INSPIRING: SAFETY AND EFFICACY OF DOLUTEGRAVIR-BASED ART IN TB/HIV COINFECTED ADULTS AT WEEK 24

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1 UK/DGR/14/18 Dte of prep: April 218 INSPIRING: SAFETY AND EFFICACY OF DOLUTEGRAVIR-BASED ART IN TB/HIV COINFECTED ADULTS AT WEEK 24 Dooley KE, 1 Kpln R, 2 Mwelse T, 3 Grinsztejn B, 4 Ticon E, 5 Lcerd M, 6 Chn P, 7 Belonosov E, 8 Ait-Khled M, 9 Angelis K, 1 Brown D, 11 Singh R, 12 Tlrico C, 13 Tenorio A, 13 Aboud M 9 1 Johns Hopkins University School of Medicine, Bltimore, MD, USA; 2 Desmond Tutu HIV Foundtion, Cpe Town, South Afric; 3 Clinicl HIV Reserch Unit, Johnnesburg, South Afric; 4 Instituto de Pesquis Clínic Evndro Chgs FIOCRUZ, Rio de Jneiro, Brzil; 5 Hospitl Dos de Myo, Lim, Peru; 6 Fiocruz/Tropicl Medicine Foundtion Dr Heitor, Vieir Dourdo, Mnus, Brzil; 7 Fundción Huésped, Bueno Aires, Argentin; 8 Regionl Center for Prevention nd Tretment of AIDS nd Infectious Diseses, Russi; 9 ViiV Helthcre, Brentford, UK; 1 GlxoSmithKline, Stockley Prk, UK; 11 ViiV Helthcre, Melbourne, Austrli; 12 ViiV Helthcre, Upper Merion, PA, USA; 13 ViiV Helthcre, Reserch Tringle Prk, NC, USA Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

2 Introduction Dolutegrvir (DTG)-bsed regimens re now recommended by WHO s lterntive first-line regimens; severl countries with high HIV prevlence hve dopted DTG-bsed regimens s first-line tretment Chrcterizing the efficcy, sfety, nd drug-drug interctions of DTG in ptients with tuberculosis (TB) co-infection is high priority Efvirenz (EFV) is commonly used, but lterntives to EFV re needed, prticulrly in the setting of dverse events nd trnsmitted drug resistnce to NNRTIs DTG hs some fetures tht my fvour its use: Good long term efficcy nd fvorble sfety profile High brrier to HIV-1 resistnce nd no impct of primry NNRTI resistnce (with prevlence ~1% in some regions) DTG hs low potentil for drug interctions nd is not n inducer of CYP45 enzymes In helthy volunteers, the ntituberculosis drug rifmpicin (RIF) reduced DTG C tu by 72% nd AUC -tu by 54% Decresed DTG plsm exposure is compensted for by incresing DTG dosge to 5 mg twice dily The INSPIRING study is being conducted to estimte the ntivirl efficcy nd evlute the sfety of DTG in ART-nive dults with HIV/TB coinfection Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA Dooley et l. CROI 218; Boston, MA.

3 INSPIRING: Phse IIIb Study Design Phse IIIb, rndomized, multicenter, open-lbel, non-comprtive, ctive-control prllel-group study TB therpy HRZE (2 months) HR (4 months) DTG dose switch 2 weeks post-completion of TB tretment HIV/TB coinfected ART-nive dults DTG (5 mg BID) + 2 NRTIs (n = 69) EFV (6 mg QD) + 2 NRTIs (n = 44) DTG (5 mg QD) + 2 NRTIs Screening 28 to 14 dys Dy 1 Inclusion criteri HIV-1 RNA 1 copies/ml nd CD4+ 5 cells/mm 3 Pulmonry, pleurl, or lymph node tuberculosis with RIF-sensitive MTB confirmed by culture or GeneXpert RIF-contining TB tretment strted up to mximum of 8 weeks before rndomiztion nd no lter thn the screening dte 24 weeks Interim nlysis: % <5 c/ml (Snpshot) 52 weeks End of rndomized phse Primry endpoint t Week 48: % <5 c/ml (Snpshot) DTG:EFV 3:2 rndomiztion strtified by Screening plsm HIV-1 RNA 1, or >1, copies/ml Screening CD4+ 1 cells/mm 3 or >1 cells/mm 3 ART, ntiretrovirl therpy; DTG, dolutegrvir; EFV, efvirenz; HR, isonizid, rifmpin; HRZE, isonizid, rifmpin, pyrzinmide, ethmbutol; NRTI, nucleoside reverse trnscriptse inhibitor; RIF, rifmpin; TB, tuberculosis. Durtion of continution phse of TB tretment ccording to locl guidelines (continution phse up to 7 months in some countries). ClinTrils.gov NCT Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA Dooley et l. CROI 218; Boston, MA.

4 Study Endpoints Primry Endpoint Proportion of DTG subjects with plsm HIV-1 RNA <5 c/ml t Week 48 using the modified Snpshot lgorithm in the ITT-E popultion Secondry Endpoints Proportion of subjects with plsm HIV-1 RNA <5 c/ml t Week 24 using the modified Snpshot lgorithm in the ITT-E popultion Proportion of EFV subjects with plsm HIV-1 RNA <5 c/ml t Week 48 using the modified Snpshot lgorithm in the ITT-E popultion Chnges from bseline in CD4+ counts t Week 24 nd Week 48 Incidence nd severity of ll AEs, SAEs, nd lbortory bnormlities Proportion of subjects with TB- nd non-tb-ssocited IRIS s ssessed by the IRIS independent djudiction pnel Incidence of tretment-emergent genotypic nd phenotypic resistnce to DTG, EFV, nd other on-study ART in subjects meeting confirmed virologic withdrwl criteri Modified snpshot: NRTI switch for tolerbility not counted s filure Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA Dooley et l. CROI 218; Boston, MA.

5 INSPIRING Globl Enrollment (n=113) Totl number of sites: 37 First Subject First Visit: 23/1/215 Lst Subject First Visit: 13/1/217 Recruitment period: 21 months 1 SUBJECTS South-Afric Peru Brzil Mexico Russi Argentin Thilnd Prticipting Country Screened Rndomised Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

6 Demogrphic nd Bseline Chrcteristics Age, medin (min, mx), yers 5 yers, n (%) Prticipnts could hve hd pulmonry TB with pleurl or lymph node TB. DTG (n=69) 33 (18, 62) 9 (13) Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA EFV (n=44) 32 (2, 5) 2 (5) Femle, n (%) 3 (43) 16 (36) Africn-Heritge/Africn, n (%) 47 (68) 29 (66) HIV-1 RNA, medin (Q1, Q3), log 1 copies/ml >1, copies/ml, n (%) CD4+ cell count, medin (Q1, Q3), cells/mm 3 1 cells/mm 3, n (%) 5.1 (4.74, 5.47) 44 (64) 28 (128, 41) 13 (19) 5.24 (4.5, 5.67) 24 (55) 22 (92, 354) 12 (27) CDC ctegory C, n (%) 69 (1) 44 (1) Current TB conditions, n (%) Pulmonry TB Lymph node TB Pleurl TB Time from strt of TB therpy to Dy 1, medin (Q1, Q3), dys Most common NRTI bckbone TDF/FTC TDF/3TC 65 (94) 5 (7) 5 (7) 44 (1) 1 (2) 35. (28., 44.) 33.5 (26., 52.) 47 (68) 4 (6) 31 (7) 3 (7) Dooley et l. CROI 218; Boston, MA.

7 Snpshot Outcomes t Week 24 Prticipnts, % DTG ITT-E (n=69) EFV ITT-E (n=44) DTG + 2 NRTIs n=69 n (%) EFV + 2 NRTIs n=44 n (%) Virologic Success (HIV-1 RNA <5 c/ml) 56 (81) 39 (89) Virologic nonresponse 7 (1) 3 (7) Dt in window not <5 c/ml 5 (7) 2 (5) Discontinued for other reson while not <5 c/ml 2 (3) 1 (2) Chnge in ART No virologic dt 6 (9) 2 (5) Discontinued due to AE or deth 1 (2) Discontinued for other resons 5 (7) 1 (2) Missing dt during window but on study 1 b (1) Virologic success Virologic nonresponse No virologic dt Discontinued for other resons: 4 lost to follow-up (dys 25, 8, 177, 181); 1 withdrwl of consent (dy 116). b <4 c/ml t Wk 12. Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

8 Confirmed Virologic Withdrwls Through Week 24 DTG n=69 EFV n=44 Confirmed virologic withdrwl (CVW), n (%) 1 (1) b Tretment-emergent resistnce-ssocited muttions NRTI n/ NNRTI n/ INSTI n/ Confirmed plsm HIV-1 RNA 4 copies/ml t or fter Week 24 (two consecutive vlues). b CVW t Wk 24: Prticipnts screening HIV-1-RNA ws 1,934,3 c/ml; their Dy 1 virl lod ws missing but their Dy 14 virl lod ws 14,867 c/ml nd their virl lod ws still declining through Wk 29. Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

9 Prticipnt with Confirmed Virologic Withdrwl 7 5-yer-old mle rndomized to DTG NRTI bckground regimen: ddi/3tc Screening HIV-1-RNA ws 1,934,3 c/ml (Dy 1 virl lod missing) HIV-1 RNA, log 1 c/ml No tretment-emergent NRTI, NNRTI, or INSTI resistnce observed Dy -27 Screening Dy 14 [18-Apr-16] Week 4 Week 8 Week 12 Week 24 [2-Sep-16] Week 24 Retest [6-Oct-216] Week 29 Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

10 Percentge, % Virologic nd Immunologic Results in the ITT-E Popultion Through Week Modified FDA snpshot nlysis (ITT-E) Proportion of Prticipnts With HIV-1 RNA <5 copies/ml, % (95% CI) Week DTG (n=69) EFV (n=44) 89 (79, 98) 81 (72, 9) INSPIRING Phrmcokinetic Dt Pre-dose concentrtion: DTG 5 mg BID with RIF Time n DTG Conc (ng/ml) Geomen (9%CI) %CV Wk (28-234) 118 Wk (19-338) 276 Pre-dose concentrtion: DTG 5 mg QD without RIF (post-tb tretment phse) Time n DTG Conc (ng/ml) Geomen (9%CI) %CV Wk (8-437) 151 Wk (19-331) 359 INSPIRING DTG C tu when dministered twice dily with RIF were similr to DTG 5 mg once dily without RIF nd to previously reported dt for DTG 5 mg once dily in Phse 2/3 HIV trils. Medin chnge from Bseline CD4+ cell count (Q1, Q3) t Week 24: DTG, 146 cells/mm 3 (71, 214); EFV 93 cells/mm 3 (47, 178) Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

11 Adverse Events At Time of Week 24 Dt Cut-off Dte n (%) DTG (n=69) EFV (n=44) Any AE 5 (72) 4 (91) AEs occurring in 1% of prticipnts in either group Hedche Upper respirtory trct infection Dirrhe Vomiting Dizziness Arthrlgi Gstroenteritis Any serious AE (SAE) Drug-relted SAEs Any drug-relted AE Grdes 1-2 Grde 3 Grde 4 9 (13) 5 (7) 2 (3) 5 (7) 3 (4) 8 (12) 1 (1) 4 (6) 1 (1) 17 (25) 15 (22) 2 (3) 5 (11) 7 (16) 8 (18) 5 (11) 6 (14) 5 (11) 5 (11) 1 (2) 13 (3) 12 (27) 1 (2) AEs leding to withdrwl 2 (5) b Any psychitric AE Grde 1-2 Grde 3-4 SAE 5 (7) 5 (7) 6 (14) 6 (14) 1 (2) c No ftl serious AEs in either group. b One prticipnt with EFV drug hypersensitivity nd one with γ-glutmyltrnsferse elevtion. c Grde 2 suicidl idetion, considered unrelted to study drug nd resolved the sme dy. Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

12 Prticipnts With TB nd Non TB-Associted IRIS n (%) Prticipnts with events sent to djudiction committee for TB-ssocited IRIS Met criteri for TB-ssocited IRIS Possibly met criteri for TB-ssocited IRIS Prticipnts with events sent to djudiction committee for non TB-ssocited IRIS Met criteri for non-tb-ssocited IRIS Possibly met criteri for non-tb-ssocited IRIS DTG (n=69) 9 (13) 4 (6) 2 (3) 1 c (1) 1 d (1) EFV (n=44) 12 (27) 4 b (9) 3 (7) No prticipnt in either rm permnently discontinued tretment due to IRIS 1 x Grde 1, 2 x Grde 2 nd 1 x Grde 3. b 3 x Grde 2 nd 1 x Grde 4. c Grde 2 (IRIS nd strongyloidisis; lso experienced TB-ssocited IRIS). d Grde 1 (Herpes zoster). Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA Dooley et l. CROI 218; Boston, MA.

13 Prticipnts With Liver Chemistry Abnormlities Through Week 24 Dt Cut-off Dte Mximum post-bseline toxicity, n (%) DTG (n=69) EFV (n=44) ALT 3 ULN to <5 ULN 1 (2) ALT 5 ULN to <1 ULN 1 (1) 1 (2) ALT 1 ULN No subject discontinued study tretment due to liver chemistry bnormlities ALT, lnine minotrnsferse; ULN, upper limit of norml. Prticipnts were summrized on the bsis of mximum post-bseline vlue. Prticipnts with missing bseline dt were ssumed to be norml t bseline. Dooley et l. CROI 218; Boston, MA. Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA

14 Conclusions DTG 5 mg BID during concomitnt RIF-bsed TB therpy demonstrted high efficcy nd good immunologicl response through Week 24 ITT-E popultion: 81% (95% CI: 72%, 9%) One prticipnt receiving DTG met CVW criteri nd no tretment-emergent resistnce-ssocited muttions detected Five (7%) of snpshot non-responders in the DTG group were due to discontinution for non-tretment-relted resons (minly lost to follow-up while suppressed) DTG C tu when dministered twice dily with RIF were similr to DTG 5 mg once dily without RIF nd to previously reported dt for DTG 5 mg once dily in Phse 2/3 HIV trils DTG ws well tolerted, the mjority of AEs were grde 1 or 2, with low rtes of drug-relted AEs nd serious AEs, nd no AEs leding to withdrwl Low rtes of TB- nd non TB-ssocited IRIS in both groups; none led to discontinution No AEs meeting the stopping criteri for drug-induced liver injury; none led to discontinution This study provides evidence tht DTG is effective nd well tolerted in dults with HIV/TB coinfection who re receiving RIF-bsed TB tretment Conference on Retroviruses nd Opportunistic Infections; Mrch 4-7, 218; Boston, MA Dooley et l. CROI 218; Boston, MA.

15 Prescribing Informtion Tivicy dolutegrvir 1mg, 25mg nd 5mg tblets See Summry of Product Chrcteristics before prescribing Indiction: HIV in >6 yers nd >15kg s prt of combintion therpy. Dosing: Adults & dolescents >4kg: 5mg once dily with or without food if no proven/ suspected integrse resistnce. Children 6 to <12 yers: dose ccording to bodyweight: 15-<2kg: 2mg once dily (2x1mg); 2-<3kg: 25mg once dily; 3-<4kg: 35mg once dily (1 x 25mg + 1 x 1mg); When codministered with efvirenz, nevirpine, tiprnvir/ritonvir, etrvirine (without boosted PI), crbmzepine, oxcrbzepine, phenytoin, phenobrbitl, St John s Wort or rifmpicin, Tivicy 5mg twice dily in dults/dolescents or the weight-bsed once dily dose twice dily in peditric ptients. Adults with proven/ suspected integrse resistnce: 5mg twice dily preferbly with food. Limited dt in peditric ptients with proven/suspected integrse resistnce. Elderly: Limited dt in 65+ yrs. Cution in severe heptic impirment. Contrindictions: Hypersensitivity to ny ingredient. Co-dministrtion with dofetilide. Wrnings/precutions: Risk of hypersensitivity rections. Discontinue dolutegrvir nd other suspect gents immeditely if suspected. Risks of osteonecrosis, immune rectivtion syndrome. Monitor LFTs in Heptitis B/C co-infection nd ensure effective Heptitis B therpy. Cution with metformin: monitor renl function nd consider metformin dose djustment. Use with etrvirine requires boosted PI or incresed dose of dolutegrvir. Use with Mg/Al-contining ntcids, clcium, multivitmins or iron requires dosge seprtion. Pregnncy/ lcttion: Not recommended. Avoid brest-feeding. Side effects: See SmPC for full detils. Hedche, GI disturbnce, insomni, bnorml drems, depression, nxiety, dizziness, rsh, pruritus, ftigue, elevtions of ALT, AST nd CPK, rthrlgi, mylgi, hypersensitivity, suicidl idetion or suicide ttempt. Bsic NHS costs: for 3 x 5mg tblets EU/1/13/892/ for 3 x 1mg tblets (EU/1/13/892/3) for 3 x 25mg tblets (EU/1/13/892/5). MA holder: ViiV Helthcre UK Ltd, 98 Gret West Rod, Brentford, Middlesex TW8 9GS. Further informtion vilble from Customer Contct Centre, GlxoSmithKline UK Ltd, Stockley Prk West, Uxbridge, Middlesex UB11 1BT. POM S1A Trde mrks re owned by or licensed to the ViiV Helthcre group of compnies. Dte of pprovl: Mrch 218. Zinc code: UK/DLG/55/13(12) Adverse events should be reported. For the UK, reporting forms nd informtion cn be found t or serch for MHRA Yellowcrd in the Google Ply or Apple App store. Adverse events should lso be reported to GlxoSmithKline on Adverse events should be reported. For Irelnd, dverse events should be reported directly to the HPRA; Freepost, Phrmcovigilnce Section, Helth Products Regultory Authority, Erlsfort Terrce, Dublin 2, Tel: , medsfety@hpr.ie. Adverse events should lso be reported to GlxoSmithKline on