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Antimicrobial Agents and Chemotherapy, January 2001, p. 236-242, Vol. 45, No. 1
Departments of Experimental and Clinical
Pharmacology1 and Infectious
Diseases,3 University of Minnesota Academic
Health Sciences Center, and HIV and AIDS Program, Regions
Hospital,2 St. Paul, and Abbott
Northwestern Hospital, Minneapolis,4 Minnesota
Received 6 July 1999/Returned for modification 14 December
1999/Accepted 12 October 2000
Conventional antiretroviral therapy involves administration of
standard fixed doses to adults and adolescents. This approach ignores
interindividual variability in pharmacokinetics and results in
substantial differences in systemic concentrations among patients. Thus, variability in systemic concentrations contributes to variability in response to therapy. This study was designed to evaluate the feasibility and safety of a regimen of zidovudine, lamivudine, and
indinavir designed to achieve select target concentrations versus
standard dose therapy. Twenty-four antiretroviral-naïve subjects completed the 24-week study; 13 received standard therapy, and
11 received concentration-controlled therapy. There were no differences
in baseline characteristics. Oral clearance for all three drugs was not
different between weeks 2 and 28; average ratios of week 2 oral
clearance to week 28 oral clearance were 0.95, 1.09, and 1.06 for
zidovudine, lamivudine, and indinavir, respectively, with 95%
confidence intervals including 1. The selected target concentrations
were average steady-state concentrations of 0.19 mg/liter for
zidovudine and 0.44 mg/liter for lamivudine and a trough concentration
of 0.15 mg/liter for indinavir; mean concentrations achieved at week 28 in the concentration-controlled arm were 0.20, 0.54, and 0.19 mg/liter,
respectively. Concentration-controlled therapy significantly reduced
interpatient variability in zidovudine concentrations and significantly
increased indinavir concentrations. There was no difference in adverse
drug effects or adherence. This investigation has provided a
pharmacologic basis for concentration-controlled therapy by
demonstrating that it is feasible and has a safety profile no different
from that of standard therapy. Additional studies to evaluate the
virologic effect of the concentration-controlled approach to
antiretroviral therapy are warranted.
Combination therapy with three or
more highly active antiretroviral agents is advocated for the treatment
of human immunodeficiency virus (HIV) infection (b; Panel on Clinical
Practices for Treatment of HIV Infection
[http://www.hivatis.org/trtgdlns.html]. Recommended first-line
regimens include the use of two nucleoside reverse transcriptase
inhibitors with either one or two protease inhibitors, or with a
nonnucleoside reverse transcriptase inhibitor. Among these combination
regimens, zidovudine, lamivudine, and indinavir have demonstrated the
most effective and most durable response to date (15-17,
20). Unfortunately, not all patients adequately respond to
highly active antiretroviral therapy. This heterogeneity has been
attributed to pharmacologic, virologic, immunologic, and behavioral
differences among patients. Conventional antiretroviral therapy
involves the administration of standard fixed doses to adults and
adolescents. This approach ignores interindividual variability in
pharmacokinetic processes and results in substantial differences in
systemic concentrations among patients. It is becoming increasingly
evident that pharmacodynamic relationships exist between antiretroviral
drug concentrations and response for all classes of antiretrovirals
(1, 4, 5, 11, 14, 18, 19, 22, 23, 31, 33; E. P. Acosta et al., 7th Conf. Retrovir. Opportun. Infect., abstr. 455, 2000;
A. S. Joshi et al., 39th Int. Conf. Antimicrob. Agents Chemother.,
abstr. I-1201, 1999; D. Slain et al., 38th Int. Conf. Antimicrob.
Agents Chemother., abstr. A-74, 1998). Therefore, heterogeneity in the
response to antiretroviral therapy may arise from variability in
systemic antiretroviral concentrations. Employing dosing regimens to
achieve a target systemic concentration may improve clinical outcome by reducing variability in the pharmacologic contribution to therapeutic success. The specific aims of this study were, first, to determine whether a novel dose adjustment strategy we developed to achieve and
maintain selected concentrations of zidovudine, lamivudine, and
indinavir in plasma was feasible and, second, to evaluate the safety of
the concentration-controlled approach versus the standard dose regimen.
Human subjects and study design.
This investigation was
approved by the Human Subjects Committee of the University of Minnesota
and was conducted at the Outpatient Clinic of the General Clinical
Research Center at the University of Minnesota. Subjects were informed
about the study and gave written consent prior to participation.
Antiretroviral-naïve, HIV-infected persons (age, 18 to 60 years) with plasma HIV RNA levels of
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.236-242.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Pharmacological Basis for Concentration-Controlled
Therapy with Zidovudine, Lamivudine, and Indinavir
ABSTRACT
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
5,000 copies/ml and CD4
T-lymphocyte counts of 100 cells/µl were eligible for
participation. Exclusion criteria included active opportunistic
infection that would require interruption of antiretroviral therapy and
known history of nonadherence with medications or scheduled physician
and clinic visits. After enrollment, individuals missing scheduled
clinic visits and not rescheduling within 1 week or in <85% adherence
with their assigned regimen as assessed by medication counts or
interview were discontinued from the study.
consisting of
zidovudine (300 mg twice daily), lamivudine (150 mg twice daily), and
indinavir (800 mg every 8 h)or concentration-controlled therapy.
Randomization was performed using a permuted block approach with
assignments contained in sealed, opaque envelopes sequentially numbered. Patients randomized to standard therapy received separate zidovudine and lamivudine tablets for the 6-month study period. Study
participants randomized to concentration-controlled therapy received an
individualized regimen developed to maintain targeted antiretroviral
drug concentrations in plasma. An average steady-state concentration in
plasma (Css) of 0.19 mg/liter was selected for zidovudine. This concentration was based on our previous experience with concentration-controlled zidovudine monotherapy (12).
The target Css selected for lamivudine was 0.44 mg/liter. This target was selected because it is the
Css that persons receiving 150 mg of lamivudine
would have if they were perfectly adherent and had average values for
lamivudine bioavailability and total body clearance (30).
This was the same conceptual approach originally used to define the
target concentration for zidovudine. The Css was
chosen for both drugs based upon in vitro data showing that the amount
of intracellular triphosphate formed is related to the extracellular
concentration of the parent drug (21). A trough concentration (Cmin) of 0.15 mg/liter was
selected for indinavir based on two considerations. First, the
concentration of indinavir necessary to inhibit 95% of HIV replication
in vitro ranges from 0.015 to 0.061 mg/liter for wild-type HIV
isolates. Plasma protein binding of indinavir is approximately 56%;
therefore, a concentration in plasma above 0.110 mg/liter in vivo would
theoretically be necessary to achieve unbound concentrations sufficient
to inhibit 95% of wild-type virus. Second, an exploratory study of
indinavir concentrations and effect in a cohort of 23 persons receiving nucleoside therapy plus indinavir found that the median indinavir Cmin in patients with undetectable HIV RNA was
0.147 mg/liter, whereas it was 0.037 mg/liter (P = 0.007) in those with detectable HIV RNA (1). Taken
together, these considerations led us to choose 0.15 mg/liter as the
target Cmin for indinavir.
Pharmacokinetic and adherence evaluations. Blood samples for plasma zidovudine, lamivudine, and indinavir concentrations were obtained from all study participants at weeks 2 and 28 at the following times: predose and 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h postdose. All subjects received the standard dose of zidovudine, lamivudine, and indinavir for the week 2 pharmacokinetic studies. At the week 28 pharmacokinetic study, standard therapy recipients received their doses of zidovudine and lamivudine as a single tablet (Combivir; Glaxo Wellcome) twice daily. Concentration-controlled recipients received their individualized doses for the week 28 visit. Patients were not allowed to eat 1 h before or 2 h after ingestion of their medications since food has been shown to affect absorption of these drugs (3, 7, 24, 26, 32, 35). Blood samples were also obtained between 2 and 5 h following drug administration at weeks 4, 8, 12, 16, 20, and 24. This time frame was chosen to avoid the absorption phase and obtain postabsorption concentrations within an optimal window, as assessed by D-optimality criteria, as previously described for zidovudine (27).
Zidovudine and lamivudine were quantitated by a validated simultaneous high-performance liquid chromatography procedure. The mobile phase consisted of 8.5% acetonitrile and 91.5% 50 mM phosphate buffer containing 50 mM triethylamine at pH 7. The chromatographic separation was performed on a Waters Spherisorb, 4.6- by 250-mm reversed-phase octyl column with a 5-µm particle diameter. Detection was achieved by a SpectraFocus forward-scanning UV detector at 266 nm with Chrom Perfect software used for data capture and quantification. A GBC model LC1650 autoinjector and model LC1150 pump were used. A 200-µl sample volume was spiked with 25 µl of 50 µM
-hydroxyethyl-theophylline as the internal standard and applied to an Empore C18 SPE
cartridge. The final elution of 300 µl of 100% methanol was dried
under nitrogen and reconstituted in the mobile phase and 50 µl was
injected. Standards for both zidovudine and lamivudine ranged from 25 to 2,500 ng/ml. The within-day coefficient of variation (CV) ranged from 5.3 to 1.5% for zidovudine and 9.3 to 4.8% for lamivudine. Accuracy ranged from 98 to 105.5% for zidovudine and 97.2 to 102.7% for lamivudine. Quality controls were used at 75,300, and 1,500 ng/ml.
These within-day CVs ranged from 5.3 to 1.5% for zidovudine and 14.8 to 6.7% for lamivudine. Accuracy ranged from 97.2 to 102.5% for
zidovudine and 92.6 to 99.2% for lamivudine. Analysis of variance
(ANOVA) calculations were also performed on the quality controls using
triplicate determinations on five separate days to determine the total
assay variation expected between days for a single replicate. The CVs
ranged from 1.0 to 3.8%, with an overall accuracy of 99.2%, for
zidovudine and from 5.5 to 9.4%, with an overall accuracy of 93.7%,
for lamivudine. Indinavir concentrations in plasma were quantitated by
high-performance liquid chromatography (13). The lower
limit of quantitation was 0.02 mg/liter, with a CV of <10% at all
concentrations. Interday and intraday CVs were less than 7 and 5%,
respectively, for each of the three quality control samples.
Pharmacokinetic parameters for zidovudine, lamivudine, and indinavir
were calculated for all subjects at week 2 and week 28. A
one-compartment model with first-order absorption, an absorption lag
phase, and first-order elimination was fit to the concentration-time data using maximum a posteriori probability-Bayesian estimation (ADAPT
II, version 4.0) (9). A proportional variance model was
used to describe the error associated with the concentration-time data.
The nominal values and the variances of the population parameters used
in the Bayesian estimator were taken from published work with
zidovudine and indinavir and literature sources for lamivudine (1, 2, 30). Model construction was guided by Akaike's information criterion and visual inspection of actual versus fitted concentrations (34). For only those patients randomized to
concentration-controlled therapy, these parameters were used to
calculate initial individualized doses, which were implemented at study
week 4. Pharmacokinetic parameters were reevaluated every 4 weeks,
incorporating the most-recent plasma concentration information, and
further dose adjustments were made for the concentration-controlled
recipients if necessary. The zidovudine dose (in milligrams/day) was
calculated according to the formula dose = (CL/F)(0.19
mg/liter)(24 h), where CL/F is the individual patient's
estimate of oral clearance in liters per hour and 0.19 mg/liter is the
targeted concentration. Calculated doses were rounded to the nearest
100 mg, and an attempt was made to keep administration to three times a
day (e.g., if a patient required 800 mg/day, the daily regimen would be
300 mg in the morning, 200 mg in the afternoon, and 300 mg in the
evening). Twice-daily dosing of zidovudine was not used in the
concentration-controlled regimens. Commercially available 100-mg
zidovudine capsules (Glaxo Wellcome) were used. The daily dose of
lamivudine (in milligrams/day) was calculated in a similar fashion:
dose = (CL/F)(0.44 mg/liter)(24 h). Doses were adjusted
to the nearest 75 mg; lamivudine dosing intervals were either twice or
three times daily. Commercially available 150-mg lamivudine tablets
(Glaxo Wellcome) were used.
Dose adjustment for indinavir was based on the following rearrangement
of an equation for steady-state Cmin:
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is the elimination rate constant, and 
is the dosing interval.
Both 200- and 400-mg capsules (Merck and Co., Inc.) were available for
dose adjustments. Dosing intervals were restricted to every 8 or every
6 h for patient convenience. At no point were patients' doses
below the recommended daily doses of zidovudine (600 mg/day),
lamivudine (300 mg/day), and indinavir (2,400 mg/day).
Medications were provided to the study participants at each visit in
quantities sufficient to last until the next visit (i.e., 15- or 30-day
supply). Thus, a total of eight visits per patient encompassing weeks 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 16, 16 to 20, 20 to 24, and 24 to
28 were possible. Study participants were requested to return their
unused medications at each clinic visit. To be eligible for evaluation
of adherence, a study participant must have returned their medication
for at least 4 of the 8 visits. Adherence for each visit was calculated
as the ratio of the number of dosage units taken, as determined by
medication count adjusted for time lapsed between visits, to the number
expected. Additional adherence assessments included a formal interview
with the patient and inspection of plasma drug concentrations at each visit.
Laboratory evaluations. A clinical assessment and measurement of hematologic parameters and clinical chemistries were performed with every clinic visit. Urinalysis and cholesterol and triglyceride analyses were performed every 3 to 4 months. Adverse reactions were graded and managed using the approach developed by the AIDS Clinical Trials Group (10). CD4 lymphocytes and plasma HIV RNA (Roche Amplicor Ultrasensitive Assay) were measured at baseline and every 4 weeks during the study.
Statistical analyses.
The sample size for this study was
based on two considerations: first, the ability to detect a >40%
difference in the variance of Css for zidovudine
between the standard and concentration-controlled regimen, and second,
the ability to detect a difference in Cmin of
0.09 mg/liter for indinavir. The effect size for indinavir was selected
because it is the difference in indinavir Cmin
found in an earlier study of patients with undetectable plasma HIV RNA levels compared with those that had HIV RNA detectable in plasma (1). For both of these considerations, a sample size of 24 patients was sufficient at an 
of 0.05 and 80% power.
10% of and more than the defined
target was considered acceptable. Safety parameters were compared
between groups by using the 
2 test. Assessment of
adherence data was done by ANOVA. Excel 98 (Microsoft Inc., Redmond,
Wash.) was used to maintain the patient database. Statview 5.0.1 (SAS
Institute, Inc., Cary, N.C.) was used for statistical analyses. For all
statistical analyses, a P value of <0.05 was considered significant.
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RESULTS |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Human subjects.
Thirty-two
antiretroviral-naïve persons with HIV consented to participate
in this study; all were determined to be eligible based upon laboratory
criteria and were subsequently enrolled in the study. No potential
participant was excluded from participation for a known history of
nonadherence with medications or scheduled physician and clinic visits.
Eight patients did not complete the 28-week study period. One subject
moved out of state. Two participants at study weeks 4 and 8, respectively, were lost to follow-up. One participant randomized to
concentration-controlled therapy withdrew from the study at week 8 because of an unwillingness to meet protocol requirements. Four
individuals withdrew prior to week 28 for medical reasons or because of
drug toxicity: two people (one each randomized to
concentration-controlled and standard therapy) withdrew for
gastrointestinal intolerance, one person (standard therapy) withdrew
after the development of peripheral neuropathy at study week 4, and one
person (standard therapy) was discontinued after the development of a
brain lesion and anemia at week 12. Of the remaining 24 subjects, 13 were randomized to standard therapy and 11 were randomized to
concentration-controlled therapy. There were no differences in baseline
characteristics between the two treatment groups (Table
1).
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Pharmacokinetic evaluations.
The week 2 and 28 pharmacokinetic
parameters for zidovudine, lamivudine, and indinavir for both arms of
the study are presented in Table 2. There
was no difference in CL/F for zidovudine, lamivudine, and
indinavir between week 2 and week 28 or between standard and concentration-controlled therapy recipients. Figure
1 presents CL/F values for all
24 patients at week 2 and week 28. The average ratios of week 2 to week
28 CL/F (and 95% confidence interval) for the following
medications were as indicated: zidovudine, 0.95 (0.78 to 1.12);
lamivudine, 1.09 (0.96 to 1.22); and indinavir, 1.06 (0.9 to 1.22).
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Adherence evaluations. Among the 24 study participants, 18 (75%) were eligible for adherence evaluation. These 18 subjects returned study medication for 87.5% (126 of 144) of the clinic visits. The overall mean adherence values were 96% for zidovudine, 97% for lamivudine, and 96% for indinavir. Standard therapy recipients (n = 10) had mean adherence values of 96, 95, and 94% for zidovudine, lamivudine, and indinavir, respectively. The mean adherence values for concentration-controlled patients were 96% for zidovudine and 98% for both lamivudine and indinavir. There was no difference in adherence between the two groups. No particular time period during the 28-week study was associated with more or less adherence. No subject was discontinued from the study for poor adherence.
Safety. Overall, there was no significant difference in the number of adverse events between the standard and concentration-controlled treatment arms. Asymptomatic hyperbilirubinemia was the most frequent objective side effect noted. Grade I or II elevations in total bilirubin occurred in nine standard therapy recipients and seven concentration-controlled recipients. Two patients who received concentration-controlled therapy developed grade III hyperbilirubinemia; one patient was on 800 mg of indinavir every 8 h at the time, and the other was on 800 mg every 6 h. Three concentration-controlled recipients had grade I or II elevations in liver enzymes; a fourth patient had grade IV elevations but also had hepatitis C coinfection at the time.
Crystalluria was present in two patients, one from each group, during the study. The crystals were not specifically identified for origin but were believed to be indinavir related. Neither patient reported flank pain, dysuria, or any other symptoms related to nephrolithiasis. Flank pain was reported at weeks 12 and 16 in two patients randomized to standard therapy; one patient also had dysuria. One patient randomized to concentration-controlled therapy developed nephrolithiasis at week 28, requiring hospital admission. This patient was receiving an indinavir dose of 800 mg every 8 h. Hematologic toxicities were mostly mild to moderate, with the exception of the one previously described case. Four patients receiving concentration-controlled therapy and three patients receiving standard therapy experienced a grade I decrease in absolute neutrophil count; one standard patient each developed a grade II and a grade IV drop. None of the 24 patients that completed 24 weeks of therapy required discontinuation or modification of therapy or supportive medications (i.e., transfusion or erythropoietin) for hematologic toxicities. Six patients (three in each arm) had nausea and fatigue during the initial part of therapy despite the zidovudine titration scheme. The majority of patients reported feeling better after 4 weeks of therapy. Nausea was not associated with the use of higher zidovudine doses. Other side effects that were possibly related to study medications included partial hair loss (n = 3), hypercholesterolemia (n = 2), hyperglycemia (n = 1), and hypertension (n = 1). None of the patients developed fat redistribution syndrome or excessive weight gain or loss.| |
DISCUSSION |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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We have shown that the administration of zidovudine, lamivudine, and indinavir in a regimen designed to achieve a specific target concentration was feasible and had a safety and tolerance profile not different from the standard dose regimen. The concentration targets selected were average Css of 0.19 and 0.44 mg/liter for zidovudine and lamivudine, respectively, and a Cmin of 0.15 mg/liter for indinavir. The actual mean values at week 28 in the concentration-controlled recipients were 0.20 mg/liter for zidovudine, 0.54 mg/liter for lamivudine, and 0.19 mg/liter for indinavir. A significantly higher proportion of subjects receiving concentration-controlled compared with standard dose therapy achieved these targets for zidovudine and indinavir.
The 24 subjects who participated in this study and were randomized to receive either standard dose or concentration-controlled therapy were well balanced with respect to baseline characteristics, including CL/F (determined at week 2) for zidovudine, lamivudine, and indinavir. Thus, differences in concentrations accomplished with the use of a concentration-controlled regimen did not arise because of baseline differences in pharmacokinetic behavior. A necessary element for the successful application of a concentration-controlled strategy is for intrapatient pharmacokinetic variability to be less than interpatient variability. Figure 1 shows individual patient CL/F values at weeks 2 and 28 and illustrates a general consistency within patients over the 28-week study duration. There was no difference in CL/F for zidovudine, lamivudine, and indinavir between weeks 2 and 28. The mean week 2- to 28-week ratios of CL/F for all three drugs were between 0.95 and 1.09, with 95% confidence intervals encompassing 1. These data provide clear evidence that intrapatient variability over a 6-month period was low and did not result in statistically significant differences in CL/F.
The target concentrations selected for zidovudine and lamivudine were the average Css expected in a patient perfectly adherent with the standard dose regimen of 600 mg/day for zidovudine and 300 mg/day for lamivudine and who had the population average values for bioavailability and total body clearance. Thus, the concentration-controlled strategies for zidovudine and lamivudine were designed not to produce average Css values that were different from those with the standard dose but rather to reduce interpatient variability in Css, as we have previously shown in a study of zidovudine monotherapy (11). Use of the concentration-controlled regimen for lamivudine did not result in a significant reduction in interpatient variability in Css. This is not surprising, as only two persons in the concentration-controlled arm required a lamivudine dose adjustment to achieve the desired concentration. For zidovudine, however, interpatient variability in Css was significantly reduced by 50% with the concentration-controlled regimen. This magnitude of reduction is consistent with that found in an earlier concentration-controlled study with zidovudine monotherapy. The range of zidovudine doses used in the present study, 600 to 900 mg/day (average, 690 mg/day), to achieve a target Css of 0.19 mg/liter is less than the range needed in a previous study (with doses up to 1,200 mg/day) to reach the same target (11). The discrepancy between these studies may in part be due to a drug interaction between zidovudine and indinavir. Indinavir has been shown to increase zidovudine area under the curve by 17 to 36% (25).
The target concentration strategy for indinavir was designed to achieve
a Cmin of 0.15 mg/liter. The average
Cmin with the concentration-controlled approach
was 0.19 mg/liter, which was significantly greater than the 0.10 mg/liter produced with the standard dose. Indinavir doses necessary for
concentration-controlled regimens ranged from 2,400 to 3,200 mg/day;
dosing intervals of every 8 h and every 6 h were employed.
Even with these efforts, 2 of the 11 concentration-controlled
recipients could not be dosed to attain the desired target
concentration, as we chose to not exceed an indinavir dose of 3,200 mg/day for safety considerations. Such patients may represent rapid
metabolizers of indinavir, and perhaps other drugs that are substrates
for similar metabolic pathways, and may explain why some
antiretroviral-naïve patients fail highly active antiretroviral
therapy at standard doses despite good adherence. Attempts to
prospectively identify these patients may prove useful. The
erythromycin breath test has been suggested as a tool for this purpose,
but a prospective study failed to demonstrate any utility (Slain et
al., 38th ICAAC).
As assessed by counts of returned medications, overall adherence in this study was high for all three drugs. Furthermore, adherence was equally good between the concentration-controlled and standard therapy recipients. We were concerned that the more frequent dosing and greater capsule or tablet burden necessary to implement the concentration-controlled regimens would affect adherence adversely. However, we found no evidence to support this concern. This observation is consistent with a study of adherence that found no difference in patient adherence to a regimen of protease inhibitors given twice daily compared with thrice daily (29). These data indicate that factors distinct from the complexity of the regimen play an important role in adherence to a medication regimen; a patient's understanding of disease and drug therapy, motivation, and relationship with his or her health care provider are likely possibilities. The participants in this study may have been biased towards a more adherent population, as an exclusion criterion was a known history of nonadherence with medications or scheduled physician and clinic visits. While no potential participant was excluded based upon this criterion, we do not know if some individuals were not referred by their physician for potential participation in this study because of this criterion. Thus, the overall high degree of medication adherence achieved in both the concentration-controlled and standard therapy recipients may not extrapolate to a larger population of HIV-infected persons receiving antiretroviral therapy.
Overall, zidovudine, lamivudine, and indinavir were safe and well tolerated by the participants during this 28-week study. The adverse reactions of primary concern with this regimen were anemia, neutropenia, and nephrolithiasis. Grade III or IV adverse events occurred in 4 of the 24 patients (17%); there was no difference in events between the concentration-controlled and standard therapy recipients. This is consistent with the finding in our previous study of concentration-controlled zidovudine therapy where, despite an overall higher dose, systemic concentrations, and intracellular zidovudine triphosphate concentrations, there were no differences in the rates of anemia and neutropenia between standard dose and concentration-controlled therapy (11). This 17% rate is consistent also with the 26% incidence of grade III or IV adverse reactions in the AIDS Clinical Trials Group study (study 320) of zidovudine, lamivudine, and indinavir (17). We found no difference in the incidence of urologic complaints in standard dose recipients compared with concentration-controlled recipients. Frank nephrolithiasis developed in one patient during the course of treatment, and two others reported flank pain. All three patients had no prior history of renal disease. The concentration-controlled patient who developed the kidney stone had been receiving indinavir (800 mg every 8 h) throughout the course of study. It has been suggested that higher plasma concentrations of indinavir are associated with a higher incidence of urologic complaints, including nephrolithiasis (9). However, the basis for a higher dose in a patient receiving concentration-controlled therapy is to adjust for a higher-than-average clearance of the drug. Therefore, these patients may not have the same risk of dose- or concentration-related nephrolithiasis as would a person with average clearance receiving an increased dose. Nevertheless, antiretroviral therapy is a long-term undertaking, and a more prolonged comparative assessment of the safety and tolerance of concentration-controlled versus standard dose therapy would be important.
Irrefutable progress in the pharmacotherapy of HIV infection has been made (28). Improving the use of currently available antiretroviral agents is as important as the rational development of promising new compounds in order to advance therapeutics further. This investigation has provided a pharmacologic basis for concentration-controlled combination antiretroviral therapy by demonstrating that it is feasible and that it has a short-term safety profile comparable with the standard dose regimen. Studies to learn whether concentration-controlled therapy provides a virologic advantage over the conventional approach of administering the same dose of antiretroviral agents to all adults now appear warranted.
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ACKNOWLEDGMENTS |
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This work was supported by grants RO1-AI33835-07 from the National Institute of Allergy and Infectious Diseases and MO1-RR00400 from the National Institute of Health, Center for Research Resources General Clinical Research Centers Program.
We thank Cynthia Gross for comments on study design and data analysis; Rory P. Remmel for his guidance with development of the zidovudine, lamivudine, and indinavir assays; Dennis Weller, Lane Bushman, Shao Mei Han, and Sagar Kawle for their technical assistance; Henry H. Balfour, Jr., Alejo Erice, and Carolyn Beatty of the Clinical Virology Laboratory for their assistance; the laboratory of J. Brooks Jackson at Johns Hopkins University Medical School for measurement of HIV RNA in plasma; the staff of the General Clinical Research Center for their outstanding patient care; Glaxo Wellcome for their donation of zidovudine, lamivudine, and Combivir; Merck and Co., Inc., for their donation of indinavir; and the patients for their involvement in this study.
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FOOTNOTES |
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* Corresponding author. Mailing address: University of Minnesota, 7-151 WDH, 308 Harvard St., S.E., Minneapolis, MN 55455. Phone: (612) 624-6489. Fax: (612) 625-9931. E-mail: fletc001{at}tc.umn.edu.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Antimicrobial Agents and Chemotherapy, January 2001, p. 236-242, Vol. 45, No. 1
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.1.236-242.2001
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