected] If you have experienced an occupational exposure such as a needle stick, please call 518-262-4043. You will be given an opportunity on the telephone menu to speak to a physician 24 hours a day. www.amc.edu/hiv Questions?[email protected] 52