NEW AIDS DRUGS STILL A DISTANT GLIMMER

By Thomas Maugh

Los Angeles Times 11 March 2002

With current therapies bedeviled by serious side effects and growing viral resistance, hopes are fading for a quick breakthrough.

AIDS researchers don't like to admit that the field is in a slump, but it is hard to escape that conclusion.

There have been no major breakthroughs since the development of protease inhibitors six years ago. Many patients have stopped taking anti-AIDS drugs because of a growing incidence of both side effects and resistance to the drugs by the AIDS virus. And people continue to be infected at a rate that hasn't changed for a decade.

Clearly, any better control of the AIDS epidemic is going to take a lot longer than scientists had expected or predicted even a few years ago. Nowhere was this more apparent than at the ninth annual Retrovirus Conference in Seattle last month. Although researchers reported glimmers of hope in several new approaches to AIDS drugs, it will require years of hard work before any of those hopes are realized.

"It's becoming more and more difficult to make a major breakthrough" in AIDS research, said Dr. Raymond Schinazi of Emory University in Atlanta. "All the easy stuff has already been done."

Progress in the last two or three years has been "absolutely glacial," said Lee Klosinski, director of programs for AIDS Project Los Angeles.

"We weren't expecting a great deal this year, and we didn't get it," added Dr. Harvey A. Elder of Loma Linda University Medical Center.

And while the pace of research has seemingly slowed, the progress of the epidemic has not. Therapeutic advances have slashed the U.S. AIDS death rate from 40,000 per year to 15,000, but the number of new infections has held steady at about 40,000 per year. As a consequence, almost 1 million Americans are living with an HIV infection, according to new estimates from the federal Centers for Disease Control and Prevention.

And as people are spending longer times taking AIDS drugs, new complications are becoming apparent. Foremost among them are a number of side effects caused by the drugs themselves, ranging from simple nausea and lethargy to abnormal fat distribution on the body, high cholesterol levels, diabetes and now, new research suggests, an increased risk of heart attacks.

The side effects can be so severe that many patients are abandoning therapy, with disastrous consequences. New data show that those who quit taking drugs are much more likely to develop AIDS or to die.

Meanwhile, those who are doing well on the drugs are also facing some new problems that they didn't expect.

Particularly alarming to physicians at the recent meeting is the growing incidence of liver disease caused by co-infection by the hepatitis B and C viruses.

"We're becoming liver doctors as much as anything else," said Dr. David Stone, an AIDS treatment specialist at Lemuel Shattuck Hospital in Boston. "Fifty percent of our patients' deaths since 1999 have been from liver disease."

"In the past, these patients didn't live long enough for their hepatitis infections to become a problem," added Elder. "Now we have to treat for both HIV and hepatitis."

Protease Inhibitors' Side Effects Puzzle Doctors

There has been a gross change in researchers' mood since the introduction of protease inhibitors six years ago. Their powerful antiviral effect led scientists to hope that we were on the road to controlling the AIDS epidemic.

But the side effects of the drugs and the growing resistance of the virus to therapy have dampened enthusiasm.

Many of the side effects of therapy have been attributed to the protease inhibitors specifically, especially increases in cholesterol levels and dysfunctions in fat metabolism. Now, possibly as a result of those changes in lipid metabolism, the drugs are also being linked to heart attacks.

Dr. Scott Holmberg and his colleagues at the CDC in Atlanta studied 5,675 HIV-positive people in eight cities, half of whom were taking protease inhibitors. Heart attacks were rare in this group, probably because the patients were relatively young.

Nonetheless, there were 13 heart attacks among those taking protease inhibitors, compared with only two among the patients not taking the drugs -- a more than fivefold increase in risk.

"It would be unusual to see relative risk ratios like that" unless the drugs were causing it, Holmberg said. "We think we are seeing an early but still relatively small problem."

A study at UC San Diego called those results into question, however.

Dr. Samuel Bozette and his colleagues examined the records of 36,766 HIV-positive veterans over the same time period covered by the CDC study and found no increase in heart attacks among those taking protease inhibitors.

"This complication [heart attacks] does not seem to be changing," Bozette said.

It is not clear which study is correct, noted Dr. Harold Jaffe, who is in charge of AIDS programs at CDC, adding that more research is needed.

The many side effects of AIDS drugs have led some patients to stop taking them for brief periods or to quit entirely. A few researchers hope that brief periods off the drugs -- called structured treatment interruptions -- will assist viral control by exposing HIV to the immune system and stimulating a response. Several studies of this approach are underway, but no new results were presented here.

A new European study did look at the effect of total withdrawal, however. Dr. Jens D. Lundgren of the EuroSIDA Coordinating Office in Denmark presented new details from the 25-country study of AIDS treatment regimens. Among 3,610 patients in the program receiving drug cocktails, 16% stopped taking the drugs -- many because of side effects.

Those who stopped completely were six times as likely to develop AIDS or to die as those who continued receiving the drugs, he said. Those who stopped for a while and then resumed treatment were still twice as likely to die, he added.

Some patients stop taking antiviral drugs because the drugs have simply stopped working for them. HIV is a shifty, constantly mutating virus that has continually frustrated researchers by rapidly developing resistance to drugs. Indeed, the whole point of combination therapy is to reduce viral replication so sharply that the virus is not able to mutate as readily.

But patients sometimes skip drug doses, enabling the virus to mutate. At other times the virus simply mutates despite the decrease in replication. Some patients now carry viruses that are resistant to many or all of the 15 drugs used to treat HIV infections.

"These are patients who really need new options desperately," said Dr. Martin Markowitz of the Aaron Diamond AIDS research Center in New York City.

Researchers are thus looking for new drugs that can overcome this resistance and new classes of drugs that can attack the virus from entirely different directions.

When Virus Mutates, Drugs Lose Effectiveness

All of the existing AIDS drugs act against either of two HIV enzymes, called protease and reverse transcriptase, that are crucial to replication of the virus. The drugs bind to the so-called active sites of the enzymes, clogging up the sites and thereby preventing the virus from carrying out its normal function.

But the drugs bind only weakly, and when the virus develops a mutation that changes the shape of the binding site slightly, the drugs lose their effectiveness.

Tipranavir is a new protease inhibitor that binds more tightly to the active site than do existing drugs. "It interacts in a more flexible manner with protease so it is able to bind to drug-resistant HIV," Markowitz said. Unlike existing protease inhibitors, he said, it is actually more effective against resistant viruses than it is against unmutated ones.

Markowitz reported on a 48-week trial in which tipranavir was combined with another protease inhibitor, called ritonavir, in 41 patients. The combination reduced virus in the blood to undetectable levels, and none of the patients developed resistance to the new drug, he said.

Dr. Brian Gazzard of Chelsea and Westminster Hospital in London described a promising new reverse transcriptase inhibitor called TMC125, developed by the Belgian company Tibotec-Virco NV, which seems also to be effective against resistant viruses. In a preliminary study, he and his colleagues gave the new drug to 12 patients for a week. The drug slashed virus replication in the patients by 99% -- even in patients who were resistant to other reverse transcriptase inhibitors.

"That's a very large drop in viral load in the blood" for a single drug, Gazzard said. "This drug has a very impressive effect, but how long that effect will last and what the long-term side effects are, we don't know yet."

"That's a drop unlike anything we've seen before," added Dr. Joep Lange of the University of Amsterdam. "We need to understand why it has this particular potency."

Perhaps the greatest long-term promise for new drugs, however, lies in those that attack other parts of HIV's replication cycle, such as its entry into white blood cells. In order to break into the cells and initiate its own reproduction, the virus must bind to two receptors, one called CD4 and one called CCR5.

Blocking those receptors to prevent entry could provide a new way to fight the virus, and preliminary results suggest that it may be possible.

"This will be remembered as the year of the entry inhibitor," said Dr. Robert Schooley of the University of Colorado.

Researchers have been eagerly awaiting the first human trials of a new CCR5 blocker called SCH C, developed by Schering-Plough Co. Dr. Mark Laughlin of Schering said he and his colleagues administered the drug for a week to 12 patients with high virus levels. The drug reduced virus levels by at least 68% in 10 of the 12 and by 90% in four of them.

"This adds a new dimension to treatment of HIV," he said.

Bristol-Myers Squibb Co. has screened more than 100,000 compounds to find one that will block the CD4 receptor. Pharmacologist Richard Colonno of the company said they had found one, called BMS805, that seems to be the first viable candidate for a new drug. Test-tube studies show that it blocks replication of HIV that is resistant to all other drugs now in use, he said. The company plans to begin testing it in humans later this year.

Long-Lasting Interferon Can Slow Hepatitis C

And finally, there was a little bit of good news for patients who are infected with HIV and the hepatitis C virus. HIV exacerbates the effects of hepatitis C, causing cirrhosis of the liver to occur 50% faster than normal, said Dr. Raymond Chung of Harvard Medical School. But clinicians have been reluctant to use the most powerful anti-hepatitis drug, interferon, in these patients because of its strong side effects.

Chung led a government-sponsored study comparing a long-lasting form of interferon alpha 2-a, called Pegasys, with the conventional form of interferon. In the long-lasting form, interferon is attached to a polymer that allows it to stay in the bloodstream at high levels much longer than does interferon alone. Both versions were given in conjunction with the anti-hepatitis drug ribavirin, and patients continued to receive their HIV therapy as well.

At least 90% of the patients were able to tolerate the drugs, Chung said. And by 24 weeks into the study, 44% of those receiving Pegasys had undetectable levels of hepatitis C virus in their blood, compared with only 15% of those receiving conventional interferon. Even the majority of those who still had circulating virus in their blood showed liver improvements in a biopsy, he added.

"The fact that you could get 90% of these patients through six months of therapy, that is a phenomenal outcome," said Dr. Constance Benson of the University of Colorado Health Sciences Center. If you want other stories on this topic, search the Archives at latimes.com/archives. For information about reprinting this article, go to www.lats.com/rights.