A profound reduction in the morbidity and mortality associated with HIV-1 infection has been achieved through the use of highly potent combination antiretroviral regimens . Unfortunately, the optimism surrounding these benefits is tempered by rates of virological failure that have ranged from 20 to 67% in clinical trials and in general medical practice among therapy-naive individuals [2–6]. The response to therapy varies greatly because of differences among patients in virological, immunological, behavioral, and pharmacological factors that ultimately determine therapeutic success [7–10]. No direct interventions can be made to change the inherent immunological and virological characteristics of a patient; for example, the baseline susceptibility of a patient's viral strain to an antiretroviral drug cannot be enhanced. In contrast, behavioral and pharmacological characteristics can be directly manipulated in an individual. Medication counselling can be used in an effort to improve a patient's adherence, and the dose of a drug can be increased to correct for a low plasma concentration that might arise from reduced bioavailability or a faster than average elimination half-life.
The current practice of administering standard fixed doses of antiretroviral drugs results in quite different systemic, unbound, and intracellular concentrations among patients [11–15]. Drug–drug and drug–food interactions, transporter proteins, and concomitant disease states further accentuate pharmacokinetic variability [16–18]. Numerous investigations have described relationships between systemic or intracellular drug concentrations and an anti-HIV effect [19–23]. The clinical outcome has been improved when pharmacological considerations were applied to drug dosing in other disease states in which these scenarios exist. For example, adjusting the dose of methotrexate to achieve a target concentration improved the 5 year rate of continuous complete remission in children with B-lineage acute lymphoblastic leukemia . Our objectives were to demonstrate the feasibility of a concentration-controlled approach to combination antiretroviral therapy, and to compare the virological responses and safety of this strategy versus conventional fixed-dose therapy.
This study was conducted in the General Clinical Research Center Outpatient Clinic and was approved by the Human Subjects Committee at the University of Minnesota. All subjects were informed about the study and gave written consent before participation. The eligibility criteria included being aged between 18 and 60 years, a plasma HIV-RNA level of greater than 5000 copies/ml, and no previous antiretroviral therapy. Exclusion criteria were an active opportunistic infection requiring the interruption of antiretroviral therapy or a documented history of non-adherence with medications or scheduled clinic visits.
This was a prospective, randomized, 52 week, open-label trial. The drugs and conventional doses were zidovudine 300 mg twice a day; lamivudine 150 mg twice a day; and indinavir 800 mg every 8 h. Medication counselling and information was provided to all subjects, which included instructions to take indinavir on an empty stomach or with a light meal, and to drink at least 48 ounces of water per day to maintain adequate hydration. After 2 weeks of conventional therapy (except zidovudine, which was started at 100 mg twice a day for the first week, then 200 mg twice a day for the second, to minimize gastrointestinal adverse effects ) participants were randomly assigned to the conventional therapy arm or the concentration-controlled arm.
Pharmacokinetic and adherence evaluations
All participants underwent 8 h pharmacokinetic evaluations at weeks 2 and 28. Observed doses of zidovudine, lamivudine, and indinavir were administered simultaneously, and blood samples were obtained pre-dose and 0.5, 1, 2, 3, 4, 5, 6, 7, and 8 h post dose. Patients were not allowed to eat 1 h before or 2 h after the ingestion of their medications. The 8 h sampling scheme for zidovudine and lamivudine encompassed over 85% of the total concentration area from a 12 h dosing interval. Zidovudine, lamivudine, and indinavir plasma concentrations were quantitated in each of these samples by high-performance liquid chromatography . Pharmacokinetic parameters for each drug were calculated and used to change doses only in the concentration-controlled participants if necessary to achieve the desired target concentrations . The targets were: zidovudine and lamivudine, average steady-state concentrations of 0.17 mg/l or greater and 0.40 mg/l or greater, respectively; and indinavir, 8 h post-dose (trough) concentration of 0.13 mg/l or greater. No upper limits were defined. Dose changes, based upon week 2 pharmacokinetic data, were implemented at week 4. Doses were calculated as previously described; dosing intervals were constrained to no more frequent than every 6 h, and the final interval was selected on the basis of the calculated interval and investigator's judgment . A single blood sample, obtained 2–5 h post dose, was obtained at each visit. This time-frame was chosen to obtain post-absorption concentrations within an optimal window, as assessed by D-optimality criteria [25,26]. Drug concentrations in these samples were used in a Bayesian estimation feedback approach to reassess whether the desired concentrations had been achieved and to make any further dose adjustments [14,25].
Medications were provided in quantities sufficient until the next visit (i.e. 30 day supply). Participants were requested to return their unused medications at each visit. Adherence was calculated as the ratio between the number of dosage units taken, as determined by medication count, to the number expected.
Clinical assessments were performed at entry and weeks 2, 4, and every 4 weeks thereafter to week 52 (15 visits in total). A complete blood count with differential, blood chemistries, and lymphocyte subpopulations were determined at each visit, except after week 28, when lymphocyte subpopulations were determined every 8 weeks. Urinalysis was performed and cholesterol and triglycerides were measured every 3 months. Blood samples for the quantitation of HIV RNA (Roche Amplicor HIV-1 Ultrasensitive Assay; Roche Diagnostic Systems, Branchburg, NJ, USA) were obtained at each visit. Adverse reactions were managed using the approach of the AIDS Clinical Trials Group .
The sample size was selected on the basis of three considerations: first, the ability to detect a greater than 40% difference in the variance of zidovudine steady-state concentrations and a greater than 0.09 mg/l difference in indinavir trough concentrations; second, the ability to detect a 0.8 g/dl difference in hemoglobin (anemia is a primary dose-limiting toxicity of zidovudine); and third, the ability to detect a greater than 30% difference in the proportions of patients with undetectable HIV RNA between the conventional and concentration-controlled arms. For all considerations, a sample size of 40 patients was sufficient at an alpha of 0.05 and 80% power.
Study participants were randomly assigned to either the conventional or concentration-controlled arm after the first 2 weeks of therapy and completion of the week 2 intensive pharmacokinetic evaluations. Random selection was performed using a permuted block approach with assignments contained in sealed, opaque envelopes sequentially numbered. The randomization cards were prepared by the protocol statistician (C.R.G.), and only provided to the clinical investigators on a case-by-case basis. After week 4, both study investigators and participants were blinded to the HIV-RNA results for the first 6 months of therapy. Those individuals with plasma HIV-RNA levels greater than 200 copies/ml at the completion of the first 6 months of therapy, or anytime thereafter, were discontinued from the study but included in the assessment of study endpoints.
The three primary endpoints of this study were: (i) the proportion of patients who achieved the desired concentration for each drug following observed doses at the week 28 intensive pharmacokinetic evaluation; (ii) the proportion with HIV-RNA levels below 50 copies/ml at week 52; and (iii) the safety and tolerance of conventional compared with concentration-controlled therapy. The endpoints of the proportions of participants achieving the desired concentrations, and the proportions with HIV-RNA levels below 50 copies/ml at week 52 were compared with Fisher's exact tests using a modified intention-to-treat approach, whereby individuals who discontinued participation before week 8 were excluded because there had not been sufficient time to establish and verify the intended experimental condition in the concentration-controlled patients. Patients who discontinued the study after week 8 were included in all response analyses using the last observation carried forward method. Logistic regression was used to evaluate the impact of treatment on undetectable HIV-RNA status at week 52. The events of the times to undetectable HIV-RNA levels in plasma, and to virological rebound were analysed using the Kaplan–Meier method, log rank tests, and Cox proportional hazards regression models [28,29]. The time to undetectable HIV-RNA levels was defined as the number of days from the start of therapy to reach the first of two consecutive plasma HIV-RNA levels of less than 50 copies/ml. This event did not require the subsequent maintenance of HIV RNA suppression. The time to virological rebound was taken as the number of days to reach the first of two consecutive HIV-RNA levels greater than 50 copies/ml after reaching a nadir or an undetectable HIV-RNA level as defined above. Adverse events were compared between the arms in a standard intention-to-treat approach using Fisher's exact tests. All statistical tests were two-sided and were performed at a 5% level of significance.
Forty individuals were enrolled in this study between June 1997 and September 1999; the last subject completed the study in September 2000. No imbalances, including entry virological, immunological, and pharmacokinetic characteristics, were noted between individuals randomly assigned to receive concentration-controlled versus conventional therapy (Table 1; all P > 0.05). Seven of the 40 subjects had early (before week 8) treatment discontinuations and were not included in the analysis of pharmacokinetic or virological outcomes. One patient moved out of state after week 4, two were lost to follow-up at weeks 4 and 8, one was dropped from the study at week 8 for an unwillingness to comply with protocol requirements, and three withdrew for adverse events (described below).
Based on the week 28 pharmacokinetic assessment (Fig. 1), the proportions of concentration-controlled (n = 16) versus conventional (n = 17) therapy recipients achieving the desired targets were: zidovudine 100 versus 53% (P = 0.003); lamivudine 100 versus 65% (P = 0.018); and indinavir 88 versus 18% (P < 0.001). Doses of zidovudine, lamivudine, and indinavir were changed in 44, 31, and 81%, of concentration-controlled therapy recipients, respectively. The modified dosing regimens (and number of subjects) were as follows: zidovudine 700 mg/day (four), 800 mg/day (two), 900 mg/day (one); lamivudine 450 mg/day (five); and indinavir 600 mg every 6 h (three), 800 mg every 6 h (four), 1000 mg every 8 h (six). The monthly single concentrations and the week 28 intensive evaluation provided a total of 12 opportunities per patient for dose adjustments after the initial adjustment (if necessary) at week 4. Dose adjustments after week 4, however, were rare. Two participants required an increase in their zidovudine dose from 600 to 700 mg/day (week 36) and 800 mg/day (week 32); one patient needed an increase in their lamivudine dose from 300 to 450 mg/day (week 48); and one subject's indinavir dose was increased from 800 to 1000 mg every 8 h (week 40). All conventional therapy subjects were receiving the standard doses of all three drugs at the completion of therapy. Average adherence rates for both the concentration-controlled and conventional therapy recipients to zidovudine, lamivudine, and indinavir exceeded 90% and were not significantly different between the two groups for each drug.
Thirty-three participants were eligible to be included in the analyses of virological responses. Five subjects (one in the concentration-controlled arm and four in conventional therapy) had HIV-RNA levels greater than 200 copies/ml at the completion of the first 6 months of therapy. Four additional conventional therapy recipients subsequently developed HIV-RNA endpoints. Fig. 2 shows the percentage of individuals by treatment arm who achieved the endpoint of HIV-RNA levels below 50 copies/ml. At week 52 the rates were 15 out of 16 in the concentration-controlled group compared with nine out of 17 in the conventional therapy group [mean difference in proportions, 40.7%; 95% confidence interval (CI) 10.3–71.1%;P = 0.017]. In a univariate logistic regression model, assignment to treatment strategy, age, and the time to reach undetectable plasma HIV-RNA levels were identified as potentially important (P < 0.1) factors associated with the likelihood of having undetectable HIV-RNA levels at week 52. Factors considered, but not associated, included baseline HIV RNA (P = 0.54) and CD4 lymphocyte count (P = 0.45). In the logistic regression model with the predictor variables included, assignment to concentration-controlled therapy remained significantly (P = 0.03) associated with undetectability at week 52, when the effects of age (P = 0.02) and the time to reach undetectable HIV-RNA levels (P = 0.07) were controlled.
Secondary analyses were conducted in which patients were grouped according to whether they achieved the target concentrations for zidovudine, lamivudine, and indinavir at week 28, independent of random assignment to concentration-controlled or conventional therapy. Fifteen patients achieved the target values for all three drugs, whereas 18 patients did not. Of the 15 who achieved all three target concentrations, 14 had less than 50 copies/ml of HIV RNA at week 52. This is in contrast with the group of 18 individuals who did not achieve all target concentrations, in which only 10 had undetectable HIV-RNA levels (P = 0.02). In a logistic regression model, the presence of target concentration conditions for all three antiretroviral drugs was associated (P = 0.05) with undetectable HIV-RNA levels at week 52, when the effects of age (P = 0.02) and the time to reach undetectable HIV-RNA levels (P = 0.03) were controlled.
The recipients of concentration-controlled therapy reached undetectable levels of HIV RNA in a shorter period of time than those who received conventional therapy (log rank test, P = 0.01). The median number of days was 108 for concentration-controlled compared with 225 days for conventional therapy (Fig. 3). This finding remained significant after controlling for baseline viral load (relative risk 3.53; 95% CI 1.43–8.7;P = 0.006). Other covariates including age, sex, and baseline CD4 cell count were not significantly related to the time to reach undetectable HIV-RNA levels. The recipients of concentration-controlled therapy also had a longer time to virological rebound (Fig. 4, log rank test, P = 0.013). Assignment to concentration-controlled therapy remained a significant factor in reducing the hazard of virological rebound (relative risk 0.09; 95% CI 0.01–0.88;P = 0.039) after adjustment for age and the time to reach undetectable HIV-RNA levels.
No significant differences were found in the change in CD4 lymphocytes at week 52 between the concentration-controlled and conventional therapy recipients. The mean change in CD4 cell counts from baseline was 214 cells/μl for the concentration-controlled arm, and 167 cells/μl for the conventional arm (P = 0.26). The number of days after the initiation of therapy to reach a CD4 cell count increase of 100 cells/μl was marginally significantly different between the two treatment strategies, with a median of 56 days for the concentration-controlled group compared with 86 days for the conventional dose group (log rank test, P = 0.06).
No significant differences were observed between the concentration-controlled (n = 21) and the conventional therapy groups (n = 19) in the occurrence of drug-related clinical events or laboratory abnormalities. In total, six participants (three in each arm) chose to withdraw for adverse events. Three patients withdrew at week 4, two (one in each arm) for gastrointestinal intolerance, and one (conventional therapy arm) for peripheral neuropathy. At week 12, one conventional therapy recipient withdrew for headache and grade II anemia (week 12 HIV-RNA level of 504 copies/ml); a subsequent magnetic resonance imaging scan was normal and there were no central nervous system complaints on follow-up examinations. Nephrolithiasis occurred in one conventional compared with three concentration-controlled therapy recipients (P > 0.5). The conventional therapy recipient had an indinavir trough concentration of 0.33 mg/l; the three concentration-controlled subjects were receiving indinavir doses (and had trough concentrations) of 800 mg every 8 h (0.27 mg/l), 1000 mg every 8 h (0.14 mg/l), and 800 mg every 6 h (0.14 mg/l). Two of these concentration-controlled recipients elected to withdraw from the study at week 28; both had HIV-RNA levels below 50 copies/ml. No difference was found in the rates of nephrolithiasis between study patients who achieved the target trough concentration for indinavir compared with those who did not. No participant had greater than grade I elevations in glucose (> 161 mg/dl) or triglyceride concentrations (> 400 mg/dl); no patient had excessive weight gain/loss or reported fat redistribution. The rates of clinically important laboratory abnormalities (grade III or greater unless noted) in concentration-controlled versus conventional therapy recipients were: hemoglobin less than 8 g/dl (grade II or greater), none versus one; absolute neutrophil count less than 750/mm3, none versus one; platelet count less than 50 000/mm3, none; total serum bilirubin equal to or greater than 2.5 times normal, three versus one; and hepatic transaminases greater than five times normal, one versus none.
We have shown that concentration-controlled therapy implemented simultaneously for three antiretroviral agents was feasible, was tolerated as well as conventional therapy, and resulted in a greater proportion of recipients having undetectable HIV-RNA levels after 52 weeks of therapy. Our approach to concentration-controlled therapy was designed to achieve selected average steady-state concentrations of zidovudine and lamivudine, and a trough concentration for indinavir. The study was conducted using commercially available drug formulations in ambulatory, antiretroviral-naive patients attending an outpatient clinic. Significantly more subjects randomly assigned to concentration-controlled versus conventional dose therapy achieved the desired target concentrations, indicating that the desired experimental conditions were achieved.
There are currently no accepted therapeutic ranges of plasma concentrations for zidovudine, lamivudine, and indinavir. The value selected for zidovudine was based upon previous work that demonstrated that a concentration-controlled zidovudine monotherapy regimen targeting the same steady-state plasma concentration used in this study resulted in a significantly improved anti-HIV response when compared with conventional dose therapy . The target concentration for lamivudine was the level that individuals would reach if they were perfectly adherent to the standard dose regimen and had average values for bioavailability and total body clearance (i.e. the hypothetical average individual) according to the manufacturer's package insert. This was the same conceptual approach initially used to select the zidovudine target concentration for the monotherapy study . The pharmacological active moiety for zidovudine and lamivudine is not the parent compound in plasma but the triphosphate anabolite formed intracellularly. The relationships between plasma concentrations and intracellular triphosphate concentrations of these nucleoside agents are complex and multifactorial. Nevertheless, data support proportionality between the dose of zidovudine and lamivudine and the corresponding increase in intracellular triphosphate concentrations, and provide a basis to target plasma concentrations [14,30]. However, it is likely that improved precision in optimizing the anti-HIV response could be achieved by using the intracellular triphosphate as a target concentration, and future work should examine this possibility. The trough concentration selected for indinavir was based upon a pilot clinical study that found that the average value for virological responders was 0.15 mg/l .
In order to implement concentration-controlled therapy, zidovudine, lamivudine, and indinavir dose increases were necessary for 44, 31, and 81%, of the individuals assigned to this strategy, respectively. These rates are consistent with our past experience with zidovudine and with expectations for lamivudine and indinavir. In a previous study with concentration-controlled zidovudine monotherapy, 50% of participants required a dose increase to achieve the same target value used in this study. The participants in this study had oral clearance values for zidovudine, lamivudine, and indinavir in agreement with previously published values [11,14,31]. It was expected that less than 50% of concentration-controlled recipients would require an increased dose of lamivudine, because the target concentration was based upon average values for bioavailability and total body clearance. Previously published data for indinavir found the median 8 h post-dose concentration was 0.07 mg/l . Given that that target selected for this study was 0.13 mg/l or greater, we expected that more than 50% of patients would require a dose increase. Importantly, no statistically significant differences were seen between the concentration-controlled arm compared with the conventional dose arm in the frequency of the common drug-limiting adverse events of anemia (0 versus 5%), neutropenia (0 versus 5%), and nephrolithiasis (14 versus 5%). As this study was not designed to find a difference in the rates of nephrolithiasis, it is appropriate to exercise some caution around the confidence in this finding. In general, these data replicate previous work with zidovudine, and support the hypothesis that in individuals who have lower than average systemic concentrations, dose increases to achieve average systemic concentration values should not increase rates of toxicity . Finally, we found no evidence that concentration-controlled therapy, despite the need for an increased medication burden and frequency, affected medication adherence adversely. Admittedly, medication counts are a crude measure and tend to overestimate adherence; any bias in the estimation of medication adherence, however, should be equally distributed between the two treatment arms .
The virological response to the conventional dose regimen of zidovudine, lamivudine, and indinavir has been well characterized in antiretroviral-naive individuals and in patients who have been treated previously with zidovudine [33,34]. A trial in antiretroviral-naive individuals found that 46% of subjects who received this regimen had HIV-RNA levels less than 20 copies/ml after 52 weeks of therapy . A recent meta-analysis of 3275 patients enrolled in 23 clinical trials found that 46% (95% CI 41–52%) of patients receiving a dual nucleoside plus protease inhibitor (PI) regimen had HIV-RNA levels of less than 50 copies/ml at 48 weeks . This demonstrates excellent comparability between our control group and other studies that used the same regimen and standard doses. An analysis of baseline reverse transcriptase and protease viral DNA sequences in 26 of the participants from this study found patterns expected in individuals never exposed to antiretroviral drugs (data not shown). Therefore, drug-resistant mutations at the start of therapy do not provide an explanation for differences observed in virological response between the concentration- controlled and conventional therapy arms. A greater proportion of subjects who received concentration-controlled therapy achieved undetectable HIV-RNA levels, and concentration-controlled recipients took a shorter time to reach an undetectable level. Others have shown that a longer time to reach viral suppression is an independent predictor of the loss of viral suppression [36–39]. We found that assignment to concentration-controlled therapy significantly reduced the risk of virological rebound independent of the impact of age and the time to reach undetectable HIV-RNA levels.
In HIV therapeutics, it is common to administer dual PI in which one agent is given primarily to inhibit the metabolism of the other (e.g. indinavir, lopinavir, or saquinavir in combination with ritonavir). The potential advantages of this approach are a decrease in the frequency of drug administration and an increase in antiviral potency . Disadvantages include the additional side-effects associated with ritonavir and, as demonstrated in the ATHENA study, a need to lower the indinavir dose in certain patients in order to improve tolerance . It is likely that had this study been designed after the advent of the dual PI regimen of indinavir and ritonavir, the frequency of low indinavir concentrations found, and the necessity to use dosing intervals of every 6 h in some concentration-controlled recipients to achieve the desired concentrations would have been reduced. However, it cannot be confidently concluded that an indinavir plus ritonavir strategy would have ameliorated the contribution of pharmacokinetic variability to variability in virological response and maximized antiretroviral potency. Indeed, the sparse comparative data available do not support a dramatic improvement in potency with dual PI regimens. A randomized trial of lopinavir/ritonavir compared with nelfinavir in antiretroviral-naive individuals also receiving stavudine and lamivudine found that the proportion of subjects with HIV-RNA levels less than 50 copies/ml (intention to treat approach) was 64% for the lopinavir arm versus 52% for the nelfinavir arm at week 60 . Virological responses were not different in a trial in 318 individuals randomly assigned to receive indinavir, ritonavir, or saquinavir plus ritonavir, all with double nucleoside therapy; 52, 41, and 58% of patients assigned to these three regimens, respectively, had less than 20 copies/ml of HIV RNA at week 72 . A pharmacokinetic evaluation of the saquinavir plus ritonavir regimen (400 mg of each twice a day) showed that saquinavir trough concentrations varied at least sevenfold among patients . These pharmacokinetic findings are not unique to the saquinavir plus ritonavir dual PI combination, and illustrate considerable interindividual pharmacokinetic variability, even in the presence of ritonavir-associated metabolic inhibition . Collectively, these data indicate that the dual PI strategy is not maximally potent, and does not eradicate the significant differences observed in concentrations among patients. Furthermore, pharmacokinetic variability also arises from other components of an antiretroviral regimen, such as nucleoside or non-nucleoside reverse transcriptase inhibitors. Therefore, even in the setting of dual PI regimens, efforts to mitigate the contribution of pharmacokinetic variability to variability in virological response are relevant. The results of the present study support the hypothesis that pharmacological variability affects the anti-HIV response, and that strategies to accommodate interpatient variability can improve response. These findings provide a scientific basis to challenge the accepted practice of administering the same doses of antiretroviral drugs to all adults, thereby ignoring the concentrations actually achieved.
Antiretroviral therapy is a complex, costly, long-term undertaking associated with serious potential complications. Nevertheless, the major goal of therapy when initiated is the suppression of HIV RNA to undetectable levels, as this offers the most enduring response and lessens the emergence of resistant strains of HIV. Clearly, new drug development initiatives are needed to improve both the response and tolerance to therapy. However, the lessons from the therapy of childhood acute lymphoblastic leukemia also appear instructive. Overall survival improved from 21% in 1966 to 86% in 1997 through efforts that included combination chemotherapy and pharmacological approaches that optimized systemic exposure to already existing agents such as methotrexate . On the basis of the results of this trial of concentration-controlled combination antiretroviral therapy compared with conventional fixed-dose therapy, we believe that efforts to improve the response to antiretroviral agents must include strategies to optimize the pharmacological determinants of response. Several issues and questions remain to be addressed. Some of these include: the widespread availability of analytical and pharmacokinetic methods to accomplish dose adjustment; the determination of maximally tolerated concentrations; the identification of concentration targets for naive and treatment-experienced individuals; improved methods to quantitate medication adherence; and a scientific framework to integrate pharmacological considerations with measures of virus susceptibility to antiretroviral drugs.
The authors are indebted to Drs Linda M. Page, Edward P. Acosta, Frank S. Rhame, Alejo Erice and Henry H. Balfour Jr., for their contributions to the design and implementation of this study and the referral of study participants; to Lane Bushman, Dennis Weller, Sagar Kawle, and Shao Mei Han for performing the pharmacological assays; to the laboratory of J. Brooks Jackson at Johns Hopkins University Medical School for the measurement of HIV-RNA levels in plasma; to Glaxo-Smith Kline for their donation of zidovudine and lamivudine and Merck and Co. for their donation of indinavir; to the staff of the General Clinical Research Center for their outstanding patient care; and to the individuals who agreed to participate in this study.
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Keywords:© 2002 Lippincott Williams & Wilkins, Inc.
Antiretroviral therapy; combination therapy; drug concentrations; pharmacokinetics; therapeutic drug monitoring