Medical Advocates for Social Justice Conference Poster 1st International AIDS Society Conference on HIV Pathogenesis and Treatment. Buenos Aires, Argentina -  July 8 - July 11, 2001 Kaletra vs. Nelfinavir in Antiretroviral-Naïve Subjects: Week 60 Comparison in a Phase III, Blinded, Randomized Clinical Trial. P. Ruane1, J. Mendonca2, A. Timerman3, P. Cernohous4, E. Bauer4, B. Bernstein4, and E. Sun.4 1Tower ID of Los Angeles, 2Hospital do Servidor Publico Estadual de São Paulo, 3Secretaria de Estado de Saude for Hospital Heliópolis - São Paulo, 4Abbott Laboratories, Abbott Park, IL

BACKGROUND

Kaletra (formerly known as ABT-378/r, lopinavir/ritonavir) is a protease inhibitor (PI) that has shown significant antiviral activity and tolerability in clinical trials to date.

Lopinavir is exquisitely sensitive to pharmacokinetic enhancement by ritonavir, resulting in substantially increased LPV drug exposure, even at low ritonavir doses. At the dosage selected for phase III clinical trials, 400 mg LPV/100 mg ritonavir BID (as 3 co-formulated capsules BID). The mean LPV C_trough/EC₅₀ ratio (Inhibitory Quotient or IQ) for wild-type HIV is >75 when dosed at 400/100 mg BID, potentially providing superior antiviral activity and a pharmacologic barrier to the emergence of viral resistance.¹

M98-863 is a double-blind, randomized trial comparing the safety and antiviral activity of Kaletra (LPV/r)+d4T+3TC vs. that of nelfinavir (NFV)+d4T+3TC in antiretroviral naive subjects. It is being conducted at 93 centers in 13 countries, covering 5 continents and it is one of the largest prospective, randomized clinical trials of protease inhibitor therapy.

The primary efficacy analyses included:

• The proportion of subjects with HIV RNA level <400 copies/mL at Week 24.
  
• Time to loss of virologic response through Week 48

This update is a summary of results through Week 60.

METHODS

Entry Criteria

• Age >12 years
  
• HIV positive with an HIV RNA level > 400 copies/mL by the Roche Amplicor assay
  
• No CD4 cell count restriction
  
• No prior d4T or 3TC use
  
• No more than 14 days of any other antiretroviral therapy

Study Design and Analysis

653 antiretroviral-naïve subjects were randomized to receive either:

• LPV/r BID and NFV placebo TID plus d4T and 3TC
  
• NFV TID and LPV/r placebo BID plus d4T and 3TC

RESULTS

• Overall discontinuation rates were similar in the two treatment groups
  
• The incidence of study drug related discontinuations occurred in similar frequency in both treatment groups
  
• Discontinuations due to virologic failure were more common in NFV-treated subjects than in LPV/r-treated subjects
  
• All subjects who discontinued due to virologic failure had reached a protocol defined virologic endpoint

• Adherence was measured by pill count of the active protease inhibitor (number of pills taken overall compared to number of pills expected to be taken)
  
• Adherence rates were similar between treatment groups

• Moderate events are defined as events that interrupt normal daily activities

• Severity grades were based on The Division of AIDS Grading Severity of Adult Adverse Events criteria
  
• There was a statistically significant difference in the incidence of grade 3/4 triglyceride elevations in LPV/r-treated subjects compared to NFV-treated subjects, 11% and 2% respectively (p<0.001)
  
• The incidence of other grade 3/4 laboratory abnormalities were not statistically significantly different between treatment groups

• The mean change in CD4 cell count from baseline to Week 60 was 247 cells/µL in the LPV/r-treated group and 224 cells/µL in the NFV-treated group

• In subjects with a baseline CD4 cell count <50 cells/µL, the mean change in CD4 cell count from baseline to Week 60 was significantly greater in subjects treated with LPV/r than NFV, 266 cells/µL and 198 cells/µL respectively

• A statistically significantly higher proportion of LPV/r-treated subjects vs. NFV-treated subjects had VL <400 copies/mL at all study visits after Week 12

• A statistically significantly higher proportion of LPV/r-treated subjects vs. NFV-treated subjects had VL <50 copies/mL at all visits after Week 24

 81% and 65% of LPV/r and NFV-treated subjects maintained a viral response through Week 60

INCIDENCE OF PI RESISTANCE

• Plasma viral isolates from all subjects with HIV RNA >400 copies/mL at least once between Weeks 24 and 60 while on treatment were examined for evidence of resistance.
  
  • 65 LPV/r subjects
    
  • 106 NFV subjects
    
• Resistance Definition
  
  • NFV: Presence of D30N and/or L90M mutation in protease
    
  • LPV/r: Presence of any primary or active site mutation*
    
    * Selected from 10 primary or active site mutations including protease amino acid positions 8, 30, 32, 46, 47, 48, 50, 82, 84 and 90

Of subjects with a viral load >400 copies/mL through Week 60, 38% of the LPV/r-treated subjects vs. 81% of the NFV-treated subjects had developed resistance to 3TC (p<0.001).

CONCLUSIONS

• LPV/r demonstrated superior efficacy when compared to NFV in achieving HIV RNA <LOQ at Week 60.
  
  • <400 copies/mL: 74% vs. 61% (ITT NC=F, p <0.001)
    
  • <50 copies/mL: 64% vs. 52% (ITT NC=F, p =0.002)
    
• Kaplan-Meier estimates of duration of viral load response at Week 60 were 81% and 65% for LPV/r and NFV, respectively.
  
• Of subjects with a viral load >400 copies/mL through Week 60, 37% of the NFV-treated subjects vs. 0% of the LPV/r subjects had resistance detected in the protease gene.
  
• Both regimens were well tolerated with low study drug-related discontinuation rates.
  • 4% for LPV/r
  • 4% for NFV

REFERENCES

1. Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of LPV/ritonavir (LPV/r) in HIV+ subjects. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 1999 (abstract 0327).

ACKNOWLEDGEMENTS

• M98-863 Study Subjects
  
• M98-863 Clinical Investigators and Study Coordinators

  Anthony M. Allworth, M.D. Frederick Altice, M.D. Keikawus Arasteh, M.D. Jose Arribas, M.D. Carlos Barros, M.D. Jeffrey Beal, M.D. Gildon Beall, M.D. John David Brand, M.D. Andrew Badley, M.D. Paul Cimoch, M.D. Bonaventura Clotet Sala, M.D. Calvin Cohen, M.D. Timothy Cooley, M.D. Prof. Jean-Francois Delfraissey Charles Farthing, M.D. Gerd Faetkenheuer, M.D. Judith Feinberg, M.D. Margaret Fischl, M.D. Martin Fisher, M.D. Markus Flepp, M.D. Joel Gallant, M.D., M.P.H. Joseph Gathe, M.D. Jan Gerstoft, M.D.

  Mitchell Goldman, M.D. Juan Gonzalez-Lahoz, M.D. Frank M. Graziano, M.D. Stephan Green, M.D. Howard A. Grossman, M.D. David Haas, M.D. Stephen Hauptman, D.O. Charles Hicks, M.D. Andrzej Horban, M.D. James Horton, M.D. Newton Hyslop, M.D. Dave Johnson, M.D. Margaret Johnson, M.D. Robert Kalayjian, M.D. Powel Kazanjian, M.D. Jay Kostman, M.D. Richard Lalonde, M.D. Harry Lampiris, M.D. Francois LaPlante, M.D. Jeffrey Lennox, M.D. Roberta Luskin-Hawk, M.D. Simon Mallal, M.D. Lars Mathiesen, M.D.

  Joao Mendonca, M.D. Robert Myers, M.D. Peter Miao, M.D. Donna Mildvan, M.D. Steve Miller, M.D. Julio Montaner, M.D. Prof. Yves Mouton Andy Pavia, M.D. Court Pedersen, M.D. Gerald Pierone, M.D. Richard Pollard, M.D. Anton Pozniak, M.D. Anita Rachlis, M.D. Frank Rhame, M.D. Peter Ruane, M.D. Rafael Rubio, M.D. Prof. Adrien G. Saimot James H. Sampson, M.D. Ian Sanne, M.D. Jorge Santana Bagur, M.D. Daniel Seekins, M.D. Prof. Daniel Sereni Gladys Sepulveda, M.D.

  Sheetal Sharma, M.D. Renslow Sherer, M.D. Leon Smith, M.D. Kathleen Squires, M.D. Schlomo Staszewski, M.D. Roy T. Steigbigel, M.D. Corklin R. Steinhart, M.D. Albrecht Stoehr, M.D. Donna E. Sweet, M.D. Karen Toshima, M.D. Albert Theisen, M.D. Rejean Thomas, M.D. James A. Thommes, M.D. Melanie A. Thompson, M.D. Artur Timermann, M.D. Pompeyo Viciana, M.D. Daniel Vittecoq, M.D. Sharon Walmsley, M.D. Prof. Jonathan Weber Lutwin Weitner, M.D. I. P. van der Westhuizen, M.D. David Wheeler, M.D. David P. Wright, M.D. Bienvenido G. Yangco, M.D.

TOP

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Poster
  Kaletra vs. Nelfinavir in Antiretroviral-Naïve Subjects: 
Week 60 Comparison in a Phase III, Blinded, Randomized Clinical Trial

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© 2001 Medical Advocates for Social Justice
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