Is dolutegravir a magic bullet for HIV/TB programmes?

Transcription

1 Francois Venter Is dolutegravir a magic bullet for HIV/TB programmes? March 2018 Thanks Michelle Moorhouse, Graeme Meintjes, Gary Maartens, Celicia Serenata, Andy Hill, Polly Clayden, Gloria Maimela, Tom Boyles, Clinical Care Options

2 Optimising ART Consortia The USAID-funded OPTIMIZE consortium includes five leading private and public sector partners, and led by Wits RHI. OPTIMIZE leverages efforts by a wide range of donors and key stakeholders (e.g., Unitaid and its implementing partners, WHO and Global Fund). OPTIMIZE operates under the assumption that aligning the collective power of scientists, regulators, drug companies, donors, programmers and advocates to achieve its singular goal -- accelerating access to simpler, safer and more affordable HIV treatment -- can rapidly advance ART optimization efforts.

3 The Evolving HIV Treatment Paradigm????? 3TC=lamivudine; ZDV=zidovudine Long Acting Injectable? Single-Tablet Regimens The Integrase Era HIV-1 discovered ZDV/3TC ZDV monotherapy Triple-Drug Therapy

4 ART trials 114 studies through 2012, up to 3 years of f/u: ITT analyses Virologic responses Safety and tolerability Lee et al. PLoS One 2014

5 Current WHO ART guidelines What to use in first-line therapy in adults ARV regimen *, Preferred option TDF + XTC ǂ + EFV 600 Alternative options AZT + 3TC + EFV 600 AZT + 3TC + NVP TDF + XTC ǂ + NVP TDF + XTC ǂ + DTG TDF + XTC ǂ + EFV 400 NEW NEW *ARV regimens as fixed-dose combinations is the preferred approach because of clinical, operational, and programmatic benefits Countries should discontinue d4t use in first-line regimens because of its well-recognized metabolic toxicities ǂ XTC = 3TC or FTC These alternative regimens are expected to be available only in Safety data PLHIV with TB coinfection and in HIV+ pregnant women still pending Courtesy of M Vitoria: WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection Recommendations for a public health approach - Second edition. June Available at:

6 Efavirenz has served us VERY well TB Pregnancy And in the field

7 First-line TDF XTC EFV Desirable Property EFV/TDF/FTC Cost driver Toxicity High resistance barrier Well tolerated No lab tox monitoring Safe in pregnancy Low pill burden No Not initially TDF creat Yes Yes FDC Toxicity driver Pill size Low genetic barrier Cost Once a day Yes Use with TB (rif) Yes

8 Efavirenz s warts Neuropsychiatric Ann Intern Med. 2005;143:714 PLoSMed 2004;1:e19 JAIDS 2012;60:33 Lancet Infect Dis 2012;12:111 Clin Infect Dis 2006;42:273 Lancet 2009; 374: 796 AIDS 2014;28(10):145 JAIDS 2011;57:2841 Karamchand Medicine 2016 Metabolic Suicide Ann Intern Med. 2014;161:1-10 Efavirenz Dave PLoS ONE 10(12): e Bone mineral density Late encephalopathy Variava JAIDS 2017 DILI Sonderup AIDS 2016

9 Current ART Tenofovir XTC Efavirenz Failure AZT (zidovudine) Darunavir 3TC Failure XTC, other nukes Dolutegravir Protease/r (LPV or ATV) Etravirine

10 Alternatives to efavirenz Protease inhibitors toxic, expensive Rilprivine food, TB, availability issues Integrase inhibitors

11 Pre-treatment NNRTI resistance in 11 LMICs Source: WHO HIV Drug Resistance Report 2017

12 Future first-line. TAF XTC DTG Safer Cheaper Safer Resistance barrier Cheaper FDCs Less drug interactions (contraception)

13 Phase 3 studies of DTG-based ART in ARV-naive patients Randomised, non-inferiority phase 3 studies Primary endpoint: HIV-1 RNA < 50 copies/ml at week 48 SPRING-2 (active controlled) SINGLE (placebo controlled) FLAMINGO (open label) ART-naive pts VL 1000 c/ml (N = 822) ART-naive pts VL 1000 c/ml HLA-B*5701 neg CrCl > 50 ml/min (N = 833) ART-naive pts VL 1000 c/ml (N = 484) DTG 50 mg QD + 2 NRTIs* (n = 411) RAL 400 mg BID + 2 NRTIs* (n = 411) DTG 50 mg QD + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) DTG 50 mg QD + 2 NRTIs* (n = 242) DRV/RTV 800/100 mg QD + 2 NRTIs* (n = 242) *Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC. Clinical Care Options 2014 Raffi et al. Lancet Infect Dis 2013 Walmsley et al. N Engl J Med 2013 AbbVie Group Consultancy, Johannesburg, South Africa September 17, 2016 Company Clotet Confidential et al. Lancet

14 Proportion of patients (%) SINGLE study: DTG vs. EFV DTG + ABC/3TC for HIV-1 treatment in ARV-naïve adults with HIV infection: 96 and 114 week results from the randomised SINGLE study Proportion of participants with HIV-1 RNA <50 c/ml 88% 81% Difference in response Week 96: 8.0% (95% CI, 2.3% to 13.8%); p=0.006 Week 114: 8.3% (95% CI, 2.0% to 14.6%); p= DTG + ABC/3TC QD (n=414) EFV/TDF/FTC QD (n=419) Baseline Week 80% 72% 71% 63% Walmsley et al. N Engl J Med 2013 Walmsley et al. J Acquir Immune Defic Syndr 2015

15 US Weekly Treatment Market Share In US and EU, DTG-based regimens have become the top Since DTG Launch prescribed ARVs, affirming DTG s clinically superior profile In Feb 2013, the US Health and Human Services Guidelines on ARVs recommends INSTI-based regimens as the preferred for ART-naïve patients EFV no longer included in DHHS guidelines As of 2Q16, DTG treatment volume of >21,000 patients weekly, with nearly 1 in 5 patients on a DTG regimen in the US DTG now leads US/EU markets: US: #1 core agent in treatment share and volume EU: #2 prescribed regimen in treatment-naïve patients The US and EU has long moved on from EFV-based treatment Source: GILD and GSK earnings. Note: Graph depicts single tablet regimen plus core agent market

16 Why aren t these drugs used? Not preferred options in WHO guidelines Many drugs are not registered and no coformulations are available Limited data on use in TB (almost all new drugs) Limited data on use in pregnancy (almost all new drugs) Costs: abacavir, all integrase inhibitors hope for dolutegravir

17 ADVANCE ADVANCE

18 PK studies Study/substudy Collaborator(s) Comments/details WRHI 052: DRV PK ADVANCE UCT; UoL (AO) UCT UCT (PS) UCT; other DRV troughs; SCLO1B1 polymorphisms? DTG/TAF in TB and pregnant women EFV/INH PG-PK-PD (GWAS; ADME genomics) DaRifi UCT Intensive PK DTG and TAF, n=40 UCT (HM); Desmond Tutu HIV Centre; University of Turin Adjusted DRV dose troughs with Rif versus DRV alone (steady state); safety; population PK TAF/Rif UCT (GM) TAF/Rif in patients after SSAT in HV DTG/Rif UCT (GM) DTG/Rif in patients after SSAT in HV

19 DTG in the real world Discontinuation due to neuropsychiatric AE Factors associated with DTG discontinuation Hoffmann et al. HIV Medicine 2017; Libre et al. CROI 2017 abstract #615; Hsu et al. CROI 2017 abstract #664

20 BUT! A strong caution Most patient who interrupt therapy do NOT do so for side effects Life challenge: Depression/anxiety Relationship breakdown Changing/losing jobs Alcohol use Inability to pay Poverty and health care access remain a major challenge

21 START and Temprano the CD4 debate Thanks: Simon Collins

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23 A ceiling price agreement has just been announced This ceiling price agreement could yield billions of rand in savings through TLD rollout and enable widespread access to a clinically superior regimen 2002 d4t/3tc/nvp Historical launch prices for new regimens 2006 AZT/3TC/NVP 2010 TDF/3TC/EFV 2018 TDF/3TC/DTG $280 $240 $300 $75 The TLD agreement lasts four years: 01 April March 2022 Applies to over 90 countries Results of collaboration from many partners: Governments of Kenya and South Africa, the Bill & Melinda Gates Foundation; Clinton Health Access Initiative; Global Fund to Fight AIDS, Tuberculosis and Malaria; President s Emergency Plan for AIDS Relief (PEPFAR); United Kingdom s Department for International Development; Unitaid; UNAIDS; and USAID, with Mylan Laboratories and Aurobindo Pharma.

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25 What if we switch from EFV to DTG? Millions of patients will need to be switched huge undertaking and the manufacturing changes will likely be slightly chaotic Moving from EFV to DTG unlikely to be a big deal (?VL) ; reverse a problem Training how big an issue? Probably NB if VL?harmonisation between and within different countries private vs public sector, cross borders Pregnancy limited data TB studies are needed Studies largely done in men It s a new agent what happens if: it doesn t work in TB? Pregnancy? New side effect?

26 Significant technical/programmatic work is required for full transition to TLD in 2018 Revision processes for programmatic guidelines, STG and EML inclusion Tender extension to align with expected MCC registration timelines SA HIV Clinicians Society, clinicians, community groups etc. to communicate transition plans Updates to RSA Supplier Performance Database and Visual Analytics Network (VAN) to create modules for collection and analysis of demander data; providing visibility into consumption and stock availability Adoption Product Registration Procurement KOL/ Partner Engagement National Transition Planning Facility-level Support Monito -ring Uptake From Dec 2016: Supplier communication on phase-in plans to accelerate product registrations Develop tender forecast and documentation tender date TBC Supply security analysis ongoing; Monitoring MCC registration; Communication of transition to provinces and validation of forecast at province level will be required Rollout plan to be developed

27 Some programme considerations As HIV testing programmes improve, CD4 rises with less TB at initiation (South Africa from 25% to 8%) TB remains common within patients on successful ART TB programme and HIV programme still separate and vary and deal with very different patients (sick vs healthy)

28 What are the options for prevention and treatment for programmes in a DTG era? TDF/XTC/DTG likely to replace all 1st line and a big chunk of 2 nd line in 2019 Prevention with INH On initiation no problem (proposed for SA) During treatment - no problem (proposed for SA) Treatment options for alternative regimens? Treatment option for people initiating ART with active TB Use existing efavirenz regimen (con: another regimen in system) Double dose DTG (50mg BD/100mg daily) (con: needs singles); possible future with 50mg FDC

29 Your life is in the hand of (an often unreliable) distributor SA experience: Almost NO stockouts of FDCs Singles an issue

30 A TB person s view on DTG Well, if there is a drug interaction, you can t use DTG then! Response: Seriously??? INH works DTG is going to save a fortune DTG is significantly better The failure with IPT is clearly programmatic why would shorter regimens help? A second ART regimen in the system just for TB prevention? But probably OK TAF is coming? going to have to repeat all the studies

31 Conclusion re DTG Likely 1 st line (and possibly 2 nd line) everywhere in Africa Resistance benefit, cost compelling -?any second line Side effect profile somewhat compelling TB a pretty major headache for treatment and future new rifamycin based regimens But needs to be a proper priority not an also-ran Lack of data with TAF a major problem Addressing poverty and the health system remains a priority BUT: Imagine a drug without a resistance barrier and minimal side effects..

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33 I am not a defaulter A lack of attention to health systems and the drag on adherence is a major issue Time, cost of getting treatment Queues and a new health care worker each time Lost files Drug stock outs Little attention to explaining what is going on