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Clinical Science

Pharmacokinetics, Safety, and Efficacy of Tipranavir Boosted With Ritonavir Alone or in Combination With Other Boosted Protease Inhibitors as Part of Optimized Combination Antiretroviral Therapy in Highly Treatment-Experienced Patients (BI Study 1182.51)

Walmsley, Sharon L MD*; Katlama, Christine MD; Lazzarin, Adriano MD; Arestéh, Keikawus PhD§; Pierone, Gerald MD; Blick, Gary MD; Johnson, Margaret MD#; Meier, Ulrich PhD**; MacGregor, Thomas R PhD††; Leith, Johnathan G PhD‡‡

Author Information
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2008 - Volume 47 - Issue 4 - p 429-440
doi: 10.1097/QAI.0b013e318160a529

Abstract

The availability of new and more potent antiretroviral (ARV) drugs has improved outcomes for HIV-1-infected patients.1,2 The emergence of drug-resistant viral strains frequently accompanies failure of initial therapy, however, and may impede the virologic success of subsequent regimens.

Long-term exposure to ARV agents in the face of suboptimal HIV RNA suppression results in the development and propagation of drug-resistant HIV strains, primarily as a consequence of incomplete adherence.3,4 Studies conducted in the United States and Europe report that nearly 80% of patients failing ARV therapy have strains of HIV-1 that are resistant to at least 1 ARV drug, with approximately 50% of patients exhibiting some virus resistance to protease inhibitors (PIs).5,6 The high degree of structural similarity of available PIs imparts extensive cross-resistance within this class.7 Thus, regimen failure associated with the emergence of drug resistance may compromise the efficacy of subsequent regimens, highlighting the need for agents that have lower cross-resistance to available ARV agents.7-9

Tipranavir (TPV) is a nonpeptidic PI with a structure distinct from that of peptidomimetic PIs. TPV potently suppresses the replication of HIV-1, including clinical isolates with resistance to other PIs.10,11 Consistent with the in vitro activity of TPV against PI-resistant isolates, TPV-based regimens produced sustained reductions in viral load (VL) in a substantial proportion of highly treatment-experienced patients with 1 or more primary mutations in the HIV-1 protease gene.12 Diminished responses were observed in patients with more than 2 genotypic mutations at codons 33, 82, 84, and 90,12 however, suggesting that TPV must, if at all possible, be combined with other active ARV agents for long-term efficacy in patients whose virus demonstrates such extensive resistance. At the time of study conduct, limited data existed regarding the value of dual-boosted PI regimens as a strategy in this setting and whether such a resistant patient population could be successfully treated.13

The Boehringer Ingelheim (BI) study 1182.51 was a companion study to the pivotal Randomized Evaluation of Strategic Intervention in multi-drug reSistant patients with Tipranavir (RESIST) clinical trials for highly treatment-resistant patients.14 At that time, given few options for patients with such high-level resistance, an ARV regimen based on concomitant use of 2 ritonavir (RTV)-boosted PIs was considered a possible therapeutic option. There were concerns that, because of the contrasting effects of TPV (inductive) and RTV (inhibitory) on CYP3A4 metabolism, there is potential for drug interactions when RTV-boosted TPV (TPV/r) is coadministered with other boosted PIs. In this context, the 1182.51 study was designed to provide an option for individual patient needs while providing informative data on the pharmacokinetics (PK), safety, and efficacy of the following dual-boosted PI-based regimens: TPV/lopinavir (LPV)/r, TPV/saquinavir (SQV)/r and TPV/amprenavir (APV)/r.

METHODS

Study Design and Drug Administration

BI study 1182.51 was an open-label, multicenter, randomized, phase 2, parallel-group trial of TPV/r, alone or in combination with other available RTV-boosted PIs, plus an optimized background regimen in highly treatment-experienced HIV-1-infected subjects. Patients were first screened for participation in one of the RESIST clinical trials. If patients fulfilled all study entry criteria for RESIST clinical trials except that their screening HIV-genotype showed 3 or more mutations at protease codons 33, 82, 84, and 90, they were offered participation in study 1182.51. Before entering the study, patients had previously received multiple ARV regimens containing the available nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), and PIs, with at least 2 regimens containing different PIs, including their ongoing regimen at study entry. Patients also needed to have documented genotypic protease resistance (TruGene, version 6.0, Visible Genetics, Toronto, ON, Canada; or VirtualPhenotype, VIRCO, Bridgewater, NJ). Patients were randomized to receive one of the following PIs for the first 2 weeks: TPV/r (500 mg/200 mg) twice daily; 400 mg of LPV plus 100 mg of RTV twice daily; 1000 mg of SQV plus 100 mg of RTV twice daily; or 600 mg of APV plus 100 mg of RTV twice daily. After 2 weeks, TPV/r (500 mg/100 mg twice daily) was added to the LPV, SQV, and APV arms to form a dual-boosted PI regimen (Fig. 1). In addition to PI therapy, all patients received an optimized non-PI background regimen chosen by the investigator before randomization on the basis of the results of baseline genotypic screening and treatment history. At week 4, patients receiving TPV/r could add a second boosted PI and patients in dual-boosted PI groups were allowed to switch to a different dual-boosted PI regimen if needed for better virologic control. Adherence to treatment from weeks 1 to 4 was determined, using pill counts and a medication questionnaire, and was calculated as a percentage of expected use.

FIGURE 1
FIGURE 1:
Patient disposition.

The common entry criteria for the present trial included a genotypic report at screening demonstrating 3 or more primary PI mutations at codons 33, 82, 84, and 90; treatment experience with all 3 classes of ARV medications, including at least 2 PI-containing regimens for more than 3 months each, which could include a patient's current regimen; and baseline plasma HIV-1 RNA levels at or exceeding 1000 copies/mL while on a patient's current PI-based regimen. Patients who had been treated with investigational medications or immunomodulatory drugs within 30 days of study entry or during the trial were not eligible to participate. Patients provided written informed consent, and the protocol and informed consent were reviewed and approved by the independent ethics committee or institutional review board at each of the 100 centers in the United States, Canada, Australia, and Europe that participated in the trial. The trial was carried out in accordance with the principles laid down in the Declaration of Helsinki (version 1996); the guidelines for Good Clinical Practice; the International Conference on Harmonisation (ICH) guidelines; US requirements for the experimentation on human subjects; the 21 Code of Federal Regulations (CFR), Parts 50 and 56; and other relevant local regulatory guidelines. The relevant regulatory authorities were notified about the study.

The primary objective of the study was to analyze the plasma concentration ratio of LPV, SQV, or APV 12 hours after dosing (C12h) with and without the coadministration of TPV. The secondary PK endpoints compared changes in the C12h of TPV and RTV with and without coadministration of a second PI. Other secondary endpoints included the change from baseline in VL; the proportion of virologic responders at weeks 2, 4, and 24; the reasons for treatment failure; the proportion of patients experiencing laboratory abnormalities; and the adverse events (AEs) and serious AE occurrences at week 4. The virologic response over time was assessed by the percentage of patients in each treatment arm having a VL decrease of ≥1 log10 copies/mL from baseline or a VL <400 copies/mL (Amplicor HIV-1 Monitor Standard test; Roche Diagnostic Systems, Branchburg, NJ) or <50 copies/mL (Amplicor HIV-1 Monitor UltraSensitive test; Roche Diagnostic Systems). An exploratory analysis of all endpoints was conducted at week 24.

Plasma Sampling

Blood sampling taken as close as possible to 12 hours after dosing the evening before and preceding the administration of the PI in the morning was done on days 7, 14, 21, and 28. Selected sites also participated in an optional intensive PK study at weeks 2 and 4, which consisted of a complete 12-hour PK profile collected during 1 dosing interval at steady state in the presence and absence of TPV in a subset of patients. For this analysis, blood samples were collected before treatment administration and then at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 12 hours after treatment administration.

Samples were analyzed by NOTOX B.V. (‘s-Hertogenbosch, The Netherlands). PI concentrations were quantified by validated liquid chromatography coupled with tandem mass spectrometry methods. For all the PIs, the within-batch and between-batch precision was within 10% and 15%, respectively. The lower limit of quantitation for the APV, LPV, and RTV assays was 25 ng/mL, and for the SQV assays, it was 10 ng/mL. The lower limit of quantitation for the TPV assay was 1000 ng/mL.

PK Analyses

For the primary PK analysis, the differences between the means of the log-transformed 12-hour concentration (C12h) of LPV, SQV, or APV at weeks 1 and 2 and the means at weeks 3 and 4 of the log-transformed trough C12h of LPV, SQV, or APV were calculated. After exponentiation, these values indicate the relative trough concentration when TPV was added to the regimen. Comparisons were made using analysis of variance on log-transformed concentration values. The change from the first time interval to the second time interval was summarized by geometric means and 90% confidence intervals (CIs) derived from this analysis of variance.

The area under the 12-hour concentration-time curve (AUC0 to 12h) for the intensive PK substudy was calculated by using the trapezoidal method of adding areas between observed samples employing WinNonlin Pro, version 4.0 (Pharsight Corporation, Mountain View, CA). Area slices were calculated linearly on the upward slopes and log-linearly on the downward slopes. The observed peak plasma concentration (Cmax) value was used for the intensive PK assessment. For each intensive PK substudy patient visit, the final PK data set contained the trough value, area under the curve (AUC), and Cmax values, as appropriate, to compare changes in LPV, SQV, and APV PK in the presence and absence of TPV. Analysis of variance within each treatment group was carried out using log(AUC0 to 12h), log(Cmax), and log(C12h) as response variables with fixed effect factors for the week 2 or week 4 visit and patient in the model. The data were summarized by geometric means and 90% CIs.

Statistical Analyses

The primary statistical analysis was an analysis of variance of the log-transformed primary PK parameters. Exponentiation of the arithmetic mean changes of these log-transformed endpoints provided the estimate for the ratio of the geometric means. Accordingly, the limits of the CIs were also exponentiated.

With respect to efficacy data, the last observation carried forward (LOCF; to week 24) approach was used for continuous endpoints (RNA VL and CD4 cell count) and the noncompleters considered as failures (NCF) approach was used for binary response criteria (1-log10 reduction in HIV RNA level, VL <400 copies/mL, and VL <50 copies/mL). Apart from descriptive statistical methods, analysis of variance methods were used for continuous endpoints and logistic regression models were used for binary endpoints. Efficacy analyses were generally performed according to the intention-to-treat principle; an analysis excluding those patients who switched their treatment regimen after week 4 was also performed for sensitivity. In particular, the association of baseline covariates and PI trough plasma concentrations with virologic response at week 24 (>1-log10 VL reduction from baseline) was investigated using logistic regression models. The latter (posthoc) analyses were based on the log-transformed geometric mean of patients' PI trough concentrations at weeks 3 and 4.

RESULTS

Demographics

Three hundred 15 patients were randomized, received at least 1 dose of study medication, and were included in this analysis. At baseline, the 4 treatment groups exhibited similar demographic characteristics (Table 1). Sixty-seven patients were randomized to the TPV/r arm, 83 to the LPV/r arm, 82 to the SQV/r arm, and 83 to the APV/r arm. Most of the patients were between 41 and 55 years of age (56.5%), male (93.3%), and white (76.2%). The median plasma HIV RNA concentration at baseline was 5.0 log10 copies/mL, and the median CD4 cell count was 138 cells/mm3. Patients in the 4 treatment arms had received a median of 13 prior ARV drugs, including medians of 5 PIs, 6 NRTIs, and 2 NNRTIs. Prior use of enfuvirtide was also even across treatment groups, with 19.4% of patients overall.

TABLE 1
TABLE 1:
Demographic Data and Baseline Disease Characteristics

HIV-1 isolates from each group of patients had a median of 18 total protease gene mutations, defined as any deviation from the Los Alamos Consensus B gene sequence. A total of 72.4% of patients' isolates had 3 to 4 primary protease gene mutations, and 23.2% had 5 to 6 primary mutations. In addition, most patients (76.8%) demonstrated 3 protocol-specified mutations at codons 33, 82, 84, and 90, whereas 15.2% of patients had isolates with 4 such mutations and 8% had <3 mutations at baseline. The baseline genotypes were derived from visit 3 of the 1182.51 study, which meant that some patients had fewer than the inclusion criteria-specified 3 mutations at protease codons 33, 82, 84, and 90 in the genotype taken at visit 1 of RESIST trials. Although patients were required to continue therapy between visit 1 of the RESIST trials and the baseline visit (visit 2) of the 1182.51 study, it is likely that the 2 genotypes would yield different results. Nonetheless, because the 1182.51 baseline genotype was sampled just prior to treatment intiation in the 1182.52 study, these genotypes were utilized as baseline genotypes as they were the most current pretreatment genotype.

Patients were allowed to switch treatment arms after 4 weeks of treatment if experiencing virologic failure (ie, patients in the TPV/r control arm were permitted to add a second PI and patients in dual-boosted PI arms could switch to a different dual PI arm). Overall, 13.3% of patients switched dual-boosted treatment arms, with the greatest number and proportion of patients (20 [29.9%] of 67) switching from the TPV/r arm. Nine patients in the SQV/r arm (11%) and 13 patients in the APV/r arm (15.7%) changed regimens after 4 weeks of treatment. Of these 42 patients who switched to another regimen, 28 (66.7%) moved to the dual-boosted TPV plus LPV arm. Overall, 100 (31.8%) of 315 patients were treated with enfuvirtide, of whom 64 (20.4%) used enfuvirtide for the first time during the study period. At least 95% adherence to planned treatment was observed in 70% to 80% of patients, as determined by pill counts, and adherence was similar in all groups.

LPV, APV, and SQV PK Parameters With TPV Use

Plasma samples were collected from 328 patients. Data for 61 to 75 patients per arm were included in the trough analysis, and data for 12 to 21 patients per arm were included in the intensive PK analyses. Most patients receiving LPV and APV and nearly all patients receiving SQV experienced a decrease in the trough levels of these PIs at weeks 3 and 4 with coadministration of TPV (Fig. 2; Table 2). The decrease in steady-state trough levels was greatest and most consistent for SQV (80%), whereas LPV and APV trough levels decreased 52% and 56%, respectively, and had much higher interpatient variability. In the absence of formal recommendations by major national or international guidelines regarding treatment-experienced patients, target trough concentrations of 4 μg/mL for LPV and 1.2 μg/mL for APV were based on therapeutic drug monitoring (TDM) guidelines (available at: www.hivpharmacology.com). On this basis, some patients in the LPV and APV arms seemed to have adequate plasma troughs (see Fig. 2). Reductions in the AUC and Cmax were also observed after the addition of TPV/r to the other PI regimens. Exposure to SQV, LPV, and APV decreased 76%, 55%, and 44%, respectively, whereas maximal plasma concentrations decreased 70%, 47%, and 39%, respectively.

TABLE 2
TABLE 2:
Comparison of Steady-State PK Parameters of LPV, SQV, and APV Before (Weeks 1 to 2) and After (Weeks 3 to 4) Coadministration of TPV
FIGURE 2
FIGURE 2:
A, Comparison of steady-state trough plasma concentrations of LPV in the absence of TPV (weeks 1 to 2) and in the presence (weeks 3 to 4) of TPV. B, Comparison of steady-state trough plasma concentrations of SQV in the absence of TPV (weeks 1 to 2) and in the presence (weeks 3 to 4) of TPV. C, Comparison of steady-state trough plasma concentrations of APV in the absence of TPV (weeks 1 to 2) and in the presence (weeks 3 to 4) of TPV.

TPV/r PK Parameters Alone and in the Presence of Boosted PIs

One subset of patients received TPV/r as the sole PI for the first 4 weeks of treatment, allowing a comparative assessment of the effect of other PIs on TPV/r PK parameters (Table 3). The TPV AUC increased by 36% and 48% when TPV was given with LPV and APV, respectively. In contrast, the TPV AUC decreased by 6% when TPV was coadministered with SQV.

TABLE 3
TABLE 3:
Comparison of Steady-State PK Parameters of TPV Given as Single PI and in Combination With LPV, SQV, and APV

RTV PK Parameters With TPV and Other PI Monotherapy and Combination Therapy

TPV is a CYP3A4 inducer and lowers systemic RTV concentrations when the drugs are coadministered.12 Despite giving 200 mg of RTV with TPV, the RTV trough concentration remained similar to or lower than the RTV concentrations achieved when 100 mg of RTV was given with LPV, APV, or SQV. The addition of TPV to the other boosted PIs resulted in a reduction of systemic RTV concentrations by approximately 50% to 60% for the dual-boosted LPV and APV groups and by 75% for the dual-boosted SQV group. Because a total of 200 mg of RTV was given in the dual-boosted arms, however, there was no net change in RTV concentrations in patients receiving dual-boosted LPV or APV, as shown by geometric mean ratios (weeks 3 to 4 vs. weeks 1 to 2), approximating 1.00 for these regimens. The actual values of the ratios for dual-boosted LPV, APV, and SQV were 1.18 (1.00 and 1.38), 0.88 (0.76 and 1.02), and 0.50 (0.44 and 0.58), respectively.

Safety

Of the 315 patients who received at least 1 dose of study drug, 279 patients (88.6%) experienced at least 1 AE, with most AEs being of mild to moderate severity. The most frequently observed AEs were gastrointestinal (GI) disorders, which affected 49.7% of all patients, with diarrhea (22.7%), nausea (13.3%), and vomiting (7.1%). There were no bleeding events reported during the study. Overall, the type and frequency of drug-related AEs were similar in all treatment groups and were consistent with AEs commonly associated with other RTV-boosted PI regimens (Table 4). Significant proportions (2.2% to 14.1%) of patients in each treatment group experienced grade 3 or 4 alanine aminotransferase (ALT) elevations; however, ALT elevations of any grade were attributed to the study drug in only 4 cases (1.3%). Likewise, grade 3 and grade 4 aspartate aminotransferase (AST) elevations were experienced by 1.5%, 0.0%, 2.2%, and 7.1% of patients in the TPV group, LPV plus TPV group, SQV plus TPV group, and APV plus TPV group, respectively. Most patients (8 of 12) with grade 3/4 ALT/AST elevations were treated through to study completion.

TABLE 4
TABLE 4:
AEs That Were Assessed as Drug Related by the Investigator and Occurred in At Least 3% of Patients in At Least 1 Treatment Group

Over the course of the study, 20 patients (6.5%) experienced AEs that led to study discontinuation: 1.5% in the TPV/r group, 2.8% in the LPV/TPV/r group, 11.8% in the APV/TPV/r group, and 12.4% in the dual-boosted SQV/TPV/r group. Rash, or pruritic rash, led to discontinuation of 2 patients in the APV/TPV/r group. In all other groups, there were no individual AEs that led to discontinuation in more than 1 patient.

Virologic Response

At baseline, the median VL was 5.0 log10 copies/mL across all treatment groups. After 2 weeks of single-boosted PI therapy, the median decrease in VL was 1.06 log10 copies/mL for patients receiving TPV/r (Fig. 3). Patients on single-boosted LPV, SQV, or APV demonstrated variable reductions in VL over the first 2 weeks, that are difficult to interpret comparatively because of variability in the proportion of patients in each group who continued their previous PI after randomization. At week 4, patients who began treatment with a TPV-containing regimen sustained this reduction in VL, with a median decrease of 1.27 log10 copies/mL. Patients who added TPV to their regimens at week 2 achieved similar decreases in VL, with median reductions from baseline of 1.19 log10, 0.96 log10, and 1.12 log10 copies/mL in the dual-boosted LPV, SQV, and APV groups, respectively. Median VL trended toward baseline from weeks 8 to 24 in all treatment groups but remained significantly (P < 0.0001) lower than at baseline at the last observation through week 24 (Fig. 3).

FIGURE 3
FIGURE 3:
Median change from baseline in log10 VL over time (LOCF).

The proportion of patients with an undetectable VL increased until week 8 and remained stable thereafter. At week 2, more patients receiving TPV/r than other single-boosted comparator PIs had a VL <400 copies/mL (17.9% vs. <5.0%) (Table 5). At week 4, 23.9% of patients in the TPV/r control arm demonstrated a VL <400 copies/mL, a response that was sustained through 24 weeks of treatment. In each of the dual-boosted comparator arms, the greatest increase in the proportion of patients reaching a VL <400 copies/mL occurred after week 2 with the addition of TPV and remained at 26.5%, 17.1%, and 25.3% for patients in the LPV/r, SQV/r, and APV/r arms, respectively. By week 24, between 13.4% and 16.9% of patients in each of the treatment arms had an HIV RNA VL <50 copies/mL. At week 24, no significant difference existed between the proportions of patients achieving an undetectable VL (<50 copies/mL) for patients receiving TPV/r (16.4%) as the sole PI compared with patients receiving a dual-boosted PI regimen.

TABLE 5
TABLE 5:
Summary of Key Efficacy Results

Because the study design allowed for change of therapy after week 4, sensitivity analyses excluding the 42 patients who switched their PI regimen after week 4 were performed for several efficacy endpoints, including virologic response, defined as >1-log10 VL reduction from baseline. The results of these sensitivity analyses were comparable with the results obtained for the full study population.

Among the significant predictors for virologic response at week 24 were disease-related parameters, such as lower baseline VL (P < 0.0001), higher baseline CD4 cell count (P = 0.0026), and a lower number of baseline PI gene mutations (P = 0.0211) (Table 6). Factors relating to the drug regimen itself also had strong effects on virologic response, including the number of additional active drugs in the background regimen (P < 0.0001) or concomitant first-time use of enfuvirtide (P < 0.0001).

TABLE 6
TABLE 6:
Logistic Regression Analyses for Potential Predictors of Virologic Response (>1-log10 VL Reduction from Baseline) At Week 24

Increased TPV trough plasma concentrations were associated with higher response rates (P = 0.0257); however, no such relation with virologic response was observed for the trough plasma concentrations of the second PIs after the addition of TPV/r (P = 0.7975), to which patients showed marked resistance at baseline. Likewise, no difference in virologic response was observed between patients who reached or failed to reach the usual therapeutic concentration for the second PI after the addition of TPV/r (P = 0.8281).

Immunologic Changes

All treatment groups experienced increases in CD4 cell counts through week 24, and the overall median increase was 29 cells/mm3 (Fig. 4). Patients receiving dual-boosted LPV/r plus TPV demonstrated the greatest improvement, with a median increase of 43 cells/mm3 at week 24 compared with median increases between 19.5 and 22.0 cells/mm3 for the other study arms (Table 5).

FIGURE 4
FIGURE 4:
Median change from baseline in CD4 cell count over time (LOCF).

DISCUSSION

This study showed that TPV/r had significant activity against highly resistant HIV, despite significant baseline resistance to the PI class of drugs. Patients who entered the study had received a median of 13 prior ARV drugs. At baseline, they had a median HIV-1 RNA concentration of 5.0 log10 copies/mL and median CD4 cell count of 138 cells/mm3. TPV/r activity was lost after continued therapy, largely, because of the background regimen lacking similar activity. Most importantly, the relative contribution of the second PIs (LPV/r, SQV/r, and APV/r) was minimal even in those with sustained trough concentrations regarded as likely to be adequate in this study.

Significant PK interactions were observed when TPV/r was added to regimens containing RTV-boosted LPV, SQV, or APV, with the greatest effect on SQV concentrations. When coadministered at a dose of 500 mg/200 mg twice daily, TPV/r decreased steady-state trough (C12h) blood levels of SQV by 80%, APV by 56%, and LPV by 52%. Reductions in trough levels occurred within 7 days of adding TPV/r and were paralleled by reductions in the Cmax and AUC. The reductions in trough concentrations of SQV, APV, and LPV after the addition of TPV/r were not predicted based on preliminary PK modeling. RTV almost completely inhibits the CYP3A4 isoenzyme and increases the concentrations of coadministered PIs.17 The observed reductions in the boosted PIs may be indirectly or directly related to the addition of TPV, an inducer of CYP3A4 and intestinal P-glycoprotein (P-gp).18 TPV lowers systemic RTV concentrations and, as a result, may have affected the concentrations of the other PI indirectly.13 At the time of study design, the mechanism for boosting PIs with RTV was inhibition of hepatic CYP3A4 to prevent systemic metabolism of the PI. This hepatic mechanism was consistent with in vitro microsomal data demonstrating that RTV was an avid inhibitor of CYP3A4 and that RTV doses of 100 mg administered once to twice daily were sufficient to boost all PIs. Additionally, at the time of the study, it was recognized that the steady-state PK of TPV boosted with RTV (and the PK of other RTV-boosted PIs) was markedly different in treatment-experienced AIDS-infected patients compared with normal volunteers, because hepatic enzymes were greatly induced by chronic multiple therapies. Because this induction could not be realistically modeled, and the PK data obtained by administering dual-boosted PIs for multiple weeks to normal volunteers would provide minimal benefit for the risk, a decision was made to enroll patients into the study who were already on an RTV-boosted PI but receiving marginal benefit from that therapy. In this manner, the patient would receive a new therapy potentially capable of benefiting his or her treatment, and the mechanism of interaction, increasing or decreasing systemic exposure of both boosted PIs, could be evaluated. The induction properties of TPV on CYP3A4 and P-gp in the presence of 200 mg of RTV administered twice daily observed in this study permitted the drug interaction potential of TPV/r to be elucidated and also permitted an evaluation of the impact of altering CYP3A4 and P-gp activity on each of the RTV-boosted PIs studied.

Because the dose of RTV in the dual-boosted PI period of the study was increased from 100 to 200 mg twice daily, plasma concentrations of RTV were effectively unchanged in the LPV and APV treatment groups. Another possible explanation might be that TPV induced a pathway capable of metabolizing the other PIs directly or transporting them by means of intestinal efflux directly from the systemic circulation through a mechanism unaffected by RTV.19 Further study is required to determine the precise pathways for the metabolism of LPV, SQV, and APV in the presence of TPV/r.20

One could assume that the ability of a dual-boosted PI regimen to suppress viral replication optimally may be impaired by the observed reductions in the plasma concentrations of the second PI. However, no difference in virologic response was observed between patients who reached or failed to reach the usual therapeutic concentrations for the second PI (4 μg/mL for LPV, 1.2 μg/mL for APV, and 0.3 μg/mL for SQV; P = 0.8281).

The similar >1-log10 response by week 4 with the addition of TPV/r to the other PIs at week 2 further demonstrates the inherent potency of TPV/r in this highly treatment-experienced population. The subsequent return of HIV-1 RNA levels to baseline in most patients further highlights the importance of constructing fully active HAART regimens in treatment-experienced patients to maintain virologic response.

All treatment groups demonstrated similar degrees of efficacy at 24 weeks. Although the median VL reduction trended back toward baseline, nearly 25% of patients achieved and maintained a VL less than the 400-copies/mL limit of detection at 24 weeks. Key predictors of virologic response at week 24 were baseline VL, CD4 cell count, number of PI gene mutations or TPV-associated mutations, new enfuvirtide use, and TPV trough concentrations. In contrast, the trough concentrations of the second PI did not have an impact on response at week 24. Therefore, the loss of virologic response through 24 weeks of treatment was most likely attributable to a lack of activity of the second PI and other agents in the background regimen rather than to reduced plasma levels from the observed drug interaction. It is important to note that this study was conducted in 2003 when there were few options other than enfuvirtide to be used to construct an active ARV regimen in conjunction with TPV/r in highly treatment-experienced patients.

The study design allowed patients to switch therapy after the PK analysis at week 4, potentially confounding the subsequent efficacy and safety analyses beyond this time point. Dissatisfaction with the initial regimens may have biased switches to regimens perceived to be more efficacious or tolerable. Indeed, most patients who changed therapies switched to a single arm (TPV/LPV/r). However, an analysis of virologic response excluding the switched patients showed comparable results; therefore, although an effect of the study design cannot be ruled out, it is apparent that the overall poor response of patients in this study was attributable to the lack of activity of the second PI and/or other supporting ARV medications. Furthermore, this poor response cannot be attributed to adherence problems, because good adherence to medication was observed.

Overall, the safety and tolerability of TPV was similar to that of comparator PIs with respect to the types and frequencies of observed events. Similar to those reported in early trials of TPV, the most common AEs were GI disorders (diarrhea, nausea, and vomiting), which occurred with similar frequencies in all arms, notably during the first 2 weeks of single-boosted PI therapy.11,15,20 Importantly, no unexpected safety concerns arose with the addition of TPV/r to the dual-boosted regimens. Drug-related elevations in triglycerides, ALT, and AST of any grade occurred in 3.5%, 1.3%, and 1.3% of patients, respectively, in all 3 arms. During the dual-boosted phase of the study, the highest frequency of drug-related hypertriglyceridemia occurred in patients receiving LPV plus TPV (6.4% of patients), whereas drug-related elevations in liver enzymes occurred in similar proportions throughout the treatment groups. These laboratory abnormalities were generally asymptomatic, manageable, and not associated with treatment interruption or discontinuation.

In conclusion, this clinical study showed that despite the use of a potent next-generation PI in a highly treatment-experienced population, virologic response can only be sustained if additional active drugs are included in the treatment regimen. Thus, the optimum benefit of TPV/r can be realized when it is used before the development of resistance to all other available agents and/or is combined with ARV agents (eg, enfuvirtide) to which the patient has not been previously exposed. TPV/r used alone as the PI component resulted in a treatment response as good as that obtained with the dual-boosted PI regimens studied; the clinical utility of these dual-boosted PI regimens in treatment-experienced patients remains unproven. Although significant drug interactions were observed in this trial, it was clear that recycled LPV, APV, and SQV had limited ARV activity in this highly drug-resistant patient population, even in those with plasma trough concentrations regarded as likely to be adequate on the basis of TDM guideline recommendations. As previously noted, however, major national and international guidelines currently lack recommendations regarding adequate plasma trough concentrations of these ARVs in treatment-experienced patients. The role of dual-boosted regimens combining 2 fully active PIs requires further study in this population of highly treatment-experienced patients.

ACKNOWLEDGMENT

The authors thank C. Samuels, Boehringer Ingelheim, Bracknell, United Kingdom, for conducting statistical analyses of trial data.

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APPENDIX

List of Investigators

Australia: Prof. D. Cooper, HIV Clinical Trials Unit-IBAC, NSW; Dr. Julian Gold, Albion Street Center, NSW; Dr. Cassy Workman, AIDS Research Initiative/Ground Zero, NSW; Dr. Mark Bloch, Holdsworth House General Practice, NSW; Dr. David Baker, 407 Doctors Pty Ltd, NSW

Belgium: Prof. N. Clumeck, Brussels; Dr. B. Van Der Gucht, UZ Ghent, Ghent; Prof. R. Colebunders, Inwendige geneeskunde, Antwerpen

Canada: Dr. Pierre Cote, Clinique Medicale du Quartier Latin, Quebec; Dr. Frederic Crouzat, Canadian Immunodeficiency Research, Ontario; Dr. Richard Lalonde, Montreal Chest Institute, Quebec; Dr. Anita Rachlis, Sunnybrook and Women's College Hospital, Ontario; Dr. Fiona Smaill, McMaster University Medical Center, Ontario; Dr. Beniot Trottier, Clinique medicale l'Actuel, Quebec; Dr. Chris Tsoukas, Immune Deficiency Treatment Center, Montreal General Hospital, Quebec; Dr. Sharon Walmsley, Toronto General Hospital, Ontario

Denmark: Dr. Jan Gerstoft, Rigshospitalet, Copenhagen; Dr. Lars R. Mathiesen, Hvidovre Hospital Infektionsmedicinsk, Hvidovre; Dr. Niels Obel, Odense Universitetshospital, Odense C

France: Prof. François Boue, Hôpital Antoine Beclere, Clamart; Dr. Laurent Cotte, Hôpital de l'Hotel Dieu, Lyon; Prof. Pierre Dellamonica, Hôpital de l'Archet, Nice; Prof. Michel Dupon, Groupe Hospitalier Pellegrin, Bordeux; Prof. Pierre Marie Girard, Hôpital Saint Antoine, Paris; Prof. Christine Katlama, Hôpital Pitié-Salpêtrière, Paris; Prof. Michel Kazatchkine, Hopital Européen G. Pompidou, Paris; Prof. Jean Marie Lang, Hôpital Civil, Strasbourg; Prof. Thierry May, Hopital Brabois Adultes, Vandoeuvre les Nancy; Prof. Christian Michelet, Hôpital de Pontchaillou, Rennes; Prof. François Raffi, Hôpital Hotel Dieu, Nantes; Dr. Renaud Verdon, Hôpital Côte de Nacre, Caen; Prof. Daniel Vittecoq, Hôpital Paul Brousse, Villejuif; Prof. Patrick Yeni, Hôpital Bichat Claude Bernard, Paris

Germany: Dr. Keikawus Arastéh, Epimed GmbH, Berlin; Dr. Frank Bergmann, Universitätsklinikum Charité, Berlin; Dr. Stefan Esser Universitätsklinikum Essen, Essen; Dr. Gerd Fätkenheuer, Klinik 1 für Innere Medizin der Iniversität zu Köln, Köln; Dr. Frank-Detlef Goebel, Medizinische Poliklinik, Klinikum der Universität München, München; Dr. Thomas Harrer, Universität Erlangen-Nürnberg, Erlangen; Dr. Martin Hartmann, Universitätsklinikum Heidelberg Hautklinik, Heidelberg; Dr. Eva Jägel-Guedes, Praxis Dr. Hans Jäger Karlsplatz, München; Dr. Heribert Knechten, Praxis Dr. Knechten, Aachen; Dr. Arne Kroidl, Universitätsklinikum Düsseldorf, Düsseldorf; Dr. Stefan Mauss, Praxis Dr. Mauss Graftenberg, Düsseldorf; Dr. Antonius Mutz, Klinikum Natruper Holz, Osnabrück; Dr. Andreas Plettenberg, Ifi-Institut für interdisziplinäre Infektiologie und Immunologie GmbH, Hamburg; Dr. Jürgen Rockstroh, Med. Universitätsklinik Bonn Allgemeine, Bonn; Dr. R. E. Schmidt, Medizinische Hochschule Hannover Abt., Hannover; Dr. Eiko Schnaitmann, Praxis Eiko Schnaitmann, Stuttgart; Dr. D. Schuster, Praxis Dr. Schuster, Mannheim; Dr. Schlomo Staszewski, Klinikum der J.-Wolfgang Goethe, Frankfurt; Dr. Jörg-Andres Rump, Praxis Dr. Jörg-Andres Rump, Freiburg; Dr. Jan van Lunzen, Universitätsklinikum Eppendorf, Hamburg; Dr. Ulrich Walker, Kliniken der Universität Freiburg, Freiburg

Greece: Prof. Nicolaos Stavrianeas, Andreas Syggros Hospital, Athens; Dr. George Panos, First Social Insurance Foundation (IKA) Penteli, Athens

Italy: Prof. Adriano Lazzarin, Infectious Disease Department, UVS San Raffaele, Milano; Prof. Giovanni Di Perri, Clinica Universitaria, Torino; Antonella Castagna, Infectious Disease Department, UVS San Raffaele, Milano

The Netherlands: Dr. K. Brinkman, Onze Lieve Vrouwe Gasthuis, Amsterdam; Dr. M. E. van der Ende, Erasmus Medical Center, Rotterdam; Dr. P. P. Koopmans, University Medical Center Nujmegen St., Nijmegen; Dr. P. L. Meenhorst, Slotervaart Hospital, Amsterdam; Dr. J. H. ten Veen, OLVG, location Prinsengracht, Prinsengracht, Amsterdam; Dr. R. Vriesendorp, Medical Centrehaaglanden, Den Haag

Switzerland: Prof. Manuel Battegay, Kantonsspital Basel, Basel; Prof. Milos Opravil, Universitätsspital Zürich, Zürich; Dr. Pietro Vernazza, Kantonsspital St. Gallen, St. Gallen

United Kingdom: Prof. Brian Gazzard, Chelsea and Westminster Hospital, London; Prof. Jonathan Weber, St. Mary's Hospital, London

United States: Dr. Bisher Akil, Health Innovations Research, Los Angeles, CA; Dr. Stephen Becker, Pacific Horizon Medical Group, San Francisco, CA; Dr. Gary Blick, Circle Medical, Norwalk, CT; Dr. Claire Borkert, East Bay AIDS Center, Berkeley, CA; Dr. Paul Cimoch, Orange County Center for Special Immunology, Fountain Valley, CA; Dr. Edwin DeJesus, (IDC) Research Initiative, Altamonte Springs, FL; Dr. Lawrence Schwartz, Northwest Medical Specialties, Tacoma, WA; Dr. Jerome Ernst, AIDS Community Research Initiative of America (ACRIA), New York, NY; Dr. Charles Farthing, AHF Research Center, Los Angeles, CA; Dr. Richard Greenberg, University of Kentucky Medical Center, Lexington, KY; Dr. Howard Grossman, Pollari Medical Group, New York, NY; Dr. Trevor Hawkins and Dr. Michael Palestine, Southwest CARE Center, Santa Fe, NM; Dr. James Hellinger, Community Research Initiative of New England, Boston, MA; Dr. Charles Hicks, Duke University Medical Center, Durham, NC; Dr. Joseph Jemsek, Jemsek Clinic, Huntersville, NC; Dr. Harold Katner, Mercer University School of Medicine, Macon, GA; Dr. Ann Labriola, Washington VAMC, Washington, DC; Dr. Harry Lampiris, San Francisco VA Medical Center, San Francisco, CA; Dr. David Margolis, Dallas VA Medical Center, Dallas TX; Dr. Norman Markowitz, Henry Ford Hospital, Detroit, MI; Dr. Annie Morris, Community Research Initiative of New England, Springfield, MA; Dr. Gerald Pierone, Treasure Coast Infectious Disease, Vero Beach, FL; Dr. Peter Piliero, Albany Medical College, Albany, NY; Dr. Robert Schwartz, Associates In Research, Fort Myers, FL; Dr. Michael Sension, North Broward Hospital District, Fort Lauderdale, FL; Dr. Roy Steigbigel, University of New York at Stony Brook, Stony Brook, NY; Dr. Corklin Steinhart, Steinhart Medical Associates, Miami, FL; Dr. Melanie Thompson AIDS Research Consortium of Atlanta, Atlanta, GA; Dr. Vilma Vega, Infectious Disease Associates, Sarasota, FL; Dr. David Wheeler, Infectious Disease Physicians Research, Annendale, VA; Dr. Michael Wohlfeiler, Wohlfeiler, Piperato & King, MD, Miami Beach, FL; Dr. Bienvenido Yangco, Infectious Disease Research Institute, Tampa, FL; Dr. Daniel Kuritzkes, Brigham and Women's Hospital, Boston, MA; Dr. William Mazur, Early Intervention Program (EIP) Clinic, Camden, NJ; Dr. Joseph Gathe, Donald R. Watkins Memorial Foundation, Houston, TX; Dr. Robert Myers, Phoenix Body Positive, Phoenix, AZ; Dr. W. Jeffrey Fessel, Kaiser Permanente Medical Center, San Francisco, CA

Keywords:

combination antiretroviral therapy; dual-boosted protease inhibitor regimen; nonpeptidic; protease inhibitors; tipranavir

© 2008 Lippincott Williams & Wilkins, Inc.