February 25, 2005
There is a rapidly expanding number of patients with HIV infection who have multi-drug resistant virus and/or medication intolerances. New treatment options are desperately needed for these people. Tipranavir (TPV) is one medication currently in the pipeline that promises to help fill this urgent treatment gap. It is a non-peptidic protease inhibitor (PI) that demonstrates high-level antiretroviral activity against viral isolates that are resistant to all currently available PIs. In order to be effective, tipranavir, like several other PIs, requires boosting with ritonavir (RTV, Norvir).
There were 2 pivotal phase III companion trials to determine the potential effectiveness of ritonavir-boosted tipranavir in people with multi-drug resistant virus who were failing antiretroviral therapy. One of them, known as RESIST-1, was conducted in multiple locations throughout the United States and Australia, while the second trial, RESIST-2, was carried out throughout Europe and Latin America.
These trials were designed to compare the safety and effectiveness of ritonavir-boosted tipranavir versus the standard-of-care comparator PI (CPI) also boosted with ritonavir. To qualify for these twin trials, participants had to be triple-class experienced and experiencing virologic failure (HIV RNA greater than 1,000 copies/mL), with at least one primary PI mutation. Excluded from the trial were people whose baseline resistance testing showed more than 2 PI-associated mutations. The doses used in these trials were tipranavir 500 mg twice daily paired with ritonavir 200 mg twice daily.
The 24-week results from these trials were recently reported at ICAAC 2004 and they clearly demonstrated the superiority of ritonavir-boosted tipranavir over the pre-selected standard-of-care CPI.1,2 The combined results of the 2 RESIST studies showed that 41.2% of ritonavir-boosted tipranavir trial participants had 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 benefit of ritonavir-boosted tipranavir in these heavily pretreated patients was much more apparent in those who also received enfuvirtide (T-20, Fuzeon) as a component of their optimized regimen. Overall, in the ritonavir-boosted tipranavir group, 47% of the participants who also received enfuvirtide achieved a viral load below 400 copies/mL, compared with 34% who did not receive enfuvirtide.
CROI 2005 Studies
Now that we know the benefit of using ritonavir-boosted tipranavir in heavily pretreated patients, there are many things we need to learn about using it. There were a few studies at CROI examining different aspects of ritonavir-boosted tipranavir.
Effect of baseline genotype on response to tipranavir/ritonavir (TPV/r) compared with standard-of-care comparator (CPI/r) in treatment-experienced patients: the phase 3 RESIST-1 and -2 trials
This presentation, given by Jonathan Schapiro from the Center for AIDS Research at Stanford University Medical School, detailed a resistance sub-study conducted by him and his colleagues of the pivotal RESIST-1 and RESIST-2 trials. Their study was designed to explore the impact of a patient's pre-existing mutations on the success or failure of ritonavir-boosted tipranavir-based salvage therapy. Baseline resistance mutations were examined in several different ways in this trial.
First, the total number of baseline protease gene mutations was enumerated and divided into 4 categories. This chart shows the percentage of subjects in each study arm with a given number of gene mutations.
|# of Gene Mutations||TPV/r Subjects||CPI/r Subjects|
As you can see, these numbers were quite well matched between the ritonavir-boosted tipranavir group and the comparator group.
The chart that follows shows the rates of successful virologic response stratified by the number of baseline protease mutations patients had. A successful response was defined as a confirmed greater than 1 log reduction in viral load at 24 weeks compared to baseline, with no viral rebound reported and no change in treatment.
|# of Gene Mutations||TPV/r Subjects||CPI/r Subjects||P value|
This table clearly shows that ritonavir-boosted tipranavir offers better results than the comparator PI. A not-unexpected finding was that these differences were most evident in trial participants who had highly PI-resistant virus.
Another manner in which baseline resistance was assessed was by counting the number of primary PI mutations in patients. These mutations included 30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V and 90M. For the purpose of this analysis, trial participants were divided into 1 of 3 categories based on how many primary PI mutations they had: 1 or 2 mutations, 3 or 4 mutations, and 5 or 6 mutations. The chart that follows shows the treatment response rates for each category.
|# of Primary PI Mutations||TPV/r Subjects||CPI/r Subjects|
In the ritonavir-boosted tipranavir group, the consistent degree of virologic suppression -- despite extensive PI resistance -- attests to the potency of this agent in this setting.
The final manner in which resistance was assessed was based on the number of so-called PRAMs (PI resistance-associated mutations at codons 33, 82, 84 and 90). This analysis produced results similar to those from the primary PI mutation analysis. There was evidence of similar success rates from ritonavir-boosted tipranavir across all strata, but a progressive decline in response as the number of PRAMs increased in the control group.
In conclusion, ritonavir-boosted tipranavir was found to be superior to the comparator arm, especially in participants who had extensive viral genotypic PI mutations.
Population pharmacokinetic assessment of systemic steady-state tipranavir concentrations for adults administered tipranavir/ritonavir 500/200 mg twice daily
This study, conducted by Chan-Loi Yong, from Boehringer Ingelheim, and colleagues, examined a combination of ritonavir-boosted tipranavir pharmacokinetic data from 4 studies involving 67 healthy volunteers and an additional 2 clinical trials in 120 HIV-infected patients. The goal of this study was to better understand the effects of demographic factors on ritonavir-boosted tipranavir steady-state concentration.
The pharmacokinetic database generated from these data consisted of a pool that was 79% male, 85% white, 11% black and 4% of other race. Participants ranged in age from 18 to 73, and in weight from 47 to 123 kg. Tipranavir concentration-time data were fitted to a 1-compartment model with first-order absorption.
The study found that tipranavir clearance can be affected by both body weight and HIV status. Trial participants with HIV infection had an 18.8% increase in tipranavir clearance and a 44.5% increased volume of tipranavir distribution compared to HIV-uninfected subjects. These differences translated into lower steady-state tipranavir concentrations for HIV-infected subjects (13% lower in males, 22% lower in females). Body weight had an independent effect on tipranavir clearance (P<.001).
In conclusion, this study found that body weight, HIV status and gender were covariates that may affect steady-state tipranavir concentration. However, due to the modest impact of these factors, no dosage adjustment of tipranavir was recommended based on these population-based models.
24-week RESIST study analyses: the efficacy of tipranavir/ritonavir is superior to lopinavir/ritonavir, and the TPV/r treatment response is enhanced by inclusion of genotypically active antiretrovirals in the optimized background regimen
David Cooper from Sydney, Australia conducted a substudy of RESIST-1 and RESIST-2 to better understand how resistance mutations would impact the success of therapy. His key finding detailed the relationship between treatment response and the number of genotypically active antiretroviral agents. As expected, the more active agents that could be included in a salvage regimen, the greater the likelihood there would be of virologic suppression.
Overall, 41.2% of the patients randomized to ritonavir-boosted tipranavir demonstrated a greater than 1 log reduction in HIV RNA at week 24.
As this chart shows, there was a graded response of success (defined as a greater than 1 log reduction in viral load) based on the number of active background agents that could be used.
|# of Background Agents||TPV/r Subjects||CPI/r Subjects|
Some of the most disappointing results were seen among participants who had no active agents in their background regimen. In this group, only 13.1% of subjects responded -- a finding that is not entirely surprising, since these subjects were effectively receiving monotherapy with ritonavir-boosted tipranavir. These results underscore how critical it is to have more than 1 active agent in a salvage regimen.
This study also looked at the impact of adding enfuvirtide to ritonavir-boosted tipranavir as an element of the optimized regimen. Overall, 58.2% of participants treated with the addition of enfuvirtide had a greater than 1 log reduction in their viral load at week 24. Among participants who were naive to enfuvirtide treatment, 69.6% had success with this agent in their regimen. Not unexpectedly, however, participants who had prior exposure to enfuvirtide had a much lower response rate of 30.6%, presumably due to previously acquired mutational resistance.
Health-related quality of life with tipranavir in combination with an optimized background regimen in 2 randomized clinical trials
Yet another sub-study of the RESIST protocols, conducted this time by Albert Wu, from Johns Hopkins University, and colleagues, was aimed at exploring health-related quality of life measurements for participants who were taking ritonavir-boosted tipranavir versus those who were taking a comparator ritonavir-boosted PI.
To measure quality of life, the researchers administered a health survey to participants at pre-defined intervals throughout the RESIST studies. The survey chosen was the Medical Outcomes Study-HIV Health Survey (MOS-HIV). This is a validated quality-of-life survey that has been used extensively in HIV-related trials. MOS-HIV reports scores for physical health and mental health. The primary endpoint of this study was the change in these 2 scores from baseline to week 24.
In both RESIST studies, the overall quality-of-life scores were found to be higher in the ritonavir-boosted tipranavir groups compared to the comparator + ritonavir groups and these differences were statistically significant. The differences were more pronounced in the RESIST-2 trial. Of note, many more participants who were on the comparator + ritonavir arms of the studies had discontinued therapy by week 24 due to virologic failure, as is demonstrated in the following chart.
|Study||TPV/r Dropout Rate||CPI/r Dropout Rate|
Overall, the improvements in health-related quality-of-life measurements for ritonavir-boosted tipranavir patients in these trials were modest. However, they were in contrast to the slight decline in quality-of-life measurements in the control group. It is also quite likely that the health-related quality-of-life differences between the groups were significantly underestimated, since so many more subjects in the control arm had dropped out by week 24. It is likely that subjects with virologic failure, who were more common in the control group, would be more likely to have experienced deterioration in their overall quality of life.
From all these studies it is clear that ritonavir-boosted tipranavir has demonstrated superiority over comparative protease inhibitor treatment for treatment-experienced patients who have multi-drug resistant HIV. Tipranavir should become available within the coming months, pending approval by the U.S. Food and Drug Administration.