CROI 2019: ARV for Prevention and Treatment, HIV Pathogenesis, and Cure Joseph J. Eron, Jr, MD Professor of Medicine University of North Carolina Chapel Hill, North Carolina

Financial Relationships With Commercial Entities Dr Eron has served as an ad hoc consultant to Janssen, ViiV Healthcare, Merck, and Gilead Sciences, Inc. His institution receives contracts for clinical research on which Dr Eron is the local principal investigator from Janssen Therapeutics, ViiV Healthcare, and Gilead Sciences, Inc. (Updated 05/15/19)

Learning Objectives After attending this presentation, learners will be able to: Describe trends in new HIV diagnoses in the United states Discuss results the recent Phase III preexposure prophylaxis study of tenofovir alafenamide/emtricitabine Contrast the changes in weight seen with different antiretroviral medications and classes

ARS Question #1: According to the CDC, from 2013 to 2016 the number of new HIV Infections in the United States has: Continued to decrease at a greater (steeper) rate than the previous 4 years Continued to decrease at a similar rate than the previous 4 years Stabilized and is no longer declining Increased

Issued Feb 2019 Courtesy of Raj Gandhi

Resources targeted to 48 highest burden counties; Washington, D. C Resources targeted to 48 highest burden counties; Washington, D.C.; San Juan, Puerto Rico; 7 states with substantial rural HIV burden. Slide courtesy of Raj Gandhi

CROI 2019 Prevention

The Phase 3 DISCOVER Study: Daily F/TAF or F/TDF for HIV Pre-exposure Prophylaxis

Effects of PrEP on Drug Resistance and Acute HIV Infection in New York City Surveillance Population 3685 patients diagnosed with HIV in NYC over a 12 month period – 91 previously used PrEP Median time from last PrEP use was 106 days Identification of FTC but not TDF resistance mutations more common among PrEP users vs never-users K65R identified in 4 individuals, all never-users Diagnosis with acute HIV infection more common among PrEP users vs never-users Resistance Mutation Analysis, % PrEP Users (n = 91) Never-Users (n = 3594) All Patients (N = 3685) Genotype data available 75 63 Resistance mutations M184I/V/IV/MV K65R 29 2 < 1 3 < 1 Acute HIV infection 33 9 10 FTC, emtricitabine; PrEP, pre-exposure prophylaxis; TDF, tenofovir disoproxil fumarate. Misra. CROI 2019. Abstr 107.

Testing, Treatment and complications CROI 2019 Testing, Treatment and complications

STREAM: POINT-OF-CARE VIRAL LOAD TESTING IMPROVES HIV VIRAL SUPPRESSION AND RETENTION IN CARE Open-label, randomized controlled trial at public clinic in Durban, South Africa 390 HIV patients 6 months after HIV initiation randomized to point of care testing or usual care Point of care included HIV RNA by Xpert HIV-1 VL, CD4 and creatinine Clinic visits every 2 mos; HIV-1 RNA testing at 6 and 12 mos, then annually. 99.5% received VL same day in POC arm vs. median 41 days with blood draw Primary endpoint: retention in care with HIV-1 RNA < 200 copies/mL at 12 mos 89.7% vs. 75.9% were retained in care with HIV RNA < 200 c/mL at 12 month Absolute difference 13.9 (6.4-21.2) Drain. CROI 2019. Abstr 53.

DAWNING: Study Design International, randomized, open-label phase IIIb study Primary endpoint: 84% vs. 70% < 50 c/mL at 48 week Two participants developed INSTI resistance on DTG Primary Endpoint Wk 48 Stratified by number of fully active NRTIs (2 vs < 2), HIV-1 RNA (≤ vs > 100,000 c/mL) Wk 52 Patients with HIV infection and VF (2 instances of HIV-1 RNA ≥ 400 copies/mL) on first-line NNRTI + 2 NRTIs; receiving first-line regimen ≥ 6 mos; no primary resistance to INSTIs or PIs (N = 624) DTG + 2 NRTIs* (n = 312) DTG + 2 NRTIs continuation phase LPV/RTV + 2 NRTIs*† (n = 312) DTG, dolutegravir; LPV, lopinavir; RTV, ritonavir; VF, virologic failure. *Investigator-selected NRTIs; included ≥ 1 fully active NRTI according to HIV genotypic resistance testing at screening. †Based on recommendation by monitoring committee, protocol amended to allow d/c of LPV/RTV arm and crossover to DTG arm. Brown. CROI 2019. Abstr 144. Aboud. Lancet Infect Dis. 2019;19:253.

DAWNING: Virologic Response by Presence of M184V/I ± Other NRTI Mutations and Use of 3TC or FTC HIV-1 RNA < 50 copies/mL at Wk 48 in ITT-E Analysis, % (n/N) DTG + 2 NRTIs LPV/RTV + 2 NRTIs Treatment Difference, % Overall M184V/I* present Use of 3TC or FTC No use of 3TC or FTC No M184V/I 84 (261/312) 84 (220/261) 85 (187/220) 80 (33/41) 80 (41/51) 70 (219/312) 72 (182/252) 72 (152/210) 71 (30/42) 62 (37/60) 13.8 12.1 12.6 9.1 18.7 3TC or FTC use M184V/I only M184V/I + ≥ 1 NRTI RAM M184V/I + ≥ 1 TAM M184V/I + K65R 82 (47/57) 86 (140/163) 90 (54/60) 85 (23/27) 68 (44/65) 74 (108/145) 72 (46/64) 68 (15/22) 14.8 11.4 18.1 17.0 3TC, lamivudine; DTG, dolutegravir; FTC, emtricitabine; ITT-E, intention-to-treat–exposed; LPV, lopinavir; RAM, resistance associated mutation; RTV, ritonavir; TAM, thymidine analog mutation. *Alone or with other NRTI mutations. The other NRTI has to have full activity based on resistance testin6 Brown. CROI 2019. Abstr 144.

DAWNING: Virologic Response by Use of TDF With K65R or ZDV With TAMs HIV-1 RNA < 50 copies/mL at Wk 48 in ITT-E Analysis, % (n/N) DTG + 2 NRTIs LPV/RTV + 2 NRTIs Treatment Difference, % K65R present 84 (80/95) 74 (68/92) 10.3 Use of TDF in presence of K65R 86 (6/7) 88 (7/8) -1.8 ≥ 1 TAM present 87 (62/71) 75 (61/81) 12.0 Use of ZDV in presence of ≥ 1 TAM 86 (30/35) 78 (40/51) 7.3 DTG, dolutegravir; ITT-E, intention-to-treat–exposed; LPV, lopinavir; RTV, ritonavir; TAM, thymidine analog mutation; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine. What proportion of the participants with K65R received ZDV? – presumably most or all What other nucleoside was used in participants with one or more TAMs who received ZDV? Did this include the small number of participants who did not have M184V or M184I? Brown. CROI 2019. Abstr 144.

Neural Tube Defects* (%, 95% CI) Tsepamo Interim Analysis: DTG Exposure at Conception and During Pregnancy Tsepamo: ongoing birth outcomes surveillance study among Botswanan women ± HIV infection[1,2] At latest analysis on July 15, 2018[2] NTD prevalence with DTG exposure at conception: 4/596 (0.67%; 95% CI: 0.26% to 1.70%) NTD prevalence with DTG started during pregnancy: 1/3104 (0.03%; 95% CI: 0.01% to 0.18%) ARV Pregnancy Registry (7/31/18): No NTDs in women with first trimester or any DTG, EVG, or RAL exposure reported to Antiretroviral Pregnancy Registry[4] DTG Any Non-DTG ART EFV HIV Negative Pregnancy Neural Tube Defects* (%, 95% CI) Conception 0.94 0.12 0.05 0.00 0.09 2.5 1.5 0.5 2.0 1.0 DTG, dolutegravir; EFV, efavirenz; NTD, neural tube defects. *In 89,064 births as of May 1, 2018. Zash. NEJM. 2018;379:979. 2. Zash. AIDS 2018. Abstr TUSY15. 3. Zash Lancet Global Health 2018 6:e804-810. ARV Pregnancy Registry Interim Report 7/31/2018.

Neural tube Defects with RAL and EVG/cobi No NTDs with first trimester EVG or RAL exposure in Antiretroviral Pregnancy Registry (APR) as of July 2018 Gilead global safety database assessed for NTDs in infants exposed to EVG in utero: database includes pregnancy outcomes from clinical trials, APR, spontaneous post- marketing and solicited cases, literature N = 630 pregnancies with EVG exposure identified No prospectively identified NTD cases n = 2 retrospectively identified NTD cases (anencephaly, myelomeningocele; (TAB)) 4 retrospective reports in Merck database 1 preconception live birth Shamsuddin et al CROI 2019; APRegistry 2018; Farrow T, et al. Glasgow 2018. Abstract P030

ARS Question #2 In the NA-ACCORD observational study, which medication was associated with the greatest weight gain over 2 years following initiation of therapy? Elvitegravir Dolutegravir Raltegravir NNRTI Unsure

NA-ACCORD: Weight Gain Among 24,001 Treatment-Naive Patients Initiating ART Multivariate analysis of weight gain after ART initiation Jan 2007 - Dec 2016 INSTI-based regimens: n = 4740 EVG: n = 2124 RAL: n = 1681 DTG: n = 935 PI-based regimens: n = 7436 NNRTI-based regimens: n = 11,825 NR, not reported. More weight gain with INSTI- vs NNRTI-based treatment and with DTG or RAL vs EVG Weight gain with INSTIs did not vary by sex or race Bourgi. CROI 2019. Abstr 670.

Weight Gain After Switch to INSTI by Agent, Pre-Switch ART Class, and NRTI Backbone at Switch Prospective, observational cohort study of weight gain after switch to INSTI-based ART in patients enrolled on ACTG A5001, A5322: 2007-2017: N = 691 HIV-1 RNA < 200 copies/mL at time of switch required for inclusion Change in weight gain rate greater with DTG vs EVG or RAL Annual weight gain increased following switch to INSTI, with greater increases among women, blacks, and individuals 60 yrs of age or older Lake. CROI 2019. Abstr 669.

CROI 2019 Persistence and Cure

ARS Question #3 Most patients who are on stable antiretroviral therapy with low level viremia (HIV RNA levels between 20-100 c/mL) have ongoing replication and are at risk of resistance emergence: True False Unsure

Elias K. Halvas, Ph.D. and Colleagues Non-Suppressible Viremia on ART is From Large Cell Clones Carrying Intact Proviruses Elias K. Halvas, Ph.D. and Colleagues March 4th, 2019 Seattle CROI 2019 HIV Dynamics and Replication Program National Cancer Institute at Frederick

Suspected Clones with Replication-Competent Proviruses in Blood (“Repliclones”) Donor ID % Identical Plasma HIV RNA Single Genome Sequences (SGS) (% matching) Do Proviral SGS Match Plasma HIV RNA SGS? Do qVOA SGS Match Plasma HIV RNA SGS? % of qVOA p24+ Wells Matching Plasma HIV RNA SGS Do Proviral SGS Match qVOA SGS? R-09 45.2% Yes (11.2%) Yes 100% (10/10) C-03 57.1% Yes (2.5%) 66.7% (2/3) C-02 85.4% Yes (6.9%) 100% (3/3) F-07 48.7% Yes (0.3%) No 0% (0/4) T-13 28.3% Yes (14.7%) 35.3% (6/17) K-01 33.3% Yes (3.9%) No (<3.9%) P-08 85.7% Yes (8.0%) 0% (0/3) No (<8.0%) T-05 76.7% No (<0.7%) A-06 No (<0.9%) 0% (0/2) A-04 Replication/Resistance

Photo courtesy of Pablo Tebas, MD Gupta RK et al. Nature 2019 Mar 5; [e-pub]. Photo courtesy of Pablo Tebas, MD

London Patient 2003: Diagnosed with HIV 2012: Initiated ART. Diagnosed Hodgkin lymphoma; multiple rounds of chemotherapy to achieve remission 2016: stem cell transplant from CCR5 Δ32/Δ32 donor. Reduced intensity conditioning; no total body irradiation Course complicated by EBV reactivation (received rituximab), mild GVHD 100% donor chimerism (all of his CD4 cells lacking CCR5) 16 months after transplant, ART stopped HIV undetectable on multiple tests, including virus outgrowth assay Declining HIV specific immune responses Gupta RK et al. Nature 2019 Mar 5; [e-pub]. 32

London and Berlin Patients: Comparison London Patient Donor: CCR5 Δ32/Δ32 Recipient: CCR5 WT/WT R5 virus Hodgkin lymphoma Single HSCT; no irradiation; reduced intensity conditioning; T cell depletion: anti-CD52 Mild GVHD 100% T cell donor chimerism Duration of remission: 18 m Berlin Patient Donor: CCR5 Δ32/Δ32 Recipient: CCR5 Δ32/WT R5 virus AML 2 HSCT; total body irradiation; full intensity conditioning; T cell depletion: ATG Mild GVHD 100% T cell donor chimerism Duration of cure: 12 y 33

Question-and-Answer