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Long-Term Efficacy and Safety of Tipranavir Boosted With Ritonavir in HIV-1-Infected Patients Failing Multiple Protease Inhibitor Regimens: 80-Week Data From a Phase 2 Study
 
 
  JAIDS Journal of Acquired Immune Deficiency Syndromes:Volume 45(4)1 August 2007pp 401-410
 
Markowitz, Martin MD*; Slater, Leonard N MD; Schwartz, Robert MD; Kazanjian, Powel H MD; Hathaway, Bruce MD; Wheeler, David MD; Goldman, Mitchell MD#; Neubacher, Dietmar**; Mayers, Douglas MD**; Valdez, Hernan MD**; McCallister, Scott MD**; and the BI 1182.2 Study Team
 
From the *Aaron Diamond AIDS Research Center, Rockefeller University, New York, NY; Oklahoma University Health Sciences Center, Oklahoma City, OK; Associates in Research, Fort Myers, FL; University of Michigan Health System, Ann Arbor, MI; East Carolina University School of Medicine, Greenville, NC; Infectious Diseases Physicians, Inc., Annandale, VA; #Indiana University School of Medicine, Indianapolis, IN; and **Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.
 
Originally funded by Pharmacia and Upjohn and later by Boehringer Ingelheim Pharmaceuticals, Inc.
 
Abstract
Background: BI 1182.2, an open-label, randomized, multicenter, phase 2 study, evaluated efficacy and tolerability of the protease inhibitor (PI) tipranavir (TPV; 500 mg twice daily or 1000 mg twice daily) administered with ritonavir (100 mg twice daily) in combination with 1 nucleoside reverse transcriptase inhibitor and 1 nonnucleoside reverse transcriptase inhibitor in multiple PI-experienced HIV-1-infected patients.
 
Methods: Forty-one patients were evaluated in 2 arms: low-dose (19 patients) or high-dose (22 patients) ritonavir-boosted tipranavir (TPV/r). Primary endpoints were change from baseline in HIV-1 RNA concentrations at weeks 16, 24, 48, and 80 and percentage of patients with plasma HIV-1 RNA levels lower than the limit of quantitation. Safety was evaluated by adverse events (AEs), grade 3/4 abnormalities, and serious AEs.
 
Results: Of all patients, 59% were still receiving TPV/r (14 in low-dose arm and 10 in high-dose arm) at week 80. Patients in both arms had a median >2.0-log10 reduction in plasma viral load. Intent-to-treat analysis demonstrated that a similar proportion of patients in the high-dose and low-dose groups achieved plasma HIV-1 RNA levels <50 copies/mL at week 80 (43% vs. 32%; P = 0.527). The most frequently observed AEs were diarrhea, headache, and nausea.
 
Conclusion: TPV/r combined with other active antiretroviral agents can provide a durable treatment response for highly treatment-experienced patients.
 
The advent of highly active antiretroviral therapy (HAART) has dramatically reduced HIV-related mortality and morbidity.1 Despite the clinical success of HAART, however, up to 50% of patients experience virologic failure during the first year of protease inhibitor (PI)-containing antiretroviral (ARV) therapy.1-3 Failure of PI-containing regimens is frequently associated with the presence of mutations in the protease gene,4 and exposure to an increasing number of PIs is associated with the accumulation of a larger number of mutations in the protease gene.4,5 Resistance to ARV drugs often develops in patients with incomplete viral suppression and may limit the magnitude and duration of the response to treatment.6-8 There are now a substantial number of patients infected with HIV-1 strains who are resistant/cross-resistant to several classes of ARV drugs9 and who require treatment with agents that have resistance profiles distinct from those of currently available drugs.
 
Additionally ARV therapy is associated with short-term and long-term adverse events (AEs). Rash, central nervous system (CNS) disturbance, nausea, vomiting, and diarrhea often result in the cessation of treatment.10 A retrospective review of HIV-infected individuals who initiated HAART between 1997 and 2001 indicated that treatment was most frequently discontinued because of AEs. Nausea, diarrhea, and dizziness were cited as the most common causes of treatment cessation among patients discontinuing their initial regimen.11 Additionally, elevated liver function test results are common with HAART,12 with up to 60% of patients treated with ARV drugs developing increases in serum levels of liver transaminases, which may necessitate discontinuation of therapy.13 Although the main aim of treatment should be to achieve and maintain viral suppression while sustaining improvements in immune function, safety considerations are also important and should account for underlying conditions, concomitant medications, and history of drug intolerance.14
 
Tipranavir (TPV) is a nonpeptidic protease inhibitor (NPPI) that has demonstrated potent inhibitory activity against clinical HIV-1 isolates in vitro and in vivo.15-17 TPV has a structure distinct from that of currently available PIs, and therefore may be expected to have a different susceptibility/resistance profile when compared with other PIs.18 Larder et al18 examined 105 highly PI cross-resistant clinical HIV-1 viral isolates; 89 (85%) of those isolates had a ≥2-fold increased 50% inhibitory concentration (IC50) value compared with wild-type virus for TPV. Similarly, other studies have shown that TPV may have activity against HIV-1 isolates resistant to currently available PIs.17,19,20 Studies of clinical isolates from highly treatment-experienced patients treated with TPV have shown that 16 to 20 protease gene mutations/polymorphisms may be required to confer reduced susceptibility to TPV.21,22 This high number of mutations suggests that TPV may maintain antiviral activity and provide the basis for a durable regimen in treatment-experienced patients.
 
Here, we report the long-term durable efficacy of TPV coadministered with low-dose ritonavir (TPV/r), as measured by virologic and immunologic responses in patients who had multiple PI experience and had an additional fully active drug to use with TPV. Furthermore, we show that TPV/r is well tolerated by patients who continued on the study up to 80 weeks.
 
METHODS
Boehringer Ingelheim Trial 1182.2 was a phase 2, randomized, multicenter, open-label, parallel-group study conducted between January 1999 and August 2001 in HIV-1-positive patients who had clinically failed 2 or more PI-containing regimens (or a single regimen containing 2 PIs) but were naive to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and had at least 1 new nucleoside reverse transcriptase inhibitor (NRTI) available, as determined by genotypic resistance testing. The sample size for this exploratory study was fixed at 15 to 20 patients per group, resulting in a total of between 30 and 40 patients. Assuming a probability of 0.75 that a patient's change from baseline in HIV-1 RNA levels in treatment group 1 is smaller than in treatment group 2, a 2-sided Wilcoxon rank sum test at a level of α = 0.10 would have a statistical power of 85% to detect a difference in a sample size of 20 patients per group.
 
Eligible patients had CD4+ cell counts ≥50 cells/mm3, had plasma HIV-1 RNA levels ≥5000 copies/mL, and had been taking a stable PI-containing regimen for ≥3 months before entry to the study (plus 4 months of exposure to previous PI therapy). Patients were excluded from the study if they had prior exposure (defined as >7 days of treatment) to NNRTIs or TPV and/or any clinically significant medical problems (with onset within the month before study entry). Additionally, patients were excluded if they had taken any cytochrome P (CYP) 450 3A enzyme-inducing drugs within 30 days of study entry.
 
After randomization to low-dose or high-dose TPV/r, patients stopped their prior regimen and started the assigned dose of TPV/r in combination with efavirenz (EFV; 3 200-mg capsules once daily) and a new NRTI. Subjects unable to tolerate the side effects of EFV were allowed to change to nevirapine at dose of 200 mg twice daily. Patients with favorable virologic and safety outcomes and who met specified response criteria (HIV-1 RNA levels ≥0.5 log10 lower than baseline values) at weeks 24 and 48 were given the option of extending treatment. This would allow patients to continue their study regimen with the benefit of maintaining viral suppression. After study discontinuation, patients could continue to receive TPV/r in a rollover study.
 
At the time of initiation of this study, TPV was formulated as 300-mg hard-filled capsules (HFCs). Patients in the low-dose group took 1200 mg of TPV as HFCs with 100 mg of ritonavir twice daily, and those in the high-dose group took 2400 mg of TPV as HFCs with 200 mg of ritonavir twice daily. Subsequently, the self-emulsifying drug delivery system (SEDDS) soft-gel 250-mg TPV capsules became available. Conversion from HFCs to SEDDS took place at each subject's next scheduled study visit after SEDDS availability. The conversion occurred at different points in the protocol for different subjects. By the week 24 visit, however, all subjects were receiving the SEDDS formulation. Because the SEDDS formulation increased bioavailability compared with HFCs, patients in the low-dose arm switched to 500 mg of TPV with 100 mg of ritonavir twice daily and those in the high-dose arm received 1000 mg of TPV with 100 mg of ritonavir twice daily. The change in TPV dose form was based on a single-dose bioavailability study in healthy volunteers that demonstrated the bioavailability of the SEDDS formulation to be 2- to 3-fold that of the HFC formulation. This increased bioavailability enabled patients in this trial to take approximately half the number of TPV capsules on a daily basis once switched to the SEDDS formulation, possibly leading to better patient adherence.
 
Plasma HIV-1 RNA levels were measured using the Roche Amplicor HIV Monitor test (Roche Diagnostic Systems, Pleasanton, CA). Samples having HIV RNA levels of <400 copies/mL were retested using the Roche Amplicor UltraSensitive Assay (Roche Diagnostic Systems; limit of quantitation = 50 copies/mL). CD4+ cell counts were measured using flow cytometry. Sponsorship of this clinical trial changed during the course of the study. During the earlier part of the trial, plasma HIV RNA levels and CD4+ cell counts were assayed and quantified by laboratories at Pharmacia and Upjohn (Somerset County, NJ) and by SmithKline Beecham Quest (Van Nuys, CA), respectively. Subsequently, Boehringer Ingelheim (Ingelheim, Germany) assumed responsibility for this trial, and assays were performed by Consolidated Laboratory Services (CLS; Van Nuys, CA). Patients were evaluated at baseline, weeks 2 and 4, every 4 weeks until week 32, and every 8 weeks thereafter. HIV-1 RNA assays, CD4+ cell counts, clinical assessments, hematology, and chemistry laboratory testing were performed at each visit.
 
Phenotypic and genotypic assays were performed at baseline; additionally, for all patients with a sufficient viral load, assays were performed at weeks 24, 48, 72, and 80 and at selected time points depending on loss of virologic response. Phenotypic assays were performed by VIRCO NV (Mechelen, Belgium) using the Antivirogram phenotypic resistance test. Genotyping assessments were initially performed by CLS using the Visible Genetics Trugene Assay (earlier samples up through week 48), and the later study visit assessments were performed by VIRCO NV. The Affymetrix Gene Chip Method (Affymetrix, Santa Clara, CA) was used for measurement before study initiation.
 
AEs were coded according to the World Health Organization Adverse Reaction Terminology List (WHO-ARTL) and summarized in frequency tables by preferred term. Onset of AEs up to 3 days after stopping treatment and preexisting AEs that worsened during treatment were considered treatment emergent. In cases in which patients experienced a specific AE more than once, each event was counted, but only the maximum severity was included on the severity scale for each patient. A serious adverse event (SAE) was defined as any AE that resulted in death, was immediately life-threatening, resulted in persistent or significant disability or incapacity, required patient hospitalization, or was deemed serious for any other reason. All patients had clinical laboratory tests for safety at the second screening visit and at every study visit.
 
The primary efficacy endpoints were viral load change from baseline and the proportion of patients with a viral load <400 and <50 copies/mL through weeks 24, 48, and 80. The primary null hypotheses were that there are no differences between the 2 treatment groups with respect to viral load change from baseline and the occurrence of viral loads <400 and <50 copies/mL at weeks 16, 24, 48, and 80. The primary analysis for viral load reduction was a Wilcoxon rank sum test; for percentages lower than the limit of quantitation, a Fisher exact test was used. All statistical tests used were 2-sided. Statistical significance was defined as: (1) P ≥ 0.05 for any within-group mean change from baseline comparison, (2) P ≥ 0.05 for any between-group comparison of nonefficacy endpoints, and (3) P ≥ 0.10 for any between-group comparison of efficacy endpoints. Because of the exploratory nature of the study, no adjustments for multiple testing were planned or performed. The magnitude of the viral load change was determined using an intent-to-treat last observation carried forward (ITT-LOCF) analysis. When the proportion of patients who had plasma viral loads lower than the limit of detection was compared between groups, patients with missing values were considered to have experienced failure.
 
RESULTS
Forty-one patients were enrolled in the study: 19 in the low-dose (500 mg twice daily) TPV/r arm and 22 in the high-dose (1000 mg twice daily) TPV/r arm. Most patients were white (68.3%) and male (78%), with a median age of 40 years (Table 1). Overall, both treatment arms were equally weighted for distribution of patient characteristics and risk factors. Median baseline plasma HIV RNA levels for the low- and high-dose TPV/r arms were 4.43 and 4.45 log10 copies/mL, respectively; median baseline CD4+ cell counts were 259 and 275 cells/mm3, respectively. Patients were heavily PI experienced, with 37 patients (90.2%) having prior exposure to saquinavir for a median of 17 months, 25 patients (61%) having prior exposure to nelfinavir for a median of 14 months, 23 patients (56.1%) to having prior exposure to ritonavir for 19 months, and 18 patients (43.9%) having prior exposure to indinavir for 9 months (Table 2). Current guidelines recommend that, in general, when switching therapy, the cause of treatment failure should be explored by reviewing the treatment history and performing a physical examination to assess for signs of clinical progression. In addition, when designing a new treatment regimen, past and current resistance test results should be used to identify active agents (preferably at least 2 fully active agents). In general, 1 active drug should not be added to a failing regimen, because drug resistance is likely to develop quickly.14
 
A summary of phenotypic resistance at baseline by class of drug and treatment group is presented in Table 3. The median fold change from baseline in IC50 was similar between the low-dose and high-dose groups for most ARV drugs evaluated. Lamivudine and ritonavir had considerably higher phenotypic resistance in the low-dose group compared with the high-dose group, however. In addition to phenotypic assays at baseline, genotyping of HIV-1 from all randomized patients was performed (Table 4). Most patients (approximately 76%) had virus PI mutations observed in at least 1 of the following positions: 46, 82, 84, and 90. Almost half of all patients had reverse transcriptase (RT) mutations in position M184V at baseline. No patients presented with RT mutations in positions K103N, V106A, Y181C, and Y188L, and no thymidine analog mutations were observed at baseline.
 
Abacavir was selected as the new NRTI for most (27 of 41) of the patients. Other nucleosides or nucleotides used included didanosine, adefovir, stavudine, and zidovudine. Five patients used nevirapine instead of EFV. Most patients were exposed to HFC TPV for 4 weeks or longer; only 7 patients enrolled into the study after the TPV SEDDS formulation became available. Patients received the HFC formulation for a mean of 89 days (12.7 weeks) and 76 days (10.9 weeks) in the low-dose and high-dose groups, respectively. At week 48, 29 patients (16 in the low-dose group and 13 in the high-dose group) chose to continue participation in the trial for an additional 48 weeks. A total of 14 (73.7%) patients receiving low-dose TPV/r and 11 (50%) receiving high-dose TPV/r were still on the study at week 80 (Table 5). In the low-dose group, 4 patients discontinued treatment prematurely because of reasons other than protocol-specified criteria. Two of these discontinuations occurred during the first 24 weeks of the study (1 because of an AE and 1 because of lack of efficacy), and 2 occurred during the 24- to 48-week period (1 because of lack of efficacy and 1 because of loss to follow-up). In the high-dose group, 9 patients discontinued prematurely because of reasons other than protocol-specified events. Seven of these discontinuations occurred during the first 24 weeks (3 because of loss to follow-up, 2 because of lack of efficacy, 1 because of an AE, and 1 because of a protocol violation). The remaining 2 patients in the high-dose group discontinued after week 48 (1 because of lack of efficacy and 1 withdrew consent). Although primary efficacy and safety data were reported out to week 80, a number of subjects were followed for 5.5 to 6.5 years. Sixteen subjects, 9 (47.4%) in the low-dose group and 7 (31.8%) in the high-dose group, have been followed for 288 weeks and terminated the long-term follow-up study as responders. By week 336, there was 1 patient (4.5%) in the high-dose arm who still remained on treatment as a responder.
 
Patients in both TPV/r dose groups experienced a consistent and durable reduction in viral load through 80 weeks of treatment (Fig. 1). At week 80, patients in the TPV/r low-dose arm had a slightly greater median change in plasma HIV-1 RNA levels (-2.55 log10) when compared with patients in the TPV/r 1000-mg/100-mg arm (-2.43 log10); however, this difference was not statistically significant (P = 0.6).
 
ITT analysis demonstrated that a greater proportion of patients in the TPV/r low-dose arm had a viral load reduction <400 copies/mL compared with those in the high-dose arm at week 24 (79% vs. 50%), week 48 (79% vs. 50%), and week 80 (47% vs. 43%) (Fig. 2). When calculated according to an on-treatment (OT) analysis, however, a larger proportion of patients in the high-dose arm at week 80 had plasma HIV-1 RNA levels <400 copies/mL compared with the low-dose arm (90% vs. 64%). This difference is likely attributable to the attrition rate in the high-dose arm. Similar trends were observed in the ITT analysis for the low versus high doses of TPV/r for the <50-copies/mL analysis, but such trends were only demonstrated at week 24 (58% vs. 50%) and week 48 (68% vs. 41%). At week 80, the proportion of patients with a viral load <50 copies/mL in the high-dose arm (43%) was greater than in the low-dose arm (32%); however, this difference was not statistically significant. A similar trend was seen with the OT analysis, but this time, a significantly greater proportion of patients in the high-dose arm reached a viral load <50 copies/mL at week 80 (P = 0.033). Once again, this may be a result of the greater attrition rate attributable to AEs that occurred early in the trial in the high-dose arm. In an analysis of time to virologic failure, in which the failure time curves were compared for the 2 treatment groups, the estimated median time to virologic failure, defined as an inability to maintain an HIV RNA level <400 copies/mL or a 0.5-log10 reduction in HIV RNA from baseline in patients who did not achieve an HIV RNA level <400 copies/mL, was essentially the same in both groups: 490 days and 483 days in the low-dose and high-dose groups, respectively.
 
The significant virologic responses achieved in patients in both TPV/r arms were reflected in the observed immunologic responses (Fig. 3). There was an increase in CD4+ cell counts at all time points, out to week 80, relative to baseline. After week 80 of therapy, patients in the low-dose TPV/r arm had a median CD4+ cell count increase of 176 cells/mm3 compared with an increase of 143 cells/mm3 in the high-dose group. The difference between the 2 groups was not statistically significant, however (P = 0.78).
 
Changes from baseline in HIV-1 RNA values were compared for patients who had a PI mutation at position 46, 82, 84, or 90 with those who did not have any of these mutations. Results of this analysis showed that in the subgroup of patients without PI mutations at positions 46, 82, 84, or 90, both treatment groups showed similar changes from baseline in median HIV-1 RNA values. An analysis of covariance (ANCOVA) was performed to investigate the influence of study treatment; baseline viral load; genotypic sensitivity score; and the number of mutations that are related to NRTI, NNRTI, and PI resistance on changes from baseline in HIV-1 RNA values at weeks 16, 24, 48, and 80. The genotypic sensitivity score, derived as a measure of sensitivity to the ARV background regimen, represents the sum of the genotypically sensitive background drugs in the regimen. Of these variables, the baseline viral load, genotypic sensitivity score, and number of mutations related to PI resistance showed a consistent effect on reduction in viral load (P < 0.05). With each additional baseline PI mutation, viral load at week 80 increased by 0.3 log. Data were analyzed using the full analysis set (LOCF analysis) to evaluate the effect of TPV phenotypic resistance at baseline on the change from baseline in HIV-1 RNA values. The influence of baseline phenotypic resistance on viral load at weeks 16, 24, 48, and 80 was explored using an ANCOVA, with the factors of study treatment, baseline viral load, phenotypic sensitivity score, and log10 fold-change in TPV IC50. Neither the phenotypic sensitivity score nor the baseline susceptibility to TPV significantly influenced changes from baseline in HIV-1 RNA values. A total of 5 patients showed decreased susceptibility to TPV (4-10-fold change in IC50) after treatment, although 1 patient had demonstrated a >10-fold change in IC50 at baseline.
 
Increased median phenotypic resistance at the last measurement on treatment was observed in both treatment groups for the following NNRTIs: delavirdine, EFV, and nevirapine (see Table 3).
 
Seventeen patients receiving low-dose TPV presented with no or partial resistance to delavirdine, EFV, and nevirapine at baseline. Of these, only 2 patients developed resistance to each of the 3 drugs by the last OT measurement. Eleven of the 17 patients had missing measurements, however. Twenty-two patients receiving high-dose TPV had no resistance to delavirdine, EFV, and nevirapine at baseline. One patient developed partial resistance and 5 patients developed resistance to delavirdine and EFV, and 6 patients developed resistance to nevirapine by the last OT measurement. The remaining 13 patients receiving high-dose TPV had missing measurements. In the high-dose group, the median phenotypic resistance for TPV increased. Twenty patients receiving high-dose TPV had a 4-fold change in IC50 at baseline (2 patients had missing measurements). Of these, 5 patients remained with a 4-fold change in IC50 and 3 patients had an increase in phenotypic resistance to between a 4- and 10-fold change in IC50. Genotypic resistance testing identified that the most frequent mutations were V82T, L33I, L24M, L10I, and I84V (Table 6). At position 33, there were 2 further mutations: L33F and L33V. At position 20, 2 different mutations were observed: K20L and K20T.
 
Overall, TPV/r was well tolerated in this group of patients with advanced disease on multiple ARV agents and concomitant medications. The mean duration of exposure to TPV/r for both dose groups was approximately 14 to 19 months (2.5-3 months for the HFC formulation combined with 15-18 months for the SEDDS formulation). Most AEs were mild to moderate. Table 7 lists the most common AEs attributed to TPV, regardless of treatment group. These included diarrhea (58.5%), headache (39%), nausea (34.1%), upper respiratory infections (34.1%), rash (36.6%), dizziness (29.3%), and fatigue (29.3%). The difference in AEs between treatment groups varied, however. More patients in the high-dose arm experienced diarrhea, headache, and nausea compared with those in the low-dose arm, whereas more patients in the low-dose arm experienced dizziness or upper respiratory infections compared with those in the high-dose arm. Interpretation of data that compare the HFC formulation with the SEDDS formulation is problematic because of the small number of patients in these groups overall, the difference in the number of patients in the HFC groups compared with the SEDDS groups, and the difference in the duration of treatment for each formulation. In general, the most notable differences up to day 14 were observed for vomiting, nausea, abnormal dreaming, and abnormal thinking, which occurred in a higher percentage of patients receiving the HFC formulation compared with the SEDDS formulation in the low-dose and high-dose groups. Five patients experienced SAEs, with 3 of these events (sinusitis, avascular necrosis of the femoral head, and possible cytomegalovirus infection) considered unrelated to study drug administration. The patient who experienced avascular necrosis of the femoral head had been randomized to the low-dose arm, whereas the other patients had been randomized to the high-dose arm. One patient in the low-dose arm who had received the HFC and SEDDS formulations discontinued study participation because of grade 4 elevations in gamma-glutamyl transpeptidase (GGT) levels, and a second patient in the high-dose arm was discontinued because of numerous AEs that were moderate in intensity. Overall, the most frequently observed clinically significant laboratory abnormalities, defined as grade 3 or 4 elevations, were increased triglycerides in 27% of the patients, with 18% in the high-dose arm and 37% in the low-dose arm, and increased alanine aminotransferase (ALT) in 22% of the patients, with 27% in the high-dose arm and 16% in the low-dose arm. It should be noted that 47.4% and 22.7% of patients in the low-dose and high-dose arms, respectively, had elevated ALT levels at baseline. In addition, 65.9% of all patients entered the study with some degree of elevated triglyceride levels. Median triglyceride values at baseline in the low-dose and high-dose arms were 268 mg/dL (range: 65 to 1440 mg/dL) and 228 mg/dL (range: 73 to 1525 mg/dL), respectively. The percentage of patients with clinically significant triglyceride levels (grade 3 or 4) was higher in the low-dose group (15.8% vs. 4.5%), however.
 
DISCUSSION
As HAART has evolved, it has become increasingly more effective in suppressing HIV-1 replication in vivo. Nevertheless, despite therapy, some patients experience viral load rebound, the development of resistance to ARV drugs, and CD4+ cell count decline. In some cases, treatment failure can occur for many reasons, including lack of potency of early agents, serial monotherapy or bitherapy, poor adherence, and poor pharmacokinetics and pharmacodynamics.23 For PI-experienced HIV-1-infected patients failing their current treatment regimens, treatment options that offer a sustained clinical benefit may be limited.
 
The results of this study demonstrate that TPV/r-based therapy achieved a potent and durable reduction in the viral load of multiple PI-experienced patients. The >2.0-log10 decrease in viral load was maintained at all time points, with almost 75% of the patients in the low-dose TPV/r group and 50% of the patients in the high-dose group still receiving treatment at week 80. Furthermore, the estimated median time to virologic failure was essentially the same in both treatment groups, 490 days in the low-dose group and 483 days in the high-dose group, indicating that TPV/r-based salvage therapy was successfully able to maintain virologic control for >1 year in this cohort of highly treatment-experienced patients. After the completion of this study, patients were able to continue receiving TPV/r in a rollover trial. A number of these patients (n = 16) have now received TPV-based HAART for more than 5 years and continue to have a meaningful virologic response. This indicates that when TPV/r is used in combination with other active ARV agents, it can maintain a potent and durable response.
 
TPV/r decreases the area under the curve (AUC) of abacavir, zidovudine, and didanosine, although the clinical relevance of these reductions has not been established.24 Despite this documented decrease in the AUC, patients in this study experienced a consistent and durable reduction in viral load through 80 weeks of treatment. Fortunately, the interactions between TPV/r and medications commonly used in HIV-infected patients are well characterized; thus, TPV/r can be administered with confidence, even in patients with advanced disease who require complex ARV regimens.25
 
One of the secondary objectives of the trial was to evaluate the development of drug resistance. Results of phenotypic testing showed that TPV resistance (>10-fold change in IC50) was infrequently observed in this highly treated subject population at baseline or during the course of treatment, with reduced susceptibility to TPV (4-10-fold change in IC50 compared with wild type) detected in the HIV isolates of few patients over 80 weeks of exposure to study drugs. Development of reduced viral susceptibility to TPV was associated with HIV isolates demonstrating a greater number of protease gene mutations at baseline and at follow-up visits. Furthermore, patient viral isolates with reduced susceptibility had the emergence of the V82T mutation combined with an L33 (I for V) codon mutation on treatment with TPV. This suggests that reduced susceptibility to TPV may occur when these 2 mutations are present along with at least 10 other mutations. The presence of single PI mutations at codon 46, 82, 84, or 90 did not seem to influence the virologic response to TPV. These results imply that TPV may be useful in patient populations whose HIV isolates have developed extensive resistance to peptidic PIs and need treatment alternatives. This trial had a small population; therefore, additional supportive data are necessary to confirm this finding.
 
Overall, TPV/r, combined with a new NNRTI and NRTI, was relatively well tolerated in this multiple PI-experienced patient population. Most of the AEs observed during the trial were of mild to moderate intensity, with gastrointestinal events being most often associated with TPV/r. The most frequently observed clinically significant laboratory abnormalities were grade 3/4 triglycerides and increased ALT. As would be expected in this population of patients who had received prior multiple PI-based regimens, most patients (65.9%) entered the study with elevated triglyceride values. The most frequently observed clinically significant laboratory abnormality was increased GGT in 24.4% of the patients. It should be noted that elevations in GGT levels are frequently associated with administration of drugs that induce the CYP 450 enzyme system. These AEs are consistent with those seen in HIV-1-positive patients administered ritonavir-boosted PI regimens. Most AEs seen with TPV in this trial, as with other trials of TPV, occurred during the first few weeks of treatment.17,26 One limitation of this study is that the number of trial participants was low. Although the patient population was sufficient to demonstrate the primary efficacy endpoint, it may not provide meaningful data on the safety of this therapy. The 2 Randomized Evaluation of Strategic Intervention in multidrug reSistant patients with Tipranavir (RESIST) studies are multicenter, open-label, phase 3 trials evaluating the efficacy and safety of TPV/r (500 mg/200 mg twice daily) versus an investigator-selected ritonavir-boosted comparator protease inhibitor (CPI/r). These were administered with an optimized background regimen (OBR), which also included ≥2 RT inhibitors (with or without the HIV-1 fusion inhibitor enfuvirtide) in triple-class ARV-experienced patients with HIV-1 infection. Safety data are available for 749 patients receiving TPV/r from the RESIST trials.26-29
 
Given that patients in this study were NNRTI naive, questions were raised about the relative contributions of boosted TPV and the NNRTI. Phenotypic data from this study showed a gradual emergence of resistance to the NNRTIs. Although there was no evidence of a negative pharmacokinetic interaction between TPV and the NNRTIs, there is a possibility that some antagonism developed later in the study. Although difficult to determine, the lack of rapid emergence of resistance to the NNRTI component of the regimen supports the important contribution of TPV/r. These data are in agreement with those reported in phase 2 studies of lopinavir/RTV in patients who were naive to NNRTIs and PI experienced.30 It has now been well documented that responses to novel agents in salvage studies are most robust and sustained when combined with other active agents.17,26,31
 
With the advent of HAART, infection with HIV-1 is now regarded as a chronic manageable disease. Although first-line HAART has demonstrated durable responses in drug-naive patients, treatment-experienced patients pose a greater challenge. These data, along with those from other early-phase TPV/r studies, contributed to the decision to use a TPV/r dose of 500 mg/200 mg in the pivotal RESIST trials. These phase 3 studies have provided data that resulted in the approval and commercial availability of TPV for use in drug-experienced HIV-1-infected patients. These longer term data, although limited with regard to patient numbers, should provide clinicians with evidence that TPV/r-based salvage therapy can provide a durable treatment response for highly treatment-experienced HIV-1-infected patients.
 
 
 
 
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