The FDA’s approval of TPV was based on two randomized, controlled, open-label, multicenter phase 3 clinical trials, RESIST-1 and RESIST-2 (Randomized Evaluation of Strategic Intervention in Multidrug-Resistant Patients with Tipranavir). The trials enrolled a combined 1,159 triple antiretroviral class-experienced patients with a history of at least two prior PI-based antiretroviral regimens, including one therapeutic failure and at least one (but not more than two) primary protease gene mutations.
The patients received TPV in combination with ritonavir 200 mg plus an optimum background regimen (OBR) or a control regimen of an approved PI (i.e., lopinavir [Kaletra, Abbott], amprenavir [Agenerase, GlaxoSmithKline], saquinavir mesylate [Fortovase, Invirase, Roche], or sulfate [Crixivan, Merck]) in combination with ritonavir plus OBR for 24 weeks.
As observed from the trial data, TPV therapy, compared with other FDA-approved PIs, resulted in an increase in the number of virological responders. Forty percent of subjects achieved a viral load reduction of HIV-1 RNA of at least 1 log10 (the virological responders), compared with 18% for the control group. Furthermore, fewer individuals who received TPV experienced virological failure than did patients receiving approved drugs.
Thirty percent of the TPV patients were unable to achieve at least a 0.5 log10 decline from baseline and a viral RNA load below 100,000 copies by the eighth week.
Twelve percent achieved an initial response but experienced viral rebounding by week 24, whereas 7% did not respond at all, compared with 59%, 11%, and 8% for the control group, respectively. These results indicate that TPV may provide superior efficacy compared with other PIs in second-line or later regimens of antiretroviral therapy for HIV-1 infection.9
The approval of tipranavir/(TPV/r) was based on an analysis of plasma HIV-1 RNA levels in two controlled, phase 3 studies of 24 weeks’ duration. In both studies, treatment-experienced adults with evidence of HIV-1 replication, despite ongoing anti-retroviral therapy, were evaluated for their responses to clinically advanced, antiretroviral agents from three drug classes: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNR-TIs), and PIs.
In the two phase 3 studies, 40% of the HIV-1-positive patients who received TPV/r responded to treatment, whereas 18% of the comparator group responded. Treatment response was defined as a confirmed 1 log10 or greater decrease in HIV RNA copies from the baseline evaluation.
ADVERSE DRUG EVENTS
In clinical studies, adverse drug effects (ADEs) were more common in the TPV/r arm than in the standard of care comparator PI/ritonavir (CPI/r) arm in both RESIST 1 and RESIST 2 trials. Most of these ADEs were mild or moderate and asymptomatic, with the most common being gastrointestinal. Diarrhea occurred in 24.1% of patients in the TPV/r arm in the RESIST 1 trial and in 22.5% of patients in the TPV/r arm in the RESIST 2 trial.
Other ADEs that occurred in more than 10% of patients in the TPV/r arm included nausea, vomiting, fatigue, and headache.
In general, most ADEs occurred with a TPV dose of 1,200 mg. Significant laboratory abnormalities reported in RESIST 1 and RESIST 2 included elevated liver enzymes, particularly alanine transaminase (ALT), and elevated cholesterol and triglyceride levels. Patients in both trials who had preexisting elevated liver function test results or who had hepatitis B or C virus infection were at higher risk of experiencing elevations in AST and ALT.
In RESIST 1, elevated cholesterol and triglyceride levels were more common in the TPV/r arm than in the CPI/r arm. Elevated cholesterol levels occurred in 4.2% of patients in TPV/r arm vs. 0% of patients (P < .001) in the CPI/r arm and elevated triglyceride levels occurred in 21.7% of patients in the TPV/r arm, in contrast to 12.5% of patients (P < .01) in the CPI/r arm.
New-onset diabetes mellitus, exacerbation of pre-existing diabetes, and hyperglycemia have been reported in postmarketing surveillance data.
Mild-to-moderate skin disturbances, including urticarial and maculopapular rashes, as well as possible photosensi-tivity, have been reported with frequencies of 14% in females and 8% in males. In a drug-interaction trial of TPV/r and ethinyl estradiol, rashes occurred in 33% of the women participating in the study.
Other less common ADEs include bronchitis (in 2.9%), depression (in 2%), asthenia (in 1.5%), insomnia (in 1.2%), cough (in 0.8%), vertigo, mood changes, impaired concentration, and slowed thinking or movement.
Long-term studies have not been performed, but the short-term ADEs of TPV are similar to those associated with other PIs on the market. It can therefore be expected that TPV will have a long-term ADE profile similar to that of its predecessors, for example, in terms of fat redistribution.
A boxed warning on the product label for TPV states that when this drug is given with 200 mg of ritonavir, it has been associated with reports of clinical hepatitis and hepatic decompensation, including some fatalities. Extra vigilance is warranted in patients with chronic hepatitis B or hepatitis C co-infection.
Boehringer Ingelheim and the FDA have informed health care professionals of important new safety information for the capsules, when administered with ritonavir (500 mg/200 mg). An addition to the drug’s boxed warning mentions reports of both fatal and nonfatal intra-cranial hemorrhage (ICH). The company has identified 14 reports of ICH, including eight fatalities, in 6,840 HIV-1-infected patients receiving TPV capsules in combination antiretroviral therapy in clinical trials. Many of the patients experiencing ICH in the TPV clinical development program had other medical conditions, such as central nervous system (CNS) lesions, head trauma, recent neurosurgery, or alcohol abuse, or they were receiving concomitant medications, including antiplatelet agents, that might have caused or contributed to these events.