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 Safety of Kaletra: Data from Phase II and Phase III Clinical Trials. B Bernstein, M King, S Brun, P Cernohous, A Potthoff, J Moseley, M Sullivan, K Grebner, and E Sun.  Abbott Laboratories, Antiviral Venture, Abbott Park, IL USA

BACKGROUND

Lopinavir is an HIV protease inhibitor (PI) that is co-formulated with ritonavir, an inhibitor of cytochrome P450-3A, as Kaletra. The standard dose of Kaletra is 400 mgLPV/100 mg ritonavir, as 3 co-formulated capsules, BID. Kaletra has been studied in clinical trials in over 500 patients ranging from antiretroviral (ARV) naïve to multiple PI experienced (Figure 1 and Table 1). Superior efficacy has been demonstrated with data from Study M98-863, a Phase III comparative trial of ARV-naïve patients comparing Kaletra (n=326) to nelfinavir (n=327) (Figure 2). In Phase II trials, antiviral activity has been demonstrated in ARV-naïve patients (Study M97-720, n=100), in single PI-experienced patients (Study M97-765, n=70), and in multiple PI-experienced patients (Study M98-957, n=57) (Figure 3).

METHODS

The safety and tolerability of Kaletra were examined in Phase II and III clinical trials through collection of adverse events (AEs) with severity/relationship assessed by investigator. Laboratory tests were conducted without regard to fasting. Results are expressed as the cumulative incidence over the durations noted.

RESULTS

Study Drug-Related Discontinuations

• Study drug-related discontinuations were infrequent in Phase II/III clinical trials, reflecting the overall tolerability of Kaletra (Table 2).

Adverse Events

• Adverse events of at least moderate severity and possible, probable, or unknown relationship to study medication as determined by the investigator are summarized in Tables 3 and 4. Moderate is defined as "causing discomfort and interrupting the subject's normal activity."

• Gastrointestinal (GI) symptoms (diarrhea and nausea) were the most common AEs observed in both Phase II and Phase III clinical trials. These occurred with similar frequency in the Kaletra and nelfinavir arms of the Phase III trial.

• In both Phase II and Phase III trials, study drug discontinuations and interruptions due to GI AEs were infrequent (Table 5).
  
• The higher rates of GI AEs seen in some Phase II trials may reflect the use of doses of LPV/r greater than 400 mg/100 mg in some patients as well as the longer duration of follow-up.

• In general, laboratory determinations were obtained monthly for the first six months of the trials, then every two months through Week 48, and quarterly thereafter.
  
  • Laboratory determinations were performed without regard to fasting.
    
  • Severity grades based on the Division of AIDS Grading Severity of Adult Adverse Events criteria.
    
• The most common laboratory abnormalities observed in Phase III were elevations in triglycerides and total cholesterol.

Laboratory Abnormalities Observed in the Phase III Trial Through Week 60

• Hyperlipidemia-Triglycerides
  
  • Elevations of triglycerides were reported more commonly in Kaletra than nelfinavir treated patients (11% vs. 2%, see Table 6).
    
  • The maximum triglyceride level experienced by the majority of patients in both treatment groups was <400 mg/dL (Figure 4).
    
• Hyperlipidemia-Cholesterol
  
  • The maximum cholesterol level experienced by the majority of patients in both treatment groups was < 240 mg/dL (Figure 5).

• Hyperlipidemia-Intermittency
  
  • Participants had an average of 7 laboratory determinations performed during the study obtained without regard to fasting. In participants with Grade 3/4 triglyceride or cholesterol elevations, the abnormality was generally intermittent, with most having only 1-2 measurements reach this magnitude.
    
  • Grade 3/4 triglyceride elevations were not associated with pancreatitis.
    
• Lipid Subfraction Determination
  
  • Both total cholesterol (TC) and high density lipoprotein (HDL) cholesterol rose between baseline and Week 24 in Phase III subjects receiving Kaletra or nelfinavir therapy (Figure 6). Measurements were performed on these patients who were fasting at both baseline and Week 24. The change in the TC/HDL ratio was not statistically significant (p=0.179) in subjects treated with Kaletra. A small, but statistically significant (p<0.001) increase in the ratio was observed in nelfinavir-treated patients.

• Lipid elevations, when present, tended to occur early and were generally non-progressive over time (Figure 7 and Figure 8).

• In the Phase II/III trials, no patient discontinued due to study drug-related Grade 3/4 lipid elevations. o Grade 3/4 lipid elevations occurred more frequently in Kaletra trials involving PI-experienced patients (Figure 9).
  
• A multivariate analysis was performed across all trials through Week 48 to identify the potential risk factors for Grade 3/4 triglyceride and/or cholesterol elevations.
  
  • Risk factors for Grade 3/4 triglyceride elevations were found to be:
    
    • Elevated baseline triglycerides
      
    • Prior PI/current NNRTI use
      
  • Risk factors for Grade 3/4 cholesterol elevations were found to be:
    
    • Elevated baseline cholesterol
      
    • Prior zidovudine (AZT) and PI use
      
    • >1 year since HIV diagnosis
      
    • Hepatitis C negative
      
• Treatment for lipid elevations was left to the discretion of the investigator with basic management guidelines discussed in the clinical protocols. Less than half the patients who experienced a Grade 3/4 lipid elevation received pharmacologic therapy for hyperlipidemia. When prescribed, treatment with pharmacologic lipid-lowering agents resulted in a median decrease in cholesterol values of 17% and a median decrease in triglyceride values of 48%.

Treatment-Emergent Body Fat Composition Changes

• Investigators were instructed to report as AEs all episodes of central adiposity, peripheral fat wasting, breast hypertrophy, dorsal fat pad, multiple lipomas, and Cushingoid appearance. Also considered as body fat composition changes were episodes of abdomen enlargement, obesity, lipodystrophy, breast enlargement, and gynecomastia.
  
• Through 60 weeks of treatment, AEs consistent with body composition changes were noted in 7% of patients in either treatment arm in the Phase III comparative trial (Table 7). There was no association between these events and Grade 3/4 lipid elevations.
  
• The incidence of body fat composition changes across all Kaletra trials is presented in Figure 10.

Safety in Patients with Hepatitis B or C in the Phase III Comparative Trial

• In the Phase III comparative trial, 115 patients who were hepatitis B surface antigen positive (n=39) or hepatitis C antibody positive (n=76) at baseline had on-study laboratory determinations performed.

• Patients were allowed to participate in the Phase III comparative trial if their screening LFTs were <3x ULN. Patients were allowed to remain on medication unless their LFTs exceeded 10x ULN, provided they remained asymptomatic without concomitant Grade 3+ elevations in total bilirubin or alkaline phosphatase. The incidence of Grade 3+ AST/ALT elevations is summarized in Table 8.

• Kaletra has been well tolerated in Phase II/III trials as reflected by the low rates of study drug-related discontinuations observed.
  
• In both Phase II and Phase III trials, the most common AEs were gastrointestinal in origin and infrequently resulted in study discontinuation or interruption.
  
• Lipid elevations were the most commonly observed laboratory abnormalities observed in the Phase II and Phase III trials and occurred more often in patients with prior PI-experience and higher baseline lipid levels. Study discontinuations or interruptions due to elevated lipids were infrequent. Elevated lipid levels were generally intermittent and responded to lipid lowering agents.

CONCLUSIONS

• Risk of Grade 3/4 AST/ALT elevations was greater in hepatitis B/C+ patients compared to hepatitis B/C-. Risks of elevation were comparable between hepatitis B+ and hepatitis C+ patients.The relative risk (95% CI) of Grade 3/4 elevations based on hepatitis status was 3.3 (1.4, 8.2) for the Kaletra group and 10.2 (3.8, 27.5) for the nelfinavir group.
  
• Within each treatment group, the mean change in AST/ALT from baseline was similar regardless of hepatitis status.
  
• Four study drug interruptions occurred as a result of Grade 3/4 AST/ALT elevations (1 Kaletra patient, 3 NFV patients). No hepatitis B/C+ patient discontinued the study due to Grade 3/4 LFTs.

ACKNOWLEDGEMENTS

The subjects, investigators, and coordinators from studies M97-720, M97-765, M98-863, and M98-957

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Poster 
  Safety of Kaletra: Data from Phase II and Phase III Clinical Trials

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