Antiretroviral Updates: New Treatments for HIV C. Ryan Tomlin, Pharm.D., BCPS, AAHIVP Mercy Health Saint Mary’s Grand Rapids, Michigan

Outline Newly Released Antiretroviral Medications Isentress HD® (raltegravir) Juluca® (dolutegravir/rilpivirine) Biktarvy® (bictegravir/emtricitabine/tenofovir alafenamide) Trogarzo® (Ibalizumab) Updates To The DHHS Guidelines Medications In The Pipeline Darunavir-based single tablet regimen Cabotegravir Doravirine Fostemsavir Dolutegravir/Lamivudine

Once-Daily Raltegravir Additional drug interactions with: antacids, calcium carbonate, rifampin, tipranavir, etravirine, strong CPY 3A4 inducers One 400mg Tablet Twice Daily Two 600mg Tablets Once Daily

Dolutegravir / Rilpivirine “First”, two-medication regimen for HIV Indicated for patients: Virally suppressed on another HIV regimen for at least 6 months No history of prior treatment failure No known resistance to dolutegravir or rilpivirine

SWORD 1 and 2 Screening Phase INSTI, PI, or NNRTI + 2 NRTIs Switched to dolutegravir / rilpivirine (n=513) Continued baseline regimen (n=511) HIV RNA <50 for 6 months Day 1 Week 48 Median Age Sex Ethnicity CDC classification CD4 count Baseline third agent DTG/RPV 43 years 77% male 23% female 82% white 11% AIDS 11% <350 cells/mm3 54% NNRTI 26% PI 20% INSTI Baseline ART 79% male 21% female 78% white 10% <350 cells/mm3 27% PI 19% INSTI Llibre JM, et al. Phase III SWORD 1&2. Program and abstracts of the 2017 Conference on Retroviruses and Opportunistic Infections; February 13-16, 2017; Seattle, Washington. Abstract 44LB.

(One patient developed a K101E at 36 weeks) SWORD 1 and 2 Results DTG/RPV Baseline ART Rate of viral failure (HIV-1 ≥50 copies/mL) <1% (3) 1% (6) Treatment-emergent INSTI mutations with decreased susceptibility Treatment-emergent NNRTI mutations with decreased susceptibility (One patient developed a K101E at 36 weeks)

Same Medications / New Package Must be taken with a meal Based on the rilpivirine component Adverse effects Rash, Depressive Symptoms, Diarrhea, Headache Common drug interactions Significant CYP3A4 inducers or inhibitors Acid suppressants Polyvalent cations

Bictegravir Newest in the class of integrase inhibitors Available as a fixed dose combo with tenofovir alafenamide and emtricitabine Studied in both treatment naïve and treatment experienced patients

Bictegravir Treatment Naïve Studies Study 1489 Study 1490 Treatment Naïve Adults with HIV VL ≥ 500 and GFR ≥ 50 Abacavir / Lamivudine / Dolutegravir Tenofovir alafenamide / Emtricitabine / Bictegravir Day 1 Week 48 Treatment Naïve Adults with HIV VL ≥ 500 and GFR ≥ 30 Tenofovir alafenamide / Emtricitabine + Dolutegravir Tenofovir alafenamide / Emtricitabine / Bictegravir Gallant J,, et al. Lancet. 2017;390(10107):2063-2072. Sax PE,, et al. Lancet. 2017;390(10107):2073-2082. Day 1 Week 48

Bictegravir Treatment Naïve Results Study 1489 – TAF/FTC/BIC vs ABC/3TC/DTG Study 1490 – TAF/FTC/BIC vs TAF/FTC, DTG Gallant J, Lazzarin A, Mills A, et al. Lancet. 2017;390(10107):2063-2072. Sax PE, Pozniak A, Montes ML, et al. Lancet. 2017;390(10107):2073-2082.

Bictegravir Switch Studies Study 1844 Study 1878 Patients currently on ABC/3TC/DTG with HIV VL <50 and GFR ≥ 50 Abacavir / Lamivudine / Dolutegravir Tenofovir alafenamide / Emtricitabine / Bictegravir Day 1 Week 48 Patients currently on ABC/3TC or TDF/FTC with ATV or DRV with HIV VL <50 and GFR ≥ 50 Stayed on baseline PI regimen Tenofovir alafenamide / Emtricitabine / Bictegravir Daar E, et al. ID Week Conference, San Diego, Oct 2107. Abstract LB-4 Day 1 Week 48

Bictegravir Switch Results Study 1844 Study 1878 Daar E, et al. ID Week Conference, San Diego, Oct 2107. Abstract LB-4

In Vitro Bictegravir Resistance Tsiang M, Jones GS, Goldsmith J, et al. Antimicrob Agents Chemother 2016. 60:7086-7097.

Bictegravir Administration Once daily with or without food Not recommended in patients with estimated creatinine clearance < 30 mL/min Common adverse effects: Nausea Diarrhea Headache

Bictegravir Interactions Strong inducers of both CPY3A and UGT1A1 Carbamazepine, Oxcarbazepine, Phenobarbital, Phenytoin Rifabutin, Rifampin, Rifapentine St. John’s Wort Metformin Dofetilide

Bictegravir and Polyvalent Cations Antacids containing Al/Mg or Calcium: BIKTARVY can be taken under fasting conditions 2 hours before antacids containing Al/Mg or calcium. Routine administration of BIKTARVY simultaneously with, or 2 hours after, antacids containing Al/Mg or calcium is not recommended. Supplements containing Calcium or Iron: BIKTARVY and supplements containing calcium or iron can be taken together with food. Routine administration of BIKTARVY under fasting conditions simultaneously with, or 2 hours after, supplements containing calcium or iron is not recommended.

Ibalizumab CD4-directed post attachment inhibitor Indicated for patients with heavy multidrug resistance failing their current therapy Given as an IV infusion every 14 days

Changes In Medication Recommendations Most recently updated 3/27/18 Initiation of ART Other Regimens Alternative Regimens Recommended Regimens Recommended For Most People With HIV Recommended In Certain Clinical Situations Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services

First Line Regimens For Most People Tenofovir Emtricitabine Elvitegravir Cobicistat NRTI NRTI Integrase Inhibitor Booster Tenofovir Emtricitabine Raltegravir NRTI NRTI Integrase Inhibitor Tenofovir Emtricitabine Dolutegravir NRTI NRTI Integrase Inhibitor Tenofovir Emtricitabine Bictegravir NRTI NRTI Integrase Inhibitor Abacavir Lamivudine Dolutegravir NRTI NRTI Integrase Inhibitor

Why Integrase Inhibitors? Faster Viral Load Suppression Fewer Drug Interactions (save for elvitegravir) Fewer Side Effects INSTI PI NNRTI T-20

DHHS First Line Regimens Genvoya / Stribild Truvada/ Descovy + Tivicay Truvada/ Descovy + Isentress Triumeq Biktarvy # of Pills 1 2 3 Frequency Daily BID or Daily Potential for Interactions High Low Food Requirement Yes No

Recommended In Certain Clinical Situations Protease Inhibitor Regimens NNRTI Regimens Integrase Inhibitor Regimen Tenofovir / Emtricitabine Darunavir / booster Or Or Abacavir / Lamivudine Atazanavir / booster Efavirenz Tenofovir / Emtricitabine Or Rilpivirine Abacavir / Lamivudine Raltegravir

HIV Medications In The Pipeline Tenofovor AF/Emtricitabine/Darunavir/ Cobicistat Cabotegravir Doravirine Fostemsavir Dolutegravir/Lamivudine

Tenofovor AF/Emtricitabine/ Darunavir/Cobicistat Tenofovir AF Emtricitabine Darunavir Cobicistat ?

Symtuza®? Administration Side Effect Profile Drug Interactions One pill, once-a-day, with food Side Effect Profile Headache, diarrhea, nausea, fatigue, rash Drug Interactions Similar to individual agents (3A4 boosting) Role In Therapy Patients requiring a very “durable” regimen

Cabotegravir Novel integrase inhibitor Potential indications: HIV treatment when combined with rilpivirine Pre-exposure prophylaxis Formulations: Long-acting intramuscular injection Oral

LATTE-2 Trial Phase 2b, randomized, open label trial Inclusion: Age ≥ 18 ART naïve HIV VL ≥ 1,000 CD4 ≥ 200 CrCl ≥ 50 No major drug resistance Margolis DA, et al. Lancet 2017. 390:1499-1510.

LATTE-2 Methods Cabotegravir 30mg PO Daily + Abacavir/ Lamivudine Cabotegravir 400mg IM Q4Weeks + Rilpivirine 600mg IM Q4Weeks (n=115) Cabotegravir 600mg IM Q8Weeks + Rilpivirine 900mg IM Q8Weeks (n=115) Cabotegravir 30mg PO Daily + Abacavir / Lamivudine (n=56) Day 1 Week 20 Week 98 Post Treatment Change Margolis DA, et al. Lancet 2017. 390:1499-1510.

LATTE-2 Results 4 Week IM 8 Week IM Daily Oral Viral Response 87% 94% 84% Viral Non-Response 0% 4% 2% No Viral Data 13% 14% Margolis DA, et al. Lancet 2017. 390:1499-1510.

Doravirine Novel NNRTI Being studied in a single tablet regimen with tenofovir DF and lamivudine Current clinical trials: DRIVE-AHEAD: compared to efavirenz DRIVE-FORWARD: compared to darunavir

DRIVE-FORWARD Trial Patients with HIV viral load >1,000, ART naïve, and no resistance Doravirine + 2 NRTIs + Boosted-Darunavir placebo Boosted-Darunavir + 2 NRTIs + Doravirine placebo Day 1 Week 48 Molina JM, et al. CROI. February 13-16, 2017, Seattle, Abstract 45LB

In Vitro Doravirine Resistance Lai MT, et al. International Workshop on Antiviral Drug Resistance. 2014, Berlin, Germany

Fostemsavir gp 120 attachment inhibitor Potential indication: Prevents binding to host CD4 receptors Binds directly to the virus Potential indication: Highly treatment-experienced patients with multidrug-resistant HIV

BRIGHTE Study Randomized Cohort: Treatment experienced patients failing current ART with only 1 or 2 active medications left FTR + Failing ART Open Label FTR + Optimized Background ART Random 3:1 Placebo + Failing ART Day 1 Day 8 Week 96 Non-Randomized Cohort: Treatment experienced patients failing current ART with 0 active medications left Open Label FTR + Optimized Background ART Non-Random M Kozal M, et al. 16th European AIDS Conference, October 25-27, 2017. Milan, Italy

BRIGHTE Results – Day 8 M Kozal M, et al. 16th European AIDS Conference, October 25-27, 2017. Milan, Italy

BRIGHTE Results – Viral Load Week 24 <400 77% 210 <200 71% 192 M Kozal M, et al. 16th European AIDS Conference, October 25-27, 2017. Milan, Italy

Dolutegravir / Lamivudine Being studied as dual therapy in treatment naïve patients Phase III Trials GEMINI 1 and 2 aim to compare dolutegravir/lamivudine to dolutegravir + emtricitabine/tenofovir DF Not to be confused with the Gemini study of saquinavir

Antiretroviral Updates: New Treatments for HIV C. Ryan Tomlin, Pharm.D., BCPS, AAHIVP Mercy Health Saint Mary’s Grand Rapids, Michigan