JAC Advance Access originally published online on April 4, 2006
Journal of Antimicrobial Chemotherapy 2006 57(6):1161-1167; doi:10.1093/jac/dkl112
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The use of pharmacokinetically guided indinavir dose reductions in the management of indinavir-associated renal toxicity
1 The HIV Netherlands Australia Thailand Research Collaboration, The Thai Red Cross AIDS Research Centre Bangkok, Thailand 2 National Centre in HIV Epidemiology and Clinical Research, University of New South Wales Sydney, Australia 3 Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders University Bedford Park 5042, South Australia, Australia 4 Faculty of Medicine, Chulalongkorn University Bangkok, Thailand 5 Centre for Poverty-related Communicable Diseases, Academic Medical Centre, University of Amsterdam, and International Antiviral Therapy Evaluation Centre Amsterdam, The Netherlands 6 Department of Clinical Pharmacy, Radboud University Medical Centre Nijmegen, The Netherlands 7 Nijmegen University Centre for Infectious Diseases Nijmegen, The Netherlands
*Correspondence address. Room 5D304.1, Department of Microbiology and Infectious Diseases, Flinders Medical Centre, Flinders University, Bedford Park 5042, South Australia, Australia. Tel: +61-8-8204-4948; Fax: +61-8-8204-4733; E-mail: mark.boyd{at}fmc.sa.gov.au
Received 16 January 2006; returned 14 February 2006; revised 28 February 2006; accepted 12 March 2006
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Abstract |
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Objectives: Indinavir is associated with nephrotoxicity. Therapeutic drug monitoring of indinavir improves clinical outcome, but there is little data regarding therapeutic drug monitoring for patients with established indinavir-associated renal impairment. We prospectively studied the use of therapeutic drug monitoring in patients with virological success but established nephrotoxicity on an indinavir-containing regimen.
Methods: We measured indinavir Ctrough/C2h, serum creatinine, pyuria, blood pressure (BP), weight and HIV RNA. The major endpoint of interest was the number of patients achieving a normal creatinine level 20 weeks following final indinavir dose adjustment. Primary analysis was by intention to treat (ITT).
Results: A total of 35 patients were enrolled; mean (SD) age 40.3 (5.8) years; mean (SD) BMI 21.5 (2.8) kg/m2. At baseline 6/35 (17%) had a serum creatinine concentration within normal limits, but were offered enrolment because of previous nephrotoxicity (nephrolithiasis and/or abnormal serum creatinine), and a screening pharmacokinetic profile associated with increased nephrotoxicity risk. By ITT analysis 11/35 (31%) had normal creatinine at study end (P = 0.18). Of the 29 patients with abnormal creatinine at baseline, 7/29 (24.1%) had normal creatinine at study end (P = 0.016). Patients had a median (IQR) indinavir per dose adjustment over the study of 400 (400–800) mg. We observed improvements in estimated creatinine clearance, pyuria, resting BP and indinavir pharmacokinetic profile. HIV RNA control was maintained with continued immune recovery despite lower indinavir doses.
Conclusions: Patients experiencing nephrotoxicity on an indinavir-containing regimen were safely maintained on indinavir by means of therapeutic drug monitoring. Parameters of renal function improved but did not return to baseline values, at least in the short-term.
Keywords: HIV , nephrotoxicity , pyuria , pharmacokinetics (PK) , therapeutic drug monitoring , serum creatinine , creatinine clearance , blood pressure (BP) , Thailand , resource-limited setting
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Introduction |
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Indinavir is a protease inhibitor licensed for the treatment of HIV infection in combination with other antiretroviral agents at a dose of 800 mg three times daily taken away from food. In recent years there has been an overwhelming trend towards combining protease inhibitors with low doses of ritonavir in order to take advantage of the capacity of this agent to inhibit the cytochrome P-450 mediated metabolism of protease inhibitors, thereby allowing for dosing regardless of food intake in twice daily, and in some instances once daily, dosing schedules.1 Clinical experience with indinavir has demonstrated that it has a relatively narrow therapeutic window and is frequently associated with nephrotoxicity, which may manifest as a syndrome of renal colic, tubulo-interstitial nephritis or even acute renal failure. Prolonged use of indinavir is associated with chronic elevations in serum creatinine.2–6
There is a wide inter-individual variation in the pharmacokinetics (PK) of indinavir.7,8 Relationships between the pharmacokinetics of indinavir and its pharmacodynamic effects have been described. Dieleman et al.7 have demonstrated an association between maximal indinavir concentrations and nephrotoxicity. In a cohort of patients using indinavir 800 mg three times daily or ritonavir-boosted indinavir 800/100 mg twice daily the indinavir plasma concentration at 2 h post-indinavir ingestion (C2h) was discriminating for patients with and without nephrotoxicity (indinavir C2h > 7.5 mg/L for three times daily dosing and indinavir C2h > 10 mg/L for twice daily dosing); similarly, indinavir trough levels (Ctrough) correlated with antiviral response (indinavir Ctrough > 0.1 mg/L for three times daily dosing and indinavir Ctrough > 0.25 mg/L for twice daily doing).8 Other studies have demonstrated that the use of therapeutic drug monitoring of indinavir in the period immediately following commencement of combination antiretroviral therapy leads to improved outcomes measured in terms of toxicity, efficacy and drug discontinuation.9,10 The outcome of patients experiencing nephrotoxicity who cease indinavir treatment has been favourable, with prompt resolution of urinary abnormalities and return of serum creatinine to normal.11–13 However, there are no data to determine whether it is safe to continue indinavir by optimizing the indinavir dose in patients experiencing indinavir-associated nephrotoxicity.
Indinavir has been used in a number of studies at the HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), and nephrotoxicity has been observed in all.14,15 Despite this, however, and for a number of reasons, very few patients experiencing indinavir-associated nephrotoxicity have actually ceased indinavir; patients demonstrating nephrotoxicity had benefited immunologically and virologically from their antiretroviral therapy and had not suffered further progression of their HIV disease; patients had nearly all previously failed a combination nucleoside regimen, and a switch to a non-nucleoside reverse transcriptase inhibitor-containing regimen was thought ill-advised; lifelong supply of indinavir without cost to the patient had been guaranteed by the major study sponsor (Merck & Co.) for all patients who participated in Merck & Co. sponsored clinical trials at HIV-NAT and who continued to derive benefit; and finally, studies had indicated that the decrease in renal function associated with indinavir therapy was reversible, generally within 4 months of ceasing the drug.11–13 We therefore elected to investigate the use of pharmacokinetically guided indinavir dose optimizations in patients with evidence of indinavir-associated nephrotoxicity as part of an approved clinical protocol.
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Patients and methods |
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Patients were eligible for enrolment if they were participating in HIV-NAT studies in which indinavir formed part of their antiretroviral regimen. Patients who had undergone indinavir dose reduction prior to the availability of therapeutic drug monitoring at HIV-NAT were eligible for inclusion if study criteria were met.
Inclusion criteria were the following:
- ACTG grade I renal toxicity (a serum creatinine concentration between 1.1 and 1.6 times the upper limit of normal) or higher, determined on at least two visits with at least 3 months between visits. The upper limit of normal serum creatinine concentration for this study was defined as 124 µmol/L.
- HIV RNA <50 copies/mL.
- Patients who were receiving indinavir three times daily must have had an indinavir level at 2 h post-ingestion >7.5 mg/L.
- Patients who were using indinavir plus ritonavir twice daily must have had an indinavir level at 2 h post-ingestion >10.0 mg/L.
- Patients who were using indinavir three times daily must have had an indinavir trough level >0.10 mg/L.
- Patients who were using indinavir plus ritonavir twice daily must have had an indinavir trough level >0.25 mg/L.
- Willing and able to give written informed consent.
Those patients fulfilling the inclusion criteria and giving informed consent followed a protocol that included regular assessments of indinavir PK levels (Ctrough and C2h), plasma HIV RNA, serum creatinine and urine microscopy performed at 4 weekly intervals while indinavir dose adjustments were undertaken, and then at 2 monthly intervals once a new stable indinavir dose with acceptable PK parameters was established. Indinavir pharmacokinetic levels were assessed according to the patient's record of last indinavir intake (indinavir Ctrough) and with (twice daily dosing regimen) or without (three times daily dosing regimen) food for the indinavir C2h level. Pyuria on microscopy was graded according to a scale: Grade I, normal [0–5 cells/high powered field (HPF)]; Grade II, mild (6–25 cells/HPF); Grade III, moderate (26–50 cells/HPF); and Grade IV, severe (>50 cells/HPF). Because of the known association between renal impairment and hypertension the study also mandated routine monitoring of resting blood pressure (BP) at all study visits according to a standard procedure. Creatinine clearance was estimated from the serum creatinine according to the Cockcroft–Gault equation [(140 – age) x weight (kg)]/[814 x serum creatinine (mmol/L)]; the result was multiplied by 0.85 for females. Indinavir dose reductions were made in 200 mg increments according to the protocol-defined acceptable limits of the indinavir Ctrough and C2h, and an indinavir dose reduction to a minimum of 200 mg per dose (with or without ritonavir boosting) was allowed as long as PK parameters were met. Follow-up was planned until at least 20 weeks after the final indinavir dose reduction to assess the outcome. In the event that the clinician considered an adjustment in the ritonavir dose (rather than the indinavir dose) to be warranted in order to optimize the pharmacokinetics of indinavir this was allowed.
Indinavir in plasma was analysed using a previously published HPLC method.16 Accuracy ranged from 104% to 108% and intra-day and inter-day precision ranged from 2.12% to 7.48% and from 0.43% to 3.46%, respectively. The calibration range was 0.04–30 mg/L. Serum creatinine levels were measured using Vitalab Flexor equipment (Vital Scientific, The Netherlands).
The primary endpoint of the study was the number of patients achieving a serum creatinine concentration within normal limits 20 weeks following achievement of an optimal indinavir dosing schedule. Secondary endpoints included changes in creatinine clearance, pyuria, resting BP and control of HIV RNA. An absolute serum creatinine value of 300 µmol/L was set for cessation of indinavir therapy during the study. For comparisons regarding changes in serum creatinine and calculated creatinine clearance we determined results for three time-points: pre-indinavir exposure (at screening for the original HIV-NAT study in which patients were first commenced on an indinavir-including regimen), at baseline for the currently described indinavir dose reduction study and at a time-point at least 20 weeks after the final indinavir dose adjustment as per protocol. Data on concomitant medications were collected in order to assess their possible contribution to nephrotoxicity. The protocol was reviewed and approved by the Ethics Committee of The King Chulalongkorn Memorial Hospital and all patients gave written informed consent prior to participation.
The primary analysis was an intention to treat (ITT) analysis using a last observation carried forward analysis imputation for continuous variables and a missing = failure imputation for dichotomousvariables. Differences over time were assessed by the measured change in scores from baseline to last follow-up. Results were described as either mean (±SD) or median (IQR) depending upon the data distribution, as well as in percentages. Paired t-test and Wilcoxon signed ranks test were used to compare the means and medians of changes between two related time-points, respectively, while McNemar test was used to compare the percentage of patients for each outcome. A P value of <0.05 was used to indicate statistical significance.
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Results |
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A total of 61 patients were screened of whom 24 were found to be ineligible. This left 37 eligible patients of whom 2 were excluded from the analysis, one because of withdrawal of consent and another because of an indinavir dose reduction prior to PK monitoring. Therefore 35 patients were enrolled and the analysis was carried out based on these. Of these 35 patients not all fulfilled the study criteria for an elevated creatinine at screening, but were allowed to enter the study because of symptoms suggestive of clinical nephrolithiasis and/or a previously abnormal serum creatinine result, and because the screening results demonstrated a pharmacokinetic profile associated in our experience with indinavir-associated nephrotoxicity. All patients were enrolled from other clinical studies conducted at HIV-NAT, and as such they had undergone investigation for other possible causes of renal impairment during the course of routine clinical follow-up. Of the 35 patients enrolled, 3 were terminated during the study. One switched to ritonavir-boosted saquinavir, one was lost to follow-up, and the third ceased indinavir-containing therapy after an episode of recurrent renal colic despite dose optimization to ritonavir-boosted indinavir 400/100 mg twice daily and acceptable indinavir pharmacokinetics (Ctrough = 0.14 mg/L, C2h = 3.46 mg/L). The trial disposition is summarized in Figure 1.
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The baseline characteristics of the cohort are summarized in Table 1. The patients in the cohort were predominantly male with a mean age of 40.3 (5.8) years and a mean body weight of 56.7 (9.1) kg. The cohort had a median of 3.5 (1.6–3.6) years of exposure to indinavir. A total of 27 patients (77%) of the cohort had received concomitant medications associated with renal toxicity prior to the study commencement, although the majority had used these on an ‘as required’ (p.r.n.) basis only. The only potentially nephrotoxic medication received regularly by a large proportion of patients prior to study was co-trimoxazole prophylaxis 800/160 mg daily (25/35 patients, 71%). Of interest, of patients enrolled into the study from the HIV-NAT treatment cohort who had received indinavir the longest (>3 years)14 all qualifying patients had continued to receive co-trimoxazole prophylaxis (14 of an original enrolment of 104 patients). However, despite this, we did not find a relationship between receipt of co-trimoxazole prophylaxis and the presence of renal impairment at study baseline (data not shown).
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Figure 2 expresses the numbers of patients using different doses of indinavir and ritonavir at baseline and at final follow-up. The median change of indinavir dose during the study (per dose) was 400 (400–800) mg (P < 0.001). Of the 35 patients, 28 (80%) required a single dose adjustment, 6 (17%) underwent two dose adjustments and 1 patient (3%) had three dose adjustments. At baseline one patient was using ritonavir 200 mg twice daily in combination with indinavir, and by study end a further six patients had increased the ritonavir dose to 200 mg given twice daily with indinavir. The reason given for the increased ritonavir dose was to optimize indinavir pharmacokinetics in situations of an unacceptably high indinavir C2h and a low, but acceptable, indinavir Ctrough (i.e. the indinavir dose was reduced in order to minimize nephrotoxicity, but the ritonavir dose was concomitantly increased in order to maintain a therapeutic indinavir Ctrough).
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Changes in serum creatinine and estimated creatinine clearance are summarized in Table 2. For the primary study endpoint (ITT analysis) 11/35 (31%) had a normal serum creatinine at study end compared with 6/35 (16%) who had a normal serum creatinine at baseline (P value for difference from baseline = 0.18). Confining the analysis firstly to those patients who completed the full study protocol (31 patients) and secondly to only those 29 patients who had an abnormal baseline creatinine value and who completed the study protocol (27 patients), the number of patients with a normal creatinine value at study end was 11/31 (35.5%; P = 0.02) and 7/27 (26%; P = 0.02), respectively. Prior to indinavir exposure the cohort had a mean serum creatinine of 82 (12.7) µmol/L, corresponding to an estimated creatinine clearance of 84 mL/min. At baseline for the present study the serum creatinine concentration was 149 (27.7) µmol/L, representing an estimated creatinine clearance of 46 mL/min, and a mean (SD) percentage reduction of creatinine clearance from pre-indinavir exposure of 44 (14) %. After indinavir dose optimization the mean serum creatinine returned to 135 (29) µmol/L, representing an estimated creatinine clearance of 53 (15) mL/min. The mean change in creatinine clearance from study baseline to endpoint was 6.6 (10) mL/min (P = 0.001). At baseline the majority of patients had Grade 2 pyuria (48.6%) and at study end the majority (51.4%) had Grade 1 pyuria (P = 0.09).
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Figure 3 (a and b) expresses the changes in indinavir C2h and Ctrough at baseline and pharmacokinetic steady state 4 weeks following final indinavir dose reduction, respectively. The overall change in indinavir C2h was –4.8 (–6.1 to –3.5) mg/L; (P < 0.001). The overall change in indinavir Ctrough was –0.8 (–1.1 to –0.4) mg/L; (P < 0.001). The percentage of patients experiencing an indinavir C2h associated with nephrotoxicity (C2h > 10 mg/L) fell from 69% to 6% (P < 0.001); the corresponding figures for those with an acceptable indinavir Ctrough (Cmin > 0.1 mg/L) before and after dose adjustment were 97 and 86%, respectively (P = 0.05). Two patients demonstrated increases in C2h following final indinavir dose reduction when compared with baseline; one patient switched from a three times daily regimen to a ritonavir-boosted twice daily regimen; the other probably represents an error. One patient demonstrated a very high indinavir Ctrough at baseline, which responded well to dose adjustment from ritonavir-boosted indinavir 800/100 mg twice daily to 400/100 mg twice daily. This case was a male with an exceptionally low BMI (16 kg/m2).
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Figure 4 demonstrates changes in resting BP between baseline and study endpoint. The figure also includes data from 15/35 (43%) patients for whom a formal BP assessment had been documented prior to commencement of indinavir-based therapy. In an ITT analysis of BP changes in the entire cohort from the present study baseline to study end we observed a reduction in both median systolic BP [baseline 120 (110–130), endpoint 110 (110–120) mm Hg; P = 0.2] and diastolic BP [baseline 80 (70–90), endpoint 80 (70–80) mm Hg; P = 0.02]. Restricting the analysis to the 15 patients for whom a pre-indinavir BP measurement existed, we observed a substantial rise in systolic BP [mean (SD) = 20 (10–30) mm Hg; P = 0.013] and diastolic BP [mean rise = 10 (0–20) mm Hg; P = 0.011] after exposure to indinavir and before indinavir dose optimization took place.
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At baseline 7/35 (20%) subjects had an HIV RNA >50 copies/mL but were entered into the indinavir dose reduction protocol because of evidence of both prior long-term virological control (the result was therefore considered likely to represent a virological ‘blip’) and indinavir pharmacokinetics consistent with toxicity or persistent renal symptoms at the screening assessment. At study end on an ITT analysis the same proportion (20%, but not all the same patients) had HIV RNA >50 copies/mL. However, continued routine follow-up of the cohort has demonstrated that all patients who registered an HIV RNA result >50 copies/mL at study end subsequently registered an HIV RNA <50 copies/mL at the following visit, without any further adjustment to drug dosages or regimen. Measured in terms of immune status there was an improvement observed in CD4 count over the course of the study despite the overall reduction in total indinavir dose [median change in CD4 count = 32 cells/mm3 (0–86); P = 0.002].
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Discussion |
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In this study we have demonstrated an association between the use of pharmacokinetically guided indinavir dose reductions and amelioration of indinavir-associated renal toxicity, at least in the short-term. The implication of this finding is that in settings in which there may not be an option to switch from indinavir to a protease inhibitor associated with less nephrotoxicity, optimization of the indinavir dosage is a reasonable alternative that is safe and allows maintenance of antiviral efficacy.
Recent studies have suggested that indinavir may be used at lower doses than those currently recommended without loss of efficacy and with reduced nephrotoxicity.17,18 A pharmacokinetic study performed in Thai patients receiving ritonavir-boosted indinavir 400/100 mg twice daily demonstrated PK levels consistent with reasonable efficacy and minimal nephrotoxicity, and the clinical study of the cohort from which this patient sample was drawn has demonstrated this to be the case.19,20 In the present study we have demonstrated benefits of indinavir dose reduction measured in terms of improvements in serum creatinine and thereby calculated creatinine clearance. Importantly, calculated creatinine clearance rose by a mean of 6.6 (10.2) mL/min and attained a mean (SD) level of >50 mL/min [52.7 (14.9)], a level consistent with maintenance of reasonable clinical renal function. In association with this we found that pyuria improved. A number of studies have suggested that pyuria is a potential marker of renal damage,11,21 and we found that the majority of patients entering this study displayed a urinary leucocytosis. Despite this improvement the results might be considered a disappointment in that renal function improved only marginally and did not return to normal. It should be remembered however that this patient cohort had had substantial exposure to indinavir for a median (IQR) of 3.5 (1.6–3.6) years and that previous reports of resolution of renal impairment in patients receiving indinavir were in the context of cessation of the drug soon after the identification of renal toxicity. The study cohort continues in clinical follow-up and it remains to be seen whether the short-term changes in renal status translate into more substantial long-term benefits.
Concern might reasonably be expressed that three patients with HIV RNA <50 copies/mL at the beginning of the study had detectable HIV RNA following indinavir dose adjustment, suggesting that indinavir dose adjustment may dispose patients to virological failure. However, in all three cases the indinavir pharmacokinetic parameters after dose adjustment fell well within the limits considered to be consistent with maintenance of virological control in indinavir treatment naive patients,22 suggesting that other temporary factors may have been responsible for the increases in viral load. Indeed, further follow-up of this patient cohort at HIV-NAT has demonstrated that all patients with an HIV RNA >50 copies/mL at study end subsequently returned an HIV RNA <50 copies/mL at the following clinic visit.
Because of the known association between renal impairment and hypertension, we elected to monitor resting BP throughout the study. We also managed to collect pre-indinavir BP assessments on 43% of patients, which we were able to compare with BP assessments at study baseline and following indinavir dose adjustment. We found that patients qualifying for study in whom measurements of BP were available from before exposure to indinavir had experienced substantial elevations in both systolic and diastolic BP after indinavir exposure. After indinavir dose adjustment, systolic and diastolic BP improved in the cohort as a whole (n = 35), although this only reached statistical significance for the diastolic component (P = 0.02). In a restricted analysis of the 15 patients for whom we had documented pre-indinavir BP values, we found a clinically significant median elevation in systolic and diastolic BP of 20 and 10 mm Hg, respectively, from the period between indinavir exposure and baseline for the current indinavir dose-optimization study. Changes in systolic and diastolic BP parameters following indinavir dose-optimization in this restricted group of 15 were similar to that observed for the cohort as a whole. From a clinical point of view minimization of nephrotoxicity is an important end in itself, but the increased risk for elevated BP in the presence of renal impairment makes this goal even more imperative. Given the potential for metabolic disturbance in patients receiving indinavir, the added risk of hypertension would likely increase the risk of cardiovascular disease further.23,24 Recent studies suggest that when indinavir is commenced at lower doses there is likely to be less toxicity and therefore less risk of the additional complication of hypertension.17,20
Another feature of note in the study is that indinavir dose-optimization necessitated not only reduction of indinavir doses, but also concomitant increases in the ritonavir dose in some cases. This was the case in patients for whom the indinavir C2h remained comparatively high despite an acceptable Ctrough following indinavir dose reduction. Therefore, the indinavir dose was decreased (by 200 mg) and ritonavir dose was increased (by 100 mg) in an attempt to lower the indinavir C2h but maintain a therapeutic Ctrough. A number of reports have demonstrated the large patient inter-individual PK variability of indinavir,7,8,25,26 and the one patient with dramatically high Ctrough at screening in this study is an illustrative case in point. This patient also had an extremely low BMI (16 kg/m2) and as a result was probably at increased risk for indinavir toxicity.4,27 Given this physiological and pharmacokinetic variation it follows that a variety of different combinations of indinavir and ritonavir will be necessary in order to fully optimize indinavir pharmacokinetics on an individual basis.
As a result of the limited sample size we had little statistical power to assess other potential risk factors for nephrotoxicity in this cohort. However, we did find that nearly three-quarters of the cohort had been exposed to co-trimoxazole prophylaxis, and interestingly, that every single patient from the longest running HIV-NAT study of indinavir-containing therapy (>3 years) who qualified for enrolment in the present indinavir dose optimization study had received uninterrupted co-trimoxazole prophylaxis since at least the time of enrolment in their original (non-dose optimized) indinavir-containing sutdy.14 This might be interpreted as suggestive that co-trimoxazole prophylaxis is indeed an important risk-factor for nephrotoxicity,4 but may also reflect that older patients (mean age of this cohort was 40 years), and/or those with a longer period of HIV-infection, or with poorer immune reconstitution, are at greater risk. These confounders cannot be disentangled in this study.
There are a number of weaknesses of our study. First, we were unable to include a control group with nephrotoxicity who remained on full-dose indinavir. While published data suggested that the indinavir-associated renal impairment was reversible, this was based on short-term experiences of renal impairment only.11–13 We believed that many of the patients experiencing indinavir-related nephrotoxicity were at risk for chronic, irreversible renal impairment, and given the emerging evidence at the time regarding the utility of therapeutic drug monitoring for optimization of indinavir dosing, it was considered unjustifiable not to offer therapeutic drug monitoring to all patients experiencing renal toxicity. Second, we were unable to perform pharmacokinetics in those patients who had not manifested symptoms or signs of nephrotoxicity to determine whether indinavir PK profiles differed significantly from those in whom toxicity was manifest. In previous analyses of indinavir-associated renal toxicity, associations have been found with factors other than pharmacokinetics [e.g. low body mass index (<20 kg/m2)] as well as gender (female > male) and exposure to co-trimoxazole].4,11,27 However, these analyses were conducted without the inclusion of pharmacokinetic data. It is possible that the determinants of renal toxicity are unrelated to indinavir pharmacokinetics or, more likely, that the individual pharmacokinetics of indinavir are a necessary but not sufficient condition for the development of nephrotoxicity [i.e. patients with low body weight/body mass index and/or receiving co-trimoxazole prophylaxis may be at increased risk for nephrotoxicity (sufficient conditions), but may develop nephrotoxicity if certain key threshold pharmacokinetic values are reached (necessary condition)]. Third, the study sample size was small, not allowing us to authoritatively investigate the role of other potential risk factors for nephrotoxicity. Finally, the follow-up period in this study is short. A longer duration of follow-up would allow a better understanding of the long-term implications of indinavir-associated nephrotoxicity, the improvements observed in renal function following indinavir dose adjustment, as well as continued virological control.
In conclusion, this study has demonstrated that dose adjustments of indinavir in targeted patients experiencing indinavir-associated nephrotoxicity can improve renal function in the short term and allow safe continuation of indinavir-based combination antiretroviral therapy in those with little option for switch. This finding is useful because indinavir is an attractive option as a first-line PI option in resource-limited settings, particularly in patients failing first-line therapy with an NNRTI/2NRTI combination or in those with hypersensitivity to the NNRTIs. Further study of ritonavir-boosted indinavir in resource-limited settings at doses lower than those currently recommended is warranted.
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Transparency declarations |
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The authors have no conflicts of interest to declare.
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Acknowledgements |
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We acknowledge the patients who participated in the study as well as the physicians, nursing staff, and laboratory and administrative personnel who all contribute to patient care at HIV-NAT. Financial support for the study was from HIV-NAT funds; it was not sponsored by a pharmaceutical company or any external agency.
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References |
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