AIDSWEEKLY Plus; Monday, October 19, 1998
Daniel J. DeNoon, Senior Editor

"New agents derived from the existing drug classes ... are in development and hopefully will provide potency and activity against drug-resistant strains," Hammer said. "The next true breakthrough, however, will occur when clinically effective agents directed at new targets become a reality."

Hammer spoke in a plenary address to the American Society for Microbiology's 38th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held September 24-27, 1998, in San Diego, California.

Currently approved anti-HIV drugs have two main targets: the viral reverse transcriptase enzyme, and the viral protease enzyme.

The reverse-transcriptase inhibitors (RTIs) fall into two subgroups: those based on nucleosides (the NRTIs) and non-nucleoside inhibitors (NNRTIs). Current NRTIs include zidovudine (AZT), didanosine (ddI), stavudine (d4T), lamivudine (3TC), and zalcitabine (ddC). Current NNRTIs include nevirapine, delavirdine, and, most recently, efavirenz.

Protease inhibitors (PIs) brought about the first true breakthrough in AIDS therapy by providing a means of attacking HIV on a second front. Current PIs include ritonavir, indinavir, nelfinavir, and saquinavir.

The availability of these drugs now makes possible a range of strategies for patients who have not previously been treated (and whose virus remains susceptible to all of these drugs): a PI plus two NRTIs, an NNRTI and two NRTIs, two PIs, a PI and an NNRTI, or three NRTIs.

Hammer noted that advanced clinical trials are underway with the new NRTIs abacavir, amprenavir, and adefovir dipivoxil (the latter is actually a nucleotide rather than a nucleoside).

He reported early results showing that the abacavir/AZT/3TC combination can be as effective as treatment including a PI, with some 60 to 70 percent of patients achieving viral load declines to below 400 copies/mL after 24 weeks of treatment. Similar results were seen with the amprenavir/AZT/3TC combination.

The abacavir/amprenavir combination was also very effective, with 60 percent of patients achieving viral loads of less than 5 copies/mL and 90 percent achieving viral loads of less than 500 copies/mL.

Moreover, the new drugs may be useful in the salvage therapy of patients failing protease inhibitors. In this regard, the abacavir/amprenavir/evfavirenz combination has been effective in such patients if their viral loads are less than 40,000 copies/mL and if they have never been treated with NNRTIs. Unfortunately, the combination appears ineffective in patients with higher viral loads and prior NNRTI experience.

There are several other NRTIs in the development pipeline:

* Lodenosone (FddA, U.S. Bioscience) has entered Phase II testing.

* BCH-10652 (dOTC, Biotech Pharma) is active against 3TC-resistant viral isolates. HIV is slow to develop resistance to this drug, which is seen as a potential alternative to 3TC. Phase I/II trials are planned.

* FTC (Triangle Pharmaceuticals). Another potential alternative to 3TC. Its pharmacokinetics permit once-daily dosing.

* DAPD (Triangle Pharmaceuticals). This is actually a prodrug which is intracellularly converted to dioxolane guanosine.

* bis-POC PMPA (Gilead), a prodrug of PMPA with once-daily dosing. NNRTIs under development are intended to overcome resistance to existing NNRTIs, which requires only a single mutation and can develop rapidly. The new NNRTIs include:

* The HEPT derivative MKC-442 (Triangle Pharmaceuticals). Clinical trials of MKC-442 began in 1996. The drug decreases clearance of AZT, permitting decreased AZT dosages.

* The imidazole compound S-1153 (Agouron). This drug is effective in vitro at nanomolar concentrations.

* The thiopyrimidine compound PNU-142721 (Pharmacia & Upjohn). A Phase I trial is planned.

Novel protease inhibitors include:

* ABT-378 (Abbott), a peptidomimetic compound already in advanced clinical trials.

* Tipranovir (PNU-140690, Pharmacia & Upjohn), a dihydropyrone compound.

* PD-178390 (Parke-Davis), a dihydropyrone compound.

* BMS-232632 (Bristol Myers Squibb), a peptidomimetic compound.

* DMP-450 (Triangle), a cyclic urea.

* JE-2147 (Agouron), a peptidomimetic compound active against PI- resistant HIV in vitro.

But AIDS therapy will not take its next major leap forward until new classes of HIV inhibitors become available, Hammer said. Each of these classes may be roughly grouped by its target:

* Fusion inhibitors. These drugs are designed to prevent HIV from fusing with the cell during the earliest stage of infection. This can be done in two ways: by targeting the chemokine receptor(s) needed by HIV to enter cells, and by targeting conserved regions on the HIV gp41 transmembrane glycoprotein, the so-called coiled-coil that physically penetrates the cell. This latter approach is taken by T-20 (Trimeris), already in phase II clinical trials. Targeting cellular chemokine receptors, however, may be more problematic: the virus may evolve new receptor use, anti-HIV activity may be cell-type specific, and blockade of these cellular receptors may be toxic.

* HIV Integrase inhibitors. HIV produces this enzyme to permit it to integrate its genetic material into host DNA. Such drugs were thought by many to be the next major step forward in AIDS therapy, Hammer said, but no clinically usable inhibitor now exists. Challenges to development are current HIV integrase inhibition assays do not always correlate with viral inhibition, and the finding that candidate compounds are non-selective for HIV integrase.

* HIV Nucleocapsid Inhibitors. The AIDS virus's tiny p7 nucleocapsid (NC) protein not only is needed for encapsidation of the viral genome, but also plays critical roles in virus maturation and in the earliest stages of infection. Moreover, NC facilitates reverse transcription. Candidate compounds, such as dithianes, attack the protein's vulnerable zinc-finger domain.

* HIV Tat, Rev, and Vpr Inhibitors. Most observers believe that the HIV Tat, Rev, and Vpr regulatory proteins are vital to viral infectivity, replication, and/or virulence. Inhibitors are actively being pursued. At least one Tat inhibitor has been tested in humans (Ro 24-7429, Roche) although clinical development was halted. Another Tat inhibitor (CGP64222, Novartis) is in preclinical studies. Vpr inhibitors are in an earlier stage of development.

Testing of new anti-HIV drugs has already become more complex, and is not likely to become easier.

"Clinical evaluation of any new agent is a severe challenge," Hammer observed. "Teasing out activity and efficacy without inducing resistance is a major challenge."
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