February 8, 2006
There are many HIV-infected patients who have multi-drug resistant virus and/or medication intolerances and thus are faced with limited treatment options. Tipranavir (TPV, Aptivus) was approved in June 2005 for patients in need of new antiretroviral options and as such represents an important new antiretroviral option. Tipranavir is a non-peptidic protease inhibitor (PI) that demonstrates high level antiretroviral activity against viral isolates that are resistant to all currently approved PIs. Tipranavir, like several other PIs, requires boosting with ritonavir (RTV, Norvir) in order to be effective.
RESIST-1 and RESIST-2 (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) are the pivotal phase 3 trials for tipranavir + ritonavir. RESIST-1 was conducted in the United States and Australia, while RESIST-2 was carried out in Europe and Latin America.
These trials were designed to compare the safety and effectiveness of twice-daily, 500-mg tipranavir boosted by 200-mg ritonavir twice daily versus the standard-of-care, comparator PI also boosted with ritonavir.
To qualify for these twin trials, participants had to be triple-class experienced, have virologic failure (HIV RNA greater than 1,000 copies/mL) and have at least one primary PI mutation. Patients with baseline resistance testing that showed more than two key tipranavir-associated mutations (codons 33, 82, 84 and 90) were excluded from the trials.
The 24-week results from RESIST-1 and RESIST-2 were reported previously and demonstrated the superiority of ritonavir-boosted tipranavir over the pre-selected standard-of-care, comparator PI.1,2 The combined RESIST studies showed that 41.2% of those treated with tipranavir + ritonavir experienced a greater than 1-log reduction in viral load, versus 18.9% of participants on the standard-of-care comparator. These differences were highly significant (P < .0001) and highlight the potential usefulness of ritonavir-boosted tipranavir in heavily treatment-experienced patients.
The anticipated 48-week data from the RESIST trials were presented at CROI 2006 and will be discussed below, along with new data on drug-drug interactions and the use of therapeutic drug monitoring and tipranavir + ritonavir resistance assays to assist in clinical management.
RESIST Trials -- 48-Week Results
This poster presentation by Christine Katlama,3 from Pitié-Salpétrière Hospital in Paris, and colleagues provided the 48-week data from the pivotal RESIST-1 and RESIST-2 trials, which led to the approval of tipranavir. Table 1 below demonstrates that tipranavir + ritonavir resulted in better outcomes than the other comparator PIs.
|Table 1: Week-48 Treatment Response and Baseline Viral Load (%; n/N) by PI Stratum (ITT NCF)|
|Tipranavir + Ritonavir||Treatment Response||33.0|
|Comparator PI + Ritonavir||Treatment Response||17.0|
|ITT NCF = intent-to-treat normalized counting function|
Table 2 below shows the expected results: Lower CD4+ cell counts and higher viral loads in treatment-experienced patients are associated with a lower response rate.
|Table 2: Week-48 Treatment Response Rate by CD4+ Cell Count and Viral Load Strata (ITT NCF)|
|Tipranavir + Ritonavir||Comparator PI + Ritonavir|
|CD4+ Cell Count (cells/mm3)|
|Viral Load (copies/mL)|
|ITT NCF = intent-to-treat normalized counting function|
The 48-week results of this study confirmed the positive findings from the 24-week data: In triple-class-experienced patients with limited treatment options, tipranavir + ritonavir is superior to the comparator PI. Furthermore, tipranavir + ritonavir-treated patients had better outcomes than the control group regardless of the PI chosen, baseline viral load or CD4+ cell count. And finally, in the tipranavir + ritonavir group, there was no significant loss of virologic activity and CD4+ cell counts continued to increase between week 24 and 48.
Tipranavir Drug-Drug Interaction Studies
When a new medication is approved for clinical use, the full complement of studies on potential drug-drug interactions is virtually never complete. This is largely a matter of practicality -- there is a vast array of medications on the market and it would be virtually impossible to perform drug-interaction studies on all of them. Moreover, new investigational agents continue to be tested and developed and interaction studies with these agents eventually need to be performed as well. However, some interaction studies clearly take priority over others. These studies tend to focus on drugs that are likely to be paired together with the new medication as part of an antiretroviral regimen.
One example of this potential convergence of new antiretroviral agents is that of tipranavir and TMC125 (etravirine). TMC125 is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with potent antiretroviral activity against viral isolates that are resistant to currently available NNRTIs. This agent is currently being tested in phase 3 trials for salvage therapy for HIV infection. Since tipranavir is currently approved for treatment-experienced patients with drug-resistant virus, it is anticipated that there will be some overlap between the use of TMC125 and tipranavir.
A short-term (8- and 16-day) study to detail the pharmacokinetic interactions between TMC125 and tipranavir + ritonavir in 24 healthy HIV-uninfected participants was presented by Monika Schöller, from Tibotec, and colleagues.4 In this trial, participants received either TMC125 alone, tipranavir + ritonavir alone, or the combination of the two agents in a crossover design. Unfortunately, there was a 76% reduction in exposure to TMC125 produced by coadministration with tipranavir + ritonavir. Because of this clinically significant interaction, it was recommended that tipranavir + ritonavir and TMC125 not be used together.
There was also a presentation by Andrea Calcagno and colleagues from the University of Turin5 describing a surprising potential interaction between tipranavir + ritonavir and enfuvirtide (T-20, Fuzeon). This was a single-center, retrospective analysis of tipranavir concentrations in a group of patients at one institution who either were on treatment with enfuvirtide (n=20) or were not (n=19). The trough levels of tipranavir were found to be approximately 54% higher in patients who were on enfuvirtide as compared with those who were not on enfuvirtide. Although these observations are interesting, no firm conclusions can be made until these data are confirmed by a formal pharmacokinetic study. This study does highlight the potential usefulness of therapeutic drug monitoring in the management of HIV-infected patients on highly active antiretroviral therapy (HAART).
Tipranavir and Therapeutic Drug Monitoring
Gilles Peytavin, from Bichat Hospital in Paris, and colleagues presented a study6 focusing on the interactions from double-PI boosting of tipranavir with lopinavir (LPV) or fosamprenavir (FPV, 908, Lexiva, Telzir). It had previously been shown7 that coadministration of tipranavir + ritonavir resulted in a major decline in drug concentrations of lopinavir and fosamprenavir. This study sought to determine if increasing the dose of lopinavir and fosamprenavir could overcome this negative pharmacokinetic interaction.
Following baseline pharmacokinetic measurements, 32 patients on fosamprenavir had their dose increased from 700 mg twice daily to 1,400 mg twice daily. This dose adjustment led to a 48% increase in the trough concentrations of fosamprenavir. In 20 patients who were on lopinavir/ritonavir (LPV/r, Kaletra), the dose was increased from 400 mg/100 mg twice daily to 533 mg/233 mg twice daily. This dose modification resulted in a 58% increase in trough levels of lopinavir.
The key finding of this study was that the negative drug-drug interaction between tipranavir and fosamprenavir or lopinavir can be overcome by increasing the dose of the coadministered PI. This trial provides some data to guide clinicians in the dose selection of lopinavir and fosamprenavir for cases in which double-PI boosting of tipranavir may be necessary in salvage patients.
Another study, this one presented by Marianne Harris, from the British Columbia Center for Excellence in HIV/AIDS, and colleagues,8 examined two different dose adjustment strategies to determine the optimal means of overcoming the negative pharmacokinetic interaction between tipranavir and lopinavir/ritonavir.
Participating in the study were 13 HIV-infected males who were on a stable lopinavir/ritonavir-based regimen for more than 11 months with no other PI or NNRTI. The researchers added tipranavir + ritonavir to the regimen with concurrent adjustment of the lopinavir/ritonavir and ritonavir doses.
The first group of seven trial participants had twice-daily tipranavir 500 mg + twice-daily ritonavir 200 mg added to the standard dose of twice-daily 400-mg/100-mg lopinavir/ritonavir.
The second group of six trial participants had twice-daily tipranavir 500 mg + lopinavir/ritonavir 133 mg/33 mg also twice daily + ritonavir 100 mg twice daily added to the standard dose of lopinavir/ritonavir 400 mg/100 mg twice daily.
Both of these dosing schedules resulted in lopinavir trough concentrations similar to the levels obtained before the addition of tipranavir. However, there was a greater rate of adverse events observed in the first group that received the higher dose of ritonavir (5/7; 71%) versus the second group (2/6; 33%). On the basis of these limited data, it seems reasonable to select the 533-mg/133-mg dose of lopinavir/ritonavir to add to tipranavir + ritonavir 500 mg/100 mg twice daily when these agents need to be coadministered.
How to best adjust the lopinavir/ritonavir dosage with the new 200-mg/50-mg tablet formulation of lopinavir/ritonavir is now open for discussion and potential study.
Therapeutic drug monitoring may be helpful for antiretroviral selection and management. Therapeutic drug monitoring may be used in the context of either genotypic or phenotypic resistance testing to generate an inhibitory quotient.
A presentation by Stefano Bonora, from the University of Turin, and colleagues9 looked at the potential usefulness of the tipranavir genotypic inhibitory quotient (gIQ) as a predictor of virologic response to tipranavir-based therapy. This study was a pharmacokinetic substudy of RESIST in which the gIQ for tipranavir was determined by dividing the trough tipranavir concentration by the number of primary tipranavir-associated mutations.
There were 27 multi-drug-experienced participants enrolled in this trial -- the median number of tipranavir-associated mutations was three. Baseline viral load and CD4+ cell count were 4.7 log (4.17 to 5.07) and 226 cells/mm3 (189 to 311), respectively. The mean tipranavir trough concentration was 30,760 ug/mL and this resulted in a median tipranavir gIQ of 9149 ug/mL.
At week 12 of follow-up, 7/9 participants with a tipranavir gIQ over 13,000 demonstrated plasma HIV RNA of under 50 copies/mL in contrast with only 4/18 participants with a tipranavir gIQ below 13,000 (P = .011).
Although there are no immediate, practical applications for this research in the clinical setting (due to the lack of commercial availability of a tool to measure plasma tipranavir concentrations), it does add to the growing body of literature that link antiretroviral drug concentrations and resistance testing results with clinical outcomes.
Greater commercial availability of therapeutic drug monitoring would provide clinicians with a better means of making individual dosing and treatment decisions, especially for patients on regimens with complex drug-drug interactions.
|Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.|
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