Infectious and Other Complications of New Immunobiologic Agents Used by HIV-Infected Individuals

Transcription

1 Infectious and Other Complications of New Immunobiologic Agents Used by HIV-Infected Individuals Peter Chin-Hong, MD Professor of Medicine University of California San Francisco San Francisco, CA Learning Objectives After attending this presentation, learners will be able to: List the types of conditions for which biologic agents may be prescribed for people with HIV infection Explain the mechanism of action in general of these agents to a patient in your practice so that he or she may understand why certain opportunistic infections and other complications may arise Describe the array of infectious and other complications that may arise with these agents Design strategies that you can use in clinic to prevent infectious and other complications in your patients Slide 3 of 36 HIV-infected patients living longer Slide 4 of 36 Lohse N et al, 2016, Ann Intern Med;165(10):749; ART cohort collab, 2017, Lancet ID, 4(8):e349

2 Slide 5 of 36 HIV-infected patients living longer Autoimmunity Malignancy Lohse N et al, 2016, Ann Intern Med;165(10):749; ART cohort collab, 2017, Lancet ID, 4(8):e349 Life expectancy in US declines for 2 years in row Slide 6 of 36 OEDC, CDC, The Economist Jan 4, 2018 Autoimmune disease and cancer increase with age Rheumatoid arthritis Vasculitis Crohn disease Ulcerative colitis Psoriasis Lymphoma Melanoma Slide 7 of 36 Prostate cancer Leukemia

3 Slide 8 of 36 Immunobiologics treat autoimmune disease and cancer TNF-α inhibitors Infliximab Rheumatoid arthritis Vasculitis Crohn disease Ulcerative colitis Psoriasis Anti-CD20 Rituximab Lymphoma Melanoma Prostate cancer Leukemia Checkpoint block CAR-T cells What is a biologic? Any biologically derived product Binds or interferes with a specific molecular target Monoclonal antibodies Receptor analogues Chimeric small molecules Abbreviations placed at the ends of the names of therapeutic agents convey specific information relating to their structure: "-cept" refers to fusion of a receptor to the Fc part of human IgG1 "-mab" indicates a monoclonal antibody (mab) "-ximab" indicates a chimeric mab "-zumab" indicates a humanized mab Slide 9 of 36 Who is the most immune suppressed? Heme malignancy/stem cell transplant Organ transplant Autoimmune disease treatment Solid tumor treatment Congenital/acquired immune deficiency Hyposplenism Slide 10 of 36

4 Slide 11 of 36 Type of immune defect related to drugs used Cellmediated immunity Solid organ transplant Stem cell transplant TNF-α inhibitors Steroids Other biologics Humoral immunity Rituximab (anti-cd20) Hyposplenism CVID (low IgG) Cancer chemorx Chronic gran dz (CGD) Innate (PMNs) immunity How is this different from HIV immunosuppressed patients? Immune defect OI risk stratification HIV Death of CD4 + T-cells CD4 + count Non-HIV Heterogeneous No reliable tests available Slide 12 of 36 Case 56 year-old woman with HIV (CD4 360, VL <50) with Crohn disease managed with infliximab and 6-MP Presents to ED complaining of shortness of breath x 3 weeks What else do you want to know? Slide 13 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard

5 Slide 14 of 36 Case 56 year-old woman with HIV (CD4 360, VL <50) with Crohn disease managed with infliximab and 6-MP Presents to ED complaining of shortness of breath x 3 weeks PPD negative prior. Lives in New York. Came back 4 weeks ago from a trip to Puerto Rico where she visited family and helped with property clean up Case courtesy Dr. Camille Kotton, MGH/Harvard Case 56 year-old woman with HIV (CD4 360, VL <50) with Crohn disease managed with infliximab and 6-MP Presents to ED complaining of shortness of breath x 3 weeks What do you check next? Slide 15 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Case 56 year-old woman with HIV (CD4 360, VL <50) with Crohn disease managed with infliximab and 6-MP Presents to ED complaining of shortness of breath x 3 weeks Urinary histoplasma antigen positive. Chest CT: symmetric nodules Slide 16 of 36 Diagnosis: Acute histoplasmosis Case courtesy Dr. Camille Kotton, MGH/Harvard

6 Slide 17 of 36 TNF-α inhibitors: tuberculosis Post-marketing survey of TB cases following release of infliximab ( ) 70 cases of TB Median time to diagnosis: 12 weeks (range 1-52) TB characteristics Extrapulmonary disease: 57% Disseminated disease: 24% Keane J. NEJM CXR showing disseminated TB in patient on infliximab TNF-α inhibitors: mycobacteria and fungi Survey of serious infection on TNF-α inhibitors in the US Non-tuberculous mycobacteria: 32 TB: 17 Histoplasmosis: 56 FDA alert 2008: 256 cases of histoplasmosis in patients on TNF-α inhibitors Slide 18 of 36 Winthrop KL. CID Endemic mycoses in the US Case 42 year-old male with Crohn disease x 3 years, started on infliximab after persistent diarrhea 5 months prior Admitted with 3 weeks shortness of breath, low grade temps, dry cough. No help with amoxicillin x 1 week What is your differential diagnosis? Slide 19 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong

7 Slide 20 of 36 Case 42 year-old male with Crohn disease x 3 years, started on infliximab after persistent diarrhea 5 months prior Admitted with 3 weeks shortness of breath, low grade temps, dry cough. No help with amoxicillin x 1 week What diagnostic tests do you send? Case courtesy Dr. Ivan Hung, University of Hong Kong Case Sputum AFB negative x 3 Sputum AFB Cx negative Respiratory virus PCR negative Chest CT: ground glass opacities BAL DFA+ P. jiroveci HIV Ab positive Diagnosis: Pneumocystis pneumonia Treated with clindamycin and primaquine (TMP/SMX allergic) Started ART Slide 21 of 36 Case courtesy Dr. Ivan Hung, University of Hong Kong Case 74 year-old HIV-negative man with interstitial lung disease and chronic lymphocytic leukemia on idelalisib Admitted with progressive shortness of breath on exertion and dry cough for 1 month Diagnosis: Pneumocystis pneumonia Slide 22 of 36 Case courtesy Dr. Jen Mulliken, UCSF

8 Slide 23 of 36 Biologics and PCP Retrospective analysis of 2198 patients (across 8 studies) with relapsed CLL or NHL Patients on idelalisib +/- cotherapy (ritux or ritux/benda) PCP RR: 12.5 Median time to PCP: 141 days No standard PCP prophylaxis guidance Sehn LH, Blood, 2016 Furman, NEJM, 2014 Case 69 year-old HIV-negative woman with low grade lymphoma, treated only with rituximab (anti-cd20) Months after treatment, develops slowly progressive mental status changes CSF PCR positive for JC virus and MRI consistent with PML Diagnosis: Progressive Multifocal Leukoencephalopathy (PML) Slide 24 of 36 Case courtesy Dr. Camille Kotton, MGH/Harvard Biologics and viral infections Hepatitis B reactivation Reactivation with TNF-α inhibitors reported Rituximab common JC virus (progressive multifocal leukoencephalopathy) Natalizumab must check JCV IgG Rituximab reports, less common Varicella zoster virus Slide 25 of 36 Langer-Gould A. NEJM, 2005

9 Slide 26 of 36 Cancer immunotherapy in the beginning Slide courtesy Dr. Gabe Mannis, UCSF How Jimmy Carter beat cancer TIME January 20, 2017 New immunotherapy drug behind Jimmy Carter s cancer cure The Guardian December 6, 2015 Slide 27 of 36 Checkpoint blockade: a billion dollar industry Block the inhibitory receptor with monoclonal antibodies (CTLA-4, PD1) Target the immune system not the cancer May lead to autoimmune disease & immune-related adverse events Infection risk may increase as immune suppression used to treat complications of therapy Slide 28 of 36 Skin and hair depigmentation after treating melanoma with anti-ctla-4 Del Castillo M et al, CID, 2016

10 Slide 29 of 36 Case 52 year-old male with HIV (CD4 450, VL <50 on abacavir/ dolutegravir/lamivudine) with skin squamous cell cancer. Enrolled in AMC-095 trial. On nivolumab x 1 year. Presents with fecal incontinence and diarrhea Diagnosis: Checkpoint inhibitor associated colitis Treated with prednisone high dose and infliximab. Nivolumab stopped Skin cancer in partial remission Severe colitis Case courtesy Dr. Jackie Wang, UCSF Gene therapy was a boy s last chance to stop leukemia. And it worked. PBS March 4, 2018 Slide 30 of 36 CAR Adoptive T cell therapy: CAR T cells Chimeric Antigen Receptor (CAR) T cells are genetically modified T cells T cells respond when tumor cell surface antigen recognized Substantial immune-related adverse events (cytokine release syndrome) Infection risk may increase as immune suppression used to treat complications of therapy Slide 31 of 36 Lee DW et al, Lancet, 2015 KQED, March 4, 2018

11 Slide 32 of 36 Evaluation prior to TNF-α inhibitor use HIV Is patient adequately immune reconstituted? CD4>200. Any drug interactions? TB risk Check PPD or IGRA, CXR, take TB history Endemic mycoses/fungi Take travel history, symptom check Hepatitis B Vaccines Check hepatitis B surface antigen and core antibody Evaluation during biologic use HIV Is patient maintaining good immune function? CD4? Infection vs Infection Is patient experiencing any known adverse effect associated with the biologic? Vaccines Live vaccines usually contraindicated Be vigilant Your patient may have a new complication not previously reported Slide 33 of 36 Learning Objectives After attending this presentation, learners will be able to: List the types of conditions for which biologic agents may be prescribed for people with HIV infection Explain the mechanism of action in general of these agents to a patient in your practice so that he or she may understand why certain opportunistic infections and other complications may arise Describe the array of infectious and other complications that may arise with these agents Design strategies that you can use in clinic to prevent infectious and other complications in your patients Slide 34 of 36

12 Thanks Michelle Hermiston, Ivan Hung, Camille Kotton, Jen Mulliken, Brian Schwartz, Paul Volberding

13 Update From CROI 2018: What You Need to Know Timothy J. Wilkin, MD, MPH Associate Professor of Medicine Weill Cornell Medical College New York, New York Resources from CROI 2018 Searchable poster and abstract database: Webcasts: Abstract ebook, conference agenda, and more: Slide 3 of 48 Learning Objectives After attending this presentation, learners will be able to describe new data and advances presented at CROI 2018, regarding: Advances in prevention of HIV transmission Investigational drugs being developed for the treatment of HIV and its complications Optimal management with antiretroviral therapy Complications and comorbidities of HIV infection Slide 4 of 48

14 ANTIRETROVIRAL THERAPY: Treatment Slide 5 of 48 Switch from DTG/ABC/3TC to Bictegravir/F/TAF Slide 6 of 48 Molina, Abstract 22 Switch from DTG/ABC/3TC to Bictegravir/F/TAF B/F/TAF non-inferior to DTG/ABC/3TC No significant differences in bone density or adverse events Slight differences in renal function (2.8 ml/min) and triglycerides favoring B/F/TAF Slide 7 of 48 Molina, Abstract 22

15 Slide 8 of 48 Tri-specific monoclonal antibodies for HIV prevention and tx Pegu, Abstract 113LB ANTIRETROVIRAL THERAPY: Strategies Slide 14 of 48 REALITY: Addition of 12 weeks of RAL at ART initiation, CD4<100 Slide 10 of 48 Gibb, Abstract 23

16 Slide 11 of 48 REALITY: Addition of 12 weeks of RAL at ART initiation, CD4<100 Extended prophylaxis reduced fatal/non-fatal IRIS Prior study showed this reduced mortality Additional RAL did not worsen IRIS or improve outcomes Gibb, Abstract 23 Rapid ART initiation for new Diagnoses in San Francisco All New HIV dx linked to care in <5 days ART initiated same day unless concern for fatal IRIS Comprehensive education of providers/clinics Slide 12 of 48 Bacon, Abstract 93 Same day ART initiation after home based testing in Lesotho 69% 43% 50% 34% Slide 13 of 48 Labhardt, Abstract 94

17 Slide 14 of 48 Naltrexone therapy to improve viral suppression 2 randomized, placebo-controlled trials of naltrexone in participants with opioid use disorder (NEW HOPE, n=93) or alcohol use disorder (INSPIRE, n=100) during release from incarceration to improve virologic suppression. Springer, Abstract 96 ARCA Database: Impact of M184V on 2-drug outcomes with 3TC Retrospective review of patients simplifying to 2-drug regimen of PI/r+3TC or INSTI+3TC Genotype required 347 pts without M184V;87 pts with M184V Slide 15 of 48 Gagliardi, Abstract 498 HIV Cure: TLR-7 agonist + broadly neutralizing antibody Monkeys treated with ART for 96 weeks followed by 4 strategies TLR7 agonist activates HIV bnab target infected cells Slide 16 of 48 Barouch, Abstract 73LB

18 ANTIRETROVIRAL THERAPY: Preexposure Prophylaxis Slide 22 of 48 Effect of PrEP implementation on HIV incidence in NSW Australia Expanded PrEP Implementation in Communities in New South Wales (EPIC-NSW) Goal: recruit 3700 MSM at high risk of HIV in NSW from 3/16-12/16 in >20 clinics and follow for new HIV infections Results: 499 MSM/month recruited Of the first 3700, 97% had f/u HIV test 2 new HIV seroconversions documented; both were OFF PrEP; rate; 0.05/100 (vs. 2/100 expected) 32% compared with the prior year Recruitment continues (N=7293) Slide 18 of 48 Grulich, Abstract 88 Long-acting cabotegravir protects against penile SHIV infection Validated penile infection model using oral TDF/FTC Slide 19 of 48 Dobard, Abstract 83

19 Slide 20 of 48 Long-acting cabotegravir protects against penile SHIV infection Infected animal had cabotegravir levels that fell below 4xIC90, Protected animals maintained levels above 4xIC90 Dobard, Abstract 83 TAF/FTC for protection of HIV by vaginal transmission Slide 21 of 48 Massud, Abstract 85 MK-8591 protects against rectal SHIV infection at very low dose Dose achievable with 250mcg weekly or 10 mcg daily in humans Slide 22 of 48 Markowitz, Abstract 89LB

20 TUBERCULOSIS Slide 29 of 48 Audience Response Question #1 Which statement is true regarding ART interactions with rifampinbased tuberculosis treatment? 1. Dolutegravir concentrations are not appreciably changed by rifampin co-administration 2. Rifampin lowers TAF concentrations intracellularly to levels precluding co-administration 3. Twice daily dolutegravir plus NRTIs results in reasonable virologic outcomes in patients receiving rifampin 4. Twice daily dosing of bictegravir overcomes pharmacokinetic interaction with rifampin to allow co-administration Slide 24 of 48 ACTG A5279: 1 month of INH/rifapentine for treatment of LTBI 3000 HIV-infected adults high TB country IGRA+ or TST+ 54% female median CD % on ART 80% suppressed Randomized INH daily x 9mo INH/RFP daily x 1mo Slide 25 of vs 32 TB cases 0.67 vs cases/100 pt years INH/RFPx1 mo non-inferior to INHX9mo Chaisson, Abstract 37LB

21 Slide 26 of 48 Interaction of rifampin and tenofovir alafenamide TFV-DP levels 36% lower with TAF+RIF compared to TAF alone TFV-DP levels with TAF+RIF much higher than TDF alone Cerrone, Abstract 28LB Bictegravir/FTC/TAF with rifampin Slide 27 of 48 Costudio, Abstract 34 TB treatment with dolutegravir based regimens Slide 28 of 48 Dooley, Abstract 33

22 Slide 29 of 48 TB treatment with dolutegravir based regimens Dooley, Abstract 33 ACUTE HCV Slide 36 of 48 Audience Response Question #2 Which is true about a MSM living with HIV you just diagnosed with acute HCV infection? 1. Spontaneous clearance will happen most of the time, so treatment should not be considered 2. If the HCV viral load does not decline 2 log 10 in 4 weeks, spontaneous resolution is unlikely. 3. Viral relapse from failure of HCV treatment occurs commonly in this population 4. Spontaneous clearance is more likely if the patient is male. Slide 31 of 48

23 Slide 32 of 48 HCV treatment as prevention in HIV-infected MSM Phase A: Swiss HIV-cohort systematically screened for acute and chronic HCV Phase B: Treatment for all (99.5% SVR) Phase C: rescreen Universal HCV treatment resulted in a dramatic decrease in chronic HCV. Acute HCV reduced by half suggesting treatment as prevention is a viable strategy. Braun, Abstract 81LB Treatment of acute HCV in MSM Slide 33 of 48 Treatment of acute HCV with 8 weeks of grazoprevir/elbasvir 63 MSM with acute HCV, 91% were HIV-infected 3 were re-infected and were not counted as endpoint 1 relapse was observed Success observed in 62/63 (99%, CI 91%-100%). Large European cohort of acute HCV (n=464) Spontaneous clearance of HCV occurred in 11.9% Predicted by 2 log decline in HCV RNA over 4 weeks HCV re-infection observed in 17% of those with SVR Supports universal treatment of acute HCV to impact epidemic (treatment as prevention) Borenkamps, Abstract 128; Boescecke, Abstract 129 METABOLIC COMPLICATIONS Slide 40 of 48

24 Slide 35 of 48 Effect of switch from TDF to TAF +/- bisphosphonates Pooled data from TAF switch studies BP use not additive with TAF switch, especially at the hip for unclear reasons. Can consider a sequential strategy of TAF switch followed by BP, but there are no data. Brown, Abstract 724 Statin exposure and risk of cancer: matched pairs in VA database Similar results for reduction of lung and prostate cancer Virus-related cancers Death rate 45% lower with statin use Slide 36 of 48 Bedimo, Abstract 132 MATERNAL AND CHILD HEALTH Slide 43 of 48

25 Slide 38 of 48 Efavirenz lowers vaginal ring hormonal contraception Effectiveness of vaginal ring likely compromised by co-administration of efavirenz ATV/r co-administration is unlikely to impact vaginal ring effectiveness Scarsi, Abstract 141 RCT of INH LTBI treatment during pregnancy vs post-partum Guidelines for treatment of LTBI during pregnancy should be reconsidered because of adverse pregnancy outcomes Gupta, Abstract 142LB Slide 39 of 48 Conclusions HIV Prevention: There are emerging PrEP strategies including injecting cabotegravir, TAF/FTC, MK HIV Cure: TLR7 agonist + bnabs resulted in sustained aviremia in a subset of monkeys Complications: statins associated with reduced cancer risk Coinfections: data for universal treatment for acute HCV in MSM Tuberculosis: new effective LTBI treatment, 1 month of INH and rifapentine; dolutegravir-based treatment +rifampin-based TB outcomes reasonable Maternal-child health: INH treatment of LTBI during pregnancy resulted in worse birth outcomes; interaction of contraceptive ring and efavirenz. Slide 40 of 48

26 Slide 1 of 51 Antiretroviral Therapy Interactive Cases From the Clinic(ians): Case-Based Panel Discussion Michael S. Saag, MD Professor of Medicine Associate Dean for Global Health University of Alabama at Birmingham Birmingham, Alabama Learning Objectives After attending this presentation, learners will be able to select antiretroviral therapy in patients who are: Starting initial therapy Persistently low-level viremic Pregnant Older Slide Slide 3 3of of 5153 Question What regimen should I use as initial therapy? Slide 4 of 53

27 Slide 5 of 53 Case 1 48 yo Male presents with newly diagnosed HIV infection Asymptomatic Initial: HIV RNA 28,000 c/ml CD4 count 650 cells/ul Other labs are normal; HLA-B57 positive Genotype is Wild-type virus No prior medical history. Normal renal function Ok to start therapy if you think he should Slide 6 of 53 At this point which regimen would you choose? 1. TDF / 3TC / low dose (400mg) EFV (fdc; generic) 2. DTG / 3TC (fdc) 3. ABC/ 3TC / DTG (fdc) 4. TAF/ FTC (fdc) + DTG 5. TAF / FTC/ ELV / cobi (fdc) 6. TAF/ FTC / BIC (fdc) 7. TAF / FTC (fdc) + RAL (once daily) 8. TAF / FTC / RPV (fdc) 9. TAF/ FTC (fdc) + DRV/r (or cobi / fdc) 10. Some other option (e.g., DRV/r + DTG or ) Tenofovir and COBI Interact with Distinct Renal Transport Pathways Slide 7 of 53 Anion Transport Pathway Cation Transport Pathway OAT1 ATP Tenofovir OAT3 MRP4 Creatinine OCT2 COBI MATE1 H + Blood (Basolateral) Active Tubular Secretion Urine (Apical) Blood (Basolateral) Active Tubular Secretion Urine (Apical) The active tubular secretion of tenofovir and the effect of COBI on creatinine are mediated by distinct transport pathways in renal proximal tubules Ray A, et al. Antimicro Agents Chemo 2006; Lepist E, et al. ICAAC 2011; Chicago. #A1-1724

28 Slide 8 of 53 EFV/FTC/TDF QD EFV/FTC/TDF QD Case 2 48 yo Male presents with newly diagnosed HIV infection Asymptomatic except for weight loss / fatigue Initial: HIV RNA 760,000 c/ml CD4 count 21 cells/ul Other labs are normal; HLA-B57 negative Genotype is Wild-type virus No prior past medical history. Normal renal function Ok to start therapy if you think he should Slide 9 of 53 Slide 10 of 53 At this point which regimen would you choose? 1. TDF / 3TC / low dose (400mg) EFV (fdc; generic) 2. DTG / 3TC (fdc) 3. ABC/ 3TC / DTG (fdc) 4. TAF/ FTC (fdc) + DTG 5. TAF / FTC/ ELV / cobi (fdc) 6. TAF/ FTC / BIC (fdc) 7. TAF / FTC (fdc) + RAL (once daily) 8. TAF / FTC / RPV (fdc) 9. TAF/ FTC (fdc) + DRV/r (or cobi / fdc) 10. Some other option (e.g., DRV/r + DTG or )

29 Slide 11 of 53 The 7-8 initial regimens we ll probably be using most INSTI-based PI-based NNRTI-based BIC/FTC/TAF DTG + FTC/TAF DTG/3TC/ABC DTG/3TC RAL + FTC/ TAF (once daily) DRV/c + FTC/TAF RPV/FTC/TAF (DOR /3TC / TDF) ( ) indicates not yet available Minimum Costs of ARV treatments Combination Estimated price / year TDF/3TC/ATV/r $279 TDF/FTC/ELV/c $184 ABC/3TC/DTG $179 GREEN FULLY GENERIC TDF/FTC/EFV600 $144 WORLDWIDE IN 2017 RED STILL PATENTED TO : TDF/3TC/EFV600 $130 VOLUNTARY LICENSES TDF/3TC/EFV400 $100 TAF/3TC/DTG $60 DTG/3TC $46 Slide 12 of 53 Question What is likely the best approach to Long-Acting ARV formulations? Slide 13 of 53

30 Slide 14 of 53 Case 3 (Long-acting LA Agents Available) 48 yo Male presents with newly diagnosed HIV infection Asymptomatic except for weight loss / fatigue Initial: HIV RNA 160,000 c/ml CD4 count 221 cells/ul Other labs are normal; HLA-B57 negative Genotype is Wild-type virus No prior past medical history. Normal renal function Ok to start therapy if you think he should Among the LA agents which type would you choose if or when they become available? 1. Long acting Pill Formulation (1 tab every week) 2. Very long acting Pill Formulation (1 tab every 4-8 weeks) 3. Long-acting injectable (1 injection every 2 months) 4. Implantable disc (placed in provider s office q 6 months) 5. Would not use Long-Acting formulations 6. No opinion Slide 15 of 53 Question How should I counsel a patient with undetectable HIV RNA re sexual transmission risk? Slide 16 of 53

31 Slide 17 of 53 Case 4 48 yo Male presents with newly diagnosed HIV infection Asymptomatic except for weight loss / fatigue Initial: HIV RNA 160,000 c/ml CD4 count 221 cells/ul Other labs are normal; Started on ARV Rx Returns for a 3 month follow up visit HIV RNA < 20 c/ml; CD4 390 cells/ul Assuming he remains undetectable, you tell him that his risk of transmitting HIV to a seroneg partner via sex is: 1. Zero risk (under these circumstances) 2. Virtually zero risk (no one knows for sure) 3. Very low risk 4. Possible 5. It depends on which ARV regimen he s on 6. C mon Saag, I don t like this question! Slide 18 of 53 Question What regimen should be used as initial therapy when an M184V mutation is present? Slide 19 of 53

32 Slide 20 of 53 Case 5 30 yo Female presents with newly diagnosed HIV infection Asymptomatic Initial: HIV RNA 128,000 c/ml CD4 count 350 cells/ul Other labs are normal; HLA-B57 neg Genotype shows M184V mutation No prior medical history. No children. Does not plan to become pregnant. Ok to start therapy if you think she should At this point which regimen would you choose? 1. TDF / 3TC / low dose (400mg) EFV (fdc; generic) 2. DTG / 3TC (fdc) 3. ABC/ 3TC / DTG (fdc) 4. TAF/ FTC (fdc) + DTG 5. TAF / FTC/ ELV / cobi (fdc) 6. TAF/ FTC / BIC (fdc) 7. TAF / FTC (fdc) + RAL (once daily) 8. TAF / FTC / RPV (fdc) 9. TAF/ FTC (fdc) + DRV/r (or cobi / fdc) 10. Some other option (e.g., DRV/r + DTG or ) Slide 21 of 53 Question What regimen should be used in a treatment-experienced patient with an S147G InSTI mutation? Slide 22 of 53

33 Slide 23 of 53 Case 6 30 yo male presents with newly diagnosed HIV infection Asymptomatic Initial: HIV RNA 128,000 c/ml CD4 count 350 cells/ul Other labs are normal; HLA-B57 neg Started on ELV/c/TAF/FTC; regimen failed (two VL > 1000/ml) Genotype shows S147G mutation (also with M184V) Patient and provider wants to continue an InSTI based Rx? 1. ABC/ 3TC / DTG (fdc) 2. TAF/ FTC(fdc) + DTG once daily 3. TAF/ FTC (fdc) + DTG twice daily 4. TAF / FTC/ ELV / cobi (fdc) 5. TAF/ FTC / BIC (fdc) 6. TAF / FTC (fdc) + RAL (once daily) 7. TAF / FTC (fdc) + RAL (twice daily) 8. Some other option Slide 24 of 53 HHS Guidelines Slide 25 of 53

34 Wensing et al. Top Antivir Med. 2017;24(4). Mutations in the Integrase Gene Associated With Resistance to Integrase Strand Transfer Inhibitors Dolutegravir Elvitegravir Raltegravir Slide 26 of 53 Updates, user notes, and references available at Slide 27 of 53 Question Seems like we are now starting ARV therapy for about everyone, what about starting therapy immediately at time of diagnosis? Slide 28 of 53

35 Slide 29 of 53 Case 7 30 yo Male was diagnosed with HIV infection 4 hours ago in the ER Asymptomatic Initial: HIV RNA unknown CD4 count unknown Other labs are normal; HLA-B57 unknown Genotype pending No prior medical history. Ok to start therapy if you think he should When would you choose to start therapy? 1. Right now in the ER 2. Within 1-2 days (outpt Clinic) 3. In the next 2 weeks (outpt Clinic) 4. Within 2 4 weeks 5. Some other option Slide 30 of 53 Expedited ART Experience in Atlanta Grady reduced barriers, with goal to begin ART within 72hrs Pre-intervention days to ART = 22, Post-intervention days to ART= 4. Slide 31 of 53 Colasanti #1109

36 Slide 32 of 53 Question Should I change a regimen when low level detectable virus is present? Slide 33 of 53 Case 8 55 yo male referred to you for evaluation Diagnosed 18 years ago with HIV infection Initial: HIV RNA 936,000c/ml CD4 count 70 cells/ul Current: HIV RNA 85 c/ml (prior value 62 c/ml) CD4 count 525 cells/ul Started on NEL/D4T/3TC; subsequently treated with LOP-r / TDF/FTC, EFV/ FTC/ TDF (fdc). Now DTG / DRV/c / 3TC No historical resistance tests are available 1. Yes 2. No 3. Not sure Should you change ARV therapy now? Slide 34 of 53

37 Slide 35 of 53 Question What regimen should I use as initial therapy in a pregnant patient? Case 9 30 yo Female presents with newly diagnosed HIV infection Asymptomatic, 2.5 months pregnant Initial: HIV RNA 28,000 c/ml CD4 count 650 cells/ul Other labs are normal; HLA-B57 neg Genotype is Wild-type virus No prior medical history. First pregnancy Ok to start therapy if you think she should Slide 36 of 53 At this point which regimen would you choose? 1. TDF / FTC / EFV (fdc) 2. ABC/ 3TC / DTG (fdc) 3. TAF / FTC/ ELV / cobi (fdc) 4. TDF / FTC / RPV (fdc) 5. TAF/ 3TC (fdc) / DTG (fdc) 6. TDF/ FTC (fdc) / DRV/r (or cobi / fdc) 7. TAF/ FTC / ATV/r (or cobi / fdc) 8. TDF / FTC / ATV/r (or cobi / fdc) 9. Some other option Slide 37 of 53

38 Slide 38 of 53 TAF PK - Fetus Intracellular concentration of Tenofovir-DP is 4-5 times higher for TAF compared to TDF Does this expose the fetus to a higher risk of birth abnormalities? Does this lower the risk of vertical transmission? Andrew Hill, 2016 WHO meeting Dolutegravir in pregnancy: Background No fetal toxicity or teratogenicity in animal studies described in manufacturer s submission for regulatory approval 1 High placental transfer of DTG relative to other ARVs in an ex vivo study 2 Unexpected placental transfer of DTG with fetal accumulation and then slow neonatal clearance 3 1. European Medicines Agency. INN-dolutegravir. Annex I: Summary of Product Characteristics. _Product_Information/human/002753/WC pdf 2. Schalkwijk S, Greupink R, Colbers AP, Wouterse AC, Verweij VGM, van Drongelen J, et al. Placental transfer of the HIV integrase inhibitor dolutegravir in an ex vivo human cotyledon perfusion model. J Antimicrob Chemother Nov 3 pii: dkv358. [Epub ahead of print] Available from: 3. Pain JB, Lê MP, Caseris M, Amiel C, Lassel L, Charpentier C, et al. Pharmacokinetics of Dolutegravir in a Premature Neonate after HIV Treatment Intensification during Pregnancy: FIG 1. Antimicrob Agents Chemother [Internet] Jun;59(6): Available from: Slide 39 of 53 Question Should I stop abacavir in older patients? Slide 40 of 53

39 Slide 41 of 53 Case yo male started on ARV Rx years ago (resistance history: wild type virus) returns to you for care after 4 years (Rx d elsewhere) Has been through several regimens; now on ABC/ 3TC / DTG (fdc) Now: HIV RNA < 20 c/ml (persistently) CD4 560 cells/ul Cholesterol 180 mg/dl (HDL 52 / LDL 100) Creat 1.3 / ecrcl = 80 cc/min Smoker PMHx negative (No cardiac history) On atorvastatin and daily low-dose ASA Besides asking him to quit smoking, what would you do? 1. Continue his current ARV Rx 2. Change his ABC/3TC to TAF / FTC containing Rx 3. Change his ABC/3TC to DRV/rit (continue DTG) 4. Some other option Slide 42 of 53 Question Should I switch from EFV / FTC / TDF (fdc) in a patient who has been on it for the last 10 years? Slide 43 of 53

40 Slide 44 of 53 Case yo Female referred to you for evaluation Diagnosed 14 years ago with HIV infection Initial: HIV RNA 36,000c/ml CD4 count 150 cells/ul Current: HIV RNA <20 c/ml CD4 count 525 cells/ul Started on EFV + FTC/ TDF (fdc) in Jan 2004 Changed to STR in Only regimen. Reports no symptoms currently. Creatinine 0.8 (egfr > 60 cc/min) Generally feels well 1. Continue her current ARV Rx At this point you would: 2. Change her ARV Rx to generic low-dose (FDC) EFV (400mg) / 3TC / TDF 3. Change her ARV Rx to 2 nucs and RPV 4. Change her ARV Rx to 2 nucs and a boosted PI 5. Change her ARV Rx to 2 nucs and an InSTI (integrase inhibitor) 6. Something else Slide 45 of 53 Question Should I recommend coming off of disability for a fully functioning patient? Slide 46 of 53

41 Slide 47 of 53 Case yo male started on ARV Rx years ago (resistance history: wild type virus) returns to you for care after 4 years (Rx d elsewhere) Has been through several regimens; now on ABC/ 3TC / DTG (fdc) Now: HIV RNA < 20 c/ml (persistently) CD4 560 cells/ul He has been on disability (SSI) since 1999 when he was first diagnosed with advanced AIDS Now, he is fully functional, volunteers at a Homeless Shelter 5 days a week He brings in paperwork for you to confirm his disability. What do you tell the patient? 1. Sure. Happy to fill this out. No problem 2. Gee, I will support your disability as best I can but I can t lie on the forms 3. I will fill the forms out, but based on your current functional status I cannot support continuing your disability 4. Some other option Slide 48 of 53 Question How do I manage a patient on chronic opioid therapy for chronic neck and shoulder pain? Slide 49 of 53

42 Slide 50 of 53 Case yo male started on ARV Rx years ago returns to you for care after 4 years (Rx d elsewhere) His HIV is well controlled and his CD4 count is 560 cells/ul All other labs (renal / liver) are normal He has chronic neck and shoulder pain for over 5 years MRI: moderate osteophytes, some foramen narrowing, but no indication for surgical intervention He has been on MS Contin 40 mg twice daily for > 4 years, with IR morphine sulfate for breakthrough pain He now says his pain is not responding to the MS Contin any longer and he needs a higher dose In addition to referral to physical therapy, you recommend: 1. Continuing his pain regimen as is, augmenting his pain regimen with NSAIDs as needed 2. Increase his morphine (slow release) dose 3. Reduce his morphine (slow release) dose 4. Change his pain regimen to fentanyl patches 5. Rx methadone for pain and weaning off of morphine (slow release) 6. Some other option Slide 51 of 53 Conclusion Undetectable = Untransmissable (U = U) Debate about how soon to initiate ARV Rx after diagnosis of HIV Presence of M184V does not effect initial Rx much (except for use of ABC at higher viral load) Solitary S147G InSTI mutation does not impair activity of DTG or RAL DTG now OK in pregnant women; TAF pending more data Do not need to change ARV therapy if persistent low level viremia Slide 52 of 53

43 Preexposure Prophylaxis (PrEP): Challenges and Opportunities Onyema E. Ogbuagu, MBBCh, FACP Assistant Professor of Medicine Yale University New Haven, Connecticut Learning Objectives After attending this presentation, learners will (be able to): Identify opportunities and challenges with PrEP uptake focusing on MSM and other risk groups Discuss gender differences around PrEP efficacy Describe the role of PEP for PrEP users Slide 3 of 42 Case 1 A 19 year old African American man who has sex with men presents to your clinic to discuss PrEP which he heard about from a friend at a bar. He has just begun a new relationship and while he has not had anal intercourse, he thinks that he and his partner will possibly be intimate in a few months. He relates that his partner has HIV infection but is on treatment and told him that he has an undetectable viral load. During the visit, you screen him for hepatitis B and other STIs, a rapid 4 th generation HIV test is negative. Slide 4 of 42

44 Slide 5 of 42 Regarding PrEP, you would recommend: 1. Initiate daily PrEP now 2. Recommend on-demand PrEP 3. Defer, discuss PEP, initiate PrEP after anal sexual debut 4. No PrEP or condoms. Reassure him that transmission risk is low in a monogamous relationship between two partners who are serodifferent with the infected partner having either very low or non-detectable viral loads. 5. Encourage condom use with all future encounters, no PrEP Minority MSM are highest risk group for HIV infection Slide 6 of 42 Heterogeneous risk: Location matters for HIV risk MSM in South are disproportionately at risk - 9/13 of highest risk states are in the Southern US NY and NJ are in highest risk group Slide 7 of 42

45 Slide 8 of 42 Young MSM and HIV 93% infections among men acquired through male-male sexual contact 26% increase over 4 year period Black and Hispanic YMSM with highest numbers, increasing incidence of new HIV infections nationwide Why are minority YMSM disproportionately at risk? Risk misperception Alcohol/ drug use-fuelled risk behaviors Limited awareness of HIV infection among HIV + Feelings of rejection and isolation Sexual network HIV prevalence / older MSM fuel transmission cycle Clinical care access and use Structural barriers (low income, unemployment, incarceration, low education, stigma) Slide 9 of 42 Disparity in HIV prevalence possible explanations? Black MSM have less substance use, fewer no. sex partners, less disclosure of same sex behavior; HIV positive black MSM less likely to be on cart, higher STD rates (Millet AIDS 2007, Bohl SexTransm infect 2009) Sexual concurrency (same time / overlapping partnerships) associated with increased HIV risk and higher among black MSM (Mah AIDS behav 2010, Bohl SexTransm infect 2009, Admiora Am J Pub Health 2007) and partners likely to be of same race and older (Berry AIDS 2007) Social isolation, stigma and stress impact status disclosure and sexual risk behaviors (Pachankis Health Psychol 2015) Slide 10 of 42

46 Slide 11 of 42 Disparities exist in PrEP uptake by race/ethnicity and age Data are from a cohort of 5857 patients who were HIV uninfected and had been screened for rectal STIs in a Community Health Center in Boston Mayer K et al, CROI 2018, Abstract # PrEP coverage among racial/ethnic groups varies by region TDF/FTC Slide 12 of 42 CROI 2018 presentation, By race/ethnicity, blacks have highest number needing PrEP in the United States, 2015, Dawn Smith, CDC Disparities by region in PrEP prescriptions Active PrEP defined as >1day of PrEP use 2016 new HIV diagnoses used as proxy for need PrEP to need ratio in Northeast 3x > than Midwest and South Medicaid expansion states had higher PrEP use prevalence Slide 13 of 42 Siegler et al, CROI 2018 abstract # 1022LB

47 Slide 14 of 42 PrEP deserts exist particularly for rural MSM! For PrEP eligible MSM, 23% and 8% lived 30 and 60 minutes (drive time in ideal traffic conditions) away from nearest PrEP provider respectively. PrEP deserts (>60min drive time distance) are primarily in micropolitan areas Weiss, CROI 2018 poster #1006 PrEP navigation works but is insufficient for uptake PrEP cascade at NYC sexual health clinics Priority groups defined as MSM who had used PEP, were interested in PrEP, had recent STI, high risk partners or needle sharing in 1 year prior to study 19.5% Only 34% who were referred received PrEP PrEP navigation uptake was high (62%) but Slide 15 of 42 Pathela et al, 2018 CROI abstract # 1007 PrEP navigation works but is insufficient for uptake PrEP cascade at NYC sexual health clinics Only 19.5% who were PrEP eligible received PrEP Slide 16 of 42 Pathela et al, 2018 CROI abstract #1007

48 Slide 17 of 42 Beyond initiation PrEP discontinuation rates are high PrEP discontinuation by type of insurance (n=1715) Seroconversions occurred in those who discontinued PrEP Age group had highest discontinuation rates Shover et al, UCLA 2018 CROI abstract 1007 Multimodal strategies have to be employed to stem HIV infections among MSM Slide 18 of 42 Beyrer et al, Strategic framework on action for HIV among MSM, Lancet 2012 San Francisco experience- HIV diagnoses dropping coincident with PrEP scale-up CROI 2018 oral presentation on Getting to zero new HIV diagnosis in San Francisco: What will it take Susan Slide 19 of 42 Buchbinder, San Francisco health department

49 Slide 20 of 42 PrEP coverage and HIV prevention projections On demand PrEP efficacy and concerns ANRS IPERGAY study 86% relative risk reduction Advantages Improved adherence Less long-term drug toxicity convenience Concerns Drug levels Unplanned sexual encounters Efficacy not shown in all risk groups Slide 21 of 42 Molina et al, NEJM 2015 Condom use patterns among MSM/ unplanned sexual events Condomless anal intercourse (CAI) proportion and patterns by day of week Nearly half (46%) of participants reported engaging in unplanned CAI at least once in the last 3 months % CAI Planned CAI Slide 22 of 42 Conor JAIDS 2016

50 Slide 23 of 42 Chem sex is very common Substance use by MSM by hair analysis (ANRS IPERGAY) 60/69 (87%) had drugs of abuse detected New psychoactive substances (NPS) typically used in conjunction with cocaine (96%), MDMA (88%) and ketamine (69%) Chas, ANRS IPERGAY study group, CROI poster, Abstract # 1029 PrEP not approved but multiple demonstration projects show PrEP is acceptable, tolerable, safe and effective in adolescents but challenges exist In the US and in S. Africa Katherine Gill et al. Pluspills: an open label, safety and feasibility study of oral preexposure prophylaxis (PrEP) in year old adolescents in two sites in South Africa IAS 2017 Over 48 weeks of PrEP use, protective drug levels (surrogate for optimal adherence ) declined from 54% to 22% over study period 23 STIs in 12 participants Seroconversion rate of 6.4 / 100 personyears (all occured below protective levels of TDF) 148 enrolled 3(HIV+), 6(pregnant) Baseline STI-40% 18% opted out at 12 weeks Plasma TFV levels detectable in 57% (12 weeks) declining to 38% (end of study) 1 infection in individual who had discontinued PrEP Slide 24 of 42 Case 2 A 55 year old man who has sex with men who has secondary hypogonadism and osteopenia (T score -2.0, Z score 1.5), no hx of fractures presents for PrEP evaluation. He reports engaging in unprotected receptive anal intercourse with partners a month. Labs show he is immune to hepatitis B, Creatinine is 1.5 (GFR-70mL/min). Slide 25 of 42

51 Slide 26 of 42 Regarding PrEP eligibility, you recommend: 1. Enroll in PrEP clinical trial - TAF vs TDF 2. Avoid TDF/FTC, recommend strict condom use, wait for future PrEP options 3. Place on TDF/FTC, check BMD in 1 year 4. Place on TDF/FTC, use calcium + vitamin D to counteract TDF effect on bone 5. Use Maraviroc off label DISCOVER study TAF vs TDF + FTC for PrEP is ongoing GS DISCOVER Study Randomized 1:1 TAF/FTC daily TDF/FTC daily Slide 27 of 42 Ongoing at 92 sites across US, Canada and Western Europe >6000 participants enrolled Endpoints include to assess comparative safety and efficacy of TAF/FTC versus TDF/FTC for PrEP TDF and BMD decline in HIV negative persons Significant BMD changes occur in HIV negative persons on TDF/FTC PrEP In TDF2 study, ~7% of young adults had abnormal baseline bone density test results! Kathleen Mulligan et al. Effects of Emtricitabine/Tenofovir on Bone Mineral Density in HIV-Negative Persons in a Randomized, Double-Blind, Placebo- Controlled Trial. Clin Infect Dis Aug 15; 61(4): Slide 28 of 42

52 Slide 29 of 42 BMD screening for patients on TDF- guidance Age <40 years (no screening) Age years, calculate FRAX score, if >=10% check DEXA All post menopausal women / men > age 50- DEXA Available at Calcium/vitamin D mitigate but may not eliminate TDF effects on bone Percentage of BMD change from baseline to week 48 50% less BMD decline observed overall in Vit D / Ca group Authors? if this a strategy for 1 st 48 weeks of TDF exposure when peak bone loss occurs? Slide 30 of 42 HIV prevention (PrEP) pipeline Slide 31 of 42 Available at

53 Slide 32 of 42 Case 3 A 25 year old woman who is a sex worker presents to your clinic reporting a high risk sexual exposure to an HIV positive male 1 day ago. Her OBGYN prescribed PrEP 2 weeks ago but she reports missing about 3 doses of her pills each week. Her male partner is reluctant to share information on his HIV status. On exam, she has an active genital herpes outbreak. She is concerned about contracting HIV. In addition to prescribing acyclovir, you recommend: 1. Continue TDF/FTC PrEP, reassure her that her risk of acquiring HIV is low 2. Add DTG to TDF/FTC for 28 days as PEP, then resume TDF/FTC for PrEP 3. Because of uncertainty about her HIV partner s treatment status and virus resistance profile, add DRV/COBI + RAL to TDF/FTC for 28-day PEP 4. Acyclovir has some activity against HIV, continue TDF/FTC alone Slide 33 of 42 PrEP and women require greater adherence to achieve protective ARV levels in genital tract TDF/FTC TDF/FTC TDF/FTC TDF/FTC Slide 34 of 42 Bekker, LG CROI 2018 presentation on 5 controversies in PrEP scale-up

54 Slide 35 of 42 Longer time to achieving mucosal protective levels in women TDF/FTC Bekker, LG CROI 2018 presentation on 5 controversies in PrEP scale-up The Pregnancy concern real world data Pregnancy incidence and birth outcomes of women on PrEP TDF TDF/FTC Placebo P-value Number of women Number of pregnancies (incidence ) Pregnancy loss 53 (30.8%) 64 (40%) 31 (32.3%) 0.46 Pre-term birth (live) 4 (3.4%) 7 (7.3%) 5 (7.7%) 0.16 Any abnormality (live born) 6 (5%) 6 (6.1%) 5 (7.6%) 0.51 Slide 36 of 42 Mugo NR et al. Pregnancy incidence and outcomes among women receiving preexposure prophylaxis for HIV prevention: a randomized clinical trial. JAMA Jul 23-30;312(4): PEP and PrEP when to use PEP Consider in Patients with suboptimal use of PrEP (<4 doses for men, <6 doses for women) with high risk exposure Partner who is HIV + or of unknown status following unprotected intercourse Slide 37 of 42

55 Slide 38 of 42 Seroconversions on PrEP an instructive case Index patient (50 year old MSM) participated in Amsterdam PrEP project assessing feasibility and acceptance of daily and event driven PrEP. Had ~50 partners/3 mos pre-prep including URAI with 37/50; on PrEP had partners/month, often receptive days/month had condomless intercourse Had multiple STIs- on months 3 and 6 had BOTH anal gonorrhea and chlamydia On Month 8, had fever and dysuria Screened positive for E. coli in urine and anal LGV 4 th gen test positive (Ab not Ag), western blot with GP 160 Abs, HIV VL negative. PrEP discontinued. TDF level 2258 (1560 is mean with daily dosing) HIV VL-13K 3 weeks later (started ART then-drv/rtv/dtg/tdf/ftc with Undetectable VL in 1 month) PrEP seroconversions lessons learned -Viral inoculum matters? (heavy vol of sex partners, also used injection drugs)? Contribution of mucosal injury from sexual trauma/lubricants +STIs e.t.c lead to loss of PrEP efficacy. Ag/Ab testing for HIV in combination with viral load testing may need to be employed in select cases Frequent STD screening and treatment among at risk individuals should be incorporated in PrEP programs Adherence monitoring is critical to explaining seroconversion events. Use of PEP while on PrEP to be encouraged? Encourage use of PrEP as adjunctive and not stand alone tool for HIV prevention Slide 39 of 42 Luckily TDF/FTC resistance among viremic MSM is low PrEP resistance among MSM (Kings county Seattle, WA) Substantial viremia defined as 10K copies/ml Slide 40 of 42 Buskin, CROI 2018 Abstract # 1042

56 Slide 41 of 42 Acknowledgements Colleagues at Yale AIDS Program Yale New Haven Nathan Smith Clinic (YNHH) Center for Interdisciplinary research on AIDS Gilead Sciences, Inc AIDS Project New Haven PrEP clients IAS USA NY course organizers

57 Investigational Approaches to Antiretroviral Therapy Rajesh T. Gandhi, MD Massachusetts General Hospital Professor of Medicine Harvard Medical School Boston, Massachusetts Learning Objectives After attending this presentation, learners will be able to: Discuss the appropriate use of novel antiretroviral agents Identify new approaches for treating people with HIV infection Slide 4 of 40 Investigational Approaches to Antiretroviral Therapy Are there any new options for initial treatment of HIV? Are two antiretrovirals as good as (or better than) three? Update on 2- drug therapy What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development What are new medicines for treating someone with multi-drug resistant HIV? What s on the horizon?

58 Case Scenario What to Start? 29 yo M with positive HIV Ag/Ab and confirmatory test HIV RNA, HIV genotype, CD4 count, BUN/Cr, other labs pending You decide to initiate same-day ART Which regimen would you choose? 1. Efavirenz/FTC/TDF 2. Rilpivirine/FTC/TAF 3. EVG/c/FTC/TAF 4. DTG/ABC/3TC 5. DTG + FTC/TAF 6. BIC/FTC/TAF Case Scenario What to Start? 29 yo M with positive HIV Ag/Ab and confirmatory test HIV RNA, HIV genotype, CD4 count, BUN/Cr, other labs pending You decide to initiate same-day ART 1. Efavirenz/TDF/FTC risk of non-response if transmitted NNRTI resistance 2. Rilpivirine/FTC/TAF less effective if VL >100 K, CD4 < EVG/c/FTC/TAF lower barrier to resistance than DTG 4. DTG/ABC/3TC need HLA-B701 first 5. DTG + FTC/TAF 6. BIC/FTC/TAF New Antiretroviral Drugs New medications in current classes Bictegravir (INSTI) (approved Feb 2018) Doravirine (NNRTI)

59 Bictegravir (BIC) Unboosted integrase inhibitor; high barrier to resistance; low potential for drug interactions Phase 3 trials in treatment naïve people: BIC/FTC/TAF vs DTG/ABC/3TC; BIC/FTC/TAF vs. DTG + FTC/TAF BIC non inferior to DTG in terms of virologic suppression; no resistance 1,2 As compared to DTG/ABC/3TC, similar changes in proteinuria, bone mineral density and lipids Randomized switch studies in virologically suppressed persons: Switching to BIC/FTC/TAF non-inferior to continuing boosted PI 3 or a DTG, ABC, 3TC-containing regimen 4 1 Gallant J et al, Lancet 2017; 2 Sax P et al Lancet 2017; 3 Daar E et al IDWeek Molina J-M et al, CROI 2018 abstract 22 Bictegravir/FTC/TAF: Treatment Naïve Trials Proportion of Participants, % % (-4.8 to 3.6%) HIV-1 RNA < 50 c/ml Study ,2 Study ,4* -3.5% (-7.9 to 1.0%) 1 HIV-1 RNA 50 c/ml B/F/TAF (n=314) ABC/3TC/DTG (n=315) No HIV-1 RNA Data Bictegravir/FTC/TAF has non-inferior efficacy vs DTG-containing regimens in treatment-naïve populations at Week HIV-1 RNA < 50 c/ml HIV-1 RNA 50 c/ml B/F/TAF (n=320) DTG + FTC/TAF (n=315) 5.8 No HIV-1 RNA Data Gallant J et al, Lancet 2017; Sax P et al Lancet 2017 Indications: Initial treatment of adults with HIV Replacement for regimen in persons who are virologically suppressed and have no history of treatment failure or known resistance to its components Pharmacology and dosing: One-pill, once a day, with or without food. Not recommended if estimated CrCL <30 ml/minute Drug resistance: Bictegravir/FTC/TAF Active in vitro against HIV isolates that carry some integrase resistance mutations Efficacy in people with prior INSTI failure or resistance is unknown

60 Bictegravir/FTC/TAF Drug interactions: Rifampin contraindicated 1 ; other rifamycins not recommended. Metformin AUC increased 39%; no effect on glucose 2 ; assess benefit/risk BIC chelated by polyvalent cations; time doses according to label Pregnancy: Not recommended -- insufficient safety data Side effects: Diarrhea, nausea and headache Increase in serum creatinine (median 0.1 mg/dl) because of inhibition of tubular secretion 1 Custodio JM et al CROI 2018, #34; 2 Custodio J et al ID Week 2017, 1386 Doravirine (DOR): Investigational NNRTI Active in vitro against HIV that is resistant to first-generation NNRTI (isolates with K103N, Y181C, G190A, E101K, E138K, K103N/Y181C) 1 Once daily without regard to food Low potential for drug interactions In phase 3 clinical trial (DRIVE- FORWARD) 2, DOR non-inferior to darunavir/r in terms of virologic suppression with superior lipid profile 1 Lai AAC 2014;58: Molina JM, et al, CROI 2017, Abstract 45LB 3 Molina JM et al, Lancet HIV, 2018 DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection Phase 3 Double-blind Doravirine/3TC/Tenofovir DF (n=364) Treatment-naïve Efavirenz/FTC/Tenofovir DF HIV RNA 1000 copies/ml (n=364) Stratified by HIV RNA HCV or HBV allowed Week Primary Endpoint Primary outcome: HIV RNA <50 copies/ml (FDA snapshot algorithm). HIV RNA <50 copies/ml Non-inferiority: -10%. Baseline demographics: Male: 85%. Age: years. White: 48%. History of AIDS: 14%. HIV RNA: log 10 copies/ml. CD4: cells/mm 3. Squires KE, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract TUAB0104LB

61 DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection DOR/3TC/TDF non-inferior to EFV/FTC/TDF at Wk 48 in terms of virologic suppression HIV RNA <50 Copies/mL Doravirine/3TC/TDF Efavirenz/FTC/TDF Virologic failures in DOR arm (6%) Primary NNRTI resistance: 1.6% Primary NRTI resistance: 1.4% DOR superior to EFV in terms of lower incidence of neuropsychiatric adverse events; more favorable changes in lipids New drug applications for DOR/TDF/3TC and for DOR alone submitted to FDA in Jan 2018; PDUFA date: Oct 2018 Patients (%) Difference (%): 3.5 (-2.0, 9.0) % 91% % 81% Overall ITT (n=364/364) 100K (n=277/258) 81% 81% >100K (n=69/73) HIV RNA (copies/ml) (Observed Failure Approach) Squires KE, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract TUAB0104LB; Orkin C et al, CROI 2018, abstract 491 Case Scenario: Update on 2-drug therapy 50 yo HIV+ M with diabetes, hypertension, chronic renal insufficiency (creatinine clearance of 25) HIV RNA 30,000, CD4 cell count 450 HLA-B5701 positive You want to choose a regimen that avoids TAF, TDF, ABC 1. Darunavir/cobicistat + FTC 2. Darunavir/ritonavir + raltegravir 3. Darunavir/ritonavir + dolutegravir 4. Darunavir/ritonavir + 3TC 5. Dolutegravir + 3TC 6. Dolutegravir + rilpivirine OR FEW

62 Current NRTI-limiting Regimens for Initial Therapy LPV/r + 3TC (GARDEL) 1 Non-inferior to LPV/r + 2 NRTI Disadvantages: high pill burden, toxicities DRV/r + RAL (NEAT001) 2,3 Non-inferior to DRV/r + TDF/FTC CD4 <200: DRV/r + RAL inferior to DRV/r + 2 NRTI VL >100 K: more failures with DRV/r + RAL 1 Cahn P et al, Lancet ID 2014; 2 Raffi F et al, Lancet, 2014; 3 Lambert-Niclot S et al, J Antimicrob Chemother, 2016; 4 Figueroa MI et al, 15 th EACS, 2015 Dolutegravir + 3TC for Initial Therapy PADDLE: single arm study 20 pts with VL <100K: HIV RNA <50 in 90% at wk 48 ACTG A5353: Phase 2 single-arm study HIV RNA 1000 to <500, participants enrolled Week 24, HIV RNA <50 in 90% Virologic failure (n=3); suboptimal adherence 1 person: R263RK and M184V GEMINI-1 and -2: ongoing phase 3 trials; results anticipated this year ACTG A5353 Wk 24 Virologic Outcomes Baseline HIV RNA >100K 100K (n=37) (n=83) <50 (%) VL Virologic non-success (%) HIV RNA >50 copies/ml 8 0 Other reasons 0 2 Figueroa MI et al, 15 th EACS, Taiwo BO et al, Clin Infect Dis, DRV/r + 3TC for Initial Therapy Randomized trial (ANDES) DRV/r + 3TC (n=75) DRV/r + 3TC/TDF (n=70) VL <50 at wk 48: 93 94% Baseline VL >100K: high response rate Dual therapy non-inferior to triple therapy at wk 48 Promising results; larger trial warrant Patients (%) HIV RNA <50 (ITT) Darunavir/r +: 3TC 3TC + tenofovir DF Difference (%): -1.0% (-7.5 ; 5.6%) 93% 94% % 92% Overall (n=70/66) Baseline HIV RNA >100K Copies/mL (n=20/12) Figueroa et al, CROI 2018, Abstract 489

63 Switching to NRTI-limiting regimens after virologic suppression (maintenance) LPV/r + 3TC/FTC (OLE) 1 ATV/r + 3TC (SALT, ATLAS-M) 2-3 DRV/r + 3TC (DUAL) 4 DRV/r + RPV (small trial, n=60) 5 DRV/r + DTG (DUALIS) being studied DTG + 3TC (LAMIDOL, ASPIRE favorable results 6,7 ; TANGO large RCT just launched 8 ) 1 Arribas JR et al, Lancet ID, 2015; 2 Perez-Molina JA et al, Lancet ID, 2015; 3 Di Giambenedetto S et al, J Antimicrob Chemother 2017; 4 Pulido T HIV Drug Therapy 2016 Glasgow, O331; 5 Maggiolo F, JAIDS, 2016; 6 Joly V et al CROI 2017, abstract 458; 7 Taiwo B et al CID, 2017 ; 8 Switching to DTG + RPV in Virologically Suppressed Patients: SWORD-1 and -2 Pts on stable 1 st or 2 nd ART (no change due to VF) and VL <50 for >12 mo. Randomized 1:1 to continue antiretroviral regimen (CAR) or switch to DTG + RPV DTG + RPV non-inferior to CAR DTG/RPV single pill regimen available Food, acid lowering therapy, cation considerations HIV RNA <50, % Virologic outcomes at wk DTG + RPV (n=513) CAR (n=511) 5 4 <1 1 <1 1 Virologic Virologic No virologic success non-response data Llibre JM et al. CROI 2017; Abstract 44LB.; Llibre JM et al, Lance 2018 Long-acting Antiretrovirals 55 yo M with HIV, achalasia, dysphagia Long-standing difficulty swallowing pills Virologically suppressed on dolutegravir and rilpivirine He asks whether there are long-acting HIV medicines that he can take intermittently instead of having to take a daily oral regimen 1. Yes 2. No 3. Not yet 4. I don t know 23

64 LATTE-2: Long-Acting Cabotegravir + Rilpivirine as Maintenance Therapy Cabotegravir (integrase inhibitor) and rilpivirine (NNRTI): long-acting formulations 1,2 LATTE-2: Phase 2a 3 Open-label 18 years of age ART-naïve CD4 200 Creatinine clearance 50 No HBV or ALT 5x ULN *In virologically suppressed patients, oral RPV added during last 4 weeks of induction phase. Qualification for maintenance phase: HIV RNA <50 between wk -4 and day 1. Baseline characteristics: Median age: 35 years. Male: 92%. Median HIV RNA: 4.4 log 10 copies/ml. HIV RNA >100K copies/ml: 18%. Median CD4: 489 cells/mm Spreen HIV Clin Trials 2013;14: Spreen JAIDS 2014;67: Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print]. LATTE-2: Virologic Outcomes With LA Cabotegravir + Rilpivirine as Maintenance Therapy HIV RNA <50 Copies/mL (%) % 87% 94% Week 96 Results Oral cabotegravir + 3TC/ABC daily (n=56) IM cabotegravir + IM rilpivirine Every 4 weeks (n=115) Every 8 weeks (n=115) 2% 4% 0% 2% Success Failure No Protocol-defined virologic failure: q8 weeks (n=2 at weeks 4 and 48 [INI + NRTI resistance]) and oral cabotegravir (n=1 at week 8 [no resistance]) 14% 13% Virologic Data Eron J, et al. J Int AIDS Soc. 2017;20(suppl 4): Abstract MOAX0205LB.; Margolis DA, et al. Lancet. 2017Jul 21. [Epub ahead of print]. Injection site reactions: mild/moderate; transient High participant satisfaction Ongoing phase 3 trials (FLAIR, ATLAS): every 4-wk dosing; results in 2018 ATLAS-2M: every 8-wk dosing; results in 2019 Available in a limited expanded access program how/nct Long-acting NRTTI: MK-8591 (EFdA) Nucleoside RT translocation inhibitor (NRTTI) Half life of active anabolite: hr Humans: single oral dose as low as 0.5 mg suppressed HIV RNA for >7 days Change From Baseline HIV-1 RNA (log 10 copies/ml) Phase 1b, single-dose, monotherapy study Study population: ART naïve (N=30) MK mg MK mg MK mg Time (days) MK mg MK mg Grobler et al CROI 2017 #435 Matthews et al IAS 2017 #TUPDB0202LB

65 Long-acting NRTTI: MK-8591 (EFdA) Study in healthy volunteers: daily doses as low as 0.25 mg expected to lead to HIV suppression MK-8591 achieve target levels with only 0.25 mg dose Phase 2b trial in people with HIV, in combination with doravirine (NNRTI) and 3TC, has started (DRIVE2Simplify) Daily dosing Long half-life and its accumulation in tissues supports possible role in PrEP, long-acting implantable therapy Matthews RP et al CROI 2018 #26 Markowitz M et al IAS 2017 #MOAX0203LB Matthews RP et al CROI 2018 #26 Markowitz M et al CROI 2018, #89LB Case Scenario 60 yo F diagnosed with HIV in Multiple previous regimens HIV RNA 20,000; CD4 cell count 150 HIV phenotype: resistance to NRTI, NNRTI, PIs. Sensitive to INSTI Which of following classes are in/have completed phase 3 trials for treatment? 1. Entry/attachment inhibitors 2. Maturation inhibitors 3. Capsid inhibitors 4. Broadly neutralizing antibodies New Medications for Multi-drug Resistant HIV - Phase 3 trials Ibalizumab Fostemsavir

66 A Approved HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion fostemsavir ibalizumab gp41 gp120 V3 loop CCR5 Inhibitors maraviroc* enfuvirtide* CD4 Cell Membrane * = FDA approved CCR5/CXCR4 (R5/X4) Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100: Humanized monoclonal Ab: binds CD4 on host cells; blocks HIV entry (post attachment inhibitor) 1 Active against CCR5 and CXCR4 tropic HIV No cross resistance with other ARVs 2 IV infusion: 2,000 mg loading dose then 800 mg every 2 wks Duration of infusion: min Ibalizumab 1 Emu B et al, Abstract 1686, IDWeek 2017; 2 Weinheimer S et al, CROI Ibalizumab in Persons with Multi-Drug Resistant HIV Phase 3 trial: 40 heavily treatment experienced pts with 3-class ARV resistance, 1 active drug Primary endpt: VL drop >0.5 log 10 c/ml: 3% during control period 83% after loading dose After loading dose, regimen optimized at day 14 Wk 24: VL <200 in 50% Expanded access: viral suppression to wk 48 March 6, 2018 Emu B et al, Abstract 1686, IDWeek 2017; Weinheimer S et al, CROI 2018, #561 32

67 Fostemsavir (FTR): Oral HIV Attachment Inhibitor Prodrug of temsavir: binds to gp120, inhibits HIV attachment to CD4 Phase 3 trial in heavily treatment experienced patients with virologic failure (BRIGHTE) Kozal M et al, 16th EACS, 2017 Fostemsavir (FTR): Phase 3 Trial (BRIGHTE) Adjusted Mean (95% CI) Mean VL Change at day 8 N=69 N=201 Placebo FTR 600mg BID Difference (95% CI) = (-0.810, ) P< Virologic response through wk 24 (observed analysis) Kozal M et al, 16th EACS, 2017 Regulatory submissions are currently anticipated to take place in the 2019/2020 timeframe At wk 24, 54% of randomized and 36% of non-randomized ppts who received FTR + OBR achieved VL <40 HIV Maturation Inhibitors (MI) Slide courtesy of Trip Gulick, MD Treated with maturation inhibitor Immature virus Morales-Ramirez IAS 2017 #MOAB0103:BMS /GSK development halted due to GI toxicity

68 36 On the Horizon Broadly neutralizing antibodies Other novel agents Broadly Neutralizing Antibodies against HIV Slide courtesy of Pablo Tebas, MD Scheid J et al, Nature, 2016 Similar results with VRC01. Bar K et al, NEJM 2016 Combination bnab, long-acting bnab being studied for treatment, prevention

69 Selected other investigational drugs in the pipeline: Investigational Approaches to Antiretroviral Therapy New options for initial treatment: Bictegravir/FTC/TAF approved; Doravirine (NNRTI) under FDA review Two-drug therapy advancing: DTG + 3TC and DRV/r + 3TC being studied for initial therapy; DTG/RPV approved for maintenance What are the options in someone who has difficulty taking daily drugs? Long-acting agents in development: LA-CAB/LA-RPV in phase 3 trials; MK-8591 (EFdA); others What do you give to someone with highly drug resistant HIV? Ibalizumab approved; fostemsavir completed phase 3; other agents being developed What s on the horizon? broadly neutralizing antibodies, and many others!! Extra slides

70 DTG + 3TC switch LAMIDOL 1 : Single-arm study of switching participants (n~ 100) with virologic suppression on 3-drug ART to DTG + 3TC 97% therapeutic success LAMIDOL: % therapeutic success ASPIRE 2 : participants (n=89) with virologic suppression randomized to continue 3-drug ART or to switch to DTG + 3TC DTG + 3TC non-inferior to continuation of 3-drug ART TANGO 3 : large (n=550) RCT launched in Joly V et al CROI 2017, abstract 458; 2 Taiwo B et al CID, 2017 ; 3 HPTN 083: PrEP with IM CAB vs. oral TDF/FTC Study population: MSM and TGW, at high-risk for HIV acquisition (N=4500) Study regimen: CAB every 2 months injections (after loading dose) vs oral TDF/FTC daily Design: non-inferiority, efficacy study Currently enrolling Monoclonal Antibody against CCR5: PRO 140 Weekly subcutaneous injection Single drug maintenance of suppression study 1 : 10 pts had virologic suppression for 2 yr (out of 31 who entered) One week randomized placebo controlled phase 2b/3 trial in combination with existing ART in people failing current ART 2 N=52; CCR5 tropic HIV Resistance to 3 ARV classes or 2 or more classes with limited treatment options At 1 week, statistically significant reduction in HIV RNA of > 0.5 log 10 c/ml with PR0 140 vs placebo Participants continuing for additional 24 weeks with weekly PRO 140/optimized ART 1 Lalezari J et al, CROI 2017, abstract 437; 2

71 Why We Care About the Care Continuum (And Why We NY) Melanie A. Thompson, MD Principal Investigator AIDS Research Consortium of Atlanta Atlanta, Georgia Learning Objectives After attending this presentation, learners will be able to: Describe the anatomy of the HIV care continuum, including denominators and metrics Describe disparities illustrated by the continuum Describe an intervention to improve continuum outcomes Slide 3 of The Care Continuum Oh No! Not THAT graph again! 20 0 Slide 4 of 79

72 Slide 5 of 79 Benefits of The Continuum Based on quantifiable outcomes rather than process Focus on viral suppression impacts both individual health and public health Drop off at each step highlights challenges that can be addressed for quality improvement and resource allocation Can be implemented at international, national, state, local, clinic levels Can be used to highlight health disparities by race/ethnicity, gender, age, transmission mode, SES, geography Provides data for policy and advocacy ARS #1 The rates of viral suppression in NYC, US, and Botswana, respectively, are: 1. 70% NYC, 58% US, 35% Botswana 2. 76% NYC, 49% US, 92% Botswana 3. 49% NYC, 49% US, 78% Botswana 4. 76% NYC, 58% US, 92% Botswana 5. You have got to be kidding! Slide 6 of 79 But It s More Complicated Than It Looks! Slide 7 of 79

73 Slide 8 of The Care Continuum What s the Denominator? The Care Continuum % % of all persons living with HIV = PREVALENCE-based Slide 9 of 79 0 All PLWH The Care Continuum % % of all diagnosed with HIV = DIAGNOSIS-based Slide 10 of 79 0 All PLWH Diagnosed

74 Slide 11 of The Care Continuum % % Linked, Engaged, Receipt of care = CARE-BASED 0 All PLWH Diagnosed Care A Prevalence-Based Continuum (92% of diagnosed) 85% 83% 78% Slide 12 of 79 Example: Prevalence-Based Continuum 85% of all PLWH Denominator = All PLWH 62% of all PLWH 48% of all PLWH 49% of all PLWH Slide 13 of 79 CDC HIV Prevention and Care Outcomes, 2017

75 Slide 14 of 79 Example: Diagnosis-Based Continuum Denominator = All Diagnosed 85% 100% 62% 73% 48% 57% 49% 58% CDC HIV Prevention and Care Outcomes, 2017 Example: Care-Based Continuum 98-99% of active 86-90% of active Slide 15 of % 90% 90% Diagnosed On Treatment Virally Suppressed Slide 16 of 79

76 Slide 17 of What Does Mean? NO! Contingency-Based Continuum Diagnosed On Treatment Virally Suppressed Slide 18 of 79 What Does Mean? 90% 90 x 90% = 81% 81 x 90% = 73% Diagnosed On Treatment Virally Suppressed Contingency-Based Prevalence-Based BMJ Global Health 2016;1: e % Slide 19 of 79 UNAIDS Global AIDS Update, 2017

77 Slide 20 of 79 How about ? (86% Viral Suppression) The Care Continuum What are the Metrics? Slide 21 of 79 All PLWH Diagnosed Linkage/Receipt of Care Retention Viral Suppression Slide 22 of 79 The Care Continuum: Metrics All PLWH Diagnosed Diagnosed = # ever diagnosed and not known to be dead. But Not all people diagnosed are currently living in the jurisdiction Jurisdictions are not using the same methodology (example = NY GA)

78 Slide 23 of 79 Xia Q, et al. JAIDS Likelihood of Being in NYC NYC Care Continuum, 2012 Include-All Method: Denominator = Diagnosed , % Diagnosed Retained in Care Retained in Continuous Care 53.5% 48.9% Virally Suppressed Slide 24 of 79 Based on Xia Q, et al. JAIDS % 60% 50% 40% 30% 20% 10% 0% Slide 25 of 79 Fulton County, GA (Atlanta), 2016 Denominator: Ever Diagnosed with HIV 62% 47% 49% Engaged in Care Retained in Care Virally Suppressed 1 CD4 or VL 2 CD4 or VL Last VL < 200c/mL 3 mo apart Data: GA Dept of Public Health HIV Epidemiology

79 Slide 26 of NYC Care Continuum, 2012 Likelihood Method 80,509 34,417 (29.9%) Removed 91.0% 76.3% Diagnosed Retained in Care Retained in Continuous Care 71.1% Virally Suppressed Based on Xia Q, et al. JAIDS 2015 PROPORTION OF PLWHA IN NYC ENGAGED IN SELECTED STAGES OF THE HIV CARE CONTINUUM, % 80% 60% 100% 95% 88% 82% 76% 40% 20% 0% HIV-infected HIV-diagnosed Retained in care Prescribed ART Virally suppressed Of approximately 87,700 PLWHA in NYC in 2016, 76% had a suppressed viral load. For definitions of the stages of the continuum of care, see Technical Notes. As reported to the New York City Department of Health and Mental Hygiene by March 31, Slide 28 of 79 Fulton County, GA (Atlanta) Denominator: Diagnosed with HIV in % 80% 70% 60% 50% 40% 30% 20% 10% 0% Slide 29 of 79 78% 78% Linked to Care in 30 Days 63% 61% Engaged Retained Virally Suppressed Data: GA Dept of Public Health HIV Epidemiology

80 Slide 31 of 79 Viral suppression (%) 100% 80% 60% 40% 20% 0% VIRAL SUPPRESSION WITHIN 3 AND 6 MONTHS OF HIV DIAGNOSIS IN NYC, 2016 New Metric = Time from Diagnosis to Viral Suppression 36% Among people newly diagnosed with HIV in NYC in 2016, 36% achieved viral suppression within 3 months and 56% within 6 months of diagnosis. 56% 3 months 6 months Viral suppression is defined as viral load 200 copies/ml. As reported to the New York City Department of Health and Mental Hygiene by March 31, % 80% 60% 40% 20% 0% Slide 32 of 79 Longitudinal Retention & Viral Suppression Retention Viral Suppression N = Months 24 Months 36 Months Anytime N=633 N=595 N=582 Continuous measures unmask disparities Slide courtesy Carlos del Rio % 80% 70% 60% 50% 40% 30% 20% 10% Colasanti, J, et al. CID % 84% 85% 60% 70% 12 Months 24 Months 36 Months 63% 46% Black Non-Black Disparities Slide 33 of 79

81 Slide 34 of 79 NY Leading the Way to EtE! NY Leading the Way to EtE! Slide 35 of 79 Slide 36 of 79

82 Slide 37 of 79 Slide 38 of 79 Slide 38 of 79 New HIV Diagnoses, Fulton County, GA > > > Male Female Total 2016 Transgender = 7 December 2017 data; inclusive of persons where initial diagnosis is Stage 3 (AIDS) % 80% 60% 40% 20% 0% Fulton County, GA: New Diagnoses 2016 Breathtaking Disparities HIV/AIDS AIDS Slide 39 of 79 Data: GA Dept of Public Health HIV Epidemiology

83 Slide 40 of 79 New HIV Diagnoses, 2016 African American White Hispanic/Latino TIMELY INITIATION OF CARE AMONG PEOPLE NEWLY DIAGNOSED WITH HIV BY BOROUGH IN NYC, 2016 Timely initiation of care (%) 100% 80% 60% 40% 20% 77% 70% 77% 76% 0% Bronx Brooklyn Manhattan Queens Staten Island Among people newly diagnosed with HIV in NYC in 2016, Brooklyn and Staten Island residents were less likely to have timely initiation of care. Timely initiation of care is defined as first CD4 or VL drawn within 3 months (91 days) of HIV diagnosis, following a 7-day lag (Sabharwal CJ, Braunstein SL, Robbins RS, Shepard CW. JAIDS 2014;65(5): ) As reported to the New York City Department of Health and Mental Hygiene by March 31, % Slide 42 of 79 VIRAL SUPPRESSION AMONG DIAGNOSED PLWHA BY GENDER IN NYC, % 80% 81% 78% 73% Viral suppression (%) 60% 40% 20% 0% Male Female Transgender Among diagnosed PLWHA in NYC, transgender people had a lower viral suppression proportion than non-transgender people. Viral suppression is defined as most recent viral load in 2016 was 200 copies/ml. As reported to the New York City Department of Health and Mental Hygiene by March 31, Slide 43 of 79

84 Slide 44 of 79 VIRAL SUPPRESSION WITHIN 6 MONTHS OF HIV DIAGNOSIS BY AGE IN NYC, 2016 Viral suppression (%) 100% 80% 60% 40% 20% 43% 58% 54% 0% Among people newly diagnosed with HIV in NYC in 2016, people ages 13 to 19 were the least likely to have achieved viral suppression within 6 months of diagnosis. Viral suppression is defined as viral load 200 copies/ml.new diagnoses in the 0-12 age group not displayed. There was 1 child aged 0-12 years old newly diagnosed with HIV in As reported to the New York City Department of Health and Mental Hygiene by March 31, % 54% 63% VIRAL SUPPRESSION WITHIN 6 MONTHS OF HIV DIAGNOSIS BY TRANSMISSION RISK IN NYC, % 80% Viral suppression (%) 60% 40% 20% 62% 47% 32% 60% 57% 0% MSM IDU MSM-IDU Heterosexual contact TG-SC Among people newly diagnosed with HIV in NYC in 2016, MSM-IDU were the least likely to have achieved viral suppression within 6 months of diagnosis. Viral suppression is defined as viral load 200 copies/ml.tg-sc = Transgender people with sexual contact. New diagnoses with other/unknown transmission risk not displayed. As reported to the New York City Department of Health and Mental Hygiene by March 31, Slide 45 of 79 How Can We Improve Care Continuum Outcomes? The Easy Part Has Been Done! Slide 46 of 79

85 Slide 47 of 79 Impact of Social Determinants of Health on the Care Continuum Every step is affected by Stigma and discrimination Poverty Criminalization- HIV, immigration, addiction High incarceration rates and difficulty with transition Housing instability Employment instability Co-existing conditions: substance use, mental health; other comorbidities Slide 48 of 79 Persons Living with HIV, 2014 Slide 49 of 79

86 Slide 50 of 79 Bcheraoui et al. JAMA. 2018;319(12): doi: /jama Slide 51 of 79 Bcheraoui, et al. JAMA. 2018;319(12): doi: /jama Slide 52 of 79

87 Slide 53 of 79 Current Status of State Medicaid Expansion Decisions WA VT ME* MT* ND NH* MN OR WI* NY MA ID SD MI* RI WY CT PA IA* NJ NE OH DE NV IL IN* MD UT WV CO VA KS MO KY* DC CA Access to Care Drives Health Disparities NC TN OK AR* SC AZ* NM MS AL GA Socioeconomic Disparities Drive Access to Care TX LA AK FL HI Adopted (33 States including DC) Not Adopting At This Time (18 States) SOURCE: Status of State Action on the Medicaid Expansion Decision, KFF State Health Facts, updated January 16, Multiple co-occurring conditions magnify HIV risk Probability of remaining HIV seronegative 0 conditions 1 condition 2 conditions 4295 MSM from 6 US cities Co-occurring conditions - Depressive symptoms - Heavy alcohol use - Stimulant use - Poly drug use - Childhood sexual abuse Days from study initiation 4+ conditions 3 conditions Probability of staying HIV negative goes down as number of conditions increases Slide 54 of 79 Slide courtesy Robert Remien; CROI 2018 Source: Mimiaga et al. JAIDS, 2015 The depression treatment cascade As many as 2 in 3 youth with depression are not identified by their primary care clinicians and fail to receive any kind of care* Source: Pence et al, Psychiatry in Primary Care, 2013; *Zuckerbrot et al, Pediatrics, 2018 Slide 55 of 79 Slide courtesy Robert Remien; CROI 2018

88 Slide 56 of 79 Opportunities for intervention: Mental health screening and intervening When accessing STI testing and PrEP When testing for HIV and upon diagnosis When first accessing care Throughout care When initiating ART and ongoing Slide courtesy Robert Remien; CROI 2018 Leadership Matters: Vastly Different Realities first state in the nation committed to ending this epidemic. Quarantine VS What can we legally do...well they are carriers, with the potential to spread whereas in the past they died more readily not posing a risk Slide 57 of 79 Slide courtesy Carlos del Rio It was only when I learned about U=U that I realized that I have been living for all these years carrying this heavy weight. Because I took my meds, I kept on living. But inside I felt like I was dying. And that made me afraid to get close to anyone else. The night I heard about U=U, I couldn t stop crying. It was like that burden I didn t even realize I was carrying just fell away. Slide 58 of 79 Slide adapted from Robert Remien; CROI 2018

89 Slide 59 of 79 Criminalization of HIV Perpetuates Stigma even in states without specific HIV criminalization laws like New York, the presence of HIV increases penalties: an HIV-positive man was sentenced for 10 years for aggravated assault for biting a police officer in Perry Halkitis & Jennifer Pomeranz Huffington Post, 7/28/17 Linkage and Viral Suppression Slide 60 of 79 Strategy to End AIDS in Fulton County, GA newly diagnosed linked to care, within 72 hrs, to 85% Re-engage out-of-care PLWH within 72 hrs of identification Slide 61 of 79 Slide courtesy Jonathan Colasanti

90 Slide 62 of 79 ARS #2 What have Rapid ART Start studies NOT shown? 1. Increased rate of IRIS 2. Improved retention in care at 12 mos. 3. Decrease in time from diagnosis to viral suppression by half 4. Improved survival Days to 1 st scheduled provider visit Grady IDP REACH: Process Improvement Pre-REACH Post-REACH P N=117 N=90 Value 15 (7, 20) 4 (1, 7) < Days to 1 st attended provider visit 17 (7, 26) 5 (2, 8) < Days to ART start 21 (12, 31) 7 (3, 17) < Slide 63 of 79 Slide courtesy Jonathan Colasanti Colasanti, et al.croi, 2018, Poster #1109 Median: 41 days Median: 67 days Slide 64 of 79 Slide courtesy Jonathan Colasanti Colasanti, et al.croi, 2018, Poster #1109

91 Slide 65 of 79 RAPID ART Start: San Francisco RAPID ART Start: San Francisco Citywide RAPID Protocol: all newly diagnosed persons linked to care within 5 days 1 st care visit: Baseline labs, counseling, medical/psychosocial assessment, ART start (unless at risk for fatal IRIS) TFV/FTC + INSTI or DRV/b with option for 4 drug regimen if infected on PrEP Slide 66 of 79 Bacon O, et al. CROI 2018 Slide of 79 Bacon O, et al. CROI 2018 Slide courtesy Oliver Bacon

92 Slide 68 of 79 NYC JumpstART Immediate, on-site access to ART through 8 Sexual Health Clinics, with navigation and linkage to long term care 83% linkage to care within 30 days for newly diagnosed persons 63% linkage for previously diagnosed persons Blank S, et al. CROI 2018 Retention Slide 69 of 79 Negative Clinic Culture: What Patients Say Your clinics make me feel uncomfortable. The person at the desk looks at me funny. They think I m dumb because my English is not so good. My time is not valued I have to take a day off work to go to the doctor, and then I sit all day. Slide 70 of 79

93 Slide 71 of 79 Retention: Start with the Clinic How can the clinic better meet patient needs? Client-centered clinic culture Reduce wait times Non-traditional hours, including weekends Provide transportation: Uber/Lyft Expand clinic access: mobile units, satellite clinics Reminder phone calls, texts Deliver Client-Centered Care, Services Intercultural Awareness Subcommittee Subcommittee of HIV care providers & specialists, community members, PLWHIV, social scientists 4 Strategic Plan Phases: Assessment of intercultural competence Curriculum Development, Rollout, Sustainability Clinic Assessments: pilot surveys Surveys for patients, administrators, providers Slide 72 of 79 Implications of Missed HIV Medical Care Visits PLWH initiating outpatient HIV medical care at UAB Clinic, (N=543) Characteristic HR (95%CI) a No show visit in 1 st year 2.90 ( ) Age (HR per 10 years) 1.58 ( ) CD4 count <200 cells/ml 2.70 ( ) Log 10 plasma HIV RNA 1.02 ( ) ART started in 1 st year 0.64 ( ) a Cox proportional hazards (PH) analysis also adjusts for sex, race/ethnicity, insurance, affective mental health disorder, alcohol abuse, and substance abuse. Missed HIV medical care visits associated with: Mortality Delayed ART initiation Poor retention in care Longer time to VS Greater cumulative VL burden (viremia copy-years) Racial disparities in VS Declines in CD4 count Inpatient hospitalization Slide 73 of 79 Slide courtesy Michael Mugavero Mugavero et al. Clin Infect Dis 2009;48

94 Slide 74 of 79 Viral Suppression Interventions to Improve Viral Suppression Assess adherence BEFORE viral load rises Ensure early and continuous access to ART Remove institutional barriers that restrict medication access Rapid clinic entry and rapid ART start Revamp ADAP requalification processes Advocate against prior authorizations, step-therapy, 30 day quantity limits, and high tiering of ARV Advocate against high out of pocket costs for private insurance Slide 75 of 79 Remove Barriers! Make It Easy! Slide 76 of 79

95 Slide 77 of 79 Recent Threats To The Care Continuum Bullets dodged in 2018 Omnibus Cuts to the CDC, HRSA, NIH budget Ongoing threats ACA: market instability; waivers allow penalties for preexisting conditions; elimination of Essential Health Benefits; restoration of lifetime caps Medicaid work requirements Federal support for housing (HOPWA; HUD) Continuous access to affordable ART Copay cards not counting toward deductibles! Slide 78 of 79 Activate Your Inner Activist Mobilize, Organize, #Resist Join Slide 79 of 79

96 Slide 80 of 79 Our Goal 1,400,000 1,200,000 1,000, , , , ,000 0 Healthy, happy, and long lifespans for PLWH! No new HIV infections! Acknowledgments Slides, Data, E Oliver Bacon SF Getting to Zero Sarah Braunstein, Qiang Xia NYC DOH HIV Epi Jonathan Colasanti, Carlos del Rio Emory/Grady, ATL Demetre Daskalakis, Stacey Wilking NYC DOH Michael Mugavero U of AL, Birmingham Robert Remien Columbia U, NY State Psychiatric Inst Pascale Wortley GA DPH HIV Epi Fulton County Task Force on HIV/AIDS Slide 81 of 79

97 Slide 1 of XX Opioid Crisis in America: A Big Mistake, an Over-Aggressive Industry, a Tricky Brain, and the16 Milligrams That Will Bring Your Child Back to College Petros Levounis, MD, MA Professor and Chair Rutgers New Jersey Medical School Newark, New Jersey Learning Objectives After attending this presentation, learners will be able to: Describe the basic model of addiction. List three safe and effective treatments for opioid use disorder. Discuss mindfulness in the treatment of addiction. Slide 3 of 37 XX Outline 1. The Basic Model 2. The Neurobiology of Addiction 3. Addiction Treatments 4. New Directions 5. Conclusions Slide 4 of 37

98 Slide 5 of 37 1 The Basic Model A Biopsychosocial Illness Biological Psychological Addiction Social Use Brain Switch Slide 6 of 37 Olsen and Levounis, Sober Siblings, The Root Cause of the Disaster Slide 7 of 37 Porter and Jick, N Engl J Med, January 10, 1980.

99 Slide 8 of 37 Pharma Money and Influence Slide 9 of 37 Catan and Perez, The Wall Street Journal, December 17, Admissions: 1999 Primary non-heroin opioid admission rates (per 100,000) Slide 10 of 37

100 Slide 11 of 37 Admissions: 2001 Primary non-heroin opioid admission rates (per 100,000) Admissions: 2003 Primary non-heroin opioid admission rates (per 100,000) Slide 12 of 37 Admissions: 2005 Primary non-heroin opioid admission rates (per 100,000) Slide 13 of 37

101 Slide 14 of 37 Admissions: 2007 Primary non-heroin opioid admission rates (per 100,000) Admissions: 2009 Primary non-heroin opioid admission rates (per 100,000) Slide 15 of 37 From Pills to Heroin Slide 16 of 37 Compton, New England Journal of Medicine, 2016.

102 Slide 17 of 37 From Heroin to Fentanyl From Fentanyl to Carfentanil Slide 18 of 37 2 The Neurobiology of Addiction Slide 19 of 37

103 Slide 20 of 37 Natural Rewards % of Basal DA Output Food Empty 50 Box Feeding Time (min) DA Concentration (% Baseline) Sex Female Present Sample Number Adapted from: Di Chiara et al, Neuroscience, 1999 Adapted from: Fiorino and Phillips, J Neuroscience, 1997 Effects of Drugs on Dopamine Levels % of Basal Release MORPHINE Dose mg/kg hr % of Basal Release COCAINE hr 250 NICOTINE 250 ETHANOL % of Basal Release % of Basal Release Dose (g/kg ip) hr hr Slide 21 of 37 Adapted from: Di Chiara and Imperato, Proceedings of the National Academy of Sciences USA, 1988; courtesy of Nora D Volkow, MD Pleasure-Reward Pathways Slide 22 of 37 National Institute on Drug Abuse,

104 Slide 23 of 37 3 Addiction Treatments 1 st Wave: Psychoanalysis 24 Slide 24 of 37 Levounis, Journal of Medical Toxicology, nd Wave: Boot Camps 25 Slide 25 of 37

105 Slide 26 of 37 3 rd Wave: The Current Approach 1.Medications 2.Motivational Interviewing 3.Mutual Help (12-step) Nunes, Selzer, Levounis, Davies, Substance Dependence and Co-Occurring Psychiatric Disorders, Levounis, Arnaout, and Marienfeld, Motivational Interviewing for Clinical Practice, Renner, Levounis, and LaRose, Office-Based Buprenorphine Treatment of Opioid Use Disorder, 2 nd Ed., Mutual Help MEDICAL STAFF 1. Housing 2. Government 3. Medical Services 4. Outpatient Treat. 5. Job 6. Community 7. Trusting People 8. Inner Peace 9. God 10. Spirituality 11. AA PATIENTS 1. Inner peace 2. God 3. Medical Services 4. AA 5. Housing 6. Spirituality 7. Outpatient Treat. 8. Community 9. Government 10. Trusting People 11. Job What Med Staff Think Patients Think 1. Housing 2. Outpatient Treatment 3. Medical Services 4. Job 5. Trusting People 6. AA 7. Inner Peace 8. Community 9. Government 10. Spirituality 11. God 27 Slide 27 of 37 Goldfarb, Am J Drug Alcohol Abuse, Motivational Interviewing Slide 28 of 37 Levounis, Arnaout, and Marienfeld, Motivational Interviewing for Clinical Practice, 2017.

106 Slide 29 of Medications Agonists % Efficacy Partial Agonists Antagonists Log Dose of Opioid Renner, Levounis, LaRose, Office-Based Buprenorphine Treatment of Opioid Use Disorder, APA Publishing, Naloxone Autoinjector Slide 30 of 37 4 New Directions Slide 31 of 37