Existing Drugs Become Powerless Against AIDS Mutations

A new drug attempts to prevent the AIDS virus from penetrating the cell, but the virus has begun to outsmart even that.

A new drug attempts to prevent the AIDS virus from penetrating the cell, but the virus has begun to outsmart even that. Prof. Clotet Bonaventura, one of the top AIDS researchers in the world, visited Israel recently and said he does not see how humanity will win the war against the virus' mutations.

"Every time we save a patient," says Bonaventura, "we also save the virus that caused the disease. It seems that this disease will continue to plague humanity for another few hundred years."

Bonaventura heads the research labs at Germans Trais i Pujol in Badalona, Spain. He is considered one of the senior researchers in this field and oversees a team of 60 researchers, a tremendous number in Israeli terms. Bonaventura came to Israel for a convention organized by Roche Laboratories, manufacturers of Fuzeon, a new drug developed for AIDS patients.

Bonaventura specializes in the most troublesome aspect of AIDS research: the ability of the virus to develop resistance to drugs. This ability makes the drugs ineffective after a while. According to estimates, some 50 percent of therapies for advanced AIDS patients cannot prevent the spread of the virus in the body because the virus has developed a resistance to the drugs. Furthermore, a growing number of new patients have been infected by a strain of HIV that is resistant to all the drugs that are supposed to inhibit its growth.

Trojan horse

Bonaventura notes that this resistance stems from the virus' unique character. "HIV is a virus that belongs to the retrovirus group," he explains. "What makes retroviruses special is that they turn RNA molecules into DNA molecules. The virus penetrates the human cell and introduces its own RNA, which contains its viral data, into the cell. After a series of processes that occur in the cell, the RNA becomes DNA-type inherited data. From that moment the virus can reproduce. It is like a Trojan horse that takes over a fortress and turns it into a factory for manufacturing more Trojan horses, which will take over more fortresses."

What makes the virus so problematic is that it is a faulty virus. "Every time it copies itself to a cell, it does so with an error," explains Dr. Jonathan Schapiro of Tel Hashomer Hospital, who also teaches at Stanford University and hosted Bonaventura during his visit to Israel. The faulty copying mechanism causes each new copy of the virus to be slightly different than the virus that entered the cell in the first place.

"As a result," continues Schapiro, "the virus produces mutations arbitrarily and continuously, and they help it evade the drugs."

Schapiro stresses that contrary to conventional wisdom, AIDS is not a particularly violent virus.

"The viruses that kill people within a day or two," he says, "such as Ebola, are perfect viruses. But they kill their host before they have a chance to infect other people. That is why they are not so widespread. AIDS, on the other hand, is a defective virus, but it takes its time. It sits in the cell and waits, not in a hurry to go anywhere. It lets the sick person infect others for years before it rears its head and begins to strike at his immune system."

Paradoxically, the AIDS virus has actually been strengthened by the drugs developed over the past decade.

"Darwin's law of large numbers enters the game," says Bonaventura. "The virus constantly changes form and the mutations that cannot withstand the drugs die. This means that every time we manage to give the patient a few more years of life, we are giving the virus the impetus to change and become stronger than our drugs."

Still, Bonaventura and Schapiro do not recommend refraining from taking drugs.

"Over a decade ago, when there were not even any drugs," says Schapiro, "patients dropped like flies. We had no way of helping them. Today there are people who think that if the contract the disease, it's not so bad. They'll take the drugs and go on living. The complaints we are receiving these days are not that the patient is about to die, but that the side effects of the drugs bother him when he goes skiing. In that respect, we have accomplished what a decade ago was considered incredible." Nevertheless, the clinical treatment of AIDS patients is complicated and problematic.

"HIV is a merciless virus," says Schapiro. "You can follow the doctors orders and stick to the drug regimen to the letter 90 percent of the time, but those few instances when you forget the drugs are enough for the virus to strike at you."

Schapiro notes that when the virus develops a resistance to drugs, three things must be done: "Do a blood test, which will show that the virus has changed; consult an expert like Bonaventura, who knows which drugs you should take, depending on the change in the virus; and finally, hope that the drug companies will develop new drugs."

Schapiro says anti-AIDS drugs have been developed at an outstanding rate, creating an impressive arsenal of drugs. "Within a decade the drug companies developed 20 different drugs against the disease," Schapiro notes. "There is no precedent for this regarding any other disease."

In this context, Bonaventura says there was probably a significant breakthrough a year ago. The new drug, Fuzeon, also known as T-20, was developed by Trimeris and Hoffmann-La Roche, and was approved by the American Food and Drug Administration. Fuzeon inaugurated a new category of drugs to combat the virus.

"In the past," explains Bonaventura, "all the drugs fought the virus after it had entered the cell. Fuzeon is the first drug that stops the virus at the door, even before it fuses itself with the cell."

Third stage trials of the drug conducted among patients in whom the virus has developed resistance to all the other drugs on the market were declared a success.

"A few years ago," says Schapiro, "when the idea was first proposed, some people dismissed it as not serious. No one believed it was possible to prevent the virus from penetrating the cell. Today it seems the turning point created by this drug in the war against the virus is similar to the one in 1996, when doctors began giving patients the three-drug cocktail."

At this stage the drug is given mainly to patients for whom no other drug is helping in the battle against the spread of AIDS in their bodies. Bonaventura contends that this approach is a mistake.

"Experiments that we conducted showed that treatment with Fuzeon, along with any other drug to which the virus has not developed a resistance, is the best treatment the medical world can offer," said Bonaventura.

Bonaventura is currently examining the feasibility of giving Fuzeon for short periods, specifically to new patients, to slow down the spread of the virus to a minimum - and then to begin a regimen based on other drugs.

Fuzeon, however, has two drawbacks. The first is that the drug is administered by injection twice daily, unlike most of the other anti-AIDS drugs, which are taken orally. The second drawback is its tremendous cost - $20,000 per year, four times the price of the second most expensive drug currently offered to AIDS patients. Fuzeon is not yet included in the Israeli Health Ministry's basket of drugs.

"I find this incredible," says Schapiro. "There were always restrictions regarding the basket of drugs, but there was never an instance in which a drug of this type, which helps AIDS patients, is not being offered to Israeli patients. Today not one patient in Israel is receiving this drug."

Worst yet to come

Despite the success of Fuzeon, Bonaventura and Schapiro have no delusions. The virus will eventually develop resistance to Fuzeon, too. In fact, there are already mutations of HIV thatcan penetrate the cell even though the patient is taking Fuzeon.

The question now is how long it will take for those mutations to develop among enough people to have a negative effect on the drug's ability to contend with the virus.

"I believe that from the perspective of the disease's spread, it will get a lot worse before it gets a bit better," says Bonaventura. "We are far from the worst situation. Whole generations of people around the world will die from this disease without our being able to help them. At this stage I do not see how we can beat this virus."

Schapiro tries to be a little more optimistic. "In the past, no one believed we could fight viruses. Today I think that even during our lifetimes we will have the tools to cure people who have contracted AIDS. The fact that so many people are working on finding a drug leads me to believe that eventually someone will find the right formula. Like Bonaventura, however, I also believe that hundreds of years will pass before we succeed in eradicating this disease, as we have done with other diseases, such as polio and smallpox."