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Best Practices in Antiretroviral Therapy: Switching ART in Virologically Suppressed Patients and After Virologic Failure
This activity is supported by an independent educational grant from ViiV Healthcare
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Faculty
Joseph J. Eron, Jr., MDProfessor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina
Program Director
Paul E. Sax, MDClinical Director HIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts
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Disclosures
Joseph J. Eron, Jr., MD, has disclosed that he has received funds for research support paid to the University of North Carolina from GlaxoSmithKline/ViiV and Janssen and consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ ViiV, Merck, Tibotec/Janssen, and Tobira.
Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and funds for research support (paid to Brigham and Women’s Hospital) from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.
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Overview
Switching ART in virologically suppressed patients to improve tolerability
Switching ART in virologically suppressed patients with comorbid conditions
Switching ART after virologic failure
Switching ART in Virologically Suppressed Patients
to Improve Tolerability
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Reasons to Consider Regimen Switching in Virologically Suppressed Pts Simplification
Avoid toxicity
Improve tolerability or convenience
Manage drug–drug or drug–food interactions
Pregnancy
Cost
DHHS Guidelines. May 2015.
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Principles of Regimen Switching in Virologically Suppressed Pts Review ART history for intolerance or possible virologic failure
Review all available drug resistance testing results
If prior resistance uncertain, only consider switch if new regimen likely to maintain suppression of resistant virus
– Care needed when switching from PI/RTV to another class if full treatment or resistance history is not known
Consult an expert when switching a pt with resistance to ≥ 1 class
Within class switches usually maintain virologic suppression if no resistance to drugs in that class are present
Increase monitoring during first 3 mos after switch
DHHS Guidelines. May 2015.
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Study 102: Persistence of EFV-Related Symptoms Over Time
Wohl D, et al. ICAAC 2013. Abstract H-672a.
Incidence of Common Neuropsychiatric AEs Through Wk 144
Most events were grade 1– Abnormal dreams (EVG 96% vs EFV 86%); dizziness (EVG 93% vs EFV 87%)
25
20
15
10
5
0
25
20
15
10
5
0
DizzinessAbnormal Dreams
WksWks1449648
14%
14496480
1%
14%
8%
15%
8% 5%1%4%
1%5%
EVG/COBI/TDF/FTC (n = 348)
Incidence (bar): Pts with new onset AEs at each 4-wk window.Prevalence (line): Pts with AEs at each 4-wk window.
Patie
nts
With
AE
(%)
9%
0
EFV/TDF/FTC (n = 352)
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Risk of Suicidality in Pts Treated With EFV-Containing Regimens in ACTG Trials Treatment with EFV associated
with increased risk of suicidality– Absolute risk is small
Trend towards higher incidence of attempted or completed suicide with EFV use (HR: 2.58; 95% CI: 0.94-7.06; P = .065)
EFV also associated with increased risk of death from injury, substance use, or unknown causes
HR: 2.28 (95% CI 1.27-4.10; P = .006)
47 events/5817 PY (8.08/1000 PY)
15 events/4099 PY (3.66/1000 PY)
Mollan K, et al. Ann Intern Med. 2014;161:1-10.
Multivariate Analysis of Factors Associated With Suicidality in ACTG Clinical Trials
Variable HR (95% CI) P Value
Randomly assigned EFV 1.94 (1.17-3.23) .011
Age category, yrs < 30 vs ≥ 45 30-44 vs ≥ 45
3.58 (1.71-7.48) 1.81 (0.90-3.63)
.001NA
Hx IDU 2.70 (1.50 -4.88) < .001
Psychiatric hx or psychoactive rx 3.75 (2.33 -6.03) < .001
EFVEFV free
0.05
0.04
0.03
0.02
0.01
0
Prob
abili
ty
1920 24 48 72 96 120 144 168Wks to Suicidality
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UK Multicenter Study: Switch From EFV/FTC/TDF to RPV/FTC/TDF for CNS Toxicity
All 40 pts (100%) maintained virologic suppression following switch; median CD4+ cell count at Wk 12 was 584 cells/mm3 (P = .156 vs BL)
Grade 2-4 CNS AEs significantly decreased at Wks 4 and 12 (P < .001 vs BL)
Each CNS AE, except headache, showed statistically significant improvement (P < .05)
Nelson M, et al. ICAAC 2013. Abstract H-672b.
100
80
60
40
20
0
P = .008
P = .029P = .001
P = .021
P = .005
P = .008 P = .003
P = .034
P < .001
P = .564
Individual Grade 2-4 CNS AEs Through Wk 12 Following Switch
Baseline Wk 4 Wk12
Pts
(%)
Dizziness Depression Insomnia Anxiety/Nervousness
Confusion ImpairedConcentration
HeadacheSomnolence AbnormalDreams
AggressiveMood
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STRATEGY-NNRTI: Switch From NNRTI + TDF/FTC to EVG/COBI/TDF/FTC Randomized, open-label switch study in pts virologically suppressed on an
NNRTI-based regimen (with TDF/FTC) for ≥ 6 mos
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-1 RNA < 50 copies/mL, 2 previous regimens,
no resistance to study drugs or prior INSTI use, and
eGFR ≥ 70 mL/min(N = 439)
Switch to EVG/COBI/TDF/FTC QD(n = 290)
Remain on NNRTI + TDF/FTC(n = 143)
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
Wk 96Wk 48
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STRATEGY-NNRTI: Outcomes at Wk 48 Switch to EVG/COBI noninferior to
stable NNRTIs at Wk 48
Regimens: EFV 78%; NVP 17%; RPV 4%; ETR < 1%; 74% on EFV/TDF/FTC; 91% on first regimen
Results similar across all baseline virologic and demographic subgroups
3 pts with VF in EVG/COBI arm and 1 in NNRTI arm
– No pts with resistance in either arm
5 in the switch arm and 1 in the NNRTI arm discontinued due to AE
Pts
(%)
93 88
Δ +5.3%(95% CI: -0.5 to +12)
EVG/COBI/TDF/FTC (n = 290)
Stable NNRTIs (n = 143)
0
20
40
60
80
100
13
11
611
Virologic Success*
Virologic Nonresponse
No Data
n =
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm.Discontinued for AE, death, or missing data.
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
271 126 16 16
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*P < .001 †P < .01 (comparison with baseline within treatment group)
Subj
ect R
epor
ting
Sym
ptom
s (%
)
HIV Symptom Index
Vivid Dreams Insomnia Anxiety Dizziness
100
136224
75212
65101
5687
119224
84209
48100
4187
103222
71208
40100
3487
90225
49211
3799
3287
BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48
Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599.
STRATEGY-NNRTI: Outcomes in Pts Switching From EFV-Based Therapy
70605040302010
0
61
35*
64 64
53
40†48 47 46
34†40 39 40 37 37
23*
EVG/COBI/TDF/FTC NNRTI + TDF/FTC
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STRIIVING: Switch From Suppressive ART to Fixed-Dose DTG/ABC/3TC Ongoing randomized, open-label phase IIIB study
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24
HIV-1 RNA < 50 copies/mL on stable ART ≥ 6 mos;
no previous virologic failure; HLA-B*5701 negative
(N = 551)
DTG/ABC/3TC(n = 274)
Wk 48Wk 24
Trottier B, et al. ICAAC 2015.
*Containing 2 NRTIs plus NNRTI, PI, or INSTI.
Baseline ART*(n = 277)
DTG/ABC/3TC(n = 277)
Baseline ART use: PI 42%; NNRTI 31%; INSTI 26%; TDF/FTC 77%
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STRIIVING: Study Disposition at Wk 24
Trottier B, et al. ICAAC 2015.
13% of subjects withdrawn (n = 35)
Adverse event 10 (4%)
Lack of efficacy (virologic failure)
0
Protocol deviation 15 (5%)
Stopping criteria met 0
Lost to follow-up 3 (1%)
Investigator discretion 3 (1%)
Withdrew consent 4 (1%)
Randomized and treated DTG/ABC/3TC
(n = 274)
87% completed (n = 239)
Screened (N = 841)
12% of subjects withdrawn (n = 32)
Adverse event 0
Lack of efficacy (virologic failure)
0
Protocol deviation 17 (6%)
Stopping criteria met 0
Lost to follow-up 3 (1%)
Investigator discretion 3 (1%)
Withdrew consent 9 (3%)
Randomized and treated Baseline ART
(n = 277)
88% completed (n = 244)
1 with missing information
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52
STRIIVING: Outcomes at Wk 24
Switch to DTG/ABC/3TC noninferior to maintaining baseline ART
No pt met criteria for protocol-defined virologic failure; 3 pts in DTG/ABC/3TC arm (1%) and 4 pts in BL ART arm (1%) had HIV-1 RNA > 50 copies/mL but < 100 copies/mL through Wk 24
10 pts d/c for AEs in DTG/ABC/3TC arm vs 0 in baseline ART arm
Trottier B, et al. ICAAC 2015.
Primary Efficacy Analysis: ITT-Exposed and Per Protocol Populations100
80
60
40
20
0 VirologicSuccess
VirologicNonresponse
No Virologic Data
HIV
-1 R
NA
<50
c/m
L (%
)
DTG/ABC/3TC (ITT-E, n = 274)Baseline ART (ITT-E, n = 277)DTG/ABC/3TC (PP, n = 220)Baseline ART (PP, n = 215)
858893 93
1410 61 1 < 1
12-12 -8 -4 0 4 8
12-12 -8 -4 0 4 8
-4.9-0.3
4.4
2.3-9.1
ITT-E Population
PP Population
-3.4
DTG/ABC/3TCBaseline ART
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Drugs That Should Not Be Used With Antiretroviral AgentsARV Drugs That Should Not Be Used ConcomitantlyDTG[1] Dofetilide, rifapentine, St. John’s wort
EFV[1] Rifapentine, St. John’s wort, boceprevir, dasabuvir, ombitasvir, paritaprevir, simeprevir.
EVG/COBI/TDF/FTC[1]
Ranolazine, lovastatin, simvastatin, rifampin, rifapentine, lurasidone, pimozide, midazolam, triazolam, St. John’s wort, boceprevir, dasabuvir, ledipasvir, ombitasvir, paritaprevir, simeprevir, alfuzosin, cisapride, ergot derivatives, salmeterol, sildenafil for PAH.
EVG/COBI/TAF/FTC[2]
Lovastatin, simvastatin, rifampin, rifapentine, pimozide, midazolam, triazolam, St. John’s wort, phenobarbital, phenytoin, alfuzosin, carbamazepine, cisapride, ergot derivatives, salmeterol, sildenafil for PAH.
RPV[1] Rifampin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, St. John’s wort, dasabuvir, ombitasvir, paritaprevir, proton pump inhibitors (eg, omeprazole)
1. DHHS Guidelines. April 2015. 2. EVG/COBI/TAF/FTC Prescribing Information. November 2015.
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Randomized, active-controlled, open-label study
Primary endpoint: proportion of pts with HIV-1 RNA < 50 copies/mL after 48 wks of treatment
Switching From TDF- to TAF-Based Regimens in Virologically Suppressed Pts
Mills A, et al. IAS 2015. Abstract TUAB0102.
Pts with HIV-1 RNA < 50 copies/mL (≥ 96 wks) and eGFR > 50
mL/min on stable TDF-based regimen for ≥ 48
wks(N = 1436)
Switch to EVG/COBI/FTC/TAF QD*(n = 959)
Continue previous TDF-based regimen†
(n = 477)
Primary EndpointWk 48
*EVG/COBI/FTC/TAF (150/150/200/10 mg). †Previous TDF-based regimens: EVG/COBI/FTC/TDF (n = 459), EFV/TDF/FTC (n = 376), ATV/(COBI or RTV) + TDF/FTC (n = 601).
Continue through Wk 96
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Switching From TDF- to TAF-Based Regimens
Mills A, et al. IAS 2015. Abstract TUAB0102.
100
80
60
40
20
0
Wk
48 H
IV-1
RN
A <
50
c/m
L (%
)
All Prior Regimens
Prior EFV/TDF/FTC
Prior Boosted
ATV + TDF/FTC
Prior EVG/COBI/FTC/TDF
EVG/COBI/FTC/TAF TDF-based regimenPrimary Endpoint
P < .001 P = .02 P = .02 P = NS97 93 96
9097
9298 97
932/959
444/477
241/251
112/125
390/402
183/199
301/306
149/153n/N =
Switching ART in Virologically Suppressed Patients
With Comorbid Conditions
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D:A:D: Cumulative Exposure to ARVs Associated With Increased CKD RiskCKD Risk by Yrs of ARV Exposure, Incidence
Rate Ratio (95% CI)Drug 1 Yr 2 Yrs 5 Yrs
TDF 1.12 (1.06-1.18)
1.25 (1.12-1.39)
1.74 (1.33-2.27)
ATV+RTV
1.27 (1.18-1.36)
1.61 (1.40-1.84)
3.27(2.32-4.61)
LPV/RTV
1.16 (1.10-1.22)
1.35 (1.21-1.50)
2.11(1.62-2.75)
Mocroft A, et al. CROI 2015. Abstract 142.
1.80
1.60
1.40
1.20
1.00
0
Relationship Between Increasing Exposure to ARVs and CKD
ATV + RTV LPV/RTV TDF
On treatmentTDF censored
UnivariateMultivariate
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STRATEGY-PI Trial: Switch From PI + RTV + TDF/FTC to EVG/COBI/TDF/FTC Randomized, open-label switch study in pts virologically suppressed
on PI + RTV + TDF/FTC for ≥ 6 mos
Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
HIV-1 RNA < 50 copies/mL, 2 previous regimens, no resistance to study drugs
and CrCl ≥ 70 mL/min(N = 433)
Switch to EVG/COBI/TDF/FTC QD(n = 293)
Remain on Boosted PI + TDF/FTC(n = 140)
Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589.
*Pts with previous VF ineligible.
Wk 96Wk 48
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STRATEGY-PI: Outcomes at Wk 48 Switch to EVG/COBI/TDF/FTC noninferior to stable PI + RTV + TDF/FTC 2 pts with VF in each arm but no pts with resistance in either arm 5 pts in switch arm and 2 pts in boosted PI arm discontinued due to AEs
Pts
(%) EVG/COBI/TDF/FTC (n = 290)
PI + RTV + TDF/FTC (n = 139)
*HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data.Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589.
9487
Δ +6.7% (95% CI: 0.4-13.7)
0
20
40
60
80
100
1 1 6 12
Virologic Success* Virologic Nonresponse No Data
n = 272 121 16 162 2
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SPIRIT: Switch to RPV/TDF/FTC From PI + RTV in Suppressed Pts, No Prior Failure Multicenter, randomized, open-label switch study
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24
Pts with HIV-1 RNA < 50 copies/mL on
stable RTV-boosted PI + 2 NRTIs for
≥ 6 mos, no prior VL failure or resistance
to study drugs (N = 476)
Switch to RPV/TDF/FTC(n = 317)
Continue RTV-Boosted PI* +
2 NRTIs(n = 159)
Wk 48Wk 24
Switch to RPV/TDF/FTC(n = 159)
Palella F, et al. AIDS. 2014;28:335-344.
*ATV/RTV 34%; LPV/RTV 37%; DRV/RTV 21%; FPV/RTV 8%; SQV/RTV 1%.
Continue RPV/TDF/FTC(n = 317)
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RPV/TDF/FTC(immediate switch, Day 1 - Wk 24)
bPI + 2 NRTIs(continued, Day 1 - Wk 24)
RPV/TDF/FTC (delayed switch, Wk 24 - Wk 48)
SPIRIT: Virologic Suppression at Wk 24 and Wk 48 Switch to RPV/TDF/FTC noninferior to continuing boosted PI regimen at Wk 24
17/18 pts with preexisting K103N in immediate switch arm maintained virologic suppression at Wk 48
Palella F, et al. AIDS. 2014;28:335-344.
Pts
(%)
0
20
40
60
80
100
Virologic Suppression
Virologic Failure
No Data
FDA Snapshot at Wk 24
93.7 89.9 92.1
0.9 5 1.3 5.4 5 6.60
20
40
60
80
100
Virologic Suppression
Virologic Failure
No Data
FDA Snapshot at Wk 48
89.3
2.5 8.2
RPV/TDF/FTC(immediate switch, Day 1 - Wk 48)
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Simplification to NRTI-Sparing or NRTI-Limiting Regimens
Study N Switch Regimen ResultsASSURE[1] 296 ATV + ABC/3TC Similar efficacy as continued standard ART;
decline in urine β2-microglobulin creatinine ratio
MONET[2] 256 DRV/RTV Similar efficacy as continued standard ART
SALT[3] 286 ATV/RTV + 3TC Similar efficacy as continued standard ART
OLE[4] 250 LPV/RTV + 3TC or FTC
Similar efficacy as continued standard ART
NA[5] 48 DRV/RTV + 3TC Small study; encouraging efficacy
HARNESS[6] 109 ATV/RTV + RAL Less effective than standard ART
LATTE[7] 243 CAB + RPV Similar efficacy as continued standard ART
1. Wohl DA, et al. HIV Med. 2015;[Epub ahead of print]. 2. Arribas JR, et al. AIDS. 2010;24:223-230. 3. Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784. 4. Arribas JR, et al. Lancet Infect Dis. 2015;15:785-792. 5. Casado JL, et al. J Antimicrob Chemother. 2015;70:630-632. 6. Van Lunzen J, et al. AIDS 2014. Abstract LBPE19. 7. Margolis DA, et al. Lancet Infect Dis. 2015;[Epub ahead of print].
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SALT: Simplification to Dual ART With ATV + RTV + 3TC in Suppressed Pts Randomized, open-label phase IV noninferiority trial
Primary endpoint: free of VF at Wk 48
HIV-infected pts with HIV-1 RNA < 50 copies/mL;
on triple ART for 6 mos; no prior treatment failure or
resistance(N = 286)
Atazanavir + Ritonavir 300/100 mg QD +3TC QD(n = 143)
Atazanavir + Ritonavir 300/100 mg QD +2 Investigator-Selected NRTIs
(n = 143)
Wk 48primary analysis
Perez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784.
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SALT: Outcomes at Wk 48
ATV + RTV + 3TC noninferior to continued ATV + RTV + NRTIsPerez-Molina JA, et al. Lancet Infect Dis. 2015;15:775-784.
0%
Treatment Difference (95% CI)
Favors ATV + RTV + 3TC
Favors ATV + RTV + 2 NRTIs
-5% 6% 16%
-12% 12%
Pts
(%)
ATV + RTV + 3TC (n = 133)ATV + RTV + NRTIs (n = 135)
8478
0
20
40
60
80
n = 112 105
100
HIV-1 RNA < 50 copies/mL at Wk 48 (Per Protocol)
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LATTE: : Cabotegravir (GSK1265744) + RPV as Maintenance ART: Wk 96 Results
Median CD4+ count increase vs BL: +296 cells/mm3 (CAB) vs +289 cells/mm3 (EFV)
Margolis D, et al. Lancet Infect Dis. 2015;15:1145-1155.
HIV
-1 R
NA
< 5
0 c/
mL
by
Snap
shot
Alg
orith
m (%
)
100
80
60
40
20
0BL 4 12 24 28 36 48 72 96
Induction Phase* Maintenance Phase*
CAB 10 mg (n = 60)CAB 30 mg (n = 60)CAB 60 mg (n = 61)EFV 600 mg (n = 62)
68%63%
84%75%
Wks*CAB given with 2 NRTIs in induction phase and with RPV in maintenance phase. EFV given with 2 NRTIs throughout.
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Multicenter, open-label phase III trial
GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment
Gupta S, et al. IAS 2015. Abstract TUAB0103.
Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable
eGFRCG [30-69 mL/min])(N = 242)
TDF-Based ART(n = 158)
Non-TDF–Based ART(n = 84)
EVG/COBI/FTC/TAF (N = 242)
Wk 96
PI NNRTI INSTI CCR5Antag. TDF ABC Other
NRTINo
NRTIART use, % 44 42 24 3 65 22 7 5
Wk 48Wk 24
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TDF TDF
GS-112: Key Results at Wk 48Change in eGFR From Baseline to Wk
48 Changes in Spinal BMD From Baseline to Wk 48
Gupta S, et al. IAS 2015. Abstract TUAB0103.
Non-TDF
Med
ian
Cha
nge
From
Bas
elin
e
10
0
-10
+0.2
-1.8 -1.5 -2.7*
Baseline: 58 53 56 50eGFRCG
mL/mineGFRCKD-EPI Cr
mL/min/1.73 m2*P < .05
Non-TDF
*P < .05
4
2
0
-2M
ean
% C
hang
e Sp
ine
BM
D
2.95*
0.99
Baseline Wk 24 Wk 48 HIV suppression maintained No change in actual GFR at Wk 48 in subset analysis In pts on TDF, tubular proteinuria improved after switch
Switching ART After Virologic Failure
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DHHS Guidelines for Virologic Failure Assess adherence, drug–drug or drug–food interactions,
tolerability, HIV-1 RNA and CD4+ count trends, treatment history, and prior and current resistance data
Perform resistance test while the patient is on failing ART, or within 4 wks of discontinuation; testing after this point may still provide useful information
Goal of treatment for ART-experienced pts with drug resistance and virologic failure is to suppress HIV-1 RNA
New regimen should include ≥ 2, and preferably 3, fully active agents, ie, agents with uncompromised activity based on treatment and resistance, and/or novel action
DHHS Guidelines. May 2015.
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LPV/RTV + RAL(n = 270)
LPV/RTV + 2-3 NRTIs*(n = 271)
HIV-infected patients with confirmed VF
on NNRTI + 2 NRTIswith no previous PI
or INSTI use(N = 541)
Wk 96
*NRTIs selected by genotypic resistance test or by algorithm.
SECOND-LINE: Study Design Randomized, open-label, multicenter trial
Amin J, et al. PLoS One. 2015;10:e0118228
Wk 48
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LPV/RTV + RAL(n = 433)
LPV/RTV + 2-3 NRTIs*(n = 426)
HIV-infected patients with confirmed VF
on NNRTI + 2 NRTIswith no previous PI
use(N = 1277)
Wk 96
*NRTIs selected by clinician.
EARNEST: Study Design Randomized, open-label, multicenter trial
Paton NI, et al. N Engl J Med. 2014; 371:234-247.
Wk 12
LPV/RTV Monotherapy(n = 418)
LPV/RTV+ RAL
(n = 418)
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First-line NNRTI Failure: Boosted PI + NRTIs Noninferior to Boosted PI + RAL
1. Amin J, et al. PLoS One. 2015;10:e0118228. 2. Paton NI, et al. N Engl J Med. 2014; 371:234-247.
EARNEST: Efficacy Outcomes At Wk 96[2]SECOND-LINE: HIV-1 RNA < 200 c/mL and < 50 c/mL at Wk 96 (ITT)[1]
81%
83%
Pts
(%)
Treatment difference (< 200 c/mL): 4.4% (95% CI: -2.6 to 11.3); (< 50 c/mL) : 2.5% (95% CI: -5.3 to 10.3).
80 7670 68
VL < 200 c/mL VL < 50 c/mL
100
80
60
40
20
0
LPV/RTV + RAL (n = 270)LPV/RTV + 2/3 NRTIs (n = 271) 100
80
60
40
20
0
Pts
(%)
Good HIV Disease Control†
HIV-1 RNA < 50 copies/mL
LPV/RTV + RAL (n = 433)LPV/RTV + 2/3 NRTIs (n = 426)LPV/RTV monotherapy* (n = 418)
6460 55
74‡73‡
44
*Monotherapy given following LPV/RTV + RAL induction phase.†Alive with no new stage 4 events, CD4+ count > 250 cells/mm3, and HIV-1 RNA < 10,000 c/mL or no PI mutations.‡P < .0001 vs LPV/RTV monotherapy.
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LPV/RTV + RALLPV/RTV + 2/3 NRTIs
50
40
30
20
SECOND-LINE Resistance Substudy:Predictors of Virologic Failure
Boyd M, et al. AIDS 2014. Abstract TUAB0105LB.
Variable Multivariate OR (95% CI)
P Value
Black race(ref: Asian)
3.49 (1.68-7.28) .007
BL VL > 100,000 c/mL (ref: ≤ 100,000)
3.43 (1.70-6.94)
< .001
Adherence (Wk 4)* 2.18 (1.07-4.47)
.032
Adherence (Wk 48)* 3.43 (1.09-5.69)
.03
Low resistance by gGSS (ref: high resistance)
4.73 (1.04-11.46) .002
*< All ART taken in last 7 days (ref: all ART taken).
Predictors of Virologic Failure at Wk 96
10
0
Pts
(%)
914 1312
4338
Wk 96 Virologic Failureby Baseline gGSS
117134 7786 2116High Moderate Low
Level of Resistance
n =
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DHHS Guidelines: Management of First-line ARV FailureFailing Regimen Comments
NNRTI + NRTI Even pts with NRTI resistance can often be treated with a boosted PI + NRTIs or RAL
Boosted PI + NRTI A systematic review of multiple randomized studies of first-line boosted PI therapy showed that maintaining the same regimen, presumably with efforts to enhance adherence is as effective as changing to new regimens
INSTI + NRTI Pts should respond to a boosted PI + NRTIs A boosted PI + INSTI may also be a viable option if there is no
INSTI resistance If RAL or EVG resistance detected, DTG + a boosted PI “can be
used”
DHHS Guidelines. May 2015.
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VIKING-3: Dolutegravir After Failure of Integrase Inhibitor–Based Regimen Mutlicenter, open-label, single-arm phase III trial
Wk 24 population (n = 183) includes the total number recruited
Wk 48 population (n = 114) includes those subjects who had the opportunity to reach Wk 48 at time of data cutoff
Castagna A, et al. J Infect Dis. 2014;210:354-362.
Pts with HIV-1 RNA ≥ 500 c/mL, RAL and/or
EVG resistance, and resistance to ≥ 2 other antiretroviral classes*
(N = 183)
Dolutegravir 50 mg BID +
Continue Failing
Regimen
Dolutegravir 50 mg BID +Optimized Background Regimen
With Overall Susceptibility Score ≥ 1 (ie, ≥ 1 active drug)
Day 8 Wk 24 Wk 48
*Detected at screening or based on historical evidence.
Functional monotherapy
Optimized therapy
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HIV
-1 R
NA
< 5
0 c/
mL*
Baseline INSTI Mutations
n = 183 126 36 21
69
24
79
58
Overall No Q148 Q148 + 1* Q148 + ≥ 2*
100
80
60
40
20
0
*Key secondary mutations were G140A/C/S, L74I and E138A/K/T. Vavro CL, et al. EUDRW 2014. Abstract O_10.
VIKING-3: DTG BID in Previously Treated Pts With RAL and EVG Resistance
4 of 33 pts with N155 mutation at baseline had protocol-defined virologic failure
HIV-1 RNA < 50 c/mL At Wks 24 and 48 (ITT-E)
63
183 126
71
36
56
21
29
Wk 24 DTG 50 mg BID + OBR
Wk 48 DTG 50 mg BID + OBR
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Summary Switching ART in pts with virologic suppression can improve
tolerability and maintain virologic efficacy
– Consider previous ART intolerance, failure, resistance history, and comorbidities when selecting a new ART regimen for virologically suppressed pts
Goal of treatment for ART-experienced pts with drug resistance and virologic failure is to suppress HIV-1 RNA
– Assess adherence, DDIs, tolerability, HIV-1 RNA and CD4+ cell count trends, treatment and resistance history
– Select a new regimen that includes ≥ 2, and preferably 3, fully active agents
– First-line failure with limited resistance may not require 3 fully active agents
Go Online for More CCO Educational Programming on
Antiretroviral TherapyDownloadable PowerPoint slideset for use as a self-study resource or in your own presentations
Additional CME-certified program on managing patients receiving antiretroviral therapy
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