Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The.

Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The Only Thing That Stays the Same is Change FORMATTED: 04/19/2016 San Francisco, California: May 6, 2016 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA.

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Learning Objectives After attending this presentation, participants will be able to: Discuss reasons for new ARV agents List advantages of recently approved agents Describe new mechanisms of action of ARV that are in development

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Goals of Antiretroviral Therapy Maintain or restore the health of people living with HIV-1 (PLWHIV) through suppression of HIV-1 replication Minimize or eliminate short and long-term adverse effects of the therapy Have therapies that are accessible to all PLWHIV Prevent transmission of HIV-1 to others via any route of exposure

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Published July 20, 2015 at NEJM.org

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Why Do We Need New Antiretroviral Agents? A 25 year old started on therapy today may need treatment for 6 decades! An infected infant – 8 decades Therapy must be incredibly safe, maximally tolerated and include a range of choices – Renal, cardiovascular, liver and bone toxicity – Safety of ART in pregnancy – Therapy options for infants and children – Adherence, life chaos, treatment fatigue, tolerability – Aging and drug interactions (e.g. CYP 3A4 inhibition) TREATMENT GAP -Not all PLWHIV in care are treated – Stigma, substance use, mental health, access to clinics, transportation, clinic capacity, country stocks, availability of 3 rd line therapy HIV-1 resistance will always be with us

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Continued Improvement Currently Available ART Classes Tenofovir alafenamide fumarate (NtRTI) – Similar efficacy to TDF, less bone toxicity and renal tubular effects – Smaller mg dosing (25 mg), Use in renal dysfunction (CrCl down to 30 cc/min) – Activity against NRTI-resistant variants (?) Doravirine (NNRTI) – Limited CNS side effects – No food requirement or PPI interaction – Phase III underway GS-9883 (integrase inhibitor) – No boosting required, co-formulated with TAF and FTC – Phase III underway Two drug therapy – Less expensive, fewer toxicities?

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. How will you manage your patients who are currently on TDF containing regimens? 1.I will continue TDF in those who are stable without side effects 2.I will switch all my TDF patients to TAF-containing regimens 3.I will prioritize specific patients (e.g. older, those with co- morbidities like HTN and DM, osteopenia) 4.Not sure

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Mills et al, Lancet Infect Dis 2016; 16: 43–52. See Abstract 29 Gallant et al ART to Decrease Long-term Toxicity Switch from Tenofovir DF to Tenofovir alafenamide–containing therapy in patients with suppressed plasma HIV RNA levels. Improvements in proximal renal tubular function

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Study 112: Week 96 Changes After Switch to E/C/F/TAF in Patients With Renal Impairment Median eGFR change after E/C/F/TAF switch – CDK-EPI Cr: 1.0 mL/min (n=158) – CDK-EPI CysC: 3.9 mL/min (n=157) Significant improvements (P<0.05) – Proteinuria – Renal tubular function – Spine and hip bone mineral density Maintained HIV RNA <50 copies/mL: 88% – Virologic failure: 2% (5/242) – No virologic data: 10% (23/242) 5 discontinuation due to increasing eGRF – All 5 had HTN and 2 had DM – No discontinuations due to tubular injury Post FA, et al. 23 rd CROI. Boston, 2016. Abstract 680. Median Change in eGFR (CDK-EPI Cr) Median eGFR (mL/min) 0 24 48 72 96 Baseline eGFR (mL/min) >60 (n=76) 31-40 (n=24) 51-60 (n=78) <30 (n=10) 41-50 (n=54) Week

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Doravirine Versus Efavirenz in ART-Naïve Patients Phase 2b study (n=216) – HIV RNA >1000 copies/mL – CD4 >100 cells/mm 3 Randomized arms – DOR 100 mg or EFV 600 mg + FTC/TDF Non-success at week 48 – Doravirine arm (n=18) – Efavirenz arm (n=14) Discontinuations due to AE – Doravirine arm: 3% – Efavirenz arm: 6% Overall (NC=F) HIV RNA <40 Copies/mL (Week 48) Patients (%) 78% Doravirine Efavirenz 79% 87% 74% <100K (OF) Gatell J-M, et al. 23 rd CROI. Boston, 2016. Abstract 470. >100K (OF) Baseline HIV RNA (copies/mL) 87% 84% NC=F: non-completer=failure; OF: observed failure

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. DOR vs. EFV: Clinical Adverse Events Gatell JM, et al. CROI 2016. Abstract 470. Clinical AEs, [1] % DOR + TDF/FTC (n = 108) EFV + TDF/FTC (n = 108) ≥ 1 AE87.088.9 Serious AEs6.58.3 Discontinued for AEs2.85.6 Drug-related AEs*31.556.5  Diarrhea0.96.5  Nausea7.45.6  Dizziness6.525.9  Headache2.85.6  Abnormal dreams5.614.8  Insomnia6.52.8  Nightmares5.68.3  Sleep disorder4.66.5 *Specific AEs occurring in ≥ 5% of pts included.

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Have you used two drug therapy (like a boosted PI or dolutegravir plus 3TC or FTC) as initial therapy or as maintenance therapy? 1.Yes 2.No 3.What are you talking about?

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Two drug ART to Achieve and Maintain Suppression Dolutegravir plus 3TC 24 week data: PADDLE Study #SCRBSLDAY 2DAY 4DAY 7DAY 10W.2W.3W.4W.6W.8W.12W.24 1 5.58410.9093.70138310171< 50 2 8.88710.2335.671318< 50 3 67.335151.56937.6041.5651.1782669753< 50 4 99.291148.37011.7973.30343217917855< 50 5 34.36220.5444.6801.292570168107< 50 6 16.02414.4993.7541.634162< 50 7 37.60418.5972.94881961< 50 8 25.07124.3686.2641.377Not done268105< 50 9 14.70710.832Not done516202< 50 10 10.6797.9785.671318< 50 11 50.089273.676160.97468.1293.8802.247784290288147< 50 12 13.50864.1033.4963.296135351 8467< 50 13 28.09333.82937.35026.34353926861< 50 14 15.34815.1513.99479119898< 506164< 50 15 23.18523.50015.8304.21719269< 50 Not done< 50 16 11.3773.91037097143< 50 17 39.10025.82811.8791.97046014752< 50 18 60.77173.06931.1702.174692358156< 50 19 82.803106.32035.5172.90289735216876< 50 20 5.1907.3683.43314756< 50 From week 8 onwards all patients had pVL < 50 copies/mL Figueroa et al (Pedro Cahn) 15 th European AIDS Conference 2015

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Two Drug ART Maintains Suppression Latte: Cabotegravir (InSTI) + rilpivirine maintenance vs. EFV- based therapy Margolis DA, et al Lancet Infect Dis 15;1145 2015

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Maintaining therapy for Life in all PLWHIV Adherence – Hard to reach populations, substance use, depression, children, adolescents ……. Life Chaos – Travel, dislocation for work or safety, surgery, drug interactions, pill fatigue, patient preference …… Long acting antiretroviral Therapy!

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Cabotegravir LA and Rilpivirine LA Nanosuspensions Drug nanocrystal suspended in liquid = nanosuspension Nanomilled to increase surface area and drug dissolution rate Allows ~100% drug loading vs. matrix approaches for lower inj. volumes R H. Müller, et al. European Journal of Pharmaceutics and Biopharmaceutics 78 (2011) 1-9 ComponentFunction GSK1265744 (d50 ~200 nm)Active MannitolTonicity agent Surfactant SystemWetting/Stabilizer Water for InjectionSolvent GSK744 200mg/mL TMC278 300mg/mL ComponentFunction TMC278 (d50 ~200 nm)Active GlucoseTonicity agent Surfactant SystemWetting/Stabilizer Water for InjectionSolvent Spreen et al. IAS 2013; Kuala Lumpur. Abstract WEAB0103.

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Mean Plasma cabotegravir Concentration-Time Profiles Following Single 100-800 mg LAP Doses (200mg/mL nanosuspension) Differences observed between split and unsplit dosing Spreen et al. IAC 2012; Washington, DC. Abstract TUPE040.

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) MK8591 EFdA (MK-8591) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) Sub-nanomolar potency in vitro 1 and prolonged suppression of SIV in macaque model 2 Prolonged persistence of triphosphate form in PBMC and macrophage Potential for once weekly dosing Long-acting formulations under development 1 Michailidis et al J Biol Chem 284: 35681-91; 2009 2 Murphey-Corb et al AAC 56:4707-12; 2012

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. MK-8591: Reduction in HIV RNA for at Least 10 Days After Single Oral Dose Open-label study (n=6) – Treatment-naïve males – CD4 >500 cells/mm 3 MK-8591 (NRTI) – Single, 10-mg oral dose Intracellular MK-8591-TP in PBMC – T1/2 (geometric mean): 103 hours No evidence of resistance out to day 10 HIV RNA reduction (log 10 copies/mL) – Day 7: 1.67 – Day 10: 1.78 Generally well tolerated Friedman E, et al. 23 rd CROI. Boston, 2016. Abstract 437LB. HIV RNA After Single Dose Mean Change in Log 10 Copies/mL 0 50 100 150 200 250 Time (hours)

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Antiretroviral Therapy: The Next Generation? Implantable (and removable) combination antiretrovirals Vectored delivery of combinations of antibody-based therapy or protein based therapy

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. RESISTANT HIV-1 WILL ALWAYS BE WITH US Four to eight decades of therapy! Previous exposure to suboptimal treatment developed world Limited monitoring of virologic response world-wide Transmitted drug resistance

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. How often in your practice do you see patients with virologic rebound and resistance to one or more drugs in three or more classes? 1.Once a week 2.Once a month 3.Once every 6 months 4.Almost never

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. In the next 5 years how many patients in your practice will need a new drug from a new class to treat resistant HIV-1? 1.I am not sure I will see even one 2.1 to 5 patients 3.5 to 10 patients 4.10 to 25 patients 5.More than 25 patients

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. 8,746 patients in UK CHIC study who initiated TDF-based first-line ART between 1998 and 2012 VF defined as 2 consecutive viral loads >200 copies/ml Considered major IAS-USA mutations from resistance tests at time of initial failure Multiple imputation used to account for missing resistance tests (56%) Analysis ignores treatment switches/interruptions Virologic failure and resistance emergence on current first-line regimens is RARE Courtesy of Ellen White, David Dunn and colleagues

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Resistance in Developing World Second-line study: NNRTI/NRTI first line virologic failure – 15 countries – majority of participants from Africa or Asia – Baseline resistance - 492 participant samples – 97% had resistance and almost all had both NRTI and NNRTI mutation 61% had at least 2 NRTI mutations 15% K65R or K70E and 13.4% had multi-nucleoside mutations (69 insertion or 151 complex) Boyd, M et al Lancet 2013; 381: 2091–99 The TenoRes Study Group Lancet Infect Dis 2016 Published Online January 28, 2015 – Abstract 503

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. New Agents for Resistant HIV-1 Integrase Inhibitors – Dolutegravir (approved) – GS-9883 (Phase III) N(t)RTI – TAF (approved) – EFdA (4'-ethynyl-2-fluoro-2'- deoxyadenosine)(Phase I-II) NNRTI – Doravirine (Phase III) Maturation Inhibitors – BMS 955176 (Phase II) Attachment inhibitors – BMS 663068 -> 626529 (Phase III) Broadly neutralizing monoclonal antibodies New Targets: e.g. LEDGF, combination entry, additional maturation sites, HIV-1 RNA processing

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Maturation Inhibitors (MIs): BMS-955176 Mode of Action Gag polyprotein Lataillade et al. CROI 2015, Abstract 114LB

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Gag polyprotein Protease Untreated Maturation Maturation Inhibitors (MIs): BMS-955176 Mode of Action Mature virus Lataillade et al. CROI 2015, Abstract 114LB

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Gag polyprotein Immature virus Maturation Inhibitors (MIs): BMS-955176 Mode of Action Untreated BMS-955176 Maturation Inhibitor BMS-955176 inhibits the last protease cleavage event between capsid (CA) protein p24 and spacer peptide 1 (SP1) in Gag, resulting in the release of immature, non-infectious virions Adamson et al. Expert Opin Ther Targets 2009; 13:895–908 Sundquist et al. Cold Spring Harb Perspect Med 2012; 2:7. Protease Maturation Mature virus Protease Treated with BMS-955176 Lataillade et al. CROI 2015, Abstract 114LB

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. BMS-955176: Median Change in HIV-1 RNA over Time Median change in HIV-1 RNA from baseline to Day 11 reached ~-1.4 log 10 c/mL Median change in HIV-1 RNA from baseline, log 10 copies/mL Study days Dosing period Lataillade et al. CROI 2015, Abstract 114LB See Abstract 425, 464

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. BMS-955176 + ATV ± RTV vs. TDF/FTC plus ATV/r Small Pilot study in Treatment Naïve Pts Hwang et al EACS 2015. TDF/FTC 300 mg/200 mg + ATV 300 mg + RTV 100 mg N=4 BMS-955176 40 mg + ATV 300 mg + RTV 100 mg N=8 BMS-955176 40 mg + ATV 400 mg N=8 BMS-955176 80 mg + ATV 400 mg N=8 –2.5 –2 –1.5 –1 –0.5 0 0.5 1 Median change in HIV-1 RNA (log 10 c/mL) from baseline Study day 10152025303540455050 Dosing period

of 38 BMS-626529 Attachment Inhibitor: Proposed Mechanism of Action 1. Langley DL et al. Manuscript in development.

of 38 AI438011: BMS-663068 Monotherapy Substudy: Mean Change in HIV-1 RNA from Baseline* *Error bars represent standard error of the mean. Lalezari et al CROI 2014 abstract 86 Abstract 472

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Attachment Inhibitor – Clinical Development BMS-663068 HIV-1 variants have a range of susceptibility – In Phase IIB study 6% had a BMS-626529 IC 50 >100 nM at screening Phase IIB study in participants with limited resistance – Attachment Inhibitor (over a range of doses) plus RAL and TDF had similar activity over 48 weeks to ATV/r plus RAL plus TDF Phase III study: highly ARV-experienced pts with MDR HIV – If at least one fully active ARV then BMS-663068 600 mg or placebo BID for 8 days no change in background ART then BMS-663068 600 mg BID for 48 weeks or longer with optimized background – If no fully active ARV then BMS-663068 600 mg BID for 48 weeks or longer with OBT

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. BROADLY NEUTRALIZING ANTIBODIES Can they be harnessed as therapy?

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Combined Antibodies: Improved Potency and Breadth Kong, Montefiori Korber et al. J. Virol (2015) 2 mAbs > 98% coverage

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. Broadly Neutralizing Antibodies as Therapy Can they be used successfully as therapy? – Single antibodies lack needed breadth – Combinations of antibodies with differing targets – Modifiable to increase half-life – Bispecific antibodies – Antibody-like inhibitors (e.g. eCD4-Ig) – In combination with long-acting antiretrovirals? But… – Cumbersome delivery, increasing potency = decreasing dose – Virus escape – frequency of monitoring – Anti-idiotype or other inhibitory antibodies – Advantages over antiretrovirals – other than being sexy? Caskey et al Nature 2015; Lynch et al Sci Transl Med 2015; Bar et al Abstract 32LB; Chun et al Abstract 311LB

of 38 From JJ Eron, Jr, MD, at San Francisco, CA: May 6, 2016, IAS-USA. HIV-1 discovered ZDV monotherapy Triple Drug Therapy Single Tablet Regimens The Integrase Era Long Acting Therapy? ????? 1983 1987 1996 2006 2012-13 2020 2025 Antiretroviral Therapy: The Future

Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The.

Similar presentations

Presentation on theme: "Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The."— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The.

Similar presentations

Presentation on theme: "Joseph J. Eron Jr, MD Professor of Medicine University of North Carolina at Chapel Hill Chapel Hill, North Carolina Antiretroviral Therapy New Drugs: The."— Presentation transcript:

Similar presentations

About project

Feedback