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Managing Treatment-Experienced Patients With Multidrug Resistance-Emerging Options and Strategies for Success.2017
1. Managing Treatment-Experienced Patients
With Multidrug Resistance: Emerging Options
and Strategies for Success
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About These Slides
3. Faculty
Eric S. Daar, MD
Chief, Division of HIV Medicine
Harbor-UCLA Medical Center
Professor of Medicine
David Geffen School of Medicine
at UCLA
Los Angeles, California
Daniel R. Kuritzkes, MD
Chief, Division of Infectious
Diseases
Brigham and Women’s Hospital
Professor of Medicine
Harvard Medical School
Boston, Massachusetts
4. Faculty Disclosures
Eric S. Daar, MD, has disclosed that he has received consulting
fees from Bristol-Myers Squibb, Gilead Sciences, Merck, Teva,
and ViiV and funds for research support from Gilead Sciences,
Merck, and ViiV.
Daniel R. Kuritzkes, MD, has disclosed that he has received
consulting fees from CytoDyn, Gilead Sciences, Janssen, Merck,
and ViiV and funds for research support from Gilead Sciences
and Merck.
6. History of MDR HIV
In the pre-HAART era, MDR HIV emerged as a result of sequential, partially
suppressive ARV regimens[1,2]
Combination ART transformed HIV into a manageable condition, but early
suboptimal 3-drug regimens led to continued selection for resistant HIV[2,3]
– Low-potency ARVs with adherence challenges due to toxicity[3]
– Cross-resistance within drug classes[3,4]
Improved efficacy of modern ARVs has led to even less resistant HIV[2]
– Expansion of ARVs and ARV classes allows for virologic suppression in pts with
MDR HIV via informed use of combination regimens[4]
1. Lima VD, et al. Am J Epidemiol. 2010;172:460-468. 2. Richman DD. Clin Infect Dis. 2016;62:1318-1319.
3. Harris M, et al. AIDS Res Treat. 2012;2012:595762. 4. Tang MW, et al. Drugs. 2012;72:e1-e25. Slide credit: clinicaloptions.com
7. Decrease in Prevalence of MDR HIV in the US in
Recent Era of HIV Treatment
Assessment of phenotypic drug resistance patterns in US samples submitted to Monogram
Biosciences for HIV resistance testing from 2003-2012 (N = 62,397)
Slide credit: clinicaloptions.comPaquet AC, et al. Antivir Ther. 2014;19:435-441.
0
10
20
30
40
50
60
ResistantSamples(%)
1-Class Resistance
PI
NRTI
NNRTI
0
10
20
30
40
50
60
2-Class Resistance
PI and NRTI
PI and NNRTI
NRTI and NNRTI
0
10
20
30
40
50
60
3-Class Resistance
8. Prevalence of Transmitted MDR HIV in the US:
Selected Studies
Transmission of HIV resistant to a single class of ARV more common
than HIV resistant to multiple classes[1,3]
– 13.6%, 2.1%, and 0.5% of transmitted HIV resistant to 1, 2, and 3 ARV
classes, respectively[3]
1. Baxter JD, et al. HIV Med. 2015;16:77-87. 2. INSIGHT START Study Group.
N Engl J Med. 2015;373:795-807. 3. Kim D, et al. CROI 2013. Abstract 149. Slide credit: clinicaloptions.com
Prevalence of Transmitted Drug-Resistant HIV
(2009-2013), %[1-3]
Overall
NRTI
NNRTI
PI
12.6-16.2
3.7-6.7
8.1-8.4
2.0-4.5
9. Current Status of INSTI Resistance in the US
Transmitted INSTI resistance remains rare and rates of on-treatment INSTI
resistance continue to be low[1-3]
1. Hernandez AL, et al. CROI 2017. Abstract 478. 2. Davy T, et al. CROI 2017. Abstract 483.
3. Koullias Y, et al. CROI 2017. Abstract 493. Slide credit: clinicaloptions.com
Study Key Findings
CDC National HIV
Surveillance System[1]
Prevalence of INSTI resistance for HIV diagnoses through 2014:
65/14,468 (0.4%)
Pre-ART prevalence of INSTI resistance (ie, transmitted): 2/4631
(0.04%)
UNC CFAR HIV Clinical
Cohort[2]
2015 INSTI resistance prevalence in 685 pts who began ART in
2007 or later: 1%
Modeling study[3]
Assuming 0.1% rate of transmitted INSTI resistance and $250
cost per test: pre-ART INSTI resistance testing correlated with
worse outcomes, higher costs vs no test
10. MDR Still a Significant Concern in HIV
Despite modern ARV combination regimens revolutionizing the treatment of HIV,
MDR HIV remains relevant
Contributions to MDR HIV in today’s pts include
– Nonadherence
– Inadequate past treatment in pre- and early-HAART eras
– Transmission of harbored MDR HIV variants
– Pharmacokinetic factors
Due to cross-resistance within a drug class, fully active ARV options diminish with
each successive viral failure
Pts harboring MDR HIV pose increased risk of drug-resistant virus transmission
Tang MW, et al. Drugs. 2012;72:e1-e25. Imaz A, et al. AIDS Rev. 2011;13:180-193.
Lima VD, et al. Am J Epidemiol. 2010;172:460-468 Slide credit: clinicaloptions.com
12. Causes of Treatment Failure
DHHS Guidelines.
Poor adherence
Insufficient drug level
Viral replication in the
presence of drug
Resistant virus
Social/personal issues
Regimen issues
Toxicities
Suboptimal
potency
Wrong dose
Host genetics
Poor absorption
Rapid clearance
Poor activation
Drug interactions
Virologic failure
Transmitted or Acquired
Slide credit: clinicaloptions.com
13. Results used to inform design of new ART regimens for pts experiencing VF
DHHS: Recommendations for Resistance
Testing
DHHS Guidelines.
Question Recommendation
Who should receive
resistance testing?
Pts with VF and HIV-1 RNA levels > 1000 copies/mL
May be considered for pts with 500-1000 copies/mL
When should testing be
conducted?
While on failing ART regimen or < 4 wks from treatment end
May still be considered after 4 wks
What types of testing
should be conducted?
First-/second-line failure: genotypic testing
Suspected MDR: genotypic plus phenotypic testing
When considering CCR5 antagonist: tropism assay
If prior failure on INSTI-containing regimen, test for INSTI resistance
Other considerations Prior treatment history should be obtained
Slide credit: clinicaloptions.com
15. Randomized, open-label, multicenter phase III trial in sub-Saharan Africa
LPV/RTV + RAL
(n = 433)
LPV/RTV + 2-3 NRTIs*
(n = 426)
HIV-infected pts
> 12 yrs of age
with confirmed VF on
NNRTI + 2 NRTIs
and no prior PIs
(N = 1277)
Wk 96
LPV/RTV 400/100 mg and RAL 400 mg dosed BID.
*New or recycled NRTIs chosen WITHOUT genotype by clinician.
EARNEST: Second-line LPV/RTV ± RAL or 2-3
NRTIs in PI-Naive Pts
Wk 12
LPV/RTV Monotherapy
(n = 418)
LPV/RTV + RAL
(n = 418)
Paton NI, et al. N Engl J Med. 2014;371:234-247. Slide credit: clinicaloptions.com
Stratified by study center,
CD4+ cell count (< 200 vs
≥ 200 cells/mm3)
16. EARNEST: Boosted PI + RAL Comparable to
Boosted PI + NRTIs
SECOND-LINE[3] and ACTG 5273[4,5] showed similar results
LPV/RTV + RAL
(n = 433)
LPV/RTV + 2/3 NRTIs
(n = 426)
LPV/RTV monotherapy
(n = 418)
References in slidenotes. Slide credit: clinicaloptions.com
100
80
60
40
20
0
Pts(%)
HIV-1 RNA < 50 copies/mL,
Wk 96[1]
7473
44
P < .001
HIV-1 RNA < 400 copies/mL
Through Wk 144[2]
0
20
40
60
80
100
LPV/RTV + NRTI
(Number of Active NRTIs)
Pts(%)
88
0 LPV/
RTV +
RAL
77 8185
61
1 2-3 LPV/
RTV
17. DHHS: Management of First-line Failure
DHHS Guidelines.
*If RAL or EVG resistance detected, DTG + boosted PI can be used if DTG susceptible.
Slide credit: clinicaloptions.com
Failing Regimen (+ NRTIs)
Boosted PI: Enforce adherence
Modify for convenience or toxicity
NNRTI: Boosted PI + NRTIs
Boosted PI + INSTI
INSTI: Boosted PI + NRTIs
Boosted PI + active INSTI*
18. Randomized, double-blind, placebo-controlled, multicenter phase III trials
BENCHMRK: Raltegravir + OBR for MDR HIV
Steigbigel RT, et al. N Engl J Med. 2008;359:339-354.
Eron JJ, et al. Lancet Infect Dis. 2013;13:587-596.
HIV-infected pts ≥ 16 yrs of age with
HIV-1 RNA > 1000 copies/mL,
no prior INSTIs,
and multiclass resistance*
(N = 703)
Placebo + OBR†
(n = 237)
Raltegravir 400 mg BID + OBR†
(n = 466)
Wk 156
*Documented phenotypic or genotypic resistance to ≥ 1 drug in each of 3 oral ARV classes (ie, NRTI, NNRTI, and PI).
†Investigator-selected based on ART history, BL resistance, and lab data; DRV and TPV investigational at time of studies but permitted.
Wk 48Wk 16Randomized 2:1; stratified
by enfuvirtide use and PI
resistance (1 vs > 1)
All pts offered
open-label
raltegravir to
Wk 240
Baseline: median yrs of ART, 10; median previous drugs, 12;
> 95% resistant to > 1 PI
Slide credit: clinicaloptions.com
19. BENCHMRK: Efficacy of Raltegravir + OBR
Through Wk 156
Placebo + OBR
Raltegravir + OBR
Eron JJ, et al. Lancet Infect Dis. 2013;13:587-596.
59
45 43
60
24
8 5
20
233/
396
51/
209
2/437/93
26/
61
68/
152
13/
64
76/
126
69
38
156/
226
43/
112
66
29
17/
58
81/
123
0
20
40
60
80
100
0 ≥ 1
PtsWithHIV-1RNA
<50copies/mL(%)
n/N =
Overall
Active PIs in OBR
0 1
Agents in OBR for Which
Phenotypic Sensitivity Demonstrated
2
61
43
16/
37
39/
64
≥ 3
Slide credit: clinicaloptions.com
20. DHHS: Management of ART Failure Second-line
ARV Failure
Goal: fully suppressive ARV regimen
If susceptible to boosted PI, regimen can
be similar to those for first-line failure
If not susceptible to boosted PI, new
regimen should have a minimum of 2
(preferably 3) fully active drugs if possible
– Susceptibility to drug predicted from pt
treatment history, prior and current
resistance and tropism testing, MoA of
novel drug class
Not recommended to add single agent to
failing regimen due to risk of developing
resistance to entire regimen
DHHS Guidelines.
Boosted PI + NRTIs
Boosted PI + active INSTI
2 and preferably
3 fully active drugs
Yes No
PI
Susceptible
Slide credit: clinicaloptions.com
22. DHHS: Treatment of Pts With MDR HIV for Whom
Optimal Virologic Suppression Is Not Possible
Goals: minimize toxicity, preserve immunologic function, delay
clinical progression, minimize further resistance
– Reduction of HIV-1 RNA > 0.5 log10 copies/mL correlated with
clinical benefit
– If resistant, rarely a reason to continue NNRTIs, ENF, EVG, or RAL:
no evidence of clinical benefit; may promote further resistance, limit
future treatment options
Consider enrolling pt in clinical study, expanded access program,
or FDA single-pt access to investigational agent
DHHS Guidelines. Slide credit: clinicaloptions.com
23. Emerging Investigational Agents for Pts With
MDR HIV
1. Lalezari JP, et al. Lancet HIV. 2015;2:e427-437. 2. Granados-Reyes ER, et al. HIV Glasgow 2016.
Abstract O335A. 3. ClinicalTrials.gov. NCT02362503. 4. Lewis S, et al. CROI 2017. Abstract 449LB.
5. Lin H-H, et al. CROI 2017. Abstract 438. 6. Lalezari J, et al. CROI 2017. Abstract 437. Slide credit: clinicaloptions.com
Investigational Agent Phase MoA
Fostemsavir[1-3] III
Prodrug; when metabolized binds gp120
to prevent CD4+ cell attachment, entry
Ibalizumab[4,5] III Humanized anti-CD4 receptor mAb
PRO 140[6]
IIb/III Humanized anti-CCR5 mAb
24. TMB-301: Ibalizumab in Pretreated Pts Infected
With Multidrug-Resistant HIV
Ibalizumab: humanized mAb to CD4 receptor that blocks HIV entry into CD4+ T-cells
– FDA breakthrough and orphan drug designations
Single-arm, open-label phase III trial
– Primary endpoint: ≥ 0.5 log10 HIV-1 RNA decrease at Day 14
Lewis S, et al. CROI 2017. Abstract 449LB. Slide credit: clinicaloptions.com
Pts with HIV-1 RNA
> 1000 copies/mL;
on ART ≥ 6 mos, on stable
ART ≥ 8 wks; resistant to
≥ 1 ARV from 3 classes,
sensitive to ≥ 1 ARV for OBR
(N = 40)
Wk 25
Ibalizumab
2000 mg IV Day 7
(loading dose)
Continue Failing ART
Days 0-14
Ibalizumab
800 mg IV Day 21, Q2W
(maintenance dose)
Switch to OBR
Day 14
Primary Endpoint:
Day 14Control Period:
Day 0-7
25. TMB-301: Pt Characteristics
Lewis S, et al. CROI 2017. Abstract 449LB.
Baseline Characteristic Pts
(N = 40)
Mean age, yrs 51 ± 11
Male, % 85
Mean duration of HIV infection, yrs 21
Mean VL, copies/mL
VL ≥ 100,000 copies/mL, %
100,287
18
Mean CD4+ cell count, cells/mm3 150
Median CD4+ cell count, cells/mm3 73
Previously treated with ≥ 10 ARVs, % 28
Fostemsavir required in OBR, % 43
Slide credit: clinicaloptions.com
Characteristic, % Pts
(N = 40)
Phenotypic/genotypic resistance
NRTI
NNRTI
PI
INSTI
93
93
88
68
Number of exhausted ARV classes
≥ 1
≥ 2
≥ 3
≥ 4
All
88
73
53
35
15
26. TMB-301: Efficacy
Lewis S, et al. CROI 2017. Abstract 449LB.
Virologic Outcome
Ibalizumab
+ OBR
Day 14
≥ 0.5 log10 HIV-1 RNA decrease, % 83*
≥ 1.0 log10 HIV-1 RNA decrease, % 60
Mean HIV-1 RNA decrease, log10 1.1
Wk 24
≥ 1.0 log10 HIV-1 RNA decrease, % 55
≥ 2.0 log10 HIV-1 RNA decrease, % 48
HIV-1 RNA < 50 copies/mL, % 43
HIV-1 RNA < 200 copies/mL, % 50
Mean HIV-1 RNA decrease from BL, log10 1.6
*Primary endpoint; P < .0001 vs 3% at end of control period.
Slide credit: clinicaloptions.com
Outcome,
cells/mm3
Baseline CD4+ Cell Count
(cells/mm3)
< 50
(n = 17)
50-200
(n = 10)
> 200
(n = 13)
Mean baseline
CD4+ cell count
12 109 363
Mean increase in
CD4+ cell count at
Wk 24
Missing equals
failure analysis
9 75 78
Per protocol
analysis
15† 75 81‡
†n = 7. ‡n = 10.
27. TMB-301: Safety
9 pts reported 17 serious AEs[1]
– 1 drug-related serious AE (IRIS) resulted in discontinuation
9 other pts discontinued
– Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma)
– Consent withdrawal (n = 3)
– Lost to follow-up (n = 2)
No cases of anti-ibalizumab antibodies
Phase III TMB-311 study ongoing; extension for pts from TMB-301; accepting new
pts[2]
IM dosing may be viable as administration route as compared with IV dosing[3]
1. Lewis S, et al. CROI 2017. Abstract 449LB. 2. ClinicalTrials.gov.
NCT02707861. 3. Lin H, et al. CROI 2017. Abstract 438. Slide credit: clinicaloptions.com
28. AI438011: Fostemsavir + RAL + TDF in
Treatment-Experienced Pts
Fostemsavir: prodrug; proposed MoA: binding HIV-1 gp120 prevents viral attachment and
entry into host CD4+ cells
Randomized, active-controlled phase IIb study, blinded to dose
– Primary endpoint: HIV-1 RNA < 50 c/mL at Wk 24
Granados-Reyes ER, et al. HIV Glasgow 2016. Abstract O335A.
Llamoso C, et al. HIV Glasgow 2016. Abstract O335B. Slide credit: clinicaloptions.com
Fostemsavir 600 mg QD* PO + RAL + TDF
(n = 51)
HIV-infected pts with exposure
to ≥ 1 ARV for ≥ 1 wk;
HIV-1 RNA ≥ 1000 c/mL;
CD4+ ≥ 50 cells/mm3; virus
susceptible to RAL, TDF, ATV, and
fostemsavir IC50 < 100 nM
(N = 254)
Wk 48Wk 24: 1̊ endpoint
ATV/RTV 300/100 mg QD + RAL + TDF
(n = 51)
Fostemsavir 1200 mg QD PO + RAL + TDF
(n = 50)
Fostemsavir 400 mg BID* PO + RAL + TDF
(n = 50)
Fostemsavir 800 mg BID* PO + RAL + TDF
(n = 49)
Wk 96
*Fostemsavir dose changed to 1200 mg QD from Wk 48 to Wk 96.
29. AI438011: Efficacy, Safety of Fostemsavir + RAL
+ TDF
At Wk 96, 90% of pts had HIV-1 RNA < 50 copies/mL in both fostemsavir and
ATV/RTV arms in observed analysis[1]
– No significant differences in virologic efficacy regardless of race, sex, age, BL HIV-1
RNA, BL CD4+ cell count, or IC50 subgroups[1]
– Fostemsavir generally well tolerated, with higher rates of grade 2-4 treatment-emergent
AEs (37% vs 9%) and d/c for AEs (10% vs 3%) for ATV/RTV arm vs fostemsavir arm[2]
Phase III trial of fostemsavir in heavily treatment–experienced pts ongoing[3]
1. Granados-Reyes ER, et al. HIV Glasgow 2016. Abstract O335A. 2. Llamoso C, et al.
HIV Glasgow 2016. Abstract O335B. 3. ClinicalTrials.gov. NCT02362503. Slide credit: clinicaloptions.com
Wk 49
Placebo
Pts with HIV-1 RNA ≥ 400 c/mL
on current regimen; ≤ 2 classes of active
approved ARVs left to compose OBR due to
resistance, intolerance, or contraindications Fostemsavir + OBR
Day 8*
Fostemsavir Fostemsavir + OBR
FostemsavirAs above but with no active approved ARV options remaining
*1° endpoint: mean log10 HIV=-1 RNA change from BL.
30. PRO 140 for Heavily Treatment–Experienced Pts
PRO 140: humanized IgG4 CCR5 mAb
Ongoing phase IIb/III study of PRO 140 plus OBR for heavily treatment–
experienced pts (estimated N = 30)
– Primary endpoint: proportion with > 0.5 log10 HIV-1 RNA change from BL at Day 7
– PRO 140 dose: 350 mg QW SC
ClinicalTrials.gov. NCT02483078.
Wk 25
Placebo +
Current Regimen
Pts with CCR5-tropic virus and
HIV-1 RNA ≥ 400 c/mL on current regimen;
resistance to ≥ 1 ARV in ≥ 3 classes or
≥ 2 classes plus options limited by
intolerance or cross resistance;
must have ≥ 1 fully active drug available
Day 7
PRO 140 +
Current Regimen
PRO 140 + OBR
Slide credit: clinicaloptions.com
31. Options When Limited Information Available for
Tx-Experienced Pt With Suspected Resistance
If have treatment history, but lack results of resistance testing
– Start regimen of 2-3 drugs predicted to be active based on treatment
history
In absence of self-reported history, medical records, and resistance
testing results
– Restart on most recent ARV regimen followed by drug resistance testing
at Wk 2 or 4 to guide selection of next regimen
DHHS Guidelines. Slide credit: clinicaloptions.com
32. Take-home Points
For pts with virologic failure and potential MDR HIV, genotypic and phenotypic
resistance testing results and treatment history should inform the construction of new
ART regimens
– When considering CCR5 antagonist, tropism assay should be performed
For pts with confirmed MDR, the goal of a new regimen is a minimum of 2 (preferably
3) active drugs if possible
– For pts with resistance to currently available agents, consider enrolling pt in clinical study,
expanded access program, or FDA single-pt access to investigational agent
Investigational agents with novel MoAs may provide options for pts with MDR HIV
– Fostemsavir (gp120 binder; prevents CD4+ cell attachment), ibalizumab (anti-CD4
receptor mAb), PRO 140 (anti-CCR5 mAb)
Slide credit: clinicaloptions.com
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