Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.
Newsday - Thursday, May 27, 1999, pp.A08
Laurie Garrett - Staff Writer
The findings call into question the long-term effectiveness of the best HIV therapy now available.
Since 1996, hundreds of thousands of HIV patients worldwide have benefited from the combinations of potent antiviral drugs that constitute HAART, or Highly Active Antiretroviral Therapy.
But the new studies in today's New England Journal of Medicine suggest that HAART patients may have to stay on the potent, often toxic drug cocktails for 60 or more years, an improbable prospect.
"The real question is whether patients can stay on therapy for really long periods of time," Alan Perelson explained, "possibly the rest of their lives."
Perelson, a mathematician in the Theoretical Division of Los Alamos National Laboratory in New Mexico, analyzed the complex data obtained in both studies. One study, led by Dr. David Ho of the Aaron Diamond AIDS Research Center in Manhattan, followed eight men who started HAART within six weeks after infection. The men stayed on the drugs for at least five months with no post-treatment evidence of HIV in their blood.
The second study, led by Dr. Steven Wolinsky of Northwestern University Medical School in Chicago, scrutinized five men who started HAART at least two years after infection, in some cases more than 10 years post-infection. All of Wolinsky's patients showed complete suppression of HIV in their blood for at least 20 months - in one case for nearly three years. All of Wolinsky's volunteers came from the Multicenter AIDS Cohort, which has been following a pool of gay American men for more than 15 years, documenting their HIV histories.
"We looked for those people who absolutely were able to maintain therapy," Wolinsky said in an interview. "This study was biased towards the most successful patients."
And that's why the results are so striking. For if HIV activity was found in these two patient groups, the findings bode poorly for the vast majority of less successfully treated HIV-positive people.
Both research teams used sophisticated new techniques for finding evidence of HIV replication in hidden cells - what Wolinsky calls "the footprint of the virus within the cell."
The method is so refined that the scientists could study individual cells, one by one, and look for evidence of newly formed viruses. In both studies, cells - and the viruses within - were examined every few weeks.
The Ho group consistently found HIV in cells of all their patients. In two of the eight men they found more: "hypermutation," as they termed it, with striking changes occurring over time in the viruses.
All five of Wolinsky's patients had evidence of continued viral production. And the types of viruses in the five changed over time, indicating HIV was mutating. In one patient, this resulted in resistance to a key HAART drug, AZT.
Why isn't HAART killing these hidden viruses, halting their ability to reproduce and mutate?
Three years ago, Perelson and Ho, using complex mathematic models, predicted that the second stage of HIV response to HAART would be one of slower decay in viral numbers, with all of the HIV killed off after about three years on the drugs.
"We made models where we assumed the therapy was a hundred percent effective," Perelson explained. "And this is showing us that those models were very idealized."
Are the drugs actually pushing those hidden viruses to mutate?
"My guess would be yes," Perelson said, hastily adding, "even though we don't have direct evidence for that."
Where do researchers go from here?
"We can now starting getting at the mechanism which underlies why this [hidden HIV] pool is made," Wolinsky said.
Carl Dieffenbach, of the National Institute of Allergy and Infectious Diseases, noted that the technologies developed by these investigators provide "new tools, so that if we ever have a patient in whom it appears the virus has been eradicated, we'll be able to verify that."
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