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 Lopinavir/ritonavir (Kaletra) in Antiretroviral Naïve HIV+ Patients: Week 144 Follow-Up. AC White, Jr.1, S Brun11, M King11, T Marsh11, R Murphy2, R Stryker3, C Hicks4, J Eron5, R Gulick6,M Glesby6, M Thompson7, C Benson8, M Albrecht9, H Kessler10, and E Sun11for the M97-720 Study. 1Baylor, 2Northwestern, 3Pacific Oaks Research, 4Duke, 5U. N. Carolina, 6Cornell, 7AIDS Research Consortium of Atlanta, 8U. Colorado, 9Harvard, 10Rush and 11Abbott Laboratories

BACKGROUND

Lopinavir (LPV) is an HIV protease inhibitor (PI) that is co-formulated with ritonavir, which functions as an inhibitor of cytochrome P450 3A. Even at low ritonavir doses, there is a substantial increase in LPV exposure. At a dosage of 400 mg of LPV/100 mg ritonavir twice daily (3 co-formulated tablets BID), ritonavir concentrations are below those required for antiviral activity.¹ By contrast, the mean LPV C_trough/EC₅₀ ratio (Inhibitory Quotient or IQ) for wild-type HIV is >75 when dosed at 400/100 mg twice a day, potentially providing a barrier to emergence of viral resistance and activity against resistant virus. Lopinavir/ritonavir (LPV/r, marketed as Kaletra) has been studied in both anti-retroviral naive and experienced HIV-infected patients. However, few long-term data are available on continued safety and efficacy. The M97-720 study is an ongoing phase II double-blind trial of LPV/r in combination with d4T and 3TC in antiretroviral-naive patients. This was the first trial of LPV/r in HIV-infected patients and hence provides the longest duration of follow-up for patients treated with LPV/r. This poster presents data on safety and efficacy through 144 weeks.

METHODS

Entry Criteria

• Antiretroviral-naïve patients.
  
• Plasma HIV RNA >5,000 copies/mL with no CD4 cell count restriction.

Study Design and Analysis

• One hundred antiretroviral-naïve patients were randomized to receive one of three dosage levels of LPV/r (200/100 mg BID, 400/100 mg BID or 400/200 mg BID), together with d4T (40 mg BID) and 3TC (150 mg BID) given either after 3 weeks of monotherapy (Group I) or from study entry (Group II) (Figure 1).

• Enrollment into Group II began following an evaluation of preliminary efficacy and safety of LPV/r in Group I.

• After 48 weeks, all patients began conversion to open-label LPV/r 400/100 mg BID dosing.

• Plasma HIV RNA was quantified using Roche Amplicor HIV-1 Monitor (lower limit of quantitation [LLQ] 400 copies/mL) and the Roche Amplicor HIV-1 Monitor Ultrasensitive Quantitative PCR, Version 1.0 (LLQ 50 copies/mL).

Antiviral Activity

• Proportion with HIV RNA below the LLQ (on treatment) at each visit: Patients who discontinued prior to the visit, patients with missing values, and values obtained during a treatment interruption of at least 3 days were excluded from the analysis.
  
• Proportion with HIV RNA below the LLQ (intent-to-treat [noncompleter=failure]) (ITT NC=F) at each visit: Patients who discontinued prior to the visit were considered non-responders (HIV RNA > LLQ). Patients with missing values at a visit were considered non-responders unless HIV RNA was below the LLQ at the immediately preceding and immediately following visits.
  
• Duration of virologic response was defined as the time from study initiation to the time of loss of virologic response (two consecutive HIV RNA measurements above 400 copies/mL following any measurement below 400 copies/mL). If the final measurement for a patient was above 400 copies/mL (and the patient had not previously demonstrated a loss of response), the time of loss of response was defined to be the time of the last measurement. Subjects who had never experienced a loss of response were considered censored at the time of their final measurement, including subjects who prematurely discontinued prior to demonstrating a loss of response. Subjects who never achieved an HIV RNA level below 400 copies/mL were considered to have had a loss of response at Day 1.

RESULTS

Baseline Characteristics

• Ninety-six male and 4 female patients: 65% Caucasian, 29% Black, 6% Hispanic.
  
• Mean age: 35 years (range 21-59).
  
• Median Plasma HIV RNA: 4.8 log 10 copies/mL (range 3.3-6.3).
  
• Median CD4 count: 326 cells/mm 3 (range 3-918).

Viral Load Suppression Below the LLQ Through Week 144

• Based on the ITT NC=F analysis, 79% of patients had HIV RNA <400 copies/mL at Week 144 (on-treatment analysis: 99%) (Figure 2).
  
• Based on the ITT NC=F analysis, 76% of patients had HIV RNA <50 copies/mL at Week 144 (on-treatment analysis: 96%) (Figure 3).

Duration of Virologic Response Analysis

• Through Week 144, the Kaplan-Meier estimate of the proportion of patients maintaining virologic response was 85.3% (Figure 4).
  
• 8/14 (57%) patients who experienced a loss of virologic response remained on study through Week 144; all 8 patients had HIV RNA <400 copies/mL at Week 144.
  
• Of 5 patients meeting loss of virologic response criteria with viral load >400 copies/mL at Week 144 or final evaluation, three patients had documented noncompliance.

CD4 Cell Count Response

• Among subjects with values at both baseline and Week 144, the mean CD4 cell count increased from 290 cells/mm³ to 659 cells/mm³, an increase of 369 cells/mm³ (Figure 6).
  
• CD4 cell count response appeared to be consistent regardless of baseline CD4 cell count. Among 17 patients with baseline CD4 cell count <50 cells/mm³, mean CD4 cell count increased from 24 cells/mm³ to 412 cells/mm³, an increase of 388 cells/mm³.

U.S. Department of Health and Human Services (DHHS) Guidelines

• In April 2001, DHHS issued updated guidelines for the use of ARV therapy in adults and adolescents,² recommending initiation of ARV treatment in therapy-naive HIV-infected patients with CD4 cell count <200 cells/mm³ or viral load above 55,000 copies/mL by RT-PCR.
  
• LPV/r is included in the "Strongly Recommended" category of agents to consider for initial treatment of established HIV infection.²
  
• At baseline in study M97-720, 65/100 (65%) patients met the above DHHS criteria recommending ARV therapy initiation. Virologic and immunologic response among these 65 patients (Figures 7 and 8) compare favorably to results from all subjects reported above.

CONCLUSIONS

• LPV/r-based therapy exhibits sustained virologic response through 144 weeks in antiretroviral-naive patients, with 79% (on treatment: 99%) and 76% (on treatment: 96%) of patients demonstrating HIV RNA <400 copies/mL or <50 copies/mL, respectively, by ITT NC=F analysis.
  
• The Kaplan-Meier estimate of the proportion of patients maintaining virologic response through Week 144 was 85.3%.
  
• 9/14 patients (64%) who experienced loss of virologic response through Week 144 demonstrated resuppression of HIV RNA level to <400 copies/mL at Week 144 or final study visit without change in ARV regimen.
  
• Among subjects for whom ARV therapy would be recommended by current DHHS guidelines, virologic and immunologic response appear comparable to overall results from the study.
  
• LPV/r was well tolerated, as indicated by the low rate of study discontinuations due to LPV/r-related adverse events (5/100, 5%).

ACKNOWLEDGEMENTS

M97-720 Study Subjects
Covance Central Laboratory Services
AIDS Research Consortium of Atlanta Sullivan M
Beth Israel Deaconess Medical Center Fitch H
Cornell Clinical Trials Unit Stroberg T
Duke University Medical Center Giner J, Harmon L
Northwestern University Bruce J
Pacific Oaks Research Perry B, Walker S
Rush Presbyterian St. Luke's Medical Center Narkiewicz E
Thomas Street Clinic Sepcie B
University of Colorado Canmann S, Putnam B, Ray MG
University of North Carolina at Chapel Hill Ngo L
PPD Development McCarley S, Nicks B, Wheat R
Abbott Laboratories Kempf D, Potthoff A, Rode R, Sheehan K, Yang G

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).

2. Department of Health and Human Services. Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. Updated 23 April 2001.*Amplicor HIV-1 Monitor is a trademark of Roche Molecular Diagnostics

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Poster    
Lopinavir/ritonavir (Kaletra) in Antiretroviral Naïve HIV+ Patients: 
Week 144 Follow-Up

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