2003
Verona, Italy
Dose-Timing Information Improves The Clinical Explanatory Power Of Data On Patient Adherence To Antiretroviral Drug Regimens
B. Vrijens(1-2), S.L. Mayer(1),R.Rode(3), R. Bertz(3), J. Urquhart(1)
(1) AARDEX Ltd., Zug, Switzerland; (2) Dept of Biostatistics, University of Liège, Belgium; (3) Abbott Laboratories, Chicago, United States
Objectives: Variable adherence to prescribed antiretroviral (ARV) therapy in HIV-infected individuals may result in variable exposure to the ARV drugs used. Large deficits in ARV drug exposure clearly have a negative effect on virologic outcomes, [1-3]; however, appreciable rates of virologic failure are seen even in patients who take >95% of prescribed doses, suggesting that dose-timing errors play a crucial role in virologic failure. This analysis aims to assess the effect of variations in ARV dose-timing on virologic response measured repeatedly over time in HIV-infected individuals.
Methods: The analysis from this phase I/II randomized clinical trial involved 35 ARV-naïve, HIV-infected individuals, prescribed lopinavir/ritonavir (QD: 800/200 mg or BID: 400/100 mg), stavudine, and lamivudine. Observations on plasma viral load (VL; copies/mL) were categorized into 4 clinically meaningful states, 0-49, 50-399, 400-1999, and >1999. A time-dependent continuation ratio model was used to analyze longitudinal ordinal responses. Several measures of adherence were investigated including taking compliance, correct dosing, and time spent below EC50. A new variable, Timing Error, was derived from the third moment of the inter-dose interval distribution. Explanatory power for changes in VL of each adherence parameter was assessed through changes in model deviances.
Results: Improvement and deterioration in VL were modelled separately and both were significantly associated with lopinavir plasma concentration (p=0.0002 and p<0.0001, respectively). The most significant PK-derived predictor, the time that Internal Exposure fell below the EC50, appeared to be insensitive to between-patient variability in PK parameters. Changes in VL were most significantly driven by within-patient dose-timing errors. For example, the probability of VL deteriorating from 0-49 to >50 copies/mL was 8% for perfect dose-timing and 14% for "moderate" Timing Errors.
Conclusion: Dose-timing information increases the explanatory power of patient adherence data and its association with ARV treatment outcomes. After initial viral suppression, lopinavir/ritonavir was not highly dependent on Timing Errors. Further research is needed to evaluate the relative "forgiveness" of lopinavir/ritonavir and other drugs regarding Timing Errors. This analysis reveals a potential reason for virologic failure and can also guide the practitioner in determining when to consider an adherence intervention strategy.
References
[1] Paterson DL, Swindells S, Mohr J, et al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Int Med 133: 21-30, 2000.
[2] Liu H, Golin CE, Miller LG, et al. A comparison study of multiple measures of adherence to HIV protease inhibitors. Ann Inter Med 134: 968-77, 2001.
[3] Arnsten J, Demas P, et al. Antiretroviral therapy adherence and viral suppression in HIV-infected drug users: comparison of self-report and electronic monitoring. Clin Inf Dis 33: 1417-23, 2001.