Simpler HIV drug regimen may improve results, Science study on monkeys suggests

November 23, 2000

Regular holidays from HIV drugs may help the immune system control the virus on its own, at least in monkeys. These findings, reported in the 24 November 2000 issue of the international journal, Science, raise hopes for finding a cheaper, simpler, and better-tolerated method of treating HIV than the current regimen.

Researchers cautioned, however, that people with HIV should never stop taking their medications except on the advice of a physician.

"More research is necessary to learn how these findings could work in a clinical setting," said lead author Franco Lori of the Research Institute for Genetic and Human Therapy in Washington, DC.

But, he added, "Our results suggest that patients might be able to take fewer drugs, which is an attractive possibility in itself. On top of that, it seems we can stimulate the immune system to better control the virus, which is a completely different way of looking at treatment."

The current approach to treating HIV involves a complex "cocktail" of drugs called HAART (for Highly Active Antiretroviral Treatment). While HAART usually keeps the virus in check over the long term, it frequently causes side effects and requires careful attention to a rigorous regimen of pills. HAART is also prohibitively expensive for many patients.

If patients stop taking HAART, the virus typically resumes its attack on the immune system. There are some exceptions, however, such as the "Berlin patient," who interrupted his therapy several times, and then stopped it altogether. His immune system has continued to suppress the virus on its own.

Since identifying the Berlin patient, Lori and Science coauthor Julianna Lisziewicz of the Research Institute for Genetic and Human Therapy have been investigating whether periodically interrupting therapy in other patients might fortify their immune systems as well.

Lori, Lisziewicz, and their colleagues infected rhesus macaques with the monkey version of HIV. Using animals instead of humans meant that the scientists could study a genetically similar group of individuals and infect them all at the same time, with a known strain of the virus.

Scientists have reported previously that interrupting therapy (known as "structured treatment interruption," or "STI-HAART,") may work in humans, but these reports have been largely anecdotal, according to Lori and his coauthors.

"This is the first randomized, controlled study showing the difference between interrupted and continued therapy," Lori said. "In the past, we've taken a few humans and followed them up to see what happens, but we couldn't define the exact role of treatment interruptions before this study."

The research team waited until seroconversion (the period after the initial infection, when the body has produced enough antibodies to temporarily quell the virus) to start the STI-HAART treatment.

"Such a delay may raise questions in terms of appropriateness in treating humans, but represents a more realistic scenario," Lori said.

One group of six monkeys was treated continuously with antiretroviral drugs, while another group switched between three weeks on therapy and three weeks off. A third "control" group of monkeys received no treatment at all.

"This is the first structured treatment interruption protocol that gives a potential recipe for how to treat patients. Every clinical center could follow this protocol," said Lisziewicz.

Twenty-one weeks later, both groups of monkeys on treatment were controlling the virus successfully. The animals had similarly low levels of virus in their blood, and similar levels of important immune cells called CD4 T lymphocytes.

A striking difference emerged after the 21-week period, when the researchers permanently stopped the treatment. The virus rebounded in animals that had received the conventional treatment, and their CD4 cells dropped to levels just as low as those of the untreated monkeys.

In contrast, six months after discontinuing the interrupted therapy, virus levels were still virtually undetectable in the STI-HAART monkeys. Their CD4 cell numbers hadn't changed significantly either.

To confirm that the immune system was really fighting back against the virus, the researchers developed a test for measuring the activity of another key immune cell, the CD8 T lymphocyte. The test, called "VIR, for Virus Specific Immune Response," specifically identified CD8 T cells that had been exposed to the virus and were activated to fight it.

"This new assay is very important, because it offers a way to correlate a virus-specific immune response with long term viral control," Lisziewicz said.

The results showed that animals on HAART had extremely low levels of CD8 activity, while the animals on STI-HAART showed a vigorous CD8 response.

"Our goal was to train the immune system to control the virus, and it appears this is what happened," Lisziewicz said.

Lori speculated that, with proper assistance, the immune system might ultimately be able to dominate HIV throughout an individual's life. Thus, while it may not be possible to eradicate the virus, HIV might conceivably become more akin to herpes, a common viral infection that cannot be cured, but in many cases produces no symptoms. AID, NIH.
The other authors of the study are Mark G. Lewis, Carrol Crabbs, Wendeline Wagner, Jack Greenhouse, Peter Silvera, and Jake Yalley-Ogunro, of the Southern Research Institute, in Frederick, MD; JianqingXu, Georg Varga, and Donald E. Zinn Jr., of the Research Institute for Genetic and Human Therapy, in Washington, DC; and Carmine Tinelli, of IRCCS Policlinico S. Matteo, in Pavia, Italy. Funding for this research was provided by RIGHT, a not-for-profit medical research institute supported by charitable contributions. Animals and animal care provided by the division of AIDS, NI

American Association for the Advancement of Science

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