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Long-Term Clinical and Immunologic Outcomes Are Similar in HIV-Infected Persons Randomized
to NNRTI versus PI versus NNRTI+PI-based Antiretroviral Regimens as Initial Therapy:
Results of the CPCRA 058 FIRST Study
MacArthur RD, Novak RM, Peng G, Chen L, Xiang Y, Huppler Hullsiek K, Kozal MJ, van den Berg-Wolf M,
Henely C, Schmetter B, Dehlinger M for the CPCRA 058 Study Team and the Terry Beirn Community Programs for
Clinical Research on AIDS
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Introduction and Rationale
• Long-term data from randomized trials on the consequences of initiating therapy with a protease inhibitor (PI), non-nucleoside reverse transcriptase inhibitor (NNRTI), or both (PI + NNRTI) are lacking.
• FIRST, ACTG 3841, and INITIO2 all were initiated between 1998-1999 to compare these 3 strategies.
• Unlike ACTG 384 and INITIO, FIRST was designed exclusively as a treatment strategy trial, without specifying which antiretroviral regimens were to be used within each strategy.
1Shafer RW et al; N Engl J Med 2003;349:2304-152INITIO Trial International Co-ordinating Committee; Lancet 2006;368:287-98
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Target Population
• ART naïve persons 13 years of age or older
planning to start ART and willing to be
randomized.
• No prior PI or NNRTI treatment; no more than 4
cumulative weeks of prior NRTI treatment and no
more than 1 week of prior 3TC treatment.
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Design and Follow-up
PI Strategy:
PI + NRTIs
(N=470)
NNRTI Strategy:
NNRTI + NRTIs
(N=463)
3-class Strategy:
PI + NNRTI + NRTI(s)
(N=464)
1,397 Participants Randomized
Median follow-up: 60 months (IQR 52-69 months)
Lost to Follow-up: 9.67%(No study visit within 6 months of study closure for surviving participants)
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Primary Objectives
• To compare the NNRTI and PI strategies for the composite outcome of HIV disease progression to AIDS; death; or CD4+ cell count < 200 cells/mm3*
• To compare the 3-class strategy with the pooled results of the two 2-class strategies for difference in CD4+ cell count beginning at 32 months
*for those with CD4+ > 200 cells/mm3 at baseline
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• All analyses are intent-to-treat
• Primary outcomes are adjusted for clinical unit and baseline CD4+ cell count
– NNRTI versus PI comparison: Kaplan-Meier survival curves and proportional hazards regression models
– 3-class versus pooled 2-class comparison: longitudinal regression models and analysis of variance
Statistical Methods
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Baseline Characteristics
Age (years) 38.0 (32-44)
Female (%) 20.6
Race/Ethnicity Black (%) 53.8 Latino (%) 17.0 White/Other (%) 29.2
CD4+ Count (cells/mm3) 162.5 (36-332)
CD4+ < 200 (cells/mm3) (%) 56.0
Prior AIDS Event (%) 37.7
Viral Load (log10 copies/mL) 5.1 (4.5-5.6)
Hepatitis B (%) 6.2
Hepatitis C (%) 19.6
Median (IQR) or PercentBaseline Characteristic
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PI and NNRTI Drugs Prescribed at Study Entry
• PI Strategy:– Nelfinavir 61%– Ritonavir-boosted PI 26%
• NNRTI Strategy:– Efavirenz 63%– Nevirapine 36%
• 3-class Strategy:– Nelfinavir 63%– Efavirenz 52%
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NRTI Background Prescribed At Entry
Strategy
PI NNRTI 3-class
Zidovudine + Lamivudine (%) 55.5 57.5 44.8
Stavudine + Didanosine (%) 9.1 8.4 8.4
Abacavir + Lamivudine (%) 8.9 8.6 9.3
Stavudine + Abacavir (%) 3.8 2.6 0.9
Stavudine + Lamivudine (%) 21.1 20.3 11.0
Single NRTI (%) 0.2 0.2 23.9
Other NRTIs (%) 1.3 2.4 1.5
No NRTI (%) 0.0 0.0 0.2
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AIDS or Death or CD4+ Cell Count< 200 cells/mm3 *
*Among patients with baseline CD4 ≥ 200 cells/mm3
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AIDS or Death or CD4+ Cell Count< 200 cells/mm3*
All 126 (6.6) 122 (6.7)
GenderMale 97 (6.5) 95 (6.6)Female 29 (7.2) 27 (7.0)
RaceLatino 26 (8.5) 16 (5.6)Black 75 (7.5) 74 (7.6)White/Other25 (4.2)32 (5.6)
PI NNRTINo. With Event (Rate)Group
0.1 1 10
1.02
1.01
0.97
0.66
1.01
1.34
Favors NNRTI Favors PI
Hazard Ratio(95%CI)
*Among patients with baseline CD4 ≥ 200 cells/mm3
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All 126 (6.6) 122 (6.7)
Prior AIDS 64 (9.2) 67 (10.6)No Prior AIDS
CD4 ≤ 200 22 (4.8) 21 (4.5)CD4 > 200 40 (5.3) 34 (4.6)
HIV RNA (copies/mL)<100,000 49 (5.9) 35 (4.3)
100,000 + 77 (7.2) 87 (8.6)
AIDS or Death or CD4+ Cell Count< 200 cells/mm3*
PI NNRTINo. With Event (Rate)Group Hazard Ratio
(95%CI)
Favors NNRTI Favors PI0.1 1 10
1.02
1.13
0.96
0.86
0.73
1.18
*Among patients with baseline CD4 ≥ 200 cells/mm3
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0.1 1 10
Outcomes
0.1 1 10
AIDS or deathor CD4+ < 200
Death
AIDS or death
Grade 4 event
AIDS or death orgrade 4 event
Discontinuation of AR due to toxicity
NNRTI vs. PI 3-class vs. 2-class
Hazard Ratio (95% CI)Event
Favors NNRTI Favors 3-classFavors PI Favors 2-class
1.07
0.95
1.02
1.15
1.28
1.06
1.01
1.15
1.04
1.02
0.93 1.58
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CD4+ Cell Count Change From Baseline
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-100 -80 -60 -40 -20 0 20 40 60 80 100
All 227.0 233.5
Prior AIDS 252.0 289.1No Prior AIDS
CD4 ≤ 200 247.1 256.2CD4 > 200 190.2 177.7
HIV RNA (copies/mL)<100,000 182.8 188.2100,000 + 259.3 270.6
2-class 3-classChange in CD4
GroupDifference*
(95%CI)6.7
28.8
1.8-10.3
8.3
7.4
Mean Change in CD4 Beginning at Month 32
Favors 2-class Favors 3-class
* Adjusted mean difference
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Adherence To Treatment Strategies During Follow-up
Strategy
PI NNRTI 3-class
Switched strategy at least once (%) 43.2 31.7 79.5
Time to first switch (median months) 18.2 23.5 8.8
Percent of follow-up time
On PI, not on NNRTI 63.9 13.5 21.3
On NNRTI, not on PI 15.4 69.9 15.5
On PI+NNRTI 2.8 0.9 45.8
On NRTI only 4.7 2.8 3.7
Not on antiretroviral therapy 13.3 12.9 13.7
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Percent With HIV RNA < 50 copies/mL
*Odds ratio (NNRTI versus PI) for achieving HIV RNA < 50 copies/mL
OR* = 1.63 (95% CI 1.36 – 1.95)
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Time to Initial Virologic Failure*
* HIV RNA > 1000 copies/mL at or after the 4-month visit
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Genotypic Mutations1
Detected At Initial Virologic Failure
PI NNRTI 3-class
None (%)2 54.9 46.2 47.4
Single-class (%)2 31.3 31.4 38.4
Multi-class (%)2 13.8 22.3 14.2
Number with genotype
326 264 268
1 IAS October 2004 list
2 Percent is of those with a genotype
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Distribution of Specific Mutations At Initial Virologic Failure
Class Mutation N Percent1
PI 30N 30 3.5
90M 18 2.1
Any PI mutation 74 8.6
NNRTI 103N 154 17.9
181 C/I 61 7.1
190 A/S 39 4.5
Any NNRTI mutation 252 29.4
NRTI 184 I/V 206 24.0
118 I 31 3.6
Any NRTI mutation 260 30.3
1 Percent is of those with a genotype
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Comparison of FIRST, INITIO & ACTG 384
FIRST INITIO ACTG 384
Participants (n) 1397 915 987
CD4+ cell count
(median cells/mm3 at baseline)163 198 278
HIV RNA
(median log10 copies/mL at baseline)5.1 4.9 4.9
Follow-up (years)
Median
Minimum
5.0
3.7
3.7
2.3
2.3
2.0
Date ended Sep 05 Jun 04 Nov 01
AIDS or Death (n)
New and non-recurrent
Including recurrent events
291
302
108 44
Deaths (n) 188 40 12
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Summary: PI versus NNRTI Strategies
• The PI and NNRTI strategies do not differ significantly for a composite outcome of CD4+ cell count decline, progression to AIDS, and death. Results are consistent across subgroups.
• The NNRTI strategy resulted in better and more sustained virologic suppression compared to the PI strategy (as was found in ACTG 384 and INITIO).
• At initial virologic failure the NNRTI strategy resulted in the selection of more class-specific mutations than did the PI strategy.
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Summary: 3-class Strategy versus Pooled 2-class Strategies
• A 3-class strategy is not superior to 2-class strategies for immunologic and clinical outcomes.
• These findings were consistent for all subgroups, including those with CD4+ cell counts < 200 and 200+ and for those with VL < 100,000 and 100,000+ copies/mL.
• More patients assigned the 3-class strategy had ART discontinued due to toxicity compared to the 2-class strategies.
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Conclusions• The results of FIRST extend and corroborate the
findings of ACTG 384 and INITIO.
– The difference between the NNRTI strategy and the PI strategy for AIDS/death/CD4 < 200 and AIDS/death is not likely to be large:
• AIDS/death/CD4 < 200 95% CI = 0.79 – 1.31• AIDS/death 95% CI = 0.80 – 1.41
– This finding will be explored further in a planned meta-analysis of the 3 studies.
• These results also are consistent with data from the EuroSIDA study1 which showed that for a fixed HIV RNA level/CD4+ cell count, the rate of AIDS or death does not differ based on ART regimen.
1Olsen CH, et al; AIDS 2005;19:319-30
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Conclusions
Initiation of therapy with either an NNRTI or a PI (ritonavir-boosted or unboosted), but not both together, are good and effective strategies for long-term antiretroviral management in treatment-naïve HIV-infected persons with a wide range of baseline CD4+ cell counts and diverse demographics
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Acknowledgements
• The 1397 participants• The CPCRA staff and physicians• James D. Neaton, Ph.D.• Other FIRST presentations at World AIDS
– Body Composition Results (WEPE0143; CL Gibert)
– Metabolic Substudy (THAB0101; J Shlay)
– NNRTI Substudy (THPE0104; M van den Berg-Wolf)
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Backup Slides
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AIDS or Death or 126 6.6 122 6.7 140 7.8CD4+ <200
Death 60 2.8 56 2.6 72 3.4
AIDS or Death 95 4.8 98 5.1 109 5.7
Grade 4 Events 147 8.7 147 8.9 145 8.9
AIDS or Death or 187 11.5 191 12.4 192 12.5Grade 4 Event
Discontinued AR due 171 11.2 158 10.3 226 17.6to toxicity
Clinical Outcomes
PI (N=470)
NNRTI (N=463)
3-class (N=464)
Rate Rate Rate
Number of Events and Rate per 100 Person Years
No. No. No.Outcome
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-100 -80 -60 -40 -20 0 20 40 60 80 100
Mean Change in CD4 Beginning at Month 32
All 227.0 233.5
GenderMale 220.7 232.3Female 249.5 238.9
RaceLatino 259.7 283.5Black 201.4 199.1White/Other 253.8 265.9
2-class 3-class Change in CD4 Difference
(95% CI)
Favors 2-class Favors 3-class
6.7
11.5
-7.8
Group
21.0
-0.3
11.3
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VL > 50 copies/mL 403 52.8 342 31.9 385 45.0
or death
VL > 1000 copies/mL 328 36.2 266 22.5 272 24.6
VL < 50 copies/mL 360 52.3 383 78.7 383 78.7
Viral Load (VL) Outcomes
PI (N=470)
NNRTI (N=463)
3-class (N=464)
Rate Rate Rate
Number of Events and Rate per 100 Person Years
No. No. No.Outcome
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Hazard Ratios for Viral Load Outcomes -1
PI NNRTI 3-class
Hazard Ratios (95% Confidence Interval)
VL > 50 copies/mL 1.00 (ref) 0.63 (0.55-0.73) 0.86 (0.75-0.99)
or death
VL > 1000 copies/mL 1.00 (ref) 0.66 (0.56-0.77) 0.70 (0.60-0.83)
VL < 50 copiesmL 1.00 (ref) 1.43 (1.24-1.65) 1.34 (1.16-1.55)
Outcome
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VL > 50 copies/mL 0.63 (0.55-0.73) 1.08 (0.96-1.23)
or death
VL > 1000 copies/mL 0.66 (0.56-0.78) 0.87 (0.75-1.00)
VL < 50 copies/mL 1.42 (1.23-1.64) 1.13 (1.00-1.28)
Hazard Ratios for Viral Load Outcomes - 2
Hazard Ratios (95% Confidence Intervals)
3-class vs. 2-classNNRTI vs. PIOutcome
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Time to Viral Load < 400 copies/mL After Initial Virologic Failure
Kozal MJ, et al; Abstracts of the XV International HIV Drug Resistance Workshop, June 13-17, 2006, Sitges, Spain