Transcript ART Initiation: PrEP and Treatment

Modifying Therapy in the
Treatment-experienced Patient:
When should it be done?
Joseph J. Eron, Jr., MD
Professor of Medicine
UNC Chapel Hill School of Medicine
Disclosures
• Principal Investigator (Research Grants to University of North
Carolina): GlaxoSmithKline/ViiV
• Ad hoc Consultant: Abbvie, Bristol-Myers Squibb, Gilead
Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, Tobira
• Data and Safety Monitoring Board: Vertex (Inactive 2/1/2014)
Treatment-experienced Patient
• Two broad categories
– Suppressed HIV RNA; candidates for regimen modification
 Convenience, tolerability, toxicity, cost
– Virologic failure, usually in the context of poor medication
adherence
 Reestablish virologic suppression while avoiding complex or poorly
tolerated therapy (whenever possible)
Changing Therapy when HIV RNA
Is Suppressed
Switching the regimen may improve safety, tolerability, convenience, or
cost.
• Pro – My job as a clinician is to make sure each patient is on an
optimal regimen weighing multiple factors
• Con – Any switch could lead to unanticipated toxicity, medication
error, drug-drug interactions, and subsequent HIV RNA rebound
Regimen Switching
with Virologic Suppression
•
The vast majority of patients in care on ART have HIV RNA below the limit of detection
– Example: 87% of Hopkins Cohort, 85% UNC Clinical Cohort
•
Possible reasons to change treatment
– Reduce pill burden and dosing frequency
– Enhance tolerability
– Decrease anticipated short-term or long-term toxicity
– Decrease food requirements
– Optimize treatment in anticipation of pregnancy
– Reduce costs
– Improve immunologic response (?)
Moore R, et al. Clin Infect Dis. 2011; 53:600-604.
DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.
Disadvantages of
Regimen Switching
• A new agent may lead to new adverse event
• Virologic rebound may lead to resistance
– Risk increased if previous resistance testing not done or unavailable or
– Complete treatment history is not known
• Increased monitoring in the short term
• What is said is not always what is heard
– Medication errors occur including DDI
• Cost of new regimen may be higher
Candidates for Regimen Switching
• Optimal: Patients with no suspected drug-resistant virus
• Selected patients with documented or suspected drug
resistance may also be candidates
– Focus on those who changed regimens when
treatment options were much more limited
 Similar agents with better formulation, frequency, or potency; FDCs;
and dosing simplification
• Key is to review treatment history, treatment responses,
tolerance, and resistance test results
• Maintaining virologic suppression a priority
DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.
SPIRIT: Switching from
PI/r to Rilpivirine
n=317
HIV-1 RNA <50 copies/mL
Stable PI/r + 2 NRTIs
≥ 6 months
On 1st or 2nd regimen
No prior NNRTIs
No known genotypic
resistance to study ARVs
RPV/FTC/TDF
STR
RPV/FTC/TDF
STR
PI/r
+2 NRTIs
RPV/FTC/TDF
STR
2:1
n=159
n=476
24 weeks
48 weeks
Primary Endpoint:
•
Noninferiority (12% margin) to PI + RTV + 2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 c/mL at 24 weeks
Palella F, et al. 19th IAC; Washington, DC; July 22-27, 2012; Abst. TUAB0104.
Proportion of Subjects, Percentage
SPIRIT: Virologic Suppression
at Weeks 24 and 48
FDA Snapshot at 24 Weeks
100 93.7 89.9 92.1
90
80
70
60
50
40
30
20
10
0
RPV/FTC/TDF
(Immediate switch, Day 1 to W24)
PI+RTV+2NRTIs
(delayed, Day 1 to W24)
RPV/FTC/TDF 2
(delayed switch, W24 to W48)
Virologic Suppression
(HIV-1 RNA <50
c/mL)
0.9 5 1.3
5.4 5 6.6
Virologic Failure
No Data
•
23/24 subjects with preexisting K103N maintain virologic suppression
•
Pretherapy VL NOT associated with rebound
•
Fewer adverse events on rilpivirine-based therapy
•
Lipid levels improved substantially
•
3 patients on RPV failed with resistance
Fisher M, et al. HIV11; Glasgow, Scotland; November 11-15, 2012; Abst. P285.
FDA Snapshot at 48 Weeks
100
89.3
90
80
70
60
50
40
30
20
10
0
(Immediate switch, Day 1 to W48)
RPV/FTC/TDF
2.5
Virologic
Suppression
Virologic
Failure
8.2
No Data
STRATEGY-PI: Switch from PI/r to
TDF/FTC/EVG/c
STRATEGY-PI Study
PI at Randomization
n =293
PI + RTV +
FTC/TDF
EVG/C/FTC/TDF
ATV
40%
DRV
40%
LPV
17%
FPV
3%
2:1
n =140
PI + RTV + FTC/TDF
SQV <1%
Week 48
Week 96
EVG/C/FTC/TDF: coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, tenofovir DF
300 mg. PI + RTV + FTC/TDF: ritonavir-boosted PI and emtricitabine/tenofovir DF.
Reasons subjects chose to enroll in study
Desire to simplify current regimen
86%
Concerned about long-term side effects of current regimen
12%
Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.
STRATEGY-PI:
Virologic Outcome at Week 48
EVG/C/FTC/TDF
(n=290)
PI + RTV + FTC/TDF
(n=139)
HIV-1 RNA <50 copies/mL*
272 (93.8%)
121 (87.1%)
Virologic failure (VF) at week 48
2 (0.7%)
2 (1.4%)
HIV-1 RNA ≥ 50 copies/mL
2
1
Discontinued study drug due to lack of efficacy
0
0
Discontinued study drug due to other reasons and last
available HIV-1 RNA ≥50 copies/mL
0
1
No virologic data in week 48 window
16 (5.5%)
16 (11.5%)
Discontinued study drug due to AE
5
2
11 (3.7%)
14 (10.1%)
0
0
Virologic success at week 48
Discontinued study drug due to other reasons and
last available HIV-1 RNA <50 copies/mL
Missing data during window but on study drug
No subject met the protocol-defined criteria for
treatment-emergent resistance testing with virologic rebound ≥400 c/mL
Modest/significant improvement in diarrhea and bloating
Arribas J, et al. 21st CROI; Boston, MA; March 3-6, 2014. Abst. 551LB.
* 6.7% (+0.4%, +13.7%) P=0.025 for superiority
SPIRAL Study
Switch to RAL vs Continue PI/r
•
Very low rates of VF
•
Patients with NRTI experience
•
•
ABC/3TC vs TDF/FTC
•
•
Similar success
Similar results
Improvement in lipids
•
Including TC/HDL
•
Not in endothelial function
hsCRP
IL-6
Insulin
D-Dimer
Change after switch
from PI/r to RAL
-40%
-46%
-26%
-8%
P value
<0.0001
<0.0001
<0.0001
0.018
Martinez E, et al. AIDS. 2010. AIDS 2012, AHR 2013 and Masia, et al. J Antimicrob Chemother. 2013.
Novel Strategies for Switch
•
Simplification from 3-drug therapy to 2 drugs
– PI/r plus 3TC alone
 GARDEL study (in treatment naïve), AtLaS study
– PI/r plus integrase inhibitor
– Integrase inhibitor plus NNRTI
 Multiple small studies
•
♦
NVP plus raltegravir
♦
Etravirine plus raltegravir
Beware of noncomparative studies
– RAL plus maraviroc – stopped due to VF
•
RPV plus DTG vs continued NNRTI plus 2NRTI
Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. Monteiro P, et al. J Antimicrob Chemother. 2014;69:742-748.
Reliquet V, et al. Antivir Ther. 2014;19:117-123. Calin R, et al. Antivir Ther. 2012;17:1601-1604. Di Giambenedetto S, et al.
J Antimicrob Chemother. 2013;68:1364-1372. van Lelyveld S, et al. Presented at: CROI. Atlanta, GA; March 3-6, 2013.
LATTE: Study Design
•
Phase 2b randomized, multicenter, partially blind, dose-ranging study
comparing S/GSK744 plus RPV to EFV plus NRTIs
HIV ART-naïve
HIV RNA >1,000 c/mL
1:1:1:1
Randomization
stratified by
VL and NRTI
Oral induction phase
Oral maintenance phase**
744 10 mg + 2 NRTIs*
744 10 mg + RPV 25 mg
744 30 mg + 2 NRTIs*
744 30 mg + RPV 25 mg
744 60 mg + 2 NRTIs*
744 60 mg + RPV 25 mg
EFV 600 mg + 2 NRTIs*
D1
Week
16
20
*ABC/3TC or TDF/FTC
**Patients on 744 + NRTI: If week 20 VL <50 c/mL - simplify to 744/RPV at week 24
Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1.
24
48
72
96
Two-drug 744 + RPV Maintained Suppression
Comparable to EFV-based Therapy
744 overall response W48
82%
744 overall response W24
87%
Induction Phase
Maintenance Phase
100
Proportion, %
80
60
EFV response W24
EFV response W48
74%
71%
Median (IQR) change from
baseline CD4+ cell count
(cells/mm3)
Week 48
+219
(141,343)
744 overall
+227 (134,369)
EFV
40
20
0
BL
2 4
8
12
16
744 10 mg (N=60)
744 60 mg (N=61)
Margolis D, et al. CROI 2014; Boston, MA. Abstract 91LB.
24 2628
Week
32
36
40
744 30 mg (N=60)
EFV 600 mg (N=62)
48
Long-acting Injectable Study
LATTE 2
• Rilpivirine LA plus 744 LA monthly or every other month vs
• Oral 744 + 2NRTI
Margolis D, et al. 14th EACS; Brussels, Belgium; October 16-19, 2013. Abst. PS7/1; Margolis D, et al. CROI 2014; Boston, MA.
Abstract 91LB; Levin J. Presented at 21st Conference on Retroviruses and Opportunistic Infections. Boston, MA. March 3 - 6, 2014.
Treatment Experienced Patient
with Virologic Failure
Selected Factors Associated with Virologic Failure
Patient factors
ART factors
Higher baseline HIV RNA
Side effects and toxicities
Lower nadir CD4 cell count
Suboptimal pharmacokinetics
Prior AIDS diagnosis
Food/fasting requirements
Substance use, depression
Drug-drug interactions
Presence of drug-resistant virus
Suboptimal virologic potency
Prior treatment failure
Prescription errors
Suboptimal ART adherence/missed clinic appointments
DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.
Virologic Failure: Next Steps
• Assess patient’s past medication history, adherence, and potential
medication intolerance, previous resistance tests
• Order drug resistance test
– For patients on an integrase inhibitor, specific testing for integrase inhibitor resistance should
be performed if available
• The goal of ART is to reestablish virologic suppression
– At least 2 (preferably 3) fully active drugs as part of new regimen
 Eron Corollary: 3 fully active drugs – may increase complexity, decrease tolerability, and increase
cost – partially active drugs likely contribute
DHHS Guidelines 2014. Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Revision May 2014.
Second-line: LPV/RTV + RAL vs LPV/RTV + NRTIs
after First-line VF
Randomized, open-label, international, multicenter trial
Week 48
primary endpoint
Stratified by clinical site,
baseline HIV-1 RNA
(≤ or > 100,000 copies/mL)
HIV-infected patients with
virologic failure on firstline regimen of 2 NRTIs +
NNRTI
(n=541)
TDF + FTC/3TC: 46%
AZT + FTC/3TC: 18%
Lopinavir/ritonavir 400/100 mg BID +
Raltegravir 400 mg BID
(n=270)
Lopinavir/ritonavir 400/100 mg BID +
2-3 NRTIs QD or BID
(n=271)
Of 492 participants with baseline GRT:
−89% had ≥1 N(t)RTI resistance mutation
−60% had M184V plus 1 or more additional N(t)RTI mutations
Boyd MA, et al. Lancet. 2013;381:2091-2099.
Second-line Study: Results
HIV RNA <200 copies/mL (ITT)
100
82.6% (78.1 – 87.1)
Percent Patients
80
80.8% (76.1 – 85.5)
60
P-value=0.59
40
20
LPV/r + 2-3N(t)RTI
LPV/r + RAL
0
0
12
Boyd M, et al. 20th CROI; Atlanta, GA; March 3-6, 2013. Abst. 180LB.
24
Week
36
48
Therapy for Later Treatment Failure
• Adherence remains the most common cause
• For patients who initiated therapy in the ART era – multiclass,
high-level resistance is rare
• Resistance testing is critical
– Use at least 2 fully active drugs if possible
– Partially active drugs likely add benefit
– NRTI may not be necessary
– Knowledge of a drug’s barrier to resistance and activity against resistant virus
is essential
Modifying Antiretroviral Therapy in Treatment-experienced
Patients: Summary
• Patients with HIV RNA suppression
– Goals include: simplify, improve tolerability, reduce toxicity, sustain virologic
suppression
– Need: Treatment history, resistance data, clear patient understanding and
follow-up
• Patients with virologic failure
– Adherence must be addressed
– Resistance testing is critical
– At least 2 fully active agents – most patients have several options
– Full suppression is the goal.