Bay Area Reporter - June 15, 2001
Jeff Getty, Survive AIDS Writers' Pool

"Though the drugs don't eradicate the virus, they're effective in treating the disease because they produce drug-resistant virus, which appears to be much less capable of causing damage to the thymus," said Dr. Mike McCune, an investigator who worked on the study. The news follows similar findings from nearly a year ago when UCSF's Dr. Steven Deeks reported less clinical progression and higher T-cells in patients with protease inhibitor drug-resistant virus. Taken together, these findings indicate that patients who have run out of options should still consider continuing HIV therapies, even when they don't appear to be keeping virus level low.

The Gladstone Institute has been a leading research site focusing on HIV patients' thymuses and disease progression since the early 1990s. Earlier papers from Gladstone also showed that the thymus in HIV-infected folks was not showing as much damage as might have been expected. All this is good news to long-term survivors who have exhausted all 15 approved anti-HIV drugs and live with high levels of HIV circulating in their bodies. Also these findings may shed light on why the death rate has remained low, even through apparent HIV drug failure. Undetectable viral levels may be optimal to achieve, but they are often not attainable.

The Gladstone study indicated that protease inhibitor-resistant virus was deemed less destructive to the thymus. Longtime HIV-treating physicians have suspected that maintaining resistant virus at higher levels was better than having patients go off drugs altogether - with HIV returning to untreated or wild strain virus.

"I urge my patients to stay on maximal therapy even in the presence of high viral loads. I am delighted to see Dr. McCune now showing proof of what those of us in the trenches have been sure of," said Dr. Mary Romayne, a San Francisco HIV practitioner. It follows that patients who are multi-drug-resistant should consider continuing to treat while finding the least harmful drug combinations. With the new findings, treatment regimes should also maintain protease inhibitor resistance in order to protect the thymus and immunity.

Scientists also indicated that the less destructive virus might help keep T-cells from falling as well. "Just because they have high viral loads and drug-resistant virus, doesn't mean their T-cell counts are going to plummet," said the paper's lead author, Cheryl Stoddart, Ph.D. That's because the study showed that protease inhibitor-resistant HIV was less likely to infect the thymus, which produces disease-fighting T-cells. The first clues to the new findings came when researchers discovered that drug-resistant HIV did not replicate as well in various cells. The new research shows that this impairment is much greater when it comes to thymus cells.

In the study, Stoddart and her research team inoculated both non-drug-resistant and drug-resistant virus into human thymus which was then implanted into mice. Weeks later, the non-drug-resistant virus grew substantially and began depleting the thymus of its cells. Drug-resistant virus, on the other hand, barely replicated and did not tamper with the thymus cells.

"The difference in the way the thymus grew could not be more extreme," said Stoddart.

In another experiment, researchers added virus directly to human thymus cell cultures. Viral replication was measured and results indicated that whereas many cells were infected by the non-drug-resistant virus, far fewer were infected by the drug-resistant strains. In actual virus isolates taken from patients, 12 times fewer thymus cells became infected with drug-resistant virus than untreated virus.

Finally, researchers scanned 14 HIV-positive patients to see how their thymuses were holding up. Many patients with protease resistant virus had more abundant thymus than would have been expected in people their age. It seems that just as with certain other body parts, a more abundant thymus is thought to be more beneficial than a less abundant one. Unfortunately the report also indicated that patients with resistant virus had no guarantee of a good, functional thymus either.

Given the new findings, will the body now be able to live into old age with high viral levels and multiple drug therapies?

This question is still unanswered and is the primary challenge facing the advanced AIDS patient today. Maintaining protease inhibitor resistance does not necessarily mean staying on a protease inhibitor indefinitely either. Viral phenotypes show protease resistance long after drug cessation. Perhaps now researchers may be able to recommend less toxic drug combinations and interruptions for long-term immune maintenance and side effect management. We await these recommendations.

Still, the news is hopeful - for a change. Such treatment refinements are long overdue for late-stage AIDS patients given the lack of effective new anti-HIV drugs in the pipeline.
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