New drugs and treatment strategies

1. New drugs andtreatment strategies David A Cooper National Centre in HIV Epidemiology and Clinical Research The University of New South Wales Sydney, Australia

2. IAS Accountability. Right Here, Right Now… Where is Robin?

3. new drugs treatment strategies

4. Approved antiretroviral drugs 2010

5. Fusion inhibitors • use declining because of emergence of new classes • patients and providers have abandoned injections • development of unmet needs put on hold • will remain an option for deep salvage

6. Choice of FEI 2010-2014 • initial therapy may be best place for the class given high prevalence of R5 virus in naives • tropism assay in viraemic patients required for us • genotypic methods should replace tropism testing in aviraemic patients • reassuring data on safety for D/M or X4 virus • immunomodulatory effects should be explored including long-term effects of blocking a cellular receptor

7. N(t)RTIs first class of antiretroviral drugs strong evidence base activity ranges from 0.3 log to 1.7 log - less so in treatment experienced patients cross resistance can be a problem - TAMs, 69SS insert, Q151M, K65R they reduce viral fitness (3TC/TDF) - used even when treating multiresistant virus

8. Choice of N(t)RTIs 2010-2014 • N(t)RTI FDCs will remain the backbones of choice for several years • low potential for TFV renal and bone toxicity but will require long-term surveillance • implementation of HLAB5701 testing has allayed concerns about ABC hypersensitivity • concern about potency of ABC containing regimens and cardiovascular risk • use of TANRTIs will decrease but will be useful for NRTI second line

9. N(t)RTIs in development: the pipeline

10. ATC AVX-201 phase 2b: virologic response day week 16 20 24 12 4 8 0 -0.2 -0.4 -0.6 -0.8 -1.0 -1.2 300mg 3TC -1.4 -1.6 600mg ATC -1.8 800mg ATC -2.0 primary endpoint P<0.005 both doses time weighted average log10 change in HIV RNA (per protocol population) Poster #793, CROI 2008

11. Future role of N(t)RTI’s class has been the backbone of therapy for 20 years only three drugs TDF and FTC/3TC are preferred options mitochondrial toxicity and its variations are hard to overcome do we need to cover M184V and K65R given new classes? pipeline is partially active but no blockbuster in sight unless safer members of the class are developed, the future of the class is uncertain

12. Choice of NNRTI’s 2010-2014 • NVP can't be used above CD4+ count thresholds and rash/hepatitis is problematic EFV EFV containing regimens have never been beaten, but EFV is category D and CNS side-effects are sometimes problematic • RPV is equivalent to EFV in phase 3 so may be an alternative qdcoformulated regimen • QD FDC’s have become initial therapy of choice

13. Choice of integrase STI’s 2010-2014 anchor drug for treatment naive and experienced patients safety profile so far excellent bid dosing but qd being investiagted choice of InSTI with or without pharmacoenhancement resistance profile will need further exploration possibility of novel dual therapy class-sparing regimens to avoid RTI or PI toxicity

14. Gilead Quad: primary endpoint (ITT M=F) % with HIV RNA <50 copies/mL week 24 stratum-weighted difference +5% (95% CI: -11.0% to 21.1%)

15. once daily, unboosted INI in clinical development1 low PK variability and predictable exposure-response relationship with a low mg dose2,3 excellent antiviral activity in a phase 2a study1 favourable in vitro resistance profile with potential for higher genetic barrier to resistance4,5,6 S/GSK1349572: next generation integrase inhibitor dosing period follow-up period 0.5 0.0 mean change from baseline in HIV-1 RNA (log10 copies/mL) -0.5 -1.0 -1.5 -2.0 2 mg 10 mg -2.5 50 mg placebo 2 1(BL) 3 4 7 8 9 10 11 14 21(FU) day 1 Lalezariet al, IAS 2009; 2 Min et al, IAS 2009 3 Song et a, IAS 2009; 4 Sato et al, IAS 2009 5 Underwood et al, IAS 2009; 6 Seki et al, CROI 2010

16. Choice of PI’s 2010-2014 • ATV/r, DRV/r are preferred choices • LPV/r coformulation is an important option • difficult to develop resistance to boosted PI’s • alternatives for ritonavir boosting are in development • metabolic toxicity and drug interactions will remain problematic • unboosted ATV and fAPV have a role in those unable to use ritonavir • pipeline is dry

17. Why do we need new Rx paradigms? reasons to seek RTI and PI sparing strategies

18. new drugs treatment strategies

19. DHHS 2009: guidelines the evidence for second-line ART after failure of first-line ART is ‘insufficient’ there are noRCTs that address the topic Cochrane review; October 2007* DHHS guidelines for management of all failing patients recommends: expert advice adding at least 2 (and preferably 3) fully active agents to an OBR aiming for HIV RNA <50 copies/ml *Cochrane Database of Systematic Reviews 2007, Issue 4. Art. No. CD006517

20. WHO 2009: second line ART • a boosted protease inhibitor plus two nucleoside analogues are recommended for second-line ART (strong recommendation, moderate quality of evidence) • ¨ATV/r and LPV/r are the preferred boosted PI's for second line ART (strong recommendation, moderate quality of evidence) • simplification of second NRTI options is recommended • if d4T or AZT has been used in first-line use TDF+3TC or FTC as the NRTI backbone in second-line • if TDF has been used in first-line use AZT+3TC as the NRTI backbone in second-line (strong recommendation, moderate quality of evidence) The panel placed high value on using simpler second-line regimens and the availability of heat-stable, fixed-dose combinations

21. Patients virologically failing first line cART in RLS often continue the failing regimen for long periods Why? Guidelines: limitations • receive clinical ± immunological monitoring only • clinical or immunological failure may lag virological failure by years • boosted-PIs often not available • drug interruption not recommended

22. many patients switching to second line cART in resource-limited settings will have NNRTI mutations numerous NRTI mutations ≥ 3 NAMs will compromise all future NRTI activity Guidelines: limitations • in this situation patients may be effectively receiving boosted-PI monotherapy • as well as unnecessary toxicity from NRTIs • third line cART is highly unlikely for public sector funding

23. Second line: trial description A randomised, international, multi-centre, open label, non-inferiority trial to compare the safety and efficacy of LPV/r 400mg bid + 2-3N(t)RTI’s versus LPV/r 400mg bid + raltegravir bid 400 mg bid in patients virologically failing first line NNRTI+2N(t)RTIs:

24. EARNEST: trial design 1200 eligible patients randomise bPI + RAL (12 week induction) bPI + 2 NRTI (NRTIs according to local standard of care) bPI + RAL bPI (monotherapy) follow-up for 144 weeks • primary outcome: • good HIV disease control – defined as: • no new WHO Stage 4 events during clinical trial • CD4 cell count > 250 cells/µLat wk 96 and • VL < 10,000 copies/ml or • VL >10,000 copies/ml with no PI resistance mutations (wk 96)

25. optimal second line cART is poorly informed by high quality evidence a relevant question for high, middle and low income countries an opportunity to explore the use of RAL plus a boosted-PI in properly powered international RCT’s an opportunity to test a strategy of using 2 new classes in second-line therapy potentially of major importance for LMIC the importance of the question to LMIC is made more urgent by increasing numbers of patients failing first-line cART a potential looming disaster a genuine threat to the progress of efforts to promote universal access to HIV care Second line therapy