Introduction: There is an increased interest in developing once-daily regimens for the treatment of HIV-infected patients. A Phase II study was conducted to investigate the pharmacokinetics, and short-term safety and efficacy of an indinavir/ritonavir combination as part of a once-daily regimen.
Methods: HIV-infected patients with either proven poor compliance to HAART regimens in the past or an anticipated poor compliance to such a regimen in the future were eligible for this study. They received a once-daily regimen consisting of indinavir 1200 mg, ritonavir 400 mg, and one or two nucleoside reverse transcriptase inhibitors (NRTIs), also administered once daily with food. A 24 h pharmacokinetic profile was constructed in a subset of patients. Short-term safety and efficacy were evaluated at 4, 12 and 24 weeks after initiation of treatment.
Results: A total of 64 patients were included in this study, of whom 27 (42.2%) were treatment-naive. The geometric mean (+95% CI) of indinavir AUC0-24h, Cmax and Cmin as determined in an unselected group of 16 patients were 84.9 (69.7-103.5) mg/l x h, 12.0 (10.2-14.1) mg/l and 0.15 (0.09-0.26) mg/l, respectively. A large interpatient variability was observed, with five out of the 16 subjects having a Cmin value below the minimum effective concentration of 0.10 mg/l. During the 24 weeks of follow-up nine patients (14.1%) discontinued study medication, two due to medication-related toxicity. Gastrointestinal adverse events were reported most frequently (50.0%), followed by skin effects (45.3%), joint pain (9.4%) and urological complaints (7.8%). No patient developed nephrolithiasis. The median (+interquartile range) serum creatinine level in the 64 patients increased slightly from 74 (63-88) micromol/l to 79 (66-92) micromol/l during the 24 weeks of follow-up. One new patient reached a grade 1 elevation in serum creatinine, which normalized during the follow-up; five other patients with elevated serum creatinine at baseline remained stable. During the 24 weeks of follow-up, the proportion of patients with a viral load <500 copies/ml increased from 35.1% at baseline to 71.4% (ITT NC=F analysis) or 83.3% (OT analysis), and from 0% at baseline to 76.2% (ITT NC=F analysis) or 100.0% (OT analysis) in treatment-experienced and -naive patients, respectively. This was accompanied by a mean increase in CD4 cell count of 52 and 220 cells/mm3 in these two sub-groups, respectively.
Conclusion: The 24-week follow-up data of this study indicate favourable pharmacokinetics of an indinavir/ritonavir 1200/400 mg combination as part of a once-daily regimen consisting also of one or two NRTIs. Short-term safety and efficacy were also satisfactory. Long-term follow up is planned to evaluate the durability of these results.