Cerebrospinal fluid HIV-1 RNA during treatment with ritonavir/saquinavir or ritonavir/saquinavir/stavudine

Objective: To assess the HIV-1-RNA response and drug concentrations in cerebro-spinal fluid (CSF) and serum during treatment with saquinavir (SQV)/ritonavir (RIV) or SQV/RIV plus stavudine (d4T) in HIV-1-infected patients. Design: A multicentre, open-label, randomized controlled trial. Methods: A total of 208 protease inhibitor (PI) and d4T-naive, HIV-1-infected patients were treated with RTV 400 mg twice daily and SQV 400 mg twice daily with or without d4T 40 mg twice daily. Intensification with reverse transcriptase inhibitors was allowed if serum HIV RNA remained above 400 copies/ml after 12 weeks. In 27 volunteers, CSF and serum HIV RNA were measured at baseline, weeks 12 and 48, using the Roche Amplicor and the ultrasensitive assay. In 22 patients, serum and CSF drug concentrations were determined at week 12. Results: The median baseline serum and CSF HIV-RNA concentrations were 4.81 and 3.21 log10 copies/ml, respectively. A difference in the proportion of patients with a CSF HIV-RNA level below the limit of quantification ( LLQ at week 12 in logistic regression analysis (P= 0.005). CSF RIV and SQV concentrations were < LLQ in most patients. Conclusion: RTV/SQV alone cannot suppress detectable CSF HIV-1-RNA levels to < LLQ after 12 weeks of treatment in the majority of patients. CSF drug concentrations of RTV and SQV < LLQ may explain the suboptimal antiretroviral effect in the CSF. (C) 2000 Lippincott Williams and Wilkins

The steady-state pharmacokinetics of nevirapine during once daily and twice daily dosing in HIV-1-infected individuals

Objective: To investigate and to compare the steady-state plasma pharmacokinetics of nevirapine in a dosing regimen of 400 mg once daily versus 200 mg twice daily in HIV-1-infected individuals. Design: Open-label, randomized, cross-over study. Methods: Twenty HIV-1-infected individuals who already used nevirapine as part of their antiretroviral regimen were randomized to continue their current regimen (200 mg twice daily) or to switch to the alternate regimen (400 mg once daily). The steady-state plasma pharmacokinetics of nevirapine were assessed after 2 weeks during a 24-h period. Subsequently, patients were switched to the alternate regimen and the pharmacokinetics of nevirapine were assessed again after 2 weeks. Noncompartmental methods were used to calculate the area under the plasma concentration versus time curve (AUC([24 h])), and the maximal (C(max)) and minimal plasma concentration (C(min)), the time to C(max) (t(max)), the plasma elimination half-life (t(1/2)), the apparent oral clearance (Cl/F) and the apparent volume of distribution (V/F). Differences in these pharmacokinetic parameters for the two dosing regimens were tested using ANOVA. Results: The exposure to nevirapine, as measured by the AUC([24 h]), was not significantly different between the 400 mg once daily and 200 mg twice daily dosing regimen (P = 0.60). Furthermore, the values for t(max), t(1/2) Cl/F and V/F were not significantly different between the two dosing regimens (P ≥ 0.08). However, C(max) and C(min) were higher and lower, respectively, when nevirapine was used in the once daily regimen as compared with the twice daily regimen. The median values for C(max) and C(min) as measured for the once daily and twice daily regimens were 6.69 and 5.74 μg/ml, respectively (P = 0.03), and 2.88 and 3.73 μg/ml, respectively (P < 0.01). Conclusion: These data show that the daily exposure to nevirapine, as measured by the plasma AUC([24 h]), is not different between a 400 mg once daily and a 200 mg twice daily dosing regimen. However, C(max) and C(min) are higher and lower, respectively, for the once daily regimen as compared with the twice daily regimen. The clinical implications of these differences remain to be established. (C) 2000 Lippincott Williams and Wilkins

Limited patient adherence to highly active antiretroviral therapy for HIV-1 infection in an observational cohort study

Background: Adherence to highly active antiretroviral therapy (HAART) for human immunodeficiency syndrome type 1 (HIV-1) infection is essential to sustain viral suppression and prevent drug resistance. We investigated adherence to HAART among patients in a clinical cohort study. Methods: Patients receiving HAART had their plasma concentrations of protease inhibitors or nevirapine measured and completed a questionnaire on adherence. We determined the percentage of patients who reported taking all antiretroviral medication on time and according to dietary instructions in the past week. Drug exposure was compared between patients reporting deviation from their regimen and fully adherent patients. Among patients who received HAART for at least 24 weeks, we assessed the association between adherence and virologic outcome. Results: A total of 224 of 261 eligible patients completed a questionnaire. Forty-seven percent reported taking all antiretroviral medication on time and according to dietary instructions. Patients who reported deviation from their regimen showed lower drug exposure compared with fully adherent patients (median concentration ratio, 0.81 vs 1.07; P=.001). Among those receiving HAART for at least 24 weeks, patients reporting deviation from their regimen were less likely to have plasma HIV-1 RNA levels below 500 copies/mI. (adjusted odds ratio, 4.0; 95% confidence interval, 1.4-11.6) compared with fully adherent patients. Conclusions: Only half of the patients took all antiretroviral medication in accordance with time and dietary instructions in the preceding week. Deviation from the antiretroviral regimen was associated with decreased drug exposure and a decreased likelihood of having suppressed plasma HIV-1 RNA loads. Patient adherence should remain a prime concern in the management of HIV-1 infection