• TMC125 Is a Highly Potent Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) in Antiretroviral Therapy (ART)-Naive, HIV-1 Infected Subjects
  Abstract 668
  Authored by B. Gruzdev (Inf. Dis. Hosp, Moscow, Russian Federation), A. Rakhmanova (Med. Acad. Postgraduate Studies, St. Petersburg, Russian Federation), K. De Dier (Tibotec-Virco, Mechelen, Belgium), S. Comhaire (MediSearch Int, Mechelen, Belgium), P. Baede-Van Dijk (Kinesis, Breda, Netherlands), G. Van T Klooster (Tibotec-Virco, Mechelen, Belgium)
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The field of NNRTI research is wide open at the moment. The three drugs on the market, nevirapine, efavirenz and delavirdine, do have some advantages over the nucleosides: They don't cause long-term toxicity to mitochondria. They also have some advantages over the protease inhibitors: They don't cause insulin resistance and body habitus changes. They also share one big fault -- the K103N mutation, which renders HIV resistant to all members of the class.

Many companies are working on NNRTIs now. There was a large stable in Dupont's portfolio, but it is unclear what if anything Bristol is going to do with them now that the takeover is nearly complete. GSK also has several promising candidates for K103 resistance viruses in its pipeline.

This Tibotec drug looks very promising in early trials. It is a novel compound with a flexible molecule and potent antiviral activity at very low (nanoMolar) levels. It is active not only against the K103N mutation, but also the L100I, Y181C, Y188L and the G190A/S mutations which cause all known resistance to NNRTIs. This trial was a randomized double-blind placebo-controlled trial of 900mg po BID as monotherapy for seven days in ART naive patients. Standard ART was offered after the seven-day period.

All the patients in the study were male with a median age of 23 years -- which is young for an HIV trial. Twelve received active drug and six received a placebo. One person dropped out of the study. Baseline viral loads ranged from 5,000 to 125,000 copies (median 57,619 copies or 4.26 log). CD4 count median was 650.

The results were quite impressive. In the TMC125 group there was a drop in median viral load by 1.99 log at seven days and no change in the placebo with a highly significant p value. Eight out of the twelve went to <400 copies and two out of the twelve went to <50 copies. Mild somnolence was the only real adverse effect. This appears to be a highly potent NNRTI in ART naive patients. Rumor also has it that in seven days in NNRTI resistant patients, this may be at least a one log drop which is also spectacular! This is a potentially promising addition to the NNRTI portfolio, if all goes well from here with clinical trials.