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P285 SPIRIT: switching to emtricitabine/rilpivirine/tenofovir DF single-tablet regimen from boosted protease inhibitor maintains HIV suppression at week 48Fisher, M*; Palella, F; Tebas, P; Gazzard, B; Ruane, P; van Lunzen, J; Shamblaw, D; Flamm, J; Ebrahimi, R; White, K; Guyer, W; Porter, D; Fralich, T (Brighton, UK)
P286 A randomized pilot study of tenofovir/emtricitabine (TDF/FTC) + boosted atazanavir (ATV/r) vs. raltegravir (RAL BID) + ATV/r vs. RAL BID + ATV BIDCohen, C*; Green, J; Olivet, H; Khanlou, H; Burman, W; Corales, R; Pierone, G; DeJesus, E; Vanig, T; Tribble, M; Sweet, D; Appelbaum, J; Garb, J (Boston, USA)
P287 Effects of switching to PI monotherapy on measures of lipoatrophy: meta-analysis of six randomized HIV clinical trialsArribas, JR*; Bernardino, J; Hill, A; Sawyer, W; van Delft, Y; Moecklinghoff, C (Madrid, Spain)
P288 Novel Kivexa-based regimens in early courses of treatment for HIV infectionConway, B; Alenezi, O; Wong, L; Wang, J; Qian, C; Tossonian, H* (Vancouver, Canada)
P289 Etravirine with 2 NRTIs: an effective switch option for ARV simplification and side effect managementSmith, G*; Brunetta, J; Loutfy, M; Crouzat, F; Hedgecock, M; Merkley, B; Chang, B; Tilley, D; Kovacs, C; Fletcher, D (Toronto, Canada)
P290 Effectiveness and tolerability of abacavir-lamivudine-nevirapine (ABC/3TC/NVP) in a multicenter cohort of HIV-infected ARV-experienced patientsPodzamczer, D*; Ferrer, E; Llibre, J; Leal, M; Crusells, M; Knobel, H; Curto, J; Puig, J; Górgolas, M; Gómez-Sirvent, J; Domingo, P; Rozas, N; López-Bernaldo de Quirós, J; Ocampo, A; Vergas, J (Barcelona, Spain)
P291 TRANxITION 144-week results: switching virologically stable HIV patients from immediate-release nevirapine (NVP IR) to extended-release NVP (XR)Arastéh, K*; Drulak, M; Guo, J; Livrozet, J; Orkin, C; Quinson, A; Ward, D (Berlin, Germany)
P292 Reasons for antiretroviral treatment changes in Spanish HIV 1 patients in 2011: SWITCH AUDIT studyTasias, M*; Viciana, P; Deig, E; Arranz, J; Pasquau, J; Vera, F; Pujol, E; Vergas, J; Bernardino, J; Pedrol, E (Tarragona, Spain)
TREATMENT STRATEGIES – SWITCH STUDIES – PART ONE
*Indicates presenting author.
M Fisher1, F Palella2, P Tebas3, B Gazzard4, P Ruane5, J van Lunzen6, D Shamblaw7, J Flamm8, R Ebrahimi9, K White9, B Guyer9, D Porter9, T Fralich9
1Brighton and Sussex University Hospitals; 2Northwestern University Feinberg School of Medicine; 3University of Pennsylvania; 4Chelsea and Westminister Hospital Foundation Trust; 5Peter J. Ruane, MD, Inc.; 6Infectious Disease Unit, University Medical Center Hamburg-Eppendorf;
7La Playa Medical Group and Clinical Research; 8Kaiser Permanente; 9Gilead Sciences, Inc.
Through 24 weeks, switching to RPV/FTC/TDF was Through 24 weeks, switching to RPV/FTC/TDF was • • non-inferior to remaining on PI+RTV+2NRTIs (93.7% versus non-inferior to remaining on PI+RTV+2NRTIs (93.7% versus 89.9%)89.9%)
In the delayed switch arm, virologic suppression was In the delayed switch arm, virologic suppression was ––maintained through 24 weeks with RPV/FTC/TDF (92.1%) maintained through 24 weeks with RPV/FTC/TDF (92.1%) In the immediate switch arm, virologic suppression was In the immediate switch arm, virologic suppression was ––maintained through 48 weeks after switching to maintained through 48 weeks after switching to RPV/FTC/TDF (89.3%) RPV/FTC/TDF (89.3%)
Lower rate of virologic failure observed in subjects Lower rate of virologic failure observed in subjects • • switching to RPV/FTC/TDF (0.9%) compared to remaining on switching to RPV/FTC/TDF (0.9%) compared to remaining on PI+RTV+2NRTIs (5.0%) at Week 24PI+RTV+2NRTIs (5.0%) at Week 24
Low rate of virologic failure (1.3%) was also seen in the Low rate of virologic failure (1.3%) was also seen in the ––delayed switch arm delayed switch arm Through 48 weeks, RPV/FTC/TDF maintained a low rate Through 48 weeks, RPV/FTC/TDF maintained a low rate ––(2.5%) of virologic failure(2.5%) of virologic failure
Resistance development was infrequent with switching Resistance development was infrequent with switching • • to RPV/FTC/TDF to RPV/FTC/TDF Switching to RPV/FTC/TDF resulted in improvement in Switching to RPV/FTC/TDF resulted in improvement in • • fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at Week 24 and was maintained through Week 48Week 24 and was maintained through Week 48
11th International Congress onDrug Therapy in HIV Infection11-15 November, 2012Glasgow, UK
Poster Number
P285
Background Results (cont'd)
Methods
Conclusions
Acknowledgements
Results
Regimen simpli cation cation• Improves quality of life– 1-3
Increases long-term adherence– 1-3
Reduces virologic failure (VF)– 1-3
Reduces long-term toxicities– 1-3
RPV/FTC/TDF is a well-tolerated, once daily single-tablet regimen –(STR) treatment option4,5
This is the rst study to evaluate the safety and ef rst study to evaluate the safety and ef rst study to evaluate the safety and ef rst study to evaluate the safety and ef cacy of switching cacy of switching • from ritonavir-boosted protease inhibitor (PI+RTV) based HAART to a simpli ed regimen of the STR RPV/FTC/TDF in virologically ed regimen of the STR RPV/FTC/TDF in virologically suppressed patients
Figure 1. Study Design
Figure 2. Antiretroviral Therapy at Screening (n=476)
Figure 7. eGFR (Cockcroft-Gault) from Baseline to Week 48
Figure 6. Changes from Baseline in Fasting Lipids
Gilead Sciences, Inc.333 Lakeside Drive
Foster City, CA 94404Tel: (650) 574-3000
Fax: (650) [email protected]
Table 1. Baseline Characteristics
Table 5. Grade 3 or 4 Adverse Events and Laboratory Abnormalities
Table 3. RPV/FTC/TDF NNRTI and NRTI Resistance Through Week 48
Table 4. Treatment Response Among RPV/FTC/TDF-treated Subjects with Pre-Existing K103N
SPIRIT: Switching to Emtricitabine/Rilpivirine/Tenofovir DF Single-Tablet Regimen from Boosted Protease Inhibitor
Maintains HIV Suppression through Week 48
© 2012 Gilead Sciences, Inc. All rights reserved.
Scan this QR code to link to this poster and to download a PDF copy. You will be prompted to enter the following passcode: P285
Claxton, Clin Ther. 2001;23(8): 1296-13101. Stone, J Acquir Immune De c Syndr. 2004;36(3) c Syndr. 2004;36(3) 2. DHHS Guidelines. March 27, 2012.3. COMPLERA4. ®COMPLERA®COMPLERA . US Prescribing Information 08/2011. Gilead Sciences, Inc.EVIPLERA5. ®EVIPLERA®EVIPLERA . Summary of Prescribing Characteristics 12/2011. Gilead Sciences, Inc
Clinical trial number: GS-US-264-0106 Clinical Trials.gov: NCT01252940
We greatly appreciate the involvement of all study subjects, Investigators and their staff, and the • SPIRIT Study Team
Switching boosted PI to Rilpivirine In-combination with Truvada as an STRMulticenter, international, randomized, open-label, Phase 3b, 48-week study
RPV/FTC/TDF STR
24 weeks 48 weeksPrimary Endpoint Secondary Endpoint
7
PI + RTV +2 NRTIs
2:1
(N=476)
RPV/FTC/TDF STR
RPV/FTC/TDF STR
Primary Endpoint: Non-inferiority (12% margin) of RPV/FTC/TDF to PI+RTV+2 NRTIs by FDA snapshot analysis HIV-1 RNA <50 copies/mL at 24 weeks1
Secondary Endpoints: Proportion of subjects on RPV/FTC/TDF who have HIV-1 RNA <50 copies/mL at Week 48 Change in fasting lipid parameters and CD4 cell count at 241,2 and 48 weeks Safety and tolerability to PI+RTV+2NRTIs at 241 and 48 weeks Proportion of subjects who have HIV1 RNA <50 copies/mL (missing = excluded) through Week 48
1. Palella F, et al. IAC 2012; Washington, DC. Oral TUAB0104 2. Tebas P, et al. LIPO 2012; Washington, DC. #018
RPV/FTC/TDFN = 317
PI+RTV+2NRTIsN = 159
Median age, years (IQR)Median age, years (IQR) 42 (35, 48)42 (35, 48) 43 (36, 49)43 (36, 49)
Male Male 86%86% 91%91%
White raceWhite race 76%76% 78%78%
Black raceBlack race 19%19% 14%14%
Latino ethnicityLatino ethnicity 16%16% 20%20%
Median time since Median time since rst ART, years (IQR) rst ART, years (IQR) rst ART, years (IQR) 2.9 (1.9, 4.4) 2.6 (1.7, 4.8)2.9 (1.9, 4.4) 2.6 (1.7, 4.8)2.9 (1.9, 4.4) 2.6 (1.7, 4.8)2.9 (1.9, 4.4) 2.6 (1.7, 4.8)
Mean CD4 cell count, cells/mmMean CD4 cell count, cells/mm33 (SD) (SD) 576 (237)576 (237) 600 (259)600 (259)
3TC/ZDVABC
FTC3TC
TDFd4T
ZDV
SQVAPV
RTV-boosted PI†NRTI
3.41.1
0.80.80.60.20.2
3.41.1
0.80.80.60.20.2
1.70.21.70.2
% Subjects
FTC/TDF81%
3TC/ABC13%
ATV37%
LPV33%
DRV20%FPV
8%
% Subjects
3TC: lamivudine; d4T: stavudine; ABC: abacavir; APV: amprenavir; ATV: atazanavir; DRV: darunavir; FPV: fosamprenavir; FTC: emtricitabine; LPV: lopinavir; RTV: ritonarvir; SQV: saquinavir; TDF: tenofovir disoproxil fumarate; ZDV: zidovudine† Includes all treated subjects. 2 subjects enrolled on EFV/FTC/TDF instead of a boosted PI (protocol violation)
Resistance development was infrequent (<1% RPV/FTC/TDF treated subjects)Resistance development was infrequent (<1% RPV/FTC/TDF treated subjects)
Switching to RPV/FTC/TDF resulted in improvement in fasting lipids, including Switching to RPV/FTC/TDF resulted in improvement in fasting lipids, including TC, LDL, TGs, and TC:HDL ratio at Week 24 and maintained through Week 48TC, LDL, TGs, and TC:HDL ratio at Week 24 and maintained through Week 48
In vitroIn vitro RPV and RTV inhibit OCT2 and MATE1, renal transporters for creatinine RPV and RTV inhibit OCT2 and MATE1, renal transporters for creatinine tubular secretion, respectively.tubular secretion, respectively.1,21,2
RPV/FTC/TDF-treated subjects with pre-existing K103N had a high response rateRPV/FTC/TDF-treated subjects with pre-existing K103N had a high response rate
Figure 4. Virologic Failure HIV-1 RNA >50 c/mL at Weeks 24 and 48 (FDA Snapshot Analysis)
0.9
5
1.32.5
0
5
10
15
20
25
8/1593/317 2/152 8/317
24 Weeks 48 Weeks
(immediate) (delayed) (immediate)PI+RTV+2NRTIs
RPV/FTC/TDF RPV/FTC/TDF
RPV/FTC/TDFAll Subjects*
N = 469
Subjects Analyzed for ResistanceSubjects Analyzed for Resistance††, , n (% study arm)n (% study arm) 7 (1.5%)7 (1.5%)
Subjects with Resistance to ARV Regimen, Subjects with Resistance to ARV Regimen, n (% study arm)n (% study arm) 4 (0.9%)4 (0.9%)
Emergent NNRTI and NRTI Resistance Emergent NNRTI and NRTI Resistance Mutations by SubjectMutations by Subject
Subject 1Subject 1‡‡: K103N + L100I + M184I: K103N + L100I + M184ISubject 2: M184ISubject 2: M184ISubject 3: E138E/K + M184M/I/VSubject 3: E138E/K + M184M/I/VSubject 4: E138K + V108V/I + M184VSubject 4: E138K + V108V/I + M184V
RPV/FTC/TDF(Immediate,
Day 1 to W24) N = 317
RPV/FTC/TDF(Delayed,
W24 to W48)N = 152
RPV/FTC/TDF(Immediate,
Day 1 to W48)N = 317
RPV/FTC/TDF (Total,
D1 to W48)N = 469
Subjects with Subjects with Pre-existing K103N, nPre-existing K103N, n 1818 66 1818 2424
Snapshot OutcomeSnapshot Outcome Virologic Suppression Virologic Suppression 1818 55 1717 2222 Virologic Failure Virologic Failure 0 0 10 0 10 0 10 0 10 0 10 0 1aa 11aa
No Data Window No Data Window 0 10 10 10 1bb 0 10 10 10 1bb
eGFR: estimated Glomerular Filtration Rate
* Includes Day 1 to Week 48 data on immediate switch arm and Week 24 to Week 48 data on delayed switch arm† Subjects who experienced virologic rebound (two consecutive visits with HIV-1 RNA ≥400 c/mL) or had HIV-1 RNA ≥400 c/mL at last visit‡ History of efavirenz use
a Failed with resistance, pre-existing K103N and V179I and acquired M184V, E138K, and V108V/I while on study drug b Missing data during window but on study drug; suppressed at prior visit
RPV/FTC/TDF N = 317
(Immediate switch, at W48)
PI+RTV+2NRTIsN = 159(at W24)
RPV/FTC/TDFN = 152
(Delayed switch, at W24)
Grade 3 or 4 Grade 3 or 4 Adverse EventsAdverse Events 18 (5.7%)18 (5.7%) 11 (6.9%)11 (6.9%) 12* (7.9%)12* (7.9%)
Grade 3 or 4 Grade 3 or 4 Laboratory Laboratory AbnormalitiesAbnormalities
28 28†† (8.8%) (8.8%) 18 18‡‡ (11.3%) (11.3%) 2323§§ (15.2%) (15.2%)
Adverse events and laboratory abnormalities occurring in ≥1% of subjects: * creatine kinase increase† ALT, AST, creatine kinase, hematuria‡ AST, bilirubin, creatine kinase, triglycerides§ ALT, AST, creatine kinase, glycosuria
TC - total cholesterol, LDL - low-density lipoprotein, TG - triglycerides, HDL - high-density lipoprotein
1. Mills, et al. ICAAC 2011; Chicago. #H2-794c2. Lepist E-I. ICAAC 2011; Chicago. #A1-1724
0
20
40
60
80
100
120
RPV/FTC/TDF (BL to W48)
PI+RTV+2NRTIs (BL to W24)
RPV/FTC/TDF (delayed switch, W24 to W48)
Week
eGFR
by
Coc
kcro
ft-G
ault
(mL/
min
)
106.3
BL 12 24 36 48
106.3
Table 2. Week 24 and 48 FDA Snapshot Analysis
RPV/FTC/TDF(Immediate,
Day 1 to W24) N = 317
PI+RTV +2NRTIs(Day 1 to
W24)N = 159
RPV/FTC/TDF(Delayed,
W24 to W48)N = 152
RPV/FTC/TDF(Immediate,
Day 1 to W48)N = 317
Virologic Success, %Virologic Success, % HIV-1 RNA <50 copies/mL HIV-1 RNA <50 copies/mL 93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%93.7% 89.9% 92.1% 89.3%
Virologic Failure, n (%)Virologic Failure, n (%) 3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)3 (0.9%) 8 (5.0%) 2 (1.3%) 8 (2.5%)
HIV-1 RNA HIV-1 RNA ≥≥50 copies/mL50 copies/mL 1 8 1 41 8 1 41 8 1 41 8 1 41 8 1 41 8 1 41 8 1 41 8 1 4 Discontinued due to lack Discontinued due to lack of ef of ef of ef of ef of ef of ef cacy cacy cacy 1 0 1 21 0 1 21 0 1 21 0 1 21 0 1 21 0 1 21 0 1 21 0 1 2
Discontinued due to other Discontinued due to other reasons & last available reasons & last available HIV-1 RNA HIV-1 RNA ≥≥50 c/mL50 c/mL
1 0 0 21 0 0 21 0 0 21 0 0 21 0 0 21 0 0 21 0 0 21 0 0 2
No Virologic Data, n (%)No Virologic Data, n (%) 17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%)17 (5.4%) 8 (5.0%) 10 (6.6%) 26 (8.2%) Discontinued due to AE Discontinued due to AE 6 0 5 76 0 5 76 0 5 76 0 5 76 0 5 76 0 5 76 0 5 76 0 5 7 Discontinued due to other Discontinued due to other reasons & last available reasons & last available HIV-1 RNA <50 c/mL HIV-1 RNA <50 c/mL
1111 55 33 1616
Missing data during Missing data during window but on study drug window but on study drug 0 3 2 30 3 2 30 3 2 30 3 2 30 3 2 30 3 2 30 3 2 30 3 2 3
Figure 3. Virologic Suppression at Weeks 24 and 48 FDA Snapshot Analysis – ITT Population
CD4 mean change (cells/mmCD4 mean change (cells/mm33):):Week 24: RPV/FTC/TDF immediate switch +20, PI+RTV+2NRTIs +32 (p=0.28), Week 24: RPV/FTC/TDF immediate switch +20, PI+RTV+2NRTIs +32 (p=0.28),
RPV/FTC/TDF delayed switch -7 RPV/FTC/TDF delayed switch -7 Week 48: RPV/FTC/TDF immediate switch +10Week 48: RPV/FTC/TDF immediate switch +10
eGFR at baseline (mL/min):RPV/FTC/TDF = 109.5PI+RTV+2NRTIs = 108.6
Figure 5. Virologic Suppression at Weeks 24 and 48 ITT Missing = Excluded*
*Secondary endpoint: Proportion of subjects who have HIV1 RNA <50 copies/mL (missing = excluded) through Week 48
99.7 94.7
0
20
40
60
80
100
24 Weeks 48 Weeks
RPV/FTC/TDFPI+RTV+2NRTIs(D1-W24)
RPV/FTC/TDFImmediate(D1-W24)
Delayed (W24-W48)
Immediate(D1-W48)
Subj
ects
with
viro
logi
c su
ppre
ssio
n, %
143/15 140/1411297/298
99.3
RPV/FTC/TDF
p<0.001
98.6
283/287
AUSTRIA Greil, RichardHaas, BernhardRieger, ArminSchalk, Horst Vetter, Norbert
BELGIUM Clumeck, NathanVandekerckhove, LinosVan Wijngaerden, Eric
CANADA Brunetta, Jason Conway, BrianKasper, KenLaplante, Francois Rachlis, Anita
FRANCE Cotte, LaurentDurant, JacquesGirard, Pierre Marie Katlama, Christine Molina, Jean-Michel Pellegrin, Jean-LucRaffi, Francois Slama, Laurence Yeni, Patrcik
GERMANY Arasteh, KeikawusFatkenheuer, GerdKnecht, Gabriele Mauss, StefenRockstroh, JurgenStellbrink, Hans-Jurgenvan Lunzen, Jan
ITALYAntinori, Andrea D'Arminio Monforte, AntonellaLazzarin, Adriano Maggiolo, Franco Rizzardini, Giuliano
SPAIN Berenguer, Juan Clotet, Bonaventura Gatell, Josep Maria Moreno, Santiago
UNITED KINGDOM Fisher, Martin Gazzard, BrianJohnson, Margaret Orkin, Chloe Reeves, Iain Wilkins, Edmund
UNITED STATES Albrecht, HelmutBellos, NicholaosBenson, Paul Berger, DanielBolan, RobertBrachman, PhilipBredeek, Fritz Brinson, CynthiaBurack, JefferyCasanas, BeataCimoch, PaulCohen, CalvinCrofoot, GordonCruickshank, FrederickDeJesus, EdwinDietz, CraigDretler, Robin Edelstein, HowardFlamm, JasonFollansbee, StephenGallant, Joel Garcia, Fernando Gathe, Joseph Georgescu, GeorgianaGreiger-Zanlungo, PaolaHenry, W Keith Horton, JamesHsu, RickyJefferson, Thomas TJohnson, MarcJordan, Wilbert
Schrader, Shannon Shalit, Peter Shamblaw, DavidSlim, Jihad Tebas, Pablo Thompson, Melanie Towner, William Vanig, ThanesWade, BarbaraWard, DouglasWheeler, DavidWilkin, AimeeWohlfeiler, Michael Zolopa, Andrew
SPIRIT Study TeamChung, DevonDas Wadhwani, BabiDa Costa, MarilynDe-Oertel, ShampaNicolellis, Amy
COMPLERA Project TeamChuck, SusanHilton, JohnKalra, AnshuLin, HelenLai, MaeSaba, DinaWeber, TomWhite, Kirsten
Khanlou, HomayoonKinder, FordKlein, DanielLamarca, AnthonyLubelchek, RonaldLucasti, ChristopherMarkowitz, MartinMartorell, ClaudiaMayer, Cynthia McCurdy, LewisMcDonald, CherylMcGowan, JosephMildvan, DonnaMills, Anthony Morales Ramirez, Javier Mounzer, KaramPalella, FrankPollard, Richard Prelutsky, DavidRamgopal, Moti Rashbaum, BruceRichmond, GaryRobbins, WilliamRodriguez, JorgeRodwick, BarryRuane, PeterSaag, MichaelSantiago, StevenSax, PaulScarsella, AnthonySchneider, Stefan
One subject in the PI+RTV+2NRTIs arm developed resistance prior to switch at • Week 24 (M184K+K70E/K)There were no subjects with detected resistance after delayed switch to RPV/FTC/TDF•
* Primary endpoint, delta 3.8 (-1.6, 9.1)
Subj
ects
with
viro
logi
c fa
ilure
, %
FTC/RPV/TDF
• Stable PI + RTV + 2 NRTI 6 months with HIV-1 RNA <50 c/mL
• On 1st or 2nd regimen• No prior NNRTI use• No known resistance to study
agents
RPV/FTC/TDF (immediate, D1-W24)
PI+RTV+2NRTIs (D1-W24)
RPV/FTC/TDF (delayed, W24-W48)
RPV/FTC/TDF (immediate, D1-W48)
Mea
n C
hang
es fr
om B
L, m
mol
/L (m
g/dL
)
TC LDL TG HDL
(-25)
(-1)
(-25)(-24)
(-16)(-14)
(-16)
(-53)
(3)
(-80)
(-64)
(-4)(-1) (-2) (-2)
0
-0.03
-0.41
-0.05-0.05-0.1
-.60
-.41
-.65
-.03
.03
-.90
-.36
-.65-.72
-.62
-0.9-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.1
0
TC:HDL ratio
Cha
nge
in T
C:H
DL
ratio
-0.27
.08
-0.21
-0.35
-0.5
-0.4
-0.3
-0.2
-0.1
0
0.1
witching boosted ilpivirine
Prop
ortio
n of
Sub
ject
s, %
(HIV-1 RNA <50 c/mL)
RPV/FTC/TDF (immediate switch, Day 1 to W24)
PI+RTV+2NRTIs (delayed, Day 1 to W24)
0.95.4
RPV/FTC/TDF (delayed switch, W24 to W48)
92.1
1.36.65 5
93.789.9
0102030405060708090
100
Virologic Suppression Virologic Failure No Data
Switching to RPV/FTC/TDF was non-inferior* to remaining on PI+RTV+2NRTIs for 24 weeks. Similar rates of virologic suppression were also seen with 48 weeks of treatment
with RPV/FTC/TDF
2.58.2
89.3
0102030405060708090
100
VirologicSuppression
Virologic Failure
No Data
RPV/FTC/TDF (immediate switch, Day 1 to W48)
2.58.2
89.3
0102030405060708090
100
VirologicSuppression
No Data
RPV/FTC/TDF (immediate switch, Day 1 to W48)
143/159140/152 3/317 8/159 2/152 17/317 8/159 10/152 283/317 8/317 26/317297/317
Community Research Initiative of New England Boston, United States
1
C. Cohen1, J.Green1, H. Olivet1, H. Khanlou2, W. Burman3, R. Corales4, G. Pierone5, E. DeJesus6, T. Vanig7, M. Tribble8, D. Sweet9, J. Appelbaum10, J. Garb11 1Community Research Initiative of New England, Boston, United States, 2Medical Institute of Immunology and Infectious Diseases, Los Angeles, United States, 3Denver Public Health, Denver, United States, 4AIDS Care, Rochester, United States, 5Treasure Coast Infectious Diseases, Vero Beach, United States, 6Orlando Immunology Center, Orlando, United States, 7Spectrum Medical Group, Phoenix, United States, 8Uptown Physicians Group, Dallas, United States, 9Via Christi Research, Wichita, United States, 10Florida State University College of Medicine, Tallahassee, United States, 11Baystate Medical Center, Springfield, United States
A Pilot Study of the Novel Antiretroviral Combination of Atazanavir and Raltegravir in HIV-1 Infected Subjects with Virologic Suppression on a Standard Regimen of Boosted Atazanavir, Tenofovir and Emtricitabine
The BATAR Study Boosted Atazanavir Truvada vs. Atazanavir Raltegravir
P286
Background 2
Patients virologically suppressed on ATV/r + TDF/FTC may require alternative regimens that maintain suppression while addressing specific drug related side effects.
We explored two alternative regimens that replace continued ritonavir and/or TDF/FTC.
This open-label exploratory pilot trial enrolled 43 patients virologically suppressed on ATV/r + TDF/FTC.
Methods-1 3
Subjects: HIV-1-positive virologically suppressed adults (HIV RNA < 50 copies/ml) on a “preferred” regimen of ritonavir-boosted atazanavir plus tenofovir and emtricitabine.
Primary Objective: to compare virologic outcomes of three regimens in patients with virologic suppression on ritonavir-boosted atazanavir plus tenofovir and emtricitabine.
At baseline, subjects randomly assigned (1:1:1) to one of the three study arms:
ATV/rtv/RAL: atazanavir/ritonavir 300/100 mg once daily plus raltegravir 400 mg twice daily [stop TDF/FTC]
ATV/RAL: atazanavir 300 mg twice daily plus raltegravir 400 mg twice daily [stop TDF/FTC and rtv]
ATV/rtv/TDF/FTC: continue atazanavir/ritonavir 300/100 mg once daily plus co-formulated tenofovir and emtricitabine
Methods-2 4
Secondary Objectives: to compare the safety, tolerability, and satisfaction of the three study regimens.
Measures HIV viral load: Abbott Real Time HIV-1 assay (<40 c/mL) Safety: clinical and lab adverse events (ACTG toxicity grading
scale) ECG: 12 lead ECG conducted at screening, week 2, week 4, and
week 24 QOL: self-report on 100 point Numerical Rating Scale Adherence: three day self-report of missed and taken doses
Definition of Virologic Failure: HIV RNA level > 200 confirmed on consecutive, repeat measurements.
Inclusion Criteria 5
Inclusion Criteria
CD4 count ≥ 200/mm3 at screening
Undetectable HIV RNA (<40 c/mL) at screening and no HIV RNA >200 c/mL during the 180-day period prior to screening
Stable on a regimen of once-daily ATV 300mg + rtv 100mg + TDF/FTC at screening and for at least 90 days prior to screening
History demonstrates either lack of evidence of resistance to any of the drugs that were used in any of the three arms, or treatment history consistent with atazanavir sensitive virus
Raltegravir naïve
No acute or chronic hepatitis B infection
No ECG demonstrating atrioventricular block, prolonged QRS interval > 12ms or known complete bundle branch block
Results: Disposition 6
Baseline characteristics were generally similar in the three study arms
88% male; mean age 46 years 74% white; 21% African American; 5% other race Mean CD4: 532 cells/mm3
N=43
ATV/r QD + RAL BID N=15
N=1 loss to follow-up
ATV BID + RAL BID N=14
N=1 withdrawal due to an AE
N=3 confirmed virologic failures
QD ATV/r/TDF/FTC N=14
N=1 withdrawal
Results: Primary Endpoint 7
*One subject on prohibited medication (phenytoin) but responded. ^One subject with elevated viral load at week 48 but <50 on consecutive draw after week 48.
Outcomes through Week 48
N=43 Enrolled N
Virologic Response N (%)
Confirmed Virologic Failure N (%)
Withdrawal due to AE; VL <50 N (%)
Other Withdrawal; VL <50 N (%)
ATV/rtv/ RAL
15 14 (93%)* 0 0 1 (7%)
ATV/RAL 14 10 (71%) 3 (21%) 1 (7%) 0
ATV/rtv/ TDF/ FTC
14 13 (93%)^ 0 0 1 (7%)
Results: Quality of Life
Quality of Life: change from baseline by self-report on 100 point Numeric Rating Scale
No difference in QOL change across arms
8
N=31* ATV/rtv/RAL ATV/RAL ATV/rtv/ TDF/ FTC Total
mean sd mean sd mean sd mean sd
Baseline 77.4 16.1 82.5 11.6 92.9 8.6 84.2 14.1
Week 48 78.2 22.6 81.3 17.5 90.5 11.1 83.3 18.2
Change 0.8 20.0 -1.3 12.7 -2.5 8.2 -0.9 14.4
*Note: Results only for patients on study through week 48; all other data censored.
Results: Adherence by Self Report
Adherence: percent of doses reported taken during three days prior to study visit
9
Summary: ≥ 95% adherence reported by most subjects in all three arms at both baseline and week 48 Note: There were 3 virologic failures on ATV/RAL that were attributed to adherence issues. Their adherence values are discussed on the next panel; 3 early withdrawals and 2 with missing data points are excluded from the calculations.
N=35 ATV/rtv/RAL ATV/RAL ATV/rtv/ TDF/ FTC
Total
mean sd mean sd mean sd mean sd
baseline 97.5 9.2 96.7 10.4 100.0 0.0 98.1 7.8
week 48 97.5 9.2 95.0 15.8 100.0 0.0 97.6 10.0
change 0.0 13.5 -1.7 19.9 0.0 0.0 -0.5 13.0
Results:CD4 and Virology Outcomes
Mean CD4 count changes from baseline to week 48
Median CD4 change was significant comparing ATV/RAL to Control (p=0.010) and comparing ATV/rtv/RAL to Control (p=0.018).
Virology
Through week 48, there were n=3 observed virologic failures (>200 c/mL on 2 consecutive tests), all on ATV/RAL.
These three had self-reported 100% adherence at one or both study visits associated with viremia. However, study staff documented a history of difficulty adhering to the
regimen
Resistance testing was attempted in all subjects with confirmed virologic failure; results either did not detect resistance or were non-amplifiable.
10
ATV/rtv/RAL ATV/RAL ATV/rtv/TDF/ FTC Total
Mean change 12.1 -31.9 75.4 21
Median change 10.5 -12.5 61.5 19.5
Results: Adverse Events and Safety
Adverse events (AE) were categorized by body system. Most AEs were transient. In this pilot, only differences of >5 events within a category between arms is summarized below.
Frequency (n) of AEs by category regardless of assessment of causation:
Frequency (n) of AEs by category judged possibly related to study drug:
11
Adverse Event ATV/rtv/RAL ATV/RAL ATV/rtv/TDF/FTC
Neurologic 5 2 0
Adverse Event ATV/rtv/RAL ATV/RAL ATV/rtv/TDF/FTC
Neurologic 7 6 1
ENT 3 6 9
Musculoskeletal 3 7 1
Results: Adverse Events and Safety
One subject randomized to ATV/RAL discontinued due to an Adverse Event: Experienced heart palpitations without chest pains starting on day 2
Stopped study medications and restarted the pre-study regimen prior to the week 4 visit
Symptoms resolved within two days of discontinuation of the study regimen
The subject withdrew at the week 4 visit
No significant differences across arms were noted in lipid fractions (Total Chol, HDL, LDL, TG) or other lab tests
There were no clinically significant ECG changes across arms
12
Results: Serious Adverse Events
N=5 SAEs; one judged possibly related to study: ATV/rtv/RAL: Hospitalization for asthma; Hx of sarcoidosis Prostate Cancer
ATV/RAL: Two hospitalizations for recurrent depression Deep vein thrombosis; judged possibly/probably related
ATV/rtv/TDF/FTC: Myocardial infarction; Hx of CAD s/p stent
13
BATAR Study: Conclusions
In this study, the use of ATV/rtv with either TDF/FTC or RAL was similarly successful over 48 weeks in maintaining virologic suppression.
Unboosted twice-daily atazanavir with twice-daily raltegravir had several concerns emerge during study: N=3 (21%) virologic failures without resistance detection CD4 count change was significantly less than Control More neurologic and musculoskeletal adverse events
In sum, these data support the continuation of TDF/FTC with ATV/rtv when tolerated; replacing TDF/FTC with RAL maintained suppression in this pilot though an increased number of neurologic events was observed. The use of twice-daily ATV instead of ATV/rtv is not recommended
for use based on the observations in this pilot
14
Acknowledgements
Funding provided by Bristol-Myers Squibb Study drug supplied by Bristol-Myers Squibb and
Merck TDF/FTC and rtv not provided by the study
All study data collection, monitoring, and analysis were performed independently of both supporters
Additional funding provided by Jonathan Crutchley and other donors to Community Research Initiative
15
Studies included in the meta-analysis: of the six trials included in the meta-analysis, 471/821 randomised patients (57%) were tested for changes in body composition by DEXA. Results from the 48 week analysis were used for five trials, and the 96 week results were used for one trial (Abbott 613). Design of the trials included in meta-analysis _______________________________________________________________________________________________ Trial / design Treatment arms Baseline Limb fat Baseline Trunk fat DEXA Median kg (IQR) Median kg (IQR) n _______________________________________________________________________________________________ Kalesolo LPV/r monotherapy 3.6 (2.0-6.4) 8.5 (5.0-13.4) n=19 (Switch) LPV/r + 2NRTIs 4.4 (2.9-6.0) 8.2 (5.4-12.0) n=23 MONOI DRV/r monotherapy 4.8 (3.4-8.3) 9.8 (6.0-12.5) n=75 (Switch) DRV/r + 2NRTIs 5.2 (2.9-8.3) 8.9 (6.0-12.5) n=81 Monarch DRV/r monotherapy 8.9 7.2 (5.8-11.1) n=15 (Switch) DRV/r + 2NRTIs 8.3 7.8 (6.4-10.9) n=15 KRETA LPV/r monotherapy 2.5 (1.9-5.3) 8.5 (5.0-11.1) n=34 (Switch) LPV/r + ABC/3TC 2.5 (1.6-3.6) 8.2 (5.1-10.8) n=40 Abbott 613 LPV/r +ZDV/3TC, 8.2 (4.7)* 9.3 (6.2)* n=74 (I/M) switch to LPV/r after HIV RNA suppression. EFV + ZDV/3TC 7.4 (4.7)* 8.3 (6.3)* n=32 Monark LPV/r monotherapy 7.1 (4.5)* 8.1 (4.8)* n=41 (Naïve) LPV/r + ZDV/3TC 8.7 (4.7)* 8.8 (3.9)* n=22 _______________________________________________________________________________________________ I/M – Induction / Maintenance * mean and standard deviation Mean change in limb fat: There were greater rises in limb fat in the PI monotherapy arm compared to the control arm for four of the five trials. This difference was statistically significant in two of the trials when analysed individually (p<0.05 for the Monark trial, p=0.011 for the MONOI trial). However in the KRETA trial, there was a non-significant trend for greater rises in limb fat in the control arm at Week 48. In the meta-analysis, there was a significantly greater rise in limb fat for the PI monotherapy arms compared to the triple therapy control arms (p=0.024). Mean change from baseline to Week 48 in limb fat, by treatment arm _______________________________________________________________________________________________ Clinical trial Mean change from baseline in limb fat: PI/r arm Triple therapy arm Difference (PI/r – Triple) Mean (s.e.) Mean (s.e.) Mean (95% CI) _______________________________________________________________________________________________ Kalesolo +160g (267g) -50g (242g) +210g (-495, +915g) Monark -60g (181g) -700g (248g) +640g (+39, +1241g) MONOI +340g (134g) -20g (129g) +360g (-5, +725g) Monarch -57g (300g) -288g (300g) +231g (-600, +1062g) KRETA +215g (199g) +324g (184g) -127g (-658, +404g) _______________________________________________________________________________________________ Overall +277g (+36, +517g) , p=0.024 Mean change in trunk fat: there were no significant differences between the treatment arms, either for the trials analysed individually, or in the meta-analysis. Mean change from baseline to Week 48 in trunk fat, by treatment arm _______________________________________________________________________________________________ Clinical trial Mean change from baseline in trunk fat: PI/r arm Triple therapy arm Difference (PI/r – Triple) Mean (s.e.) Mean (s.e.) Mean (95% CI) _______________________________________________________________________________________________ Kalesolo +470g (581g) +640g (528g) -170g (-1709, +1369g) Monark -600g (396g) -200g (540g) -400g (-1712, +910g) MONOI +730g (292g) +600g (281g) +130g (-666, +926g) KRETA -84g (455g) +110g (411g) -194g (-1396, +1008g) _______________________________________________________________________________________________ Overall -73g (-621, +475g), p=n.s. Lipoatrophy: There were significantly fewer patients with lipoatrophy in the PI monotherapy arms compared to the control arms for three of the trials analysed individually (p<0.05, chi-square tests), and for the overall meta-analysis (p=0.03). Percentage of patients developing lipoatrophy*, by treatment arm _______________________________________________________________________________________________ Clinical trial Percentage of patients developing lipoatrophy* PI/r arm Triple therapy arm Difference (PI/r – Triple) n/N, (%) n/N, (%) % (95% CI) _______________________________________________________________________________________________ Abbott 613 4/74 (5.4%) 11/32 (34.4%) -29.0% (-46.2%, -11.7%) Monark 2/41 (4.9%) 6/22 (27.3%) -22.4% (-42.1%, -2.7%) MONOI 1/67 (1.5%) 8/74 (10.8%) -9.3% (-17.0%, -1.7%) KRETA 6/34 (17.6%) 6/40 (15.0%) +2.6% _______________________________________________________________________________________________ Overall -13.6% (-1.5%, -25.6%), p=0.03 * lipoatrophy defined as 20% reduction from baseline in limb fat Lipohypertrophy: there were no significant differences between the arms, either for individual trials or the meta-analysis. Percentage of patients developing lipohypertrophy*, by treatment arm _______________________________________________________________________________________________ Clinical trial Percentage of patients developing lipohypertrophy* PI/r arm Triple therapy arm Difference (PI/r – Triple) n/N, % n/N, % % (95% CI) _______________________________________________________________________________________________ Abbott 613 33/74 (44.6%) 14/32 (43.8%) +0.8% (-19.7%, +21.4%) Monark 8/41 (19.5%) 3/22 (13.6%) +5.9% (-12.9%, -24.7%) MONOI 18/67 (26.9%) 17/74 (23.0%) +3.9% (-10.4%, +18.2%) KRETA 5/34 (14.7%) 9/40 (22.5%) +7.8% _______________________________________________________________________________________________ Overall +0.9% (-7.7%, +9.6%), p=n.s. * lipohypertrophy defined as 20% rise from baseline in trunk fat
Effects of switching to PI monotherapy on measures of lipoatrophy: meta-analysis of six randomized HIV clinical trials Jose Arribas, Hospital la Paz, IdiPAZ, Madrid, Spain; Jose Ignacio Bernadino, Hospital la Paz, IdiPAZ, Madrid, Spain; Andrew Hill, MetaVirology Ltd, London, UK; Will Sawyer, MetaVirology Ltd, London, UK, Yvon van Delft, Janssen, Tilburg, Netherlands; Christiane Moecklinghoff, Janssen, Neuss, Germany
P287 Correspondence to: Dr Jose Arribas, idiPAZ, Hospital la Paz, Madrid, Spain [email: [email protected]]
Long-term antiretroviral treatment has led to two unexpected changes in fat distribution – lipoatrophy and lipohypertrophy - which can affect patient quality of life, stigma and cardiovascular morbidity. Changes in body composition are accurately measured using DEXA (Dual-energy X-ray absorptiometry) scanning. Switching from triple combination treatment to protease inhibitor (PI) monotherapy may prevent or reverse adverse events related to long-term nucleoside analogues. Lipoatrophy is associated with long-term use of thymidine analogues (zidovudine, stavudine). The aim of this meta-analysis was to collect all data from randomized clinical trials of protease inhibitor monotherapy versus triple combination therapy, and compare measures of lipodystrophy between the two treatment strategies.
Background
Presented at: Eleventh International Congress on Drug Therapy in HIV Infection (HIV11), Glasgow, UK, November 2012 [abstract P287]
Statistical Methods
Conclusions
Six randomised trials of PI monotherapy versus triple therapy had data available in changes in either limb or trunk fat, using DEXA scanning. In the meta-analysis, the risk of lipoatrophy was significantly lower for patients taking PI monotherapy, compared to triple therapy. There was no significant difference between the arms for lipohypertrophy. However, several of the trials included zidovudine in the control arm, which carries a higher risk of lipoatrophy than the more widely used alternatives: tenofovir and abacavir.
A detailed MEDLINE search was conducted to identify randomised clinical trials of triple combination treatment versus PI monotherapy. Summary results from analysis of changes in body composition (DEXA analysis) were collected: the mean change in limb fat and trunk fat from baseline to Week 48 (or 96), and the percentage of patients with lipoatrophy (20% reduction from baseline in limb fat) or lipohypertrophy (20% rise from baseline in trunk fat). The same methods were then used to compare three other measures of lipodystrophy, all measured by DEXA: (i) the mean change from baseline to Week 48 in trunk fat (ii) the number of patients with a 20% decrease from baseline to Week 48 in limb fat (lipoatrophy), and (iii) the number of patients with a 20% increase from baseline to Week 48 in trunk fat (lipohypertrophy). The primary endpoint for this analysis was the mean change in limb fat from baseline to Week 48 (or 96) – this continuous measure of change in limb fat was predicted to have the highest statistical power to detect differences between treatment arms. This measure was compared between the PI monotherapy arm and triple combination therapy arm across the trials using inverse variance weighting. We used estimates of variability (standard deviation of the mean change from baseline) from the available trials for the meta-analysis. Heterogeneity of treatment effects was investigated using Cochran’s Q tests. All analyses were conducted using Statistical Analysis Software (SAS, Cary, North Carolina, USA).
Methods
Results
References
Abbott 863: Cameron DW et al. JID 2008,198: 234-240. MONARK: Kolta S et al. Current HIV Research 2011, 9: 31-39 KALESOLO: Meynard J et al. J Antimicrob Chemother 2010. MONOI: Valentin M et al. HIV Med 2012, March 14th [epub ahead of print]. MONARCH: Guaraldi G et al. European AIDS Conference, Belgrade, Serbia, October 2011 [abstr PE7.5/4] KRETA: Bernardino J et al: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, USA, March 2012 [abstr 846].
A retrospective chart review was undertaken with informed consent for patients seen at the Vancouver Infectious Diseases Centre.
We identified all patients in whom KVX was prescribed (following appropriate HLA-B5701 screening and CCR5 tropism testing) with either raltegravir (RGV) or maraviroc (MVC) as initial therapy or as a switch from another regimen.
Follow-up was according to clinical standards at months 1, 3 and then quarterly.
The key endpoints were the achievement or maintenance of virologic suppression (HIV RNA < 50 copies/mL), changes in the CD4 cell count on KVX-based therapy as well as the evaluation of drug-associated toxicity, adherence, resistance and regimen modifications.
As the long-term efficacy of antiretroviral therapy regimens is confirmed, there is a need to identify additional combinations that exhibit long-term safety and potency, while also favoring simplicity of administration.
With this in mind, we undertook a review of the use of abacavir/lamivudine (Kivexa, KVX)-based regimens using integrase or CCR5 inhibitors as the third agent.
11th International Congress on Drug Therapy in HIV Infection, November 11-15, 2012, Glasgow, United Kingdom
Novel Kivexa-Based Regimens in Early Courses of Treatment for HIV InfectionBrian Conway1, Osamah Alenezi1, Leala Wong1, Jeffrey Wang1, Christina Qian1, Harout Tossonian1
1Vancouver Infectious Diseases Centre, Vancouver, Canada
Harout Tossonian MD, PhD Vancouver Infectious Diseases Centre 201-1200 Burrard Street Vancouver, BC V6Z 2C7 Canada Tel: (604) 642-6429 Fax: (604) 642-6419 Email: [email protected]
Table 1. Baseline patient characteristics
n=5
P288
BACKGROUND
METHODS
RESULTS
DISCUSSION
OBJECTIVE
Figure 1. Antiretroviral medications used with Kivexa
In patients treated with KVX in combination with RGV or MVC, virologic suppression was achieved or maintained in 89%of the patients. Immunologic responses (CD4 cell counts) were generally improved and there were no significant drug-related toxicities.
KVX-based regimens are safe and effective alternatives to more commonly used regimens in clinical practice, and offer the benefit of good long-term tolerability and little or no need to enhance follow-up for laboratory-based abnormalities.
Consideration should be given to non-NNRTI and non-PI-based regimens to address issues of toxicity and simplification without apparent loss of efficacy.
Figure 2. Antiretroviral efficacy at most recent follow-up
1
13
24
0 5 10 15 20 25 30
RGV
MVC
MVC/RGV
Number of Subjects (n) 38
Gender (n)MaleFemale
335
Age (Years)MedianRange
5335-78
Mode of HIV Transmission (n)MSMIDUOther
17129
HCV antibody positive, n (%) 17 (45)
Antiretroviral experienced, n (%) 35 (92)
Follow-up period (Months)MedianRange
239-54
CD4 cell count (cells/mm3)MedianRange
41010-990
Viral Load (copies/mL)MedianRange
66< 40 - >100,000
Suppressed viral load at baseline, n (%) 18 (47)
Viral Load <50 copies/mL
465
Mean CD4 Cell Countcells/mm3
Median adherence to KVX-based therapy exceeded 88%.
Virologic failure (confirmed HIV RNA> 50 copies/mL) occurred in 4 cases (11%) all due to incomplete adherence.
Virologic failure with the development of M184V mutation was observed in 3/4 non-suppressed patients.
Loss of CCR5 tropism was observed in one case; however, the subject was not taking MVC.
RGV resistance (N155H) was observed in one non-suppressed patient taking RGV.
There were no treatment discontinuations for toxicity and no medication-associated serious adverse events.
89%
34/38
+80
Mean Change in CD4 CellCount cells/mm3
Switches to these regimens included replacement of the third agent with MVC or RGV (n=13), replacement of the NRTI backbone with KVX (n=13) or both (n=9).
MAPLE LEAF MEDICAL CLINIC14 College Street, Toronto, Ontario, Canada, M5G 1K2
www.mapleleafmedical.com
Switch to Etravirine and Dual Nucleotide/side for ARV Simplification and Side Effect Management - Poster # 289
G. Smith, J. Brunetta, F. Crouzat, M. Loutfy, I. Sandler, B. Chang, D. Fletcher, B. Merkley, M. Hedgcock and D. Tilley
Maple Leaf Medical Clinic Eleventh International Congress on Drug Therapy in HIV Infection
11-15 November 2012 Glasgow, UK
Results
Results (con’t)Background Discussion
DisclosureThis work was supported through an unrestricted research grant from Janssen Pharmaceuticals Canada
• Current treatment guidelines recommend efavirenz, boosted PI and just re- cently added, raltegravir based ARV therapy in �rst line. o Efavirenz and boosted PI therapy are associated with predictable side e�ects and the discontinuations rates are signi�cant
o 20 - 35% of patients change their �rst ARV therapy during the 1st year of treatment - see Crouzat et al. poster p273
• Etravirine, a second generation NNRTI, has been shown to have rates of CNS side e�ects similar to placebo in it’s registrational trial (Duet), has a favorable lipid pro�le and has shown robust antiretroviral activity. These, and other prop erties, make it an excellent candidate as a replacement for efavirenz or a boosted PI in patients with side e�ects on their initial regimen.
o Nguyen et al, reported that patients on long term efavirenz did not prefer a switch to etravirine. - In this small study (n=58), patients who did not complain of CNS side e�ects were switched.
o In our study, 27/31 patients switching from efavirenz had complaints of CNS symptoms - in all but 1, CNS symptoms were reported to have improved or re- solved.
o Supporting the results of our study, Nelson et al showed, in a random- ized trial of efavirenz compared to etravirine in treatment naïve HIV in- fected individuals, that the rate of CNS side e�ects was signi�cantly lower in the etravirine group.
• Both boosted PIs and efavirenz have increase lipid levels. In our study, we were able to show a decrease of TC, LDL and triglycerides and no change in HDL
o In the switch study by Nguyen mentioned above, there was an im- provement of lipid pro�les in patients after switching to etravirine.
o In our study, there was minimal amount of change in statin use making it unlikely that the changes in lipids where driven by changes in statin use. - 4 patients added a statin after the switch - 1 patient stopped his statin. o Patients switching from boosted atazanavir had minimal change in their lipid levels. - This is not unexpected as the lipid changes associated with lopinavir/rit have been shown to be greater than those associated with the use of atazanavir/rit. (Molina et al. 2010)
• Limitations:
o non-comparative study
o the majority of patients were MSM men, thus limiting the generalizabil- ity to other populations.
o As this was a retrospective analysis of patients in a clinical practice, some patients are missing lipid data.
o with the availability of new single tablet regimens that include new well-tolerated medications such as rilpivirine/tenofovir/emtribiticine will provide more choices for simpli�cation and side e�ect manage- ment
• Because HIV-infected individuals are being treated earlier in the course of their chronic disease management, the duration of exposure to medications is longer.Current antiretrovirals (ARVs) may have side e�ects that limit their long term use in many patients.
• 2 common sets of side effects are: Neuropsychiatric symptoms associated with efavirenz Dyslipidemia associated with both PI and efavirenz use
• Newer ARVs such as etravirine and raltegravir have comparatively less reported side e�ects of these types in clinic trials
• Switching patients to etravirine is an option to reduce the long-term side e�ect burden of ARVs
• Etravirine has a number of properties that make it a good choice as part of a sim-plified, well tolerated regimen: 1) Potent NNRTI 1.99 log decrease in VL in phase I/ll 7 day mono-therapy study – Grundev et al 2) Good lipid pro�le 3) Good side e�ect pro�le i.e. few neuropsychiatric side e�ects 4) Higher Genetic barrier than 1st gen NNRTIs Vingerhoets et al 5) QD dosing Lalezari, J et al
Methods• Retrospective cohort analysis• Data extracted from an electronic medical record data base HealthScreenTM• Medical charts were reviewed for the reason to switch to etravirine (ETV)
Inclusion Criteria• All HIV + patients on ARV treatment• Switched to ETV and 2 nucleos(t)ides• HIV viral load < 200 copies/ml within 2 months prior to the switch.
Follow-up variables• VL and CD4 count• Lipid pro�le• E�ect on “ reason for switch”
Table 1a: Baseline Characteristics
ReferencesVingerhoets J, Azijn H, Fransen E, et al. TMC125 displays high genetic barrier to the development of resistance:evidence form invitro selection experiments. J Virol 2005:79:12773-12782.
Gruzdev B, Rakhmanova A Doubovskaya E et al. A Randomized, double-blind, placebo-controlled trial of TMC 125- as 7 day immunotherapy in anti-retroviral naïve , HIV-1 infected subjects. AIDS. 2003:17:2487-2494
Lalezari J, Dejesus E, Osiyemi O et al. Pharmacokinetics of once-daily etravirine(ETR) without and with once-daily darunavir/ritonavir in antiretroviral-naïve HIV-1 infected adults [abstract PO413]. In : Program and Abstracts of 9th In-ternational Conference on Drug Therapy in HIV Infection; 2008, Glasgow, UK
F. Crouzat, G. Smith, I. Sandler et al. Retention on third agents in HAART regimens at the Maple Leaf Medical Clinic in Toronto, Ontario, Canada 11th International congress on Drug Therapy in HIV infection , Glasgow 2012, poster # 273
A Nguyen, A Calmy, C. Delhumeau, et al. A randomized crossover study to com-pare Efavirenz and etravirine treatment, AIDS 2011, 25:57–63
M Nelson, H-J Stellbrink, D Podzamczer, et al. A comparison of neuropsychiatric adverse eventsduring 12 weeks of treatment with etravirine and efavirenz in a treatment-naïve HIV-1-infected population, AIDS 2011, 25:335–340
Mollina JM, Andrade-Villanueva J, Echevarria J et al. Once-daily atazanavir / ritona-vir compared to twice-daily lopinavir/ritonavir, each in combination with tenofo-vir and emtricitabine, for management of antiretroviral-vaive HIV-1 -infected patients:96-week efficacy and safety results of the CASTLE study, J. Acquire Immune Defic Syndrome 2010 Mar:52(3):323-32.
Number of patients at baseline 87Median age at baseline (IQR) 42 ( 34 - 50 )Number (%) males 79 ( 90.8% )Risk Factors - Proportion of patients(%)
MSM 70 ( 80.5% )IDU 2 ( 2.3% )ENDEMIC REGION 4 ( 4.6% )heterosexual 4 ( 4.6% )unknown 7 ( 8.0%)
mean duration of HIV infection (years) 12.6 +/- 7.1Baseline CD4 (mean) 625 +/- 268# of patients with VL 50 - 200 4Baseline Chol (mmol/L) 4.76 +/- 1.02Baseline LDL (mmol/L) 2.72 +/- 085Baseline HDL (mmol/L) 1.21 +/- 0.36Baseline Triglycerides (mmol/L) 2.02 +/- 1.75
“3rd drug” prior to ETV # of ptsSUSTIVA ® 31
KALETRA® 19
REYATAZ® 25
CRIXIVAN® 1
INVIRASE® 1
VIRAMUNE® 1
RESCRIPTOR® 2
ISENTRESS® 2
PREZISTA® 4
UNKNOWN 1Proportion of patients exposed to Sustivaor Viramune prior to ETV 35 ( 40.2% )
Mean time on prior regimen (weeks) 187.5 +/- 150.7
Table 1b: Baseline Treatment Status
reasons for change
Neuro/Psych Lipids GI Simpli-
ficationLipodys-trophy other not
recordedfrom Sustiva 27 1 0 0 1 2 0
from Kaletra 0 0 7 6 2 4 0
from Reyataz 0 2 12 4 0 4 3
from Crixivan 0 0 0 1 0 0 0
from Invirase 0 0 0 0 0 0 1
from Viramune 0 0 0 0 0 0 1
from Rescriptor 0 0 0 1 0 1 0
from Isentress 1 0 0 0 0 0 0
from Prezista 0 1 2 0 0 0 1
Table 1c: Reasons for Change of ARV
Follow-up• Median follow up 1.3 (IQR 0.6 – 2.1) years• Nucleoside/tide backbone used with ETR o TDF/FTC: 62 pts o ABC/3TC: 25 pts
Discontinuations• 5 pts d/c’ed prior to week 24 • 2 pts d/c’ed wks 24 - 48
Reasons for Disontinuations
Response of “Reasons for Change”• 26/27 of efavirenz switches due to neuropsychiatric symptoms reported improvement
Exploratory analysis• Lipid changes driven by changes in patients who changed from efavirenz or kaletra• minimal change in patients who came from atazanavir
Conclusions• Switching from a PI or efavirenz based regimen was associated with continued virologic suppression and CD4 increase in 92% (week 24) and 90% (week 48) of patients
• Discontinuations were for non-virologic reasons except for 2 patientsPatients on efavirenz who switched for neuropsychiatric reasons had clinically sig-ni�cant improvement of their symptoms
• Lipid pro�le improvement was seen mainly in patients switching from efavi-renz or lopinavir/ritonavir
Weeks 0 – 24• 1 cost• 2 A/Es o Nausea o Increase of psoriasis• Pt pref, re pill burden
Weeks 25 – 48• 1 drug interaction• 1 Vl failure at wk 28
Table 2a: Virologic outcomes
Week 24 Week 48
D/C 5 7
Not yet at F/U time 9 14
VL suppressed 70 65
VL 50 - 200 2 1
VL > 200 1 0
Table 2b: Immunologic outcomes
Week 24 Week 48
Median change inCD4 from BL (IQR)
35 ( -45 : 110 ) 60 ( -10 : 135 )
Table 2c: Lipid Changes
Week 24 Week 48
CHOL (mmol/L) -0.49 ±0.78 P<0.05 -0.55 ± 0.91 P<0.05
LDL (mmol/L) -0.35 ± 0.72 P<0.05 -0.24 ± 0.81 P<0.05
HDL (mmol/L) -0.03 ± 0.23 P=0.33 -0.02 ± 0.25 P=0.44
TRIG (mmol/L) -0.64 ± 1.88 p=<0.05 -0.97 ± 1.57 P<0.05
n 62 37
Table 2d: Lipid lowering agent use
n (%)
No lipid lowering agents 54 ( 62.1% )
Lipid lowering agents only after baseline 5 ( 5.7% )
Lipid lowering agents only before baseline 1 ( 1.1% )
Lipid lowering agents before and after baseline 27 ( 31% )
D. Podzamczer1*, E. Ferrer1, JM. Llibre2, M. Leal3, MJ. Crusells4, H. Knobel5, J. Curto1, J. Puig2, M. Górgolas6, JL. Gómez-Sirvent7, P. Domingo8, N. Rozas1, JC. López-Bernaldo de Quirós9, A. Ocampo10, J. Vergas11 for the KIVI study group
CONCLUSIONS•In this particular cohort of ARV-experienced patients, a combination of ABC/3TC/NVP was safe and maintained virologic suppression in the vast majority of patients, with rates similar to other switch strategies.
•A favourable lipid profile was observed after 96 weeks of follow up.
The objective of this study was to present the clinical experience with the combination of ABC/3TC/NVP in a cohort of adult HIV-infected patients.
BASELINE CHARACTERISTICS OF 227 EVALUABLE PATIENTS AIDS AND OTHER DISEASES AT BL
1
2
3
6
8
7
Although it is currently being used in clinical practice in many centers in Spain, very scarce information has been published to date with the combination of ABC/3TC/NVP.
Follow-up: baseline, month 1, and every 3-4 months thereafter. Baseline data are presented.
Primary outcome: To estimate if HIV-1 viral load (VL) < 40 c/mL after 48 weeks of ABC/3TC/NVP therapy. Statistical analysis: data were analyzed by intent-to-treat (ITT) (non completer = failure) and on treatment (OT) analyses. Descriptive statistics were expressed as median (range) for quantitative variables and as frequencies and percentages for qualitative variables.
Design: Retrospective, multicenter, cohort study. Setting: 11 Hospitals in Spain with extensive experience in HIV management. Patients: Consecutive adult HIV-infected ARV-experienced patients, HLA-B*5701-negative, who started ABC/3TC/NVP between 2005-2010, with at least one follow-up visit.Intervention and follow-up: Clinical assessment: demographic characteristics, HIV status, ARV regimens (first and current). Laboratory assessment: metabolic parameters, viral load and CD4 counts.
EFFECTIVENESS AND TOLERABILITY OF ABC/3TC/NVP IN A MULTICENTER COHORT OF HIV-INFECTED ARV-EXPERIENCED PATIENTS
ARV REGIMENS AT BL AND REASONS FOR SWITCHING TO ABC/3TC/NVP
CHANGES IN AST AND ALT
OBJECTIVE
BACKGROUND
METHODS
CHANGES IN LDLc, HDLc AND TC/HDLc RATI
9
CHANGES IN VIRAL LOAD AND CD4 COUNT
Correspondence to: Daniel Podzamczer, PhD, MDInfectious Disease Service.Hospital de Bellvitge. L’Hospitalet del Llobregat. 08907 Barcelona. SPAIN. Fax: 34-932607669e-mail: [email protected]
P-290
1Hospital Universitari de Bellvitge, Barcelona; 2Hospital Germans Trias i Pujol, Badalona; 3Hospital Virgen del Rocío, Sevilla; 4Hospital Lozano Blesa, Zaragoza; 5Hospital del Mar, Barcelona; 6Fundación Jiménez Díaz, Madrid; 7Hospital Universitario de Canarias, Canarias; 8Hospital Sant Pau, Barcelona; 9Hospital Gregorio Marañón, Madrid; 10Hospital Xeral Cies, Vigo; 11Hospital Clínico San Carlos, Madrid
This work was supported by Boehringer Ingelheim España S.A. The authors were fully responsible for all content and editorial decisions, and were involved at all stages of poster development. The authors received no compensation related to the development of the poster.
RESULTS
CHANGES IN TRIGLYCERIDES AND TOTAL CHOLESTEROL
4
5
**: In many patients with the aim of reducing drug cost.
BASELINE LABORATORY PARAMETERSOUTCOME AND DRUG DISCONTINUATION
N (%)
Undetectable VL 205 (90.31)
N Mean (Sd) Median (Min-Max)
VL copies/ml 227 1,641.2 (12,005.3) 39.0 (39.0-126,000.0)
CD4 count 227 605.8 (267.9) 570.0 (32.0-1,404.0)
ALT (ukat/l) 225 0.55 (0.56) 0.38 (0.16-6.30)
AST (ukat/l) 203 0.54 (0.57) 0.40 (0.13-5.73)
Triglycerides (mmol/l) 219 1.89 (1.25) 1.58 (0.49-8.45)
Total Cholesterol (mmol/l) 224 5.18 (1.06) 5.11 (2.90-9.08)
TC/HDLc ratio 182 4.22 (1.62) 3.91 (1.81-14.80)
HDLc (mmol/l) 182 1.38 (0.48) 1.28 (0.26-3.10)
LDLc (mmol/l) 162 3.02 (0.91) 2.96 (1.34-6.70)
N (%)
AIDS 47 (20.7)
Other diseases (previous) 66 (29.1)
Arterial hypertension 36 (15.9)
Diabetes 17 (7.5)
Myocardial infarction 3 (1.3)
Renal insufficiency 3 (1.3)
Chronic Hepatitis
HBV 1 (0.4)
HCV 29 (12.8)
Prior treatment: HBV/HCV 19 (8.4)
SVR 17 (7.5)
N (%) NRTI 220 (96.9)
NNRTI 182 (80.2)
PI 44 (19.4)
Other 1 (0.4)
AZT 3TC NVP 70 (30.8)
TDF FTC NVP 38 (16.7) Most frequent combinations at BL
ABC 3TC EFV 19 (8.4)
NVP 144 (63.4)
ABC 56 (24.7) NVP and/or ABC at BL
Both 10 (4.4)
Toxicity 96 (42.3)
Simplification 80 (35.2) Reasons for switching to ABC/3TC/NVP
Other* 51 (22.5)
Not specified medical decision** 41 (80.4)
Patient decision 2 (3.9)
Treatment discontinuation 1 (2.0)
CD4 decrease 1 (2.0)
Virological failure 1 (2.0)
HCV treatment 1 (2.0)
Interactions 1 (2.0)
Poor adherence 1 (2.0)
Optimization of antiretroviral therapy 1 (2.0)
*Other Reasons
ART reinitiation 1 (2.0)
N Mean (Sd) Median (Min-Max)
Follow-up, months 227 30.4 (13.9) 30.3 (0.5-76.3)
Age, years 225 47.9 (9.7) 47.5 (24.4-82.8)
N (%) Male 170 (74.9)
Gender Female 57 (25.1)
Heterosexual 84 (37)
Homosexual 74 (32.6)
Drug users 46 (20.26) Risk practice
Other 23 (10.1)
White 202 (89)
Hispanic 13 (5.7)
Africa Subsaharian (Black) 7 (3.1) Race
Other 5 (2.2)
N (%) Drug discontinuation (1 or more drugs) 41 (18.1)
Toxicity 17 (41.5)
Other* 9 (22.0)
Virological failure 7 (17.1) Reasons of discontinuation
Lost to follow-up 7 (17.1)
Medical decision 4 (44.4)
Unrelated death 1 (2.4)
Not specified 2 (22.2) *Specification of other reasons
Enrollment in clinical trials 2 (22.2)
A significant increase of 7 % was observed in total cholesterol after 96 weeks. No significant differences were observed in triglycerides changes during follow up.
No significant differences were observed in ALT or AST changes during follow up.
A significant increase of 10% and 14% was observed in LDLc and HDLc, and a significant decrease in TC/HDL ratio (-5%, p=0.04) after 96 weeks, respectively.
After 48 weeks, VL was < 40 c/mL in 82% (ITT) and 94% (OT), and in 94% (OT) after 96 weeks. Median CD4 count at baseline, 48 weeks and 96 weeks was 570, 598 and 673, respectively.
TRANxITION 144-Week Results: Switching Virologically Stable HIV Patients FromNevirapine Immediate-Release (NVP IR) to NVP Extended-Release (NVP XR)
Keikawus Arasteh,1 Murray Drulak,2 Junhai Guo2, Jean-Michel Livrozet,3 Chloe Orkin,4 Anne-Marie Quinson,2 and Douglas Ward5
1EPIMED Vivantes Auguste-Viktoria-Klinikum, Berlin, Germany; 2Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 3Edouard Herriot Hospital, Lyon, France; 4Barts and the London NHS Trust, London, UK; 5Dupont Circle Physicians Group, Washington, DC, USA
• Adherence is important to the long-term success of antiretroviral regimens.1-3
Once-daily regimens have been shown to improve regimen adherence, leadingto better safety and efficacy.4
• Nevirapine (NVP) has been shown to have minimal untoward effects on serumlipids and therefore should be considered as the NNRTI of choice in patientswho have an elevated cardiovascular risk profile.
• NVP plus tenofovir/r/r emtricitabine (TDF/FTC) has been shown to havenoninferior safety and efficacy compared with atazanavir/r/r ritonavir plus TDF/FTCas well as a less atherogenic lipid profile.5
• Recently, NVP extended-release (NVP XR; 400 mg) was approved for once-daily dosing, based on studies that demonstrated comparable efficacy totwice-daily regimens of NVP immediate-release (NVP IR; 200 mg twice daily)in treatment-naïve individuals.6
• The present report describes the efficacy and safety of switching patients whoare virologically controlled on NVP IR 200 mg twice daily to NVP XR 400 mgonce daily.
• TRANxITION was an open-label, randomized, parallel-group study to assess theefficacy and safety of switching HIV-V-V 1-infected patients who were establishedon a NVP IR–based regimen to a NVP XR–based regimen.
• Upon meeting the screening criteria, patients were randomized 2:1 to receiveeither NVP XR 400 mg once daily or to continue receiving NVP IR 200 mgtwice daily. Baseline randomization was stratified by background NRTI therapy,which patients maintained throughout the trial.
Treatment switch• After week 48, patients initially randomized to NVP IR were allowed to switch
to NVP XR.Key inclusion criteria• HIV-V-V 1-infected patients aged ≥18 years who were stable on a NVP IR–based
regimen for a minimum of 18 weeks. Permissible background NRTI regimenswere fixed-dose combinations or the same drugs in combination withlamivudine/abacavir (3TC/A/A/ BC), emtricitabine/t/t/ enofovir (FTC/T/T/ DF), orlamivudine/zidovudine (3TC/A/A/ ZT).
• An undetectable HIV-V-V 1 viral load (VL) in the preceding 4-month period (lowerlevel of detection <100 copies/mL) and HIV-V-V 1 VL of <50 copies/mL at baselinescreening.
Key exclusion criteria • Currently on an HIV protease inhibitor• Participation in another trial or use of an investigational medicine in the
preceding 2 months• Baseline laboratory results that exceed any of the following laboratory
parameters: Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade2 (coagulation, hematology, biochemistry) or Grade 3 (total triglycerides);hepatic cirrhosis stage Child-Pugh B or C
Study endpoints• Primary endpoint
– Proportion of patients with sustained virologic response (SVR) defined as VL<50 copies/mL (lower limit of quantification [LLOQ]) = 50 copies/mL TaTaT qMan,full analysis set [FAFAF S]) through week 24.
• Secondary endpoints included– Efficacy endpoints
• Proportion of patients with SVR defined as VL <50 copies/mL throughweek 144 (week 144 ± 6-week window)
• Proportion of SVR (VL <400 copies/mL)• Time to loss of virologic response (TLOVR)• Change in VL and CD4+ cell counts from baseline at each visit
– Safety endpoints• Adverse events (AEs) (including treatment-related and treatment-
unrelated events)• Serious adverse events (SAEs) (including AIDS-defining events)• Occurrences of rashes and hepatic events• Abnormal laboratory measurements• Changes in laboratory test values from baseline to end of treatment (EOT)• Incidence of AIDS progression or death between baseline and EOT
Introduction
Methods
Presented at the 11th International Congress on Drug Therapy in HIV Infection; November 11-15, 2012; Glasgow, UK
• The 400 mg XR formulation was generally well tolerated, safe, andeffective up to 144 weeks, both in patients who were randomized toswitch from IR to XR in the initial phase (completing at least 144 weeks onXR) as well as in those who switched to XR after 48 weeks on IR(completing at least 96 weeks on XR.
– Efficacy
• At week 48, 96% of patients in the IRpost48XR and 97% of those inthe XRpost48XR groups had undetectable VL (VL <50 copies/mL).
• At week 144, 95% of patients in the IRpost48XR and 95% of patientsin the XRpost48XR groups had undetctable VL (VL <50 copies/mL).
• At the last available observation for all patients, 93.8% had VL<50 copies/mL.
– Safety
• Post 48 week data showed that the frequencies of various AEcategories were similar to but slightly lower for NVP IR patients whoswitched to NVP XR after week 48 compared with patients who tookNVP XR from the beginning of the study.
• The most frequent AEs post week 48 were consistent with thosereported over the 144-week duration of the trial, with the majority ofreported AEs being of either mild or moderate intensity.
• Less than 3% of patients discontinued treatment due to an AE overthe 144 weeks of the trial.
Conclusions
1. Mannheimer S, et al. Clin Infefef ct Disisi 2002;34:1115-1121.2. Garcia de Olalla P,P,P et al. J Acquir Immune Defifif c Synyny drdrd 2002;30:105-110.3. Flandre P,P,P et al. Antiviviv r ThThT er 2002;7:113-121.4. Bangsberg DR, et al. AIDS 2010;24(18):2835-2840.5. Fisac C, et al. J Clin Endocririr nol Metab 2003;11:5186–5192.6. Gathe J, et al. Antiviviv r ThThT er 2011;16(5):759-769.
The authors meet criteria for authorship as recommended by the International Committttt ee of MedicalJournal Editors (ICMJE), were fully responsible for all content and editorial decisions, and wereinvolved at all stages of poster development.The authors received no compensation related to thedevelopment of the poster.This work was supported by Boehringer Ingelheim Pharmaceuticals, Inc.(BIPI). Drs. Arasteh, Livrozet, Orkin, and WaWaW rd declare no conflicts of interest. Writing, editorialsupport, and formattttt ing assistance was provided by José L. WaWaW lewski, PhD, of Envision ScientificSolutions, which was contracted and compensated by BIPI for these services.
References
Disclosures
IRpost48XRa IRpost48b XRpost48c ToToT talN (%) N (%) N (%) N (%)
No. of patients 130 ((100.0)) 13 ((100.0)) 276 ((100)) 419 ((100))Baseline HIV-1 RNA ((copies/mL))dd
<50 120 (92.3) 12 (92.3) 263 (95.3) 395 (94.3)>50 10 (7.7) 1 (7.7) 13 (4.7) 24 (5.7)
Baseline CD4+ T-T-T cell counts(cells/mm3)d
N 129 13 276 418Mean 571.9 595.0 559.2 564.2SD 202.8 330.1 212.8 213.7
Baseline CCD4+ T-T-T cell counts(cells/mm3)d
>50–200 2 (1.5) 0 (0.0) 6 (2.2) 8 (1.9)>200–350 13 (10.0) 2 (15.4) 38 (13.8) 53 (12.6)>350–<400 11 (8.5) 0 (0.0) 19 (6.9) 30 (7.2)>400 103 (79.2) 11 (84.6) 213 (77.2) 327 (78.0)Missing 1 (0.8) 0 (0.0) 0 (0.0) 1 (0.2)
History of AIDSS-defining illnessNo 105 (80.8) 8 (61.5) 200 (72.5) 313 (74.7)Yes 25 (19.2) 5 (38.5) 76 (27.5) 106 (25.3)
a Patients randomized to NVP IR and elected to change to NVP XR after week 48.b Patients randomized to NVP IR and who chose to remain on NVP IR after week 48.c Patients randomized to NVP XR who elected to remain on NVP XR after week 48.d Baseline values are calculated as average of last 2 measurements prior to start of randomized treatment. HIV-1RNA viral load is based on TaTaT qMan assay results.
Table 1. Baseline characteristics – post week 48
Background: TRANxITION, which compared the efficacy and safety ofswitching virologically suppressed patients from NVP IR (200 mg BID) toNVP XR (400 mg QD) demonstrated the non-inferior efficacy of NVP XR invirologically suppressed patients at 48 weeks. Safety and efficacy results ofpatients initially randomized to NVP IR and switched to NVP XR at 48 weekscompared to patients on NVP XR throughout the study are presented here.
Methods: TRANxITION was an open-label, parallel-group, non-inferiorityclinical trial where adult HIV-V-V 1 patients receiving NVP IR plus a fixed-doseNRTI combination of either lamivudine (3TC)/abacavir (ABC), tenofovir(TDF)/emtricitabine (FTC), or 3TC/zidovudine (ZDV) with undetectable viralloads (VL) were randomized (2:1) to NVP XR or NVP IR. After week 48,patients initially randomized to NVP IR were allowed to switch to NVP XR.Primary endpoint was continued virologic suppression (VL <50 copies/mL)at week 24. Secondary endpoints included long-term follow-w-w up at 48, 96, and144 weeks. The 96-week analysis was used for the US label update and willbe in the US label. Even if not presented here, it should be indicated that ananalysis was done at 96 weeks.
Results: At week 48, proportions of patients with virologic response (LLOQ= 50 copies/mL TaTaT qMan, FAFAF S) were 88.5% (131/148) NVP IR BID arm and88.8% (262/295) NVP XR QD, with an observed difference of 0.3% (95% CI,–6.1, 6.7). Division of Acquired Immunodeficiency Syndrome (DAIDS) Grade3 and 4 events were similar for the NVP XR and NVP IR groups at week 48,6.4% (19/295) vs. 6.1% (9/148), respectively, although serious AEs wereslightly higher in the NVP XR group (10.2%, 30/295 vs. 8.1%, 12/148 for theNVP IR group). After week 48, all but 13 patients in the NVP IR arm switchedto NVP XR. At week 144, proportions of patients with virologic responsewere 115/121 (95.0%, patients switching from IR to XR after week 48[IRpost48XR]) and 238/250 (95.2%, patients on XR throughout [XRpost48]).DAIDS grade 3 and 4 events were similar for both post week 48 XR groups atweek 144, with (10/130, 7.7.77%, [IRpost48XR] vs. (31/276, 11.2% [XRpost48),while rates of SAEs were similar in the 2 treatment groups: 17/130 (13.1%)of patients in the IRpost48XR group and 54/276 (19.6%) of patients in theXRpost48 group.
Conclusions: NVP XR QD resulted in continued virologic suppression atweeks 48 and 144. While fewer patients remained in the study post week 48,both XR groups had high virologic response rates. Up to week 144, rates ofserious AEs were modestly higher than at week 24 in both post week 48 XRarms, most likely due to the open-label design of the study.
Abstract
P291
499 enrolled
54 not randomized445 randomized
443 treated
295 NVP XR 148 NVP IR
281 NVP XR (week 48)
143 NVP IR (week 48)
276 XRpost48(post week 48)
13 IRpost48(post week 48)
130 IRpost48XR(post week 48)
238 NVP XR (week 144)
7 NVP IR (week 144)
115 NVP XR (week 144)
Figure 1: PaPaP tient disisi position
• Statistics– The primary endpoint and the corresponding 95% confidence interval (CI)
were analyzed using the TLOVR algorithm by the Cochran's statistical test.A noninferiority test for the primary endpoint (12% margin) was based on a2-sided 95% CI for any difference in the virologic responses of the 2treatment arms (NVP XR vs NVP IR). All safety data were examined bydescriptive statistical methods.
Patient disposition • Patient disposition is presented in Figure 1. After enrollment, 54 patients were
excluded primarily due to failure to meet trial eligibility criteria. Of the 499patients enrolled, 445 were randomized and 443 were treated (148, NVP IR;295, NVP XR). After week 48, 130/143 patients remaining in the NVP IR armexercised their option to switch to the NVP XR formulation, whereas 13 patientscontinued on NVP IR.
Results
Patient baseline characteristics• No significant differences were observed in the baseline characteristics
between patients in any of the treatment groups (Table 1).
Efficacy results• Primary endpoint – week 24
– As measured by the primary endpoint, NVP XR was noninferior to NVP IR,with 93.6% of patients in the NVP XR arm and 92.6% of patients in theNVP IR arm achieving SVR at week 24, with an adjusted difference of 1.0%(95% CI, –4.3, 6.0), using the TLOVR algorithm and Cochran statistics, andwith adjustment for all 3 background treatments.
– No significant difference was seen in median change from baseline to week24 in CD4+ cell counts (NVP IR 32.5 cells/mm3 vs NVP XR 39.8 cells/mm3)between the 2 treatment groups.
• Post week 48 efffff icacy analysis– A total of 130 IR patients switched to NVP XR after week 48. At each visit
after week 48, more than 90% patients observed VL <50 copies/mL.– At week 48, 96.2% (95% CI, 92.8, 99.5) of remaining patients in the NVP
IR/NVP XR group observed VL <50 copies/mL (Table 2). In patientscontinuing on the NVP XR treatment, the proportion was 97.7.71% (95% CI,95.1, 99.1).
– At week 144, 95.0% (95% CI, 91.2, 98.9) of remaining patients in the NVPIR/NVP XR group had an observed VL <50 copies/mL.
– In patients continuing on the NVP XR treatment, the proportion at week 144was 95.2% (95% CI, 92.6, 97.7.78).
– At the last available observation for all patients, 93.8% had VL <50copies/mL.
– For 276 NVP XR patients remaining on NVP XR after week 48, similar rateswere observed at each visit.
– Using 400 copies/mL as the lower limit for response rate, even highernumbers (100% for all treatment groups at week 144) were observed acrossdifferent treatment groups.
IRpost48XRa IRpost48b XRpost48c ToToT talN (%) N (%) N (%) N (%)
48 125/130 (96.2) 11/12 (91.7) 268/276 (97.1) 404/4/4 418 (96.7)60 122/130 (93.8) 9/12 (75.0) 253/274 (92.3) 384/4/4 416 (92.3)72 124/4/4 130 (95.4) 9/9 (100) 265/271 (97.8) 398/410 (97.1)84 118/125 (94.4) 7/8 (87.5) 244/4/4 268 (91.0) 369/401 (92.0)96 117/124 (94.4) 9/9 (100) 242/263 (92.0) 368/396 (92.9)108 119/125 (95.2) 8/9 (88.9) 247/260 (95.0) 374/4/4 394 (94.9)120 112/121 (92.6) 7/8 (87.5) 235/258 (91.1) 354/4/4 387 (91.5)132 115/121 (95.0) 6/7 (85.7) 238/252 (94.4) 359/380 (94.5)144 115/121 (95.0) 7/7 (100) 238/250 (95.2) 360/378 (95.2)Last available visit 121/130 (93.1) 11/13 (84.6) 261/276 (94.6) 393/419 (93.8)FAFAF S, full analysis set; LLOQ, lower limit of quantification; NVP IR, nevirapine immediate release; NVP XR, nevirap-ine extended release.a Patients who received NVP IR during first 48 weeks and then switched to NVP XR.b Patients who remained on NVP IR after week 48.c Patients who remained on NVP XR after week 48.
Table 2. Proportion of virologic response using LLOQ = 50 copies/mL after week 48 by visit (FAS)
IRpost48XRb,c IRpost48d XRpost48e ToToT talN (%) N (%) N (%) N (%)
No. of patients 130 (100.0) 13 (100.0) 276 (100) 419 (100)
Patients with any AE 112 (86.2) 8 (61.5) 250 (90.6) 370 (88.3)
Patients with investigator-defineddrug-related AEs 4 (3.1) 0 (0) 7 (2.5) 11 (2.6)
Patients with AEs leading todiscontinuation of trial drug 0 (0) 0 (0) 4 (1.4) 4 (1.0)
Patients with serious AEs 17 (13.1) 3 (23.1) 54 (19.6) 74 (17.7)
Fatalf 1 (0.8) 0 (0) 2 (0.7) 3 (0.7)
Immediate life-threatening 2 (1.5) 0 (0) 2 (0.7) 4 (1.0)
Disability/y/y incapacitation 0 (0) 0 (0) 1 (0.4) 1 (0.2)
Required hospitalization 17 (13.1) 3 (23.1) 47 (17.0) 67 (16.0)
Prolonged hospitalization 0 (0) 0 (0) 1 (0.4) 1 (0.2)
Congenital anomaly 0 (0) 0 (0) 0 (0) 0 (0)
Other 0 (0) 0 (0) 7 (2.5) 7 (1.7)
Patients with DAIDS Grade 3 or 4 AEs 10 (7.7) 1 (7.7) 31 (11.2) 42 (10)
Patients with DAIDS Grade 4 AEs 2 (1.5) 0 (0) 8 (2.9) 10 (2.4)
Patients with any study drug-relatedDAIDS Grade 3 or 4 AEs 0 (0) 0 (0) 1 (0.4) 1 (0.2)
Patients with any study drug-relatedDAIDS Grade 4 AEs 0 (0) 0 (0) 0 (0) 0 (0)AE, adverse event; FAFAF S, full analysis set; NVP IR, nevaripine immediate release; NVP XR, nevaripine extendedrelease.a A patient may be counted in more than 1 seriousness category.b Percentages are calculated using total number of patients per treatment as denominator.c Patients randomized to NVP IR and elected to change to NVP XR during post week 48 exposure.d Post week 48 exposure of patients randomized to NVP IR who chose to remain on NVP IR after week 48.e Post week 48 exposure of patients randomized to NVP XR who elected to remain on NVP XR after week 48.f 4 deaths occurred during TRANxITION, none of which were determined to be related to NVP.P.PMeDRA version used for reporting: version 14.1.
Table 3. Adverse events – overall summary – post week 48 (FAS)a
• Adverse events post week 48– Any AEs were reported in 112/130 (86.2%) of patients who completed
48 weeks on IR, then switched to XR (IRpost48XR), and 250/276 (90.6%) ofpatients who were on XR through week 48, and beyond (XRpost48).
– ToToT tal number of patients (13) who continued on IR post week 48 (IRpost48)was too small to allow any meaningful analysis or interpretation.
– Investigator defined drug-related AEs: 4/130 (3.1%) of patients in theIRpost48XR group and 7/276 (2.5%) of patients in the XRpost48 group.
– SAEs: rates of SAEs were similar in the 2 treatment groups: 17/130 (13.1%)of patients in the IRpost48XR group and 54/276 (19.6%) of patients in theXRpost48 group.
– Patients with DAIDS Grade 3 or 4 AEs: 10/130 (7.7.77%) of patients in theIRpost48XR group and 31/276 (11.2%) of patients in the XRpost48 group.
– Patients with DAIDS Grade 4 AEs: 2/130 (1.5%) of patients in theIRpost48XR group and 8/276 (2.9 %) of patients in the XRpost48 group.
– Patients with any study drug-related DAIDS Grade 3 or 4 AEs: 0/130 (0.0%)of patients in the IRpost48XR group and 1/276 (0.4%) of patients in theXRpost48 group.
– Patients with any study drug-related DAIDS Grade 4 AEs: no patients werereported with study drug-related DAIDS Grade 4 AEs in either group.
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1Hosp Sant Pau I Santa Tecla, Tarragona; 2Hosp Univ Virgen del Rocío, Sevilla; 3Hosp General de Granollers, Barcelona; 4Hosp Univ Príncipe de Asturias, Madrid; 5Hosp Virgen de lasNieves, Granada; 6Hosp Santa María del Rosell, Murcia; 7Hosp Juan Ramón Jimenez, Huelva; 8Hosp.Clínico San Carlos, Madrid; 9Hospital Universitario La Paz, Madrid.
Until the past decade, immune/viral failure was the main reason for antiretroviral treatment changes. After HAART generalization the management of antiretroviral treatment toxicities was the most prevalent reason for treatmentmodification. Today, the advent of new more potent and less toxic drugs as well as more convenient combinations may have changed the situation.
Background
To describe the main reasons that today leads to ART changes in HIV+ patients in Spain in the current clinical practice.
Objetive
ReasonsReasons forfor antirretroviral antirretroviral treatmenttreatment changeschanges in in SpanishSpanish
HIV 1 HIV 1 patientspatients in 2011. SWITCH AUDIT in 2011. SWITCH AUDIT StudyStudy..M. Tasias1, P. Viciana2, E. Deig3, J. Arranz4, J. Pasquau5, F. Vera6, E.Pujol7, J.Vergas8,JL.Bernardino9, E. Pedrol1
Contacto: Enric Pedrol MD. [email protected]
MethodsMulticentre, nacional, cross sectional epidemiological study Eligible patients had to be HIV+ > 18 years old and under current ART that was going to be changed by any reason. The study consisted in a single visit (change of treatment) in which data on social and demographic characteristics, HIV disease and ARV treatment were collected.
ResultsTable 1. Social and demographic characteristics
Characteristics N=349Age, years (Mean + SD) 43,7 ( + 8,9)Males, N (%) 246 (70,5%)Race: N (%)
CaucasianBlackLatin-americanaOther
311 (89,1%)20 (5,7%)9 (2,6%)9 (2,6%)
Nationality: N (%)SpanishOther
299 (85,7%)50 (14,3%)
Work situation: N (%)EmployedUnemployedStudentRetiredOthers
180 (51,6%)69 (19,8%)
6 (1,7%)28 (8,0%)66 (18,9)
Level of education :No studiesPrimary Education StudiesSecondary Education StudiesUniversity StudiesUnknown
33 (9,5%)171 (49,0%)97 (27,8%)42 (12,0%)6 (1,7%)
Table 2. HIV Infection characteristics
Characteristics N=349Risk factor HIV: N (%)
HSHHeterosexualIVDUOthers
84 (24,1%)127 (36,4%)127 (36,4%)11 (3,1%)
Mean time from HIV diagnosis (years); Mean (IQR) 11,3 (4,2 – 17,7)a
RNA HIV-1 >50 c/mL; N (%) 125 (35,8%)CD4 (cels/µL) Median (IQR) 467 (303 - 670)
CD4 nadir (cels/µL) Median (IQR) 155 (67 – 273)
CDC category ; N (%)ABC
179 (51,3%)64 (18,3%)106(30,4%)
Coinfection VHB/VHC; n(%) 140 (40,1%)
Figure 2. Reason for changing treatment (according to lines of treatment)
Results cont.
N 73 76 51 98
Conclusions
20,1%
27,5%
37,0%
15,4%
Immune/viral failure
Treatment toxicities
Simplification
Others
Figure 1. Reasons that leads to treatment changes
No significant correlations were found between reason for changing treatment and age, gender, race, nationality and level of educationSimplification was significantly the main reason of treatment change in both employed and unemployed patients (p<0.01)
• Treatment simplification was the most prevalent reason for a change of treatment.
• Even in advanced lines of treatment. This is so probably because of the advent of ARV drugs that are more potent and effective, withless toxicity and more convenient
• Treatment simplification was significantly the first cause of treatment change in those patients who are currently working or seeking for a job. This highlights the need for simpler regimensthat can adapt to an active life.