Efficacy of initial combination antiretroviral therapy for HIV-1: a meta-analysis

1. Efficacy of initial combination antiretroviral therapy for HIV-1:a meta-analysis Frederick J. Lee1, Janaki Amin2, Andrew Carr1 Centre for Applied Medical Research, St Vincent’s Hospital 1 Kirby Institute, University of New South Wales 2 Sydney, Australia 7th IAS Conference on HIV Pathogenesis, Treatment & Infection July 2013, Kuala Lumpur, Malaysia

2. Background Overview • Initial antiretroviral therapy (ART) • ‘backbone’ (2 NRTIs) + third drug (NNRTI / rPI / INSTI) • DHHS guidelines: when to start • mostly driven by CD4 count / clinical stage • HIV viral load not a criterion since 2007 • DHHS guidelines: what to start • ‘Preferred’ &‘Alternative’ regimens • current ‘Preferred’ regimens: • TDF-FTC/3TC + EFV / rDRV / rAZV / RAL

3. Background Overview • Guidelines based on serial assessment of individual trials • Systematic review / meta-analysis • more patients / regimens, so more power to • evaluate subpopulations • identify predictors of ART success • Limitations of previous ART meta-analyses • only some regimens • short follow-up durations • more recent studies: • new drugs / studies • longer follow-up

4. Objectives Primary and secondary • Primary = overall efficacy • determined by undetectable viral load • all studies over maximum follow-up period • Secondary • efficacy over time • 48, 96, & 144 weeks • efficacy by 2012 DHHS guidelines • ‘Preferred’ vs. ‘Alternative’ ART • efficacy by baseline viral load • ≥100,000 vs. <100,000 copies/mL • predictors of efficacy and of failure

5. Methods Study selection • Inclusion criteria • treatment-naïve, HIV-1+ adults • prospective design • ≥48 weeks duration • intent-to-treat (ITT) efficacy analysis • Exclusion criteria • retrospective or cross-sectional design • combinations not recommended for toxicity/poor efficacy (e.g. monotherapy) • directly observed therapy

6. Methods Data sources • Databases sourced (to Dec 31, 2012) • MEDLINE • clinical trial registries (Cochrane, NIH, ISRCT) • conference abstracts & presentations (CROI, IAS, ICAAC, Glasgow) • product labels & medical reviews (FDA, EMA) • study synopses from manufacturers • Manufacturers approached for missing data, kindly provided by: • BMS, Gilead, MSD, ViiV Healthcare

7. Methods Data collection • Database construction • study characteristics • eligibility criteria • participant & disease characteristics • ART characteristics

8. Methods Statistics • Descriptive • unit of analysis = treatment group • variables expressed as • percentage • mean, weighted for group size • Predictive • linear regression approach • multivariable • backwards, step-wise variable selection • Analyses performed using STATA (v.11) • parameters not displayed if not significant or not of particular interest

9. Study characteristics

10. Study characteristics

11. Participant characteristics

12. ART characteristics Dosing

13. ART characteristics Key NRTI backbones & third drug classes

14. Efficacy All studies

15. Efficacy All studies

16. Efficacy: all studies from 1994 to 2010

17. Efficacy Predictors (all studies): NRTI backbone r2,NRTI backbone type = 35.3%

18. Efficacy Predictors (all studies): third drug class r2, third drug class = 43.0%

19. Efficacy Predictors (all studies): study design

20. Efficacy By pre-treatment viral load Mean difference for <100,000 vs. ≥100,000 subgroups = 8.4% (95% CI 6.0 to 10.9), p<0.001

21. Efficacy Predictors (all studies): viral load ≥100,000

22. Efficacy By DHHS regimen Mean difference for ‘Preferred’ vs. ‘Alternative’ regimens = 10% (95% CI 7.6 to 15.4), p<0.001

23. Efficacy By DHHS regimen

24. Efficacy By DHHS regimen Similar efficacy across DHHS-’Preferred’ regimens, although trend to superior efficacy with raltegravir

25. Participant decision (11%) Cessation less likely in industry-sponsored studies Adverse events (8%) Cessation less likely in industry-sponsored and phase 2 studies Cessation: all studies, 1994 to 2010 (overall cessation 25%)

26. Conclusions • Overall mean efficacy of initial ART is low • only 60% over 82 weeks • higher with ‘Preferred’ regimens (75% over 99 weeks) • Treatment determinants of greater success • TDF-FTC (vs. ABC-3TC) • INSTI (vs. NNRTI or boosted PI) - including when pre-treatment viral load ≥100,000 cp/mL • Suboptimal efficacy • most patients will interrupt initial ART • TDF-FTC + INSTI efficacy 81% when pre-treatment viral load ≥100,000 cp/mL • need for study of 3 vs. 4 drugs?

27. Conclusions • Ongoing loss in efficacy over time • participant decision > adverse events >> virological failure • Significant 8.4% difference in efficacy between higher & lower viral load groups • similar to 10% difference between ‘Preferred’ & ‘Alternative’ DHHS regimens • guidelines should recommend initiating ART before viral load reaches 100,000 cp/mL • Despite focus on co-formulation, fewer daily pills & doses not independent predictors of overall efficacy

28. Limitations • Groups the base unit, not individuals • Only some unpublished data available, mostly from industry-sponsored studies • Efficacy by viral load not randomised • No analysis of: • individual drugs within third drug class e.g. NVP vs. EFV; rLPV vs. other PI • clinical outcomes or resistance • Multivariable method of analysis • clinically irrelevant associations may emerge, relevant associations missed • dependent upon data completeness

29. Acknowledgements • Data: Fraser Drummond (ViiV) Silke Schweizer (BMS) Carolee Welebob (MSD) Howard Wraight (Gilead) Rebekah Puls, Kathy Petoumenos (UNSW) • Funding: NHMRC of Australia (FJL) • Potential conflicts of interest (AC) • research funding - Baxter, Gilead, MSD, Pfizer • consultancies - Gilead, MSD, ViiV • lectures - Gilead, MSD, Serono, ViiV • advisory boards - Gilead, MSD, ViiV