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New Drugs: TMC114 (PI) and TMC125 (NNRTI)
Reported by Jules Levin
  The reporting on new drugs in development for HIV created much stir, hope, and excitement at the Resistance Workshop. New presentations on several promising new classes of anti-HIV drugs, entry inhibitors and integrase inhibitors, were presented initially at the Retrovirus Conference in February with updates in Spain. Updates on new drugs in currently available classes of anti-HIV drugs, but which show effectiveness in early studies against HIV resistant to currently available drugs, such as tipranavir (protease inhibitor), were also reported. You can read more detailed reports at the NATAP website Conference Reports.
TMC114 is a new protease inhibitor for patients with resistance to current protease inhibitors. Preliminary data has shown this drug to be potent and effective against HIV resistant to protease inhibitors. At the Resistance Workshop (Seville, Spain July 2-5), Tibotec-Virco (Johnson & Johnson) researchers reported for the first time finding 2 resistance mutations associated with TMC114: 41 and 70. They also reported resistance developed very slowly to TMC114 and that replication capacity was reduced after the mutations developed. In vitro experiments (in the test tube) show a set of viruses with extensive resistance to currently available single protease inhibitors (9 to 250 fold resistance) were sensitive (<4 fold decreased sensitivity) to TMC114. These viruses were 5-6 fold resistant to amprenavir but 1-4 fold sensitive to TMC114.
In vitro (test tube) resistance experiments showed the emergence of resistance to TMC114 was much slower as compared to nelfinavir, amprenavir, or lopinavir (Kaletra). Resistance to amprenavir and nelfinavir occurred more quickly than to Kaletra. And the slowest with TMC114. When resistance to TMC114 did finally emerge R41T and K70E were the mutations that emerged and investigators reported that viruses with these mutations replicated poorly (they were less potent; they had less replication capacity). Viruses that were resistant (10-fold) to TMC114 appeared to have little or no cross-resistant to other PIs, except saquinavir. TMC resistant viruses with 10-fold resistance had less than 10-fold resistance to the other PIs except saquinavir. The role of 41 and 70 in leading to TMC114 resistance is under investigation. The presenting researcher, Marie-Pierre de Bethune from Tibotec, believes it's likely that further research will find other mutations than 41 and 70 that will be associated with TMC114 resistance.
This information reported on TMC114 is preliminary and based on studies in the lab with patient blood samples. These findings have to be tested in clinical trials of HIV-infected patients to see if these positive preliminary resistance study results will effect HIV-infected patients with PI resistance the same.
This is a new next generation NNRTI in early stages of development and from the same company Tibotec-Virco, and has shown in early studies to have antiviral activity HIV with or without NNRTI resistance. Test tube studies of the Tibotec non-nucleoside RT inhibitor, TMC 125 were also presented at the Resistance Workshop. When the K103N mutation was present alone, this is the signature mutation for efavirenz, there was little or no resistance to TMC125. Viruses with the double mutant K103N + Y181C, developed resistance to TMC125 comparable to that seen with currently available NNRTIs.
However, a small study in HIV-infected patients with NNRTI-resistance (efavirenz, nevirapine, delavirdine) was presented at Barcelona. Tibotec-Virco investigators reported that mutations found in the 16 study patients were K103N, Y181C, Y188L, G109A/S, L100I (all NNRTTI mutations) and combinations of these; so double NNRTI mutation combinations. This was an early open-label phase IIA study in 16 HIV-infected men who were failing NNRTI therapy and had efavirenz resistance. 80% of patients were taking nevirapine and 20% efavirenz. The patients received 900 mg TMC125 twice daily instead of the failing NNRTI but continued to take the same NRTIs for 7 days. After 7 days patients changed their NRTIs. Average patient CD4 count before switching to TMC125 was 389, viral load 10,000 copies. Before starting TMC125 the average resistance to efavirenz (change in IC50) was 111-fold while resistance to TMC125 ranged between 0.5 to 8 fold.
On day 8 the average viral load reduction was -0.86 log (range: -1.95 to +0.09). The response may be muted because patients were ART experienced and had drug resistance. In addition they did not change underlying drugs for which they probably had some resistance. 12 patients (75%) had a decrease in viral load of at least 0.5 log and 44% (7) of patients had a decrease of at least 1 log. Investigators reported 11 patients reported adverse events and TMC125 was well tolerated and safe in this early study. The most commonly reported side effects were diarrhea (5) and headache (4) and were reported to be mild in severity. This study is small and preliminary, so further studies are needed to characterize how effective and what the side effect profile are in patients with extensive NNRTI resistance.
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