New Antiretrovirals for the Treatment of HIV New & Investigational Agents Convenience, tolerability, simplicity “Quad” Pill- Stribild Released by FDA 08-27-12 Tenofovir + Emtricitabine + Cobicistat + Elvitegravir “Booster” INSTI Elvitegravir ANTIRETROVIRAL THERAPY Elvitegravir • Class: integrase strand transfer inhibitor • Approval Status: Filed for NDA October 2011 • Dose (Requires Boosting) - Standard Dosing: 150 mg once daily with food - With Atazanavir-Ritonavir or Lopinavir-Ritonavir: 85 mg once daily • Fixed Dose “Quad Pill”: Elvitegravir-Cobicistat-Tenofovir-Emtricitabine • Metabolism: via cytochrome P450 (CYP) 3A4 • Pregnancy: category unknown • Adverse Events: - Well tolerated -diarrhea reported more frequently with elvitegravir than raltegravir U.S. Food and Drug Administration website. Accessed May 15, 2013. Elvitegravir • Multicenter, Randomized, Double-Blind, Double-Dummy, Phase 3 Study of the Safety and Efficacy of RitonavirBoosted Elvitegravir (EVG/r) Versus Raltegravir (RAL) Ritonavir-boosted elvitegravir 150 mg (or a 85-mg dose if co-administered with atazanavir/ritonavir or lopinavir/ritonavir) versus raltegravir 400 mg twice daily, each in combination with a background regimen. • Additionally, elvitegravir is part of the investigational FDC tablet containing elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide Molina JM, Lamarca A, Andrade-Villanueva J, et al. ANTIRETROVIRAL THERAPY Dolutegravir Dolutegravir, (brand name: Tivicay). formerly S/GSK-572 • Class: integrase strand transfer inhibitor • Approval Staus: FDA Approved; August 13, 2013 • Dose (with or without food): - Treatment Naive: 50 mg once daily - Treatment Experienced, ISTI-Naive: 50 mg once daily - ISTI Resistant: 50 mg twice daily • Fixed Dose Combination: Abacavir-Lamivudine-Dolutegravir (572-Trii) • Pregnancy: category unknown • Adverse Events: - Small increases in serum creatinine (inhibition of creatinine secretion) ANTIRETROVIRAL THERAPY Dolutegravir (“572”) 10-Day Monotherapy Study: Results Source: Min S, et al. AIDS. 2011;25:1737-45. Dolutegravir (“572”) 10-Day Monotherapy Study: Conclusions Conclusions: “Dolutegravir demonstrated potent antiviral activity, good short-term tolerability, low pharmacokinetic variability, and a predictable pharmacokinetics/pharmacodynamics relationship, which support once daily dosing without a pharmacokinetic booster in integrase-naive patients in future studies.” Source: Min S, et al. AIDS. 2011;25:1737-45. ANTIRETROVIRAL THERAPY Dolutegravir (“572”) vs. Efavirenz in ARV-Naive SPRING-1: Study Results 48 Week Data: Virologic Response (TLOVR) All regimens included 2 NRTIs: Tenofovir-Emtricitabine or Abacavir-Lamivudine Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8. Dolutegravir (“572”) vs. Efavirenz in ARV-Naive SPRING-1: Adverse Events Adverse Effect DTG 10mg DTG 25mg DTG 50mg DTG Subtotal EFV 600mg Serious Adverse Events 3 (6%) 1 (2%) 4 (8%) 8 (5%) 4 (8%) Nausea 7 (13%) 6 (12%) 6 (12%) 19 (12%) 3 (6%) Diarrhea 4 (8%) 3 (6%) 5 (10%) 12 (8%) 3 (6%) Dizziness 2 (4%) 0 3 (6%) 5 (3%) 9 (18%) Headache 2 (4%) 4 (8%) 4 (8%) 10 (6%) 1 (2%) Fatigue 1 (2%) 3 (6%) 1 (2%) 5 (3%) 4 (8%) 0 0 3 (6%) 3 (2%) 4 (8%) Abnormal Dreams 1 (2%) 0 0 1 (<1%) 3 (6%) Rash 2 (4%) 0 0 2 (1%) 4 (8%) Insomnia Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8. Dolutegravir (“572”) vs. Efavirenz in ARV-Naive SPRING-1: Conclusions Interpretation: “Dolutegravir was effective when given once daily without a pharmacokinetic booster and was well tolerated at all assessed doses. Our findings support the assessment of once daily 50 mg dolutegravir in phase 3 trials.” Source: van Lunzen J, et al. Lancet Infect Dis 2011;12:111-8. SINGLE STUDY • A total of 833 participants received at least one dose of study drug. Randomized, double-blind, phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more. Participants were randomly assigned to dolutegravir at a dose of 50 mg plus abacavir–lamivudine once daily or combination therapy with efavirenz–tenofovir disoproxil fumarate (DF)–emtricitabine once daily. The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48. Secondary end points included the time to viral suppression, the change from baseline in CD4+ T-cell count, safety, and viral resistance. N Engl J Med 2013; 369:1807-1818 SINGLE STUDY • First trial to show statistical superiority to an efavirenz/FTC/TDF coformulated regimen for treatment naive patients. After 48 weeks of treatment, 88% of the dolutegravir group had HIV RNA levels < 50 copies / mL versus 81% of the efavirenz group • Conclusions Dolutegravir plus abacavir–lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz–tenofovir DF– emtricitabine. N Engl J Med 2013; 369:1807-1818 ANTIRETROVIRAL THERAPY Tenofovir Alafenamide Tenofovir Alafenamide (TAF) • Other Names: GS-7340, TAF, prodrug of tenofovir, tenofovir alafenamide fumarate • Drug Class: Nucleoside Reverse Transcriptase Inhibitors • Chemical Class: Purine Nucleotides • Company: Gilead Sciences • Phase of Development: Phase II and III (as part of fixed-dose combination [FDC] tablets; one FDC tablet is in Phase II testing, and another one is in Phase III testing) Tenofovir Alafenamide (TAF) • Tenofovir alafenamide is a prodrug, which means that it is an inactive drug. Once taken, a prodrug does not work until the body converts it into an active form. In the body, tenofovir alafenamide is converted to tenofovir diphosphate (TFV-DP). • Tenofovir alafenamide is currently being studied as a component of two investigational fixed-dose combination (FDC) drugs for the treatment of HIV infection. Tenofovir alafenamide is being studied in the following combinations: elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide darunavir/cobicistat/emtricitabine/tenofovir alafenamide Edurant and Complera Rilpivirine & Co-formulated Rilpivirine + Tenofovir + Emtricitabine Rilpivirine (Edurant) • NNRTI compound with potent activity Rilpivirine-3D Structure • Once daily dose: 25 mg • Decreased potency with VL > 100,000 (do not use) • Co-formulated with Tenofovir-Emtricitabine (Complera) • Less CNS disturbances than efavirenz and nonteratogenic • Active against most efavirenz-resistant clinical isolates • Unfavorable interactions with acid suppressant medications From: Garvey L, et al. Expert Opin Investig Drugs. 2009;18:103-41. From: Azijn H, et al. AAC. 2010:54;718-27. South Dakota sees most syphilis cases in 44 years • SIOUX FALLS | South Dakota Department of Health officials say the number of syphilis cases reported last year was the most in 44 years. • An annual summary of infectious diseases in the state shows that 48 syphilis cases were reported in 2013. • The most reports of the sexually transmitted disease were in the Sioux Falls area, the largest population area in the state, with 23 cases, and Corson County, where the Standing Rock Reservation is located. Standing Rock reported 14 cases. • The Argus Leader reports that the Sioux Falls cases involve mostly men, and the Corson County cases both men and women. January 20, 2014 7:47 am • Associated Press, Rapid City Journal Questions?