Superior Efficacy of Dolutegravir/Abacavir/Lamivudine FDC Compared With Ritonavir-Boosted Atazanavir Plus Tenofovir Disoproxil Fumarate/Emtricitabine FDC.

Präsentation zum Thema: "Superior Efficacy of Dolutegravir/Abacavir/Lamivudine FDC Compared With Ritonavir-Boosted Atazanavir Plus Tenofovir Disoproxil Fumarate/Emtricitabine FDC."—  Präsentation transkript:

1 Superior Efficacy of Dolutegravir/Abacavir/Lamivudine FDC Compared With Ritonavir-Boosted Atazanavir Plus Tenofovir Disoproxil Fumarate/Emtricitabine FDC in Treatment-Naive Women With HIV-1 Infection: ARIA Study C. Orrell,1 D. Hagins,2 E. Belonosova,3 N. Porteiro,4 S. Walmsley,5 V. Falcó,6 C. Man,7 A. Aylott,8 A. Buchanan,7 B. Wynne,9 C. Vavro,7 M. Aboud,10 K. Smith7 1Desmond Tutu HIV Foundation, Cape Town, South Africa; 2Chatham County Health Department, Savannah, GA, USA; 3Orel Regional Center for AIDS, Orel, Russia; 4Fundación IDEAA, Buenos Aires, Argentina; 5University Health Network, Toronto, Canada; 6Hospital Vall d’Hebron, Barcelona, Spain; 7,9,10ViiV Healthcare, 7Research Triangle Park, NC, USA; 9Philadelphia, PA, USA; 10 Brentford, UK; 8GlaxoSmithKline Stockley Park, UK AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

2 ARIA: Introduction DTG/ABC/3TC (Triumeq) is a complete regimen built around DTG, an unboosted INSTI with a high barrier to resistance First approval of DTG/ABC/3TC: August 2014 in North America To gain additional data for women, the ARIA study was conducted to evaluate the safety and efficacy of DTG/ABC/3TC versus ATV/r +TDF/FTC in ART treatment-naive women (ClinicalTrials.gov: NCT ) The study enrolled from September 2013 to September and is ongoing. DTG/ABC/3TC, dolutegravir/abacavir/lamivudine, ATV/r+TDF/FTC, ritonavir-boosted atazanavir+tenofovir disoproxil fumarate+emtricitabine; ART, antiretroviral therapy; INSTI, integrase strand transfer inhibitor. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

3 Study Design Open-label randomised non-inferiority phase 3b study
randomized 1:1 DTG/ABC/3TC FDC DTG/ABC/3TC FDC Continuation phase ATV/r +TDF/FTC FDC Randomization Week 48 primary analysis Key eligibility criteria: women, ART-naive, HLA-B*5701 negative, HIV-1 RNA >500 c/mL, hepatitis B negative Stratification: by HIV-1 RNA (≤ or >100,000 copies/mL), CD4+ count (≤ or >350 cells/mm3) Women who became pregnant were withdrawn and, if possible, offered entry into a DTG/ABC/3TC pregnancy study Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48 using the FDA snapshot algorithm (-12% non-inferiority margin) ART, antiretroviral therapy; FDA, US Food and Drug Administration; FDC, fixed-dose combination; HLA, human leukocyte antigen. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

4 ARIA: Global enrolment
Canada 20 50 Russia 25 UK 16 France ARIA enrolled from September 2013 to September 2014; 499 women have been randomised across 13 countries. The study is ongoing. 134 USA 28 Italy 9 Portugal 54 Spain 11 Mexico 2 Puerto Rico 40 Thailand Key point ARIA was developed as an international, multicentre study; 499 women from 13 countries have been randomised to treatment. Additional notes The majority of women were randomised in the US (n=134), South Africa (n=66), Spain (n=54) and Russia (n=50). Reference Orrell C, et al. AIDS Oral THAB0205LB South Africa 66 44 Argentina Orrell C, et al. AIDS Oral THAB0205LB AT/TRIM/0006/16

5 Study Disposition Screened (N=705) Randomized and treated
DTG/ABC/3TC (n=248) Randomized and treated ATV/r +TDF/FTC (n=247) 83% completed Week 48 (n=206) 17% of subjects withdrawn (n=42) Adverse event 10 (4%) Lack of efficacy 5 (2%) Protocol deviation Lost to follow-up 11 (4%) Investigator discretion 1 (<1%) Withdrew consent 78% completed Week 48 (n=192) 22% of subjects withdrawn (n=55) Adverse event 18 (7%) Lack of efficacy 4 (2%) Protocol deviation 13 (5%) Lost to follow-up Investigator discretion Withdrew consent 7 (3%) 5 DTG/ABC/3TC subjects (2%) and 8 ATV/r+TDF/FTC subjects (3%) became pregnant and were withdrawn from the study. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

6 Demographics and Baseline Characteristics
DTG/ABC/3TC (n=248) ATV/r +TDF/FTC (n=247) Age, median (range), y 37.5 (19-79) 37.0 (20-65) Race, n (%) African heritage 102 (41) 108 (44) White 115 (46) 107 (43) Asian 22 (9) 23 (9) Hepatitis C, n (%) 16 (6) 21 (9) CDC category, n (%) Asymptomatic 210 (85) 208 (84) AIDS 11 (4) 9 (4) HIV-1 RNA (log c/mL) 4.48 4.44 >100,000 (c/mL), n (%) 69 (28) 66 (27) CD4+ cell count 370 380 <350 (cells/mm3), n (%) 130 (52) 123 (50) CDC, Centers for Disease Control. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

7 Snapshot Outcomes at Week 48: ITT-E and PP Populations
Virologic outcomes Treatment differences (95% CI) ATV/r+TDF/FTC DTG/ABC/3TC 3.1 17.8 ITT-E (primary) 2.6 16.8 PP DTG/ABC/3TC is superior to ATV/r+TDF/FTC with respect to snapshot in the ITT-E (<50 c/mL) at Week 48, P=0.005 CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

8 Snapshot Outcomes at Week 48: ITT-E
DTG/ABC/3TC (n=248) ATV/r+TDF/FTC (N=247) Virologic response 203 (82%) 176 (71%) Virologic non-response 16 (6%) 35 (14%) Data in window not below threshold 4 (2%) Discontinued while VL not <50* 12 (5%) 19 (8%) No virologic data 29 (12%) 36 (15%) Discontinued study due to AE or death 9 (4%) 18 (7%) Discontinued study for other reasons 15 (6%) 14 (6%) Missing data during window but on study 5 (2%) Differences in response rates driven by Snapshot virologic non-response and lower rates of both discontinuations due to AEs in the DTG/ABC/3TC group. *Includes categories: Discontinued for lack of efficacy and Discontinued for other reason while not below threshold AE, adverse, event; ITT-E, intent-to-treat exposed Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

9 Snapshot Outcomes by Baseline Randomization Strata at Week 48: ITT-E
ATV regimen 248 247 179 181 69 66 130 123 118 124 CD4+ count cells/mm3 HIV-1 RNA c/mL ITT-E, intent-to-treat exposed. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

10 Treatment Emergent Mutations in Patients with Confirmed Virologic Withdrawal
The resistance analysis was performed on subjects meeting confirmed virologic withdrawal (confirmed ≥400 c/mL on or after Week 24) No subject receiving DTG/ABC/3TC developed INSTI or ABC/3TC resistance- associated mutations Resistance Analysis DTG/ABC/3TC (n=6) ATV/r +TDF/FTC (n=4) INSTI NRTI 0* 1 M184V PI *Two subjects receiving DTG/ABC/3TC had either K219K/Q (TAM) or E138E/G at CVW with no reduced susceptibility to DTG/ABC/3TC. K219K/Q is not selected for by ABC or 3TC nor does it affect their fold change INSTI, integrase strand transfer inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16 21st International AIDS Conference,18-22 July 2016, Durban, South Africa

11 Summary of Adverse Events: Randomized Phase (up to Week 48)
DTG/ABC/3TC (n=248) ATV/r+TDF/FTC (n=247) Any adverse event, n (%) 195 (79%) 197 (80%)* Grade 2 to 4 AE 115 (46%) 137(55%) Drug-related AE (occurring ≥5% of subjects in either arm) 83 (33%) 121 (49%) Nausea 31 (13) 35 (14) Diarrhoea 12 (5) 18 (7) Dyspepsia 4 (2) 15 (6) Ocular icterus Headache 5 (2) 14 (6) Jaundice 13 (5) Serious AE 12 (5%) 20 (8%) Fatal AE 1+ Drug-related SAE 3 (1%) Discontinuations due to AEs 10 (4%) 17 (7%) *Additional AEs identified post-hoc for two ATV+RTV+TDF/FTC subjects at one site are not included in this table. AEs were not considered to impact overall safety findings +Death certificate noted death due to natural causes. Investigator deemed event unrelated to study drug. AE, adverse event; SAE, serious adverse event. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

12 Most Frequent AEs and Relative Risk
Favors DTG/ABC/3TC Favors ATV/r+TDF/FTC Nasopharyngitis Nausea Upper respiratory tract infection Headache Dizziness Vomiting Urinary tract infection Diarrhoea Back pain Rash Fatigue Abdominal pain Cough Dyspepsia Hyperbilirubinemia Jaundice Ocular icterus 5 10 15 20 25 .125 .25 .5 1 2 4 Most frequent AEs* (%) Relative risk with 95% CI DTG/ABC/3TC, n=248 ATV/r+TDF/FTC , n=247 * Randomized Phase (up to Week 48); All AEs reported by >5% in at least one treatment group. AE, adverse event; CI, confidence interval. Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

13 Summary of Psychiatric AEs
Event DTG/ABC/3TC FDC N=248 n (%) ATV/r+ TDF/FTC FDC N=247 n (%) Any event 35 (14) Insomnia 10 (4) 9 (4) Anxiety 5 (2) 7(3) Depression 7 (3) Suicidal ideation 4 (2) 3 (1) Depressed mood Abnormal dreams 2 (<1) Panic attack Agitation 1 (<1) Bipolar disorder Elevated mood Mood altered Mood swings Nightmare Sleep disorder Event DTG/ABC/3TC FDC N=248 n (%) ATV/r+ TDF/FTC FDC N=247 n (%) Acute psychosis 1 (<1) Affect lability Anxiety disorder Confusional state Hallucination, visual Intentional self-injury Irritability Mania Panic disorder Stress Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

14 Conclusions In treatment-naive women, DTG/ABC/3TC (Triumeq) was superior to ATV/r+TDF/FTC at 48 weeks of treatment Adjusted difference 10.5%, 95% CI: 3.1% to 17.8%, P=0.005 Difference driven by lower rate of virologic non-response (Snapshot) and fewer discontinuations due to AEs in DTG arm DTG/ABC/3TC had a favorable safety profile compared to ATV/r+TDF/FTC Similar to overall safety profile for DTG from previous studies There were no treatment-emergent primary INSTI or ABC/3TC resistance mutations in the DTG/ABC/3TC group The study provides important information to help guide treatment decisions in women AE, adverse event; CI, confidence interval; INSTI, integrase strand transfer inhibitor Orrell et al. AIDS 2016; Durban, South Africa. Slides THAB0205LB. AT/TRIM/0006/16

15 Acknowledgments We thank everyone who has contributed to the success of this study, including All study participants and their families The clinical investigators and their staff The GSK and ViiV Healthcare study teams AT/TRIM/0006/16

16 Auswahl klinisch relevanter Sicherheitsinformationen zu Triumeq®
Kontraindikationen: Überempfindlichkeit gegen einen der Inhaltsstoffe, gleichzeitige Einnahme von Dofetilid. Warnhinweise: Hypersensitivitätsreaktion gegen Abacavir oder Dolutegravir; da Triumeq Abacavir enthält, muss vor der Anwendung der HLA-B*5701 Status des Patienten überprüft werden, da Träger eine erhöhtes Risiko einer Hypersensitivitätsreaktion gegen Abacavir haben. Auftreten eines Immun-Rekonstitutions-Syndroms; eine kausale Beziehung zwischen der Behandlung mit Abacavir und dem Risiko für einen Myokardinfarkt kann derzeit weder bestätigt noch widerlegt werden. Nebenwirkungen: Überempfindlichkeitsreaktionen, Immun-Rekonstitutions-Syndrom, Laktatazidose, Pankreatitis, Rhabodmyolyse, schwerwiegende Hautreaktionen, aplastische Anämie. Für eine vollständige Auflistung der Kontraindikationen, Warnhinweise und Nebenwirkungen siehe Fachinformation. AT/TRIM/0006/16

17 Fachkurzinformation AT/TRIM/0006/16
Dieses Arzneimittel unterliegt einer zusätzlichen Überwachung. Dies ermöglicht eine schnelle Identifizierung neuer Erkenntnisse über die Sicherheit. Angehörige von Gesundheitsberufen sind aufgefordert, jeden Verdachtsfall einer Nebenwirkung zu melden. Hinweise zur Meldung von Nebenwirkungen, siehe Abschnitt 4.8 der Fachinformation. BEZEICHNUNG DES ARZNEIMITTELS Triumeq 50 mg/600 mg/300 mg Filmtabletten QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG Jede Filmtablette enthält 50 mg Dolutegravir (als Natrium-Salz), 600 mg Abacavir (als Sulfat) und 300 mg Lamivudin. Sonstige Bestandteile: Tablettenkern: Mannitol (E421), Mikrokristalline Cellulose, Povidon K29/32, Poly(O-carboxymethyl)stärke-Natriumsalz, Magnesiumstearat Filmüberzug: Opadry II Violett 85F90057 bestehend aus:Poly(vinylalkohol), Titandioxid, Macrogol, Talkum, Eisen(II,III)-oxid, Eisen(III)-oxid KLINISCHE ANGABEN Pharmakotherapeutische Gruppe: Antivirale Mittel zur systemischen Anwendung, Antivirale Mittel zur Behandlung von HIV-Infektionen, Kombinationen, ATC-Code: J05AR13 Anwendungsgebiete Triumeq ist angezeigt zur Behandlung von Infektionen mit dem Humanen Immundefizienz-Virus (HIV) bei Erwachsenen und Jugendlichen im Alter von über 12 Jahren, die mindestens 40 kg wiegen (siehe Abschnitt 4.4 und 5.1 der Fachinformation). Vor Beginn der Behandlung mit Abacavir-haltigen Arzneimitteln sollte unabhängig von der ethnischen Zugehörigkeit jeder HIV-infizierte Patient auf das Vorhandensein des HLA-B*5701-Allels hin untersucht werden (siehe Abschnitt 4.4 der Fachinformation). Patienten, bei denen bekannt ist, dass sie das HLA-B*5701-Allel tragen, sollten Abacavir nicht anwenden. Gegenanzeigen Überempfindlichkeit gegen Dolutegravir, Abacavir oder Lamivudin oder einen der in Abschnitt 6.1 der Fachinformation genannten sonstigen Bestandteile. Siehe Abschnitte 4.4 und 4.8. der Fachinformation. Gleichzeitige Anwendung mit Dofetilid (siehe Abschnitt 4.5 der Fachinformation). INHABER DER ZULASSUNG ViiV Healthcare UK Limited, 980 Great West Road, Brentford, Middlesex, TW8 9GS Vereinigtes Königreich ZULASSUNGSNUMMERn EU/1/14/940/001 EU/1/14/940/002 Abgabe NR, rezept- und apothekenpflichtig. Weitere Angaben zu Warnhinweisen und Vorsichtsmaßnahmen für die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstigen Wechselwirkungen, Schwangerschaft und Stillzeit und Nebenwirkungen entnehmen Sie bitte der veröffentlichten Fachinformation. Ausführliche Informationen zu diesem Arzneimittel sind auf den Internetseiten der Europäischen Arzneimittel-Agentur  verfügbar. Stand September 2015 AT/TRIM/0006/16

18 Hinweise zur Dosierung und Art der Anwendung: Die empfohlene Dosis von Triumeq® beträgt eine Tablette einmal täglich bei Erwachsenen und Jugendlichen ab 12 Jahren, die mindestens 40 kg wiegen. Triumeq® kann mit oder ohne eine Mahlzeit eingenommen werden. Triumeq® ist eine fixe Kombination und darf nicht für Patienten verschrieben werden, die eine Dosisanpassung benötigen (darunter: Patienten mit einer dokumentierten oder klinisch vermuteten Integrase-Inhibitor-Resistenz, bei denen Dolutegravir 50 mg zweimal täglich zusammen mit einer Mahlzeit verabreicht werden soll). Monopräparate mit Dolutegravir, Abacavir und Lamivudin stehen zur Verfügung. Die Patientensicherheit steht für GSK stets an oberster Stelle. Jeder Verdacht auf eine unerwünschte Wirkung, die bei einem Patienten auftritt, ist dem Bundesamt für Sicherheit im Gesundheitswesen/ Medizinmarktaufsicht in Übereinstimmung mit dem nationalen Erfassungssystem für Spontanberichte zu melden. Gerne steht Ihnen auch unsere Pharmakovigilanzabteilung für die Erfassung dieser Informationen zur Verfügung. Sie erreichen uns telefonisch unter 01 / – 0 oder schriftlich unter AT/TRIM/0006/16

19 Appendix

20 Observational data on the use of DTG during pregnancy
DTG clinical development program1 DTG post-marketing surveillance1 Antiretroviral Pregnancy Registry (APR)2,3 Retrospective real-world data3 Although DTG is assigned an FDA pregnancy category B (no evidence of human risk), there are currently insufficient data in the APR to detect an increase in risk of birth defects2 37 pregnancies occurred in subjects taking DTG as part of clinical trials: 18 produced normal infants 1 infant born with congenital anomaly: double-outlet right ventricle plus ventricular septal defect (trimester* 1) 9 elective terminations and 3 spontaneous abortions (no obvious abnormalities) 7 outcomes unknown 74 pregnancies reported by 16 Jan 2016 as post- marketing surveillance 18 produced normal infants 2 infants born with congenital anomaly: intracranial calcifications (trimesters* 2 and 3), polydactyly (trimesters 1, 2 and 3) 14 spontaneous abortions (1 with congenital anomaly: fetal dystrophy, trimester* 1) 1 still birth (normal infant) 39 outcomes unknown 28 pregnancies registered with the APR by 31 Jul 2015 10 infants exposed to DTG during 1st trimester: 10 normal infants 18 infants exposed to DTG during 2nd or 3rd trimesters: 17 normal infants, 1 with congenital anomaly: Hypoglossia hypodacylia syndrome (trimester 3*) 9 pregnancies in 54 women treated with DTG 1 infant exposed to DTG during first Trimester 8 infants exposed to DTG during 2nd or 3rd trimester No birth defects observed Key point Out of 148 reported pregnancies during DTG-exposure there has been only 1 report of a possibly drug-related case of congenital anomaly.1–3 Additional notes DTG clinical trials1 One infant was born double-outlet right ventricle plus ventricular septal defect that were not considered drug-related by the investigators, foetal exposure was during the first trimester only DTG post-marketing surveillance1 Two infants were born with congenital anomalies [intracranial calcifications, polydactyly] that were not considered drug-related by the investigators. The infant with intracranial calcifications was exposed to DTG during the second and third trimester The infant with polydactyly was exposed to DTG during all three trimesters There was one report of an infant with foetal dystrophy (spontaneous abortion) which was interpreted as drug related by the reporting HCP, foetal exposure was during the first trimester only Antiretroviral Pregnancy Registry2,3 One infant with DTG exposure during the third trimester was born with hypoglossia hypodacylia syndrome; the event was not reported as drug-related Retrospective real-world cohort4 British cohort of 181 patients (54 women, 127 men) treated at a single centre between 14/01/2015 and 30/11/15. No birth defects observed in 9 infants born from 9 pregnancies. Reference Data on file (Maternal Dolutegravir Pharmacokinetics, Safety, and Pregnancy Outcomes of Patients who Received a Dolutegravir-Based Regimen) Antiretroviral Pregnancy Registry International Interim Report December Data on file (Medical comment: Maternal Dolutegravir Pharmacokinetics, Safety and Pregnancy Outcomes) Simons R, et al. BHIVA Poster 9 AT/TRIM/0006/16 *Trimester of DTG exposure 1. Data on file (Maternal Dolutegravir Pharmacokinetics, Safety, and Pregnancy Outcomes of Patients who Received a Dolutegravir-Based Regimen) 2. Antiretroviral Pregnancy Registry International Interim Report December Data on file (Medical comment: Maternal Dolutegravir (Pharmacokinetics, Safety and Pregnancy Outcomes); 4. Simons R, et al. BHIVA Poster 9

21 IMPAACT P1026s: DTG PKs in HIV-infected pregnant and postpartum women1
IMPAACT P1026s is an ongoing open-label, parallel-group, multicentre, Phase IV prospective study in HIV-1-infected pregnant women in the Americas The study aims to describe the PKs of ARVs, including DTG, in HIV-1-infected pregnant women compared with post-partum kinetics Results expected Q DTG arm of P1026s study HIV-1-infected pregnant women cART containing DTG N=21 PK sampling period (maternal PK) PK sampling period (infant PK)* Key points The IMPAACT P1026s study enrolled HIV-infected pregnant women in the Americas, and aimed to assess the PK of ARVs in HIV-infected pregnant in comparison to post-partum kinetics (ClinicalTrials.gov identifier NCT ).1,2 The current preliminary analysis focuses on the DTG arm of the study.3 Additional notes1 Maternal blood samples were collected during at Weeks 20–28 and 30–38 and postpartum 3–12 weeks. Infant washout samples were collected if birth weight was >1,000 g and there were no severe malformations or medical conditions at 2–10, 18–28, 36–72 hrs and 5–9 days postpartum. DTG was measured using validated LC/MS/MS (quantitation limit: mcg/mL). PK parameters were calculated with standard non-compartmental methods. Two-tailed Wilcoxon signed rank tests compared within-subject PK parameters with a two-sided p value <0.10. Reference Mulligan N, et al. CROI Poster 398 Data on file (Medical comment: Maternal Dolutegravir (Pharmacokinetics, Safety and Pregnancy Outcomes) Screening Visit 20–28 weeks gestation 30–38 weeks gestation 3–12 weeks postpartum Washout samples 2–10 h, 18–28 h, 36–72 h and 5–9 days postpartum Maternal PK blood sampling AT/TRIM/0006/16 *Infant washout samples were collected if birth weight was >1,000 g and there were no severe malformations or medical conditions Mulligan N, et al. CROI Poster 398