1. 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

2. 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)

3. 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

4. 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

5. Issued Feb 2019
Courtesy of Raj Gandhi

6. 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

7. CROI 2019
Prevention

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

14. 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 Abstr 107.

15. Testing, Treatment and complications
CROI 2019
Testing, Treatment and complications

16. 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 ( )
Drain. CROI Abstr 53.

17. 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 Abstr 144. Aboud. Lancet Infect Dis. 2019;19:253.

19. 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 Abstr 144.

20. 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 Abstr 144.

21. 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: Zash. AIDS Abstr TUSY15.
3. Zash Lancet Global Health :e ARV Pregnancy Registry Interim Report 7/31/2018.

22. 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 Abstract P030

23. 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

24. NA-ACCORD: Weight Gain Among 24,001 Treatment-Naive Patients Initiating ART
Multivariate analysis of weight gain after ART initiation Jan 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 Abstr 670.

25. 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: : 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 Abstr 669.

27. CROI 2019
Persistence and Cure

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

29. 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

30. 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

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

32. 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

33. 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

34. Question-and-Answer