In HIV-infected patients, the rapid achievement of an undetectable viral load, which is noted in less than 70% of patients, has been linked to a long-term favourable clinical prognosis [1,2]. It is thus necessary to increase as far as possible the rate of early virological success. Improvements in adherence have proved to be of benefit in some patients . Because of the level of high interpatient variability and the efficacy–concentration and toxicity–concentration relationships, the optimization of protease inhibitor doses based on plasma concentrations could also be beneficial [4–6]. However, the benefit of therapeutic drug monitoring is under debate. A single plasma concentration interpretation in the context of common practice is often difficult, because of the high inter and intrapatient variability of pharmacokinetics, in the patient's notification of time intervals between the last drug intake and sampling, and in treatment adherence and co-medications . We showed that in non-fully adherent, protease inhibitor-naive patients receiving indinavir, the efficacy–concentration relationship disappeared when the adherence score of each patient was analysed, whereas it was maintained in fully adherent patients . This is probably explained by the fact that the plasma concentration is the indicator of individual antiretroviral pharmacokinetic characteristics with day-to-day variability, but also of adherence history during the days preceding blood sampling. Furthermore, as a result of the high intra-individual variability in plasma concentrations even in fully adherent patients, adaptation of the protease inhibitor dose has the highest chance of being effective if based on several concentration determinations, at best over several days thus creating a patient concentration ‘profile’ . However, repeated blood sampling is difficult to obtain in everyday life, and may delay necessary interventions. As indinavir accumulates gradually over time in the hair, the determination of indinavir concentrations in the hair, reflecting a longitudinal intake and therefore less susceptible to day-to-day variability, could allow an easier and more accurate determination of exposure and analysis of the efficacy–concentration relationship. It has already been shown in patients receiving indinavir 800 mg three times a day that indinavir hair concentrations were higher in patients with undetectable viral loads than in those without [9,10]. However, the concomitant indinavir plasma level was not monitored in those studies; therefore information generated by plasma measurement and hair measurement could not be compared. We thus studied in a transactional study the relationship between virological success and the indinavir hair concentration, plasma concentrations, and other factors usually associated with virological success .
Indinavir-boosted ritonavir-receiving HIV-infected patients treated for more than 4 months were included in this study. Proximal hair was cut close to the scalp and crushed to a powder; hair concentrations were expressed as μg/g of hair, as previously published . Indinavir trough plasma concentrations before the morning drug intake and hair concentrations were measured in each patient by a validated high-performance liquid chromatography method (limits of quantification: 5 ng/ml and 0.5 μg/ml, respectively) . For each patient, daily and cumulative (since the initiation of the indinavir-boosted ritonavir-containing HAART) indinavir doses were calculated; patients with concomitant HIV-RNA levels below 50 copies/ml were classified as being virological responders. Univariate and multivariate analyses of associated factors were performed using a logistic regression model in which virological success was the primary outcome. Odds ratios with 95% confidence intervals (CI) were estimated.
Of the 43 patients included, 29 (67%) were classified as being virological responders. All patients were receiving low-dose ritonavir (100 mg twice a day), 31 patients were taking indinavir 400 mg twice a day, six patients were taking indinavir 200 mg twice a day, and the six other patients were taking 600 mg twice a day. The median indinavir concentration in the hair was 10 μg/g [interquartile range (IQR) 5–15 μg/g] and the median trough plasma indinavir concentration was 390 ng/ml (IQR 212–675 ng/ml).
Median indinavir concentrations in the hair were 15 μg/g (IQR 6–21 μg/g) in virological responders and 8 μg/g (4–11 μg/g) in non-responders (Fig. 1), whereas the median plasma indinavir trough concentration was 370 ng/ml (IQR 210–680) in virilogical responders and 480 ng/ml (IQR 212–675 ng/ml) in non-responders. Neither indinavir concentrations in the hair, nor trough indinavir concentrations in plasma were correlated with indinavir daily doses. In multivariate analysis, the indinavir hair concentration remained the only factor associated with virological success [P = 0.04; odds ratio (OR) 3.88; 95% CI 1.01–14.94], whereas sex (male versus female; P = 0.06; OR 5.91; 95% CI 0.90–38.73), baseline protease inhibitor-naive patient status (P = 0.29; OR 5.22; 95% CI 0.23–115.93), high baseline HIV-RNA level (P = 0.06; OR 0.68; 95% CI 0.47–1.01), and indinavir trough plasma concentration (P = 0.13; OR 0.99; 95% CI 0.99–1.01) were not.
As already found for patients receiving non-boosted indinavir, hair concentrations were related to virological success; the concentrations observed in virological responders and non-responders were in the same range as those previously observed in patients with non-boosted indinavir . Furthermore, when also analysing the concomitant plasma concentration and other virological success-associated factors, we found that the determination of the indinavir concentration in hair was more accurate for predicting virological success than a single determination of the indinavir plasma concentration. As we have previously found in analysing the part played respectively by adherence and pharmacokinetic characteristics in the concentration–efficacy relationship, a single plasma concentration determination without concomitant data on adherence within the previous day leads to a misinterpretation of the results . It is particularly striking in the case of the four virological non-responder patients without detected resistance-associated mutations for whom indinavir plasma levels were accurate whereas the indinavir concentrations in hair were low, probably revealing a poor adherence level. Monitoring the indinavir plasma concentration in the hair allows a longitudinal assessment of indinavir impregnation in a large time window, which takes into account the individual pharmacokinetic characteristics, including intraindividual variability, and the patient's adherence history . It has recently been shown in highly adherent patients receiving protease inhibitors with sustained undetectable viral loads in whom extensive repeated plasma levels were measured that the intra-individual coefficient of variability was up to 45%, which may limit the utility of a single measurement in therapeutic drug monitoring for protease inhibitors .
Therefore, in the context of therapeutic drug monitoring, ritonavir-boosted indinavir hair sampling may be a useful tool to monitor indinavir impregnation and to help interpret concomitant plasma concentrations allowing an adequate decision based on a same day determination. This combined procedure represents a less traumatic means of patient data collection avoiding repeated plasma sampling and delays in clinical interventions.
1. Ghosn J, Lamotte C, Ait-Mohand H, Wirden M, Agher R, Schneider L, et al
. Efficacy of a twice-daily antiretroviral regimen containing 100 mg ritonavir/400 mg indinavir in HIV-infected patients. AIDS 2003; 17:209–214.
2. Chene G, Sterne JA, May M, Costagliola D, Ledergerber B, Phillips AN, et al
. Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies. Lancet 2003; 362:679–686.
3. Mannheimer S, Morse E, Matts J, Andrews L, Miller C, Schmetter B, et al.Adherence strategies using a medication manager and an electronic medication reminder system for HIV Infected patients receiving HAART.
In: XVth International AIDS Conference
. Bangkok, Thailand 2004 [Abstract LbOrB15].
4. Back D, Gatti G, Fletcher C, Garaffo R, Haubrich R, Hoetelmans R, et al
. Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 2002; 16(Suppl. 1):S5–S37.
5. Burger D, Hugen P, Reiss P, Gyssens I, Schneider M, Kroon F, et al
. Therapeutic drug monitoring of nelfinavir and indinavir in treatment-naive HIV-1-infected individuals. AIDS 2003; 17:1157–1165.
6. Burger DM, Hoetelmans RM, Hugen PW, Mulder JW, Meenhorst PL, Koopmans PP, et al
. Low plasma concentrations of indinavir are related to virological treatment failure in HIV-1-infected patients on indinavir-containing triple therapy. Antivir Ther 1998; 3:215–220.
7. Nettles RE, Kieffer TL, Parsons T, Johnson J, Cofrancesco J Jr, Gallant JE, et al
. Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring. Clin Infect Dis 2006; 42:1189–1196.
8. Duval X, Mentre F, Lamotte C, Chene G, Spire B, Dellamonica P, et al
. Indinavir plasma concentration and adherence score are codeterminant of early virological response in HIV-infected patients of the APROCO cohort. Ther Drug Monit 2005; 27:63–70.
9. Servais J, Peytavin G, Arendt V, Staub T, Schneider F, Hemmer R, et al
. Indinavir hair concentration in highly active antiretroviral therapy- treated patients: association with viral load and drug resistance. AIDS 2001; 15:941–943.
10. Bernard L, Vuagnat A, Peytavin G, Hallouin MC, Bouhour D, Nguyen TH, et al
. Relationship between levels of indinavir in hair and virologic response to highly active antiretroviral therapy. Ann Intern Med 2002; 137:656–659.
11. Woolf E, Au T, Haddix H, Matuszewski B. Determination of L-735 524, an human immunodeficiency virus protease inhibitor, in human plasma and urine via high-performance liquid chromatography with column switching. J Chromatogr A 1995; 692:45–52.