Innovative Paradigms for ART.2019

1. Innovative Paradigms for ART:
Implementation Insights From an Expert Panel
Supported by an educational grant from ViiV Healthcare

2. About These Slides
 Please feel free to use, update, and share some or all of these slides in
your noncommercial presentations to colleagues or patients
 When using our slides, please retain the source attribution:
 These slides may not be published, posted online, or used in
commercial presentations without permission. Please contact
permissions@clinicaloptions.com for details
Slide credit: clinicaloptions.com

3. Program Chair
Chloe Orkin, MBChB, FRCP, MD
Professor of HIV
Queen Mary, University of London
Consultant Physician
Lead for HIV Research
Barts Health NHS Trust
The Royal London Hospital
London, United Kingdom
Chloe Orkin, MBChB, FRCP, MD, has disclosed that she has received funds for
research support, consulting fees, and fees for non-CME/CE services from Gilead
Sciences, GlaxoSmithKline, Janssen, MSD, and ViiV Healthcare.

4. Faculty
Andrea Mantsios, PhD
Research Fellow
Center for Health, Risk, and Society
American University
Washington, DC
Anthony M. Mills, MD
President, Southern California Men’s
Medical Group
CEO & CMO, Men’s Health Foundation
President & Clinical Research Director,
Mills Clinical Research
Assistant Professor of Clinical Medicine
University of California, Los Angeles
Los Angeles, California
Omar Sued, MD, PhD
Director, Research Department
Fundación Huésped
Buenos Aires, Argentina
Babafemi Taiwo, MBBS
Gene Stollerman Professor of Medicine
Chief, Division of Infectious Diseases
Northwestern University Feinberg
School of Medicine
Chicago, Illinois

5. Faculty Disclosures
Andrea Mantsios, PhD, has disclosed that she has received funds for research
support from ViiV Healthcare.
Anthony M. Mills, MD, has disclosed that he has received consulting fees and
funds for research support from Gilead Sciences, Janssen, Merck, and ViiV
Healthcare.
Omar Sued, MD, PhD, has disclosed that he has received consulting fees from
ViiV Healthcare and other financial or material support from Gilead Sciences.
Babafemi Taiwo, MBBS, has disclosed that he has received consulting fees
from Gilead Sciences, Janssen, and ViiV Healthcare.

6. Will positive clinical trial results of two-drug and long-acting
injectable regimens translate to long-term efficacy and safety?
Babafemi Taiwo, MBBS:
 The results of clinical trials of certain two-drug ART regimens have
been favorable to date and are expected to translate to long-term
efficacy
‒ The evidence of efficacy is not generalizable to every two-drug
combination; only a few regimens—such as DTG + 3TC, or a boosted PI +
3TC—have been shown to be effective in treatment-naive individuals
‒ Long-term efficacy can be expected primarily in scenarios where the two
drugs in the regimen are active and effective, so attention must be paid to
a person’s HIV resistance profile

7. GEMINI-1 and -2: Wk 96 Outcomes of DTG + 3TC vs DTG
+ FTC/TDF in Treatment-Naive Patients
 Parallel, international, randomized, double-blind phase III noninferiority studies
 In ART-naive adults, DTG + 3TC met criteria for noninferior efficacy vs DTG + FTC/TDF at Wk 96
 No treatment-emergent resistance observed in patients with CVW
Slide credit: clinicaloptions.com
*Adjusted for BL HIV-1 RNA, BL CD4+ cell count, and study.
Endpoint, % (n)
DTG + 3TC
(n = 716)
DTG + FTC/TDF
(n = 717)
Difference,* %
(95% CI)
Responders 86.0 (616) 89.5 (642) -3.4 (-6.7 to 0)
HIV-1RNA<50copies/mL,
%(95%CI)
100
80
60
40
20
0
0 4 8 12 16 24 36 48 60 72 84 96
Wk
87.0
93.2 91.5 87.2 86.0
89.589.4
93.393.4
84.4
Cahn. IAS 2019. Abstr WEAB0404LB.

8. LATTE-2: Wk 160 Outcomes of Long-Acting Cabotegravir
IM + Rilpivirine IM for Maintenance ART
 Multicenter, open-label phase IIb study of long-acting CAB + RPV[1]
 Most ISRs grade 1/2, median duration 3 days, approximately 1% of patients had ISR leading to d/c
 Grade 3/4 AEs excluding ISRs: 21% Q8W IM, 25% Q4W IM
Margolis. Glasgow 2018. Abstr P118. Slide credit: clinicaloptions.com
Outcome at Wk 160 (Snapshot ITT-ME), n (%)
Q4W IM
(n = 115)
Q8W IM
(n = 115)
HIV-1 RNA < 50 copies/mL 95 (83) 104 (90)
HIV-1 RNA ≥ 50 copies/mL 0 5 (4)
 Data in window not
< 50 copies/mL
0 1 (< 1)
 D/c for lack of efficacy 0 1 (< 1)
 D/c for other reason while not < 50 copies/mL 0 3 (3)
No virologic data in window 20 (17) 6 (5)
 W/d due to AE or death 12 (10) 1 (< 1)
 W/d due to other reasons 8 (7) 5 (4)

9. Is there a risk of increased resistance emerging with
two-drug regimens?
Omar Sued, MD, PhD:
 The risk of emergent resistance with a two-drug regimen depends on
the regimen used
 No significant emergence of resistance has been observed to date with
two-drug regimens comprising 3TC plus a drug with higher potency,
genetic barrier, and forgiveness, such as DRV /RTV or DTG

10. Emergent Resistance With Two-Drug Regimens?
SWORD (switch to DTG + RPV)[2]
 Treatment-emergent NNRTI
mutations (n = 4) and INSTI
mutation (n = 1) in the 8 patients
with VF
ATLAS, FLAIR (switch to LA CAB +
RPV)[3,4]
 Treatment-emergent NNRTI
mutations (n = 6) and INSTI
mutations (n = 4) in the 6 patients
with VF
1. Cahn. Lancet. 2019;393:P143. 2. Aboud. Lancet HIV. 2019;[Epub].
3. Swindells. CROI 2019. Abstr 139. 4. Orkin. CROI 2019. Abstr 140LB Slide credit: clinicaloptions.com
GEMINI (initial DTG + 3TC)[1]
 No treatment-emergent resistance mutations in patients with VF

11. Is baseline resistance testing needed before starting
cabotegravir/rilpivirine in a treatment-naive patient?
Babafemi Taiwo, MBBS:
 Currently, we have no data on initiating first-line ART with long-acting
CAB + RPV in treatment-naive patients
 In the switch context, we already have data from FLAIR, ATLAS, and
LATTE-2 showing that resistance can emerge, but overall it was very
uncommon
 My opinion is that since the FLAIR study excluded persons with
baseline NNRTI resistance (except K103N) or any known INSTI
resistance, clinical practice should follow the same approach

12. What is the impact of missed doses with long-acting
injectables?
Anthony M. Mills, MD:
 There is a theoretical possibility that a patient who misses doses of long-acting CAB
and RPV could be exposed to suboptimal drug levels, leading to development of
resistance
 Although not yet published, I have heard from the study investigators that some
patients enrolled on the clinical trials missed dosing cycles during loss to follow-up
and then reengaged. None of these patients has developed evidence of resistance.
Although not a guarantee that it could not happen in the future, I find this
anecdotal evidence extremely reassuring that the risk of resistance after missing
doses is very low
 As this treatment regimen is moved into clinical practice, it will be tested outside of
clinical trials, and more data on the impact of missed doses will be obtained

13. LA CAB Pharmacokinetic “Tail”
Apparent terminal half-lives of 25-54 days
Slide credit: clinicaloptions.comSpreen. J Acquir Immune Defic Syndr. 2014;67:481.
Protein-adjusted IC90
CAB IM Dose
800 mg (split)
400 mg
200 mg
100 mg
4 x protein-adjusted IC90
MeanPlasmaCAB(μg/mL)
0.1
1.0
0 4 8 12 16 20 24 28 32 36 40 44 48
Wks
Concentration-Time Profile
After Single Dose in Healthy Volunteers

14. ATLAS and FLAIR: Safety and Injection-Site Reactions
 99% of ISRs were grade 1/2, 88% resolved within 7 days
 No drug-related serious adverse events in ATLAS,
1 in FLAIR
1. Swindells. CROI 2019. Abstr 139. 2. Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com
ATLAS Injection-Site Reactions[1]
LA CAB +
LA RPV
(n = 308)
Patients receiving injections, n 303
Injections given, n 6978
ISR events, n (%)
 Pain
 Nodule
 Induration
 Swelling
 Grade 3 ISR pain
1460 (20.9)
1208 (82.7)
54 (3.7)
54 (3.7)
48 (3.3)
20 (1.7)
Median duration of ISRs, days 3
Patients with ISR leading to d/c, n (%) 4 (1.3)
FLAIR Injection-Site Reactions[2]
LA CAB +
LA RPV
(n = 283)
Patients receiving injections, n 278
Injections given, n 7704
ISR events, n (%)
 Pain
 Nodule
 Induration
 Swelling
 Warmth
 Grade 3 ISR pain
2203 (28.6)
1879 (85.3)
86 (3.9)
82 (3.7)
38 (1.7)
38 (1.7)
12 (< 1.0)
Median duration of ISRs, days 3
Patients with ISR leading to d/c, n (%) 2 (< 1.0)

15. How can long-acting injectable ART be implemented in
low and middle income countries?
Chloe Orkin, MBChB, FRCP, MD:
 Injectable CAB + RPV needs to be refrigerated throughout the supply
chain
 Our panel agreed that maintaining this “cold chain” may be a
challenge—the same challenge we have experienced in some corners
of the globe where vaccines are not accessible
 In the words of the late, very great Dr. Joep Lange, “if we can get cold
Coca-Cola and beer to every remote corner of Africa, it should not be
impossible to do the same with drugs”

16. Will patients really choose an injectable regimen rather
than a simple daily pill?
Andrea Mantsios, PhD:
 Qualitative research with LATTE-2 participants and providers
 39 in-depth interviews (27 patients, 12 providers) in the US and Spain
Results: high satisfaction with LA ART
 Adverse events were common, but “worth it”
 Easy, convenient, discrete, reduced stigma
 “Normal life”
Slide credit: clinicaloptions.comKerrigan. PLoS ONE. 2018;13: e0190487.

17. References

18. clinicaloptions.com/hiv
Go Online for More CCO
Coverage of HIV!
CME/CE-certified video of the live symposium with expert faculty commentary
CME/CE-certified FAQ module with practical answers to key questions on innovative ART