CROI 2019:

ARV for Prevention and Treatment,

HIV Pathogenesis, and Cure

Joseph J. Eron, Jr, MDProfessor of Medicine

University of North Carolina

Chapel Hill, North Carolina

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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

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ARS Question #1: According to the CDC, from 2013 to

2016 the number of new HIV Infections in the United

States has:

1. Continued to decrease at a greater (steeper) rate than the

previous 4 years

2. Continued to decrease at a similar rate than the previous 4

years

3. Stabilized and is no longer declining

4. Increased

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Issued Feb 2019Courtesy of Raj Gandhi

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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

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PREVENTIONCROI 2019

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

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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

Effects of PrEP on Drug Resistance and Acute HIV Infection in New York City Surveillance Population

Resistance Mutation Analysis, %PrEP Users

(n = 91)Never-Users

(n = 3594)All Patients(N = 3685)

Genotype data available 75 63 63

Resistance mutations M184I/V/IV/MV K65R

290

2< 1

3< 1

Acute HIV infection 33 9 10

Misra. CROI 2019. Abstr 107.

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TESTING, TREATMENT AND COMPLICATIONSCROI 2019

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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

Drain. CROI 2019. Abstr 53.

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)

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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

*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.

DTG + 2 NRTIs*(n = 312)

LPV/RTV + 2 NRTIs*†

(n = 312)

Stratified by number of fully active NRTIs (2 vs < 2), HIV-1 RNA (≤ vs > 100,000 c/mL)

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)

Primary EndpointWk 48

DTG + 2 NRTIscontinuation phase

Wk 52

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

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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 NRTIsTreatment

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)

13.812.112.69.1

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)

14.811.418.117.0

Brown. CROI 2019. Abstr 144.

*Alone or with other NRTI mutations. The other NRTI has to have full activity based on resistance testin6

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DAWNING: Virologic Response by Use of TDF With K65R or ZDV With TAMs

Brown. CROI 2019. Abstr 144.

HIV-1 RNA < 50 copies/mL at Wk 48 in ITT-E Analysis, % (n/N)

DTG + 2 NRTIs LPV/RTV + 2 NRTIsTreatment

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

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?

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*In 89,064 births as of May 1, 2018.

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

Neu

ral T

ub

e D

efe

cts

*

(%,

95%

CI)

DTG

Conception

0.94

0.12 0.05 0.00 0.09

2.5

1.5

0.5

2.0

1.0

0

1. 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.

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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

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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?

1. Elvitegravir

2. Dolutegravir

3. Raltegravir

4. NNRTI

5. Unsure

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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

• 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.

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Weight Gain After Switch to INSTI by Agent, Pre-Switch ART Class, and NRTI Backbone at Switch

Lake. CROI 2019. Abstr 669.

• 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

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PERSISTENCE AND CURECROI 2019

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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:

1. True

2. False

3. Unsure

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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

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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?

(% matching)

Do qVOA SGS

Match Plasma HIV RNA SGS?

% of qVOA

p24+ Wells Matching Plasma

HIV RNA SGS

Do Proviral SGS

Match qVOA SGS? (% matching)

R-09 45.2% Yes (11.2%) Yes 100% (10/10) Yes (11.2%)

C-03 57.1% Yes (2.5%) Yes 66.7% (2/3) Yes (2.5%)

C-02 85.4% Yes (6.9%) Yes 100% (3/3) Yes (6.9%)

F-07 48.7% Yes (0.3%) No 0% (0/4) Yes (2.5%)

T-13 28.3% Yes (14.7%) Yes 35.3% (6/17) Yes (14.7%)

K-01 33.3% Yes (3.9%) No 0% (0/4) No (<3.9%)

P-08 85.7% Yes (8.0%) No 0% (0/3) No (<8.0%)

T-05 76.7% No (<0.7%) No 0% (0/3) No (<0.7%)

A-06 45.2% No (<0.9%) No 0% (0/2) No (<0.9%)

A-04 Replication/Resistance

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

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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].

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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

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Question-and-Answer