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Introduction and Rationale

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.

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Introduction and Rationale

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  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 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;349:2304-15 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 NNRTI Strategy: NNRTI + NRTIs (N=463) 3-class Strategy: PI + NNRTI + NRTI(s) (N=464) PI Strategy: PI + NRTIs (N=470) 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)

  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 BaselineCharacteristic Median (IQR) or Percent 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

  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

  10. AIDS or Death or CD4+ Cell Count< 200 cells/mm3 * *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 1.02 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/Other 25 (4.2) 32 (5.6) 1.01 0.97 0.66 1.01 1.34 Favors NNRTI Favors PI *Among patients with baseline CD4 ≥ 200 cells/mm3

  12. Favors PI Favors NNRTI AIDS or Death or CD4+ Cell Count< 200 cells/mm3* Group No. With Event (Rate) Hazard Ratio(95%CI) PI NNRTI 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) 1.02 1.13 0.96 0.86 0.73 1.18 *Among patients with baseline CD4 ≥ 200 cells/mm3

  13. Favors NNRTI Favors PI Favors 3-class Favors 2-class 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 orgrade 4 event Discontinuation of AR due to toxicity 1.15 1.02 0.95 1.28 1.07 1.15 1.02 1.01 1.04 1.06 0.93 1.58

  14. CD4+ Cell Count Change From Baseline

  15. Mean Change in CD4 Beginning at Month 32 Change in CD4 Difference* (95%CI) Group 3-class 2-class 6.7 All 227.0 233.5 Prior AIDS 252.0 289.1No Prior AIDS CD4 ≤ 200 247.1 256.2 CD4 > 200 190.2 177.7 HIV RNA (copies/mL) <100,000 182.8 188.2 100,000 + 259.3 270.6 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

  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 Mutations1Detected At Initial Virologic Failure • IAS October 2004 list • 2 Percent is of those with a genotype

  20. Distribution of Specific Mutations At Initial Virologic Failure 1 Percent is of those with a genotype

  21. Comparison of FIRST, INITIO & ACTG 384

  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 < 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

  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. Clinical Outcomes Number of Events and Rate per 100 Person Years NNRTI (N=463) PI (N=470) 3-class (N=464) No. Rate No. Rate Rate No. Outcome 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 17.6 to toxicity

  29. Mean Change in CD4 Beginning at Month 32 Change in CD4 Difference (95% CI) Group 2-class 3-class 6.7 All 227.0 233.5 Gender Male 220.7 232.3Female 249.5 238.9 Race Latino 259.7 283.5Black 201.4 199.1White/Other 253.8 265.9 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 NNRTI (N=463) PI (N=470) 3-class (N=464) No. No. No. Rate Rate Rate Outcome 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

  31. Hazard Ratios for Viral Load Outcomes -1 Hazard Ratios (95% Confidence Interval) PI NNRTI 3-class Outcome 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)

  32. Hazard Ratios for Viral Load Outcomes - 2 Hazard Ratios (95% Confidence Intervals) NNRTI vs. PI Outcome 3-class vs. 2-class 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)

  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

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