November 16, 2006
Issues surrounding the efficacy, safety and development of resistance to tipranavir (TPV, Aptivus) were considered in a number of abstracts headed by Boehringer Ingelheim that were presented at the 8th International Congress on Drug Therapy in HIV Infection.
Tipranavir is a protease inhibitor (PI) that possesses a very high genetic barrier to resistance. It has been shown to be efficacious in patients who have failed previous PI-based therapeutic regimens due to the acquisition of PI-associated resistance mutations. Forty-eight-week results from the RESIST-1 and RESIST-2 (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) studies demonstrated that tipranavir is an excellent drug for achieving virologic suppression in heavily PI-experienced patients, particularly when used together with other effective antiretroviral compounds in the context of an optimized background regimen.1 Notably, the use of two active agents -- typically tipranavir plus enfuvirtide (T-20, Fuzeon) -- was usually required to achieve virologic suppression among patients who had failed previous PI-containing regimens.
The durability of these results have now been confirmed by Brian Gazzard and colleagues who conducted a 96-week analysis of the RESIST trials.2 Pooled, long-term results from 1,483 patients enrolled in RESIST-1 and RESIST-2 showed that the time to treatment failure was significantly longer for patients who received tipranavir + ritonavir (RTV, Norvir) versus a comparator PI + ritonavir (hazard ratio: 0.64; P < .0001). The time to treatment failure was also significantly longer for patients who received enfuvirtide versus no enfuvirtide (hazard ratio: 0.74; P < .0001).
Moreover, although more patients assigned to tipranavir + ritonavir achieved a treatment response (defined as a drop in viral load > 1 log10 copies/mL by week 96 without viral rebound, death or treatment changes) in comparison with patients assigned to a boosted comparator PI (20.4% versus 10.7%; P < .0001), the treatment response results were considerably more striking when only patients who took enfuvirtide as a new drug in their background regimen were compared (45.2% versus 10.5%; P < .0001). These striking differences with enfuvirtide and tipranavir + ritonavir were also observed when the proportions of patients achieving undetectable viral loads (HIV-1 RNA < 400 copies/mL and < 50 copies/mL) were compared. The mean CD4+ cell count increase at week 96 was approximately two-fold higher for tipranavir + ritonavir recipients in comparison with comparator PI + ritonavir recipients, regardless of whether enfuvirtide was included in the background regimen.
|Outcome at Week 96||TPV + RTV||CPI + RTV||P Value|
|Treatment response (%)||20.4||10.7||< .0001|
|HIV-1 RNA < 400 copies/mL (%)||26.9||10.9||< .0001|
|HIV-1 RNA < 50 copies/mL (%)||20.4||9.1||< .0001|
|Mean HIV-1 RNA reduction (log10 copies/mL)||1.07||0.5||NG|
|Mean CD4+ cell count increase (cells/mm3)||49||23||NG|
CPI = comparator PI; NG = not given; OBR = optimized background regimen.
In sum, these findings reinforce the notion that together with tipranavir + ritonavir a second active drug, such as enfuvirtide, can better achieve both virologic and immunologic responsiveness and success.
In a study exploring tipranavir + ritonavir resistance, Kohlbrenner and colleagues examined the efficacy of various PIs in light of the baseline resistance profile of patients who had previously received and failed regimens that included two or more PIs.3 Viral isolates from 523 patients enrolled in the RESIST studies that were analyzed both genotypically and phenotypically were assessed for their susceptibility to boosted tipranavir, amprenavir (APV, Agenerase), saquinavir (SQV, Fortovase, Invirase), indinavir (IDV, Crixivan), nelfinavir (NFV, Viracept), atazanavir (ATV, Reyataz) and lopinavir/ritonavir (LPV/r, Kaletra).
Approximately 75% of the viral isolates tested were resistant to boosted lopinavir, amprenavir, saquinavir, indinavir, nelfinavir and atazanavir, whereas more than 70% of the isolates resistant to the other PIs remained susceptible to tipranavir based on well-established, pre-defined biological cut-offs for resistance.
The investigators also discovered that at least eight protease resistance mutations were required to confer phenotypic resistance against tipranavir, which was defined as more than a four-fold change in the 50% inhibitory concentration of tipranavir. In point of fact, over 90% of the tipranavir-resistant viruses identified possessed 10 or more such mutations.
Many isolates that remained susceptible to tipranavir contained important polymorphisms in the protease sequence that are associated with drug resistance. The major conclusion of this study is that tipranavir can maintain significant activity against the vast majority of clinical isolates that are resistant to other approved PIs. Moreover, the study suggests that tipranavir is likely to remain effective in patients who possess highly PI-resistant HIV and who have previously been on therapeutic regimens involving two or more PIs.
In a related study, Sharon Walmsley and colleagues evaluated treatment responses to tipranavir + ritonavir in comparison with lopinavir/ritonavir among patients with varying degrees of lopinavir resistance.4 The investigators specifically compared 48-week treatment responses for patients in the RESIST trials after stratification by lopinavir mutation score (i.e., 0-3, 4-5, 6-7, and > 7 lopinavir mutations). Not surprisingly, the results showed that an increased number of mutations associated with resistance to lopinavir were more likely to confer phenotypic resistance against lopinavir than against tipranavir, which was reflected in the differing proportions of tipranavir-treated and lopinavir-treated patients who attained undetectable viral loads. These results substantiate the notion that tipranavir has a higher genetic barrier to resistance than lopinavir. In addition, these data reinforce the view that tipranavir can be used in a salvage therapy setting to rescue patients who have previously failed a lopinavir/ritonavir-based regimen.
An important issue related to tipranavir usage is the potential for toxicity. This concern has been addressed in the RESIST trials, as discussed in a poster by Albert W. Wu and colleagues.5 Wu's study specifically assessed quality-of-life issues and adverse events among RESIST patients receiving tipranavir + ritonavir. The results revealed that the overall rate of adverse events was higher in the comparator PI + ritonavir arm than in the tipranavir + ritonavir arm (562.8 versus 514.4 per 100 patient-exposure years); however, the rate of treatment-related adverse events was higher among patients receiving tipranavir + ritonavir versus a boosted comparator PI (75.0 versus 56.6 per 100 patient-exposure years). Not surprisingly, patients who experienced adverse events reported significant decreases in health-related quality of life across all subscale and summary scale scores assessed (P < .05 for all), except for cognitive function and mental health.
Despite the higher rate of treatment-related adverse events in patients who received tipranavir + ritonavir, these individuals demonstrated important quality-of-life improvements relative to individuals who received boosted comparator PIs. In particular, tipranavir + ritonavir recipients reported significantly better outcomes on measures of mental health, energy/fatigue, health distress, general health perceptions and overall quality of life (all Ps < .05).
A reasonable measure of patient tolerability of any drug is the extent to which it is used when made available to patients through compassionate access programs. Bruno Hoen et al evaluated the safety and efficacy of tipranavir based on data obtained from nearly 4,000 patients who received compassionate access to tipranavir + ritonavir prior to its official approval by the U.S. Food and Drug Administration.6 Individuals enrolled in the compassionate use program were heavily treatment experienced; most had received a median of 12 prior antiretrovirals (five PIs, six nucleoside reverse transcriptase inhibitors and one non-nucleoside reverse transcriptase inhibitor). Moreover, these individuals had a median viral load of 4.83 log10 copies/mL and a median CD4+ cell count of 96 cells/mm3.
No unexpected tolerability or safety issues surfaced during the compassionate use program. A total of 1,703 adverse events were reported for the 3,920 patients; 84% (n = 1,424) were classified as serious. These adverse events occurred among only 17% of the total cohort, meaning that 83% of patients experienced no tipranavir-related adverse events that ultimately led to treatment discontinuation.
The most common adverse events included infections and gastrointestinal disorders; the high incidence of the former is not surprising given the advanced nature of infection in the patient population. The safety profile of tipranavir appeared to be similar to that documented in the RESIST trials. Most patients who had normal laboratory values at the time of tipranavir + ritonavir initiation maintained normal liver enzyme and lipid levels during follow-up or experienced only grade-1 elevations. These data corroborate findings from the RESIST trials that indicate that tipranavir is generally safe and tolerable in heavily treatment-experienced patients.
To assess the potential use of tipranavir in a first-line antiretroviral regimen, David Cooper and colleagues examined the safety and efficacy of two different doses of tipranavir + ritonavir (500 mg tipranavir + 100 mg ritonavir twice daily or 500 mg tipranavir + 200 mg ritonavir twice daily) compared with lopinavir/ritonavir (400/100 mg twice daily) in 562 drug-naive patients in a multi-center, dose-raging, open-label study called BI 1182.33.7 These agents were given in combination with tenofovir (TDF, Viread) and lamivudine (3TC, Epivir). Of the patients enrolled in the trial, approximately three quarters were male (76.5%), about three quarters were white (73.3%), their mean age was 35 years, their mean viral load was 5.03 log10 copies/mL and their mean CD4+ cell count was 207 cells/mm3.
After 48 weeks of therapy, similar percentages of patients had achieved the primary endpoint of a viral load reduction below 50 copies/mL according to intent-to-treat analysis. However, when data from week 60 were considered, the 500 mg tipranavir + 100 mg ritonavir arm fell below the 15% non-inferiority margin for virologic efficacy in comparison with the lopinavir/ritonavir arm.
CD4+ cell counts increased comparably across the three arms by week 48. Increases in triglycerides and total cholesterol were likewise similar across the three groups. However, a higher proportion of patients in the 500 mg tipranavir + 200 mg ritonavir arm experienced significant elevations in alanine aminotransferase (ALT) levels compared with the other arms of the study (17.7% versus 3.4% to 5.9%; P = .001). Accordingly, the high-dose tipranavir + ritonavir arm was subsequently closed.
|Outcome at Week 48||500 mg TPV + 100 mg RTV BID||500 mg TPV + 200 mg RTV BID||LPV/RTV 400/100 mg BID|
|HIV-1 RNA < 50 copies/mL (%)||65.8||66.7||69.2|
|Median HIV-1 RNA reduction (log10 copies/mL)||3.10||3.15||3.27|
|Median CD4+ cell count increase (cells/mm3)||172||175||207|
BID = twice daily.
The major conclusion of this study was that 500 mg tipranavir + 100 mg ritonavir twice daily was non-inferior to lopinavir/ritonavir with regard to virologic suppression in drug-naive individuals after 48 weeks of treatment, but not after 60 weeks of treatment. Given this result and the observation that 500 mg tipranavir + 200 mg ritonavir twice daily is associated with an increased incidence of ALT elevations, these findings do not appear to be sufficiently robust to warrant a recommendation that tipranavir + ritonavir be used in antiretroviral-naive patients.
In sum, these collective data on tipranavir confirm its role as an important, novel PI for use in the treatment of individuals who harbor PI-resistant HIV and who require active antiretroviral agents to achieve virologic and immunologic responsiveness.
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