A Changing Landscape: New and Pipeline HIV Therapies

A Changing Landscape: New and Pipeline HIV Therapies Sarah Turley, PharmD, BCPS PGY2 Internal Medicine Pharmacy Resident Virginia Commonwealth University Health System

Financial Disclosure I have no relevant finances to disclose.

Objectives Review updated guidelines for the management of human immunodeficiency virus (HIV) Discuss literature supporting new co formulated antiretroviral products Identify pipeline antiretroviral medications and current status in clinical investigations Evaluate the use of novel therapies and incorporation into future guidelines

Patient Case AB is a 34 year old African American male who presents to the emergency department with shortness of breath, fatigue, lethargy and a 30 kg weight loss in the past 12 months. Wt 65 kg RR 30 HR 110 BP 105/70 Temp 39 HIV positive, Hepatitis panel negative CD4 60 cells/mm 3, HIV RNA 105,000 copies/ml When should he be started on HAART? 134 3.6 104 28 8 0.85 12.9 92 20 310 39 What type of HAART regimen is most appropriate?

Epidemiology In 2013, 1,242,000 adults and adolescents were living with HIV Estimated 161,200 (13%) were undiagnosed In 2015, 39,514 were diagnosed with HIV infection Six percent (2395) were secondary to injection drug use http://www.cdc.gov/hiv/statistics/overview/ataglance.html

Epidemiology http://www.cdc.gov/hiv/statistics/overview/geographicdistribution.html

Epidemiology Virginia: 1 in 115 District of Columbia: 1 in 13 http://www.cdc.gov/hiv/statistics/overview/geographicdistribution.html

Treatment Targets 90% Diagnosed 90% On Treatment 90% Virally Suppressed Closing the treatment gap for children, adolescents and key populations 37% On Treatment Rapidly scale up and early initiation of HIV therapy http://www.unaids.org/en/resources/documents/2014/90 90 90

Early Treatment START: Strategic Timing of Antiretroviral Treatment Objective Population Methods (n=4685) Results Conclusion Risk and benefits of immediate vs. delayed initiation of ART in asymptomatic patients with HIV 18 years old, HIV+, treatment naïve Two CD4 counts 500 cells/mm 3 Immediate initiation of ART vs. Delayed initiation until CD4 350 cells/mm 3 OR condition requiring treatment Primary composite: 42 (immediate) vs. 96 (deferred), HR 0.43; p<0.001 Serious AIDS related event: HR 0.28; p<0.001 Serious non AIDS related event: HR 0.61; p=0.04 Death from any cause: HR 0.58; p=0.13 Immediate initiation of ART was superior to deferred initiation. ART should be recommended in all patients diagnosed with HIV regardless of CD4 count. Lundgren JD, et al. NEJM 2015;373:795 807

Early Treatment TEMPRANO: Trial of Early ARVs and Isoniazid Preventive Therapy Objective Evaluate the efficacy of early initiation of ART combined with isoniazid (INH) preventive therapy on reduction of severe illness in HIV infected individuals Population 18 years old, HIV+, CD4 < 800 cells/mm 3 Met no criteria for initiation of ART by WHO guidelines Methods (n= 2056) Results Conclusion Group 1: deferred ART Group 3: early ART Group 2: deferred ART + INH Group 4: early ART + INH Primary composite at 30 months: 11.4% (deferred) vs. 6.6% (early ART); HR 0.56, CI 0.41 0.76 10.7% (no INH) vs. 7.2% (INH); HR 0.65, CI 0.48 0.88 Grade 3 or 4 adverse events, 6 30 months: 7.7% (deferred) vs. 7.1% (early ART) Early initiation of ART and INH preventive therapy independently resulted in 44% lower risk of severe HIV related illness and 35% lower risk of death from any cause. Anglaret X, et al. NEJM 2015;373:808 22

Patient Case Patient is diagnosed with PCP and initiated on HAART in the hospital. He presents to a follow up visit at the infectious disease clinic three months after hospitalization Baseline genotype: No mutations Medications: SMX/TMP DS daily and efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) Patient reports he is having vivid dreams and intolerable side effects from his medication, and only takes it about three times weekly Repeat genotype: K103N, Y181C CD4 50 cells/mm 3, HIV RNA 150,000 copies/ml

Guidelines Guideline Initiation of HIV therapy Initial Regimen for ART Naive DHHS 2016 ART is recommended for all HIV infected individuals regardless of CD4 count ART is recommended for all individuals to prevent transmission Two NRTIs plus one of the following: INSTI or PI with a booster INSTI based DTG/ABC/3TC DTG + TDF/FTC or TAF/FTC EVG/cobi/TAF/FTC EVG/cobi/TDF/FTC RAL + TDF/FTC or TAF/FTC PI based DRV/r + TDF/FTC or TAF/FTC Department of Health and Human Services 2016. http://www.aidsinfo.nih.gov/contentfiles/adul tandadolescentgl.pdf. World Health Organization 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1

Guidelines Guideline Initiation of HIV therapy Initial Regimen for ART Naive DHHS 2016 WHO 2016 ART is recommended for all HIV infected individuals regardless of CD4 count ART is recommended for all individuals to prevent transmission ART should be initiated in all patients with HIV, regardless of WHO clinical stage and at any CD4 count ART should be initiated in all adults with a WHO clinical status of 3 or 4 and with a CD4 count 350 cells/mm 3 Two NRTIs plus one of the following: INSTI or PI with a booster INSTI based DTG/ABC/3TC DTG + TDF/FTC or TAF/FTC EVG/cobi/TAF/FTC EVG/cobi/TDF/FTC RAL + TDF/FTC or TAF/FTC PI based DRV/r + TDF/FTC or TAF/FTC Two NRTIs plus an NNRTI or INSTI Preferred first line: TDF + 3TC (or FTC) + EFV Alternative first line: ZDV + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + DTG TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP Department of Health and Human Services 2016. http://www.aidsinfo.nih.gov/contentfiles/adul tandadolescentgl.pdf. World Health Organization 2016. http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1

Human Immunodeficiency Virus 1. Binding: CCR5 antagonist 2. Fusion: Fusion inhibitor 3. Reverse Transcription: NNRTIs & NRTIs 4. Integration: INSTIs 5. Replication 6. Assembly New Targets? 7. Budding: PIs https://aidsinfo.nih.gov/education materials/fact sheets/19/73/the hiv life cycle

Human Immunodeficiency Virus 1. Binding: CCR5 antagonist 2. Fusion: Fusion inhibitor 3. Reverse Transcription: NNRTIs & NRTIs 4. Integration: INSTIs 5. Replication 6. Assembly New Targets? 7. Budding: PIs + maturation inhibitors https://aidsinfo.nih.gov/education materials/fact sheets/19/73/the hiv life cycle

Current HIV Therapies NRTIs NNRTIs PIs INSTIs Other PK Enhancers Abacavir Didanosine Emtricitabine Lamivudine Stavudine Tenofovir Zidovudine Zalcitabine Delavirdine Efavirenz Etravirine Nevirapine Rilpivirine Amprenavir Atazanavir Darunavir Fosamprenavir Indinavir Lopinavir Nelfinavir Saquinavir Tipranavir Dolutegravir Elvitegravir Raltegravir Enfuvirtide Maraviroc Cobicistat Ritonavir https://aidsinfo.nih.gov/guidelines/html/1/adult and adolescent arv guidelines/292/drug name abbreviations

Fixed Dose Combinations (FDCs) 2015 2000 2006 2012 ATV/cobi ABC/3TC/ZDV EFV/FTC/TDF EVG/c/FTC/TDF DRV/cobi 1997 2004 2011 2014 2016 3TC/ZDV ABC/3TC RPV/FTC/TDF DTG/ABC/3TC EVG/c/FTC/TAF FTC/TDF RPV/FTC/TAF FTC/TAF https://aidsinfo.nih.gov/education materials/fact sheets/21/58/fda approved hiv medicines

Fixed Dose Combinations (FDCs) RPV/TDF/FTC DTG Advantages Easier administration Decreased pill burden Decreased dosing errors Increased adherence Easier access to meds Disadvantages Resistance to first line therapy Difficulty swallowing Side effects Drug interactions DRV/cobi

Tenofovir Alafenamide (TAF) Pozniak A, et al. CROI 2015. Abstract 795. Seattle, WA

Tenofovir Alafenamide (TAF) Properties Tenofovir prodrug with lower plasma concentrations than TDF Significantly more stable in plasma and delivers ~30 times higher concentration intracellularly Development of a prodrug which is selectively hydrolyzed within cells Tenofovir Warnings and Precautions Lactic acidosis and severe hepatomegaly with steatosis New onset or worsening renal impairment Acute renal failure Fanconi syndrome Decreases in bone mineral density Lumbar spine Hip Badowski ME, et al. Infect Dis Ther 2016;5:329 52 Viread (tenofovir disoproxil fumarate) package insert. Gilead Sciences, Inc. 2016

Tenofovir TAF TDF Indication HIV, HBV* HIV, HBV, PrEP Plasma concentration 80 90% reduction High Intracellular concentration 5.3 fold higher compared to TDF Low Dosing With FTC: 25 mg With EVG/c/FTC: 10 mg 300 mg Renal dosing considerations Adverse event No dosing guidelines for CrCl < 30 ml/min Osteopenia/osteoporosis Nephrotoxicity Only recommended in CrCl > 50 ml/min Osteopenia/osteoporosis Nephrotoxicity Badowski ME, et al. Infect Dis Ther 2016;5:329 52

Patient Case Patient is switched from EFV/TDF/FTC to another fixed dose combination tablet EVG/c/TDF/FTC (Stribild) and is tolerating the medication well CD4 100 cells/mm 3, HIV RNA undetectable Serum creatinine: 1.5 mg/dl DEXA: hip 1.5, spine 1.2 Total cholesterol: 210 mg/dl LDL: 150 mg/dl What is the cause of these laboratory abnormalities and are changes to therapy warranted?

Tenofovir alafenamide efficacy Tenofovir alafenamide versus tenofovir disoproxil fumarate co formulated with EVG/c/FTC for initial treatment of HIV 1 infection: two randomized, double blind, phase III, non inferiority trials Objective: Methods: Inclusion: Exclusion: Confirm TAF antiviral efficacy and safety Two parallel phase III randomized, double blind, active control, multicenter trials 1:1 randomization to EVG/c/FTC/TAF versus EVG/C/FTC/TDF HIV infected treatment naïve, 18 years old, HIV RNA 1000 copies/ml, egfr 50 ml/min Positive hepatitis B or C, new AIDS defining condition within 30 days Labs: CD4 counts, HIV RNA, serum chemistry, fasting lipid parameters, urine protein evaluation Bone markers: DEXA scans of spine and hip at baseline, week 24 and 48 Primary endpoint: Proportion of patients with HIV RNA < 50 copies/ml at week 48 Sax PE, et al. Lancet 2015;385:2606 15

Tenofovir alafenamide efficacy Baseline Characteristics EVG/c/FTC/TAF (n=866) EVG/c/FTC/TDF (n=867) Age 33 (26 42) 35 (28 44) Median VL (c/ml) 38018 38018 Median CD4 404 (283 550) 406 (291 542) White 485 (56%) 498 (57%) African heritage 223 (26%) 213 (35%) Median GFR (ml/min) 117 (100 136) 114 (99 134) Virologic success (week 48) Primary Outcome 92% TAF vs. 90% TDF, CI 0.7% to 4.7% Study drug discontinuation 0.9% TAF vs. 1.5% TDF Nausea, diarrhea most common overall event Sax PE, et al. Lancet 2015;385:2606 15

Tenofovir alafenamide efficacy Renal Effects Discontinuation: 0 (TAF) vs. 4 (TDF) Significantly smaller decreases in GFR Quantitative proteinuria in TDF vs. TAF groups Bone Effects No fractures related to study drug Spine: 1.3% vs. 2.86%, p<0.0001 Hip: 0.66% vs. 2.95%, p<0.0001 Sax PE, et al. Lancet 2015;385:2606 15

Tenofovir alafenamide efficacy Conclusion: TAF was non inferior to TDF in virologic suppression and showed favorable renal and bone parameters Interpretation: Patients will be on HAART long term, therefore maximizing the safety of therapy is of utmost importance Limitation: Low number of women, exclusion of hepatitis B or C co infection, less advanced HIV infection, uncertain use for other indications Sax PE, et al. Lancet 2015;385:2606 15

Tenofovir alafenamide switch studies Switching to TAF/EVG/c/FTC in HIV infected patients with renal impairment Objective Assess safety of EVG/c/FTC/TAF in patients with mild to moderate renal impairment Population Adults, HIV 1 infection, HIV RNA undetectable for 6 months, egfr = 30 69 ml/min, CKD stable Methods, (n=242) Received EVG/c/FTC/TAF with visits at weeks 1, 2, 4, 8, 12, 16, 24, 36 and 48 Outcomes 1ᵒ: Change from baseline at week 24 in egfr 2ᵒ: Change from baseline at weeks 48 and 96 in egfr, BMD, adverse events, virologic control Results Baseline median egfr = 56 ml/min No clinically appreciable change in egfr Significant improvements in total proteinuria, albuminuria, and tubular proteinuria BMD: Hip and spine: +1.47% and +2.29% (p<0.05) Adverse events: no Fanconi s syndrome or fractures related to study drug Conclusion Interpretation EVG/c/FTC/TAF may be used in patients with mild to moderate renal dysfunction without the need for dose adjustment EVG/C/FTC/TAF (Genvoya) is approved for patients with CrCl 30 ml/min with no dose adjustment Pozniak A, et al. J Acquir Immun Defic Syndrom 2016;71:530 7

Salvage Regimen Patient October 2013 August 2014 55 yo Caucasian male Baseline CD4 count 15 cells/mm 3, history of AIDS defining illness (PCP) Treatment history with all approved ART EXCEPT dolutegravir, maraviroc, delavirdine, rilpivirine Started therapy with enfuvirtide + EVG/c/FTC/TDF SCr from 1.47 mg/dl to 4.55 mg/dl; egfr from 53 ml/min to 14 ml/min SCr improves to 2.16 mg/dl after ART discontinuation New regimen: TAF/FTC + dolutegravir + darunavir/r Upon initiation: SCr 1.3 mg/dl 15 months: SCr 1.41 mg/dl, HIV RNA undetectable, CD4 55 cells/mm 3 Conclusion: This case describes the use of TAF in a patient with TDF associated kidney injury and as part of a salvage regimen with the ability to achieve virologic suppression in the setting of six class resistance Mikula JM, et al. Antivir Ther 2016;21:553 8

Bone Changes with TAF Switching from TDF to TAF in HIV Infected Adults with Low BMD: A Pooled Analysis Objectives: Determine the % BMD change and T score change at the lumbar spine and total hip over 96 weeks in HIV infected individuals with low BMD Determine baseline factors associated with a clinically significant change in BMD over 96 weeks Methods: On a TDF containing regimen and switched to ELG/c/FTC/TAF versus continue Low BMD (T score 2) at lumbar spine or hip and egfr 50 ml/min Brown T, et al. Poster 683. CROI 2017. Seattle, WA. Feb 13 16, 2017.

Bone Changes with TAF Conclusions: HIV infected individuals with low BMD switched from TDF to TAF experience: ~2.5% lumbar spine or hip BMD increase over 96 weeks 5% BMD increase in some individuals A reversal from osteoporosis in some individuals Brown T, et al. Poster 683. CROI 2017. Seattle, WA. Feb 13 16, 2017.

Tenofovir alafenamide formulations Odefsey = TAF + FTC + rilpivirine Indication = HIV 1 infection in patients 12 years old with CrCl 30 ml/min FDA approval March 2016 Not recommended as initial therapy in DHHS guidelines THRIVE Assess non inferiority of rilpivirine to efavirenz Treatment naïve patients with HIV RNA 5000 Backbone of TDF/FTC or ZDV/3TC or ABC/3TC 947 patients enrolled Response 86% (RPV) vs. 82% EFV, p<0.0001 VL failure 7% (RPV) vs. 5% EFV Adverse events less common with RPV ECHO Assess the efficacy of rilpivirine vs. efavirenz, both combined with TDF/FTC Treatment naïve patients with HIV RNA 5000 690 patients enrolled Response 83% (RPV) vs. 83% (EFV) VL failure 13% (RPV) vs. 6% (EFV) Adverse events 55% (RPV) vs. 31% (EFV), p<0.0001 Cohen CJ, et al. Lancet 2011;378:229 37 Molina JM, et al. Lancet 2011;378:238 46 Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) package insert. Gilead Sciences, Inc. 2016

Tenofovir alafenamide formulations Odefsey = TAF + FTC + rilpivirine Indication = HIV 1 infection in patients 12 years old with CrCl 30 ml/min FDA approval March 2016 Not recommended as initial therapy in DHHS guidelines Must be administered with a meal Contraindicated with proton pump inhibitors Administer antacids 2 hours before or 4 hours after Odefsey Odefsey (emtricitabine, rilpivirine, and tenofovir alafenamide) package insert. Gilead Sciences, Inc. 2016

Tenofovir alafenamide formulations Descovy = TAF + FTC Indication = HIV 1 infection in patients 12 years old with CrCl 30 ml/min NOT indicated for use as PrEP/PEP to reduce HIV infection risk or perinatal transmission FDA approval April 2016 Preferred NRTI backbone in the DHHS guidelines Differences from TDF/FTC in drug interactions TAF: Category X drug interaction with rifampin and rifabutin Descovy (emtricitabine and tenofovir alafenamide) package insert. Gilead Sciences, Inc. 2016

TAF/FTC as PrEP Chemoprophylaxis with oral TAF/FTC prevents macaques from SHIV infection Efficacy in macaques for TAF/FTC for PrEP 12 macaques exposed to rectal SHIV infection once a week for 19 weeks Six received FTC/TAF 24h before and 2h after each exposure All six remained seronegative through 10 week follow up, all six placebos were SHIV positive Concentrations of TFV in female mucosal tissue after a single dose of TAF 100 fold higher TFV concentrations in colorectal tissue may contribute to PrEP advantages in men vs. women Phase I PK study in eight healthy women In comparison to TDF, TAF plasma AUC was 95% lower TAF was undetectable in tissue Cellular concentrations were 808% higher Massud I, et al. CROI 2016. Abstract 107. Boston, MA Garrett KL, et al. CROI 2016. Abstract 102LB. Boston, MA

TAF single formulation Currently available only as fixed dose combinations November 10, 2016 FDA approved Vemlidy for treatment of chronic hepatitis B TAF versus TDF for the treatment of patients with chronic Hep B infection Randomized, double blind, phase III, non inferiority trial Patients 18 years old, HBV DNA > 20,000 IU/mL, CrCl 50 ml/min, ALT < ten times upper limit of normal Primary endpoint: patients with HBV DNA < 29 IU/mL at 48 weeks 426 patients met inclusion criteria 94% (TAF) vs. 93% TDF with success at week 48, p=0.47 TAF was non inferior to TDF and had improved renal and bone effects Buti M, et al. Lancet Gastroenterol Hepatol 2016;1:196 206 Vemlidy (tenofovir alafenamide) package insert. Gilead Sciences, Inc. 2016

TAF single formulation Indication Testing Dosing Administration Warnings TAF for hepatitis B Treatment of chronic hepatitis B in adults with compensated liver disease Prior to initiation patients should be tested for HIV infection 25 mg once daily, no dosage adjustment in mild, moderate or severe renal impairment Not recommended in CrCl < 15 ml/min Not recommended in Child Pugh class B or C hepatic impairment Taken once daily orally with food Lactic acidosis/severe hepatomegaly with steatosis Severe acute exacerbation of hepatitis B after discontinuation of treatment Risk of developing HIV resistance in co infected patients New onset or worsening renal impairment Adverse Reactions Headache (9%), abdominal pain (7%), fatigue (6%), cough (6%), nausea (5%), back pain (5%) Pricing $1997.32 (#30) Vemlidy (tenofovir alafenamide) package insert. Gilead Sciences, Inc. 2016

TAF Dosing TAF TDF Genvoya TAF 10 mg FTC 200 mg Cobi 150 mg EVG 150 mg Stribild TDF 300 mg FTC 200 mg Cobi 150 mg EVG 150 mg Odefsey TAF 25 mg FTC 200 mg RPV 15 mg Complera TDF 300 mg FTC 200 mg RPV 25 mg Descovy TAF 25 mg FTC 200 mg Truvada TDF 300 mg FTC 200 mg Vemlidy TAF 25 mg Viread TDF 300 mg

Safety Concerns ISMP Safety Alert Two reports received about electronic health record displays of Genvoya and Stribild Computer used abbreviation: Elviteg Cobic Emtricit TenofAF Stribild was mistakenly dispensed Display brand AND generic and do not abbreviate Products are NOT interchangeable ISMP 2016;21:1 4

Future Uses Perinatal PrEP PEP

Pipeline Therapies

Cabotegravir Pharmacology Integrase strand transfer inhibitor Structural analog of dolutegravir Formulated as both an oral tablet and a long acting suspension injectable Half life = 40 hours (oral dosing) Investigated in combination with rilpivirine LATTE I Long Acting Antiretroviral Treatment Enabling Objective Assess viral suppression of cabotegravir + NRTIs compared with EFV + NRTIS followed by assessment of cabotegravir + RPV as two drug treatment regimen Population Age 18, HIV RNA 1000 copies/ml, CD4 200 cells/mm 3, ART naïve, no major mutations Methods (n=243) 24 week induction: 1:1:1:1 to cabotegravir 10 mg, 30 mg, or 60 mg once daily or EFV 600 mg once daily with ABC/3TC or TDF/FTC 72 week maintenance (207 patients): Cabotegravir dose continued with RPV 25 mg and no NRTIs Results Viral response 86% (CAB) vs. 74% (EFV), p<0.0001 At 72 weeks 76% (CAB + RPV) vs. 63% (EFV) Virologic suppression numerically higher through 96 weeks Efficacy lends support to cabotegravir 30 mg daily Conclusion As a two drug maintenance therapy, cabotegravir plus rilpivirine provided antiviral activity similar to EFV + NRTIs at week 96 Trezza C, et al. Curr Opin HIV AIDS 2015;10:239 45 Margolis DA, et al. Lancet Infect Dis 2015;15:1145 55

Cabotegravir LATTE II Phase IIb study, multicenter, parallel group, open label Induction phase with 30 mg cabotegravir + ABC/3TC 2:2:1 randomization to IM CAB LA + RPV LA every 4 weeks, 8 weeks, or remained on oral therapy 309 patients enrolled Week 32: 95% (q8week), 94% (q4week) and 91% (oral) maintained viral suppression 92% had injection site pain, otherwise well tolerated Concerns with Use and Potential Role Scheduled visits to receive injections Patient adherence Reversal in the case of hypersensitivity PK parameters in real world population Susceptibility of virus to cabotegravir + coformulated agent PrEP in certain populations? Margolis DA, et al. CROI 2016. Abstract 31LB. Boston, MA Margolis DA, et al. Curr Opin HIV AIDS 2015;10:246 52

Doravirine Pharmacology Doravirine non inferior to darunavir in phase III treatmentnaïve trial at week 48 Design Phase III, multicenter, double blind, non inferiority Non nucleoside reverse transcriptase inhibitor Selects for distinct mutations in vitro: V106A, F227L, L234I Limited cross resistance between other NNRTIs Does not inhibit or induce CYP enzymes May be taken without regard to food Population Methods (n=766) Objective Results Conclusion HIV infected treatment naïve with >1000 copies/ml 1:1 randomization to doravirine 100 mg daily or DRV/r 800/100 mg daily plus TDF/FTC or ABC/3TC Proportion with HIV RNA < 50 copies/ml Effects on fasting lipids Virologic suppression: 83.8% doravirine vs. 79.9% darunavir, diff 3.9% ( 1.6, 9.4) Adverse reactions (DOR, DRV): Diarrhea (5.5%, 12.8%), nausea (6.5%, 7.6%), headache (6.0%, 2.6%) At week 48, doravirine was non inferior to darunavir on a background of 2 NRTIs in HIV treatment naïve adults. DOR was safe and well tolerated with a superior lipid profile. Badowski ME, et al. Infect Dis Ther 2016;5:329 52 Squires K, et al. Oral abstract 45LB. CROI 2017. Seattle, WA. Feb 13 16, 2017

Ibalizumab Pharmacology Humanized murine monoclonal antibody Binds to the interface between domain 1 and 2 on CD4 cell (does not bind to gp 120) Conformational changes that prevent gp120 from interacting with CCR5 or CXCR4 Antiviral activity regardless of tropism No immunosuppressive effects seen Bruno, et al. J Antimicrob Chemother 2010;65:1839 41

Ibalizumab Long acting ibalizumab in patients with multi drug resistant HIV 1: A 24 week study Design Population Methods (n=40) Single arm, 24 week study HIV 1 infected, treatment experienced, failing current regimen, documented resistance Loading dose: 2000 mg IBA IV Maintenance: 800 mg IBA IV every 2 weeks for 24 weeks OBR added on day 14 (sensitivity to at least 1 agent) Objective Primary: Patients with 0.5 log 10 decrease in VL at day 14 Results Conclusion IBA = ibalizumab OBR = optimized background regimen Mean VL decrease of 1.6 from baseline 55% and 48% with a 1 and 2 log 10 reduction UD VL in 43% of patients In treatment experienced patients with few treatment options, IBA plus OBR maintained virologic efficacy and was well tolerated Lewis S, et al. Poster 449LB. CROI 2017. Seattle, WA. Feb 13 16, 2017

Ibalizumab IV vs. IM His Hsun, L, et al. Poster 438. CROI 2017. Seattle, WA. Feb 13 16, 2017

Mono and Dual Therapy Case Series Meta analysis, n=87 DTG monotherapy in long term virologic suppression Comorbidities, drug interactions, adverse effects, resistance Virologic suppression 91.9%, failure 8.1% 4/5 patients with failure had prior INSTI exposure DOLOMONO Multicenter randomized trial Comparing DTG monotherapy vs. continued ART (cart) HIV positive, VL < 50 copies/ml, no history virologic failure Primary endpoint: VL < 200 copies/ml at week 24 24 weeks: 92/94 on DTG monotherapy with VL < 200 48 weeks: 77/94 patients, virologic failure in 8 Led to premature study discontinuation as integrase resistance found in 3 of 6 when testing could be performed DTG Monotherapy: When should clinical practice be clinical research? Moreira J. J Antimicrob Chemother 2016;71:2675 6 Wijting I, et al. Poster 451LB. CROI 2017. Seattle, WA. Feb 13 16, 2017 Gallant J. Antivir Ther 2016:Dec 15

Dual Therapy LAMIDOL Ongoing, open label, single arm trial, multicenter trial DTG (50 mg) + 3TC (300 mg) daily On 2 NRTIs + PI, NNRTI, or INSTI CD4 nadir > 200, HIV RNA < 50 for 2 years 104 patients switched to DTG 3TC 1 patient with virologic failure at 24 weeks of dual therapy DTG 3TC well tolerated and effective at 24 weeks in virologically suppressed patients SWORD SWORD 1 and SWORD 2 Switching to dual therapy from 3 or 4 drug regimens HIV RNA < 50 for 12 months 148 week, randomized, open label, noninferiority Met non inferiority endpoint at week 48 VL < 50 copies/ml SWORD 1: 95% vs. 96% SWORD 2: 94% vs. 95% No patients developed integrase mutations Joly V, et al. Poster 458. CROI 2017. Seattle, WA. Feb 13 16, 2017 Llibre J, et al. Oral abstract 44LB. CROI 2017. Seattle, WA. Feb 13 16, 2017

Future Directions HIV maturation inhibitor HIV vaccination Toll like receptor agonist CCR5 monoclonal antibody

Learning Assessment Question 1: The DHHS 2016 guideline updates include which of the following as a recommended regimen for ART naïve patients? a) ATZ + TDF/FTC b) EFV + TDF/FTC c) EVG/cobi + TDF/FTC OR TAF/FTC d) LPV + TDF/FTC Answer: C Found on slides 11/12

Learning Assessment Question 2: Tenofovir alafenamide differs from tenofovir disoproxil fumarate in which of the following principles? a) TAF delivers 30 times higher concentrations intracellularly b) TDF delivers 30 times higher concentrations intracellularly c) TAF is a prodrug of tenofovir and TDF not a prodrug d) TAF has no risk of development of Fanconi syndrome Answer: A Found on slide 20

Learning Assessment Question 3: Ibalizumab is a pipeline HIV therapy which works by which of the following mechanisms? a) Binds to the gp120 subunit to prevent HIV entry into CD4 cells b) CCR5 antagonist preventing HIV entry into CD4 cells c) Binds to the domain 1 and 2 interface on CD4 cells d) Monoclonal antibody in a subcutaneous formulation Answer: C Found on slide 44

A Changing Landscape: New and Pipeline HIV Therapies Sarah Turley, PharmD, BCPS PGY2 Internal Medicine Pharmacy Resident Virginia Commonwealth University Health System

Abbreviations 3TC = lamivudine ABC = abacavir ATV = atazanavir CAB = cabotegravir COBI or c = cobicistat DRV = darunavir DTG = dolutegravir EFV = efavirenz EVG = elvitegravir FTC = emtricitabine INSTI = integrase strand transfer inhibitor Medications NRTI = nucleoside reverse transcriptase inhibitor NNRTI = non nucleoside reverse transcriptase inhibitor NVP = nevirapine PI = protease inhibitor RAL = raltegravir RPV = rilpivirine RTV or r = ritonavir TAF = tenofovir alafenamide TDF = tenofovir disoproxil fumarate TFV = tenofovir ZDV = zidovudine Other AIDS = acquired immunodeficiency virus ART = antiretroviral therapy ARV = antiretroviral FDC = fixed dose combination HAART = highly active antiretroviral therapy HIV = human immunodeficiency virus MSM = men who have sex with men PEP = post exposure prophylaxis PrEP = pre exposure prophylaxis https://aidsinfo.nih.gov/guidelines/html/1/adult and adolescent arv guidelines/292/drug name abbreviations

Brand Generic: FDCs ABC + 3TC + ZDV ABC + 3TC FTC + TDF EFV + FTC + TDF RPV + FTC + TDF ELV + cobi + FTC + TDF ABC + 3TC + DTG ATZ + cobi DRV + cobi ELV + cobi + FTC + TAF RPV + FTC + TAF FTC + TAF Trizivir Epzicom Truvada Atripla Complera Stribild Triumeq Evotaz Prezcobix Genvoya Odefsey Descovy