BACKGROUND

The M98-957 study is an ongoing phase II, open-label, randomized trial of Kaletra (lopinavir/ritonavir, formerly known as ABT-378/r), in combination with efavirenz, in multiple PI-experienced/NNRTI-naïve patients. Pharmacokinetic data and 48 week efficacy and safety data are reported here. Association of virologic response at Week 48 with baseline virologic genotype/phenotype is presented as well. 

METHODS

Entry Criteria

• HIV RNA >1,000 copies/mL on present PI regimen (no CD4 cell count restriction).
  
• On treatment with at least 1 PI for
  8 weeks at study entry.
  
• Multiple PI-experienced (history of sequential or concurrent treatment with at least 2 PIs for at least 3 months each).
  
• NNRTI-naïve.

Study Design and Analysis

• 57 patients received Kaletra 400/100 mg (3 coformulated capsules) BID in place of their current PI, in combination with efavirenz (600 mg QD) and NRTIs as determined by the investigator, for the first 13 days of the study (Figure 1).
  
• On study Day 14, patients randomized to Arm B (n=28) increased their Kaletra dose to 533/133 mg (4 coformulated capsules) BID, while patients in Arm A (n=29) remained on the 400/100 mg BID dose (Figure 1).
  
• Lopinavir trough levels were drawn at Week 2; full PK was performed at Week 5; efavirenz levels were also drawn at Weeks 2 and 5.
  
• Plasma HIV RNA was quantified using the Roche Amplicor HIV-1 Monitor (assay lower limit of quantitation [LLQ] 400 copies/mL) and Roche  Ultrasensitive assay (LLQ 50 copies/mL).
  
•  All patients in Arm A began conversion to the 533/133 BID dose after Week 24 and completed the process prior to their Week 48 visit.

Figure 1. Study Design

• Efficacy/safety results presented for both dose groups combined (except lipid results).

RESULTS

Pre-Study Antiretroviral Therapy

• Prior PI use included IDV (86%), RTV (77%), SQV (72%), and NFV (58%). 
  – Mean number of prior PIs=3 (range: 1-4)
  – For patients who received RTV pre-study, 66% (29/44) received it as dual PI therapy.
  
• Prior NRTI use included ZDV (93%), 3TC (91%), d4T (91%), ddl (79%), ddC (46%), and ABC (18%).
  – Mean number NRTIs at baseline=2 (range: 1-4).
  – 75% of patients did not receive a new NRTI in conjunction with Kaletra and efavirenz within the first eight weeks of study.
  
• Mean number of prior ARVs=7 (range: 3-10).

Baseline Viral Susceptibility

• Protease inhibitor phenotypic susceptibility data were available for 56 of 57 baseline viral isolates (ViroLogic, Inc. method).
  
• Sixty-eight percent (38/56) of patients had baseline viral isolates demonstrating cross resistance ( > 4-fold increase in EC ₅₀ relative to wild-type virus) to at least 3 licensed PIs.
  
• Forty-three percent of patients had baseline viral isolates (24/56) demonstrating
  10-fold increase in EC 50 of lopinavir relative to wild-type virus.

Pharmacokinetic Data

•  Lopinavir levels achieved with the 400/100 mg dose are reduced when co-dosed with efavirenz (C _trough reduced ~33%; AUC reduced ~25%).
  
• Kaletra 533/133 mg dose with efavirenz provides similar lopinavir exposures to the 400/100 mg dose without efavirenz based on historical controls.1
  
• Efavirenz levels are similar for both Kaletra dose levels studied.

Viral Load Suppression at 48 Weeks

• On-treatment analysis (OT): 80% of patients had viral load (VL) <400 copies/mL and 71% had VL <50 copies/mL at Week 48 (Figures 2 and 3).
  
• Intent-to-treat analysis (ITT M=F; missing values [M] considered as treatment failure [F]): 65% of patients had VL <400 copies/mL and 56% had VL <50 copies/mL at Week 48 (Figures 2 and 3).

• At 48 weeks, a high response rate at <400 copies/mL (93%) was observed in patients whose baseline isolates displayed <10-fold reduced in vitro susceptibility to lopinavir at baseline (Figure 4). Response rates diminished incrementally in patients with 10-40 and >40-fold reduced susceptibility to lopinavir at baseline.
  
• Similarly, a high response rate at 48 weeks at <400 copies/mL (92%) was observed in patients whose baseline isolates contained 0-5 protease mutations associated with reduced in vitro susceptibility to lopinavir (Figure 5). Response rates diminished incrementally in patients with a baseline lopinavir mutation score of 6-7 and 8-10.

CD4 Response at 48 Weeks

• Among patients on study at Week 48, the mean CD4 cell count was 392 cells/mm ³ (mean change from baseline of 94 cells/mm ³ ) (Figure 6). No significant differences between treatment groups were observed after Week 2.

Figure 6. Mean Change from Baseline in CD4 Cell Count

Safety and Tolerability

• The most common study drug related adverse events of at least moderate severity were diarrhea and asthenia, while the most common laboratory abnormality was lipid elevations (Table 4). Of note, lipid measurements were made without regard to fasting.
  
• Eleven patients discontinued the study through 48 weeks; of these, 3 discontinuations were due to adverse events/laboratory abnormalities probably or possibly related to Kaletra in the opinion of the investigator.
  
• None of the patients who experienced amylase values >2 x ULN through Week 48 had associated elevations of pancreatic amylase (>2 x ULN).

Figure 7. Mean Lipid Values Over Time

*Dose was increased from 400/100 mg to 533/133 mg at Week 24 in ongoing patients.

• There is a suggestion of greater lipid increases on the 533/133 mg dose compared to the 400/100 mg dose (Figure 7). This difference diminishes after Week 24 when all M98-957 patients were converted to the 533/133 mg dose.
  
  

• LDL/HDL cholesterol ratios were obtained in a subset of fasting patients and did not significantly change from baseline through 24 weeks of Kaletra therapy (400/100 mg=+0.14, N=12; 533/133 mg=-0.12, N=8).

CONCLUSIONS

• Kaletra exhibits a potent antiviral effect through 48 weeks in multiply PI-experienced, NNRTI-naïve patients.
  
• Virologic response decreases markedly with 8 or more baseline protease mutations or > 40-fold reduced susceptibility to LPV.
  
• Kaletra should be increased to 533/133 mg BID when coadministered with EFV in patients where reduced susceptibility to LPV is suspected.
  
• Kaletra and EFV were well tolerated and associated with a low rate of discontinuation for treatment related adverse events through 48 weeks.

REFERENCES

Efavirenz was supplied by DuPont Pharmaceuticals Company.
Phenotype testing of baseline viral isolates was performed by ViroLogic, Inc.

ACKNOWLEDGMENTS

1. Bertz R, Lam W, Brun S, et al. Multiple-dose pharmacokinetics (PK) of ABT-378/ritonavir (ABT-378/r) in HIV+ subjects. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, USA, 1999 (abstract 0327).

TOP

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Oral Presentation 525
  Kaletra (ABT-378/ritonavir) and Efavirenz: 48-Week Safety/Efficacy/Pharmacokinetic Evaluation 
in Multiple PI-Experienced Patients 

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