Increasing knowledge of the process of integration of HIV into CD4 lymphocytes has provided direction for drug manufacturers to seek and find new and effective targets for drug therapy. The possible new targets and new drugs to aim at these targets, were described in a session on Monday.
The first one, an integrase inhibitor described by Daria Hazuda of Merck Research Laboratories, will block one of three enzymes which are essential for HIV integration into the lymphocyte DNA. This occurs after reverse transcription when the viral DNA is joined to the cell DNA by a process called strand transfer.
The integrase inhibitor, a chemical known as naphtyridine carboxamide, will block this reaction. This drug will have a high barrier to resistance without cross-resistance. Animal experimentation with a 75 day follow-up has shown no drop, and even a rise, in CD4 levels, as well as a significant drop in viral load. The integrase inhibitor is efficacious in against multidrug resistant organisms, and had no observable adverse effects.
The co-receptors CCR5 and CXCR4, are also likely targets for therapeutic advances. Two CCR5 antagonists developed by Schering Plough, were discussed by Bahige Baroudi. One, coded SCH D, has been tested in healthy volunteers and showed a favourable pharmacokinetic profile. While CCR5 resistance has been shown to develop in vitro, no co-receptor switch to CXCR4 has been observed in experiments so far.
Fusion inhibitors – a new class of drug also referred to as entry inhibitors – prevent the fusion of the viral and cell membranes which would allow the virus to enter the CD4 lymphocyte. Michael Greenberg of Trimeris Inc, said that in accordance with expectations, this drug would act against resistant viruses, and it has been shown to act against both CCR5 and CXCR4 isolates. The drug, known as enfuventide or T-20, has also been shown to be active against wild type viruses and those exhibiting multiple drug resistance.
Two other drugs in the group of co-receptor inhibitors, coded as PRO 542 and PRO 140, have provided acute and sustained reduction in viral load. William Olson, of Progeris Pharmaceuticals, said that PRO 140 blocks CCR5-mediated viral entry, without blocking the natural activity of CCR5. PRO 140 has recently been successfully humanised and huPRO 140 is showing good results. Their research has shown that these entry inhibitors act synergistically when used in combination.
Robert Murphy provided an overview of new agents in early clinical development, and he included in his review all the various classes of currently available drugs such as the nucleosides, non-nucleoside reverse transcription inhibitors, protease inhibitors, in addition to those already mentioned above. Trials are continuing and a close watch is being kept on mitochondrial toxicity and pharmacokinetics.
Gary Bridger from Virologics Inc, concluded the session by discussing a CXCR4 antagonist, which has shown significant reduction of viral loads in trials. In trials on dual-tropic viruses (using both CCR5 and CXCR4) all CXCR4-using variants had been eliminated by day 11. CXCR4 is thus regarded as a validated target for HIV therapy.
AIDS 2002 Conference News produced by Health & Development Networks/Key Correspondent Team