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 & InfectionJuly 2013, Kuala Lumpur, Malaysia
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
BackgroundOverview
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
BackgroundOverview
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
ObjectivesPrimary and secondary
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
MethodsStudy selection
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
MethodsData sources
Database construction− study characteristics− eligibility criteria− participant & disease characteristics− ART characteristics
MethodsData collection
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
MethodsStatistics
Characteristics
Groups(n=216)
Participants(n=40,124)
Mean,%
Randomised yes 196 36,534 91.1Placebo yes 68 17,630 43.9Phase 2 50 4,386 10.9 3 96 26,325 65.6 4 70 9,413 23.5Sponsorship academic 55 10,681 26.6 industry 123 26,547 66.2 both 38 2,896 7.2Year commenced
pre-1996 10 641 1.61997-1999 53 8,108 20.2
2000-2002 43 9,331 23.3 2003-2005 61 13,062 32.6 2006-2008 31 6,597 16.4 2009-2010 17 2,346 5.8
Study characteristics
Characteristics
Groups(n=216)
Participants(n=40,124)
Mean,%
Eligibility restrictions
viral load 184 33,915 84.5ALT / AST 173 31,536 78.6haemoglobin 133 24,224 60.4CD4 count 122 19,428 48.4genotype 62 12,563 31.3AIDS (CDC C) 11 1,436 3.6prior IDU 5 223 0.6
Duration (weeks)
48 131 20,165 50.396 60 11,629 29.0144 25 8,330 20.8
Efficacy analysis
ITT M=F 62 7,127 17.8ITT NC=F 84 13,676 34.1
TLOVR 70 19,321 48.2
Study characteristics
Characteristic Mean (SD)
Age 37 (2)Sex men 76% (15)Race white 65% (17)
black 27% (17)
Risk factors MSM 52% (19)heterosexual 38% (15)IDU 10% (9)
Previous AIDS 12% (13)CD4 count 248 (81)HIV RNA log10cp/mL 4.9 (0.2)
≥100,000 cp/mL 43% (11)
Hepatitis C 10% (9)
Participant characteristics
Characteristics Groups,n
Participants, n
Mean,%
Pills per day, mean (SD) 216 40,124 6.3 (3.6)
Doses per day, mean (SD) 216 40,124 2.0 (0.7)
Dosing with food, % fasting only 59 9,754 24.3 fasting + food 22 5,108 12.7 food only 65 11,947 29.8 no restriction 70 13,315 33.2
ART characteristicsDosing
Groups, n
Participants, n
Mean,%
NRTI backbonesAZT-3TC 56 10,832 27.0TDF-FTC 45 10,123 25.2d4T-3TC 27 3,988 9.9ABC-3TC 26 5,516 13.7d4T-ddI 20 2,349 5.9TDF-3TC 9 1,970 4.9Third drug classesNNRTI 94 19,512 48.6PI (boosted) 56 9,724 24.2PI (unboosted) 38 5,686 14.2NRTI 12 1,771 4.4INSTI 9 2,150 5.4
ART characteristicsKey NRTI backbones & third drug classes
EfficacyAll studies
All
studies
Follow-up, weeks
48 96 144
Groups, n 216 216 85 25Participants, n 40,124 40,124 19,959 8,330Follow-up, weeks (SD) 82 (38) 48 96 144ART efficacy, % (SD) 60 (16) 66 (16) 60 (16) 52 (18)
EfficacyAll studies
All
studies
Follow-up, weeks
48 96 144
Groups, n 216 216 85 25Participants, n 40,124 40,124 19,959 8,330Follow-up, weeks (SD) 82 (38) 48 96 144ART efficacy, % (SD) 60 (16) 66 (16) 60 (16) 52 (18)
ART cessation, % (SD) 25 (11) 20 (9) 28 (11) 34 (10)
adverse events 8.1 6.9 7.5 10 patient decision 11 8.5 14 15 virological failure 3.5 2.4 4.8 4.4 other 4.7 3.3 6.4 8.3
Efficacy: all studies from 1994 to 2010
EfficacyPredictors (all studies): NRTI backbone
Efficacy,%, (SD)
Multivariable analysis Coeff 95% CI p p group
TDF-FTC 73 (10) Ref ABC-3TC 63 (7) -7.6 -12.7, -2.6 0.003 AZT-3TC 48 (15) -13.3 -18.0, -8.5 <0.001ddI-FTC 78 (-) 7.9 -11.6, 27.4 0.426TDF-3TC 69 (5) -1.2 -8.5, 6.2 0.758 ddI-3TC 65 (8) -7.9 -16.6, 0.8 0.075d4T-3TC 55 (12) -11.4 -16.8, -5.9 <0.001 d4T-ddI 44 (13) -18.4 -24.9, -12.0 <0.001 AZT-ddI 42 (4) -35.3 -51.9, -18.7 <0.001 <0.001
r2,NRTI backbone type = 35.3%
EfficacyPredictors (all studies): third drug class
Efficacy,%, (SD)
Multivariable analysis
Coeff 95% CI p p group
NNRTI 61 (15) Ref INSTI 84 (5) 11.9 4.6, 19.2 0.002 PI (boosted) 67 (9) -0.9 -4.7, 3.0 0.660 NRTI 51 (12) -10.7 -17.4, -4.1 0.002 PI (unboosted) 42 (11) -15.0 -19.4, -10.6 <0.001 r2, third drug class = 43.0%
EfficacyPredictors (all studies): study design
Efficacy,
% (SD)r2
(%)
Multivariable analysis
Coeff 95% CI p p group
Study phase
2 64 (15) 3 62 (16)
4 54 (16) 3.8 Analysis ITT M=F 53 (17) Ref ITT NC=F 59 (15) -6.4 -10.1, -2.7 0.001 TLOVR 64 (15) 2.1 -7.5 -11.5, -3.6 <0.001 <0.001Eligibility restriction Genotype yes 72 (10) no 55 (15) 21.7 CD4 yes 54 (18) no 66 (11) 6.2 Treatment Pills / day 19.2 Doses / day 22.3
EfficacyBy pre-treatment viral load
All studies
Pre-treatment viral load
<100,000 ≥100,000
Groups, n 216 98
Participants, n 40,124 13,184 9,694
Follow-up, weeks (SD) 82 (38) 81 (36)
ART efficacy, % (SD) 60 (16) 70 (15) 62 (15)
ART cessation, % (SD) 25 (11) no data
Mean difference for <100,000 vs. ≥100,000 subgroups = 8.4% (95% CI 6.0 to 10.9), p<0.001
EfficacyPredictors (all studies): viral load ≥100,000
Efficacy, % (SD)
r2 (%)
Multivariable analysis
Coeff 95% CI p p group
Placebo yes 67 (13) Ref no 57 (15) 7.9 -6.3 -12.0, -0.5 0.034 0.034Pills per day 24.0 -1.8 -2.8, -0.8 <0.001 <0.001Third drug class
NNRTI 64 (11) Ref INSTI 81 (5) 14.5 4.5, 24.4 0.005PI (boosted) 65 (11) 6.5 0.2, 12.8 0.042 NRTI 43 (17) -20.0 -29.1, -
10.8 <0.001 PI (unboosted) 43 (11) -10.0 -19.9, -0.2 0.045
EfficacyBy DHHS regimen
Mean difference for ‘Preferred’ vs. ‘Alternative’ regimens = 10% (95% CI 7.6 to 15.4), p<0.001
DHHS recommendation‘Preferred’ ‘Alternative’ other
Groups, n 27 36 153Participants, n 5,677 8,556 25,891Follow-up, weeks (SD) 99 (41) 86 (35) 77 (37)ART efficacy, % (SD) 75 (8) 65 (7) 55 (17)
EfficacyBy DHHS regimen
DHHS recommendation‘Preferred’ ‘Alternative’ other
Groups, n 27 36 153Participants, n 5,677 8,556 25,891Follow-up, weeks (SD) 99 (41) 86 (35) 77 (37)ART efficacy, % (SD) 75 (8) 65 (7) 55 (17)ART cessation, % (SD) 20 (8) 25 (8) 27 (12) adverse events 5.3 7.3 9.0 patient decision 9.0 11.0 11.0 virological failure 3.6 2.8 3.7 other 3.4 4.5 5.0
EfficacyBy DHHS regimen
TDF-FTC/3TC plus
Groups, n
Participants, n
Follow-up, weeks
Efficacy, % (SD)
EFV 14 2,729 108 72 (8)
rAZV 9 1,776 87 75 (7)
rDRV 1 343 96 79 (-)
RAL 3 829 99 82 (8)
Similar efficacy across DHHS-’Preferred’ regimens, although trend to superior efficacy with raltegravir
Cessation less likely in industry-sponsored studies
Cessation less likely in industry-sponsored and phase 2 studies
Cessation: all studies, 1994 to 2010(overall cessation 25%)
Adverse events (8%)
Participant decision (11%)
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?
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
Conclusions
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
Limitations
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
Acknowledgements