Low-dose indinavir in combination with low-dose ritonavir: steady-state pharmacokinetics and long-term clinical outcome follow-up

Abstract

Objectives

To evaluate the long-term efficacy and pharmacokinetics of indinavir (IDV)/ritonavir (RTV) 400/100 mg twice a day in combination with two nucleoside reverse transcriptase inhibitors.

Methods

The study was retrospective with a prospective pharmacokinetic study at a single centre. All HIV-1-infected patients who started the regimen in the period from January 1999 to February 2001 were included in the study. Plasma HIV RNA and CD4 cell counts were recorded from baseline to week 120. Results were evaluated as intention-to-treat and on-treatment analyses with separate analyses for protease inhibitor naive and experienced patients. Patients who were still on the regimen by August 2001 were asked to participate in a pharmacokinetic evaluation.

Results

Twenty-one patients started treatment with the regimen (median follow-up: 116 weeks). The percentage of patients with below 20 HIV-1 RNA copies/mL was 70.0% at week 120 and the median CD4 cell count increased from 320 to 607 cells/μL (P=0.062). The median IDV morning and evening C_min were 434 ng/mL and 220 ng/mL, respectively.

Conclusions

Treatment with the IDV/RTV 400/100 mg regimen appears to be efficacious for up to 2 years. However, rather low IDV C_min suggests that the regimen should be evaluated further before its widespread use and that the regimen probably should be guided by pharmacokinetic evaluation.

Introduction

The use of combination therapy with antiretroviral drugs such as indinavir (IDV) has resulted in long-term suppression of HIV replication, which has been correlated to a decrease in morbidity and mortality for HIV-infected patients [1–3]. The IDV 800 mg three times a day regimen in combination with nucleoside reverse transcriptase inhibitors (NRTIs) has to a large degree been replaced by an 800 mg twice a day regimen in combination with low-dose ritonavir (RTV) (100 or 200 mg) or a 400/400 mg regimen. RTV serves as a strong inhibitor of CYP3A4-mediated IDV metabolism resulting in increased plasma concentrations of IDV [4]. These regimens have the benefit of being administered only twice a day with no food restrictions, and with sufficient drug exposure to achieve suppression of HIV replication [5].

However, the twice a day regimens are associated with toxicity problems. RTV adverse events such as nausea and vomiting are common with the 400/400 mg regimen, and the 800/100 mg regimen has been shown to result in very high IDV C_max and C_min levels, which have been connected to nephrological, gastroenterological, cutaneous and metabolic adverse events [5–8]. In the BEST switch study (continued IDV 800 mg three times a day vs. the 800/100 mg regimen) and the MaxCmin1 trial (saquinavir/RTV 1000/100 mg twice a day vs. the 800/100 mg regimen), the 800/100 mg regimen was associated with more toxicity than the regimens it was compared to [9, 10].

With the purpose of reducing IDV-related toxicity, a regimen of 400 mg of IDV in combination with 100 mg of RTV and two NRTIs administered twice a day was chosen as standard of care at the Department of Internal Medicine, Herning County Hospital, Herning, Denmark.

This regimen has recently been evaluated by Katlama et al. in a prospective open label study of antiretroviral-therapy experienced patients, with below 200 HIV-1 RNA copies/mL who switched to IDV 400 mg with RTV 100 mg twice a day [11]. Viral load remained below 200 copies/mL over a median follow-up of 24 weeks (n=47) and no specific side effects were observed due to the therapy switch. In patients initially treated with IDV 800 mg three times a day (n=20), there was a decrease in IDV C_max and an increase in C_min suggesting a more favourable concentration profile with the IDV/RTV 400/100 mg twice a day regimen. The regimen has also been used outside clinical trials in patients initially receiving the 800/100 mg regimen in an attempt to reduce IDV-related toxicity [5].

Although the regimen might save resources and reduce the occurrence of adverse events, long-term experience is not available. We did a retrospective study supplemented with a prospective pharmacokinetic study to evaluate the long-term efficacy and pharmacokinetics of the IDV/RTV 400/100 mg twice a day regimen.

Methods

Study population

All HIV-1-infected patients starting antiretroviral combination therapy with 400 mg of IDV, 100 mg of RTV and two NRTIs twice a day at the Department of Internal Medicine, Herning County Hospital, Herning, Denmark, from January 1999 to February 2001, were included in the study. Follow-up was ended by February 2002. The department is a small unit taking care of a total of 54 HIV-1-infected patients.

Study design and assessments

The study was retrospective with a prospective pharmacokinetic study. The study protocol was approved by the local Ethics Committee (case no. 20000229).

All patient files were reviewed with regard to age, weight, body mass index, gender, race, duration of known HIV infection, AIDS diagnosis, previous antiretroviral treatment and coadministered drugs. Plasma HIV-1 RNA and CD4 cell counts were recorded at baseline to week 120. Results were evaluated as intention-to-treat and on-treatment analyses with separate analyses for protease inhibitor- (PI) naive and experienced patients.

Patients were asked to participate in a morning C_min measurement and a 12-h pharmacokinetic evaluation if still on the regimen by August 2001. The samples for the pharmacokinetic evaluation were collected predose and 0.5, 1, 2, 3, 4, 6, 8 and 12 h after the morning dose.

Plasma HIV RNA, CD4 cell counts and IDV concentrations

Plasma HIV-1 RNA was determined using a quantitative HIV-1 RNA polymerase chain reaction assay with a sensitivity of 20 copies/mL (Amplicor HIV-1 Monitor version 1.5, Roche Molecular Systems, Branchburg, NJ). CD4 cell counts were measured by flow cytometry. Plasma concentrations of IDV were determined by a validated and externally controlled assay [12, 13].

Pharmacokinetic analysis

Pharmacokinetic parameters were calculated from concentration-time data obtained, using the non-compartmental pharmacokinetic method supplied with WinNonlin Standard Edition 3.1 (Pharsight Corporation, Mountain View, CA).

Statistical analysis

Results were compared with Fisher's exact test and the Wilcoxon signed rank test. The statistical test values presented are Hodges-Lehmann estimates of median differences with exact 95% confidence intervals (CI). The statistical analyses were performed using StatXact-3 (Cytel Software Corporation, Cambridge, MA).

Results

Study population

Twenty-one patients started treatment with IDV/RTV 400/100 mg twice a day in combination with two NRTIs. Patient characteristics grouped as intention-to-treat, on-treatment; PI-naive and -experienced patients are shown in Table 1. There was a median (range) follow-up of 116 (52–124), 117 (52–124), 105 (52–120) and 119 (85–124) weeks in the four groups, respectively. Only three patients received coadministered drugs, methadone, nitrazepam, diazepam, olanzapine and sertraline, besides antiretroviral treatment.

Table 1.   Characteristics of study population by analyses

	Intention-to-treat (n=21)	On-treatment (n=17)	PI naive (n=9)	PI experienced (n=12)
PI, protease inhibitor. BMI, body mass index. a Median (range).
Age (years)	41 (17–75)a	37 (26–59)	37 (30–59)	42 (17–75)
Weight (kg)	77 (55–104)	77 (55–104)	77 (55–101)	75 (55–104)
BMI (kg m^–2)	25.7 (19.0–32.4)	25.7 (19.0–32.4)	25.7 (19.0–30.5)	24.5 (20.2–32.4)
Gender
female	9	8	3	6
male	12	9	6	6
Race
Caucasian	13	9	4	9
Black	6	6	4	2
Other	2	2	1	1
Baseline
HIV-1 RNA	4460	4460	172 000	1986
(copies/mL)	(<20–281 000)	(<20–281 000)	(1270–281 000)	(< 20–60 800)
CD4 cell count	320	388	228	448
(cells/μL)	(25–889)	(25–734)	(25–501)	(25–889)
AIDS diagnosis	4	2	2	2

Eleven of the 12 PI-experienced patients had received IDV three times a day as the only PI prior to the 400/100 mg regimen. They changed to the 400/100 mg regimen to benefit from the twice a day administration. The last patient had received saquinavir, IDV, RTV and nelfinavir before changing to the 400/100 mg regimen.

Three of the PI-experienced patients receiving the 400/100 mg regimen changed to another regimen because of virological failure (5470, 18000 and 51300 HIV-1 RNA copies/mL). They had received IDV three times a day for approximately 2 years prior to the 400/100 mg regimen. None of them had a viral load of below 20 copies/mL at baseline or during treatment with the 400/100 mg regimen. One PI-experienced patient who had a viral load of below 20 copies/mL on the 400/100 mg regimen changed treatment because of adverse events (sweat and fatigue).

None of the PI-naive patients changed treatment during follow-up.

Plasma HIV RNA

Baseline plasma HIV RNA is shown in Table 1. At baseline, 4.8% (intention-to-treat, n=21), 5.9% (on-treatment, n=17), 0% (PI naive, n=9) and 8.3% (experienced patients, n=12) of the patients had a viral load of below 20 copies/mL. At week 120, it was 70.0% (n=10), 77.8% (n=9), 100% (n=2) and 62.5% (n=8), respectively. The change from baseline to week 120 was statistically significant in all four analyses, P<0.05. Five of the PI-naive patients had a viral load of below 20 copies/mL, eight had a viral load of 50 copies/mL and all had a viral load of below 200 copies/mL at the last recorded plasma HIV-1 RNA.

CD4 cell count

Baseline CD4 cell counts are shown in Table 1. At week 120, the median and range of the CD4 cell count was 607 cells/μL (171–816, n=11), 608 cells/μL (202–816, n=10), 463 cells/μL^–1 (280–645, n=2) and 607 cells/μL (171–816, n=9) in the intention-to-treat, on-treatment, PI-naive and -experienced groups, respectively. Compared with baseline, only the on-treatment analysis showed a statistically significant increase in CD4 cell count, P=0.049, with a median difference of 150 cells/μL, 95% CI (28; 251). The intention-to-treat and experienced patients analysis had a P-value of 0.062 and 0.25, respectively. The numbers were too small to do an analysis of PI-naive patients.

Pharmacokinetics

Fifteen patients had a morning C_min measurement and nine participated in the 12-h pharmacokinetic evaluation. Of the patients participating in the pharmacokinetic evaluation, five were PI naive and four were PI experienced. The median and range of the IDV morning C_min measurement was 434 ng/mL (109–1954). The IDV pharmacokinetic parameters from the pharmacokinetic evaluation, median and range, were: C_max 4034 ng/mL (2963–7632), C_12 h 220 ng/mL (102–364), AUC_(0–12 h) 18508 ng/mL h (13414–33206), t_max 2.0 h (1.0–3.0) and t_1/2 2.3 h (1.9–2.6). Only one of the patients (11.1%) participating in the pharmacokinetic evaluation and two (13.3%) of the patients who had a morning C_min measurement were below a minimum effective concentration (MEC) of 120 ng/mL as suggested by the Liverpool TDM service [14].

Discussion

In this long-term follow-up study of a heterogeneous population of HIV-1-infected patients receiving 400 mg of IDV, 100 mg of RTV and two NRTIs twice a day, 70% of the patients had viral loads of below 20 copies/mL after 120 weeks of treatment.

Our data support the idea that this regimen may be useful in patients with steady viral suppression with the IDV 800 mg three times a day regimen as considered by Katlama et al. [11]. Our study was an exploratory evaluation of the 400/100 mg regimen, and it does not provide evidence for the use of the 400/100 mg regimen as first-line therapy in naive patients, or its use as part of salvage therapy in experienced patients with virological failure.

The 400/100 mg regimen may also be a possibility in patients experiencing IDV-related toxicity with the 800/100 mg regimen, but studies investigating this approach and the use of IDV plasma concentrations to guide dosage reductions are not yet available.

The data from the pharmacokinetic evaluation showed relatively low C_12 h (evening C_min) levels when compared to the data from Katlama et al. [11] (morning C_min), 220 vs. 475 ng/mL, whereas the morning C_min measurements were similar. This could indicate that the phenomena of diurnal variation were present [15]. Most patients were above a MEC of 120 ng/mL; however, for many of the patients in this study, the concentrations were only just above the MEC. Consequently, the regimen does not allow for any flexibility with regard to the timing of the morning and evening dose and a high level of adherence is probably required.

No serious adverse events, cases of nephrolithiasis or elevated creatinine levels were observed among the patients receiving the 400/100 mg regimen. A more detailed evaluation of adverse events was not made possible in this retrospective study. Only one patient stopped treatment because of adverse events, indicating that the regimen in general is well tolerated.

In conclusion, treatment with the IDV/RTV 400/100 mg regimen appears to be efficacious for up to 2 years. However, rather low IDV C_min suggests that the regimen should be evaluated further before its widespread use and that the regimen probably should be guided by pharmacokinetic evaluation.

Acknowledgements

The assistance of Ellen Christensen is very much appreciated. This research was supported by the Danish AIDS-Foundation.