September 29, 2006
There is a pressing need for additional drugs to manage individuals who have developed resistance to currently available antiretroviral agents. Several new protease inhibitors (PIs) have recently been developed and approved in the United States for the management of treatment-experienced individuals. One such drug is tipranavir (TPV, Aptivus), which is administered in combination with ritonavir (RTV, Norvir). Previous reports from the pivotal RESIST (Randomized Evaluation of Strategic Intervention in Multi-Drug Resistant Patients with Tipranavir) 1 and 2 trials for tipranavir demonstrated that triple-class-experienced study participants who received tipranavir + ritonavir along with an optimized background therapy experienced better virologic suppression at 24 and 48 weeks than those who received optimized background therapy plus some other ritonavir-boosted PI.1 Although these findings have defined the potential utility of this drug, obtaining long-term safety and efficacy data is critical for the management of such patients.
Charles Farthing, from the AIDS Healthcare Foundation in Los Angeles, Calif., and colleagues provided 96-week follow-up results for the RESIST 1 and 2 trials.2 A total of 1,483 individuals were enrolled in the two studies, with 746 receiving tipranavir 500 mg + ritonavir 200 mg and 737 receiving a ritonavir-boosted comparator PI. All participants had received a minimum of three consecutive months of therapy with each drug class (i.e., nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and PIs), including current treatment with a PI-based regimen for at least three months at the time of randomization into the RESIST studies. All participants also had to have at least one primary protease mutation (30N, 46I/L, 48V, 50V, 82A/F/L/T, 84V and/or 90M), but no more than two mutations at codons 33, 82, 84 or 90.
Outcomes for this study were defined as a treatment response at week 96 and the time to treatment failure. A treatment response was defined as a reduction in plasma HIV-1 RNA at or above 1 log10 copies/mL. Individuals in the control arm who did not achieve this level of viral suppression after eight weeks were able to receive tipranavir + ritonavir.
Baseline characteristics were well matched for the two treatment groups.
|Baseline Characteristic||TPV + RTV|
(n = 746)
|CPI + RTV|
(n = 737)
|Median age (years)||43||42|
|Mean HIV-1 RNA (log10 copies/mL)||4.73||4.73|
|Mean CD4+ cell count (cells/mm3)||196||195|
|History of AIDS-defining illness (%)||56.8||55.1|
|Median number of primary PI mutations||3||3|
CPI = comparator PI; TPV = tipranavir; RTV = ritonavir.
Key results of this study are summarized in the table below. Individuals taking tipranavir + ritonavir were twice as likely as controls to experience a treatment response at week 96. Moreover, an enhanced response was observed in the subset of patients who received enfuvirtide (T-20, Fuzeon) as part of their optimized background regimen. The median time to treatment failure was 115 days for the tipranavir + ritonavir group versus zero days for the control group. The mean CD4+ cell count change at week 96 for the respective groups was 49 cells/mm3 versus 23 cells/mm3.
|Week 96 Outcomes for Individuals Enrolled in RESIST 1 and 2|
|Endpoint (Week 96)||TPV + RTV|
(n = 746)
|CPI + RTV|
(n = 737)
|> 1 log10 decrease plasma HIV-1 RNA (%)||26.4||10.7|
|Mean decrease plasma HIV-1 RNA (log10 copies/mL)||1.07||0.5|
|Plasma HIV-1 RNA < 400 copies/mL, overall (%)||26.9||10.9|
|Plasma HIV-1 RNA < 400 copies/mL, with T-20* (%)||44.4||14.4|
|Plasma HIV-1 RNA < 50 copies/mL, overall (%)||20.4||9.1|
|Plasma HIV-1 RNA < 50 copies/mL, with T-20* (%)||34.7||14.4|
These analyses show that triple-class-experienced individuals achieved enhanced and durable virologic and immunologic responses when placed on a new regimen that included tipranavir + ritonavir as opposed to an available comparator PI. The data further emphasize the importance of using multiple new agents simultaneously, such as tipranavir + ritonavir and enfuvirtide, in order to optimize responses. Furthermore, this and other studies, such as those using TMC114 (darunavir, Prezista), demonstrate the utility of new drugs in existing classes in treatment-experienced patients. Defining genotypic and phenotypic predictors of response to these new agents, along with access to drugs in novel classes, will ultimately lead to optimal treatment responses.
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