The a priori definition of evaluable patients included those who were randomized and started a new regimen at baseline, hereafter referred to as the modified intent-to-treat (ITT) group. The primary hypothesis was that the true proportion of patients with nontarget PI and/or NNRTI concentrations triggering a TDM recommendation to change exposure was 40%.
The primary endpoints were (1) the proportion of subjects who had a TDM recommendation to change PI and/or NNRTI dosing and (2) the proportion of recommended changes that were carried out (TDM arm only). Secondary endpoints included (1) the proportion of recommended interventions in the TDM arm that achieved the target concentrations, (2) the proportion of patients with an HIV RNA level <400 copies/mL at 48 weeks compared between arms, and (3) the proportion of patients experiencing grade III/IV and/or treatment-limiting toxicity compared between arms.
The sample size was based on adequate power for the adherence intervention comparisons.29 With the calculated sample size of 270, the 95% confidence interval (CI) around an estimated TDM recommendation rate of 40% was 34% to 46%. Univariate analyses using χ2 (categoric) or ANOVA (continuous variables) compared factors for those with or without a TDM recommendation to change. Multivariate logistic regression models, with a TDM recommendation to change as the bivariate outcome variable, assessed the independent odds ratios of prognostic factors at weeks 2, 12, and 24. Variables included age, HIV RNA, race, prior regimen history, gender, current regimen, weight, albumin, body mass index (BMI), CD4 cell count, prior AIDS, adherence intervention group, and MEMS coverage. Virologic outcomes at weeks 24 and 48 and occurrence of treatment-limiting or grade III/IV toxicities were analyzed with t tests, Fisher exact tests, and χ2 tests, as appropriate.
Patients were enrolled between September 2001 and December 2003, with the final study visit in January 2005. Of 241 patients identified and screened during the study period, 230 were randomized (Fig. 2). Twenty-seven subjects missed the baseline visit, and 4 did not start a new ARV regimen; thus, the modified ITT population was 199 subjects. Twenty-five subjects discontinued within 24 weeks, and 27 discontinued between weeks 24 and 48. No differences were noted in time to dropout or absolute numbers of patients prematurely discontinuing between the TDM and SOC arms.
Demographics were similar between the TDM and SOC arms (Table 2) and also across the adherence intervention arms (data not shown). This group had advanced disease, with a median HIV RNA level >5.0 log10 copies/mL and CD4 cell counts <200 cells/mm3. More than two thirds of these subjects were treatment experienced. Most subjects were male and nonwhite.
Baseline ARV regimens included a ritonavir-boosted PI in more than half of the subjects, with similar regimens used in each arm (see Table 2). Common ARVs included tenofovir (66% of subjects), lopinavir/ritonavir (46%), and efavirenz (31%). Interpatient variability in concentrations was large. The median (interquartile range [IQR]) week 2 modeled Ctrough and peak and average concentrations expressed as a percentage of population-predicted values were 135% (82% to 201%), 91% (68% to 120%), and 111% (82% to 141%), with ranges from 0% to 743%, 7% to 255% and 18% to 308%, respectively. Intrapatient variability was also substantial, with median (IQR) dose-corrected percent differences in concentrations across visits of 86% (42% to 144%), 39% (18% to 68%), and 54% (27% to 97%) for Ctrough and peak and average concentrations, respectively. Median (range) intrapatient oral clearance from baseline to last study visit decreased for indinavir −21% (−45% to 6%); did not change by more than 5% for atazanavir, nevirapine, lopinavir and saquinavir; and increased for amprenavir 37% (−36% to 89%) and efavirenz 14% (−68% to 282%). A lag time in PI and/or NNRTI absorption was noted in 43 (22%) subjects taking a PI, with a mean concentration decrease of 30% ± 16% (range: 4% to 60%). Thirty-four of these 43 patients were taking lopinavir/ritonavir (ie, one third of subjects taking lopinavir/ritonavir had absorption lags).
Nine subjects never had a PI and/or NNRTI concentration drawn while on study. One hundred ninety subjects had at least 1 visit with PI and/or NNRTI concentrations determined, and 122 (64%) of 190 of these patients (89 in the TDM arm and 33 in the SOC arm) had a TDM recommendation to change PI and/or NNRTI exposure at least once during the study. At the week 2 study visit, 74 (39%) of 190 subjects (42% in the TDM arm [n = 54] and 32% in the SOC arm [n = 20]) had a recommendation to change PI and/or NNRTI exposure. The expert panel performed 502 separate TDM evaluations during the study, with 170 recommendations to change PI and/or NNRTI exposure in 122 subjects (34% of TDM evaluations, 95% CI: 30% to 38%). At week 48, an additional 145 TDM evaluations were performed, with 55 recommendations to change PI and/or NNRTI exposure. These were done to determine whether or not the patients met the pharmacologic targets but were not provided to sites, because patients had completed the study.
Among the 170 recommendations to change drug exposure, 9 were to decrease drug exposure, whereas 166 were to increase drug exposure. Several patients had recommendations to change more than 1 ARV at a single visit and were only counted once per visit in the 170 recommendations. The most common suggested change was to increase the dose of the NNRTI or primary PI (n = 111). Other suggestions included adding or increasing ritonavir (n = 7), modifying concomitant medications (n = 2), modifying diet (n = 1), decreasing dose (n = 4), discontinuing medication (n = 4), and counseling to improve adherence (n = 41). For lopinavir, the most common specific recommendation was to increase dose (n = 44 [53%]), followed closely by improving adherence (n = 35 [42%]). Doses were increased in 1 capsule (133/33-mg lopinavir/ritonavir) increments to 533/133 mg of lopinavir/ritonavir twice daily in 30 subjects, and to 666/166 mg of lopinavir/ritonavir twice daily in 2 subjects. Two subjects added supplemental ritonavir (100 mg) instead: the first to doses of 400/200 of lopinavir/ritonavir mg twice daily and the second to 800/300 mg of lopinavir/ritonavir once daily. Two subjects took decreased doses of 266/66 mg of lopinavir/ritonavir twice daily. In contrast, for NNRTIs, 52 (81%) subjects were to increase dose, with only 5 (8%) to improve adherence. For efavirenz specifically, 16 subjects took 800 mg once daily and 2 subjects further increased their doses to 1000 mg once daily. For other boosted PIs (excluding lopinavir), 12 (75%) subjects were to increase their dose, whereas only 1 (6%) was to improve adherence.
Clinicians implemented the TDM recommendations to change drug exposure 76% (95% CI: 68% to 84%) of the time. In this TDM group, 53 (60%) of 88 recommendations yielded target exposure at the next follow-up visit. In contrast, in the SOC arm, target concentrations were met at subsequent visits in subjects with nontarget exposure for only 16 (36%) of 45 recommendations to change drug exposure, in the absence of providers receiving the TDM reports. Patients with nontarget concentrations in the TDM arm subsequently achieved the pharmacologic target exposure more often, on average, than SOC-arm patients (65% vs. 45%; P = 0.09).
Predictors of Above- or Below-Target ARV Exposure
For the week 2 TDM evaluations, independent factors predicting nontarget PI and/or NNRTI concentrations included greater body weight, efavirenz use, and lopinavir use (Table 3). Patients who ever had a change recommended had similar predictors. Predictors at weeks 12 and 24 included higher BMI, lower baseline hemoglobin, male gender, prior HIV treatment experience, prior NNRTI use, and a previous recommendation to change. In the subset who achieved targeted exposure at week 12 after an initial recommendation to change exposure, adherence (therapeutic coverage at week 12 as measured by MEMS devices) was a significant predictor of success.
Safety and Tolerability
The most commonly reported adverse effect was diarrhea/loose stools. Other reported adverse effects included nausea, fatigue/malaise/asthenia, vomiting, sleeping problems/insomnia/dreams, flatulence/gas/distension, and dizziness/lightheadedness/fainting. Rates of provider-reported treatment-limiting toxicities or grade III/IV toxicities did not differ between the TDM and SOC groups at weeks 24 and 48, or within the subset of patients for whom a dose increase was recommended at the initial TDM evaluation. The time to treatment-limiting or grade III/IV toxicities also did not differ. When patients were grouped according to presence or absence of treatment-limiting toxicities, median trough percent of population-predicted concentrations were similar (161% vs. 155%), but maximum PI and/or NNRTI concentrations were higher in those with treatment-limiting toxicities (126% vs. 100%; P = 0.04). No differences were seen in pharmacokinetic parameters between the groups of patients with or without grade III/IV toxicity.
This study enrolled a heterogeneous population and was not designed to detect a virologic difference between TDM and SOC arms, and no significant differences in virologic outcomes were observed. The proportions of patients with viral loads <400 copies/mL and <50 copies/mL were similar between the groups at the study midpoint and end. At week 24, 34% of subjects in the TDM arm and 39% of subjects in the SOC arm had an HIV RNA level <400 copies/mL. At week 48, the proportions were 31% in the TDM arm and 28% in the SOC arm. An HIV RNA level <50 copies/mL was achieved in the TDM arm in 13% of subjects and in 11% of SOC subjects at week 24; at week 48, 11% and 14% of TDM and SOC patients achieved this viral outcome, respectively. Patients who dropped out of the study prematurely were considered failures.
To explore the impact of TDM-directed augmented exposure on virologic response better, a posthoc analysis stratified all subjects from both arms into 3 groups: (1) at or above the target concentrations at all TDM evaluations (n = 68), (2) nontarget concentrations triggered a recommendation to change PI and/or NNRTI exposure and achieved target at next follow-up visit (n = 53), and (3) nontarget concentrations that never achieved target (n = 32). Subjects who had a recommendation to change drug exposure but did not have a follow-up study visit to assess achievement of target concentrations were excluded (n = 37). In a linear regression model adjusting for baseline RNA and treatment experience, groups 1, 2, and 3 had mean changes from baseline to week 48 HIV RNA log10 of −2.4, −2.3 and −1.9, respectively (P = 0.09).
This study describes the use of TDM for a heterogeneous group of treatment-naive and experienced HIV-infected subjects starting a new PI- or NNRTI-based regimen. One third of subjects had nontarget concentrations 2 weeks after starting therapy, similar to that observed in prior TDM studies.16,19,20 Notably, nearly two thirds of subjects had nontarget PI and/or NNRTI exposure at least once during the 48-week study, indicating that plasma ARV concentrations are dynamic and may benefit from repeated and initial pharmacologic monitoring.
Greater baseline body weight and use of efavirenz or lopinavir/ritonavir were statistically significant independent predictors of nontarget PI and/or NNRTI concentrations. Our finding that increasing body weight is related to nontarget concentrations is consistent with the finding by van der Leur and colleagues57 that body weight was significantly inversely related to lopinavir concentration ratios (individual concentrations divided by expected concentrations). Whereas specific weight cutoffs were not assessed, a BMI >30 would be 1 SD above the mean body weight observed in our study population and suggests that TDM of PIs or NNRTIs be considered. Prediction of need for TDM by efavirenz and lopinavir use may be attributable simply to the pronounced pharmacokinetic variation observed in this group. Another potential explanation is that although most enzyme induction/inhibition by efavirenz and ritonavir occurs within a few weeks, additional minor induction/inhibition of metabolic activity may occur over longer times, eventually significantly affecting ARV concentrations. For efavirenz, this is supported by our observation that oral clearance within a patient increased over time. Our observation that amprenavir oral clearance increased over time as well is less straightforward. Oral clearances of ritonavir-boosted PIs increased, decreased, or did not change over time in this study. The effects of the primary PIs may influence this complex interplay of enzyme modification by ritonavir, or differential adherence changes between boosted regimens over time could explain these oral clearance change differences.
Our subjects and medical providers were receptive to the expert panel's recommendations, with three quarters of the recommendations implemented, similar to several other TDM studies.15-18 In contrast, 2 previous TDM trials had 30% to 35% acceptance rates.19,20 One explanation for our high provider acceptance rate was that we incorporated extensive clinical information in the dose recommendation process. This resulted in optimizing overall therapy for each patient rather than optimizing a drug concentration in isolation. Given the variability of concentrations with time, some patients in the SOC arm achieved target exposure without changing their ARV regimen. Therapy optimization in TDM-arm patients achieved target concentrations nearly twice as often as in SOC-arm patients, however.
Similar to our study, the 2 randomized controlled trials of TDM that showed virologic benefit followed patients for more than 48 weeks and used more robust pharmacologic metrics than trough thresholds to adjust therapy.16,18 In addition, Fletcher and colleagues18 reported the only TDM study to monitor all active ARVs and ARV metabolites that contribute to viral suppression in the regimen. The study regimens were unboosted indinavir and nelfinavir given to treatment-naive patients. These regimens are not widely utilized, and the impact of TDM for treatment-experienced patients was not evaluated. Four randomized controlled TDM studies did not show virologic benefit (although other benefits were discussed). Unlike our study, 2 followed subjects for only 12 weeks and 2 had low acceptance rates of the pharmacologic recommendations,15,17,19,20 probably contributing to lack of power to detect an intervention difference in those studies.
One limitation of TDM is that target ARV concentrations are poorly delineated. Our targets were to exceed the predicted median population concentrations (potentially higher if viral resistance was present) rather than minimal trough values. With this more aggressive target, assessment for and absence of increased toxicity in the TDM arm were important safety outcomes. The results of this study must be interpreted in light of our somewhat aggressive targets. Current consensus recommendations for minimum target Ctrough are lower than the average concentration targets used in this study, and fewer subjects would be deemed “below target” with these less aggressive guidelines.58 For our most common study medications, lopinavir and efavirenz, recommended guideline troughs are 1 μg/mL, as compared with our study targets of 3.8 and 1.4 μg/mL. Considering all study PIs and NNRTIs, our targets were a median (range) of 4.2 (1.4 to 11) times higher than the consensus trough targets. These consensus guideline targets are for treatment-naive patients, however, and do not apply to the two thirds of our subjects who were treatment experienced. No current validated target concentrations exist for treatment-experienced patients beyond a consensus expert opinion that they need more aggressive concentration targets.
Another limitation is that TDM is not applied to all active components of an ARV regimen that contribute to viral suppression. Also, the ideal time to perform ARV TDM is unknown. Changes should be implemented quickly to avoid prolonged therapy with suboptimal doses; however, enzyme induction/inhibition takes time, and early concentrations may not reflect ARV exposure later in therapy.59 The time delay in implementing TDM in research settings may have diminished the potential benefit in this current study and prior studies,15-17 and faster clinical care implementation (within weeks rather than a month) may contribute to benefits shown in observational and clinic-based cohorts.60,61 Finally, the optimal times to sample are unknown and may be different for each ARV. Benefits of the sparse strategy (3 samples around witnessed dosing) included the relative ease of incorporating it into clinical practice, although providing more reliable information than a single random sample. For example, we observed absorption lags that could mask subtherapeutic exposure if predose concentrations are within 30% of the minimal threshold.
One study limitation is that drug-food interactions may have contributed to the observed variability in nelfinavir and lopinavir/ritonavir capsule pharmacokinetics. Such interactions may not be as important with widespread use of the new lopinavir/ritonavir tablet formulation. Second, implementation of suggested dose changes in the TDM arm was optional, which decreases the power to show a difference between arms. This design was to allow for potential instances of patient refusal to change dose and/or cases in which additional patient information available to the caregiver but not to the centralized expert committee would have altered the recommendations. Even though dose changes were not mandatory, provider acceptance of dose change recommendations was high. The expertise of various HIV subspecialists and the rich patient information, including viral susceptibility phenotypes available for interpretation by the expert committee, may have increased provider acceptance of recommendations in this research setting over what would be seen with TDM in routine clinical practice. Finally, patient adherence is inextricably linked to pharmacologic assessments, and plasma concentrations have been used to assess adherence, although they only provide insight for the several doses before the sample.62,63 This study used adherence interventions,29 electronic monitoring, and a witnessed dose evaluation to address this confounder. Additionally, “improve adherence” was a specific recommendation to increase exposure in those with widely variable or inconsistent concentrations. Potential contributors to the large number of adherence recommendations were that this group self-identified as needing improved adherence as part of the inclusion criteria and that subjects on lopinavir had a high incidence of diarrhea, which may have triggered nonadherence or more variable absorption.
In our treatment-naive and experienced HIV-infected patients taking PIs and/or NNRTIs from 5 sites, we found that patients receiving potent HAART regimens had widely variable ARV concentrations and that nearly two thirds had nontarget concentrations at least once over 48 weeks. TDM allows detection of these at-risk patients and provides a tool for the clinician to intervene before regimen failure, approximately doubling the likelihood of achieving target concentrations. Although this study was not designed to assess virologic outcomes, our exploratory findings in this study population were that patients who achieved target concentrations of PIs and NNRTIs trended toward a better virologic response over 48 weeks than those with nontarget concentrations. In addition to factors identified in the US treatment guidelines,13 patients with increased weight are candidates for TDM as well as patients on efavirenz or lopinavir. TDM should be performed after regimen initiation and periodically thereafter, ideally basing dose change recommendations on more than a single sample result, particularly for PIs. This study described a potential TDM approach for PIs and NNRTIs that could be used in future studies of ARV TDM to explore efficacy and toxicity endpoints.
The authors thank the patients, families, and study teams at the 5 CCTG participating sites: Santa Clara Valley Medical Center (SCVMC), University of California at Irvine (UCI), Harbor-UCLA Medical Center, UCSD, and University of Southern California (USC).
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Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
anti-HIV agents; antiretroviral therapy; clinical trials; HIV; drug monitoring; pharmacokinetics