USE OF INTEGRASE INHIBITORS IN LATIN AMERICA: THE BRAZILIAN EXPERIENCE

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1 USE OF INTEGRASE INHIBITORS IN LATIN AMERICA: THE BRAZILIAN EXPERIENCE Mônica Jacques de Moraes Grupo de HIV/Aids Faculdade de Ciências Médicas UNICAMP Campinas, SP - Brasil XV Simposio Científico Fundación Huésped. Buenos Aires, Sep 5 th 2018

2 Disclosures Mônica Jacques de Moraes I have no actual or potential conflict of interest in relation to this program/presentation. I have received lecture fees from Janssen-Cilag Farmacêutica Ltda. I have received financial support for attending conferences from Janssen-Cilag Farmacêutica Ltda. I have served as consultant and received consultant fee from: Janssen-Cilag Farmacêutica Ltda. GlaxoSmithKline Brasil Ltda.

3 31 YEARS OF ANTIRETROVIRAL THERAPY NRTI PI NNRTI Fusion inhibitor CCR5 antagonist ISNTI PK enhancer cobiscistat Post-attachment inhibitor AZT - Didanosina Zalcitabina Estavudina Lamivudina Saquinavir HG Saquinavir SGC Indinavir Nevirapina Ritonavir Combivir Delavirdina Nelfinavir Abacavir Efavirenz Amprenavir Didanosina EC Lopinavir/r Trizivir (FDC) Tenofovir DF INSTI Integrase strand transfer inhibitor Atazanavir Emtricitabina Enfuvirtide Fos-APV Truvada (FDC) Tipranavir Atripla (FDC) Darunavir Maraviroque Raltegravir Etravirina Rilpivirina/TDF/FTC Nevirapina XR Rilpivirina Elvitegravir/C/F/TDF Dolutegravir Cobicistat Dolutegravir/ABC/3TC Elvitegravir/C/F/TAF Darunavir/COBI Atazanavir/COBI FTC/TAF (10, 25 mg) Rilpivirina/TAF/FTC Raltegravir HD (D/C/F/TAF)* Bictegravir/TAF/FTC Dolutegravir/RIL Dolutegravir/3TC/TDF* Ibalizumab Doravirine * and other generic FDC 1983 Adapted and updated to Sep 2018 from Calmy A. Antiretroviral Drugs and Beyond. IAS plenary session, 26 July 2017

4 PHASE 3 RANDOMIZED CLINICAL TRIALS OF DTG Clinical trial DTG + Compared to VL<50c/mL Naïve SINGLE ABC /3TC EFV/TDF/FTC 71% vs. 63% superior ARIA ABC /3TC ATV/r + TDF/3TC 82% vs. 71% comparable FLAMINGO 2 NRTI DRV/r + 2 NRTI 80% vs. 68% superior SPRING-2 2 NRTI RAL+ 2 NRTI 81% vs. 76% comparable GILEAD 1489 ABC /3TC BIC/TAF/FTC 93% vs. 92% comparable GILEAD 1490 ABC /3TC BIC 93% vs. 89% comparable INSPIRING TDF/XTC EFV/TDF/XTC 81% vs. 89% comparable GEMINI 1 & 2 3TC (dual) DTG + TDF/FTC 90-93% vs % comparable Switch NEAT 2 NRTI current PI + 2 NRTI 93% vs. 95% comparable High efficacy 80-90% VL<50 c/ml Excellent tolerance, low toxicity <4% discontinuations due AE High genetic barrier Absence of resistance mutations at failure Experienced INSTI-naïve STRIIVING 2 NRTI current regimen 85% vs. 88% comparable SWORD RPV (dual) current regimen 95% vs. 95% comparable SAILING OB* RAL + OB* 71% vs. 64% superior DAWNING 2 NRTI LPV/r + 2NRTI 82% vs. 69% superior *OB=optimized backgroung regimen Vitoria M et al. AIDS 2018, 32:

5 emerging NNRTI resistance superiority of DTG over EFV Transition to DTG first-line regimen WHO guidelines, July 2017 recommend first-line regimen that does not include NNRTIs if resistance > 10% June, 2017 Brasília ART optimization and strategies for access to dolutegravir in LA & the Caribbean

6 ART in 2018 CURRENT GUIDELINES FIRST-LINE DHHS, 2018 IAS-USA, 2018 WHO, 2018 SECOND-LINE: 2 NRTI + DTG after NNRTI-based 1rst-line after NNRTI- or PI based 1rst-line after NNRTI- or PI-based 1rst-line

7 BEYOND CLINICAL TRIALS... PRICE Dolutegravir Generic License in Countries, March 2017 Medicines Patent Pool Licenses in LAC Included in MPP license, can procure DTG at access price Bolivia El Salvador Guatemala Guyana Haiti Honduras Nicaragua Not included in MPP license, can not procure generic DTG Brasil Colombia Mexico Trinidad and Tobago Peru Chile Not included in MPP license, may benefit from MPP license to procure generic DTG 1 All others

8 BEYOND CLINICAL TRIALS...

9 867,000 PLHIV ARVs distributed by the public health system, free of charge, since % PLHIV are on ART (100% from PHS) National ART Dispensation Database (SICLOM) HIV AND ART IN BRAZIL First dispensation 70,000/year since 2013 On ART as of May ,176 Adult treatment guidelines 2013: treatment for all Labs st line 3TC/TDF/EFV (1 pill) 1st line 3TC/TDF + DTG (2 pills) 75% public laboratory CD4, VL, genotyping, tropism, HLA B*5701 National database (SISCEL) MS/SVS/Departamento de IST, Aids e Hepatites Virais

10 INSTI IN BRAZIL Pricing agreements Aug ,352 on DTG MS/SVS/Departamento de IST, Aids e Hepatites Virais

11 COMPARATIVE EFFECTIVENESS OF FIRST-LINE ANTIRETROVIRAL THERAPY REGIMENS: RESULTS FROM A LARGE REAL-WORLD COHORT IN BRAZIL AFTER THE IMPLEMENTATION OF DOLUTEGRAVIR Public Healthcare Database: ART dispensation, CD4 and VL Jan 2014 to June ,533 PLHIV aged ,240 included in the analyses Started ART (7 regimen groups*) Outcome: VL < 50 cp/ml after 6 m (180 ±90 days) Overall: 77% suppression Women, > 50y, bcd4> 500, bvl< more likely to respond *6 ART regimens + 1 others 3TC + TDF + DTG 42% superior to 3TC+TDF+EFV DTG group: > 2x more likely to respond (vs. other groups) Meireles MV, Pascom ARP, Perini F, Rick F, Benzaken A. Oral Abs TUAB0101

12 VIROLOGICAL MONITORING OF THE SWITCH FROM RALTEGRAVIR- TO DOLUTEGRAVIR-CONTAINING REGIMENS IN BRAZIL 8,790 PWH switched (RAL to DTG) Programmatic individual-level data 5,970 RAL- regimens 10 years on ART VL up to 1y before switch Switch to DTG VL >1 month after suppressed before switch low level viremia before switch failure before switch Switch from EFV to DTG in viral suppressed patients?? Poster THPEB051 Mosimann Jr, Pascom, Rick, Perini, Veloso, Benzaken, Fonseca. Brazilian Ministry of Health, Brasília, Brazil

13 MAIN ADVERSE REACTIONS MOTIVATING THE SUBSTITUTION OF DOLUTEGRAVIR IN ANTIRETROVIRAL THERAPY REGIMENS IN BRAZIL ART database SICLOM AE reported at pharmacy DTG substitution due to AE Online registration Apr Dec ,032 on DTG 1,398 reported AE (2%) 89% mild 149 (0.20%) have changed due to AE THPEE747 - Poster Exhibition

14 GENETIC BARRIER AND RESISTANCE Is dolutegravir the new PI?

15 FIRST-LINE DOLUTEGRAVIR FAILURE PRELIMINARY DATA FROM 39 PATIENTS Subtipo PREOTEASE TRANSCRIPTASE REVERSA INTEGRASE B M46L, V82A K103S,M184I,L210W,P215E,230I S B M46I B S S S B S S E138K B K103N S BC S B S M41L, M184V S B M46I V179E S B S T69N K101E M184V, Y188L B D30N V179E S S S S B S T215S S C S K70E,M184V R263K F1 S K219R S C S S S B S M184V S R. Diaz, July 2018) B S M41L,T215D S

16 1 PATIENT Unreported previous TDF/3TC/EFV Started TDF/3TC/DTG, did not respond (VL 6 months)

17 DTG SAFETY AT CONCEPTION BRAZILIAN STUDY: DTG EXPOSURE AT CONCEPTION Partnership: MoH, FIOCRUZ, Vanderbilt University, NIH Retrospective study - Jan May 31 st 2018 Databases: SINAM (HIV Surveillance), SICLOM (ART) and SINASC (live births) DTG-exposed pregnant women & babies Chart review 490 women who got pregnant while on DTG Control: on EFZ (3:1) 171 on RAL Preliminary data (Jul 2018) 168 pairs: no neural tube defects

18 DOLUTEGRAVIR IN REAL WORLD We are in the process of optimizing ART with DTG-based regimens. More information is still needed on how DTG-based therapy is likely to perform in real world, LMIC settings. Safety and efficacy data gaps: TB Preconception /pregnancy exposure Use in the context of NRTI resistance (transmitted or acquired)

19 Gracias!