Three-Drug Assault Best HIV Therapy

More effective than only one or two drugs, study says

THURSDAY, March 28, 2002 (HealthDayNews) -- A triple-drug punch against the virus responsible for AIDS appears more likely to control disease progression and prolong life than therapies involving only one drug or even two drugs.

A team of British researchers who analyzed the results of 54 published clinical trials of HIV drugs found that patients who took a combination therapy of three antiretroviral drugs did significantly better during their initial stages of therapy.

Three-drug antiretroviral therapy has been the standard-of-care in North America and Western Europe since 1997, says HIV treatment expert Dr. Charles Carpenter, the author of an editorial accompanying the study in the March 30 issue of the British Medical Journal.

Carpenter says he expects that to remain the standard treatment for years to come, although some physicians are starting to use four-drug combinations.

The increase in drug combos is one of the reasons why the research was done, says Dr. Chris Hyde, the senior investigator on the study -- to gain a greater understanding of the effect of triple therapies.

"Our particular concern was that people may be moving to explore combinations above three agents … ahead of understanding what is the optimal triple combination," says Hyde, a senior clinical lecturer in public health and epidemiology at the University of Birmingham, in England.

"As most people who've ever been unfortunate enough to have to take a retroviral therapy regime know, they're not easy regimes to deal with," he adds. "The drugs individually have difficult side effects, and sometimes in particular combinations those side effects are accentuated still further."

Antiretroviral drugs fall into two categories: reverse transcriptase inhibitors, which interfere with HIV's ability to make copies of itself, and protease inhibitors, which make it difficult for HIV to produce infectious virus particles.

The therapy fails when HIV mutates and develops resistance to the properties of specific drugs. Developing resistance to a multi-drug combination takes much longer than to a single drug, and studies have shown that it may take the virus years to develop resistance to a three-drug regimen.

The trials that were analyzed involved a total of 20,404 people between the ages of 27 and 40 years old, 80 percent of whom were men.

Looking at whether the therapies reduced disease progression and death, the researchers found that the odds for those on triple therapy were 40 percent lower than for those on a two-drug regime.

Along with examining the effect of triple therapy, the researchers also compared single-drug therapy vs. a placebo and two-drug therapy vs. a one-drug therapy. A single drug was superior to placebo, but two drugs were better than one.

Side effects from antiretrovirals include disturbances in fat metabolism causing abnormal fat deposits in the body, fatigue, peripheral nerve damage, and heart failure.

"There's good reason to question whether four agents are actually going to be better than three when you take the tolerability into account," Hyde says.

"There's no point in having a combination which is theoretically much better – that works much better in a test tube – if people can't actually maintain their particular regime because the side effects are too great or because of the interactions between the drugs," he adds.

Carpenter says that therapy options for people with HIV have improved significantly even in the last five years.

"Things are getting much better in terms of the ability to provide easier-to-take medications, less frequently, with less disturbance to the patient," Carpenter says.

But, he adds, "we still do have side effects for some people from every regimen we use."

The key is compliance. "If a patient truly takes the medications regularly, the first [regime] may be good for five, six or even seven years," he says.

"You've got to make every possible effort to make sure that the patient takes the initial therapy -- which you try to design as being one that's not going to be harmful to the patient -- as regularly as he or she can, so they don't develop resistance to it," Carpenter says. He notes that drug refinements are making once-a-day therapies more common, which makes the regimen easier on people with HIV.

At the same time, the strains of HIV that mutate to become resistant to a three-drug regimen may be less potent than the original strain, he notes.

Hyde also says it's important to find the best triple combination that could have the same benefit as adding a fourth drug, because of all the risk of side effects and interactions. And he notes there appears to be a great deal of variation between different triple-drug combinations.

"When the first round of drug treatment fails, what you're usually looking at is different drugs in your second triple-therapy combination," says Hyde. "So that's why it's so important to establish the best first-line treatment."

What To Do

Find out more about HIV treatment from the Centers for Disease Control and Prevention or check out this listing from the Food and Drug Administration on approved antiretroviral drugs.

You can also read this article on antiretroviral drugs from American Family Physician.

SOURCES: Interviews with Chris Hyde, M.D., senior clinical lecturer, Department of Public Health and Epidemiology, University of Birmingham, Birmingham, England, Charles C.J. Carpenter, M.D., physician-in-chief, The Miriam Hospital, professor, Department of Medicine, Brown University School of Medicine, Providence, R.I.; March 30, 2002 British Medical Journal
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