5/11/2017. HIV Cure Research Questions and a Few Answers

Transcription

1 HIV Cure Research Questions and a Few Answers Steven G. Deeks, MD Professor of Medicine University of California San Francisco San Francisco, California FORMATTED: 04/13/17 Financial Relationships With Commercial Entities Dr Deeks has served as a consultant for EMD Serono, Inc, on the scientific advisory board for BryoLogyx, Inc, and has received research support from Merck, ViiV Healthcare, and Gilead Sciences, Inc. (Updated 04/13/17) Slide 2 of 42 Learning Objectives After attending this presentation, learners will be able to: Describe where HIV resides during long-term antiretroviral therapy Outline the major causes of HIV persistence during therapy Describe the barriers to measuring the HIV reservoir Describe viable pathways towards a cure for HIV infection Slide 3 of 42 1

2 HIV Cure: Lots of questions and a few answers Slide 4 of 42 How much is there? How stable is the reservoir? Where does it reside? Can it be measured? Can latency be prevented? Can latency be reversed? Can the virus be controlled? How much should it cost? What do we know about the size and stability of the reservoir? Slide 5 of 42 Although ART reduces viremia > 6 to 7 log 10 some virus persists indefinitely (0.1-3 copies RNA/mL) Source of the viremia is not known but it is not from an actively replicating population Slide 6 of 42 Log vrna Copies/ml Start Treatment Weeks Post Infection 2

3 The vast majority of HIV resides in the lymphoid organs, most of it assumed to be in CD4+ T cells, but the macrophage-rich tissues are understudied? (HIV+ cells/gram tissue) (kidney) 10 6 (large bowel) (LN) (spleen) 10 5 (small bowel) Courtesy of Tim Schacker The active reservoir in nodes declines slowly over time and appears to be correlated with the level of lymphoid inflammation (germinal centers) Slide 9 of 42 What do we know about the types of CD4+ T cells that harbor HIV during ART? Slide 9 of 42 3

4 Modest enrichment of HIV has been reported in certain CD4+ T cell subsets Activated/proliferating HLA-DR, PD-1, LAG-3, CTLA-4, TIGIT T follicular helper cells (nodes) Migrating: CCR6, 4 β7 Effector cells Slide 10 of 42 1 Chomont, Nat Med Murray JV Hatano JID Cockerham PLoS ONE Wang JID Chun JCI Riddler (unpublished). 8 Lewin (unpublished). 9 Hatano JID Frometin (unpublished) HIV enriched (100 to 1000 fold) in CD32a-expressing CD4 + T cells Most (> 50%) of reservoir may be in these cells, even though they are rare (~1% of CD4+ T cell population) Slide 12 of 42 How does HIV persist indefinitely? Slide 12 of 42 4

5 Does HIV replicate (or spread) during ART? No evolution Pre-ART virus rebounds No failure Early evolution Low ART, CTL in LN Intensification Slide 13 of 42 Cell proliferation maintains the reservoir during ART Up to 50% of infected cell population (blood) is clonal in nature Integration sites enriched for genes associated with cell growth/cancer Slide 14 of 42 B cell follicles: a relative immune-privileged sanctuary for HIV-infected Tfh T cells Slide 15 of 42 Fukazawa et al., Nature Med 2015; Banga et al., Nature Med 2016; Leong et al., Nature Immunol

6 Can the reservoir be measured? Slide 16 of 42 HIV Reservoir Vast majority of genomes are defective Population of replication-competent HIV that persists during ART and ignites new rounds of replication when ART is stopped Rare, tissue-based, may be impossible to directly measure Slide 17 of 42 Slide 18 of 42 Virus in blood: often clonal and archival Virus in LN: enriched in the follicles (Tfh cells) and actively replicating Blood and tissue reservoirs are not the same 6

7 Cancer: rare tissue based cells that are similar to healthy cells and hard to detect Sensitive tracers that detect cancer (or HIV) being developed Slide 19 of 42 When is the reservoir established? Slide 20 of 42 At about the time HIV RNA becomes detectable, the reservoir size begins to increase dramatically, with an apparent 100-fold increase over the next two weeks Reservoir largely established by week 4 of infection Slide 21 of 42 7

8 Very early ART reduces the reservoir but is not curative N=8; ART in Fiebig I for >96 weeks; VL<50 c/ml; CD4>400 cells/ul Slide 22 of 42 Ananworanich J et al., CROI 2017, Seattle, WA ART (PrEP) during Fiebig 0 Stage 20 adults (and one child) who started therapy early (but not in hyperacute stage), remained on therapy for years, and had no rebound after stopping therapy Low reservoir size, low T cell activation and strong immune responses Slide 24 of 42 8

9 What will a cure have to look like to have a global impact? Slide 25 of 42 Efficacy: aviremia in absence of therapy > 2 years; early failure is tolerable, late failures must be rare Product: oral/parental; administered for limited period of time (e.g., 6 months); specialized (tertiary) care not required Target Population: effective ART initiated at any stage and in all populations (gender, subtype) Long-term safety: comparable to ART, transmission risk negligible Cost: < $1400 (RLS) Slide 26 of 42 How will we cure HIV infection? Slide 27 of 42 9

10 Viable pathways towards a durable remission/cure Slide 28 of 42 Gene and cell-based therapy Proof of concept: Berlin Patient Multiple feasible pathways, none yet scalable Early ART Sterilizing cure not possible (Mississippi case, Fiebig 0 case) Post-treatment control (VISCONTI) occurs rarely when ART is started early (not acute) Immunotherapy: remission (post-treatment control) Shock and kill: reservoir reduction How will we cure HIV infection? In absence of heroic interventions (e.g., gene therapy), it is likely that a remission will likely be easier to achieve than a complete cure Several viable combinatorial approaches are now moving towards proof-of-concept testing Slide 29 of 42 All models of durable SIV/HIV remission suggest that durable control of established infection will require (1) low disease burden, (2) low inflammation and (3) sustained T cell responses that are primed, reside in tissues, and target susceptible epitopes These same attributes apply to cancer immunotherapy Slide 30 of 42 10

11 Adjuvants TLR agonists Immunemodifying ICBs Anti-inflammatory Rx Sanctuary Disruption CD20 antibody Cytokines Vaccine CMV DNA/RNA Adeno/MVA HIV Remission Low Reservoir Early ART LRAs Slide 31 of 42 Therapeutic vaccines: Safe, generally immunogenic and associated with no benefit in most studies and modest benefit in some studies Trial Regimen Comment Author/Paper Slide 32 of 42 ACTG 5068 ALVAC (vcp1452) Intermitting interruptions but not vaccine Jacobson, JID associated with reduced VL 2006 ACTG 5024 ALVAC (vcp1452) + IL- 0.5 log VL reduction during ATI Kilby, JID ACTG 5097 Ad log10 Schooley, JID 2010 MANON-02 ALVAC-HIV No VL effect; activated CD4 cells may have Papagno, AIDS induced early failure 2011 Bionor p24 peptide mixture ATI: no VL effect at primary endpoint, mild Pollard, Lancet (Vacc-4x) benefit at later time points HIV 2014 ERAMUNE DNA prime/mva boost No effect (HIV DNA) Achenbach, 02 Lancet HIV 2015 GeneCure Replication-defective Reduced VL set-point (compared to historical Tung, Vaccine HIV with VZV fusion data) 2016 protein (HIVAX) GeoVax DNA prime/mva boost No apparent effect during ATI (uncontrolled) Thompson, (virus-like particles) PLoS ONE 16 ACTG 5281 Gag/Pol, Minimal CD4 effects, no CD8 effects, low dose Jacobson, Nef/Tat/Vif/Env and IL- IL-12 better than high dose IL-12 JAIDS plasmids (Profectus) BCN 02 ChAdV63.HIVconsv + 5/13 controlled (ATI) Mothe, CROI MVA.HIVconsv 17 Immunotherapy for HIV infection Two decades of largely failed approaches Weak immunogenicity Pre-existing immuno-dominant responses CTL escape Inflammation and counter-regulatory immunosuppression High virus burden Immune-privileged tissue sanctuaries Slide 33 of 42 11

12 Vaccine (Ad26/MVA primeboost) alone had minimal effect on reservoir Vaccine + TLR7 agonist (Gilead) reduces reservoir during ART and controls SIV post-art Slide 34 of 42 BCN02 Trial: HIV vaccine with latency reversal induces sustained HIV control in 5 individuals (8 individuals failed) Slide 35 of 42 Cancer immunotherapy is reshaping a fatal and progressive disease much as ART reshaped HIV Most therapies aim to enhance capacity of CD8+ T cells to recognize and clear rare tissue-based cells that reside in inflamed tissues Upregulation of checkpoint blockers (PD- 1, CTLA-4) Immunosuppressive cytokines (TGF-β, IL-10, IDO) Immunosuppressive immune cells (T-regs, MDSCs) Slide 36 of 42 12

13 How will we reduce the reservoir size to a level such that the immune system can conceivably control what is left? Slide 37 of 42 Shock and Kill Goals have shifted from complete eradication ( cure ), which is likely not possible, to reduction, which will be essential for immune control ( remission ) Slide 38 of 42 Slide 39 of 42 13

14 State of the ART: 2017 Location, size and stability of reservoir remains to be characterized Measuring total body replication-competent reservoir not possible Cellular reservoirs now being explored Mechanisms for persistence known: latency, poor CTL, cell proliferation The reservoir can be reduced with early ART and cell therapy but not with anything scalable It is possible to reverse latency (shock) but the impact on the reservoir is negligible and most approaches are toxic Therapeutic vaccines work in monkeys and perhaps humans Combination approaches will be needed and are now moving into the clinic (era of experimental medicine ) Slide 40 of 42 Acknowledgements Slide 41 of 42 HIV Cure Research Questions and a Few Answers Steven G. Deeks, MD Professor of Medicine University of California San Francisco San Francisco, California FORMATTED: 04/13/17 14

15 Maximizing the Benefits of Preexposure Prophylaxis (PrEP) Susan P. Buchbinder, MD Director, Bridge HIV San Francisco Department of Public Health Clinical Professor of Medicine and Epidemiology University of California San Francisco San Francisco, California FORMATTED: Financial Relationships With Commercial Entities Dr Buchbinder has participated in research trials that have received provision of medicines from Gilead Sciences, Inc. (Updated 05/10/17) Slide 2 of 53 Learning Objectives After attending this presentation, learners will be able to: Recognize trends in the US HIV epidemic Describe factors influencing preexposure prophylaxis (PrEP) effectiveness in different clinical populations Discuss PrEP counseling strategies for clinical practice Slide 3 of 53 1

16 Updates in PrEP and HIV Prevention 1. Who needs PrEP most? Epidemiology of new infections 2. PrEP effectiveness Population differences? 3. Counseling considerations Couples and condoms 4. Safety considerations Initiation and monitoring 5. Population impact Slide 4 of 53 Who needs PrEP most? NEW DIAGNOSES IN THE UNITED STATES Slide 5 of 53 Diagnoses of HIV Infection among Adults and Adolescents, by Sex United States and 6 Dependent Areas Slide 6 of 54 81% 19% Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. 2

17 Diagnoses of HIV Infection among Adults and Adolescents, by Sex and Transmission Category, 2015 United States and 6 Dependent Areas Slide 7 of 54 Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. Data for the year 2015 are preliminary and based on 6 months reporting delay. Data have been statistically adjusted to account for missing transmission category. Other transmission category not displayed as it comprises less than 1% of cases. a Heterosexual contact with a person known to have, or to be at high risk for, HIV infection. New CDC Data on HIV Infections in the US Among MSM, new diagnoses Decreasing in Whites Stable in African Americans Increasing in Latinos Slide 8 of 53 Diagnoses of HIV Infection among Adults and Adolescents by Age at Diagnosis, 2015 United States N = 39,393 Slide 9 of 54 25% Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. Data for the year 2015 are preliminary and based on 6 months reporting delay. 3

18 PrEP Effectiveness POPULATION DIFFERENCES? Slide 10 of 53 ARS 1: How do you recommend PrEP be taken? 1. I recommend daily PrEP for both men and women 2. I recommend less than daily dosing for men, but daily dosing for women 3. I recommend PrEP be taken before and after sex, but only for men 4. I recommend peri-coital PrEP for both men and women 5. I don t recommend anyone take PrEP Slide 11 of 53 Slide 12 of 53 4

19 Slide 16 of 53 Slide 17 of 53 MSM MSM Hetero SDC MSM Hetero Women (gel) Women Women TDF/FTC PrEP Effectiveness for MSM (Excellent, even with high rates of STIs, but not perfect) Slide 18 of 53 Kaiser Northern California (Marcus et al, JAIDS 2016; 73: ) 952 men, 20 women on PrEP 42% annual cumulative incidence STIs 0 HIV infections (2 occurred after d/c ed PrEP) PrEP Demo (Liu et al, JAMA Intern Med 2016;176:75-84) 557 MSM and TGW in SF, Miami, DC 51% had STI on follow-up 2 breakthrough infections: Pt A: First positive visit 37 days after last dose Pt B: First positive visit 4 weeks after last visit Breakthroughs on PrEP 2 MSM HIV-infected while treated for Hep B with daily TDF (Fox et al, Infect Dis Ther 2016;5:65-71) 2 MSM HIV-infected on TDF/FTC PrEP multi-drug resistance (Knox et al, NEJM 2017;376:5-1-2; Grossman et al, AIDS Res Hum Retroviruses 2016;32:44) 1 MSM HIV-infected on TDF/FTC PrEP no resistance (Hoornenborg, CROI 2017, Abstract 953) 5

20 Acute Infection with a Wild Type HIV 1 Virus in PrEP User with High TDF Levels Hoornenborg et al, CROI 2017, Abstract 953 DBS at 6 and 8 mos, TFV DP levels >2200 fmol/punch At 8 months, developed fever and dysuria Antibody positive, Ag negative Stopped PrEP: virus detectable 3 weeks later No resistance mutations 4 Doses/Week has Similar Efficacy to Daily TDF/FTC for MSM Anderson et al, Sci Transl Med 2012;4 (151):151ra125 # Doses/ week Estimated efficacy 95% CI 2 76% 56 96% 4 96% 90% >99% 7 99% 96% >99% IPERGAY : Sex-Driven iprep Slide 18 of 53 2 tablets 2-24 hours before sex 1 tablet every day during sexual activity 2 tablets after the last sexual intercourse Friday Saturday Sunday Monday Tuesday Wednesday Thursday Friday Saturday Sunday On demand PrEP tells you How to Start and How to Stop PrEP Molina, WEAC0102, AIDS2016 6

21 Slide 19 of 53 HIV Incidence (mitt Analysis) Treatment Follow-Up Pts-years Median Follow-up in Open-Label Phase 18.4 months (IQR: ) 97% relative reduction vs. placebo HIV Incidence per 100 Pts-years (95% CI) Placebo (double-blind) ( ) TDF/FTC (double-blind) ( ) TDF/FTC (open-label) ( ) Median # pills/month: 18 (IQR 11-25) Molina, WEAC0102, AIDS2016 Planning for the pre event dose US online survey, 1013 MSM Slide 22 of 53 Last anal sex planned? Unplanned Planned How far ahead planned? % Volk et al, JAIDS 2012; 61: MSM Behavior: Intermittent PrEP is not for everyone Slide 23 of 53 (Un)Planning for sex (Stack et al, JAIDS 2016;71:94-101) 3217 MSM in an online survey; 46% had UNPLANNED condomless anal sex in past 3 months The Hope Springs Eternal study (Parsons et al, JAIDS 2015;68:454-55) 92 HIV negative MSM asked to predict sex with casual partner x 30d; Much better at predicting when they WOULDN T have sex than when they would. Skip your daily dose only if there is a 0% chance you ll have sex tomorrow Vacation Sex or Malaria prophylaxis, 2.0 (Elsesser et al, AIDS Behav; online Nov 4, 2015) 7305 MSM online survey; 26% reported condomless anal sex with new partners while on vacation 7

22 Tenofovir Placebo Tenofovir Years in Study HR = 0.82 (95% CI: 0.40; 1.65) Placebo 5/11/2017 Vaginal microbial dysbiosis *The majority of women with dysbiosis are undiagnosed by Nugent score Slide 24 of 53 Vaginal Lumen Healthy vagina Microbial dysbiosis Gardnerella Prevotella Mobiluncus ph Lactobacilli ph Atopobium Stratified Squamous Epithelia An analysis of CAPRISA 004 (tenofovir gel) found that PrEP was only effective in women with lactobacillus-dominant microbiome Adapted from Burgener & Klatt, TUSS0605, AIDS 2016 Tenofovir gel effective against HIV with Lactobacillus dominance Slide 25 of A. Lactobacillus dominant 0.40 B. Non-Lactobacillus dominant Probability of HIV infection Efficacy, 61% 95% CI, 11 to 84% P= HR = 0.39 (95% CI: 0.20; 0.83) Years in Study Probability of HIV infection Efficacy, 18% 95% CI, -77 to 63% 0.25 P= Lactobacillus dominant non- Lactobacillus dominant Tenofovir Placebo Tenofovir Placebo # HIV-1 infections HIV-1 incidence per 100 person-years HIV-1 protection effectiveness 95% CI, P-value 61% (11, 84), p= % (-77, 63), p=0.644 Burgener & Klatt, TUSS0605, AIDS 2016 Impact of Vaginal Microbiota on Genital Tissue and Plasma Concentrations of Tenofovir Hillier et al, CROI 2017, Abstract 86LB 41 healthy, non-pregnant, HIV negative women received daily tenofovir gel or film x 7 days Sampling: To measure dysbiosis: baseline vaginal swabs (qpcr and Nugent score) To measure tenofovir: Trough: before 7 th dose: vaginal fluid and plasma Peak: 2 hours after 7 th dose: cervical biopsy and plasma Association of tenofovir levels and measures of vaginal dysbiosis If dysbiosis, lower levels of tenofovir in vaginal fluid, cervical tissue, plasma If lactobacillus predominant, higher levels of tenofovir in vaginal fluid, cervical tissue, plasma Confirms results from CAPRISA 004 suggesting that vaginal microbiota may adversely affect topical tenofovir metabolism Slide 24 of 53 8

23 Daily Oral PrEP is Effective Among Women with Abnormal Vaginal Microbiota Heffron et al, CROI 2017, Abstract 85 From Heffron et al, CROI 2017, Abstract 85 How long do you need to take PrEP before protected? 98% 89% In blood 89% achieve EC 90 after 7 doses 98% by 13 th dose Recommend for MSM: Start TDF/FTC PrEP 7 days before Continue 28 days after (based on animal data) Recommend for Women Unknown how long before: CDC recommends 21 days Women need 6 7 doses/week while men only need 4 7 doses Proportion achieving EC 90 of tenofovir in PBMCs Slide 27 of 53 Seifert CID 2015;60:

24 Need high levels of adherence to protect against injection exposure? Bangkok TDF Study in PWID Slide 31 of 53 Needed 97.5% adherence under DOT to achieve >80% effectiveness May not have the same forgiveness with injection exposures At CROI 2017, reported 5/11 breakthrough infections despite high adherence under DOT Garcia Lerma, Abstract 954 This study used TDF alone. Would TDF/FTC be more effective? Martin et al, AIDS 2015;29: Highly effective in MSM population Summary: PrEP Effectiveness Drug forgiveness in rectal tissue: achieve high effectiveness if take > 4 pills/week Insufficient data on peri-coital dosing if sex < weekly Question patients about anticipated periods of risk (e.g., vacation) Highly effective if used daily in women Less forgiveness of TDF/FTC in vaginal tissue Maximize benefit from >6 pills/week Appears that vaginal microbiota affects topical but not systemic PrEP Appears effective against injection drug use May need high rates of adherence Remember that many women who inject drugs also at risk sexually Slide 29 of 53 Counseling Considerations COUPLES AND CONDOMS Slide 30 of 53 10

25 ARS 2: How would you advise a monogamous HIV sero-different couple about condom use? 1. No need for condoms if HIV+ partner is fully virally suppressed 2. No need for condoms if HIV negative partner is on PrEP 3. Both viral suppression and PrEP are needed before stopping condoms 4. Condoms are more effective than ART and/or PrEP Slide 31 of 53 Slide 32 of 53 Potential transmission among treated patients HPTN 052 final results (Cohen et al., NEJM 2016;375: ) 36% of transmissions were unlinked (infection from outside partnership) Eight linked infections in couples 4 occurred within 90 days after HIV+ initiated ART 4 occurred after failure of viral suppression in HIV+ partner Time VL > 1500 copies (Marks, AIDS 2015, 29: ) Cohort of >14,000 patients at 6 HIV clinics followed median of >3 years 90% prescribed ARVs 54% of pts had 1 or more VL > 1500 VL > 1500 for 23% of observation time (average 84 days/patient) Slide 33 of 53 11

26 PrEP as a bridge to ART For couples initiating ART at enrollment, PrEP was offered through 6 months, then stopped: HIV+ partner ART HIV- partner PrEP For couples in which the infected partner delayed or declined ART, PrEP was continued until 6 months after ART initiation: HIV+ partner ART delayed ART HIV- partner PrEP This strategy is supported by mathematical modeling as potentially highly effective and cost-effective (Hallett et al. PLoS Med 2011; Ying et al. JIAS 2015) Adapted from Baeten, WEAC0105, AIS2016 Slide 34 of 53 HIV incidence The observed incidence is a 95% reduction compared to expected, a result that was highly statistically significant N=83 infections incidence = 4.9 (95% CI ) 95% reduction (95% CI 87-98%) P< N=4 infections incidence = 0.2 (95% CI ) 0 EXPECTED OBSERVED Slide 35 of 53 Baeten, WEAC0105, AIS2016 Condom Effectiveness Heterosexuals Meta-analysis of 25 studies, >10,000 couples Overall effectiveness: 71-77% Giannou et al, Expert Rev Pharmacoecon Outcomes Res 2016 MSM Data from 2 large cohorts 70% effective Smith et al, JAIDS 2015;68: Slide 36 of 53 12

27 Safety Considerations INITIATION AND MONITORING Slide 37 of 53 PrEP Initiation Assess for risk Tests BEFORE initiating PrEP HIV negative (4 th generation, consider viral load) If any signs/symptoms of acute infection, test for viral load first Creatinine (do not start if CrCl <60) Hepatitis B status (if HbsAg positive, monitor when d/c ing PrEP) STI, pregnancy screening Counsel about start-up syndrome (GI most common), resolves w/i several weeks Additional monitoring HIV test every 3 months counsel not to stop/restart PrEP on their own STI, pregnancy screening every 3 months Creatinine at 3 months, every 6 months thereafter Slide 38 of 53 Modest renal effects in older persons across studies In iprex OLE and SF Kaiser (Marcus JAIDS 2016), risk of egfr<70 if: Baseline egfr<90 >40-50 years old In Partners PrEP and Partners Demo (Mugwanya, JAIDS 2016) Same as above or weight < 55kg >75% of creatinine increases unconfirmed on repeat test No difference in picking up true renal effects if q 3 vs 6 month testing In Thai IDU study (Martin, CID 2014) No effect of recent IDU on creatinine More likely to have renal effects with increased age All studies Creatinine reverts to near baseline after trial Slide 39 of 53 13

28 Bone Mineral Density: Recovery after Stopping PrEP Slide 40 of 53 Minimal bone loss Recovery after PrEP stopped Grant, 48LB, CROI 2016 Similar findings in year olds (ATN 110) Hightow-Weidman, THAC0105LB, AIDS 2016 Do STIs modulate the efficacy of PrEP? No evidence STIs lower PrEP efficacy in RCTs iprex: Syphilis incidence of 7.3/100 py; no interaction with PrEP efficacy (Solomon CID 2014) Partners PrEP: No difference in PrEP efficacy among those with STIs (Murnane AIDS 2013) No evidence from open label studies PROUD in UK: 73% with baseline STI & 86% effectiveness of PrEP (McCormack Lancet 2015) US MSM PrEP Demo study: 90/100 p-yr STI incidence & 0.43/100 p-yrs HIV incidence (Liu JAMA Int Med 2015) Slide 41 of 53 Adapted from Celum, THSY0805, AIDS 2016 PrEP Safety: Summary Renal issues rare in HIV negative population with CrCl >90 Frequent screening largely leads to unconfirmed issues Increased risk for older, smaller, and those with CrCl 60-90, may warrant closer screening BMD decreases relatively small, revert to baseline off PrEP Implications for youth not known STIs common in high-risk populations, increases pre-date PrEP Screening for asx ic infection critical Remind pts that PrEP doesn t protect against other STIs Resistance uncommon if uninfected at start Screen for non-specific viral symptoms at start Caution pts about re-starting meds without testing Slide 42 of 53 14

29 Population-level Impact IS PREP SCALE-UP REACHING THE RIGHT PEOPLE? Slide 43 of 53 Background CDC: Numbers of Persons at Risk for HIV Remain High, but Percentages Vary by Population Estimated percentages and numbers of adults with indications for PrEP, by transmission risk group, United States, 2015 Slide 47 of 53 % with PrEP indication* Estimated number Transmission risk group (95% Cl) Men who have sex with men, aged yrs ,000 (212, ,000) Adults who inject drugs, (45, ,000) aged >18yrs ,000 Heterosexually active adults, (404, ,000) aged yrs ,000 Men** ,000 (62, ,000) Women ,000 (274, ,000) Total 1,232,000 (661,000-1,803,000) Abbreviation: CI = confidence interval. *Percentage of all estimated persons in each transmission risk group and demographic subset with PrEP indications. Based on National Health and Nutrition Examination Survey (NHANES) data, weighted as recommended using current population estimates. Risk factors used to define PrEP indications included two or more male sex partners and at least one of the following: any condomless sex or sexually transmitted infection diagnosis in past 12 months. Based on 2013 National Survey on Drug Use and Health. Risk factors used to define PrEP indications included injection of heroin, methamphetamine, stimulants, or cocaine, and injecting with a needle used by someone else before them. Based on National Survey of Family Growth and NHANES data, weighted as recommended using current population estimates. Risk factors used to define PrEP indications included two or more opposite sex partners and at least one of the following: sex with an HIV positive partner; or any condomless sex in the last 4 weeks and sex with a male who injects drugs or bisexual male (females only) in last 12 months. **The relative standard error for males was 30.09%. Smith D, et al. MMWR Morb Mortal Wkly Rep 2015;64:1-6 Bush, S. et al. HIV Drug Therapy 2016; Glasgow, Scotland Unique Individuals Starting FTC/TDF for PrEP in US by Gender (1Q2013-1Q2016) Slide 48 of 53 Unique Individuals Quarters Between1Q2013 and 1Q2016 quarter-over-quarter utilization grew 870%; 172% for women and 1,450% for men. Bush, S. et al. HIV Drug Therapy 2016; Glasgow, Scotland 15

30 Slide 49 of 53 Age of Individuals (2013-1Q2016) Mean age (yrs) of 28,080 unique individuals: ,485 Female 24,594 Male 5.9% 87.3% 12.7% <25 years 94.1% (mean age: 38.9) (mean age: 41.2) Bush, S. et al. HIV Drug Therapy 2016; Glasgow, Scotland FTC/TDF for PrEP Utilization by Gender and Race Q2016 Slide 50 of 53 FEMALE 3.7% 14.6% 17.1% 64.6% Black White Hispanic Asian MALE 3.6% 9.1% 11.4% 75.9% White females were 3.8 and 4.4 times more likely to be started then their Black or Hispanic counterparts White males were 8.3 and 6.7 times more likely to be started than Black or Hispanic males Bush, S. et al. HIV Drug Therapy 2016; Glasgow, Scotland PrEP Awareness/Attitudes Among Primary Care Providers 1500 providers surveyed per year from 2009 to 2015 Increased PrEP awareness over time (from 25% to 67%) However, in 2015, only 7% had prescribed PrEP When PrEP efficacy described as >75%, more than 90% of providers indicated willing to prescribe Most likely to prescribe for patients in stable serodiscordant partnerships; least likely to prescribe for patients with STIs! Need to reach persons at risk with multiple partners Slide 48 of 53 Smith, et al, PLOS One

31 Pleaseprepme.org AIDS Foundation of Chicago ( blogspot.com/) Project Inform ( prep/) San Francisco AIDS Foundation ( The Fenway Institute ( org/prepinfo/) TDF/FTC The US Centers for Disease Control and Prevention ( tion/research/prep/) The AIDS Vaccine Advocacy Coalition ( Maximizing the Benefits of Preexposure Prophylaxis (PrEP) Susan P. Buchbinder, MD Director, Bridge HIV San Francisco Department of Public Health Clinical Professor of Medicine and Epidemiology University of California San Francisco San Francisco, California FORMATTED: Slide Chicago, 50 of Illinois: 54 May 10,

32 Management of Long-Term Complications of HIV Infection With a Focus on Cardiovascular Disease Steven K. Grinspoon, MD Professor of Medicine Harvard University Boston, Massachusetts FORMATTED: 04/14/2017 Financial Relationships With Commercial Entities Dr Grinspoon has served as a consultant to Gilead Sciences, Inc, Merck, Navidea, and Theratechnologies. He has received grants awarded to his institution from Gilead Sciences, Inc, Theratechnologies, Navidea, and Kowa (Updated 04/14/17) Slide 2 of 39 Learning Objectives After attending this presentation, learners will be able to: Describe the current epidemiology of cardiovascular disease (CVD) in HIV-infected persons Describe the unique pathophysiology of CVD in HIV-infected persons Describe the potential utility and limitations of strategies to prevent CVD in HIV-infected persons Slide 3 of 39 1

33 Most Epidemiological Studies Suggest that Rates of CVD in HIV are: 1. Equal to that seen in non HIV 2. 10% higher % higher % higher Slide 4 of 39 Slide 5 of 39 Current Status of CVD Prevention in HIV Even as rates of death and mortality related to HIV have decreased with use of more potent ART, CVD rates remain increased among HIV patients and are a leading cause of morbidity and mortality There is limited understanding of the mechanisms and treatment strategies for CVD in HIV No large scale primary CVD prevention strategy has been tested in HIV Slide 6 of 39 2

34 Slide 7 of 39 CVD Risk in HIV-Infected Patients is Beyond That Predicted by Traditional Risk Factors Effect Size of MI or CHD in HIV vs. non HIV In the VACS cohort, the HR of MI was 1.48 in HIV vs. non-hiv veterans after adjusting for FRS, comorbidities, and substance use (95% CI ). (Freiberg, 2013) Which of the Following is Not a Common Feature of Coronary Plaque in HIV Patients 1. Eccentric high risk fatty plaque lesions 2. Inflamed plaque 3. Heavily calcified plaque Slide 8 of 39 Slide 9 of 39 3

35 Increased Traditional Risk Factors Account for Only a Portion of CVD Risk in HIV A 12 Events Per 1000 PYs RR 1.75 P< Hypertension Diabetes Dyslipidemia 0 HIV Non-HIV HIV+ non-hiv+ DM, HTN, and dyslipidemia, though increased, accounted for 25% of excess risk Newer studies suggest importance of genetics, inflammation and immune dysfunction, as non traditional risk factors Slide 10 of 39 Triant JCEM 2007, Rotger Clin Infect Dis HIV: a State of Immune Activation and Suppression HIV Infection CD4+ T cells Persistent viral infection Microbial translocation Viral reactivation (CMV) and coinfection (HCV) Chronic activation of T cells and monocytes Endothelial cell activation Slide 11 of 39 Acute MI Adapted from Hsue JID 2012 Immune Activation Relates to Novel Atherosclerotic Phenotype in HIV In the general population, MI does not typically result from gradual expansion of subclinical coronary plaque, but rather from rupture of vulnerable high risk plaque in 75% of cases Recent studies in HIV+ patients without known CVD, demonstrate that atherosclerotic plaques are indeed: Inflamed Non-calcified, high risk morphology features (vulnerable) Associated with immune activation markers Slide 12 of 39 4

36 Increased Arterial Inflammation in HIV Aortic TBR by PET Slide 13 of HIV p = p = FRS -Matched Controls CVD Controls Control HIV Subramanian JAMA 2012 Arterial Inflammation Linked to Immune Activation in HIV Slide 14 of 39 Aortic (TBR) ρ=0.53; P-value< Natural Log of scd163 (ng/ml) Inflamed High Risk Plaque Identified by FDG Composed of Activated Macrophages Slide 15 of 39 Rudd Circulation

37 Representative Axial Cross sections of the Aortic Arch on 99m Tc tilmanocept SPECT/CT of HIV infected subjects and Non HIV infected subjects 7 HIV infected subjects Relativ e Muscle Activity 2 7 Non HIV infected subjects Relativ e Muscle Activity 2 Zanni*, Toribio* et al. Journal of Infectious Diseases, 2017 Slide 17 of 39 Increased Rates of Atherosclerosis in HIV by Coronary CT Angiography Control HIV P value Presence of plaque 34% 59% 0.02 Mean plaque volume (µl) Agatson Score 0 (0, 9.9) 0 (0,17.9) 0.29 Segments with plaque Non-calcified segments 0.46± ±1.57 <0.05 Calcified segments 0.29± ± Any stenosis > 70% 0% 6.5% 0.06 Young HIV-infected men and matched controls Baseline FRS, FH CHD, and smoking rates similar Similar data observed from the MACS cohort Lo AIDS 2010; Post Annals 2014 Increased High Risk Morphology Plaque in HIV Patients Slide 18 of 39 LOW ATTENUATION PLAQUE (LAP) RC A POSITIVELY REMODELED (PR) PLAQUE RC A Mean minimal attenuation < 40 Hounsefield Units Plaque segment / reference segment > 1.05 % of subjects with high risk morphology plaque Naghavi Circ 2003, Schoenhanger Circ 2000 &JACC 2001; Zanni AIDS

38 A New Paradigm for Atherogenesis in HIV Persistent Viral Replication Microbial Translocation T-cell activation Monocyte Activation RCA Slide 19 of 39 High Risk Plaque Inflammation Slide 20 of 39 Current Challenges in Preventing and Treating CHD in HIV Understanding the optimal timing and use of ART to maximize effects on immune function and minimize metabolic effects Identifying patients with disease: current risk identification strategies are not adequate Developing a safe and effective strategy for primary prevention, especially for those not identified by current algorithms, but with substantial subclinical disease Developing an intervention that addresses both traditional and immune-related risk factors Slide 21 of 39 Potential Interventions For CVD in HIV Traditional Risk Modification Strategies - ASA - Statins - Antihypertensive - Antidiabetic Immune/Inflammatory Modulators -ART -Statins -CCR5 Antagonists - IL Antagonists - Methotrexate 7

39 Representative coronal images of HIV infected subject demonstrating decreased lymph node inflammation and increased aortic inflammation after cart Zanni and Toribio, et al. JAMA Cardiology, 2016 SMART and START- Effects on CVD SMART- Randomized trial of continuous vs. intermittent ART guided by CD4 count (begun when <250 and stopped when >350). Stringent viral suppression reduced AIDS and CVD events. START- Randomized trial of immediate vs. delayed ART in naïve HIV patients with CD4 > 500 (vs. initiation at CD4 < vs. 350). Earlier initiation reduced AIDS events but not CVD events. Slide 23 of 39 SMART NEJM 2006; START NEJM 2015 START- Non AIDS Endpoints Reduced but No Effect on CVD with Deferred Initiation Slide 24 of 39 START NEJM

40 ASA Use in HIV - Underutilization and Unknown Effects Slide 25 of 39 Suchindran OFID 2014 Statin Effects on CVD in non HIV Population In a meta-analysis of 26 studies with 170,000 patients, statins were shown to reduce events by 22% per 39 mg/dl lowering in LDL Slide 26 of 39 CTT Lancet ACC/AHA Statin Guidelines Unclear how these guidelines pertain to HIV Patients, relatively young with reasonable LDL levels Need for a discussion between patients and providers Need for more data Slide 27 of 39 Stone Circulation

41 Many HIV Patients with High-Risk Plaque would not Receive Recommendation for Statins by 2013 Guidelines: CHD risk underestimated by traditional risk scores Slide 28 of 39 Zanni AIDS 2014 ACC 2013 Guidelines May Under or Over Predict CVD Events in HIV Slide 29 of 39 Feinstein JAMA Cardiology 2017 Statins Have the Unique Potential to Work in HIV Because: 1. They reduce triglycerides 2. They improve glucose simultaneously with lipids 3. They lower LDL 4. They lower LDL and may have antiinflammatory effects Slide 30 of 39 10

42 Slide 31 of 39 Statins Reduce Vascular Events in Non HIV Patients with Low LDL and Increased CRP Events/100p y: Placebo: 1.36 Rosuva: 0.77 HR 0.56 LDL was reduced 47 mg/dl, and should have resulted in an HR of 0.73 based on LDL lowering alone, according to CTTC meta-analysis. Instead JUPITER showed an HR of 0.56, greater than expected based on LDL lowering alone Slide 32 of 39 Ridker N Engl J Med 2008; CTTC Lancet 2010 Statins Address Both Traditional and Immune Risk Factors in HIV LDL Lowering: Statins lower LDL by similar amounts in patients with and without HIV: (HIV-infected: -26.2%; HIV-uninfected: -26.9%) Dampening of Immune Activation: Decrease monocyte activation reflected in decreased circulating levels of scd14 and the macrophage-derived phospholipase Lp-PLA2 Slide 33 of 39 Silverberg Ann Int Med 2009, McComsey CROI 2013, Funderburg JAIDS epub 11

43 Statins are Generally Safe and Well-Tolerated in HIV Absolute rates of grade 3 or 4 adverse effects on liver and muscle low (Silverberg Ann Int Med 2009) Slide 34 of 39 Despite immune suppressant effects, no adverse effects on viral replication (Moncunill AIDS 2005, Negredo AIDS 2006) Newer Statins May Not Increase Glucose and Not Interact with PI s Drug PI Interaction Effects on Glucose LDL Lowering and Dose Pravastatin (40 mg/d) mg/dl, -25% Atorvastatin (20 to 40 mg/d) + +/- -38 mg/dl, -29% Rosuvastatin (10 mg/d) mg/dl -28% Pitavastatin (4 mg/d)* mg/dl, -28% Pitavastatin metabolized primarily by glucoronidation. Minimally metabolized by CYP3A. No known interactions with antiretroviral therapy no dose limitations. Included in 2013 ACC/AHA guidelines as a recommended moderate dose statin. *Among dyslipidemic patients with high starting cholesterol levels. Slide 35 of 39 Sponseller CROI 2014, Aberg Endo 2013, Eckard JID 2014, Stone JACC 2013 Percent Change in Noncalcified Plaque Statin Effects on Coronary Artery Plaque in HIV p =.009 p = p <.0001 p < p =.005 p =.005 Placebo Atorvastatin Absolute Change in Direct LDL (mg/dl) Change in Lp-PLA 2 (ng/ml) Placebo Atorvastatin Placebo Atorvastatin Slide 36 of 39 Decreasing non-calcified plaque in proximal left anterior descending (LAD) coronary artery in patient on atorvastatin for 12 months. Lo CROI 2015, Lancet HIV

44 Need for a Large RCT to Inform Clinical Practice HIV patients with low traditional risk scores are at increased risk for CVD with subclinical plaque and inflammation It is unknown if statins will prevent CVD and should be recommended for the HIV population Though largely well tolerated in small studies, there are no data from large RCT s in HIV investigating efficacy and tolerability How will statins uniquely work in HIV? LDL lowering Effects on inflammatory pathways Slide 37 of 39 Slide 38 of Sites Across US, Thailand and Canada Opened April Kowa Biopharmaceuticals Gilead Sciences, Inc. REPRIEVE Schema Asymptomatic HIV patients with no history of CVD and ASCVD < 15% N=6500, avg. 4-5 yrs 3 visits/year Placebo R Lifestyle Advice Pitavastatin Screening and Consent Randomization Intervention N=800, 2 yrs Mechanistic Study Coronary plaque, vascular Inflammation, immune activation Mechanistic Primary Endpoint CVD Death MI Unstable Angina TIA & Stroke Arterial Revasc PAD Clinical Primary Endpoint Slide 39 of 39 13

45 Mechanistic Substudy Objectives: To determine: Effects on high risk coronary plaque Effects on immune function in relationship to plaque Green + Red: Noncalcified Plaque Volume: 115 mm 3 Red: Low Attenuation Plaque Volume: 28 mm 3 Slide 40 of 39 Conclusions and Future Directions Traditional and non traditional risk factors contribute to increased CVD in HIV, manifesting as inflamed, noncalcified high risk plaque in association with immune activation CVD events in HIV patients may be difficult to characterize by traditional prediction algorithms Modulation of traditional and nontraditional risks is necessary to prevent CVD in HIV Statins may be effective to prevent CVD in HIV and should be tested in large trials to determine optimal practice patterns Slide 41 of 39 Management of Long-Term Complications of HIV Infection With a Focus on Cardiovascular Disease Steven K. Grinspoon, MD Professor of Medicine Harvard University Boston, Massachusetts FORMATTED: 04/14/

46 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 AU Final: 03/03/17 Financial Relationships With Commercial Entities Dr Saag has received research grants and support awarded to his institution from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck, and ViiV Healthcare. He has also served as a consultant for Bristol-Myers Squibb, Gilead Sciences, Inc, Merck, Teva Pharmaceutical Industries, Ltd, and ViiV Healthcare. (Updated 05/10/17) Slide 2 of 61 Learning Objectives After attending this presentation, learners will be able to: Select antiretroviral treatment in patients who are: Starting initial therapy Suppressed virologically Partners of seropositive persons Have coronary artery disease Slide 3 of 61 1

47 Question Seems like we are now starting ARV therapy for about everyone, what about starting therapy for an Elite Controller? Slide 4 of 61 Slide 5 of 61 Case 1 30 yo Male was diagnosed with HIV infection 4 years ago Asymptomatic Initial: HIV RNA < 50 c/ml (HIV DNA positive) CD4 count 870 cells/ul Other labs are normal; HLA-B57 neg Genotype determined from DNA is wild-type No prior medical history. Ok to start therapy if you think he should Would you choose to start therapy at this time? 1. Yes 2. No 3. Maybe Slide 6 of 61 2

48 Elite controllers have higher levels of CD8 activation than other aviremic groups, including those on HAART and HIV negatives % CD38+ HLA-DR+ CD8+ T cells P< P= HIV negative (n=84) HAART VL < 50 (n=139) Elite controllers (n=67) Noncontrollers (n=160) Activation higher in elites that other aviremic groups even after adjustment of CD4, age and other factors Slide 8 of 61 Hunt JID 2008 (see also Lopez Abstract 366) Elite controllers also have higher levels of atherosclerosis than HIV negatives, after controlling for all known risk factors Mean Intima-medial thickening (cm) P < HIV negative E lite controllers Noncontrollers HAART VL < 50 Slide 9 of 61 Hsue et al, AIDS 09 3

49 Question What regimen should I use as initial therapy? Slide 10 of 61 Case 2 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 neg Genotype is Wild-type virus No prior medical history. Normal renal function Ok to start therapy if you think he should Slide 11 of 61 At this point which regimen would you choose? 1. TDF / FTC / EFV (fdc) 2. ABC/ 3TC / DTG (fdc) 3. TAF / FTC/ ELV / c (fdc) 4. TAF / FTC / RPV (fdc) 5. TAF/ 3TC(fdc) / DTG (fdc) 6. TAF/ FTC (fdc) / DRV/r (or cobi / fdc) 7. TAF/ FTC / ATV/r (or cobi / fdc) 8. TAF / FTC / RAL (once daily) 9. DTG / 3TC 10. Some other option Slide 12 of 61 4

50 Case 3 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 neg Genotype is Wild-type virus No prior medical history. Normal renal function Ok to start therapy if you think he should Slide 14 of 61 Slide 15 of 61 At this point which regimen would you choose? 1. TDF / FTC / EFV (fdc) 2. ABC/ 3TC / DTG (fdc) 3. TAF / FTC/ ELV / c (fdc) 4. TAF / FTC / RPV (fdc) 5. TAF/ 3TC(fdc) / DTG (fdc) 6. TAF/ FTC (fdc) / DRV/r (or cobi / fdc) 7. TAF/ FTC / ATV/r (or cobi / fdc) 8. TAF / FTC / RAL (once daily) 9. Some other option 5

51 IAS-USA Guidelines, July 2016 What to Start Recommended regimens INSTI-based Alternative regimens NNRTI-based RAL + FTC/TAF (or TDF) EVG/COBI/FTC/TAF (or TDF) DTG + FTC/TAF (or TDF) DTG/3TC/ABC EVG/COBI/FTC/TAF (or TDF) EFV/FTC/TDF RPV/FTC/TAF or TDF (VL <100,000; CD4 >200) PI-based ATV/c + FTC/TDF (CrCl >70) ATV/r + FTC/TDF DRV/r + FTC/TDF (DRV/c or DRV/r) + 3TC/ABC DRV/c + FTC/TDF (CrCl >70) Slide 17 of 61 DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, January 2016 The 6 initial regimens we ll probably be using most INSTI-based PI-based NNRTI-based EVG/COBI/FTC/TAF DTG + FTC/TAF DTG/3TC/ABC RAL + FTC/ TAF (once daily) DRV/c + FTC/TAF RPV/FTC/TAF Slide 18 of 61 6

52 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 19 of 61 Question What regimen should be used as initial therapy when an M184V mutation is present? Slide 20 of 61 Slide 21 of 61 Case 4 30 yo Female 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 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 7

53 At this point which regimen would you choose? 1. TDF / FTC / EFV (fdc) 2. ABC/ 3TC / DTG (fdc) 3. TAF / FTC/ ELV / c (fdc) 4. TAF / FTC / RPV (fdc) 5. TAF/ 3TC(fdc) / DTG (fdc) 6. TAF/ FTC (fdc) / DRV/r (or cobi / fdc) 7. TAF/ FTC / ATV/r (or cobi / fdc) 8. TAF / FTC / RAL (once daily) 9. DTG / 3TC 10. Some other option Slide 22 of 61 Question Should I switch from EFV / FTC / TDF (fdc) in a patient who has been on it for the last 10 years? Slide 24 of 61 8

54 Case 5 45 yo Female referred to you for evaluation Diagnosed 10 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 Only regimen. Reports no symptoms currently. Generally feels well Slide 25 of 61 At this point you would: 1. Continue her current Antiretroviral Rx 2. Change her ARV Rx to 2 nucs and RPV 3. Change her ARV Rx to 2 nucs and a boosted PI 4. Change her ARV Rx to 2 nucs and an InSTI (integrase inhibitor) 5. Something else Slide 26 of 61 9

55 Question Should I give PrEP to a sero-negative partner of a successfully treated HIV patient? Slide 28 of 61 Case 6 45 yo Male makes an appointment to request PrEP His partner is HIV positive and has been on successful ARV Rx for 17 years (consistently <50 c/ml) Generally feels well No significant PMHx No medications Denies any partners outside of his relationship with his partner Slide 29 of 61 At this point you would: 1. Prescribe PrEP 2. Not prescribe PrEP 3. Not sure what to do Slide 30 of 61 10

56 Question Can I use TAF in patients with impaired renal function? Slide 32 of 61 Case 7 46 yo male newly diagnosed 4 years ago HIV RNA 128,000 c/ml (HLA-B5701 negative) CD4 count 280 cells/ul On DRV-r / TDF / FTC; HIV RNA < 20 c/ml (CD4 550/ul) Initial HIV resistance assay: Wild-type virus Smoker / H/o DM / Neg Fam Hx for CAD Slow increase in S-creatinine: Now 2.3 mg/dl (ecrcl = 35 cc/min) HBsAb+ HBcAb- HBsAg- Slide 33 of 61 11

57 Which regimen would you start? 1. TDF every other day, FTC, DRV/rit 2. TAF / FTC / DRV/rit 3. ABC / 3TC / DRV/rit 4. TAF / FTC / ELV / cobi 5. ABC / 3TC / DTG 6. TAF / FTC / DTG 7. DRV/ rit / DTG 8. Some other option Slide 34 of 61 TAF vs. TDF: Mechanism of Action GI TRACT PLASMA RENAL TUBULAR CELL TDF (tenofovir disoproxil fumarate) 300 mg TFV TFV LYMPHOCYTE HIV TAF (tenofovir alafenamide) 25 mg 91% lower plasma TFV RENAL TUBULAR CELL Slide 36 of 50 Slide 36 of Lee W et al. Antimicr Agents Chemo 2005;49: ; 2. Birkus G, et al. Antimicr Agents Chemo 2007;51:543-50; 3. Babusis D, et al. Mol Pharm 2013;10:459-66; 4. Ruane P, et al. JAIDS 2013;63:449-5; 5. Sax P, et al. JAIDS 2014;67:52-8; 6. Sax P, et al. Lancet 2015;385:

58 Change in egfr (Cockcroft-Gault) with TAF vs TDF Studies 104 and 111: Week 48 Combined Analysis 20 E/C/F/TAF Mean Mean (SD) change (SD) Change from baseline from Baseline egfr* egfr Cockroft-Gault (ml/min) E/C/F/TDF p < Time (Weeks) Time (Weeks) *Cockcroft-Gault (ml/min). Slide 37 of 61 GS 1089: Switch from F/TDF to F/TAF Changes in egfr 8.4 ml/min 2.8 ml/min p <0.001 * egfr calculated with Cockcroft-Gault equation Slide 38 of 50 Gallant J, et al. CROI 2016 Question Should I stop abacavir in a patient with CAD? Slide 39 of 61 13

59 Case 8 59 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 Now: HIV RNA < 20 c/ml (persistently) CD4 560 cells/ul Cholesterol 220 mg/dl (HDL 32 / LDL 172) Creat 1.3 / ecrcl = 80 cc/min Smoker / Diabetic Had a heart attack 4 months ago; medical Rx (ASA, statin, beta blocker) Slide 40 of 61 Besides asking him to quit smoking, what would you do? 1. Continue his current ARV Rx 2. Change his ABC/3TC to TAF / FTC 3. Change his ABC/3TC to DRV/rit 4. Some other option Slide 41 of 61 14

60 Universal Definition of MI Plaque rupture with thrombus Type 1 / Primary Vasospasm Supply demand mismatch Type 2 / Secondary Slide 43 of 61 Adapted from Thygesen K, et al. J Am Coll Cardiol MI Classification Protocol Universal Definition of MI: Primary MI (Type 1 traditional MI atherosclerosis) Causes of Secondary MI in HIV-infected Individuals* N (%) Sepsis/bacteremia 100 (35%) Plaque rupture with thrombus Secondary MI (Type 2 supply-demand mismatch) Cocaine induced/illicit drug 39 (14%) Hypertensive urgency/emergency 28 (10%) Respiratory failure 26 (9%) Vasospasm Secondary MIs common in HIV-infected individuals before age 50 Non-coronary cardiac 23 (8%) Hypotension 15 (5%) Procedure related 12 (4%) GI bleed 11 (4%) Neurologic 6 (2%) Overdose 5 (2%) Slide 44 of 61 *Crane et al. Am J Epidemiol Apr Other/unknown 23 (8%) Question Should I change a regimen when low level detectable virus is present? Slide 45 of 61 15

61 Slide 46 of 61 Case 9 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 Should you change ARV therapy now? 1. Yes 2. No 3. Not sure Slide 47 of 61 16

62 Question What regimen should I use as initial therapy in a pregnant patient? Slide 49 of 61 Case 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 50 of 61 Slide 51 of 61 At this point which regimen would you choose? 1. TDF / FTC / EFV (fdc) 2. ABC/ 3TC / DTG (fdc) 3. TAF / FTC/ ELV / c (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 17

63 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 Slide 53 of 61 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 54 of 61 18

64 Conclusion Debate about whether to treat Elite Controllers Presence of M184V does not effect initial Rx much (except for use of ABC at higher viral load) Primary and Secondary MIs are distributed equally in HIV patients Hold off on using TAF or DTG in pregnant women, pending more data Do not need to change ARV therapy if persistent low level viremia Slide 55 of 61 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 AU Final: 03/03/17 Question How can I simplify a complex regimen in a highly treatmentexperienced patient? Slide 57 of 61 19

65 Case year old man diagnosed with HIV in 1991; multiple opportunistic infections and complains of Pill Fatigue Has taken most existing antiretroviral drugs available; no exposure to maraviroc, DTG, or ELV Currently on TDF / FTC / ETV / DRV-r / RAL (1 st InSTI) CD4+ count 330 / ul (nadir CD4 = 6) HIV RNA <40 c/ml (max VL 667,000) Slide 58 of 61 Slide 59 of 61 At this point which regimen would you choose? 1. Continue current therapy (9 pills) OR switch to: 1. TAF / FTC/ ELV / c (fdc) /DRV/c (2 pills) 2. ABC/ 3TC / DTG (fdc) / DRV/c (2 pills) 3. TAF / FTC / RAL / DRV/c (4 pills) 4. TAF / FTC / DTG / DRV/c (3 pills) 5. Some other regimen Slide 60 of 61 20

66 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 AU Final: 03/03/17 21

67 Investigational Approaches to Antiretroviral Therapy Eric S. Daar, MD Professor of Medicine University of California Los Angeles Los Angeles, California FORMATTED: 04/26/17 Financial Relationships With Commercial Entities Dr Daar has received research and grant support from Gilead Sciences, Inc, Merck, and ViiV Healthcare. He has also received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Inc, Janssen Therapeutics, Merck, Teva, and ViiV Healthcare. (Updated 05/10/17) Slide 2 of 37 Learning Objectives After attending this presentation, learners will be able to: Summarize treatments being investigated for HIVinfected persons with viremia Describe treatments being investigated for those with virologic suppression on antiretroviral therapy Slide 3 of 37 1

68 Investigational Treatment Strategies Slide 4 of 37 PADDLE (Pilot Antiretroviral Design with Dolutegravir LamivudinE) Cahn P, et al 21 st International AIDS Conference 2016, Durban, South Africa, Abstract FRAB0104LB Slide 5 of 37 Slide 6 of 37 2

69 SWORD Studies: DTG + RPV Maintenance Slide 11 of 37 Llibre J et al. 24th CROI 2017, Abst 44LB Slide 12 of 37 Slide 13 of 37 3

70 Confirmed virologic withdrawal 2 per arm One DTG + RPV had K101K/E No INSTI resistance Slide 14 of 37 Investigational Drugs/Formulations Slide 15 of 37 Once-Daily Raltegravir Baseline Characteristics Median HIV RNA 4.6 log/ml (28% >100,000 c/ml) Median CD4 380/416 cells/ul Cahn P, et al 21 st International AIDS Conference 2016, Durban, South Africa, Abstract FRAB0103LB. Slide 16 of 37 4

71 Slide 17 of 37 AE Slide 18 of 37 Bictegravir vs. Dolutegravir for First-Line Therapy Baseline Characteristics Median HIV RNA= log10/ml (15-21% >100,000 c/ml) Median CD4= 441/455 cells/ul Sax PE, et al. 24 th Conference on Retroviruses and Opportunistic Infections 2017; Seattle, WA. Abstract 41. Sax PE, et al. Lancet HIV. 2017; 4:e Slide 19 of 37 5

72 Slide 20 of 37 Slide 21 of 37 Doravirine vs. Darunavir/ritonavir for First-Line Therapy Baseline Characteristics Median HIV RNA 4.4 log 10 c/ml (19-22% >100,000 c/ml) Median CD cells/ul 87-88% TDF/FTC Molin J-M, et al. 24 th CROI 2017, Abst 45LB Slide 22 of 37 6

73 Slide 23 of 37 Slide 24 of 37 Virologic Failure and Resistance Non PDVF patients D/C with noncompliance at week 24: V106I, H221Y, F227C and M184V with high level DOR resistance Rash at week 2 with 2.8- fold increase (from 2.2 fold at baseline) Slide 25 of 37 7

74 Slide 26 of 37 LATTE 2 Margolis D, et al. 21 st International AIDS Conference 2016, Durban, South Africa, Abstract THAB0206LB Slide 27 of 37 Slide 28 of 37 8

75 Slide 29 of 37 Slide 30 of 37 PDVF Q8wk (2); Q4wk (0); Daily (1) Only resistance in single Q8wk patient: NNRTI- K103N, E138G and K238T; INSTI- Q148R (5.8 FC to CAB) Slide 31 of 37 9

76 Slide 32 of 37 Thank you for your Attention Questions? Slide 37 of 37 Investigational Approaches to Antiretroviral Therapy Eric S. Daar, MD Professor of Medicine University of California Los Angeles Los Angeles, California FORMATTED: 04/26/17 10

77 Update on Neurologic Complications in Persons With HIV Infection: 2017 Dennis Kolson, MD, PhD Professor of Neurology University of Pennsylvania Philadelphia, Pennsylvania FORMATTED: MM/DD/YY Financial Relationships With Commercial Entities Dr Kolson has no relevant financial affiliations to disclose. (Updated 05/04/17) Slide 2 of 34 Learning Objectives After attending this presentation, learners will be able to: Recognize and list the early neurologic manifestations of acute HIV infection Describe the chronic neurologic manifestations and potential management options for neurologic complications of HIV infection in individuals on suppressive antiretroviral therapy To describe the rationale for adjunctive neuroprotective strategies for cognitive impairment in individuals on suppressive antiretroviral therapy Slide 3 of 34 Page 1 1

78 Neurological complications of chronic HIV infection are less severe with use of antiretroviral therapy/art Pre-ART era neuropathy Post-ART era HIV encephalitis neuropathy HAND HAND Slide 4 of 34 HIV-associated neurocognitive disorders (HAND) ~ 40% severe HAND: HIV encephalitis & dementia ~20% HAND prevalence remains ~ 40% BUT less severe HAND: encephalitis & dementia now ~2% neuropathy prevalence ~ 30% neuropathy prevalence < 30% with newer ARTs HIV-encephalitis (HIVE) HIV-associated neurocognitive disorders (HAND) HIV infiltrates the CNS early (days-week) after systemic HIV Infection potential CNS reservoir Slide 5 of 34 ACTIVATED MACROPHAGE/ MICROGLIA NMDA Receptor Excitotoxins Glutamate QUIN, ROS,Ntox, PAF, TNF-, & gp120, Tat NEURON Neuronal Injury (loss of synapses and dendrites proinflammatory cytokines/chemokines viral replication Glutamate CD4+ T lymphocyte Regulation MACROPHAGE ASTROCYTE Blood Brain Barrier HIV CD4+ T lymphocyte? HIV HIV Endothelial Lumen MONOCYTE Adapted from Gill & Kolson, Crit. Rev. Immunol. (2013). Slide 6 of 34 CNS compartmentalization in as early as 4 months & throughout course Independent HIV replication in infiltrating lymphocyte population (pleocytosis) Entering virus is exclusively R5, T lymphocyte-tropic Little initial independent HIV replication in endogenous CNS cell population (macrophages), which begins to emerge during the first two years of infection, suggesting establishment of a macrophage reservoir) Compartmentalization occurs in state of pleocytosis & higher viral loads Presumably from replication in a CNS pool established by infiltrating T lymphocytes Two ways to increase CSF viral load (early infection) Influx of infected T lymphocytes carrying virus into the CNS Replication in the CNS pool established by infiltrating T lymphocytes (compartmentalization) Sturdevant, PLOS Path. (2015) Page 2 2

79 Slide 7 of 34 What are the neurological complications of acute HIV infection? meningitis Acute Inflammatory Demyelinating Neuropathy (AIDP) Early neurological complications of HIV infection prior to initiation of antiretroviral therapy/art meningitis Acute IDP IRIS Chronic IDP HAND (less severe) DSPN PML Slide 7 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Early HIV infection (days 10-20) is associated with symptoms of meningitis in ~25% of individuals* *Typically HIV antibody ELISA negative at this time Meningitis (~25%) Slide 8 of 34 McMichael AJ, Nat. Rev. Immunol. (2010) Page 3 3

80 Slide 10 of 34 Early neurologic complications of HIV-1 infection: Acute Inflammatory Demyelinating Polyneuropathy (AIDP) meningitis Acute IDP IRIS Chronic IDP HAND (less severe) DSPN PML HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Early neurologic complications of HIV-1 infection: Acute inflammatory Demyelinating Polyneuropathy (AIDP) CSF: < 50 cells/ul elevated protein indistinguishable from GBS Symptoms & Natural history signs Treatment AIDP: (rare) weakness plasmapheresis most often at seroconversion (20-30d) progresses rapidly over days to < 4 weeks mild sensory sx. pain respiratory autonomic ankle reflexes absent IVIG corticosteroids Slide 11 of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Slide 13 of 34 Chronic neurological complications of HIV infection: Chronic Inflammatory Demyelinating Neuropathy (CIDP) Distal Symmetric Polyneuropathy (DSPN) HIV-associated neurocognitive disorders (HAND) Page 4 4

81 Later neurological complications of HIV infection after initiation of antiretroviral therapy/art meningitis Acute IDP IRIS Chronic IDP HAND (less severe) DSPN PML Slide 13 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Later neurological complications of HIV infection: Chronic inflammatory demyelinating polyneuropathy (CIDP) CSF: < 50 cells/ul elevated protein indistinguishable from idiopathic CIDP Peripheral nerve onion-bulb in CIDP Symptoms & Natural history signs Treatment CIDP: >1 year- later weakness plasmapheresis stages of HIV infection up to 30%of CIDP patients are HIV+* progresses over > 8 weeks relapses and remissions * mild sensory sx. pain respiratory autonomic ankle reflexes absent IVIG Slide 14 of 34 response rates probably similar to HIV-negative patients Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Later neurological complications of HIV infection: Distal symmetric polyneuropathy (DSPN) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML IRIS Slide 15 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Page 5 5

82 Later neurological complications of HIV infection: Distal symmetric polyneuropathy (DSPN) Slide 16 of 34 Natural history prevalence ~ 30% occurs with or without ART use ART associated (d-drugs): d4t (Stavudine) ddi (didanosine) ddc (zalcitabine) Stocking/glove distribution of pain in DSPN Symptoms & signs Symmetric, distal, sensory (axonal +/- demyelinating) Pain predominates burning hyperalgesia tightness numbness preserved proprioception Treatment Capsaicin (8% top.) proved effective gabapentin lamotrigine (weak evidence) modify ART regimen Simpson, Neurol. (2008), Robinson-Papp, Muscle & Nerve. (2009) Kaku M, Curr Opin HIV AIDS. (2014) Question #1 A 40 year old diabetic man presents to the ED with ascending weakness and mild numbness of the lower extremities (one week), and now he cannot walk. Two weeks prior he presented with a severe headache and neck stiffness; CSF showed a mild lymphocytosis. He had mentioned recent high-risk behavior, but was seronegative then. He is now seropositive for HIV infection. Among the following, which is most likely? 1. Diabetic Neuropathy 2. Distal Symmetric Polyneuropathy (DSPN) 3. Acute Inflammatory Demyelinating Polyneuropathy (AIDP) 4. Spinal cord infarction Slide 18 of 34 Slide 19 of 34 Page 6 6

83 Question #1 A 40 year old diabetic man presents to the ED with ascending weakness and mild numbness of the lower extremities (one week), and now he cannot walk. Two weeks prior he presented with a severe headache and neck stiffness; CSF showed a mild lymphocytosis. He had mentioned recent high-risk behavior, but was seronegative then. He is now seropositive for HIV infection. Among the following, which is most likely? 1. Diabetic Neuropathy 2. Distal Symmetric Polyneuropathy (DSPN) 3. Acute Inflammatory Demyelinating Polyneuropathy (AIDP) 4. Spinal cord infarction Slide 20 of 34 Later neurological complications of HIV infection: Immune Reconstitution Inflammatory Syndrome (IRIS) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML IRIS Slide 17 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Slide 18 of 34 Later neurological complications of HIV infection: Immune Reconstitution Inflammatory Syndrome (IRIS) Initiation of cart (1-6 months): CNS syndrome (mild or severe) resulting from heightened immunologic and/or inflammatory response against opportunistic pathogens (or other antigens associated with HIV suppression by cart) robust inflammatory CNS infiltration (MRI detection) CNS IRIS in ~1-30% of pts. initiating cart rapid decline of viral load - greatest risk with CD4 <50 and VL >100K most commonly associated with crypto meningitis, TB, PML Johnson, Ann NY Acad Sci (2010) Johnson, Curr Opin HIV AIDS (2014) Page 7 7

84 Admission: stroke HIV-associated CNS IRIS 24 days post-art: IRIS 31 days post-art: IRIS Slide of yo HIV+ man, off ART x 3 years, then re-start: 3 weeks right hemiparesis, slurred speech CD4 T cells 24 99/mm 3 CSF: 56 cells/ul 64 mg/dl prot. Zafiri et al. New Microbiologica. (2013) HIV-associated CNS IRIS in PML patient Slide of 34 Before ART 52 yo HIV+ man, ART naïve x 16 years, admitted for sub-acute cognitive decline cart started: CD4 T cells /mm 3 1 mo. post-art JC virus confirmed at autopsy Vendrely A, Acta Neuropathol. (2005) Later neurological complications of HIV infection: Immune Reconstitution Inflammatory Syndrome (IRIS) Management: Supportive Care CSF drainage (Crypto), Abscess drainage (needle aspiration) Treatment for any underlying opportunistic infection Anti-inflammatory treatment NSAIDs Corticosteroids: severe cases 2-3wks, then taper Investigational/Anecdotal treatments None yet proven Pausing HAART reserved for severe, life-threatening symptoms risks of immunodeficiency & resistance Slide 21 of 34 Page 8 8

85 Later neurological complications of HIV infection: Progressive Multifocal Leukoencephalopathy (PML) meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML IRIS Slide 22 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Slide 23 of 34 Later neurological complications of HIV infection: Progressive Multifocal Leukoencephalopathy (PML) Natural history Symptoms & signs Treatment papovavirus (JC virus) hemiparesis up to 60% None effective activation in the brain memory loss ~30-60%?inhibit JC virus white matter (myelin) damage, early in occipital areas slurred speech ~20-40%?reconstitute immune system ~4% of all untreated patients seizures ~15-30% ~1% in ART-treated patients visual sxs., ~25% blind spots Death within ~1 year in 90% sensory ~20% disturbances Later neurological complications of HIV infection: Progressive Multifocal Leukoencephalopathy (PML) Slide 24 of 34 Note lesions restricted to white matter Page 9 9

86 Later neurological complications of HIV infection: Progressive Multifocal Leukoencephalopathy (PML) typical PML: no enhancement atypical PML: patchy enhancement in HIV+, 30 y.o. man atypical PML: ring enhancement HIV+, 25 y.o. man Slide 25 of 34 Later neurological complications of HIV infection: HIV-associated neurocognitive disorders (HAND) meningitis Chronic IDP HAND Acute IDP DSPN PML IRIS Slide 26 of 34 HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) HIV associated neurocognitive disorders (HAND) have similar prevalence but decreased severity post-art Slide 27 of 34 HAND sub-groups ANI: Asymptomatic neurocognitive impairment MND: Mild neurocognitive disorder HAD: HIV-associated dementia functional impairment in certain ADLs affects ~20% of virally suppressed patients Saylor, Nature Reviews Neurology (2016) Page 10 10

87 Later neurological complications of HIV infection: HIV-associated neurocognitive disorders (HAND) 1/3 have MRI evidence of white matter abnormality, with or without brain atrophy Slide 28 of year old man, HIV+ for ~20 years, CD4 nadir 50+ cells/ul began ART after severe immunosuppresion; white matter lesions + brain atrophy HIV-associated neurocognitive disorders (HAND) How to reduce residual HAND impairment in ART- treated individuals? Using ART regimens with higher CNS penetration? multiple (conflicting) reports suggest no benefit ART drugs may directly induce oxidative stress and neuronal damage Slide 29 of 34 Intensification of ART regimens with additional classes of antivirals? * recent studies of Maraviroc (CCR5 blocker) suggest possible benefit additional studies underway Adjunctive therapies in addition to ART? focus on controlling neuroinflammation & oxidative stress * Gates, AIDS (2016) Heme oxygenase-1 protein reduction in the prefrontal cortex correlates with clinical dysfunction (HAND) HAND Diagnosis NCN Neurocognitively Normal HAND HIV-associated neurocognitive disorders HIVE HIV-encephalitis Gill et al. J Clin Invest (2014) Page 11 11

88 Slide 30 of 34 Neurological complications of HIV can persist in ART-treated individuals and require adjunctive therapies to limit morbidity meningitis Chronic IDP HAND (less severe) Acute IDP DSPN PML IRIS HAND Neuropathy (less severe) HIV-associated neurocognitive disorders (HAND) Distal Symmetric Polyneuropathy (DSPN) Question #2 A 34 year old woman came to the ED with a 3-4 day history of confusion & disorientation, which were worsening. She stated that she was diagnosed with HIV infection more than 3 years ago, when she was diagnosed with a brain infection (she was unclear what type). She started, then discontinued ART and re-started it only ~2 months ago. Her physical examination confirmed altered mental status. Her MRI showed a gadolinium-enhancing lesion of the parietal lobe, no meningeal enhancement. Cryptococcal antigen was negative. 1. HIV-associated neurocognitive disorders (HAND) 2. Immune Reconstitution Inflammatory Syndrome (IRIS) 3. HIV meningitis Slide 36 of 34 Slide 37 of 34 Page 12 12

89 Question #2 A 34 year old woman came to the ED with a 3-4 day history of confusion & disorientation, which were worsening. She stated that she was diagnosed with HIV infection more than 3 years ago, when she was diagnosed with a brain infection (she was unclear what type). She started, then discontinued ART and re-started it only ~2 months ago. Her physical examination confirmed altered mental status. Her MRI showed a gadolinium-enhancing lesion of the parietal lobe, no meningeal enhancement. Cryptococcal antigen was negative. 1. HIV-associated neurocognitive disorders (HAND) 2. Immune Reconstitution Inflammatory Syndrome (IRIS) 3. HIV meningitis Slide 38 of 34 Slide 39 of 34 Thank you! Acknowledgements Slide 32 of 34 Kolson Lab: Univ. of Pennsylvania Alexander Gill, MD, PhD student Colleen Kovacsics, PhD student Yoelvis Garcia-Mesa, PhD Rolando Garza, BS Patricia Vance, BS University of Texas Medical Branch Ben Gelman, MD, PhD University of North Carolina, Chapel Hill Kevin Robertson, PhD Penn Center for AIDS Research Ron Collman, MD (Director) Page 13 13

90 Update on Neurologic Complications in Persons With HIV Infection: 2017 Dennis Kolson, MD, PhD Professor of Neurology University of Pennsylvania Philadelphia, Pennsylvania FORMATTED: MM/DD/YY Page 14 14

91 Hepatitis C Virus Infection Management: Curing Is Caring Arthur Y. Kim, MD Associate Professor of Medicine Harvard Medical School Boston, Massachusetts FORMATTED: 04/07/17 Slide 2 of 53 Financial Relationships With Commercial Entities Dr Kim has no relevant financial affiliations to disclose. (Updated 04/07/17) In this presentation I will discuss the off-label use of investigational direct-acting agents Acute HCV infection treatment Glecaprevir/pibrentasvir Slide 2 of 53 Learning Objectives After attending this presentation, learners will be able to: Describe modifiable risks for liver disease progression in HIV/HCV-coinfected individuals Optimize choice of antiviral regimens Describe rationale for enhanced screening, prevention, and treatment for HCV infection Slide 3 of 53 1

92 Audience response Slide 4 of 52 Slide 4 of 53 How long have you been involved in the treatment of HCV? 1. I have not treated HCV and we defer to hepatology 2. I have not treated HCV but others in my practice do 3. I have just started treating HCV within the last 2 years 4. I have been treating HCV for 2-5 years 5. I have been treating HCV for 5-15 years 6. I have been treating HCV for >15 years Slide 5 of 53 Slide 5 of 53 Estimates of prevalence in the United States Slide 6 of 53 NHANES - household based survey - ~ 3.2 million % unaware of infection Not included or underestimated in NHANES estimate: Homeless (142, ,610) Incarcerated (372, ,826) Veterans (1,237,461-2,452,006) Active military (6805) Healthcare workers (64, ,234) 2.7 to 5.0 million living with chronic HCV in the United States Number of Cases, millions Baby boomers Estimated HCV Cases account for >65% of cases 7.1 Conservative estimate Upper limit estimate Total Not Included in NHANES NHANES 0. CDC data. Ann Intern Med 2006 Denniston M, et al. Ann Intern Med. 2014;160: Chak E, et al. Liver Int. 2011;31: Zalesak M, et al. PLoS One. 2013;8:e63959; Edlin B, et al. Hepatology

93 HCV deaths exceed those from 60 infectious conditions (death certificate data) Slide 7 of 53 (including HIV, pneumococcus) Ly et al. CID 2016 MMWR: Age distribution of newly reported confirmed cases of hepatitis C virus infection --- Massachusetts, 2002 and 2009 Slide 8 of 53 * N = 6,281; excludes 35 cases with missing age or sex information. N = 3,904; excludes 346 cases with missing age or sex information. Source: Onofrey et al MMWR: May 6, 2011 / 60(17); HIV outbreak among PWID in the U.S. Overlaid upon a network of HCV transmission 135 cases as of report Investigation triggered by HIV surveillance Injection of oxymorphone Multigenerational use of injection drugs 84.4% (114/135) diagnosed with HCV infection Slide 9 of 53 Need for HCV prevention and vaccine! 3

94 A perfect storm for sexual HCV transmission: HIV+MSM Slide 9 of 52 Slide 10 of 53 Bloody practices Semen exposure Other STDs Sex Drugs Crystal methamphetamine Sildenafil Internet HIV Higher levels of virus in plasma and semen Immune deficiency, especially at GI mucosa Take home points: screening Slide Slide 109 of of 52 Slide 11 of 53 HCV is a common chronic infection and a candidate for screening Mostly asymptomatic Major cause of liver disease and leading cause of mortality in US Screening is effective, life-saving for those with advanced liver disease, also costeffective Whom to screen? Baby boomers born between 1945 / 1965 Those with past and ongoing risk factors (see prior list) Injection drug use (people who inject drugs) HIV+ men who have sex with men Screen highest risk patients yearly to identify early and prevent onward transmission HCV RNA for those already HCV Ab positive Slide 12 of 53 Goal of Treatment The goal of treatment of HCV-infected persons is to reduce all-cause mortality and liver-related health adverse consequences, including end-stage liver disease and hepatocellular carcinoma, by the achievement of virologic cure as evidenced by a sustained virologic response. Recommendations for When and in Whom to Initiate Treatment Treatment is recommended for all patients with chronic HCV infection, except those with short life expectancies that cannot be remediated by treating HCV, by transplantation, or by other directed therapy. Patients with short life expectancies owing to liver disease should be managed in consultation with an expert. Adapted from 4

95 Components of HCV care Slide 13 of 53 Coffee tied to lower mortality in French HIV/HCV coinfected patients Slide Slide 139 of of Slide 14 of 53 French ANRS HEPAVIH cohort n=1035 followed for median 5 years deaths (N=77) HCV-related causes 42.8% non-aids, non-hcc cancer 11.7% AIDS 10.4% ahr for death: Unstable housing 3.7 CD4 =< HCV cured 0.2 female gender or fewer EtOH drinks or more coffee 0.5 Carrieri et al. CROI 2016 Abstract #549 Take home points: evaluation Slide 15 of 53 Care for HCV is not all about treatment Preventing transmission (and harm reduction) critical to avoid re-infection Preventing liver progression Avoid alcohol Avoid weight gain (fatty liver) Coffee probably beneficial Avoid HIV Anticipating toxicities, managing drug/drug interactions Prognosis Noninvasive liver staging is now available ID doctors (and PCPs) will be critical in addressing the provider shortage 5

96 Identifying and Managing Interactions Slide 16 of 53 Kiser JJ, Burton JR, Jr, Everson GT. Nature Reviews Gastroenterol Hepatol 2013;10: Slide 17 of 53 HBV reactivation Slide 18 of 53 HBV flares (abrupt increase in ALT) preceded by HBV DNA increase institution or withdrawal of immunosuppression HBV core IgM may be positive Steroids, transplant, chemotherapy / biologics (esp. anti-cd20 Ab) Rare cases with HCV antiviral therapy (8-12 weeks into treatment) Reported with core-ab only but rate is likely extremely low Monitoring versus prophylaxis Treat HBSAg positive patients who meet AASLD criteria Prophylaxis or closely monitor those who do not meet AASLD criteria Monitor cab only, LFTs 8 and 12 weeks Lok et al. AASLD Guidelines 2009; Hammond et al. Biol Blood Marrow Transplant 2009; Wright et al. Am J Transplant 2014; Sulkowski et al. CID 2016; Wang et al. Clin Gastro Hep

97 Potential Therapeutic Targets in the HCV Replication Cycle Slide 20 of 53 Transport and release Fusion and uncoating HCV RNA Viral assembly Translation RNA replication NS5B polymerase inhibitors NS5A inhibitors Polyprotein processing NS2 NS4B NS3/4A protease inhibitors CypA NS5B NS3 NS5A NS4B NS2 NS3 NS5A NS5B HCV NS proteins NS5A inhibitors Adapted from slide courtesy Ray Chung Worldwide genotype distribution Slide 21 of 53 Possible combinations of HCV treatments then are applied to different viral genotypes Slide 22 of 53 PEG IFN GT3 10% GT4 4% RBV GT2 9% BOC TLV SMV LDV VOX VEL PRV/r OBV DCV GZR EBR GCV PBV GT1 77% DSV SOF SOF Abbreviations: GT = genotype; PEG IFN = pegylated interferon; RBV = ribavirin PIs: BOC = boceprevir, TLV = telaprevir, SMV = simeprevir; VOX = voxilaprevir; PRV = paritaprevir; GZR = grazoprevir; GCV = glecaprevir. Pharmacologic booster: r = ritonavir; NS5A: LDV = ledipasvir; VEL = velpatasvir; OBV = ombitasvir; DCV = daclatasvir; EBR = elbasvir; PBV = pibrentasvir; NS5B nonnucleoside: DSV = dasabuvir; NS5B nucleotide: SOF = sofosbuvir 7

98 Predictors of relapse to sofosbuvir-based regimens Slide 23 of 53 RBV SOF 12 week FISSION POSITRON FUSION VALENCE n=285 RBV SOF 24 week VALENCE n=247 PEG RBV SOF 12 week ATOMIC NEUTRINO n=339 Who will do poorly with currently-available SOFbased regimens? SVR12= undetectable HCV RNA at 12 weeks after cessation of therapy Six factors associated with relapse: Treatment-experienced IL28B non-cc Male sex Weight > 75 kg Cirrhosis High viral load >800,000 IU/mL Foster et al. EASL 2014 Abstract 66 Antiviral HCV treatments (FDA-approved as of June 28, 2016) Slide 24 of 53 Monotherapies IFN-2a IFN-2b PEG-IFN 2a Combination Therapies Daclatasvir (DCV) + Sofosbuvir (SOF) IFN-2a + Ribavirin (GT1,3)* IFN-2b + Ribavirin Elbasvir (EBR) / Grazoprevir (GZR) PEG-IFN 2a + Ribavirin* PEG-IFN 2b + Ribavirin (FDC GT1,4)* PEG-IFN 2b PEG-IFN + ribavirin plus either: Boceprevir (GT1) Telaprevir (GT1) Simeprevir (GT1) In combination with other agents: Sofosbuvir Ledipasvir (LDV) / Sofosbuvir (SOF) (FDC, GT1,4,5,6)* Paritaprevir / ritonavir / ombitasvir (FDC) + dasabuvir PrOD (GT1) Paritaprevir / ritonavir / ombitasvir (FDC) PrO (GT4) Simeprevir (SMV) + Sofosbuvir (SOF) *approved for HIV/HCV coinfection (GT1) approved for GT1 - decompensated and post-liver transplant Sofosbuvir (SOF) / Velpatasvir (VEL) approved for decompensated (FDC, All GTs) Antiviral HCV treatments (FDA-approved as of June 28, 2016) Slide 25 of 53 LDV SOF Combination Therapies Daclatasvir (DCV) + Sofosbuvir (SOF) (GT1,3)* Elbasvir (EBR) / Grazoprevir (GZR) (FDC GT1,4)* Ledipasvir (LDV) / Sofosbuvir (SOF) (FDC, GT1,4,5,6)* Paritaprevir / ritonavir / ombitasvir (FDC) + dasabuvir PrOD (GT1) Paritaprevir / ritonavir / ombitasvir (FDC) PrO (GT4) EBR GZR RBV PTV/r OBV DSV VEL SOF Simeprevir (SMV) + Sofosbuvir (SOF) (GT1) Sofosbuvir (SOF) / Velpatasvir (VEL) (FDC, All GTs) 8

99 >90% cure rates for Genotype 1 Slide 26 of 53 RBV PTV/r SVR ~95% of genotype 1 patients can be cured with current regimens 455/473 OBV DSV 286/ / /214 LDV SOF SOF 102/ /215 SAPPHIRE-I SAPPHIRE-II TURQUOISE-II ION-1 ION-2 ION-3 LDV ION-1 and 2: RBV arms not shown but did not enhance SVR, therefore RBV not necessary for many receiving LDV/SOF Cirrhotics (TURQUOISE) 24 weeks 95.9% SVR Tx-Exp (ION-2) 24 wks LDV/SOF 108/109 SVR no cirrhosis naive no cirrhosis null responder 55% 100% cirrhosis 16% cirrhosis naive 20% cirrhosis Tx-Exp no cirrhosis naive SAPPHIRE 1 Feld et al. NEJM 2014, SAPPHIRE 2 Zeuzem et al. NEJM 2014, ION 1 Afdhal et al. NEJM 4/12/2014, ION 2 Afdhal et al. NEJM 2014; 370(16):1483, ION 3 Kowdley et al. NEJM 4/12/2014. SAPPHIRE/TURQUOISE are 12 week arms only. ION studies are RBV sparing arms only Major considerations for ledipasvir/sofosbuvir Slide 27 of 53 Few data for patients with egfr<30 Cirrhosis: No dose adjustment or RBV for treatment-naive patients Drug interactions: Avoid coadministration with amiodarone - life-threatening bradycardia Avoid with oxcarbazepine, carbamazepine, rifampin, St. John s wort Antacids lower absorption of ledipasvir Avoid PPIs if possible Maximum dose omeprazole 20 mg If on omeprazole, take LDV/SOF with something acidic Shortening ledipasvir/sofosbuvir to 8 weeks Slide 28 of 53 ION-3 trial established 94% cure rate with eight weeks of therapy with ledipasvir/sofosbuvir for patients naive to therapy; non-cirrhotic Most relapses occurred in those with HCV RNA > 6,000,000 IU/mL Real-world (non-rct) data confirm efficacy of 8 weeks 94-98%,? selecting favorable patients Generally African-Americans under-represented Subanalysis showed ~91% SVR rate in African Americans using 8 weeks Caution regarding those with HIV, black patients, or certain characteristics Few data in HIV/HCV coinfection, especially African- American455/ / / / / /215 Care with F3 patients as they may be harboring F4 From adherence and cost standpoint, 8 weeks is attractive ION 3 Kowdley et al. NEJM 2014; Wilder et al. compared to 12 weeks Hepatology 2016; Ingiliz et al. ClD 2016; Lai et al. Drugs 2017; Kowdley et al. Hepatology 2017; 9

100 Extension of therapy beyond 12 weeks of PrOD necessary for cirrhotic patients with GT1a Slide 29 of weeks 24 weeks TURQUOISE II 100% cirrhosis RBV PTV/r OBV DSV RBV PTV/r OBV DSV SVR /64 14/15 13/13 52/56 11/11 10/10 40/50 39/42 Partial Null Naive Relapse RBV not necessary for 1b FDA Warning issued regarding rare cases of decompensation in CTP-A cirrhosis Poordad et al. TURQUOISE II, NEJM PrOD for 8 weeks for 1b patients with easier characteristics: GARNET Slide 30 of 53 PRV/r OBV DSV 8 weeks SVR / / /162 ITT mitt-gt mitt-gt-nvf ITT = intention to treat mitt-gt (3 excluded for not having 1b) mitt-gt-nvf (denominator excludes non 1b and 1 premature discontinuation Welzel et al.easl Special Conference 2016 Major considerations for PrOD Slide 31 of 53 For treatment-naive patients, RBV generally unnecessary for GT1b 12 weeks for most patients 8 weeks for treatment naive, GT1b without cirrhosis Cirrhosis: Naive patients still may receive 12 weeks Safety concern with cirrhosis raised in post-marketing phase Avoid with decompensated cirrhosis Drug interactions: Multiple ritonavir-related drug interactions 10

101 Slide 32 of 53 C-EDGE: elbasvir/grazoprevir is a RBV and nucleoside/nucleotide sparing 12- week regimen for GT 1/4 HCV EBR GZR 12-wks Treatment naive Mean age 52 46% women 37% nonwhite 22% cirrhosis % SVR12 50 Serious AE n=12, none drug-related / / /131 18/18 8/10 All Patients GT 1a GT 1b GT 4 GT6 9 relapsers, 1 breakthrough in 1a Similar SVR for n=218 HIV co-infected individuals on DTG/RAL/RPV Zeuzem et al. Ann Intern Med 2015; Rockstroh et al. Lancet HIV 2015 Cirrhosis does not impact SVR rates for 12 weeks of EBR/GZR Slide 33 of 53 GZR EBR No cirrhosis Cirrhosis AEs are similar between cirrhotic and non cirrhotic patients in these trials % SVR /246 68/70 34/35 32/34 175/183 35/35 C-EDGE C-SALVAGE HIV C-EDGE Zeuzem et al. Ann Intern Med 2015; Rockstroh et al. Lancet HIV 2015; Buti et al. CID 2016; Jacobson et al. AASLD 2015 EBR/GZR - Resistance Associated Variants (RAVs) at NS5A positions 28, 30, 31, 93 associated with lower SVR Slide 34 of 53 EBR GZR } 28,30,31 } 93 Baseline testing for NS5A resistance recommended if using this regimen Jacobson et al AASLD 2015, San Francisco 11

102 EBR/GZR - extension of therapy to 16 weeks and addition of RBV overcame resistance Slide 35 of 53 GZR EBR RBV Jacobson et al AASLD 2015, San Francisco Major considerations for elbasvir/grazoprevir Slide 36 of 53 For treatment-naive patients, genotypes 1 and 4 12 weeks for most patients Extend 16 weeks and add RBV for GT1a harboring NS5A resistance-associated substitutions NS5A mutations: M28A/G/T Q30D/E/H/G/K/L/R L31F/M/V Y93C/H/N/S Cirrhosis: Avoid with decompensated cirrhosis Drug interactions: Transporter issues with oxcarbazepine, carbamazepine, rifampin Excellent safety and efficacy in stage 4/5 chronic kidney disease Response rates for pangenotypic regimen: Genotypes 1-6 Slide 37 of weeks for GT1,2,4,5,6 19% compensated cirrhosis 32% nonresponders VEL SOF weeks for GT3 No cirrhosis Cirrhosis SVR / / /116 34/35 41/41 GT1 GT2 GT4 GT5 GT6 8 week arms of phase II trial: lower SVRs at 100 mg VEL dos (81-88%) 0 160/163 Best available option for genotype 2/3 40/43 GT3 Naive 40/43 31/34 33/37 GT3 Tx Exp Feld et al. NEJM 2015; Foster et al. NEJM 2015; Everson et al. Ann Intern Med

103 Glecaprevir and pibrentasvir (G/P): novel pangenotypic regimen Slide 38 of 53 Glecaprevir (GCV) is a pangenotypic next-generation HCV protease inhibitor Pibrentasvir (PBV) is a pangentoypic next-generation NS5A inhibitor GCV PBV ENDURANCE-1 examined 8 versus 12 weeks in GT1 non-cirrhotic patients with or without HIV Zeuzem et al. AASLD 2016 Glecaprevir and pibrentasvir (G/P): novel pangenotypic regimen Slide 39 of 53 ENDURANCE-1 examined 8 versus 12 weeks in GT1 non-cirrhotic patients with or without HIV Zeuzem et al. AASLD 2016 A menu of options Slide 40 of 53 Due to regulations, no alcohol will be served Primo Protease boceprevir 44 telaprevir 12 grazoprevir 12 / 16 paritaprevir +ritonavir 12 / 24 simeprevir 12 / 24 NS5A inhibitors daclatasvir 12 / 24 elbasvir 12 / 16 ledipasvir 8 / 12 / 24 ombitasvir 12 / 24 Polymerase inhibitors dasabuvir 12 / 24 sofosbuvir 8 / 12 / 24 Notice: The consumption of raw or undercooked eggs, meat, poultry, seafood or shellfish, and certain combinations are not approved by the FDA for Hepatitis C Please ask your server whether Ribavirin 40 is suggested 13

104 Prix fixe menus? Slide 41 of 53 Due to regulations, no alcohol will be served Notice regarding protease inhibitors boceprevir and telaprevir will no longer be offered due to high calories, dysgeusia and/or allergic reactions Grilled Goose 8 weeks of GS-9857, pan-seared topped with velpatasvir flakes on a sofosbuvir backbone Abalone Veloute 12 weeks of paritaprevir, slow-boosted, infused with ombitasvir, served with twice-dosed dasabuvir chutney Mesclun Medley (nuc-free option) 12 weeks of sous-vide grazoprevir topped with fresh elbasvir salsa Notice: The consumption of raw or undercooked eggs, meat, poultry, seafood or shellfish, and some of these choices are not approved by the FDA for Hepatitis C Please ask your server whether Ribavirin 41 is suggested Slide 42 of 53 The continuum of care in HCV infection in the U.S. At least 3 million persons infected Slide 45 of 53 50% 38% Improving cascade necessary to reduce transmission, morbidity and mortality 23% 11% 6% 1% Adapted from Holmberg et al. NEJM

105 Incidence, prevalence and sustaining an epidemic Slide 46 of 53 Rising opiate use Lack of prevention services Asymptomatic infection Unknown serostatus Barriers to care, access restrictions and cost of treatment Can PWID be cured with novel HCV regimens? Slide 47 of 53 Dore et al. Ann Intern Med 2016 Treatment of recently active PWID with elbasvir/grazoprevir; on opiate agonist therapy, made 80% appointments 4 8 Dore et al. Annals of Internal Medicine

106 Dutch lifted restrictions on treatment in Nov 2015 Achieving 70% cure in HIV/HCV patients Slide 49 of 53 Women, former IDU less likely to be treated Boerekamps et al. CROI 2017 Abstract 136 What were the effects of de-restricting access to DAAs in the Netherlands? Slide 50 of 53 Late 2015: unrestricted access with very rapid uptake in Dutch HIV/HCV coinfection - ~70% treated No associated decrease in syphilis or LGV so behavior is an unlikely explanation indirect evidence of cure as prevention for HCV Rijnders et al. CROI Abstract 137LB Take home points regarding treatment Slide 51 of 53 Novel interferon-free and ribavirin-free paradigms Potent combinations can overcome biologic / host barriers to response 12 week regimens available for many patients Shortened courses for certain regimens if favorable traits present Pangenotypic 8-week regimen coming Special populations are being addressed: Treating high-risk populations may be a component of reducing incident infections Improving cascade of care and removing restrictions to access will be critical to maximize the impact of treatment 16