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Breaking News From the 2016 Conference on
Retroviruses and Opportunistic Infections
Jeffrey L. Lennox, MD
Professor of Medicine
Associate Dean for Clinical Research
Emory University School of Medicine
Medicine Chief of Service
Grady Health Systems
Atlanta, Georgia
FINAL: 03/29/16
Atlanta, Georgia: April 8, 2016
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Learning Objectives
After attending this presentation, participants will be able
to describe the results of studies presented at CROI 2016,
including on:
 Results of studies of new drugs, combinations, and
formulations.
 Risks and possible treatments for antiretroviral
therapy (ART)-associated bone loss
 Approaches to prevent HIV-infection.
Slide 2 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Populations and Outcomes
Slide 3 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
HIV+ vs. HIV- Life Expectancy- Kaiser California
•
Adults receiving
care at Kaiser
California, HIV- to
HIV+ 10:1 match
for those seen
between 1996-2011
•
24,768 HIV+,
257,600 HIV-, 91%
male, ~25% white,
~35% ever smoked
Marcus JL #54
Slide 4 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Life Expectancy – Much Improved, But Gaps Remain
Slide 5 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Effect of Race, Gender and Other Factors on Success on Initial ART
•
•
A5257:1809 ARV naïve began TDF/FTC + RAL or DRV/r or ATV/r
24% women; 43% Black, 22% Hispanic
Ribaudo H #476
Slide 6 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Association of Sex and Race/Ethnicity with V.F. – Adjusting for Other Factors
Women did no
worse than men,
and Hispanics
no worse than
non-Hispanic
whites, after
adjusting for
race (Women)
and income
(Hispanics)
Slide 7 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Case 1
A 22 year old male, high-school drop out diagnosed 1 year ago,
CD4 = 2 (1%). Has been hospitalized 5 times for wasting, PCP,
diarrhea. Continues to use marijuana, crack and ETOH. Has
never gone to clinic. Social work has referred him to a drug
rehabilitation program.
Slide 8 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Which of these do you think will most effectively engage him in ART?
1. A healthcare navigator
2. A navigator plus cash
incentives
3. Enroll in a trial of longacting injectable ART
4. Some other intervention
53%
19%
11%
1.
Slide 9 of 39
17%
2.
3.
4.
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Improving Substance Users ART Outcome– CTN 0049
• Hospitalized, viremic
pts in 11 hospitals
randomized to 11
sessions of patient
navigation (PN), vs
PN + $, vs usual care
• PN+$ pts can earn up
to $1160 total- $180
for 4 clinic visits,
$100 for VL<50
Metsch L #27
Slide 10 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
CTN 0049 Results- Pay me now and pay me later?
40
35
p = 0.04
30
25
Change in Viral
Suppression %
35.8
p = 0.68
28.3
27.8
23.6
23.1
24.4
20
15
10
5
0
6 mo.
12 mo.
• At 6 months engagement in care was also improved
• Southern sites had much higher rates of virologic failure (p<0.0001)
Slide 11 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Treatment Naïve Studies and New ARVs
Slide 12 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Oral Induction, Injection Maintenance- LATTE week 32
• Cabotegravir is a new
integrase inhibitor.
 Population- ART naïve
patients with mean CD4
489, 18% with HIV RNA
>100,000K
 Volume– two 3mL
injections q8 weeks or
two 2mL injections q4
weeks
Margolis DA # 31LB
Slide 13 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
LATTE Results
• Rilpivirine did not achieve desired plasma levels until ~ week 16,
methods to increase early levels being explored
• No new ART resistance detected
Slide 14 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Adverse Events and Labs—Maintenance Period
Number of injections
Number of ISRs
Grades
Grade 1
Grade 2
Grade 3
Duration, days
Median
Q 8Wk IM
Q 4Wk IM
1623
1054
2663
1228
839 (80%)
202 (19%)
12 (1%)
3.0
1021 (83%)
197 (16%)
10 (<1%)
3.0
• Number of subjects reporting ISRs decreased over time, from 86%
(Day 1) to 33% (Week 32)
• 2/230 subjects (1%) withdrew as result of injection reactions (Q 8 Wk)
Slide 15 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Efficacy and Safety of ELV/c/TAF/FTC in Adolescents
• Open label, 48 week,
single arm study of
ELV/c/TAF/FTC
• Age 12-18 yrs,
CD4>100, Wt>35kg
• 48 Subjects followed to
48 wks
• 92% (48/50) HIV RNA
<50c/mL at 48 wks
• In this small study there
were no signs of renal
tubular dysfunction
Gaur #817
Slide 16 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
New NNRTI Doravirine vs. EFV- Week 48 Results
• Doravirine active in vitro
against K103N, Y181C,
G190A, E138K
• Metabolized by Cyp3A4,
but not an inducer or
inhibitor
• Continuation of 100mg
from a dose ranging
study, plus new 100mg
pts, vs. EFV in treatment
naïve; with TDF/FTC
• 92% male, CD4 ~400,
VL>100,000 ~36%
Gatell #470
Slide 17 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Doravirine vs. EFV Results
• Doravirine 100mg QD had
similar efficacy to EFV, both
with TDF/FTC
AEs %
Nightmares
Dizziness
≥ Grade 1 LDL
> Grade 2 TG
DOR
5.6
6.5
2.0
0
EFV
8.3
25.9
5.8
1.9
Gatell JM #470
Slide 18 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Long Acting Nucleoside Analog – Potential Once Weekly Dosing
• EFdA (MK-8591) in vitro is
active against HIV, including
K65R TDF resistant ¹
• MK-8591 10mg single dose in
6 ARV-naïve patients ²
• PBMC MK-8591-TP
concentrations exceeded
target at 7 days
• 6/6 pts developed headaches
¹ Michailidis E Retrovirology 2015
Slide 19 of 39
² Friedman EJ #437LB
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Switch Study
Slide 20 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Case 2
A 28 year old Black female on chronic ART with
ELV/c/TDF/FTC. Viral load is suppressed, eGFR is
normal. She heard through a friend that she should
switch to a TAF-containing regimen.
Slide 21 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
What do you recommend?
1. There is not enough data
on efficacy in this
population, stay the course
2. Change TDF to TAF since
it is effective and less toxic
3. Wait until we have more
safety data on long-term,
TAF treated patients
66%
27%
7%
1.
Slide 22 of 39
2.
3.
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Switching Patients From TDF/FTC to TAF/FTC
• Stable patients on
ART entered a
placebo-controlled
study to change
TDF to TAF, or
remain on TDF
• TAF/FTC dosage
differs: 200/10 mg
with PI, 200/25 mg
with non-PI
Gallant J # 29
Slide 23 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
TAF Switch- Safety
• Tolerability and A/E similar
• Grade 3 or 4 LDL in 20 pts on TAF, 8 pts on TDF
• Emergent resistance in 1 pt (184V) on TAF
Slide 24 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
End Organ Disease
Slide 25 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Body Composition Changes: RAL vs. TDF/FTC
• Neat 001study- DRV/r + TDF/FTC vs. DRV/r + RAL
• DEXA Substudy of 126 pts
Week 96
Limb Fat Change
≥ 20% ↓ Limb Fat
Body Fat Change
≥ 20% ↑ Trunk Fat
DRV/r + RAL
+9.8%
10.4%
+15.8%
40.8%
DRV/r + TDF/FTC
+4.9%
17.9%
+6.0%
35.7%
Bernardino J #45
Slide 26 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Bone Fractures and Osteonecrosis – A Multi-National Risk Analysis
• EUROSIDA cohort of 11,820
patients with 86,118 PYFU
since Jan. 2004
• New Fractures – 619, rate
7.2/1,000 PYFU
Osteonecrosis – 89, rate
1.0/1,000 PYFU
• Patients who ever used TDF
were more likely (IRR 1.40)
to develop fractures, but Not
osteoporotic fractures
Borges AH #46
Slide 27 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Maternal TDF – Effect on Infant Bone?
• DXA substudy of
PROMISE: Maternal ZDV
+ sdNVP vs ZDV/3TC +
LPV/r vs TDF/FTC + LPV/r
• About 120 infants per arm
DXA scanned after birth
• No difference in LS
between arms. Whole
body BMC was lower in
both triple drug arms
Siberry G #36
Slide 28 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Stopping or Changing TDF – Effect on Bone
TAF Switch Study
• Follow on study of
IPREX: 352 pts with
DEXA at 24 weeks after
D/C TDF/FTC PrEP ¹
− Annualized BMD
↑1.13 hip, 1.81
spine
• TAF Quad Switch
Substudy ²
− ↑BMD spine and hip
¹ Grant R #48LB ² Gallant J #29
Slide 29 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Bisphosphonate to Prevent ART-Associated Bone Loss
•
•
•
•
ART naïve began TDF/FTC +
ATV/r plus either Zoledronic
acid 5mg IV or placebo IV
single dose
BMD at baseline, q 24 weeks
63 subjects completed 48 wks
− 79% male, 84% Black, CD4
~ 125
CTx, a marker of bone
resorption, was dramatically
reduced in the ZA arm
Ofotokun I #47
Slide 30 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Single Dose Zoledronic Acid Preserves BMD
Lumbar Spine
Slide 31 of 39
Hip
Femoral Neck
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Prevention
Slide 32 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Maraviroc as PrEP – A5305/HPTN 069
• Double-blind, randomized study where all pts got 3 pills daily ¹
• 404 MSM/TGW enrolled and treated
New HIV+
MVC
4
MVC+FTC
0
MVC+TDF TDF+FTC
1
0
• Of 5 newly HIV +, all had R5 HIV, 2/5 never had detectable drug
levels and 3/5 had low levels
• Rectal biopsy tissue explants from MVC only patients more easily
infected in vitro than tissues from patients in other arms ²
¹ Gulick R #103
Slide 33 of 39
² McGowan #104
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Cabotegravir as PrEP Phase 2A - Safety and PK (ECLAIR)
• Placebo-controlled, 4 week oral CAB 30mg or PBO; then Q/2 wk IM
CAB 800mg or PBO
• 127 low risk MSM enrolled
% I.S. pain
% ≥ Grade 3 pain
# days pain
PBO
27
0
20
CAB
92
10
5.4
• PK showed higher peaks, lower trough than expected.
• 2 new HIV+, 1 PBO + 1 CAB. CAB pt had low PK levels despite
I.M. injections.
Markowitz M #106
Slide 34 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Dapivirine Ring PrEP-Phase III Trials
• ¹ MTN 020 (Aspire) enrolled 2,629 women at 4 African
sites.
− 1:1 randomization to DPV ring vs. control ring
changed monthly
− Residual drug concentration of returned, used
rings were measured
• ² IPM027 enrolled 1,959 African women
− 2:1 randomization
¹ Baeten JM #109LB ² Nel A #110LB
Slide 35 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
DPV Ring Efficacy – Phase III Trials
MTN 020
DPV
PBO
IPM 027
DPV
PBO
% Efficacy
MTN / IPM
Rate/100 Pt
Rate, Age >21
Rate, Age ≤ 21
%NNRTI
Resistance
3.3
12
4.5
10
4.1
3.4
6.4
18
6.1
5.5
8.2
15
27 / 31
56 / 37
<0 / 15
n/a
Higher residual drug concentration in used rings correlated with
decreased protection
Slide 36 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
MTN 020 – Adherence and Age
Slide 37 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Opportunistic Infections
Slide 38 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.
Operational Research for Cryptococcal Antigen Screening (ORCAS) Trial
• Test WHO recommended
therapy for asymptomatic
+ CRAG
• 151 asymptomatic
CRAG+ given
Fluconazole 800mg QD x
2 wks→Add ART→400mg
QD x 8 wks
• ~25% risk for death and/or
meningitis, risk greater if
CD4<50 or CRAG>1:160
Morawski BM # 159
Slide 39 of 39
From JL Lennox, MD, at Atlanta, GA: April 8, 2016, IAS-USA.