Efficacy of lopinavir-ritonavir reduced dose in HIV-infected patients.

Abstract

Dear Editor: The approved dose of lopinavir/ritonavir is 400/100 mg twice daily. Originally, the two protease inhibitors were coformulated in a soft gelatin capsule with 133 mg of lopinavir and 33 mg of ritonavir (3 capsules twice daily). The new heatstable formulation (200/50 mg; 2 tablets twice daily) showed 18% higher plasma AUC lopinavir levels and 24% higher Cmax levels than the soft gelatin formulation, but also less variable plasma drug concentrations, no food dependence, and no need for refrigeration. The Abbott 720 trial evaluated three doses of lopinavir/ritonavir in treatment-naı̈ve patients. In sequential randomizations, two groups of treatment-naı̈ve patients were given 48 weeks treatment with D4T/3TC+LPV/r 200/100 mg twice daily and D4T/3TC+LPV/r 400/100 mg twice daily (group 1) and D4T/3TC+LPV/r 400/100 mg twice daily and D4T/3TC+LPV/r 400/200 mg twice daily (group 2). Despite the strong efficacy of the 200/100 mg twice daily dose observed in protease inhibitor (PI)-naı̈ve patients, the 400/100 mg twice daily dose was chosen for phase 3 development. The aim may have been to target both PI-naı̈ve and PI-pretreated patients with a single uniform dose. However, this leaves the possibility of using a lower lopinavir/r dose for PI-naı̈ve patients. In a recent cohort study in France, 28 patients with HIV RNA levels below 50 copies per milliliter on lopinavir/r 400/ 100 mg twice daily had their dose reduced to 266/66 mg twice daily, using the old soft gelatin capsule formulation. HIV RNA levels remained suppressed below 50 copies per milliliter for 48 weeks in 25 of the 28 patients, with 2 patients showing HIV RNA levels between 50–400 copies per milliliter and 1 true virologic failure. Without a control group it is difficult to know the true efficacy of the lower dose, but these results do rule out a substantial loss of efficacy with lopinavir/r dose reductions. In addition, the HIVNAT 019 trial evaluated two doses of lopinavir/ritonavir—400/100 mg twice daily and 266/66 mg twice daily—in combination with saquinavir in 48 treatment-naı̈ve patients. This study also showed no differences in efficacy between the doses. A metaanalysis of clinical pharmacology studies of lopinavir/ritonavir suggests that the dose of 200/50 twice daily (1 meltrex tablet twice daily) would give lopinavir drug levels 50% lower than the standard dose. The pharmacokinetics of lopinavir are highly dependent on the dose of ritonavir used, and higher doses of ritonavir can compensate for lower doses of lopinavir. So an alternative is to use a 200/150 twice daily dose (1 meltrex tablet and 1 ritonavir tablet twice daily), which would then provide predicted lopinavir drug levels close to that of the approved dose. It has been showed that therapeutic plasma concentrations of lopinavir can be achieved in HIV-negative healthy volunteers with 200/150 mg of lopinavir/ritonavir twice daily. In contrast, the 200/50 mg dose of lopinavir/ritonavir was not considered suitable for evaluation in future trials in HIVinfected patients due to lopinavir concentrations below the suggested MEC of 1000 ng/mL. We wish to report our experience in six HIV-1–infected patients (4 women) on reduced dose of lopinavir/ritonavir followed in the Outpatient Clinic, Infectious Diseases Unit, University of Verona for a median of 15 months. All patients were older than 18 years. Two patients were on lopinavir/ritonavir monotherapy at standard dose (400/ 100 mg twice daily), two were on tenofovir/emtricitabine plus lopinavir/ritonavir at standard doses, and two had chosen to autoreduce the dose of lopinavir/ritonavir (1 tablet, i.e., 200/50 mg twice daily) at the beginning of highly active antiretroviral therapy (HAART), which consisted of a combination of tenofovir/emtricitabine. Median HAART time before dose reduction was 15 months (range, 10–22 months) for the first four patients, while the latter two patients had been on the reduced dosage for 7 and 15 months, respectively, when we performed pharmacokinetic analysis. The four patients taking the standard dose of lopinavir/ritonavir had hypertriglyceridemia (plasma fasting triglycerides >1.69 mmol/L) while the two patients on reduced dose had a normal value of plasma triglycerides. The former four patients, at the switch to a lower dose, had HIV RNA less than 50 copies per milliliter. Table 1 provides body weight, body mass index (BMI), HIV RNA level, and CD4 cell count before starting HAART; HIV RNA at the time of switch (for 4 patients); and HIV RNA at the time of the last visit.

DOI: 10.1089/apc.2011.0100

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Cite this paper

@article{Lattuada2011EfficacyOL, title={Efficacy of lopinavir-ritonavir reduced dose in HIV-infected patients.}, author={Emanuela Lattuada and Massimiliano Lanzafame and Sandro Vento}, journal={AIDS patient care and STDs}, year={2011}, volume={25 8}, pages={455-6} }