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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