Understanding the unmet medical needs with current ART

Transcription

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-line regimens

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

5 Major Guidelines for Initiation of Antiretroviral Therapy Guideline AIDS or HIV-Related Symptoms CD4+ Cell Count CD4+ Cell Count 200- CD4+ Cell Count 350- < 200/mm 3 350/mm 3 500/mm 3 CD4+ Cell Count > 500 cells/mm 3 DHHS-USA, 2014 Yes Yes Yes Yes 1 Yes 2 International AIDS Society-USA, 2014 Yes Yes Yes Yes 1 Yes 2 Brazil, 2014 Yes Yes Yes Yes 1 Yes 2 European AIDS Clinical Society, 2014 British HIV Association, 2014 World Health Organization, 2014 Yes Yes Yes Consider 3 Consider 3 Yes Yes Yes Consider 3 Defer 5 Yes Yes Yes Yes 4 Defer 5 (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 SA HIV Clinicians Society 2014 SA Government, 2015 Yes Yes Yes Defer Defer Yes Yes Yes Yes Defer

6 UNAIDS Gap Report 2014 <unaids.org>

7 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

8 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

9 A widening menu of ARV use for treatment and prevention 34,000, 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 HIV+ IDU >500 HIV+ MSM > HIV+ FSW >500 Sero Discordant Couples >500 Pregnant women >500 Children HIV+ (aged 2-4) Adults HIV+/HBV+ > TB+/HIV+ >350 <350 not on ART Children in need (aged <2) - On ART (adults and children)

10 Pipeline Report

11 Think Many HIV testing programmes performing well issues such as TB and high VL less of an issue Pregnancy always an issue

12 So what we got?

13 Evolution of WHO ART Guidelines in Adults Topic When to start 1 st Line 8 options - AZT preferred 2 nd Line Boosted and non-boosted PIs CD4 200 CD4 200 CD Consider CD4 350 for TB 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDFpreferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r CD Irrespective CD4 for TB and HBV 6 options &FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r CD Irrespective CD4 for TB, HBV, PW and SDC - CD4 350 as priority 2 options & FDCs - TDF and EFV preferred across all populations Boosted PI - Heat stable FDC: ATV/r, LPV/r 3 rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No Earlier initiation Simpler treatment Less toxic, more robust regimens No (Desirable) Yes (Tertiary centers) Better monitoring Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) HIV/AIDS Department

14 Evolution of WHO ART Guidelines in Adults Topic When to start 1 st Line 8 options - AZT preferred 2 nd Line Boosted and non-boosted PIs CD4 200 CD4 200 CD Consider CD4 350 for TB 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDFpreferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r CD Irrespective CD4 for TB and HBV 6 options &FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r CD Irrespective CD4 for TB, HBV, PW and SDC - CD4 350 as priority 2 options & FDCs - TDF and EFV preferred across all populations Boosted PI - Heat stable FDC: ATV/r, LPV/r 3 rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No Earlier initiation Simpler treatment Less toxic, more robust regimens No (Desirable) Yes (Tertiary centers) Better monitoring Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) HIV/AIDS Department

15 Evolution of WHO ART Guidelines in Adults Topic When to start 1 st Line 8 options - AZT preferred 2 nd Line Boosted and non-boosted PIs CD4 200 CD4 200 CD Consider CD4 350 for TB 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDFpreferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r CD Irrespective CD4 for TB and HBV 6 options &FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r CD Irrespective CD4 for TB, HBV, PW and SDC - CD4 350 as priority 2 options & FDCs - TDF and EFV preferred across all populations Boosted PI - Heat stable FDC: ATV/r, LPV/r 3 rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No Earlier initiation Simpler treatment Less toxic, more robust regimens No (Desirable) Yes (Tertiary centers) Better monitoring Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) HIV/AIDS Department

16 Evolution of WHO ART Guidelines in Adults Topic When to start 1 st Line 8 options - AZT preferred 2 nd Line Boosted and non-boosted PIs CD4 200 CD4 200 CD Consider CD4 350 for TB 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDFpreferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r CD Irrespective CD4 for TB and HBV 6 options &FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r CD Irrespective CD4 for TB, HBV, PW and SDC - CD4 350 as priority 2 options & FDCs - TDF and EFV preferred across all populations Boosted PI - Heat stable FDC: ATV/r, LPV/r 3 rd Line None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Viral Load Testing No Earlier initiation Simpler treatment Less toxic, more robust regimens No (Desirable) Yes (Tertiary centers) Better monitoring Yes (Phase in approach) Yes (preferred for monitoring, use of PoC, DBS) HIV/AIDS Department

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

18 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)

19 $ PPPY 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 $400 $350 21% price reduction $300 $250 $200 $150 $100 $50 77% price reduction 72% price reduction $ EFV TDF ATV/r

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

21 Currently available (or near-available) coformulated antiretroviral agents and regimens Agent D4T/3TC D4T/3TC/NVP ZDV/3TC ZDV/3TC/ABC LPV/RTV ATV/RTV DTG/ABC/3TC ABC/3TC TDF/XTC TDF/XTC/EFV TDF/FTC/RPV TDF/FTC/EVG/COBI Regimen Dual NRTI NNRTI + dual NRTI Dual NRTI Triple NRTI Boosted PI Boosted PI INSTI + dual NNRTI Dual NRTI Dual NRTI NNRTI + dual NRTI NNRTI + dual NRTI Dual NRTI + INSTI + booster 21

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

23 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

24 WHO Guidelines: 2013 Update Recommended Regimens NNRTI based EFV + (TDF/FTC or AZT/3TC) Alternative Regimens NNRTI based NVP + (TDF/FTC or AZT/3TC) 2013 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. WHO; 2013 June. 24

25 Changes in D4T, AZT & TDF use ( ) Between 2 to 4 million people using AZT containing regimen in WHO AMDS database, /15/2018 (preliminary data) 25

26 Now add PrEP TDF

27 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) Major parameters TDF EFV Number of API producers in API production capacity in 2012 (in metric tons)* >1,500 >2,210 Estimated number of patients using regimens containing the API in end of 2012 Number of patients that could be treated in end of ,500,000 3,700,000 >13,800,000 >10,000,000 (*) Data from some major manufacturers were not reported. The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data)

28 Major parameters Number of API producers in 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) TDF EFV API production capacity in 2012 (in metric tons)* >1,500 >2,210 Estimated number of patients using regimens containing the API in end of 2012 Number of patients that could be treated in end of 2012 Concern: API may become a huge problem if 20 by 20 AND PrEP come into play 3,500,000 3,700,000 >13,800,000 >10,000,000 (*) Data from some major manufacturers were not reported. The manufacturers also mentioned that they are all in the process of increasing capacity. WHO HIV/AMDS, 2014 (preliminary data)

29 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 (?coformulations estimated availability to LMIC 2020) TDF analogue CHAI 200mg vs 300mg: may be available

30 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 Treatment-naive HIV-infected pts with HIV-1 RNA 1000 copies/ml, egfr 50 ml/min (N = 1733) *10/200/150/150 mg once daily. 300/200/150/150 mg once daily. TAF/FTC/EVG/COBI* single-tablet regimen (n = 866) TDF/FTC/EVG/COBI single-tablet regimen (n = 867) Wohl DA, et al. CROI Abstract 113LB.

31 Pts (%) Studies 104/111: TAF Noninferior to Δ +2.0% (95% CI: -0.7% to +4.7) n = Virologic Success* Virologic Failure TDF at Week 48 TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) 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 Abstract 113LB. Reproduced with permission. 6 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)

32 Mean Δ From BL in egfr, ml/min (Cockcroft-Gault) Renal Markers With TAF and TDF at Wk Smaller decreases in egfr with TAF [1] P < TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) In separate single-arm trial of virologically suppressed pts with egfr ml/min switched to open-label TAF/FTC/EVG/COBI [2] 65% on TDF at BL At Wk 48 after switch: Smaller changes in proteinuria with TAF [1] Marker Time (Wks) Median % Change From BL in Urine Protein:Creatinine Ratio TAF (n = 866) TDF (n = 867) P Value Protein <.001 Albumin <.001 Retinol-binding protein <.001 β 2 -microglobulin < % maintained virologic suppression No change in egfr Reduction in proteinuria and markers of renal tubular function Improvement in hip and spine BMD 1. Sax P, et al. CROI Abstract 143. Reproduced with permission. 2. Pozniak A, et al. CROI Abstract 795.

33 Mean % Change From BL Studies 104/111: Significantly Smaller Decline in Hip and Spine BMD With TAF Significantly smaller decline in hip and spine BMD with TAF TAF/FTC/EVG/COBI (n = 866) TDF/FTC/EVG/COBI (n = 867) Change in Spine BMD Higher lipid levels with TAF, but TC:HDL-C ratio same as TDF [1] n n = 845 = 850 Wk P < Change in Hip BMD Wk P < Sax P, et al. CROI Abstract 143. Reproduced with permission.

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35 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

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

37 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

38 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

39 Depression Meta-analysis n=5332, 4 RCT Efavirenz (6%) 2x higher risk for suicidality Rilpivirine (8%) Elvitegravir/COBI (5%) Raltegravir (6%) Atazanavir/r (2%) For composite endpoint Only trend for completed/attempted suicide (17 events occured) EFV EFV-free Lack of association between use of efavirenz and death from suicide: evidence from the 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

40 Alternatives Integrase inhibitors Rilprivirine

41 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

42 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?

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

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

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

46 ?: Darunavir in 2 nd 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 1 st? Studies planned

47 (Short term) future dream? (photo credit John Mellors)

48 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

49 Pill "A" to Pill "B" two single tablet regimens? Pill "A TAF/FTC/DTG (275mg) TDF/3TC/EFV400 $100 Pil?/FTC/darunavir (400mg)/rit 700+?) Pill "B" DRV400/r/DTG $250 TDF/3TC/EFV400 $100 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

50 What about the children? Granules and sprinkles lpv/rit, raltegravir, others Low dose d4t planned ABC/TDF concerns

51 Conclusions New drugs likely to be in play in our area EFV 600mg -?if will be displaced

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