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

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

3. New drugs and strategies treatment strategies new drugs

4. New drugs New drugs and strategies Why do we need new drugs? overcome resistance reduce toxicity especially metabolic complications improve adherence diversify options with new and existing classes especially drug interactions SMART study implies that once initiated long-term therapy is required coformulation

5. New drugs New drugs and strategies Approved antiretroviral drugs 2010 FEI N(t)RTINNRTIInSTIPI ENF AZTEFVRALSQV MVC ddINVPIDV d4TETVLPV 3TCATV ABCfAPV TDFDRV FTC

6. New drugs New drugs and strategies Fusion inhibitors FEI ENF 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

7. New drugs New drugs and strategies 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 FEI MVC

8. New drugs New drugs and strategies TBR-652: antiviral response with 10 days monotherapy median VL Response 10 day dosing HIV-1 RNA change from baseline (log10 copies/ml) nadir VL response note: CCR2 inhibition observed using MCP-1 level increases Cohen et al, CROI 17, 2010

9. New drugs New drugs and strategies 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 NRTI AZT ddI d4T 3TC ABC TDF FTC

10. New drugs New drugs and strategies 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 NRTI AZT ddI d4T 3TC ABC TDF FTC

11. New drugs New drugs and strategies drugcompanyphasestatusreported toxicity elvucitabineAchillon Pharmaceuticals IIongoing?myelosuppression, rash, mild headache, gastrointestinal distress dexelvucitabine (Reverset) PharmassetIIunder review after termination due to safety concerns 40% increase of elevated lipase apricitabineAvexaIIIterminated for commercial reasons nasal congestion, myalgia, low level lipase changes amdoxovirRFS PharmaIIongoingeye problems (lenticular opacities) DOTUniversity of Georgia Iongoing?none reported fozivudineHeidelberg- Pharma IIongoing? MIV-210GSK/MedivirIongoing? racivirPharmassetI/IIongoingnone reported KP-1461KoronisIIterminated due to disappointing results N(t)RTIs in development: the pipeline

12. New drugs New drugs and strategies open label ATC 800mg bd open label ATC 800mg bd open label ATC 800mg bd AVX-201 phase 2b: design 3TC 150mg bd ATC 800mg bd OBR - no 3TC or FTC ATC 600mg bd D0 D21 W24 W48 functional monotherapy optimise background change in viral load day 21 failing 3TC/FTC VL>2000 c/mL M184VCD4>50

13. New drugs New drugs and strategies time weighted average log 10 change in HIV RNA (per protocol population) ATC AVX-201 phase 2b: virologic response Poster #793, CROI 2008 071421 primary endpoint P<0.005 both doses 600mg ATC 800mg ATC 300mg 3TC -2.0 -1.8 -1.6 -1.4 -1.2 -0.8 -0.6 -0.4 -0.2 0 4 8 12 16 2024 week day

14. New drugs New drugs and strategies 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 N(t)RTI AZT ddI d4T 3TC ABC TDF FTC

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

16. New drugs New drugs and strategies RPV 25mg qd (n=93) RPV 75mg qd (n=95) RPV 150mg qd (n=91) EFV 600mg qd (n=89) Rilpivirine C-204: virologic response (TLOVR) 100 80 60 40 20 0 024812162024324048 weeks virologic responders (%, 95% CI) CI = confidence interval primary efficacy endpoint ITT population (NC=F) 81% 80% 77% 81% Pozniak et al, CROI 2007

17. New drugs New drugs and strategies 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 RAL (EVG)

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

19. New drugs New drugs and strategies Gilead Quad: small increases in serum creatinine affected estimated GFR (Cockcroft-Gault) Quad n=48 EFV/FTC/TDF n=23 GS-9350 n=50 RTV n=29 ∆ mean serum creatinine baseline to week 24 +0.14 mg/dL+0.04 mg/dL+0.18 mg/dL+0.14 mg/dL ∆ mean eGFR* baseline to week 24 -18 mL/min-7 mL/min-15 mL/min-14 mL/min mean eGFR* at week 24111 mL/min126 mL/min102 mL/min111 mL/min * estimated GFR by Cockcroft-Gault

20. New drugs New drugs and strategies S/GSK1349572: next generation integrase inhibitor once daily, unboosted INI in clinical development 1 low PK variability and predictable exposure- response relationship with a low mg dose 2,3 excellent antiviral activity in a phase 2a study 1 favourable in vitro resistance profile with potential for higher genetic barrier to resistance 4,5,6 1 Lalezari et 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 mean change from baseline in HIV-1 RNA (log 10 copies/mL) dosing periodfollow-up period -2.5 -2.0 -1.5 -0.5 0.0 0.5 21 (BL) 3478910111421 (FU) day 2 mg 10 mg 50 mg placebo

21. New drugs New drugs and strategies 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 PI SQV IDV LPV ATV fAPV DRV

22. New drugs New drugs and strategies ARTEMIS: efficacy (ITT-TLOVR)* Estimated difference in response versus LPV/r for non-inferiority: PP = 8.4% (95% CI: 1.9–14.8) p<0.001 Estimated difference in response versus LPV/r for superiority: ITT = 8.3% (95% CI: 1.8–14.7) p=0.012 patients with VL<50 copies/mL (% [±SE]) * estimated from a logistic regression model including treatment and stratification factors (baseline log 10 viral load and baseline CD4+ cell count) Mills et al, 48th ICAAC/46th IDSA 2008

23. New drugs New drugs and strategies Why do we need new Rx paradigms? toxicitydrug class bone / kidneyNRTI (TDF) CNSNNRTI cardiovascularPI, NRTI lipodystrophyNRTI, PI metabolic disordersPI reasons to seek RTI and PI sparing strategies

24. New drugs and strategies treatment strategies new drugs

25. New drugs and strategies Guidelines 2009: when to start therapy? symptomatic HIV disease ARV recommended for all patients asymptomatic HIV disease decision based on CD4 cell count CD4 count (cells/µL) ARV recommendation <350ARV recommended >350 – <500ARV generally deferred >500ARV generally not recommended DHSS, IAS-USA, BHIVA guidelines 2009

26. New drugs and strategies NA-ACCORD: inverse probability weighted Cox regression multivariate analysis *stratified by cohort and year relative hazard (RH)* 95% confidence interval P-value deferral of HAART at 351-5001.71.4, 2.1<0.001 female sex1.10.9, 1.50.290 older age (per 10 years)1.61.5, 1.8<0.001 baseline CD4+ count (per 100 cells/µL) 0.90.7, 1.00.083 results were similar when restricting the analysis to the 77% of participants with baseline HIV RNA data adjusted RH for deferral vs immediate treatment was also 1.7 95% C.I. 1.4, 2.2; p <0.0001 HIV RNA was not an independent predictor of mortality

27. New drugs and strategies NA-ACCORD: multivariate analysis *stratified by cohort and calendar year relative hazard (RH)* 95% confidence interval P-value deferral of HAART at >5001.61.3, 1.9<0.001 female sex1.20.9, 1.60.117 older age (per 10 years)1.61.5, 1.7<0.001 baseline CD4 count (per 100 cells/µL) 1.01.0, 1.10.696 HIV RNA was not an independent predictor of mortality Increased risk of mortality with deferral was similar throughout the 10 year study period Kitahata et al, CROI 2009

28. New drugs and strategies ART-CC: estimated hazard ratios for AIDS or death comparison of starting ART in a higher CD4 range versus deferring to a lower CD4 range higher CD4 rangelower CD4 rangehazard ratio (95% CI) 451-550351-4500.99 (0.76-1.29) 426-525326-4251.12 (0.87-1.43) 401-500301-4001.09 (0.85-1.38) 376-475276-3751.19 (0.96-1.47) 351-450251-3501.28 (1.04-1.57) 326-425226-3251.21 (1.01-1.46) 301-400201-3001.34 (1.12-1.61) delaying ART to <350 cells/µL is associated with an increased risk of AIDS and death Sterne et al CROI 2009

29. New drugs and strategies ART CC and NA ACCORD: mortality results from the two studies do not give a consistent picture comparison HR for death NA ACCORD n=8,362 350-500 vs < 350 1.69 (1.26 - 2.26) n=9,155 > 500 vs 350-500 1.94 (1.37 – 2.79) ART CC n=16,446350-450 vs 250-350 1.13 (0.80 - 1.60) n=10,065450-550 vs 350-450 0.93 (0.60 - 1.44)

30. Treatment strategies New drugs and strategies START: design patients with CD4+ >500 cells/µL randomise deferred ART when CD4+ declines to 350 cells/µL n=2,000 early ART start immediately following randomisation n=2,000 5 years average follow-up check recruitment feasibility of 900 patients in one year

31. Treatment strategies New drugs and strategies Why early treatment should be studied treatment reduces markers of systemic inflammation and immune activation treatment reduces non-AIDS-related complications – all of them increasing due to an aging HIV population cardiovascular disease malignancies hepatic disease renal disease treatment more effective and better tolerated now than in years past treatment reduces risk of transmission to others however, treatment may also increase the risk of transmitted resistance a randomised study of early versus deferred therapy must be done

32. Treatment strategies New drugs and strategies START: implications of showing a benefit this is one of the key remaining major strategic questions in HIV therapy if a benefit of early ART can be demonstrated it will guide management for so long as ART is used to treat HIV the findings will be applicable for hundreds of thousands of ART-naïve people with HIV currently in well-resourced settings, and for many millions worldwide in the future by reducing the size of the infectious pool, very early ART use would be likely to reduce the number of new HIV transmissions

33. Treatment strategies New drugs and strategies DHHS 2009: guidelines the evidence for second-line ART after failure of first-line ART is ‘insufficient’ there are no RCTs 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

34. Treatment strategies New drugs and strategies 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

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

36. Treatment strategies New drugs and strategies Guidelines: limitations 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 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

37. Treatment strategies New drugs and strategies 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:

38. Treatment strategies New drugs and strategies EARNEST: trial design 1200 eligible patients randomise bPI + 2 NRTI (NRTIs according to local standard of care) bPI + RAL (12 week induction) 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/µL at wk 96 and  VL < 10,000 copies/ml or  VL >10,000 copies/ml with no PI resistance mutations (wk 96)

39. Treatment strategies New drugs and strategies 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