1. 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

2. 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 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:
2INITIO Trial International Co-ordinating Committee; Lancet 2006;368:287-98

3. 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.

4. Design and Follow-up 1,397 Participants Randomized PI Strategy:
PI + NRTIs
(N=470)
NNRTI Strategy:
NNRTI + NRTIs
(N=463)
3-class Strategy:
PI + NNRTI + NRTI(s)
(N=464)
Median follow-up: 60 months (IQR months)
Lost to Follow-up: 9.67%
(No study visit within 6 months of study closure for surviving participants)

5. 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

6. Statistical Methods 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

7. Baseline Characteristics
Median (IQR) or Percent
Age (years) (32-44)
Female (%) 20.6
Race/Ethnicity Black (%) Latino (%) White/Other (%) 29.2
CD4+ Count (cells/mm3) (36-332)
CD4+ < 200 (cells/mm3) (%) 56.0
Prior AIDS Event (%) 37.7
Viral Load (log10 copies/mL) 5.1 ( )
Hepatitis B (%) 6.2
Hepatitis C (%) 19.6

8. 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%

9. NRTI Background Prescribed At Entry
Strategy PI
NNRTI
3-class
Zidovudine + Lamivudine (%)
55.5
57.5
44.8
Stavudine + Didanosine (%)
9.1
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
23.9
Other NRTIs (%)
1.3
2.4
1.5
No NRTI (%)
0.0

10. AIDS or Death or CD4+ Cell Count < 200 cells/mm3 *
Baseline characteristics for the two treatment arms are shown on this slide.
There were no significant differences in age, gender, race, mean CD4 count or mean viral load between both groups.
An equal number of patients in both arms were treated with a PI-containing regimen.
As seen in other CPCRA studies, the majority of participants were non-white.
*Among patients with baseline CD4 ≥ 200 cells/mm3

11. AIDS or Death or CD4+ Cell Count < 200 cells/mm3*
Group
No. With Event (Rate)
Hazard Ratio (95%CI) PI
NNRTI
All (6.6) 122 (6.7)
Gender Male 97 (6.5) 95 (6.6) Female 29 (7.2) 27 (7.0)
Race Latino 26 (8.5) 16 (5.6) Black 75 (7.5) 74 (7.6) White/Other 25 (4.2) 32 (5.6)
1.02
1.01
0.97
0.66
1.01
1.34
Favors NNRTI
Favors PI
*Among patients with baseline CD4 ≥ 200 cells/mm3

12. AIDS or Death or CD4+ Cell Count < 200 cells/mm3*
Group
No. With Event (Rate)
Hazard Ratio (95%CI) PI
NNRTI
All (6.6) 122 (6.7)
Prior AIDS 64 (9.2) 67 (10.6) No Prior AIDS CD4 ≤ (4.8) 21 (4.5) CD4 > (5.3) 34 (4.6)
HIV RNA (copies/mL) <100, (5.9) 35 (4.3) 100, (7.2) 87 (8.6)
1.02
1.13
0.96
0.86
0.73
1.18
Favors NNRTI
Favors PI
*Among patients with baseline CD4 ≥ 200 cells/mm3

13. Outcomes Event Hazard Ratio (95% CI) NNRTI vs. PI 3-class vs. 2-class
AIDS or death or CD4+ < 200
Death
AIDS or death
Grade 4 event
AIDS or death or grade 4 event
Discontinuation of AR due to toxicity
1.02
1.15
0.95
1.28
1.07
1.15
1.02
1.01
1.06
1.04
0.93
1.58
Favors NNRTI
Favors PI
Favors 3-class
Favors 2-class

14. CD4+ Cell Count Change From Baseline

15. Mean Change in CD4 Beginning at Month 32
Difference* (95%CI)
Group
2-class
3-class
6.7
All
Prior AIDS No Prior AIDS CD4 ≤ CD4 >
HIV RNA (copies/mL) <100, ,
28.8
1.8
-10.3
8.3
7.4
Favors 2-class
Favors 3-class
* Adjusted mean difference

16. 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
3.7
Not on antiretroviral therapy
13.3
12.9
13.7

17. Percent With HIV RNA < 50 copies/mL
OR* = 1.63 (95% CI 1.36 – 1.95)
*Odds ratio (NNRTI versus PI) for achieving HIV RNA < 50 copies/mL

18. Time to Initial Virologic Failure*
* HIV RNA > 1000 copies/mL at or after the 4-month visit

19. Genotypic Mutations1 Detected At Initial Virologic Failure
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
IAS October 2004 list
2 Percent is of those with a genotype

20. 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

21. Comparison of 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
Follow-up (years)
Median
Minimum
5.0
3.7
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

22. 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.

23. 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.

24. 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 < % 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

25. 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

26. 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)

27. Backup Slides

28. Number of Events and Rate per 100 Person Years
Clinical Outcomes
Number of Events and Rate per 100 Person Years
PI (N=470)
NNRTI (N=463)
3-class (N=464)
Outcome
No.
Rate
No.
Rate
No.
Rate
AIDS or Death or CD4+ <200
Death
AIDS or Death
Grade 4 Events
AIDS or Death or Grade 4 Event
Discontinued AR due to toxicity

29. Mean Change in CD4 Beginning at Month 32
Difference (95% CI)
Group
2-class
3-class
All
Gender Male Female
Race Latino Black White/Other
6.7
11.5
-7.8
21.0
-0.3
11.3
Favors 2-class
Favors 3-class

30. Viral Load (VL) Outcomes
Number of Events and Rate per 100 Person Years
PI (N=470)
NNRTI (N=463)
3-class (N=464)
No.
No.
Outcome
Rate
Rate
No.
Rate
VL > 50 copies/mL
or death
VL > 1000 copies/mL
VL < 50 copies/mL

31. Hazard Ratios for Viral Load Outcomes -1
Hazard Ratios (95% Confidence Interval)
Outcome PI
NNRTI
3-class
VL > 50 copies/mL 1.00 (ref) 0.63 ( ) 0.86 ( )
or death
VL > 1000 copies/mL (ref) 0.66 ( ) 0.70 ( )
VL < 50 copiesmL (ref) 1.43 ( ) 1.34 ( )

32. Hazard Ratios for Viral Load Outcomes - 2
Hazard Ratios (95% Confidence Intervals)
Outcome
NNRTI vs. PI
3-class vs. 2-class
VL > 50 copies/mL 0.63 ( ) 1.08 ( )
or death
VL > 1000 copies/mL 0.66 ( ) 0.87 ( )
VL < 50 copies/mL 1.42 ( ) 1.13 ( )

33. 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