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Understanding the unmet medical needs with current ART Francois Venter

Thanks: Polly Clayden, Francesca Conradie, Loyd Mulenga, Gary Maartens, Andrew Hill, David Ripin, Elli Katabira, Chris Duncombe, Nathan Ford, Marco Vitoria, WHO, Trip Gullik Industry: Gilead , Janssen, Viiv , Abbott, Merck, GSK. Understanding the unmet medical needs with current ART

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Understanding the unmet medical needs with current ART Francois Venter

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  1. Thanks: Polly Clayden, Francesca Conradie, Loyd Mulenga, Gary Maartens, Andrew Hill, David Ripin, Elli Katabira, Chris Duncombe, Nathan Ford, Marco Vitoria, WHO, Trip Gullik Industry: Gilead , Janssen, Viiv, Abbott, Merck, GSK Understanding the unmet medical needs with current ART Francois Venter Wits Reproductive Health & HIV Institute

  2. 28 approved drugs • Up to 10 recommended first-lineregimens

  3. What is coming next from WHO? • ?Test and Treat – vs staying at 500 • ?use of integrase inhibitors • Both are linked

  4. Major Guidelines for Initiation of Antiretroviral Therapy (1) Strong strength recommendation based on observational data (A-II) (2) Moderate strength recommendation based on expert opinion (B-III). (3 ) But treat all symptomatic patients, HIV+ pregnant women, HBV co-infection, HCV co-infection, HIVAN, HIV related neurocognitive disorders, ITP, non-AIDS cancers (including HPV) and serodiscordant couples (4) Individuals with CD4 < 350 as a priority. (5) But treat all HIV+ pregnant women ,TB co-infection with active disease and HBV co-infection with severe liver disease, and serodiscordant couples

  5. UNAIDS Gap Report 2014 <unaids.org>

  6. ART Trials: Virologic Responses 114 studies through 2012, up to 3 years of f/u: ITT analyses 78% 43% Carr PLoS One 2014;9:e97482

  7. ART Trials: Safety and Tolerability 114 studies, through 2012, up to 3 years of f/u: ITT analyses 14% 4% Carr PLoS One 2014;9:e97482

  8. A widening menu of ARV use for treatment and prevention Despite immediate increase from currently 17 million to 26 million people eligible for ART , the preventive effect will lead to decrease of number eligible after 2020 2013 2010

  9. Pipeline Report http://www.pipelinereport.org

  10. Think… • Many HIV testing programmes performing well – issues such as TB and high VL less of an issue • Pregnancy always an issue

  11. So what we got?

  12. Evolution of WHO ART Guidelines in Adults Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

  13. Evolution of WHO ART Guidelines in Adults Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

  14. Evolution of WHO ART Guidelines in Adults Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

  15. Evolution of WHO ART Guidelines in Adults Earlier initiation Simpler treatment Less toxic, more robust regimens Better monitoring HIV/AIDS Department

  16. Drug optimization Science evolved: smarter and better HIV treatment options are now available

  17. In terms of first line therapy (TDF+XTC+EFV) • Was 2013 just a brief harmonisation event? • EFV now routinely substituted in developed world due to side effects (where TB less of a problem) • Increasing concern about CNS side effects (also lipids, hepatitis, rash, gynaecomastia)

  18. With limited resources, a public health approach needs to balance both costs and effectiveness in order to maximize efficiencies Drugs that have been prioritized as having clinical superiority have shown dramatic price reductions over short periods of time even since CADO in 2010 21% price reduction 77% price reduction 72% price reduction EFV TDF ATV/r

  19. TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Raltegravir Etravirine Darunavir

  20. Currently available (or near-available) co-formulated antiretroviral agents and regimens

  21. TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Raltegravir Etravirine Darunavir

  22. Tenofovir has taken over the world! • 1st line recommendation by WHO; feature in EVERY guideline (some have ABC) • Well tolerated, FDCs galore, daily • Cheap (only alternative that is cheaper is d4T) • Hep B for free

  23. WHO Guidelines: 2013 Update 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection.WHO; 2013 June.

  24. Changes in D4T, AZT & TDF use (2006-2012) Between 2 to 4 million people using AZT containing regimen in 2012 2006 2007 2008 2009 2010 2011 2012 WHO AMDS database, 2014 (preliminary data)

  25. Now add PrEP TDF…

  26. Is API production capacity a potential treatment bottleneck? Situation of API production capacity for TDF and EFV with major API producers ( WHO API manufacturer survey, May 2013) The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data) (*) Data from some major manufacturers were not reported.

  27. Is API production capacity a potential treatment bottleneck? Concern: API may become a huge problem if ’20 by 20’ AND PrEP come into play… Situation of API production capacity for TDF and EFV with major API producers ( WHO API manufacturer survey, May 2013) The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data) (*) Data from some major manufacturers were not reported.

  28. Tenofovir alafenamide • Slightly better safety profile than TDF ( at 10 or 25mg vs 300mg). • But being tested as co-formulations • Preliminary results promising – will it simply replace TDF? Less API, less toxicity (?co-formulations – estimated availability to LMIC 2020) • TDF analogue – CHAI – 200mg vs 300mg: may be available

  29. Studies 104/111: Tenofovir Alafenamide Fumarate vs TDF in Treatment-Naive Pts • Parallel, randomized, double-blind, active-controlled phase III studies • Primary endpoint: HIV-1 RNA at Wk 48 Stratified by HIV-1 RNA, CD4+ cell count, geographic region Wk 48 Primary endpoint Wk 144 TAF/FTC/EVG/COBI* single-tablet regimen (n = 866) Treatment-naive HIV-infected pts with HIV-1 RNA ≥ 1000 copies/mL, eGFR ≥ 50 mL/min (N = 1733) TDF/FTC/EVG/COBI† single-tablet regimen (n = 867) *10/200/150/150 mg once daily. †300/200/150/150 mg once daily. Wohl DA, et al. CROI 2015. Abstract 113LB.

  30. Studies 104/111: TAF Noninferior to TDF at Week 48 • TAF also noninferior to TDF at Wk 48 in each study (104 and 111) • Results similar across all baseline virologic and demographic subgroups • 7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF • 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R • 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF • 0.9% in TAF arm and 1.5% in TDF arm discontinued due to AE • CD4+ increases greater in TAF arm: 211 vs 181 (P = .024) Δ +2.0%(95% CI: -0.7% to +4.7) 100 92 90 TAF/FTC/EVG/COBI (n = 866) 80 TDF/FTC/EVG/COBI(n = 867) 60 Pts (%) 40 20 6 4 4 4 800 784 n = 0 Virologic Success* Virologic Failure No Data *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm Discontinued for AE, death, or missing data. Wohl DA, et al. CROI 2015. Abstract 113LB. Reproduced with permission.

  31. Renal Markers With TAF and TDF at Wk 48 • Smaller decreases in eGFR with TAF[1] • Smaller changes in proteinuria with TAF[1] • In separate single-arm trial of virologically suppressed pts with eGFR 30-69 mL/min switched to open-label TAF/FTC/EVG/COBI[2] • 65% on TDF at BL • At Wk 48 after switch: • 92% maintained virologic suppression • No change in eGFR • Reduction in proteinuria and markers of renal tubular function • Improvement in hip and spine BMD TAF/FTC/EVG/COBI (n = 866)TDF/FTC/EVG/COBI (n = 867) P < .001 -6.6 Mean Δ From BL in eGFR, mL/min (Cockcroft-Gault) 20 -11.2 10 0 -10 0 12 24 36 48 -20 Time (Wks) 1. Sax P, et al. CROI 2015. Abstract 143. Reproduced with permission. 2. Pozniak A, et al. CROI 2015. Abstract 795.

  32. Studies 104/111: Significantly Smaller Decline in Hip and Spine BMD With TAF • Significantly smaller decline in hip and spine BMD with TAF • Higher lipid levels with TAF, but TC:HDL-C ratio same as TDF[1] TAF/FTC/EVG/COBI (n = 866)TDF/FTC/EVG/COBI (n = 867) 2 2 0 0 Change in Spine BMD Change in Hip BMD -2 -2 -4 -4 -6 -6 -0.66 -8 -8 -1.30 -2.86 Mean % Change From BL -2.95 P < .001 P < .001 48 24 0 0 24 48 Wk Wk n n = 845= 850 797816 784773 836848 789815 780 767 Sax P, et al. CROI 2015. Abstract 143. Reproduced with permission.

  33. What next on TDF? • d4T study will part-answer bone and renal worries; otherwise, just wait • TAF likely to replace it; TDF-CHAI 200mg • Lower doses AZT, d4T; ABC, other drugs unlikely to displace it

  34. TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Raltegravir Etravirine Darunavir

  35. Efavirenz • Daily, cheap, co-formulated, huge experience base, TB (and most everything else)-friendly • EFV side effects predictable, treatable, substitutions easy • Everyone pretty happy re teratogenicity

  36. BUT… • Increasing recognition of CNS side effects - ?Africans stoic? More nb in asymptomatics • Rash, hepatitis, gynaecomastia, lipids • ENCORE (Lancet 2013)– 400mg vs 600mg – less discontinuations, but very little change in side effects • Concerns about 400 mg dose in PMTCT and TB

  37. Depression • Efavirenz (6%) 2x higherriskforsuicidality • Rilpivirine(8%) • Elvitegravir/COBI (5%) • Raltegravir(6%) • Atazanavir/r (2%) Meta-analysis n=5332, 4 RCT For composite endpoint ‘Only’ trend for completed/attempted suicide (17 events occured) EFV EFV-free Lack ofassociationbetweenuseofefavirenzanddeathfromsuicide: evidencefromthe D:A:D study #O315 Wednesday 5 November C. Smith; L. Ryom; A. d’Arminio Monforte; P. Reiss; A. Mocroft; W. El-Sadr; R. Weber; M. Law; C. Sabin; J. Lundgren. Cohen et al., Lancet 2011; Molina et al, Lancet 2011; Elion et al., JAIDS 2013; Mollan et al, Ann Intern Med 2014

  38. Alternatives… • Integrase inhibitors • Rilprivirine

  39. What about: Dolutegravir • (raltegravir and elvitegravir expensive) • Wunderkind of the moment • 50 mg once-daily (in naïve patients) • Very good efficacy • Minimal toxicity • Pregnancy category B • Superior to EFV at 48 weeks in naïve patients– SINGLE study (compared ABC/3TC/DTG with TDF/FTC/EFV. ) – but safer, not virologically better • Potential to be low cost and coformulated Walmsley SL et al. N Engl J Med. November 2013 FDA press statement.  August 2013

  40. What is the cost if we switch from EFV to DTG? • Millions of patients will need to be switched (assuming stable patients on EFV will move, seems likely) – 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 if all you lose is side effects? • ?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?

  41. TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Raltegravir Etravirine Darunavir

  42. AZT • Toxic • ???any role for AZT in future??? • EARNEST – does it matter what the nukes are? Could we recycle TDF/FTC?

  43. TDF XTC EFV AZT XTC PI(lopinavir or atazanavir) XTC, other nukes Raltegravir Etravirine Darunavir

  44. ?: Darunavir in 2nd line • ‘Best PI’ – better side effects • If we get the dose down from 800/100… • ? 600/100 ?400/100 – lower cost, less side effects • BUT – will the virological potency be maintained? • BUT – is lopinavir all we need? EARNEST was very successful • Will we even need a second line if DTG in 1st? • Studies planned

  45. (Short term) future dream? • (photo credit John Mellors)

  46. Pill "A" to Pill "B" – two single tablet regimens? Pill "A" TDF/3TC/EFV400 $100 • Pill "B" DRV400/r/DTG $250 • Two pills, used in sequence • Simple treatment rule – task shifting • No overlapping drug resistance • Mass generic production • Low cost: $100 and $250 per person-year

  47. Pill "A" to Pill "B" – two single tablet regimens? Pill "A“TAF/FTC/DTG (275mg)TDF/3TC/EFV400 $100 • Pill "B" DRV400/r/DTG $250 • Two pills, used in sequence • Simple treatment rule – task shifting • No overlapping drug resistance • Mass generic production • Low cost: $100 and $250 per person-year Pil?/FTC/darunavir (400mg)/rit 700+?)TDF/3TC/EFV400 $100

  48. What about the children? • Granules and sprinkles – lpv/rit, raltegravir, others • Low dose d4T planned – ABC/TDF concerns

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