Moderator François Raffi MD PhD Professor of Infectious and Tropical Diseases University of Nantes Nantes France Panelists Chloe Orkin MD FRCP Professor of HIV Medicine Grahame Hayton Unit ID: 716067
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Slide1
Dual ART: Entering a New Paradigm
Moderator
François Raffi, MD, PhD
Professor of Infectious and
Tropical Diseases
University of Nantes
Nantes, France Slide2
Panelists
Chloe Orkin, MD, FRCP
Professor of HIV Medicine
Grahame Hayton Unit
Royal London HospitalLondon, UK
José R. Arribas, MDResearch Director, HIV and Infectious Diseases Unit, Hospital La Paz, IdiPAZ; Associate Professor, Infectious Diseases, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
Jürgen K. Rockstroh, MD
Professor of Medicine
Department of Internal Medicine I University Hospital Bonn
Bonn, GermanySlide3
This program will include a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.Slide4
Introduction to Dual ART
New data show that dual ART may be a viable strategy in patients meeting careful selection criteria
It may be used for toxicity sparing, cost reduction
Increased potency of some newer ARTs may allow for different therapy optionsSlide5
Raffi F, et al.
Lancet. 2014;384:1942-1951.
Dual ART With Raltegravir and Boosted
Darunavir in Treatment-Naive Patients: NEAT 001
NtRTI-sparing regimen was inferior to the standard regimen
in patients with baseline CD4 counts of less than 200 cells/μL and HIV-1 RNA concentrations higher than 100,000 copies/mL Slide6
Baril JG, et al.
PLoS One. 2016;11:e0148231.
Dual ART in Treatment-Naive Patients: Example of Miraviroc
Review of 16 studies of dual therapy regimens in the ART-naive population
Many underpowered to determine noninferiority to standard triple regimen
Study
Treatment Arm
HIV-1 RNA < 50
Copies/mL
A4001078
ATV/r
+
MVC
(n = 60)
48 wk: 74.6% (ITT)
96 wk: 67.8% (ITT)
ATV/r
+ TDF/FTC (n = 61)48 wk: 83.6% (ITT) 96 wk: 82.0% (ITT)MIDASDRV/r + MVC (N = 24)24 wk: 87.5%48 wk: 83.3%MODERNDRV/r + TDF/FTC (n = 406)48 wk: 86.8%DRV/r + MVC (n = 406)48 wk: 77.3%VEMANLPF/r + MVC (n = 26)48 wk: 100% (PP)LPV/r + TDF/FTC (n = 24)48 wk: 96% (PP)
Studies of Miraviroc as Dual ART
Combination of PI/ritonavir + integrase inhibitor raltegravir or NRTI lamivudine most definitive evidence for role of dual therapySlide7
Lambert-Niclot S, et al
. J Antimicrob Chemother. 2016;71:1056-1062.
Resistance-Associated Mutation in the NRTI-Sparing Regimen: NEAT 001/ANRS143 Trial
No RAM at virologic failure in the standard tenofovir/emtricitabine plus darunavir/ritonavir regimen
For the raltegravir plus darunavir/ritonavir NRTI-sparing regimen, RAM rate was 29.5% (mostly integrase mutations)Slide8
Cahn P, et al.
Lancet Infect Dis. 2014;14:572-580.
GARDEL Study: Noninferiority of Lopinavir/Ritonavir Plus Lamivudine
(n = 214 )
(n = 202 )
(n = 94 )
(n = 86 )
Difference 4.6%
(95% CI: -2.2, 11.8;
P
=.171)
Difference 9.3%
(95% CI: -2.8, 21.5;
P
=.145)
Patients With Viral Load <50 Copies/mL at 48 Weeks
Dual therapy with lopinavir and ritonavir plus lamivudine could be an effective first-line option for treatment-naive patientsSlide9
Dual Therapy as First-Line Treatment
Not currently recommended in guidelines
Studies have been small and more are needed
Evaluated efficacy, but some gaps in addressing safety issues
More data are available from treated patients in switching studies
Could consider the relevance of the point at which the virus replication cycle is inhibitedInhibition of reversed transcriptase may play an important role Slide10
Baril JG, et al.
PLoS One. 2016;11:e0148231.
Switching to Dual ART: Virologically Suppressed Patients
Earlier dual ART studies had not shown much success (eg, with maraviroc plus a PI)
Starting in 2015, increasing evidence that a well-chosen regimen could be effective
Eg, any boosted PI plus lamivudine has begun to achieve noninferiority to triple regimensSlide11
Orkin C, et al. EACS 2017. Poster BPD1/5.
Switching to Dual ART: SWORD-1 and -2
Study Design
Screening
Early-switch
phase
Late-switch phase
Continuation phase
Day 1
Week 52
Week 148
R
1:1
DTG
+ RPV
(n = 513)
CAR
(n = 511)
Viral load <50 copies/mL on INI, NNRTI, or PI + 2 NRTIsDTG + RPV
DTG
+ RPV
Primary endpoint at 48 weeks:
Participants with viral load <50 copies/mLSlide12
SWORD-1 and -2: Similar Virologic Outcomes for All Baseline Treatments
Orkin C, et al. EACS 2017. Poster BPD1/5.
DTG
+ RPV
(n
= 513)
CAR
(n = 511)
Virologic success
95
95
Virologic
non-response
<1
1
No virologic data
5
4
Overall Virologic Outcomes(HIV-1 RNA <50 copies/mL, %)DTG + RPV (n = 513)CAR (n = 511)PI9394NNRTI9695INSTI9495
Virologic Outcomes by Baseline ART Third-Agent Class(HIV-1 RNA <50 copies/mL, %)
Switching to dual therapy with dolutegravir and rilpivirine was noninferior to current antiretroviral regimen at 48 weeks, and virologic outcomes were similar for all baseline treatmentsSlide13
*
Bone resorption biomarker; †bone formation biomarker;
‡
also used to calculate eGFR.
Orkin C, et al. EACS 2017. Poster BPD2/10.
SWORD-1 and -2 Secondary Endpoints: Renal, Inflammatory, and Bone BiomarkersAim was to evaluate the impact of dolutegravir plus rilpivirine on markers of bone turnover, renal function, atherogenesis, and inflammationSecondary study endpoints included change from baseline to week 48 for markers of bone turnover, renal function, atherogenesis, and inflammation
Biomarkers Evaluated
Bone Turnover
Renal Function
Mechanisms of
Atherogenesis
and Inflammation
Type-1 collagen C-telopeptide*
Osteocalcin
†
Procollagen 1-N-terminal propeptide
†
Bone-specific alkaline phosphatase
†Cystatin C‡RBPβ2MUrine phosphateCRPIL-6D-dimersCD163sCD14sVCAM-1 FABP2Slide14
Orkin C, et al. EACS 2017. Poster BPD2/10.
Decrease in Renal Biomarkers With Dual ART: SWORD-1/-2 Pooled Data
Greater decreases in RBP (urine) and β2M (urine) in the dolutegravir plus rilpivirine group
Greater decreases in RBP/creatinine ratio and β2M/creatinine ratio in those on dual therapy who switched from a tenofovir regimen
No changes from baseline in the CKD-EPI eGFR (cystatin C) in either arm
(n = 487)
(n = 484)
(n = 453)
(n = 455)
(n = 319)
(n = 325)
(n = 161)
(n = 174)
RBP (urine), nmol/L
β2M (urine), nmol/L
Change in Renal Markers
From Baseline to Week 48 Compared With CARSlide15
Inflammation Biomarkers: No Consistent Pattern in SWORD-1/-2 Pooled Data
*Baseline values are actual values.
Orkin C, et al. EACS 2017. Poster BPD2/10.
No consistent pattern
of change in atherogenesis
and inflammation markers from baseline to week 48 between dolutegravir plus rilpivirine and CAR
Biomarker
Type
Biomarker*
Week 48 Difference,
DTG + RPV − CAR (95% CI)
Inflammation
Hypercoagulability
Macrophage Activation
Monocyte Activation
Endothelial Dysfunction
Fatty Acid Metabolism
CRP, mg/L Baseline Week 48IL-6, ng/L Baseline Week 48
D-dimer, nmol/L FEU
Baseline
Week 48
sCD163, µg/L
Baseline
Week 48
sCD14, ng/mL
Baseline
Week 48
sVCAM-1,
µg/L
Baseline
Week 48
FABP2, ng/mL
Baseline
Week 48
−0.36
(−1.2, 1.0)
0.16
(−0.2, 0.4)
0.04
(−0.28, 0.34)
3.89
(−22.4, 206.3)
−359.06
(−451.7, 2325.5)
−66.00
(−190.8, 4180.9)
−0.66
(−0.9, 0.3)
Difference Between Week 48 and Baseline Effect on BiomarkersSlide16
Bone Turnover Biomarkers: Significant Decrease With Dual ART in Pooled SWORD-1/-2
Significantly greater decreases in bone turnover biomarkers in serum with dolutegravir plus rilpivirine vs CAR
Change From Baseline to Week 48
*
P
<.001
Orkin C, et al. EACS 2017. Poster BPD2/10.
Mean Serum
Concentration, μg/L
Mean Serum
Concentration, μg/L
Mean Serum
Concentration, μg/L
Mean Serum
Concentration, μg/LSlide17
Patient Factors: What to Consider When Making a Treatment Change
A thorough HIV treatment history is needed when choosing a new treatment
There may be a history of transmitted resistance or occurrence of virologic failure
A proviral DNA test can help identify current unknown treatments in virologically suppressed individuals
Any necessary time should be taken to gather all relevant information Slide18
Need for Treatment History: Clinical Case Example
The longer the patient has HIV, the longer and more complicated the treatment history
Treatment failure on
EFV/TDF/FTC
K103N mutation positive
(NNRTI resistance)
Failure on subsequent
line treatment
No longer K103N
mutation positive
New resistance test shows fully susceptible to NNRTI
What treatment do you choose?
Recent test indicates an NNRTI is an option
But treatment history indicates it may not be an optionSlide19
Assessing Comorbidities and Concomitant Medications
Comorbidities and concomitant treatments should be assessed when switching treatment
Even when the change is from a PI to a boosted PI
In patients with hepatitis B coinfection, need to consider treating both infections (eg, with an NRTI with activity against both)
A treatment switch has to include a regimen active against hepatitis B
In unvaccinated patients, it can increase protectionLifestyle of patient should be considered as treatment is long-termSlide20
Potential Reasons for Switching to Dual ART
There has to be a benefit when switching a patient's treatment
Address toxicity of the current therapy
Simplify a regimen (eg, if a patient is on a complex regimen)Slide21
a. European AIDS Clinical Society Guidelines 8.2. January 2017; b. US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV.
Guidelines for Dual Therapy in Virologically Suppressed Individuals: EACS and HHS
EACS Guidelines
[a]
Dolutegravir + Rilpivirine
Lamivudine
Darunavir/
ritonavir
or
Darunavir/cobicistat Atazanavir/
ritonavir
or
Atazanavir/cobicistat
Dual
therapy
in patients
: a) without resistance to the PI; b) with viral
load suppression <50 copies/mL for at least the past 6 months; and c) absence of chronic HBV co-infectionHHS Guidelines[b]Dolutegravir + RilpivirineLamivudineAtazanavir /ritonavir orDarunavir /ritonavir orLopinavir/ritonavirLamivudine plus a ritonavir-boosted PI may be a reasonable option when the use of tenofovir, tenofovir alafenamide, or abacavir is contraindicated or not desirableDolutegravir + rilpivirine can be a reasonable option when the use of NRTIs is not desirable and when resistance to either compound is not expected++Slide22
a. Pérez-Molina JA, et al. EACS 2017. Abstract PS1/1; b. Di Giambenedetto S, et al.
J Antimicrob Chemother. 2017;72:1163-1171; c. Perez-Molina JA, et al. Lancet Infect Dis
. 2015;15:775-784; d. Arribas JR, et al.
Lancet Infect Dis
. 2015;15:785-792; e. Pulido F, et al. Clin Infect Dis. 2017. [Epub ahead of print]
Meta-Analysis of Switch to Dual Therapy TrialsMeta-analysis of individual patient data from 4 studies (N = 1051)[a]
Assess noninferiority of boosted PI plus lamivudine vs triple therapy using past and current FDA-established endpoints
(ie, a virologic failure noninferiority limit of 4%)
ATLAS-M
[b]
(n = 266)
SALT
[c]
(n = 286)
OLE
[d]
(n = 250)
DUAL
[e] (n = 249)Dual TherapyATV/r + LMVATV/r + LMVLPV/r + LMVDRV/r + LMVTriple Therapy ATV/r + 2 N(t)RTIsATV/r + 2 N(t)RTIsLPV/r + 2 N(t)RTIsDRV/r + 2 N(t)RTIsSlide23
Pérez-Molina JA, et al. EACS 2017. Abstract PS1/1.
Meta-Analysis: Primary Endpoint Results for Virologic Failure
At 48 weeks, 4% of patients on dual therapy vs 3.04% on triple therapy had HIV-RNA ≥50 copies/mL
Difference of 0.9% (95%CI: -1.3%, 3.2%)
Noninferiority margin: 4%
Favors
Dual
TherapySlide24
Pérez-Molina JA, et al. EACS 2017. Abstract PS1/1.
Secondary Endpoint: Change in Renal Function, Lipids, and CD4 Count
Variable
Dual Therapy Group
Triple Therapy Group
Difference
Dual vs Triple (95% CI)
CD4 cell
μ
/L
29.6
13.8
15.8 (-12.7, 44.3)
Total cholesterol
mg/dL
11.03
-1.66
12.6 (8.7, 16.5)
LDL mg/dL6.9-1.017.88 (4.47, 11.31)HDL mg/dL2.481.211.30 (-1.08, 3.69)Total cholesterol/HDL0.017-0.060.08 (-0.04, 0.20)Triglycerides mg/dL8.77
-4.75
13.54 (2.05, 25.02)
GFR mL/min
3.32
-1.89
5.24 (2.90, 7.58)
Change from baseline to week 48
With dual therapy, there was an improvement in eGFR and worsening of lipid levels vs triple therapySlide25
Continuous Viral Load Suppression With Dual ART: DUAL-GESIDA Trial
Pulido F, et al.
Clin Infect Dis
. 2017. [Epub ahead of print]
Trial evaluating noninferiority of dual therapy with darunavir/ritonavir and lamivudine vs triple therapy with darunavir/ritonavir plus 2 NRTIs for maintenance of HIV-1 suppression
Viral load blips were similar between the dual-therapy group (14/126) and the
triple-therapy group (17/123)
Difference: 1.2%;
95% CI: -7.8, 10.1Slide26
Pulido F, et al.
Clin Infect Dis. 2017. [Epub ahead of print]
Virologic Failures Without Resistance:
DUAL-GESIDA Trial
Resistance testing attempted in every sample with viral load >400 copies/mL
Results confirmed that dual therapy with a boosted PI was not associated with a higher risk of developing lamivudine resistance
Results
Dual Therapy
Triple Therapy
Number of
patients with
a viral load >400 copies/mL during the study
Number with virologic
failure
3
2
2
0
Mutation test resultWild-type virus in 2 patientsL10I, A71T, and L76W mutations in the protease gene in 1 sampleResistance test resultNASusceptible to DRVNegative resistance test for M184V mutation to lamivudineSlide27
Pérez-Molina JA, et al. EACS 2017. Abstract PS1/1.
European AIDS Clinical Society Guidelines 8.2. January 2017.
US Department of Health and Human Services. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV.
Evidence for Dual ART: Conclusions
A meta-analysis of 4 trials of dual vs triple therapy confirm that a boosted PI plus lamivudine is effective in maintaining virologic suppression
[a]EACS and HHS guidelines include these dual therapies as potential switching strategies in patients meeting criteria for suppression
[b,c] Slide28
Patient Management: Need for Monitoring
The studies of dual therapy had monitoring at similar endpoints and had similar outcomes
Regimens were noninferior to triple therapy or previous regimen
More frequent monitoring will depend on the regimens involved in the switch
Eg, if the switch is to 2 new regimens for the patient, then monitoring for emerging AEs will be requiredSlide29
Adverse Events Leading to Withdrawal
or Discontinuation: SWORD-1/-2
NNRTI
PI
INSTI
Adverse
Event, n (%)
DTG + RPV
(n = 275)
CAR
(n = 278)
DTG + RPV
(n = 133)
CAR
(n = 136)
DTG + RPV
(n = 105)
CAR
(n = 97)Any 8 (3)1 (<1)7 (5)2 (1)6 (6)0GI2 (<1)0
3 (2)
0
2 (2)
0
Nervous system
1 (<
1)
0
0
0
1 (<
1)
0
Psychiatric
4 (1)
1 (<
1)
3 (2)
0
2 (2)
0
Neoplasms
0
0
2(2)
2 (1)
1 (<
1)
0
Respiratory/thoracic/
mediastinal
0
0
1 (<
1)
0
1 (<
1)
0
Hepatobiliary
1 (<
1)
0
0
0
0
0
Summary of AEs by baseline ART third-agent class
Discontinuations were low at 3% in those switching from an NNRTI
Orkin C, et al. EACS 2017. Poster BPD1/5.Slide30
Dual ART: Other Considerations
May save costs to the health system or patients compared with triple therapy
No need for increased monitoring
In case of dual regimen boosted PI plus lamivudine or dolutegravir plus rilpivirine
Warn patient of possible AEs at the beginning
Still requires need to remind patients to adhere strictly to regimenSlide31
Concluding Remarks
Dual therapy is emerging as a viable strategy
Not yet first line
In virologically suppressed patients
In patients with good treatment history and genetic susceptibility
Two regimens can be proposedBoosted PI plus lamivudineDolutegravir plus rilpivirineNeed to select patients correctly and advise them to return if they experience any emerging AEs
Need to take into account ART history
Follow-up still neededSlide32
Concluding Remarks (cont)
Do not forget the protection against hepatitis B and the need for hepatitis B therapy
Do not forget the inclusion criteria for the switch studies:
Patients who are very stable, have had undetectable viral load for at least 6 months, and have high adherence
Take your time in selecting patients and review each patient's history
This era of ART provides many options for well-selected patientsSlide33
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