By Lisa Seachrist

Washington Editor

WASHINGTON * Hitting HIV hard and immediately with drug therapy proved to be an important theme at the Fourth Conference on Retroviruses and Opportunistic Infections here last week, as researchers detailed the effectiveness of current therapies and the promise of the next generation of drugs.

Early results of a study of triple-therapy for AIDS indicate that the drug combination not only reduces the amount of the virus in the bloodstream, but also boosts the patients' ravaged immune systems.

"While the results are from a pretty short duration, I think the effect on the immune system is real," said Michael Lederman, director of the AIDS Clinical Trials Unit at University Hospitals at Case Western Reserve University, in Cleveland. "It remains to be seen how long lasting the improvements will be."

Several studies have shown that combinations of nucleoside analogs and protease inhibitors, also known as highly active antiretroviral treatment (HAART), can decrease the amount of HIV circulating in the bloodstream, CD4 T cell counts, decrease the number of opportunistic infections and lower short-term mortality. However, researchers don't know whether these therapies actually restore lost immune function.

Fifty-three patients with CD4 T cells counts between 100 and 300 cells per cubic millimeter of blood have been enrolled in the AIDS Clinical Trials Group study 315. All of the patients had previously taken three months of AZT but had never received Glaxo Wellcome plc's 3TC or Abbott Laboratories' protease inhibitor ritonavir. After a 35-day wash-out period with no antiviral drugs whatsoever, the participants began taking ritonavir. Ten days later they added AZT and 3TC.

After 12 weeks, the patients' HIV burden had decreased by 700-fold and their CD4 and CD8 counts increased. CD8 cells are vital to combating intracellular parasites like viruses. In addition, the treatment decreased the levels of tumor necrosis factor alpha * a damaging cytokine that AIDS patients produce in excess.

Not only did patients produce more CD4 cells, but those increases were comprised of both experienced and naive cells * T cells primed and ready to respond as soon as they come across an antigen. The total number of naive cells doubled in the 12-week period.

"We were pretty heartened to see the increases in naive cells," said Lederman. "That's not to say all is well and good, the populations of T cells are still pretty disturbed."

Nevertheless, Lederman noted that understanding how the immune system begins to come back when the viral load is lifted may ultimately help scientists understand how AIDS demolishes the immune system in the first place and that knowledge may provide new strategies to combat the virus.

The researchers intend to follow these patients for as long as they can.

The Next Generation Of Protease Inhibitors

As combination therapies of nucleoside analogues and protease inhibitors become standard therapies for AIDS, the second generation of these drugs are beginning to be developed. Preliminary results of Phase I/II clinical trials indicate Vertex Pharmaceuticals Inc.'s protease inhibitor, VX-478, may be a potent new weapon in battling AIDS.

The compound, which the Cambridge, Mass., company is developing with Glaxo Wellcome, decreased the amount of circulating virus to undetectable levels (less than 400 copies/ml of blood) in five out of seven patients who participated in a four-week trial of the VX-478 in combination with Glaxo Wellcome's nucleoside analogue reverse transcriptase 159U89.

In addition, another four-week clinical Phase I/II trial testing VX-478 as a monotherapy in 42 patients showed that HIV didn't develop resistance to VX-478 even at the lowest dose of the drug which are the most likely to generate resistant strains. The companies in collaboration with academic centers sequenced isolates of the virus at the beginning of the four-week trial as well as at the conclusion. No mutations were detected where the drug binds to the HIV protease enzyme.

"It was quite surprising that no resistance developed," said Joshua Boger, president and CEO of Vertex, who noted that other protease inhibitors have begun to show resistance in a four-week period of time. "Of course, it is still very early, but it is quite promising for the potential of this drug."

Boger also noted that the drug was extremely well tolerated and that the highest dose tested, 1,200 mg twice a day, was the dose that the companies were going to continue to investigate. The drug produced side effects such as rash, headache and diarrhea for 10 percent of the patients.

"This drug, as it looks now, may be the most potent and well-tolerated protease inhibitor so far," Boger said.

Lynne Brum, senior director of corporate communications, said that Vertex and Glaxo Wellcome are continuing their collaboration to investigate VX-478 as well as working on developing the third generation of protease inhibitors. *