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HAART in Patients with Advanced Disease (<200 CD4 + cell/mm 3 )

A Prospective, Randomized, Open Label Trial of Efavirenz vs Lopinavir/ritonavir based HAART, among HIV infected Naïve Individuals presenting for Care with CD4 + cell counts<200 cell/mm 3 in Mexico.

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HAART in Patients with Advanced Disease (<200 CD4 + cell/mm 3 )

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  1. A Prospective, Randomized, Open Label Trial of Efavirenz vs Lopinavir/ritonavir based HAART, among HIV infected Naïve Individuals presenting for Care with CD4+cell counts<200 cell/mm3 in Mexico J Sierra-Madero; A Villasis-Keever; P. Méndez; J.L. Mosqueda; I. Torres-Escobar; F. Gutiérrez, I. Juárez; M. Magaña; C. Ramos; L. Pérez Saleme; L.E. Soto; V. Lima; F. Belaunzarán; B. Crabtree; J. Montaner

  2. HAART in Patients with Advanced Disease (<200 CD4+ cell/mm3) • Advanced disease is the most common form of presentation to care of HIV infection in resource limited countries • 74% of patients in a cohort from Latin America and 77% from one center in Mexico started HAART with <200 CD4+ • Very low CD4+ count consistently associated with poor virological outcome to HAART in different studies Tuboi S, CCASAnetgroup; Abstract MOAB0203. ; IAC 2008, Mexico city DART Virology Goup and Trail Team; AIDS 2006 Jun 26;20 (10):1391-9 Egger M, et al. Lancet 2002; 360:119–129 Charalambous S, et al, [abstract MoPe11.2C41] IAS 2005.

  3. Preferred HAART initial components(DHHS: January 2008) *Avoid in pregnant women and women with significant pregnancy potential. **Emtricitabine can be used in place of lamivudine and vice versa. NNRTI NRTI** • ABC/3TC • TNF/FTC or + PI

  4. ACTG 5142: LPV/r vs EFV vs LPV/r + EFV Week 96 Stratified by HIV-1 RNA ≤ or > 100,000, hepatitis coinfection and NRTI selection LPV/RTV SGC 400/100 mg BID + NRTIs* (n = 253) Naïve Patients with HIV-1 RNA > 2000 copies/mL, no CD4+ restriction (N = 753) EFV 600 mg QD+2 NRTI* (n = 250) LPV/RTV SGC 533/133 mg BID +EFV 600 mg QD (n = 250) *Lamivudine + ZDV, d4T XR, o TDF, selected by investigator criteria before randomization. % HIV-1 RNA > 105 51 52 51 CD4+ (median) 178 190 181 Riddler S, et al. IAC 2006. Abstract THLB0204.

  5. Objectives Primary Objective Demonstrate non inferiority of Efavirenz vs LPV/r in ARV naïve individuals with CD4+ cell counts <200 cell/mm3, Primary Endpoint Proportion of subjects with HIV RNA <50 copies at 48 weeks Secondary Endpoints Change in CD4 Change in lipids Safety

  6. Methods • 11 Clinical Sites • Registered in www.clintrials.gov Coordinator Center INCMNSZ, Mexico City Sites outsite Mexico City Higher Prevalence of HIV Methodological Support provided by the BC Centre for Excellence in HIV/AIDS, Vancouver, Canada

  7. Study Design National multicenter, open-label, randomized, 48-week study to compare the virological success of EFV vs LPV/r in treatment-naïve HIV-1 infected subjects Screened (N= 264) Screening Failure N=75 189 ARV naïve; >18 years; HIV RNA 1,000 c/mL, CD4+<200 Randomization stratified by CD4+(> and < 100 cells/mL) (1:1) EFV 600 mg QD (n = 95) LPV/r 400/100 mg BID (n = 94) ZDV/ 3TC 300/150 mg BID Substitution of AZT for ABC allowed (N= 14; EFV 6 and LPV/r 8)

  8. Follow up Virological Failure (VF) definition: After 6 months: HIV RNA >50 copies/mL (confirmed) At 8 weeks: Failure to decline > 1 log HIV RNA Days Weeks -40 to -30 1 4 8 16 24 32 40 48 -7 a -4 Screening Randomization Baseline Follow up HIV RNA, CD4+ counts, CBC, LFT and Lipid Profile

  9. Analysis Primary endpoint: - Proportion of patients with VL (<50 copies/mL) at 48 (TLOVR) - ITT Missing = Failure Non Inferiority was to be concluded if the lower limit of the 95% CI of the difference between groups in virological response was higher than -12%

  10. Results

  11. Baseline Characteristics

  12. Patient disposition at week 48

  13. Proportion of Patients with HIV RNA <50 c/mL 100 90 85.9% 80 70.5% 70 61.7% 60 % <50 copies/ mL 53.2% 50 40 30 AT (p=0.000) Efavirenz (n=78) Lopinavir/r (n=81) TLOVR (p=0.017) Efavirenz (n=95) Lopinavir/r (n=94) 20 10 Δ 17% (CI 95% 3.5 - 31) 0 0 8 16 24 32 40 48 Week Number Of Patients With Viral Load <50/ml Efavirenz 29 70 68 67 Lopinavir/r 8 53 56 50

  14. Virological Suppression Stratified by Baseline CD4+ Counts (>/< 50 cell/mm3) P = 0.012 P = 0.15 % < 50 c/mL EFV % LPV/r % % % n 53 49 42 45 Baseline CD4+ Count <50 cell/mm3 >50 cell/mm3

  15. Proportion of Patients with HIV RNA <400 c/mL 100 88% 90 80 75% 73% 70 65% % <400 copies/mL 60 50 40 30 TLOVR (p=0.275) Efavirenz (n=95) Lopinavir/r (n=94) AT (p=0.032) Efavirenz (n=78) Lopinavir/r (n=81) 20 10 0 0 8 16 24 32 40 48 Week Number Of Patients With Viral Load <400/ml Efavirenz 69 76 71 69 Lopinavir/r 40 76 68 61

  16. Change of median CD4+ cell counts

  17. Resistance Mutations in Patients with Virological Failure

  18. Percent Change of Lipids at Week 48 p = 0.37 p = 0.60 p = 0.17 p = 0.01 % Change TC HDL LDL TG

  19. Adverse Events in both Groups

  20. Summary In HIV-infected ARV naïve subjects with advanced disease, Efavirenz achieved a higher proportion of virological suppression than Lopinavir/r at <50 copies/mL in the ITT analysis at 48 weeks No difference was observed between arms when the <400 copies/ml threshold was used as the endpoint The larger proportion of subjects with <50 copies/mL at week 48 in the Efavirenz arm is accounted for both by higher rate of virologic failure and higher rate of discontinuations because of adverse events in the Lopinavir/r arm Efavirenz based HAART was associated with lower triglyceride levels after 48 weeks

  21. Caveats One country study No baseline genotypes The Nucleoside backbone was Zidovudine/ Lamivudine, which may be contributing to more discontinuations in both groups, specially in those with more advanced disease Use of Lopinavir/r capsules may have contributed to a higher pill burden and probably lower adherence

  22. Conclusions • Until we improve our capacity to detect HIV infections in earlier stages in those regions of the world in which HIV disease is presenting at such late stages we will continue to face the challenges that involve treating this group of patients • New studies should focus on this population

  23. Acknowledgments Hospital General de Zona (IMSS) # 72 Fernanda Gutiérrez Hospital General de Zona (IMSS) # 53 Patricia Méndez CMN sXXI Leticia Pérez Saleme Sigfrido Rangel-Frausto Hospital Regional de León, Guanajuato Luis Mosqueda Hospital General de Zona (IMSS) # 29 Juárez Kasusky Hospital General de Zona SLP Magaña Aquino Hospital General de Zona (IMSS) #25 Carmen Ramos Santos Vargas Madrid SEAVS Puebla Javier Reyes Mar Indiana Torres-Escobar Inst.Nacional de la Nutrición Salvador Zubirán Juan Sierra-Madero A. Villasis-Keever F. Belaunzarán-Zamudio LE Soto-Ramírez Fernando Silva L Naranjo Albarrán AudeliaAlanis Teresa Muñoz Elena García Berenice Cruz Denise Franco BarbaraAntuna Alicia Piñeirúa Gabriela Montejano Jezer Lezama Lucrecia Arreguín Raúl López Saucedo Venancio Ruíz Brenda Crabtree Norma Rivera G Ruíz Palacios Rocío Velazquez Funded by CONACyT and Infectious Diseases Dept INCMNSZ and IMSS

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