February 25, 2005
The greatest need in HIV antiretroviral therapeutics now is for agents that can effectively block viral replication in patients who have experienced virologic failure on several drug combinations, and who now harbor multi-drug resistant virus. One drug in development that answers this need is tipranavir (TPV), an experimental protease inhibitor (PI) that has demonstrated activity in phase 3 trials (RESIST 1 and 2) against virus with broad PI resistance. It is now available through expanded access; an overview of the research presented on tipranavir at this conference is available here.
TMC-114 is another experimental PI with activity against virus that is resistant to the currently available PIs. In a session at CROI focused on new antiretroviral agents, researchers presented a planned 24-week, combined interim analysis of two phase 2 dose-finding trials on TMC-114. The results, presented by Richard Haubrich of the University of California-San Diego, were impressive.
The primary objective of these ongoing trials is to compare the virologic outcomes and safety of 4 different doses of TMC-114 against a standard-of-care boosted PI combination.
The trials, TMC-114-C202 (being conducted in the United States) and TMC-114-C213 (being conducted in Australia, Canada, Europe and South America), have a similar design. Patients with PI, nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI)-experience, and at least 1, but no more than 3, primary PI mutations (i.e., from among those listed on the IAS-USA mutations list), and a plasma viral load greater than 1,000 copies/mL were randomized to NRTIs plus 1 of 5 possible PI arms:
The comparison PI and the NRTIs were selected on the basis of a virtual phenotype resistance test conducted prior to randomization. In addition, enfuvirtide (T-20, Fuzeon) could be continued or added at the discretion of the investigators. Randomization was stratified by use of enfuvirtide (yes or no), viral load (greater or less than 20,000 copies/mL) and number of primary PI mutations (1, 2 or 3).
Virologic failure was defined as: 1) less than a 0.5 log reduction in HIV RNA beyond week 8 of the study, 2) less than a 1.0 log reduction in HIV RNA beyond week 12 of the study or 3) 2 consecutive measurements in which HIV RNA was greater than 0.5 log above the patient's nadir value.
Baseline characteristics of the trial participants are provided in the following table. Participants were predominantly white men and had a baseline viral load of about 4.5 log and a baseline CD4+ cell count in the mid-100s.
In addition to the data noted in this table, participants also averaged 11 years of antiretroviral treatment experience. In each group, the median number of primary PI mutations was 3 and the median number of a PI mutation of any kind was 18. In other words, these were resistant viruses. The median fold-change in viral susceptibility was 79 to lopinavir, 29 to saquinavir and 19 to amprenavir. The median fold-change in viral susceptibility to TMC-114 was 4.
|TMC-114 (n=397)||Control PI (n=100)|
|Mean duration of infection||12 years||13 years|
|Mean baseline viral load||4.61 log||4.47 log|
|Mean CD4+ cells/mm3||136||163|
|Mean years on PI therapy||6||5|
|Mean # of agents used||11||11|
|Mean # of PIs||4||4|
In 71% of the participants, the comparative PIs selected by the investigators consisted of a single-boosted PI; double-boosted PIs were chosen in 27% of the participants and a double-PI combination in 2%. The most common PIs used were lopinavir/ritonavir (LPV/r, Kaletra), saquinavir (SQV, Fortovase, Invirase) and amprenavir (APV, Agenerase), which were used in 39%, 36% and 34% of the participants, respectively.
After 24 weeks of therapy, the following mean reduction in viral load was observed in patients on each study arm:
|Study Arm||Mean Viral Load Reduction (copies/mL)||Subjects With Viral Load <50 copies/mL|
|TMC-114 400 mg once daily||1.34 log||30%|
|TMC-114 800 mg once daily||1.43 log||31%|
|TMC-114 400 mg twice daily||1.47 log||38%|
|TMC-114 600 mg twice daily||1.85 log||47%|
|Control PI||0.27 log||9%|
Based on these data, 600 mg twice daily has been selected as the dose of TMC-114 to be used in phase 3 studies. Participants on these trials who are currently receiving lower doses will have their doses increased.
Focusing on the participants who received the 600-mg twice-daily dose in this trial, viral loads below 50 copies/mL were achieved in 37% of the patients who did not receive enfuvirtide and in 67% of the patients who did receive enfuvirtide.
Impressively, 48% of the participants who had 3 primary PI mutations in this arm achieved a viral load below 50 copies/mL. In addition, 31% of patients with no other working background agent still responded to TMC-114.
Could TMC-114 Be Better Than Tipranavir?
Although cross-study comparisons must be viewed with caution, it is difficult to resist the temptation to compare these data with those from the phase 3 tipranavir RESIST trials reported at ICAAC. This is particularly the case given the similar enrollment criteria for the 2 drug trials, as well as the fact that both of these agents are being developed with an initial indication for use in the salvage treatment setting.
It is worth noting that virologic outcomes in the tipranavir RESIST trials were reported as the proportion of patients with viral load reductions of greater than 1.0 log copies/mL; unlike the TMC-114 trial, there was no mention of the proportion of patients with viral loads less than 50 copies/mL.
Additionally, TMC-114 appears to have more sustained antiviral activity than tipranavir, and the ability to combine TMC-114 and enfuvirtide with such a high probability of success dictates the rational approach to salvage therapy in the near future (phase 3 trials will be enrolling shortly and the drug could be available through compassionate access by next year). The durability of these outcomes is obviously an important consideration, as is the activity of TMC-114 against virus with more than 3 primary PI mutations. This trial limited participation to patients with 3 or fewer.
TMC-114 is likely to be the next new antiretroviral agent following the U.S. Food and Drug Administration's approval of tipranavir. Given the need for new agents active against resistant virus, this was arguably the most important antiretroviral therapy trial presented at this conference. While the short-term activity of an investigational HIV integrase inhibitor and that of an investigational maturation inhibitor, as described in other CROI presentations, offer a great deal of hope, the excitement surrounding these agents needs to be tempered with the reality that there's still a long way to go with these novel compounds whereas the phase 3 trials of TMC-114 will begin shortly. Given the fact that tipranavir and TMC-114 fill the same need, it will be interesting to see if Tibotec, the maker of TMC-114, tries to get its product into expanded access quickly to preempt tipranavir prescriptions.
It should be disclosed that Ian Frank, M.D., the author of this article, serves as an investigator for the Open Label Trial of TMC114/RTV in HIV-1 Infected Treatment Experienced Subjects.
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