The Microbiome in HIV: The Good, Bad, and Ugly of Bugs in Health

Transcription

1 The Microbiome in HIV: The Good, Bad, and Ugly of Bugs in Health Nichole R. Klatt, PhD Associate Professor University of Washington Seattle, Washington Learning Objectives After attending this presentation, learners will be able to describe: How the microbiome contributes to HIV transmission How the microbiome contributes to HIV disease What the microbiome is Slide 3 of 45 ARS Question 1 HIV-altered microbiota can increase neutrophil accumulation in the gut by what mechanism: 1. Attaching to blood neutrophils 2. Decreasing apoptosis and increasing survival 3. Binding to viruses 4. Developing a biofilm Slide 4 of 45

2 ARS Question 2 What feature of the vaginal microbiome is associated with health and decreased HIV transmission? 1. Increased diversity 2. High inflammation 3. Decreased diversity 4. Excess mucus Slide 5 of 45 Individuals must remain on ART indefinitely Increased Non-AIDS Morbidity and Mortality Life Expectancy is Reduced Despite ART HIV Reservoir (Anatomic sanctuaries, Persistent integrated provirus) Persistent Immune Activation Mucosal Dysfunction Slide 6 of 45 Inflammation (particularly associated with mucosal dysfunction) is a key predictor of morbidities and mortality Slide 7 of 45 What are the mechanisms of mucosal dysfunction in HIV Infection?

3 Overlapping mechanisms underlying increased HIV transmission risk AND increased HIV pathogenesis TRANSMISSION 1. Barrier Damage 2. Inflammation 3. Altered Microbiome PATHOGENESIS 1. Barrier Damage 2. Inflammation 3. Altered Microbiome Slide 8 of 45 Microbiome Microbiome: Microorganisms in an environment ( trillion/person) Includes bacteria, viruses, fungi, protists, archaea Includes genes, metabolites and products Dysbiosis: An imbalanced microbial community Abundance and/or functional changes Smits LP et al., Gastroenterology Slide 9 of 45 Microbial dysbiosis is associated with many diseases Oral microbiome dysbiosis: Gingivitis Periodontal Diseases HIV Pathogenesis Lung microbiome dysbiosis: Lung Cancer Asthma COPD Cystic Fibrosis Pneumonia Skin microbiome dysbiosis: Skin Cancer Altered immunity Allergies Psoriasis Dermatitis Acne Dysplasia Vaginal microbiome dysbiosis: Vaginosis STIs Yeast Infection Preterm Birth HIV Transmission Gut microbiome dysbiosis: Colorectal Cancer Diabetes Obesity Autoimmunity Inflammatory Bowel Diseases C. difficile infection Neurological Disorders Metabolic Disorders HIV Pathogenesis Slide 10 of 45

4 Dysbiosis in HIV infection Bad/Increased in HIV: Prevotella Proteobacteria Good/Decreased in HIV: Firmicutes Bacteroides Slide 11 of 45 Slide 12 of 45 Increased colorectal neutrophil frequencies in HIV+ individuals Slide 13 of 45

5 Reduced neutrophil apoptosis in treated HIV infection Homeostatic neutrophil apoptosis Neutrophil accumulation Slide 14 of 45 Associations between colonic mucosal bacteria and neutrophil survival in vivo Caspase-3 Low,CD16 High Neutrophils vs. Prevotella (genus) Caspase-3 Low,CD16 High Neutrophils vs. Lactobacillus (genus) %Caspase-3 Low, CD16 High of Total Neutrophils Prevotella (relative abundance) %Caspase-3 Low, CD16 High of Total Neutrophils Lactobacillus (genus) Slide 15 of 45 p= Pearson R 2 = p= Pearson R 2 = Conclusions I: Neutrophils and Dysbiotic Bacteria in HIV Pathogenesis Neutrophils are increased in the GI of treated HIV infection Associated with decreased neutrophil apoptosis HIV-altered mucosal bacteria differentially affect neutrophil apoptosis Decreased Lactobacillus spp. and increased Prevotella spp may prolong neutrophil lifespan in the GI in treated HIV infection. Future directions: Further understanding how neutrophils contribute to HIV pathogenesis and barrier damage may elucidate potential targets for therapeutic interventions Slide 16 of 45

6 Overlapping mechanisms underlying increased HIV transmission risk AND increased HIV pathogenesis TRANSMISSION 1. Barrier Damage 2. Inflammation 3. Altered Microbiome PATHOGENESIS 1. Barrier Damage 2. Inflammation 3. Altered Microbiome Slide 17 of 45 Every minute, two women are infected with HIV What are the biological mechanisms leading to HIV acquisition in women? Slide 18 of 45 Women tend to get infected at a younger age Sub-Saharan Africa has 2x women ages than men with HIV infection Pregnancy / mother-tochild transmission Sexual violence, lack of condom/sexual protection negotiation rights Slide 19 of 45 (Burgener, McGowan, Klatt; Curr Opinion Immunol 2015)

7 Vaginal microbiome can be broken into distinct community type (CT) structures Grosmann; Kwon et al., Immunity 2017 Slide 20 of 45 Bacterial Vaginosis (BV) is typically clinical diagnosis of microbiome dysbiosis Most common cause of vaginitis Inflammation, discharge, discomfort Loss of Lactobacillus spp. and increased diversity of vaginal microbiome Clinically diagnosed by Nugent score (0-10) and/or Amsel s criteria Wet mount, clue cells, morphology Typical antibiotic treatment is not effective, with frequent recurrence ph < 4.7 Nugent = 0 ph > 4.7 Nugent 7-10 Amsel s + Slide 21 of 45 Clinical Bacterial Vaginosis testing by Nugent score does not accurately predict vaginal dysbiosis Slide 22 of 45 (CVLs from Miami WIHS Cohort)

8 Tenofovir Placebo Tenofovir Tenofovir Placebo Placebo Vaginal dysbiosis and BV increase HIV infection risk Grosmann; Kwon et al., Immunity 2017 Slide 23 of 45 Effectiveness of pre-exposure prophylaxis (PrEP) is highly variable in women Study TDF2 daily Tenovofir-Emtricitabine (Women & Men - Botswana)# Effect size (CI) 75%* (24; 94) Partners PrEP daily oral Tenofovir (Discordant couples Kenya, Uganda) 71%* (37; 87) Oral PrEP Partners PrEP daily Tenovofir-Emtricitabine (Discordant couples Kenya, Uganda) 66%* (28; 84) FEMPrEP daily Tenovofir-Emtricitabine (Women Kenya, South Africa, Tanzania) 6% (-52; 41) MTN003/VOICE daily Tenovofir-Emtricitabine (Women South Africa, Uganda, Zimbabwe) -4% (-49; 27) MTN003/VOICE daily Tenofovir (Women - South Africa, Uganda, Zimbabwe) -49% (-129; 3) Topical PrEP CAPRISA 004 coital Tenofovir gel (Women South Africa) 39% (6; 60) MTN003/VOICE daily Tenofovir gel (Women South Africa, Uganda, Zimbabwe) 15% (-21; 40) FACTS 001 coital Tenofovir gel (Women South Africa) 0% (-40, 30) #(Study population and countries where the study was conducted) *Effect size calculated from the incidence rate ratio for women only Effectiveness (%) Varying outcomes from PrEP trials - attributed to adherence What biological factors affect PrEP? Slide 24 of 45 Vaginal microbial groups in CAPRISA 004 alter efficacy G. vaginalis dominant Lactobacillus dominant Probability of HIV infection 0.40 A. Lactobacillus dominant Efficacy, 61% 95% CI, 11 to 84% P=0.013 Probability of HIV infection Ef HR = 0.39 (95% CI: 0.20; 0.83) Years in Study Lactobacillus dominant women at risk (Cumulative number of infections) A. Lactobacillus dominant Tenofovir 0.40 B. Non-Lactobacillus dominant 205 (0) 204 (1) 183 (3) 129 (7) 46 (9) 0 (9) Placebo (0) 196 (4) 173 (12) 123 (19) 51 (22) 0 (22) Non-Lactobacillus domin Tenofovir 140 (0) Placebo 141 (0) Probability of HIV infection <50% 0.10 Lactobacillus 0.05 Efficacy, 61% 95% CI, 11 to 84% >50% Lactobacillus P=0.013 Probability of HIV infection 0.30 Efficacy, 18% 95% CI, -77 to 63% P=0.644 Slide 25 of 45 HR = 0.39 (95% CI: 0.20; 0.83) HR = 0.82 (95% CI: 0.40; 1.65) Years in Study Klatt et al., Science 2017 Years in Study Lactobacillus dominant women at risk (Cumulative number of infections) Non-Lactobacillus dominant women at risk (Cumulative number of infections)

9 Assessing biodegradation of PrEP drugs from primary cervicovaginal lavage (CVL) samples CVL (WIHS) (29) BV - (15) BV + Tenofovir (TFV) Drug Metabolism Microbiome communities Slide 26 of 45 Dysbiotic bacteria metabolize Tenofovir (TFV) Intracellular TFV-DP (TFV) - Lactobacillus 1.5 TFV-DP (ug/ml) **** 0.0 >50% <50% Slide 27 of 45 Dysbiotic bacteria metabolize Dapivirine (DPV) Bacteria Relative Abundance α-diversity Shannon Index BV Status by Nugent Score Positive Negative DPV (ug/ml) Intracellular DPV - Lactobacillus >50% **** <50% Dapivirine Degradation Rate

10 Bacteria do not metabolize Tenofovir Alafenamide (TAF) Intracellular TFV-DP (TAF) - Lactobacillus 1.5 TFV-DP (ug/ml) >50% <50% ARV drug metabolism Inflammation Barrier damage Slide 30 of 45 (Burgener, McGowan, Klatt; Curr Opinion Immunol 2015) Conclusions Dysbiosis of vaginal bacteria is a key factor in vaginal inflammation, epithelial barrier integrity and HIV acquisition Dysbiotic bacteria can metabolize Tenofovir Potentially contributes to decreased PrEP efficacy Understanding the vaginal microbiome and how to increase Lactobacillus communities and prevent BV/dysbiosis recurrence will be essential in improving efficacy Slide 31 of 45

11 Potential therapeutics Better assessments of and interventions for vaginal dysbiosis are critically needed Current standard of care is antibiotics (Metronidazole/Flagyl, Clindamycin) Limited efficacy, frequent recurrences Probiotics/Prebiotics/Live Biotherapeutics Lactin V Microbiome material transplant Phage Therapy Gene targeting/editing Slide 32 of 45 ARS Question 1 HIV-altered microbiota may increase neutrophil accumulation in the gut by what mechanism: 1. Attaching to blood neutrophils 2. Decreasing apoptosis and increasing survival 3. Binding to viruses 4. Developing a biofilm Slide 33 of 45 ARS Question 2 What feature of the vaginal microbiome is associated with health and decreased HIV transmission? 1. Increased diversity 2. High inflammation 3. Decreased diversity 4. Excess mucus Slide 34 of 45

12 UW/WaNPRC/Pharmaceutics CAPRISA University of Miami Dept. of Pediatrics Salim Abdool Karim Klatt Lab Quarraisha Abdool Karim Ryan Cheu Lyle McKinnon Andrew Gustin Anneke Grobler Jennifer Manuzak Tiffany Hensley-McBain UW Harborview Hospital Alex Zevin Ann Collier Charlene Miller Michalina Montano Connor Driscoll Lindsay Legg Oliver Appelbe UCSF SCOPE Debbie Bratt Peter Hunt Ernesto Coronado Ma Somsouk De Neka Gary Montha Pao Courtney Broedlow Monika Deswal Jake Modesitt Rebecca Hoh Alex Roederer Acknowledgements University of Miami Maria Alcaide University of Manitoba/ National Microbiology Laboratory Adam Burgener Kenzie Birse Laura Romas Michelle Perner Slide 35 of 45 Slide 44 of 45 Northwestern University Tom Hope Mike McRaven NIH/NIAID 1K22AI NIH/NIAID 1R01AI NIH/NIDDK RO1DK NIH/NIDA 1DP13A UW CFAR CIHR Mucosal Team Grant (Burgener)

13 Update From the 2018 Conference on Retroviruses and Opportunistic Infections (CROI) Raphael J. Landovitz, MD, MSc Associate Professor of Medicine University of California Los Angeles Los Angeles, California Learning Objectives After attending this presentation, learners will be able to: Describe new advances in prevention of HIV transmission Describe new data on the optimal management of antiretroviral therapy Identify complications and comorbidities of HIV infection Slide 3 of 36 NA-ACCORD Study: Life Expectancy in U.S. and Canada Among Specific Groups 55,858 ART initiators 248,931 person-years of follow-up 3123 deaths between 2005 and 2015 Estimated life expectancy (LE) in 3 time periods: , , LE in both men and women LE in black MSM but was consistently lower than non-black MSM in all time periods Black woman had similar LE to white women in , but a greater LE in Hispanic adults had LE than non-hispanic adults in all time periods (also seen in U.S. population) People who inject drugs and those with HCV had <2 year change in LE Slide 4 of 36 Conclusion: Disparities persist despite treat all and HCV rx Althoff CROI 2018 #903

14 Slide 5 of 36 ANTIRETROVIRAL THERAPY: Treatment Slide 6 of 36 Relationship of Hair ART levels to virologic outcomes Lower ART hair levels, black race, lower education all independently associated with virologic failure Slide 7 of 36 Gandhi, Abstract 24

15 Slide 8 of 36 Tenofovir diphosphate levels in dried blood spots Castillo-Mancilla, Abstract 25 Tri-specific monoclonal antibodies for HIV prevention and tx Slide 9 of 36 Pegu, Abstract 113LB ANTIRETROVIRAL THERAPY: Strategies Slide 10 of 36

16 Slide 11 of 36 ANDES: DRV/r + 3TC Phase 4, randomized, open-label study; interim results Study population: rx-naïve, VL >1000, no drug resistance to study meds, HBsAg negative (Phase 1: N=145) Study treatment: DRV/r (generic, fixed-dose) + [3TC or TDF/3TC] Results (24 weeks): VL <50: 69% (2-drug) vs. 81% (3-drug) [ = -12%, -24, +0.5] Sued IAS 2017 #MOAB0106LB Primary endpoint: VL <50 at 48 weeks Results (48 weeks): Conclusion: 2 drugs non-inferior at week 48 by VL <50 At week 48: double therapy: 93% triple therapy 94% 1.0% (95% CI: -7.5%, +5.6%) non-inferiority Figueroa CROI 2018 #489 ACTG A5288: 3 rd line therapy in resource limited settings Slide 12 of 36 Grinsztejn, Abstract 30LB ACTG A5288: 3 rd line therapy in resource limited settings Real time genotyping can identify those who can benefit from 3 rd line therapy Need better options for those failing second line without PI resistance Slide 13 of 36 Grinsztejn, Abstract 30LB

17 Slide 14 of 36 REALITY: Addition of 12 weeks of RAL at ART initiation, CD4<100 Gibb, Abstract 23 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 Slide 15 of 36 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 16 of 36 Bacon, Abstract 93

18 Slide 17 of 36 Same day ART initiation after home based testing in Lesotho 69% 43% 50% 34% Labhardt, Abstract 94 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. Slide 18 of 36 Springer, Abstract 96 ANTIRETROVIRAL THERAPY: Preexposure Prophylaxis Slide 19 of 36

19 Slide 20 of 36 PrEP use in the United States National Prescription Database Since 2012, 140,000 prescribed PrEP in US Women, <25, southern and non-medicaid expansion states all rx and rx:need Siegler, Abstract 81022LB 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 21 of 36 Grulich, Abstract 88 Long-acting cabotegravir protects against penile SHIV infection Validated penile infection model using oral TDF/FTC Slide 22 of 36 Dobard, Abstract 83

20 Slide 23 of 36 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 24 of 36 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 25 of 36 Markowitz, Abstract 89LB

21 Slide 26 of 36 Open label dapivirine rings: Comparison to historical placebo HIV-1 incidence = 4.1 (95% CI ) MTN-020/ASPIRE placebo EXPECTED 54% reduction P=0.01 HIV-1 incidence = 1.9 (95% CI ) MTN-025/HOPE OBSERVED Expected incidence derived from 10,000 samplings from MTN-020/ASPIRE placebo group. Across 10,000 samplings, there was none with an HIV-1 incidence of 1.9 per 100 person-years Observed incidence was during open-label ring use from MTN-020/ASPIRE participants In a second trial using similar methods, expected HIV-1 incidence was 3.9 per 100 PY (95% CI: ) vs. 1.8 per 100 PY (95% CI: ) in the open-label doravirine ring period Baeten, Abstract #143LB, Nel, Abstract #144LB Subject A 43 HSV1 2 mos Seroconversion w/ MDR virus NRTI, NNRTI, INI DBS, plasma 24 mos (+) p24 ag RNA 27k (-) WB Abd. Pain Colo: Sigmoid patches Knox NEJM 2017 Subject B 26 +/- 2 wks Proviral DNA: Seroconversion w/ MDR virus NRTI, NNRTI (not partner s) DBS, hair 5 mos (+) 4 th gen (+) Qual. NAAT (-) RNA None Markowitz JAIDS 2017 Subject C 50 MP Chemsex LGV Same day Seroconversion w/ WT virus DBS 8 mos (+) 4 th gen WB gp160 only (-) QL/QT RNA (-) PBMC DNA Interruption Fever Dysuria Hoorenberg Lancet HIV 2017 Subject D 34 2 mos, Seroconversion on for 3, off w/ MDR virus for 2, restart without NRTI, NNRTI testing Plasma, hair 10 mos p restart (+) 4 th gen RNA 27K None Thaden CROI 2018 Abstract #1041 Slide 27 of 36 TUBERCULOSIS Slide 28 of 36

22 Slide 29 of 36 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 33 vs 32 TB cases 0.67 vs cases/100 pt years INH/RFPx1 mo non-inferior to INHX9mo Chaisson, Abstract 37LB METABOLIC COMPLICATIONS Slide 30 of 36 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. Slide 31 of 36 Brown, Abstract 724

23 Slide 32 of 36 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 Bedimo, Abstract 132 MATERNAL AND CHILD HEALTH Slide 33 of 36 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 Slide 34 of 36 Scarsi, Abstract 141

24 Slide 35 of 36 Treatment of chronic HBV during pregnancy 3/147 placebo infants vs. 0/147 TDF infants acquired HBV No maternal, infant, or pregnancy concerns identified Stopping TDF did not lead to more LFT increases Jourdain, Abstract 131 Thank you Thank you to Dr Timothy Wilkin, Dr Roy (Trip) Gulick, Dr Susan Buchbinder, Dr Jared Baeten, Dr Andrew Grulich, and Dr Marty Markowitz for sharing slides Slide 36 of 36

25 Antiretroviral Therapy (ART) Strategies: Interactive Case-Based Panel Discussion Eric S. Daar, MD Professor of Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles, California Learning Objectives After attending this presentation, learners will be able to describe: Evolving issues around starting ARV therapy New strategies for those on ARV therapy Slide 3 of 56 Question 1: HIV uninfected man who is worried 52 year old man with stable DM who had been HIV-negative presents to you for advice regarding how to best avoid HIV infection in his new relationship with an HIV-infected man He states that his partner has been on ARVs for nearly two years with good viral suppression He has been diagnosed with several STIs in last year They mostly use condoms but have heard that they may not be necessary if his partner is suppressed He would rather not use condoms but wants to know what his risks would be without Slide 4 of 56

26 Slide 5 of 56 Question 1 Which of the below would be closest to what you would tell him with regards to his risks of acquiring HIV from his current partner if they choose to not use condoms? 1. You would be at some risk and should ideally use condoms 2. The risk would be very low but can t tell you that it is completely safe 3. Your risk of acquiring HIV from your partner is essentially zero HPTN 052: HIV Prevention in Heterosexual Couples Linked HIV transmission to HIV-negative partner (n=46) Overall 93% reduction in risk of transmission with early therapy Linked partner infections diagnosed after index partner started ART (n=8)* Recently initiated ART (n=4) Virologic failure (n=4) No HIV transmission among people who were suppressed Timing of the linked transmission events supports the model that HIV transmission is very unlikely in the setting of viral suppression Linked Partner Infections (number) Linked HIV Transmission Delayed ART Early ART Overall *Phylogenetic methods compared HIV pol sequences from index partner pairs and controls. Linkage probability was further assessed by comparing the genetic distances between pol sequences (Bayesian analysis). Slide 6 of 56 Cohen M, et al. J Int AIDS Soc. 2015;18(suppl 4):15. Abstract MOAC0101LB. Eshleman SH, et al. J Int AIDS Soc. 2015;18(suppl 4):18. Abstract MOAC0106LB. PARTNER Study: Condomless sex No HIV transmission through condomless sex with a partner on ART and HIV RNA <200 copies/ml, despite a significant number of sex acts Median follow-up: 1.3 years ~40,000 condomless sex acts Self-reported adh to PrEP: 93% to 97% Additional follow-up needed to provide more precise estimates for transmission risk for MSM Overall Rate of Couple Transmission (per 100 Couple-Years Follow-Up) Any sex 0.3 Vaginal sex 0.59 Anal sex 0.71 Insertive anal sex 0.88 Receptive anal sex with ejaculation Rate (Upper 95% CI) Slide 7 of 56 Rodger AJ, et al. JAMA. 2016;316:

27 Slide 8 of 56 Opposites Attract Serodiscordant Cohort Opposites Attract: observational cohort of serodiscordant MSM Three Australian cities (n=157), Rio De Janeiro (=96) and Bangkok (n=106) Couples had to have regular anal sex with no condom requirement Characteristics of cohort ~75% of HIV-positive partners took ART at baseline, most did start ~75% having undetectable viral load throughout follow-up ~75% had anal sex without condoms during the study ~65% of HIV-negative partners used PrEP at some point Average f/u 1.5 years >12,000 condomless sex acts when undetectable VL and no PrEP 0 transmissions, estimated risk of 0, 95% CI 0, 1.56% (PARTNER Study was 0, 95% CI 0, 2.7%) Slide 9 of 56 Consensus Statement People living with HIV on ART with an undetectable viral load in their blood have a negligible risk (defined as so small or unimportant as to be not worth considering; insignificant) of sexual transmission of HIV Depending on the drugs employed, it may take as long as 6 months for the viral load to become undetectable Continued and reliable HIV suppression requires excellent adherence HIV viral suppression should be monitored Statement endorsed by: Physicians: Michael Brady, MD; Myron Cohen, MD; Demetre C. Daskalakis, MPH; Andrew Grulich, MD; Jens Lundgren, MD; Julio Montaner, MD; Pietro Vernazza, MD Organizations: AIDES; AIDS ACTION NOW; AIDS Foundation of Chicago; Australian Federation of AIDS Organizations; British Columbia Centre for Excellence in HIV/AIDS; Canadian Positive People's Network; CATIE; Human Rights Campaign; ICASO; NAM aidsmap; National Alliance of State and Territorial AIDS Directors; National Black Justice Coalition; New York City Department of Health and Mental Hygiene; San Francisco AIDS Foundation; Sidaction; Terrence Higgins Trust; YouthCO HIV & Hep C Society. Note: An undetectable HIV viral load only prevents HIV transmission to sexual partners. Condoms also help prevent HIV transmission as well as other STIs and pregnancy. The choice of HIV prevention method may be different depending upon a person s sexual practices, circumstances and relationships. For instance, if someone is having sex with multiple partners or in a non-monogamous relationship, they might consider using condoms to prevent other STIs. Slide 10 of 56 Prevention Access Campaign. Consensus statement (1/17).

28 Slide 11 of 56 Question 2 Same scenario but partner is not reliably on ARVs and your patient is very interested in PrEP. He is asymptomatic, 4 th generation HIV-negative, HBsAb+, has CrCl- 50 ml/min. CDC 1 Any person with an ecrcl of <60 ml/min should not be prescribed PrEP with TDF/FTC Population for PrEP MSM or Heterosexual Men and Women with: HIV(+) sex partner* Inconsistent condom use, or recent STI, or high number of sexual partners Commercial sex work In high-prevalence area or network (for heterosexual men and women only) IDU HIV(+) injecting partner Sharing injection equipment Recent drug treatment (but currently injecting) Regimen suggested TDF 300 mg + FTC 200 mg - Or - TDF 300 mg (IDU only) Timing and Once Daily Frequency Slide 12 of 56 *For any regular sex partner should consider if they are on ARVs with undetectable VL Which would be closest to what you would recommend for this high-risk individual with CrCl of 50 ml/min? 1. TDF/FTC once daily 2. TAF/FTC once daily 3. TDF/FTC around sex (on demand) 4. TDF/FTC four times per week 5. Strongly encourage him to NOT take PrEP since renal function impaired 6. Something else Slide 13 of 56

29 Slide 14 of 56 Follow-up % 26% 12% 21% 12% Risk Reduction 44% 84% 100% 100% 95% CI -31 to 77% 21 to 99% 86 to 100% (combined) Grant R, et al. 20th IAC; Melbourne, Australia; July 20-25, 2014; Abst. TUAC0105LB; Grant R, et al. Lancet ID. [Epub ahead of print July 22, 2014] iprex Open-Label Extension (iprex OLE). Slide 15 of 56 Post hoc Analysis 269 participants with 134 py f/u had below median pill taking (median of 9.5 pills/month) with 5 sexual encounters/month (25% <2 encounters per month) 6 infections occurred, all in placebo, 0 in PrEP arm with estimate reduction to be 100% (95% CI 39, 100) Slide 16 of 56 Antoni G, et al. IAS2017 Conference, Abst. TUAC0102.

30 Slide 17 of 56 Question 3: Treatment naïve patient 29 year old man presents to clinic after having a routine HIV Ab screening test that was positive in a local testing site, with a CD4 count reported as 570 cells/ul The patient was immediately referred and understands that there are good treatments available, has insurance to cover costs of care, but would prefer to defer therapy if possible He has no past medical history, is asymptomatic, has had multiple different partners of unknown HIV status during the past year Which of the following is closest to what you would recommend to this patient with regards to starting ART? 1. Strongly encourage to start 2. Recommend he start 3. Support him in his wishes to defer 4. Other Slide 18 of yo asymptomatic man, recently diagnosed with HIV CD4= 570 cells/ul START Study Outcomes Immediate ART superior to deferred ART Serious and non-serious AIDS events 68% of the primary endpoints with CD4 >500 cells/mm 3 Similar reductions in events across all subgroups No increase in AEs associated with immediate ART Number of Events Composite Endpoint 57% Reduction (P<0.001) Number of Serious Events AIDS- Related 72% Reduction (P<0.001) Deferred ART (n=2359) Immediate ART (n=2326) 47 Components (Serious Events) 39% Reduction (P=0.04) 29 Non-AIDS Related Slide 19 of 56 Lundgren J, et al. 8 th IAS Conference. Vancouver, Abstract MOSY0301. The INSIGHT START Study Group. N Engl J Med. 2015;July 20. [Epub ahead of print].

31 Slide 20 of 56 SMART and START Studies: Endpoints Combined analysis of SMART and START studies (n=10,157) AIDS events (n=123) Serious non-aids events (n=244) CVD (n=103) Cancer (n=117) Death (n=118) AIDS and serious non-aids events (n=359) Immune preservation through immediate and continuous ART significantly reduces the risk of AIDS and non-aids events Cancer risk reduction did not vary by type of cancer Hazard Ratio for Reducing Risk of Events Favors Immediate and Continuous ART AIDS Serious non-aids events CVD Cancer Death AIDS or serious non-aids event Borges AH, et al. 24 th CROI. Seattle, Abstract 474. HPTN 052: HIV Prevention in Heterosexual Couples Linked HIV transmission to HIV-negative partner (n=46) Overall 93% reduction in risk of transmission with early therapy Linked partner infections diagnosed after index partner started ART (n=8)* Recently initiated ART (n=4) Virologic failure (n=4) No HIV transmission among people who were suppressed Timing of the linked transmission events supports the model that HIV transmission is very unlikely in the setting of viral suppression Linked Partner Infections (number) Linked HIV Transmission Delayed ART Early ART Overall * Phylogenetic methods compared HIV pol sequences from index partner pairs and controls. Linkage probability was further assessed by comparing the genetic distances between pol sequences (Bayesian analysis). Slide 21 of 56 Cohen M, et al. J Int AIDS Soc. 2015;18(suppl 4):15. Abstract MOAC0101LB. Eshleman SH, et al. J Int AIDS Soc. 2015;18(suppl 4):18. Abstract MOAC0106LB. When to Start ART: Global Consensus AIDS or HIV-Related Symptoms < >500 United States DHHS (2017) Yes Yes Yes Yes Yes IAS-USA (2016) Yes Yes Yes Yes Yes British HIV Association (2016) Yes Yes Yes Yes Yes European AIDS Clinical Society (2017) Yes Yes Yes Yes Yes WHO (2015) Yes Yes Yes Yes Yes Slide 22 of 56 DHHS. Revision October 17, Günthard HF, et al. JAMA. 2016;316: EACS. Revision October BHIVA. Revision August WHO. Revision September 2015.

32 Slide 23 of 56 If you and patient decide that starting is the right thing to do, what would you recommend next? 1. Send routine laboratory studies, HIV genotype and schedule for f/u appointment when results return 2. Send routine laboratory studies without a HIV genotype and start ARVs immediately 3. Send routine laboratory studies with a HIV genotype and start ARVs immediately 4. Something else 29 yo asymptomatic man, recently diagnosed with HIV CD4= 570 cells/ul RCT in South Africa clinics (n=377) SOC had 3-5 additional clinic visits over 2-4 wks prior to ARVs Primary outcome was VL <400 c/ml within 10 months 64 vs. 51%; RR 1.26 (1.05, 1.50) Secondary outcome was initiation ART within 90 days 97 vs. 72%; HR 1.36 (95% CI 1.24, 1.49) Slide 24 of 56 Slide 25 of 56

33 Slide 26 of 56 DHHS guidelines on same day initiation of ART DHHS. Revision October He decides to start on the same day. He states that he has no specific concerns regarding adherence, side effects or dosing schedule. Which of the following would you recommend? 1. Two NRTIs + boosted PI (assume DRV/COBI/FTC/TAF is available) 2. Two NRTIs + RAL 3. DOR/FTC/TDF (assume available) 4. TDF (or TAF)/FTC/COBI/EVG 5. TDF (or TAF)/FTC + DTG 6. BIC/FTC/TAF 7. Something else Slide 27 of yo asymptomatic man, recently diagnosed with HIV CD4= 570 cells/ul VL, HLA-B5701, genotype pending Must treat before HIV Avoid NNRTI-based drug resistance results regimens available Recommended ART Regimens: DRV/r or DRV/c + tenofovir/ftc DTG + tenofovir/ftc Transmitted mutations conferring NNRTI resistance are more likely than mutations with PI or INSTI resistance Resistance to DRV/r and DTG emerges slowly; transmitted resistance to DRV is rare and has not been reported to DTG Slide 28 of 56 DHHS. Revision October 2017.

34 Slide 29 of 56 After discussion he is anxious to start but decides to wait until more data is back prior to starting therapy. What would you recommend if his VL is repeatedly copies/ml? 1. Strongly encourage to start 2. Recommend he start 3. Suggest he defer therapy for now 4. Other 29 yo asymptomatic man, recently diagnosed with HIV CD4= 570 cells/ul, VL copies/ml ACTG A5308: Effect of ART in controllers Prospective study in HIV controllers Open-label ART, non-inferiority 2 HIV RNA results <500 copies/ml for 12 months No resistance to study drugs 37% HIV RNA <40 copies/ml Lead-In: No ART for 12-Weeks Rilpivirine/F/TDF (n=35) Rilpivirine/F/TDF No ART Week 0 48 Optional 48-Week 96 Follow-Up Virologic isca <6 copies/ml before and after ART: 19% versus 94% Activation/inflammation Decline in the % CD38+HLA-DR+ CD8+ cells Weeks 24-48: -4% (P=0.001) Weeks: 72-96: -7.2% (P<0.001) Decline in markers of immune exhaustion (%PD1, %TIGIT, %CD160 on CD8+ cells and %CD160 on CD4+ cells) Slide 30 of 56 Li J, et al. 25 th CROI. Boston, Abstract 229. DHHS, IAS-USA, EACS Guidelines Class DHHS [1] IAS-USA [2] EACS [3] INSTI Boosted PI DTG/ABC/3TC DTG/ABC/3TC DTG + TDF (TAF)/FTC EVG/COBI/TDF (TAF)/FTC RAL + TDF (TAF)/FTC BIC/FTC/TAF DTG + TAF/FTC EVG/COBI/TAF/FTC RAL + TAF/FTC DTG/ABC/3TC DTG + TDF (TAF)/FTC EVG/COBI/TDF (TAF)/FTC RAL + TDF (TAF)/FTC DRV + RTV(Cobi) + TDF (TAF)/FTC NNRTI RPV/TDF (TAF)/FTC* Recommendations may vary by viral load, CD4+ count, CrCl, HLA-B*5701 status, HBsAg status, and osteoporosis status. * Not recommended with CD4<200 cells/ul or VL>100,000 copies/ml Slide 31 of DHHS Guidelines. Mar Günthard HF, et al. JAMA. 2016; 316: :. 3. EACS Guidelines. Jan 2017.

35 Slide 32 of 56 Bictegravir vs. Dolutegravir with FTC/TAF No resistance selected for in either regimen Sax P, et al. Lancet 2017; epub ahead of print Same patient but CD4=110 cells/ul, VL= 210,000 c/ml and he missed several clinic appointments after initial visit. He admits to using alcohol and experiencing mild depression. He has met with psychologist a few times and is relatively stable and drinking some what less. Which of the following would you recommend? 1. Two NRTIs + boosted DRV (including STR regimen when available) 2. Two NRTIs + RAL 3. TDF (or TAF)/FTC/COBI/EVG 4. TDF (or TAF)/FTC + DTG 5. ABC/3TC/DTG 6. BIC/FTC/TAF 7. Other Slide 33 of yo asymptomatic man, recently diagnosed with HIV Using alcohol, depressed and missed a few visits CD4= 110 cells/ul; VL 210,000 c/ml; GT wild type; HLB-B5701- HIV-1 RNA < 50 c/ml by Snapshot Analysis: 95% CI for Treatment Difference SINGLE [1] Favors Favors EFV/TDF/FTC DTG + ABC/3TC FLAMINGO [2] Favors Favors DRV/RTV DTG SPRING-2 [3,4] Favors Favors RAL DTG ARIA [5] Favors Favors ATV+TDF/FTC DTG/ABC/3TC Wk % 7.4% 12.3% 0.9% 7.1% 13.2% -2.2% 2.5% 7.1% 3.1% 10.5% 17.8% Wk % 8.0% 13.8% 4.7% 12.4% 20.2% -1.1% 4.5% 10% Wk % 2% 14.6% -5% 0 15% -12% 0 25% -12% 0 12% -5% 0 20% No resistance selected for in any DTG-containing regimen Slide 34 of Walmsley S, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 2. Molina JM, et al. Glasgow HIV Abstract O Raffi F, et al. Lancet. 2013;381: Raffi F, et al. Lancet Infect Dis. 2013;13: Orrell C, et al. IAS 2016.

36 Slide 35 of 56 BIC vs. DTG in naïve patients (48 weeks) Study 1489 HIV RNA <50 Copies/mL (%) Bictegravir/FTC/TAF (n=314) 92 Dolutegravir/ABC/3TC (n=315) 93 Favors Comparator -0.6% Favors Bictegravir Study 1490 Bictegravir/FTC/TAF (n=320) Dolutegravir + FTC/TAF (n=325) % Adjusted Treatment Difference (%) No resistance selected for in any DTG or BIC-containing regimen Gallant J, et al. Lancet. 2017;390: Sax PE, et al. Lancet. 2017;390: Cohort study of all patient starting DTG in two centers in Netherlands N=556; 102 (18.4% naïve); median f/u 225 days 85 (15.3%) stopped DTG; 76 (13.7%) for intolerability Slide 36 of 56 De Boer MGJ, et al. AIDS 2016; Question 8: Suppressed with history virologic failure 54 year old man with well controlled DM and HTN, normal renal function and long history of HIV. Previously experienced virologic failure on TDF/FTC/EFV with K103N and M184V. Has was subsequently suppressed on DRV/r + TDF/FTC for 2 years and for last year on DRV/cobi + FTC/TAF with good tolerance. He has heard about many new STR and wants to switch. He is HBsAb+ and HLAB-5701 negative. Slide 37 of 56

37 Slide 38 of 56 Which of the following would you recommend? A. TAF/FTC/RPV B. EVG/COBI/TAF/FTC C. DTG/ABC/3TC D. DTG/RPV E. Tell him there are no good STRs for him and he should hold out for DRV/COBI/FTC/TAF F. Tell him there are no good STRs for him but DTG + TAF/FTC are two small pills and good option G. Something else 54 yo man with DM/HTN, h/o viral failure with K103N and M184V Stably suppressed for years on DRV/cobi + FTC/TAF Wants STR HBsAB+, HLA-B5701 negative Same scenario except patient has progressive renal disease with CrCl having gradually declined from 80 to now 50 ml/min. Which of the following would you recommend? 1. EVG/COBI/TAF/FTC 2. DTG/ABC/3TC 3. DTG + TAF/FTC (not STR but small pills) 4. Boosted PI + ABC/3TC (and apologize that not STR) 5. DTG/RPV 6. Boosted PI + INSTI (and apologize that not STR) 7. Something else Slide 39 of yo man with DM/HTN, h/o K103N and M184V Stably suppressed for years on DRV/cobi plus TAF/FTC Progressively declining renal function (CrCl 50 ml/min) Willing to switch but want simplicity and preferably STR HBsAB+, HLA-B5701 negative GS-112: Switching to a TAF in Pt with renal dz Multicenter, open-label phase III trial Virologically suppressed, HIVpositive pts with mild-moderate renal impairment (stable egfr CG [30-69 ml/min]) (N = 242) TDF-Based ART (n = 158) Non-TDF Based ART (n = 84) Wk 24 Wk 48 Wk 96 EVG/COBI/FTC/TAF (N = 242) ART use,% CCR5 Other No PI NNRTI INSTI TDF ABC Antag. NRTI NRTI Slide 40 of 56 Gupta S, et al. IAS Abstract TUAB0103.

38 Slide 41 of 56 GS-112: Key Results Median Change From Baseline Change in egfr From Baseline to Wk Baseline: *P < TDF * egfr CG ml/min egfr CKD-EPI Cr ml/min/1.73 m 2 Iohexol Clearance (ml/min) Actual GFR by Iohexol Clearance From Baseline to Wk TDF Non-TDF GLSM Ratio vs BL (% [90% CI]): 63 BL 62 Wk 2/4/8 63 Wk BL 48 Wk 2/4/8 96 (86-108) 49 Wk 24 Non- TDF 98 (94-102) 100 (96-105) 98 (87-111) Gupta S, et al. IAS Abstract TUAB0103. Pozniak A, et al. JAIDS 2016;71: ABC possible association with CVD Study Association Description D:A:D [1] + Cohort collaboration (prospective) Danish HIV Cohort [2] + Cohort (linked with registries) Montreal study [3] + Nested case-control study SMART [4] + Post hoc subgroup analysis of RCT (use of ABC not randomized) STEAL [5] + Preplanned secondary analysis of RCT (use of ABC randomized) Swiss HIV Cohort [6] + NA-ACCORD [8] + Cohort (retrospective) Cohort collaboration (retrospective) FHDH ANRS CO4 [7] Equivocal Nested case-control study VA Clinical Case Registry [9] - Cohort (retrospective) Brothers et al analysis [10] - Post hoc meta-analysis of RCTs ACTG A5001/ALLRT [11] - Post hoc meta-analysis of RCTs FDA meta-analysis [12] - Post hoc meta-analysis of RCTs 1. Friis-Møller N, et al. N Engl J Med. 2003;349: Obel N, et al. HIV Med. 2010;11: Durand M, et al. J Acquir Immune Defic Syndr. 2011;57: Phillips AN, et al. Antiviral Ther. 2008;13: Martin A, et al. AIDS. 2010;24: Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 7. Lang S, et al. AIDS. 2010;24: Elion R, et al. JAIDS Bedimo RJ, et al. Clin Infect Dis. 2011;53: Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51: Ribaudo HJ, et al. Clin Infect Dis. 2011;52: Slide 42 of Ding X, et al. J Acquir Immune Defic Syndr. 2012;61: D:A:D Cohort: Cumulative CVD IRR Incidence Rate Ratio (95% CI) CVD Incidence Rate Ratios 1.9 Univariate analysis ( ) Multivariate analysis 1.59 ( ) 1.3 ( ) 1.0 ( ) Darunavir/r Atazanavir/r (versus no darunavir/r exposure) (versus no atazanavir/r exposure) Multivariate models adjusted for gender, age, race, HIV risk of acquisition, prior CVD, CD4 nadir, BMI, diabetes, dyslipidemia, egfr, cumulative exposure to PI, recent abacavir exposure, prior AIDS, viral load, HBV/HCV, family history of CVD, hypertension, and smoking. Slide 43 of 56 Ryom L, et al. 24 th CROI. Seattle, Abstract 128LB.

39 Slide 44 of 56 DTG with one fully active NRTI (DAWNING) Virologic outcomes Treatment differences (95% CI) HIV-1 RNA <50 c/ml, % DTG + 2 NRTIs (ITT- E, n=312) LPV/RTV + 2 NRTIs (ITT-E, n=312) DTG + 2 NRTIs (PP, n=282) LPV/RTV + 2 NRTIs (PP, n=275) LPV/RTV DTG ITT-E PP CI, confidence interval; Virologic ITT-E, intent-to-treat exposed; PP, per protocol. success DTG + 2 NRTIs is superior to LPV/RTV + 2 NRTIs with respect to snapshot in the ITT-E (<50 c/ml) at Week 24, P<0.001 Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB. SWORD Studies: DTG + RPV Maintenance Slide 45 of 56 Llibre J et al. Lancet Mar 3;391(10123): Slide 46 of 56 Llibre J et al. Lancet Mar 3;391(10123):

40 Slide 47 of 56 Question 10: Virologic failure 43 year old man with long history of HIV who has been suppressed on TDF/FTC/RPV for 2 years with good tolerance. Recent poor adherence, missed doses and documented viral rebound of >1000 copies/ml. Genotype shows E138K and M184I. He is now adherent and prepared to adhere to which ever regimen you recommend but would prefer to stay on STR if possible. He has no comorbidies and is HLAB-5701-negative Which of the following would you recommend? 1. Boosted PI with TAF/FTC (soon to be STR) 2. Boosted PI with INSTI (+/- NRTIs) 3. EVG/COBI/TAF/FTC 4. DTG + TAF/FTC 5. DTG/ABC/3TC 6. Something else 43 yo man with viral failure on TAF/FTC/RPV with E138K and M184I Ready to enhance adherence and change therapy but prefers STR if possible HBsAB+, HLAB-5701 negative Slide 48 of 56 EARNEST: First-line failure Randomized, open-label, multicenter trial in sub-saharan Africa Primary endpoint: good HIV disease control at Wk 96 Wk 12 Wk 96 HIV-infected pts with confirmed VF on NNRTI + 2 NRTIs with no previous PI use (N = 1277) LPV/RTV + RAL (n = 418) LPV/RTV + RAL (n = 433) LPV/RTV NRTIs* (n = 426) LPV/RTV Monotherapy (n = 418) Pts stratified by center, CD4+ cell count (< 200 or 200 c/mm3). LPV/RTV and RAL dosed BID. *NRTIs chosen WITHOUT genotype by clinician. Slide 49 of 56 Paton NI, et al. N Engl J Med. 2014;371:

41 Slide 50 of 56 Pts (%) EARNEST: Efficacy Outcomes at Wk 96 [1] LPV/RTV + RAL (n = 433) 100 LPV/RTV + 2/3 NRTIs (n = 426) LPV/RTV monotherapy (n = 418) 80 73* 74* Good HIV Disease HIV-1 RNA Control < 50 copies/ml *P <.0001 vs LPV/RTV monotherapy. Alive with no new stage 4 events, CD4+ count > 250 cells/mm 3, and HIV-1 RNA < 10,000 c/ml or no PI mutations. 1. Paton NI, et al. N Engl J Med. 2014;371: Amin J, et al. PLoS One. 2015;10:e La Rosa AM, et al. Lancet HIV 2016; 3:e SECOND-LINE [2] and ACTG 5273 [3] studies had similar designs and efficacy results All enrolled pts experiencing VF on NNRTI + NRTIs treated with LPV/RTV + RAL or LPV/RTV + NRTIs SECOND-LINE: no difference between arms in proportion of pts with HIV-1 RNA < 200 or < 50 c/ml at Wk 96 ACTG 5273: no difference between arms in time to VF at Wk 48 or proportion of pts with HIV-1 RNA 400, < 200, or < 40 c/ml through Wk 96 EARNEST Trial: Impact of NRTI Cross-Resistance NRTIs even with resistance exerted substantial antiviral activity Clearly better than lopinavir/r monotherapy Equivalent to adding a new drug class Paradoxical relationship between resistance and HIV RNA suppression Likely explained by adherence Resistance algorithms for NRTIs are of limited use in this setting Patients (%) HIV RNA <400 Copies/mL (week 144) 89% 85% 81% 77% 61% LPV/r + LPV/r LPV/r + NRTI RAL (Number of Active NRTIs) Slide 51 of 56 Paton N, et al. Lancet HIV. 2017;4:e341-e348. DAWNING Study Open-label randomised noninferiority phase IIIb study Open label, randomised 1:1 DTG + 2 NRTIs LPV/RTV + 2 NRTIs DTG + 2 NRTIs Continuation phase Randomisation Week 24 interim analysis Week 48 primary analysis Week 52 Key eligibility criteria: on first-line 2 NRTIs + NNRTI regimen for 6 months, failing virologically (HIV-1 RNA 400 c/ml on 2 occasions); no primary viral resistance to PIs or INSTIs, one active NRTI in regimen Stratification: by HIV-1 RNA ( or >100,000 copies/ml), number of fully active NRTIs in the investigatorselected study background regimen (2 or <2) Primary endpoint: proportion with HIV-1 RNA <50 c/ml at Week 48 using the FDA snapshot algorithm (12% noninferiority margin) Slide 52 of 56 Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

42 Slide 53 of 56 Virologic outcomes Treatment differences (95% CI) HIV-1 RNA <50 c/ml, % DTG + 2 NRTIs (ITT-E, n=312) LPV/RTV + 2 NRTIs (ITT-E, n=312) DTG + 2 NRTIs (PP, n=282) LPV/RTV + 2 NRTIs (PP, n=275) LPV/RTV DTG ITT-E Virologic success DTG + 2 NRTIs is superior to CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol. LPV/RTV + 2 NRTIs with respect to snapshot in the ITT-E (<50 c/ml) at Week 24, P<0.001 In resource limited setting do you need to do genotype testing? How important is the background regimen in this second line options? Can one extrapolate to using ABC/3TC/DTG? Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB. PP Management of ARV Failure First-line therapy Failing regimen (+ NRTI) Boosted PI Enforce adherence Modify for convenience or toxicity NNRTI Boosted PI + NRTIs Boosted PI + INSTI DTG + NRTIs (if one fully active) INSTI Boosted PI + NRTIs Boosted PI + active INSTI Yes Boosted PI + NRTIs Boosted PI + active INSTI DTG + NRTIs (if one fully active) Second line and beyond PI Susceptible No* DTG + NRTIs (if one fully active) 2 and preferably 3 fully active drugs * Rare in pts never exposed to unboosted PI (DHHS alternative since 2003 and not recommended since 2008). If RAL or EVG resistance detected, DTG + boosted PI can be used if DTG susceptible. Slide 54 of 56 DHHS Guidelines. Oct 2017

43 Anal Cancer and HPV Related Tumor Prevention Timothy J. Wilkin, MD, MPH Associate Professor of Medicine Weill Cornell Medicine New York, New York Learning Objectives After attending this presentation, learners will be able to describe: Current approaches to anal cancer prevention HPV-associated oropharyngeal cancer Current content on HPV vaccination in HIV-infected populations Slide 3 of 39 Worldwide HPV-related Disease Burden: 630,000 Cancer Cases in Men and Women Penile cancer 1 13,000 Male Female 21,000 Vulvar & vaginal cancer 1 Oropharyngeal cancer 1 28,200 7,500 Oropharyngeal cancer 1 Anal cancer 1 17,000 18,000 Anal cancer 1 530,000 Cervical cancer 1 x 60 fold 9,000,000 High-grade cervical dysplasia 2,3,* 21,900,000 Low-grade cervical dysplasia 2,3, Genital warts 4,5, 17,300,000 14,700,000 Genital warts 4,5, * Estimated 90% of high-grade cervical lesions are HPV related 3 ; Estimated 73% of low-grade cervical lesions are HPV related 3 ; Estimated gender ratio of genital warts: 54% males; 46% females 6 1. Martel C et al. Intl J Cancer. 2017;141: ; 2. World Health Organization.; 3. Guan P, et al. Int J Cancer. 2012;131: ; 4. World Health Organization.; 5. Greer CE, et al. J Clin Microbiol. 1995;33: ; 6. Public Health England.

44 Anal Cancer Anal Cancer in HIV+ people Slide 6 of 39 Schim van der Loff, HIV AIDS Curr Report 2014 Anal Cancer in HIV+ people Cerv CA prior to pap Current cerv CA in US Slide 7 of 39 Schim van der Loff, HIV AIDS Curr Report 2014

45 Natural History of HPV Infection and Potential Progression to Anal Cancer 0 1 Year 0 5 Years 1 20 Years Initial HPV Infection Higher HPV exposure Continuing Infection Anal LSIL Cleared HPV Infection Anal HSIL Invasive Anal Cancer Decreased cellmediated immunity Slide 8 of Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43: Prevention of Anal Cancer 0 1 Year 0 5 Years 1 20 Years Initial HPV Infection Continuing Infection Anal LSIL Anal HSIL Invasive Anal Cancer Cleared HPV Infection Slide 9 of Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43: Prevention of Anal Cancer Initial HPV Infection 0 1 Year 0 5 Years 1 20 Years Continuing Infection Anal LSIL Anal HSIL Invasive Anal Cancer Cleared HPV Infection Slide 10 of Pinto AP, Crum CP. Clin Obstet Gynecol. 2000;43:

46 Anal cancer HRA prevention Learning Curve Goal is to identify pre-cancerous areas of the anus that can be removed to prevent invasive cancer o SCREEN with cytology (or HPV testing *not FDA approved) o DIAGNOSE with High Resolution Anoscopy o TREAT HSIL with ablation or topical therapy Anal cancer is treated with combined chemotherapy and radiation Slide 11 of 39 Richel, AIDS 2014 Which of these is the recommended way to prevent anal cancer according to national guidelines? 1. Treatment of anal condyloma 2. HPV vaccination prior to sexual activity 3. Screening and treatment of anal HSIL 4. HPV vaccination of sexually active adults Slide 12 of 39 Anal HSIL in HIV-infected women Anal Histology Anal Cytology n (%) of Total N=255 n (%) of HSIL N=72 Normal 101 (40%) 16 (22%) ASCUS/LSIL 129 (50%) 38 (53%) ASC-H/HSIL 25 (10%) 18 (25%) Slide 13 of 39 Note: 8 were unevaluable for anal cytology, including 3 with HSIL Prevalent histologic anal HSIL: 28% Stier E, HPV 2017, CT02

47 AMC-076: Randomized, clinical trial of infrared coagulation of anal HSIL IRC Control P-value* Overall CR Rate 63% (38/60) 27% (16/60) < % CI, 50-75% 95% CI, 16-40% Overall CR/PR Rate 75% (45/60) 95% CI, 62-85% 43% (26/60) 95% CI, 31-57% <0.001 PR rate for those not achieving CR 32% (7/22) 95% CI, 14-55% 23% (10/44) 95% CI, 11-38% * One-sided stratified Mantel-Haenszel chi-square test. Strata were Laser Surgery Center (n=71) and remaining 5 sites (n=49). Slide 14 of 39 Goldstone S, HPV 2017, CT02 Controversies in anal cancer screening Most people with anal HSIL will never develop cancer. Treatment for anal HSIL is not well studied and are clearly less effective than those for cervical HSIL Recurrent HSIL is the norm; multiple treatments are usually needed to clear HSIL Accessing high resolution anoscopy and treatment for anal HSIL is difficult Not yet recommended by organizations setting standards for health care maintenance Cost effectiveness is unclear; Age for screening (35 yrs old?) No consensus on whether to include all women and men with HIV No data that treating anal HSIL will reduce the risk of anal cancer Slide 15 of 39 Oropharyngeal Cancer

48 Which of these statements is false? 1. The HPV type responsible for most HPV-related oropharyngeal cancers (OPC) is HPV Men are more likely than women to develop OPC 3. HIV-infected populations are more likely to develop OPC cancer than HIV-uninfected populations 4. HPV related OPC can be prevented in most people through active screening Slide 17 of 39 Oropharyngeal Cancer (OPC) 85% HPV 16 70% HPVrelated 94% of HPVrelated OPC are caused by HR-HPV in 9- valent HPV vaccine Slide 18 of 39 Saraiya M et al JNCI 2015 HPV-Related OPC Incidence is Higher in Men HPV-associated OPC is 2-3 times higher among people 4-fold living with HIV Slide 19 of 39 Jemal, et al. J Natl Cancer Inst 2013

49 Observed and Projected Incidence Rates for Oropharyngeal Cancers and Cervical Cancer Rates per 100, Cervix Oropharynx (overall) Oropharynx (men) Oropharynx (women) There are no accepted 2010screening or prevention modalities for prevention of HPV-related OPC United States Calendar Years Slide 20 of 39 Chaturvedi AK et al. J Clin Oncol. 2011;29: How can we reduce HPVrelated cancers in people living with HIV ANCHOR TRIAL Screen > 17,385 Enroll 5,058 Retain for 5-8 years Estimated < 50 develop cancer Slide 22 of 39 anchorstudy.org; NCT ; Sponsor: NCI

50 Slide 23 of 39 anchorstudy.org; NCT ; Sponsor: NCI Prevention of Anal Cancer with HPV vaccination Excludes those baseline vaccine infection Includes those baseline vaccine infection Slide 24 of 39 Palefsky, NEJM 2011 HPV vaccination: ACTG A5298 Study Design HIV+ 27 yrs No HPV cancers All CD4/RNA RAI for men HRA with bx Anal cyto Anal HPV x 2 Oral HPV x 2 RANDOMIZE: stratify by HSIL, sex, site 4vHPV or placebo: 0, 8, 24 Anal HPV oral HPV Cyto:q6 mo HSIL tx by local standard; HRA providers certified Slide 25 of 39

51 ACTG A5298: HPV vaccine in HIV+ >27 yrs Outcome 4vHPV (n) Placebo (n) HR (95% CI) Persistent anal HPV, or single detection at last visit (0.45, 1.26) Persistent anal HPV (0.36, 1.52) Anal HSIL ( ) Persistent oral HPV (0.02, 0.98) Slide 26 of 39 Wilkin T, CROI 2016 HPV16/18 VE at Non-Cervical Sites Costa Rica Vaccine Trial One-time detection of HPV16/18 infection 4 yrs. after vaccination Slide 27 of 39 1 Herrero R et al. PLOS ONE 2013; 2 Kreimer AR et al Lancet Oncology 2011 Slide courtesy of A Kreimer Strong Association Between Serum and Oral HPV Antibodies Among Vaccinated Men Slide 28 of 39 Pinto et al JID 2016

52 Prevalence of oral HPV by vaccine status: NHANES Slide 29 of 39 VLP Vaccines GSK Human Papilomavirus Bivalent (Type 16 and 18) Vaccine, Recombinant HPV 16 and 18 Insect cells Aluminum and TLR 4 agonist adjuvant im injection at 0, 1, 6 months Merck Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant HPV 6, 11, 16, 18 Yeast Aluminum adjuvant im injection at 0, 2, 6 months Human Papillomavirus 9-valent Vaccine, Recombinant adds 31, 33, 45, 52, 59 Slide 30 of 39 These 9 types cause 90% of HPV-related cancers!!! ACIP HPV vaccine recommendations Females Routine vaccination of girls Catch-up vaccination up to age 26 Males Routine vaccination of boys Catch up vaccination up to age 21 Routine vaccination of HIV+ males, other immunosuppressed males, men who have sex with men through age 26 Dosing schedule Two doses (0 and 6 months) when starting prior to age 15 Three doses (0, 1-2, 6 months) after age 15 and if having any immune suppression. Slide 31 of 39 Meites E et al, MMWR, 2016

53 Real world evidence of HPV vaccine efficacy Decline in Genital Warts <30 years of age Slide 32 of 39 START study: Hazard ratio for infection-related cancer Immediate ART reduced infectionrelated cancer by 76% (95% CI 36%-89%) Slide 33 of 39 Borges A, CID 2016 Early ART reducing Anal Cancer Slide 34 of 39

54 Statin exposure and risk of cancer Death rate 45% lower with statin use Virus-related cancers Statin use associated with significant protection against HPV cancers Slide 35 of 39 Summary Anal cancer is a common cancer in HIV-infected populations Screening for anal cancer should be considered for HIVinfected populations o Data to support this are limited o Existing data is from resource-rich areas o Further study is needed HPV vaccination is the best hope for prevention of noncervical disease in HIV-infected populations o Emerging data support efficacy of vaccination against HPV-related oropharyngeal cancer o Need for efficacy trial to definitively prove efficacy? World-wide push for early initiation of ART (e.g. WHO ) should lead to reduced incidence of HPV-related cancer Slide 36 of 39 Acknowledgments AIDS Malignancy Consortium Joel Palefsky Elizabeth Stier Stephen Goldstone Elizabeth Chiao National Cancer Institute Ligia Pinto Moffitt Cancer Center Anna Giuliano Slide 37 of 39 AIDS Clinical Trials Group Ross Cranston Barbara Bastow Jennifer Webster-Cyriaque Weill Cornell Medicine Christina Megill Marshall Glesby Roy Gulick Funders National Cancer Institute National Institute of Allergy and Infectious Diseases National Institute of Dental and Craniofacial Research

55 Post test question Which of the following groups are not recommended for HPV vaccination according to ACIP? 1. HIV-infected girls age HIV-infected boys age MSM up to age 26 if not previously vaccinated 4. HIV-infected women age with negative hrhpv tests Slide 38 of 39 Question-and-Answer

56 Investigational Approaches to Antiretroviral Therapy: New Strategies and Novel Agents Judith S. Currier, MD Professor of Medicine David Geffen School of Medicine University of California Los Angeles Los Angeles, California 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 3 of 44 The Long and Winding Road to New Drug Approval Slide 4 of 44

57 Slide 5 of 44 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? Updates 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? 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/TDF/FTC 2. Rilpivirine/FTC/TAF 3. EVG/c/FTC/TAF 4. DTG/ABC/3TC 5. DTG + FTC/TAF 6. BIC/TAF/FTC Slide 6 of 44 New Antiretroviral Drugs New medications in current classes Bictegravir (INSTI) (approved Feb 2018) Doravirine (NNRTI) Slide 8 of 44

58 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 Slide 11 of 44 Bictegravir/FTC/TAF Slide 12 of 44 Drug interactions: Rifampin contraindicated; other rifamycins not recommended. Metformin AUC increased 39%; no effect on glucose 1 ; 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 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 Slide 13 of 44

59 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 Slide 14 of 44 DOR/3TC/TDF non-inferior to EFV/FTC/TDF at Wk 48 in terms of virologic suppression HIV RNA >50: ~10% in each arm 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 Slide 15 of 44 DRIVE-AHEAD: Doravirine/3TC/TDF in Treatment-Naïve Persons With HIV Infection Patients (%) HIV RNA <50 Copies/mL Doravirine/3TC/TDF Difference (%): 3.5 (-2.0, 9.0) % 91% 84% 81% Overall ITT (n=364/364) 100K (n=277/258) Efavirenz/FTC/TDF 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 50 yo HIV+ M with diabetes, hypertension, chronic renal insufficiency (creatinine clearance of 25), no hep B 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 Slide 16 of 44

60 Slide 17 of 44 OR FEW 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 Slide 18 of 44 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, Slide 19 of 44

61 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 ongoing 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) Slide 20 of 44 Figueroa et al, CROI 2018, Abstract 489 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 Slide 21 of 44 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 Slide 22 of 44 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

62 23 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 Slide 23 of 44 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 3. Slide 24 of 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% 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 % Virologic Data Slide 25 of 44 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].

63 Slide 26 of 44 Long-acting NRTTI: MK-8591 (EFdA) Nucleoside RT translocation inhibitor (NRTTI) Phase 1b, single-dose, monotherapy study Study population: ART naïve (N=30) Half life of active anabolite: hr Humans: single oral dose as low as 0.5 mg suppressed HIV RNA for >7 day Study in healthy volunteers: multiple daily doses as low as 0.25 mg expected to lead to HIV suppression Phase 2b trial in people with HIV, in combination with DOR and 3TC, has started (DRIVE2Simplify) Daily dosing Grobler CROI 2017 #435 Matthews IAS 2017 #TUPDB0202LB Matthews RP CROI 2018 #26 Long-acting NRTTI: MK-8591 (EFdA) Animals: drug accumulates in lymph nodes, vagina, rectum Oral MK-8591, even at low doses, protects monkeys from rectal SHIV challenge Parenteral dosing: 6-12 months Supports possible role in PrEP Grobler CROI 2016 #98 Friedman CROI 2016 #437LB Grobler CROI 2017 #435 Markowitz IAS 2017 #MOAX0203LB Markowitz CROI 2018, #89LB Adapted from slide by Trip Gulick, MD Slide 27 of 44 Case Scenario Slide 28 of 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 the following classes of drugs is in phase 3 clinical trials? 1. Entry/attachment inhibitors 2. Maturation inhibitors 3. Capsid inhibitors 4. Broadly neutralizing antibodies

64 Medications for Multi-drug Resistant HIV Ibalizumab (approved) Fostemsavir (Phase 3) Slide 29 of 44 HIV Entry Inhibitors CD4 Binding Coreceptor Binding Virus-Cell Fusion fostemsavir gp41 CCR5 Inhibitors maraviroc* enfuvirtide* ibalizumab gp120 V3 loop CD4 Slide 30 of 44 Cell Membrane * = FDA approved CCR5/CXCR4 (R5/X4) Slide courtesy of Trip Gulick, MD; Adapted from Moore JP, PNAS 2003;100: Ibalizumab 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 Slide 31 of 44 IV infusion: 2,000 mg loading dose then 800 mg every 2 wks Duration of infusion: min 1 Emu B et al, Abstract 1686, IDWeek 2017; 2 Weinheimer S et al, CROI

65 A Approved 32 Ibalizumab in Persons with Multi-Drug Resistant HIV Phase 3 trial: 40 heavily treatment experienced pts with 3-class ARV resistance Primary endpt: VL drop >0.5 log 10 c/ml: 3% during control period 83% after loading dose After loading dose, regimen optimized to include 1 active drug Wk 24: VL <200 in 50% Expanded access: viral suppression to wk 48 March 6, 2018 Slide 32 of 44 Emu B et al, Abstract 1686, IDWeek 2017 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 Slide 33 of 44 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 Slide 34 of 44

66 Slide 35 of 44 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 HIV Maturation Inhibitors (MI) Slide courtesy of Trip Gulick, MD Treated with maturation inhibitor Immature virus Slide 36 of 44 Morales-Ramirez IAS 2017 #MOAB0103:BMS /GSK development halted due to GI toxicity On the Horizon Broadly neutralizing antibodies Other novel agents Slide 37 of 44 37

67 Slide 38 of 44 Broadly Neutralizing Antibodies against HIV Slide courtesy of Pablo Tebas, MD Scheid J et al, Nature, 2016 Slide 39 of 44 Similar results with VRC01. Bar K et al, NEJM 2016 Combination bnab, long-acting bnab being studied for treatment, prevention Other investigational drugs in the pipeline: Slide 40 of 44

68 Slide 41 of 44 Challenges to studies of new ART Treatment naïve population is (fortunately) declining Same day starts limit opportunities for studies Multi-drug resistant population often has other challenges that make study participation difficult Need multiple sites to conduct these site Investigational Approaches to Antiretroviral Therapy Slide 42 of 44 New options for initial treatment: Bictegravir/FTC/TAF approved; Doravirine (NNRTI) under FDA review Two-drug therapy advancing: DTG + 3TC and DRV/r + 3TC studies 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; PRO 140, other agents being developed What s on the horizon? broadly neutralizing antibodies, and many others!! Many thanks to Dr. Rajesh Gandhi for sharing slides for this talk Slide 43 of 44

69 Question-and-Answer

70 Opioid Withdrawal, Opioid Substitution, and HIV Infection R. Douglas Bruce, MD, MA, MS Associate Clinical Professor of Medicine Yale University New Haven, Connecticut Learning Objectives After attending this presentation, learners will be able to: Describe opioid use disorder Initiate treatment for opioid use disorders Describe the implications of opioid use disorders in people living with HIV infection Slide 3 of 30 Question 1 According to CDC data, how many people died of opioid overdose in the United States in 2016? 1. 5, , , , Over 40,000 Slide 4 of 30

71 Slide 5 of 30 Slide 6 of 30 Addiction A state in which a person engages in compulsive behavior The behavior is reinforcing (that is, pleasurable or rewarding) There is a loss of control in limiting the intake of the substance Slide 7 of 30

72 Slide 8 of 30 Why do people take drugs? To feel good To have novel: feelings sensations experiences AND to share them To feel better To lessen: anxiety worries fears depression hopelessness Why do some people become addicted? Biology/genes Biology/ Environment Interactions Environment Slide 9 of 30 Drugs Are Usurping Brain Circuits and Motivational Priorities Slide 10 of 30

73 Slide 11 of 30 People who use drugs still acquire HIV Slide 12 of 30 Even in the 21 st Century, we have outbreaks of HIV infection among people who use drugs (e.g., Indiana). But there is treatment for opioid use disorders Metzger, 1993: 2 cohorts of patients 103 out-of-treatment IDU opiate users 152 subjects receiving methadone treatment HIV antibody conversion, 18-months 22% of those out-of-treatment 3.5% of those receiving METHADONE But it isn t really a problem Transtheoretical Model of Change: Helping patients to move along the stages of change Basics of Harm Reduction Syringe exchanges When helping hurts Enabling vs. boundaries Graphic by Wayne LaMorte, MD, PhD, MPH Slide 13 of 30

74 Slide 14 of 30 What is medication assisted treatment? Opioid substitution treatment and medication assisted treatment are the same, but what is it? Buprenorphine and methadone can reduce injection related HIV risk behavior decrease psychosocial & medical morbidity increase access to and retention with ARV improve overall health status are associated with decreased criminal activity Dose effect on mu-opioid receptor availability Binding Potential (Bmax/Kd) MRI 4 - Bup 00 mg Bup 02 mg 0 - Bup 16 mg Slide 15 of 30 April 11, 2018 Bup 32 mg Slide Courtesy of Laura McNicholas, MD, PhD Question 2 How many patients do you treat with buprenorphine for opioid use disorder? 1. I don t have a waiver and so can t treat anyone 2. I have a waiver but don t do it yet 3. 0 to 10 patients to 20 patients to 30 patients to 100 patients 7. Over 100 patients Slide 16 of 30

75 Slide 17 of 30 Medications to treat opioid use disorder Methadone Only in OTP Efficacious, best retention Buprenorphine Office based Efficacious, retention less than methadone Naltrexone Office based Efficacious Retention less than methadone & buprenorphine Slide 18 of 30 Slide 19 of 30

76 Slide 20 of 30 Best Practices in Treatment Provision of low threshold, rapid access, appropriately dosed methadone Culturally appropriate counseling for heroin addiction [can be simple (NA) to more complex (CBT)] Treatment of the medical issues associated with addiction (e.g., HIV, hepatitis B/C, and Tuberculosis) Key themes for HIV and substance use People who use drugs and are infected with HIV have higher morbidity and mortality than the general population and others with HIV infection Discrimination is still evident among treating people who use drugs for HIV, Hepatitis C and tuberculosis treatments in the US and globally Adherence remains possible, even in the setting of ongoing substance use Slide 21 of 30 In the Past, Bias: PWID without ART In the past, people who inject drugs (PWID) were denied HIV therapy until they ceased drug use While multifactorial, there was a bias against drug users and a failure to recognize addiction as a medical illness PLWHA with other medical illness were not denied treatment. In some settings (e.g., HIV/HCV; HIV/TB), having another medical illness with HIV makes ART access a priority. Slide 22 of 30

77 Slide 23 of 30 In the Present: The Evidence Work from Evan Woods in British Columbia showed that in a cohort of 1191 ART naïve patients followed from ART initiation, resistance was found in 25% of the cohort during the first 30 months (PI and NNRTI resistance). No difference in resistance between people who inject drugs and people who do not inject who were started on ART. This can be done anywhere In India, directly observed therapy of DAAs with buprenorphine in the field In Tanzania, adherence support for HIV and TB medications with methadone In New Haven, HIV and HCV treatment integrated into the methadone clinic Slide 24 of 30 Practical Next Steps Screen patients for substance use disorders using standardized questions: How many times in the past year have you had 5 or more standard drinks in a day? How many times in the past year have you used an illegal drug or a prescription medication for nonmedical reasons? Slide 25 of 30

78 Slide 26 of 30 Additional Next Steps People who use drugs can take medications and should be eligible for HIV, HBV, HCV, and TB care Prescribe naloxone and consider becoming a buprenorphine provider Review guidelines on the treatment of chronic pain and re-evaluate how you prescribe opioids and review Useful websites: American Pain Society has resources available online: American Academy of Pain Medicine resources: Providers Clinical Support System (PCSS) for MAT at Buprenorphine training: Slide 27 of 30 HIV, Pain and Addiction Slide 28 of 30

79 Slide 29 of 30 Questions? Question-and-Answer Slide 30 of 30

80 Update on Hepatitis C Virus Infection Management Kristen M. Marks, MD Assistant Professor of Medicine Weill Cornell Medicine New York, New York Learning Objectives After attending this presentation, learners will be able to: Describe regimens recommended for initial treatment of HCV infection Recognize when to do testing for HCV resistance Discuss treatment as prevention for HIV-infected MSM Slide 3 of 43 Which of the following regimens would NOT be recommended for initial treatment of an HIV-infected patient with HCV G1a and no cirrhosis? 1. Sofosbuvir/velpatasvir/voxilaprevir x 8 wks 2. Sofosbuvir/velpatasvir x 12 wks 3. Sofosbuvir/ledipasvir x 12 wks 4. Glecaprevir/pibrentasvir x 8 wks 5. Elbasvir/grazoprevir x 12 wks 6. Both 1 and 4 (no 8 week regimens in HIV) Slide 4 of 43

81 Slide 5 of 43 IDSA/AASLD EASL Slide 6 of 43 Newer strategy for HCV therapy: Direct acting antivirals target life cycle ---PREVIR Protease inhibitors e.g. telaprevir, boceprevir, faldaprevir, simeprevir, danoprevir, asunaprevir, paritaprevir, grazoprevir, voxilaprevir, glecaprevir ---BUVIR Polymerase inhibitors Nucleos(t)ide analogs: e.g. tegobuvir, sofosbuvir, Non-nucs: e.g. deleobuvir, dasabuvir ---ASVIR NS5A inhibitors e.g. daclatasvir, ledipasvir, ombitasvir, elbasvir, velpatasvir, pibrentasvir Slide 7 of 43

82 Slide 8 of 43 Currently used combinations of DAA classes +/- NUC + PI RBV NUC-SPARING HCV Renal insufficiency Drug-drug interactions Duration Affordability/Access Toxicity Resistance NUC + NS5A PI PI +/- RBV NUC + NS5A +/- RBV PI + + NS5A + NS5A + nonnuc NUC-SPARING HIV Toxicity Resistance Renal insufficiency Drug-drug interactions Affordability +/- RBV Minimum to Know Pre-Treatment HCV genotype/subtype HCV resistance (sometimes) Stage of fibrosis Cirrhosis - yes/no If yes, decompensated? (e.g., ascites, encephalopathy, etc) If yes, don t use PIs! Method? Liver biopsy Transient elastography Laboratory biomarkers Imaging Prior HCV treatment? Response? DAA used? Medications To check for drug interactions Comorbidities Renal function HIV status Life expectancy < 1yr non-liver causes? Patient preference Child-bearing potential of patient/partner Ribavirin is a teratogen HIV/Hepatitis C helpline Slide 9 of 43 Approved Drug Regimens for Initial Treatment Interferon PEG RBV SOF PegIFN RBV SOF RBV +/- SMV LDV SOF SOF DAC SOF RBV +/- PTV/r OMV DAS +/- Ribavirin ribavirin ribavirin +/-ribavirin +/-ribavirin GZR EBV VEL SOF Nucs sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir sofosbuvir GLE PBV Protease inhibitors simeprevir Paritaprevir /ritonavir grazoprevir velpatasvir glecaprevir NS5A ledipasvir daclatasvir ombitasvir elbasvir pibrentasvir Non-Nucs dasabuvir G1 X X X X X X X X X G2 X X X X X G3 X X X X X G4 X X X X X X X X X Slide 10 of 43

83 Slide 11 of 43 G1b vs G1a: G1b Initial Treatment Recommended Regimens IDSA/AASLD NO CIRRHOSIS: Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 8 w Ledipasvir/sofosbuvir x 8* or 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w *8 wk not recommended for Black patients or HIVinfected. Only recommended when RNA< 6 million IU/ml CIRRHOSIS: Elbasvir/grazoprevir x 12 w Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w* (BOLDED are regimens approved since last year!) G1a Initial Treatment Recommended Regimens IDSA/AASLD NO CIRRHOSIS: Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 8 w Ledipasvir/sofosbuvir x 8* or 12 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir/velpatasvir x 12 w Paritaprevir /ritonavir/ombitasvir + dasabuvir x 12w Simeprevir x sofosbuvir 12w Daclatasvir + sofosbuvir x 12w CIRRHOSIS: Elbasvir/grazoprevir x 12 w if no hi level NS5A resistance Glecaprevir/pibrentasvir x 12 w Ledipasvir/sofosbuvir x 12 w Slide 12 of 43 *8 wk not recommended for Black patients or HIV-infected (BOLDED are regimens approved in past year) RAS Testing prior to Treatment NS5A RASs are relatively common (10-15%) Significance of NS5A RASs may depend on the RAS, the genotype, the regimen used and whether prior NS5A treatment In initial treatment, use resistance testing prior to: Treatment with grazoprevir/elbasvir for 1a Treatment of G3 if cirrhosis Slide 13 of 43

84 Slide 14 of 43 Pangenotypic Glecaprevir/pibrentasvir Slide 30 of 52 DAA combo naive (TN, PEG/RBV, SOF) & special pops ENDURANCE (Phase 3) GT 1 no cirrhosis (8 vs 12W) GT 2 no cirrhosis (12W) GT 3 no cirrhosis (8 and 12W) GT 4-6 (12W) EXPEDITION (Phase 3) GT 1, 2, 4-6 cirrhosis GT 1-6 HIV GT 1-6 Renal impairment SURVEYOR (Phase 2) GT 2, 4-6 no cirrhosis 8 weeks GT 3 cirrhosis/te 12 vs 16 W Co-formulated 3 pills once daily Pangenotypic Next generation Active vs NS3 RAS at 80, 155, 168 and NS5A RAS at 28, Q30, 31, 93 A30K associated with failure in GT3 infection Negligible renal excretion Contains a protease inhibitor Has interaction with acid suppressing meds G/P Slides courtesy of S. Naggie Glecaprevir/pibrentasvir: No Cirrhosis 8 (N=828) vs 12 (N=1076) weeks weeks 12 weeks TN and TE 80 PEG, RBV, SOF 70 No DAA otherwise 60 Relapse <1% 50 Tx emergent RAS Slide 15 of 43 Puoti et al. EASL All GT 1 GT 2 GT 3 GT 4 GT 5 GT 6 Glecaprevir/pibrentasvir: Cirrhosis Slide 34 of weeks in N=146 Compensated cirrhosis TN or TE (25%) with IFN, P/R or SOF+P/R GT1a 33%, GT1b 27%, GT2 23%, GT4 11%, GT5 1%, GT6 5% 1 relapse- GT1a Slide 16 of 43 Forns et al. EASL 2017

85 Slide 17 of 43 Glecaprevir/pibrentasvir: HIV Slide 36 of 52 GT 1-6 Primarily an 8 week study 12 weeks in 16 patients with cirrhosis TN or TE (19%) with IFN, P/R or SOF+P/R VBT on treatment GT3 with cirrhosis /136 14/15 8 week no cirrhosis 12 week cirhosis Rockstroh et al. EASL 2017 Slide 35 of 52 Glecaprevir/pibrentasvir: Renal Impairment GT 1-6 for 12 weeks Stage 4 or 5 CKD GFR<30 including HD 82% on HD TN or TE (42%) with IFN, P/R or SOF+P/R Including compensated cirrhosis (19%) GT1a 22%, GT1b 28%, GT2 16%, GT3 11%, GT4 19%, GT5 1, GT6 11 Slide 18 of 43 Gane et al. EASL 2017 v (Slide to be updated later this month with guidelines release) Slide 19 of 43

86 Slide 20 of 43 Sofosbuvir/velpatasvir x 12 wks in HIV/HCV G1-6, Naïve + Rx-exp N=106 29% Rx-exp 18% cirrhosis 12% NS5a RAVs Of 2 relapses: 1 rx-exp, 0 cirrhosis, 0 baseline RAVS Renal fxn looked unchanged in pts on boosted TDF POLARIS-2: 8-Wk SOF/VEL/Voxilaprevir vs. 12- Wk SOF/VEL Not Non-inferior for DAA-naïve 8-wk SOF/VEL/VOX did not meet criteria 0 for noninferiority vs wk SOF/VEL Treatment 60 difference: -3.4% 40 (95% CI: -6.2% to -0.6%) / 57/ 61/ 53/ 91/ 86/ n/n = / 2/ 7/ / 5/ / Overall GT1 GT1a GT1b GT GT Relapse, n LTFU, n D/c for AE, n SVR12 (%) SOF/VEL/VOX 8 wks SOF/VEL 12 wks / 56/ 17/ 30/ 9/ 2/ GT GT GT Unknown Slide 21 of 43 Jacobson IM, et al. Gastroenterology Slide credit: clinicaloptions.com G2 INITIAL TREATMENT RECOMMENDED REGIMENS IDSA/AASLD NO CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 wks CIRRHOSIS: Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 wks Slide 22 of 43

87 Slide 23 of 43 Before administering sofosbuvir/velpatasvir in a patient with renal insufficiency (CrCl 50) on TDF/FTC + darunavir/ritonavir, which of the following should be considered? 1. Change darunavir/r dosing from BID to QD 2. Change TDF to TAF 3. Change darunavir/r to efavirenz 4. No ARV adjustment needed Slide 24 of 43 HCVguidelines.org With SOF/LDV + TDF, tenofovir exposures are high in those on PIs NNRTIs Without With LDV/SOF 1,2 LDV/SOF3 RTV-Boosted PIs Without With LDV/SOF 4-9 LDV/SOF10 Range of TFV exposures with available safety data EFV RPV ATR CPA N = FPV SQV LPV/r ATV DRV ATV DRV TFV exposures are higher when TDF is coadministered with LDV/SOF compared to without LDV/SOF, but Compared to the range of TFV exposures with available safety data For EFV or RPV: TFV exposures fall within the range 1 For RTV-boosted PIs: TFV exposures partially exceed the range 2 Slide 25 of 43 1, Data on File, Gilead Sciences. 6. Zhu. 9th IWCPHT #023 (ATV+RTV & LPV/r ) 2. Hoetelmans RMW, et al. 6 th IWCPHT Quebec City, Canada. Poster # Kearney B, et al. JAIDS. 2006;43(3): (LPV/r) 3. German P, et al. ICPHHT #O6 8. Agarwala S, et al. 6th IWCPHT #16. (ATV+RTV) 4. Luber AD, et al. HIV Medicine. 2010;11:193-9 (FPV+RTV) 9.. Hoetelmans RMW, et al. BJCP. 2007;64(5): (DRV+RTV) 5. Chittick GE, et al. AAC. 2006; 50(4): (SQV+RTV) 10. German P, et al. CROI 2015 Slide courtesy of J Kiser

88 Slide 26 of 43 Guidelines Recommendation about use of LDV or VEL with TDF SOF/LDV + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR SOF/VEL + TDF CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR SOF/LDV + TDF + cobi- or ritonavir-boosted PI Any CrCl: AVOID if possible, Consider TAF SOF/VEL + TDF + cobi- or ritonavir-boosted PI CrCl < 60 ml/min: AVOID CrCl > 60: MONITOR or consider TAF Slide 27 of 43 HCVguidelines.org Drug-Drug Interactions with DAAS Acid-reducing drugs Anti-epileptics Antiretrovirals Amiodarone Lipid-lowering drugs Slide 28 of 43

89 Slide 29 of 43 ARV switches for HCV treatment do not result in HIV treatment failure: Interim analysis of multicenter international registry Marks, CROI, 2018 Which of the following is recommended for initial treatment of HCV G3 in a patient with cirrhosis? 1. Sofosbuvir/ledipasvir x 12 wks 2. Sofosbuvir/velpatasvir x 12 wks 3. Elbasvir/grazoprevir x 12 wks 4. Glecaprevir/pibrentasvir x 8 wks Slide 30 of 43 G3 INITIAL TREAMENT RECOMMENDED REGIMENS IDSA/AASLD NO CIRRHOSIS: Glecaprevir/pibrentasvir x 8 w Sofosbuvir/velpatasvir x 12 w Sofosbuvir + daclatasvir x 12w CIRRHOSIS: Glecaprevir/pibrentasvir x 12 w Sofosbuvir/velpatasvir x 12 w* Sofosbuvir + daclatasvir +/-RBV x 24w* *RAV testing for Y93H and add RBV if present or use sofosbuvir/velpatasvir/voxilaprevir Slide 31 of 43

90 Glecaprevir/pibrentasvir in GT3 Treatment-naïve without Cirrhosis Slide 32 of 52 Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure 3% G/P 4 in 12W (3 relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) BL Y93H: 5/5 SVR BL dual NS3/NS5A 71-86% SVR Tx emergent RAS 50% failures with A30K BL SURVEYOR-II G3 with Cirrhosis A30K+Y93 (69-fold R 48 patients received G/P +/- RBV x 12 w = 100% SVR Foster et al. EASL 2017 Slide 32 of 43 Slide 32 of 52 Glecaprevir/pibrentasvir and RASs -- A30K effect? Non-inferiority 12W vs DAC/SOF X12W 12W vs 8W Viral Failure 3% G/P 4 in 12W (3 relapse, 1 VBT) 1 in DAC/SOF 6 in 8W (5 relapse, 1 VBT) Tx emergent RAS 50% failures with A30K BL 6% patients overall had a BL A30K SURVEYOR-II G3 with Cirrhosis 48 patients received G/P +/- RBV x 12 w = 100% SVR Slide 33 of 43 Foster et al. EASL 2017 Krishnan et al. EASL 2017 Sofosbuvir/velpatasvir x 12 wks for G3 (ASTRAL-2) Most of this 3% w/ failure had cirrhosis Slide 34 of 43 Los Angeles, California, April 9, 2018 Foster, NEJM, 2015, hcvguidelines.org Page 11

91 Slide 35 of 43 POLARIS-3: SVR12 Rates With 8-Wk SOF/VEL/Voxilaprevir for DAA-naive Cirrhotic GT3 SVR12 (%) n/n = 0 SOF/VEL/VOX 8 wks SOF/VEL 12 wks / 105/ 72/ 76/ 34/ 29/ 80/ 76/ 23/ 23/ Overall Treatment Treatment No BL RASs Any BL RASs Naive Experienced Both regimens: P <.001 for superiority vs prespecified 83% goal Overall VF: SOF/VEL/VOX, n = 2 relapses; SOF/VEL, n = 1 each for relapse and on-treatment failure No treatment-emergent RASs in SOF/VEL/VOX arm; Y93H in both VFs in SOF/VEL arm Jacobson IM, et al. Gastroenterology Slide credit: clinicaloptions.com HCV Treatment as Prevention: DAA access and HCV Incident Infection Slide 36 of 43 Swiss HCVree Trial: Treatment as Prevention Used Swiss HIV cohort study (SHCS) Estimated 75% of HIV+ MSM are enrolled in SHCS Tests all MSM for HCV then q 12 mos Ph A, Oct Jun 2016: Test all MSM HCV PCR Ph B, Jul 2016 Feb 2017: Treat all RNA+ (SVR rate 99.5%) Ph C, Mar 2017-Nov 2017: retest HCV PCR Slide 37 of 43 Braun et al, CROI, 2018

92 Slide 38 of 43 HCV RNA decline >2 log associated with spontaneous clearance of HCV in HIV-infected MSM THE PROBE-C STUDY PV SC Univariate n=409 n=55 p-value** Median age [years] (IQR) 41 (40-42) 42 (40-46) Male gender [%] Multivariate p-value*** Multivariate Odds-Ratio (95% CI)*** 12% had spontaneous clearance Transmission risk [%] Median CD4-cells [/µl] (IQR) 580 ( ) 544 (59-666) [%] (IQR) 29 (28-31) 27 (24-31) HIV-RNA <200 copies/ml [%] cart [%] ( ) Median HCV-RNA [IU/ml] (IQR) 687,811 (518,000-1,149,994) 677,481 (149,000-2,764,000) Median maximum ALT [U/l] (IQR) 431 ( ) 591 ( ) HCV genotype [%] >2log decline in HCV week 4 [%] ( ) Median time to 1st negative HCV RNA [weeks] (IQR) - 13 (12-18) - Median time to treatment initiation* [weeks] (IQR) 11 (10-13) - - * Based upon discretion of investigator; 5 weeks **Pearson`s Chi-Square, Fisher`s Exact, Mann-Whitney-U Test; ***Binary logistic regression, inclusion Boesecke et al. CROI 2018 Abstract 129 Shortened Course Treatment for Acute HCV? Regimen SVR12 Virologic failures Germany/UK study Sofosbuvir/ ledipasvir x 6 wks 20/26 (77%) 1 reinf, 3 relapse*, 2 LTFU ACTG 5327 c2 Sofosbuvir/ ledipasvir x 8 wks 27/27 (100%) DAAHS 2 (g1,4) Grazoprevir/ elbasvir x 8 wks 59/63 (94%) 3 reinf, 1 relapse* *All relapses in patients with high baseline VL Slide 39 of 43 Rockstroh, Lancet Gastro Hep, 2017; 2(5): Naggie et al, AASLD 2017 Boerekamps et al, CROI 2018 Slide 40 of 43 It s time! Cure Everyone with HCV Remarkable advances in terms of HCV treatment tolerability & efficacy for patients with HIV Recent advances in G2, G3, ESRD SVRs for HIV/HCV very close to monoinfection Still drug interaction issues, but valuable resources to help manage RAV testing prior to initial treatment if: G1a and planned grazoprevir/elbasvir G3 & cirrhosis and planned sofosbuvir/velpatasvir Successful treatment prevents cirrhosis, end stage liver disease, and hepatocellular cancer. And prevents spread of HCV. Post SVR continue liver disease management/hcc screening, monitor HBV reactivation, and provide HCV RNA testing if ongoing risk