Editor

Although less often in the headlines during recent years, quietly murderous HIV has gone about its dark business worldwide with terrible efficiency. AIDS has killed 20 million people since beginning that sinister march across the earth, and another 40 million are infected with the virus.

Most of the newly infected (an estimated 70 percent) are in Africa, where 2.2 million died last year, but in the U.S., where new AIDS cases had been dropping until 1998, the disease has leveled out at about 40,000 new cases per year.

It's a trend that might be encouraging with regard to less sinister afflictions, but with this one is cause for serious concern.

The Centers for Disease Control and Prevention says more than 711,000 cases of AIDS have been reported since 1981, more than 420,000 Americans have died of AIDS, and as many as 900,000 more Americans are HIV-positive, although one in three is unaware of having the infection.

The band plays on, and its music is dirge-like.

Although AIDS once was tagged the "gay male disease" and men having sex with men continue to make up the largest group of HIV-positive people, at 43 percent another 27 percent of newly infected Americans got it from heterosexual contact, the fastest-growing mode of transmitting the disease. (Twenty-three percent were infected by way of intravenous drug use, which is blamed for the rising HIV infections in Russia.)

Every hour, two Americans between 13 and 24 gets infected. About half of all new infections occur in people under age 25, and about one-fourth are teenagers. More than 75 percent of high school students say they have had intercourse by the time they have reached graduation.

In Barcelona, Spain, the 14th International AIDS Conference put the media spotlight on AIDS again, and biotechnology proved a major source for new hope. One company drew particular attention during the first days of the conference: Trimeris Inc., with its fusion inhibitor T-20 (enfuvirtide).

The data had been disclosed several months earlier, but without the eye of the world focused on them. Trimeris reported results from a pair of international Phase III trials, called TORO 1 and TORO 2, with T-20, which works by blocking HIV from fusing with a host cell.

Patients given T-20, the company said, proved less likely to experience virological failure or relapse over 24 weeks, said Trimeris, which is developing the drug with Hoffmann-La Roche Inc.

TORO 1 tested 491 patients who had been treated with 12 antiretroviral agents. Patients who received T-20 as part of their combination regimen achieved a reduction in HIV levels of 1.697 log10 copies/mL, compared to 0.763 log10 copies/mL for those in the control arm. Fifty-two percent of patients receiving T-20 experienced a 1.0 log10 or greater reduction in HIV levels.

TORO 2, in 504 patients who had been treated with 11 antiretroviral drugs, also yielded encouraging results. Twenty-eight percent of patients who received T-20 in combination with an optimized background regimen had undetectable blood levels (less than 400 copies/mL) of HIV at 24 weeks, compared to 14 percent receiving an optimized background regimen alone (p<0.0001). Combination therapy with T-20 further reduced HIV viral load to less than 50 copies/mL in 12 percent of patients, compared to 5 percent who took combination therapy alone (p=0.0099).

Drug resistance, of course, is the main devil in HIV treatment. Existing drugs, which seem to work for a while, target enzymes that help the virus replicate. The hope is that T-20's alternate mode of action will mean benefit after other therapies have lost their power.

Nor are existing drugs to be discounted. More are better, it seems, as physicians mix "cocktails" of treatments, and the FDA continues to open the regulatory door. Last fall, Gilead Sciences Inc. won approval for Viread (tenofovir disoproxil fumarate), and data from its ongoing Phase III trial were among those that rained on attendees of the Barcelona AIDS conference.

Gilead's three-year trial, called Study 903, compared Viread's efficacy and safety to the HIV drug d4t (stavudine), marketed as Zerit by Bristol-Myers Squibb Co., when used as part of a first-line treatment regimen. The trial was designed to compare a regimen of Viread, lamivudine and efavirenz to a regimen of stavudine, 3TC and efavirenz in 600 patients.

In the analysis of the intent-to-treat population, 87 percent of patients in both the Viread arm and the stavudine arm achieved suppression of HIV RNA below 400 copies/mL (which was the primary efficacy endpoint), following 48 weeks of treatment. When missing data are excluded, 95 percent of patients receiving Viread compared to 96 percent of patients receiving stavudine had reductions in HIV RNA to below 400 copies/mL.

In other words, the two regimens were pretty much equivalent. But results also showed patients in the D4T arm had an increase in triglycerides, with more mitochondrial toxicities (which can mean peripheral neuropathy as well as other conditions) and more of a change in cholesterol levels making Viread safer, according to the data gathered so far. Patients will be followed for 144 weeks.

Navdeep Jaikaria, analyst with Leerink Swann & Co. and author of a 38-page analysis of the HIV market released earlier this month, noted that competition in the AIDS-drug arena is not quite the same as that in other indications, since patients typically are taking a handful of drugs.

About T-20 and Viread, which he acknowledged were rightful show-stealers in Barcelona, Jaikaria told BioWorld Financial Watch: "There is no race. We need them both. The market is huge."

And the market is growing, he said, with plenty of room for those two drugs and all the others. Jaikaria named as best in their classes Bristol-Myers' non-nucleoside reverse transcriptase inhibitor Sustiva (efavirenz) and Abbott Laboratories Inc.'s protease inhibitor Kaletra (a combination of lopinavir and ritonavir).

"The hallmark of the virus is that it attains resistance eventually pretty quickly in some cases and there has been a buildup of resistance in each of the three classes we have," he said. At the same time, "there's an expansion [since the late 1990s] of what we call the salvage population, the treatment-experienced population, which is living longer now," he added.

Enter T-20.

"Eventually, every therapy will develop resistance," Jaikaria said. "With T-20, if you use it as a monotherapy, you develop resistance very quickly. As a combination therapy, the resistance is not well documented but it's much slower."

Not only that, but T-20 is "a pretty safe drug," he said. "[AIDS patients] are already getting many therapies, four drugs or so, and all of them have side effects," whereas injection-site reactions have been the only significant side effect with T-20, he added.

"It's the new kid on the block, and it has shown beautiful efficacy," Jaikaria said, noting that T-20 "beat our expectations" in that regard.

As for Gilead, its data from the AIDS conference is an example where improvements in safety (with solid efficacy) will have "important consequences" for companies' bottom lines, whether "racing" each other or not.

"In other markets, if a good drug comes in, the others totally disappear," Jaikaria said. While that's not likely to be the case with Gilead's peers in the selling of AIDS drugs, "there will be changes in market shares," he said. "Viread continues to be as efficacious and is much safer, and what that means is it will be used more in front-line settings."

An important factor, Jaikaria added, is that "these drugs have been on the market for a while, and Gilead just introduced Viread [shortly after its approval in late October 2001]. It was the best-ever launch in HIV treatments. It's been a sensational drug, and I think it will continue to be, because it's one pill a day," which means better compliance by patients, often beset by an array of "cocktail" drugs.

Compliance, Jaikaria said, is "the name of the game."

Different as the AIDS-drug game is the field is crowded with players, vying as much against the dreadful scourge as much as they are vying against each other for market share Trimeris and Gilead have managed to stand out, Jaikaria said.

Until Barcelona, only top-line data were available on the pair, and it "doesn't give you in detail what else is going on. Here, you get to see detail."

And the details were encouraging.

"It's nothing we didn't know before," Jaikaria said, "but it's nice to see."