Duke Researchers to Use Chemotherapy Agent to Attack HIV Hiding in Lymphoid Tissue
DURHAM, N.C. -- Duke University Medical Center researchers believe that an anti-cancer drug could be an effective way to eliminate HIV hiding out of reach from the latest drug combinations. The scientists say that if this approach proves successful in clinical trial, physicians could have a new and potent tool to use against the disease.
While the latest combinations of anti-viral drugs and protease inhibitors have proven successful in reducing the amount of HIV circulating in the bloodstream to undetectable levels, reservoirs of the virus remain untouched in lymphoid tissues such as lymph nodes, spleen and tonsils.
Researchers believe that these reservoirs are a source of re-infection upon discontinuation of anti-viral drugs and drug-resistant virus.
The drug to be tested is cyclophosphamide, an inexpensive anti-cancer drug which works by killing lymphoid tissue cells. It has been used safely for years to treat various lymphomas and autoimmune diseases like lupus and Goodpasture's syndrome.
"This is the first controlled clinical trial designed to see if we can actively reduce this reservoir of virus with a chemotherapeutic agent," said Duke infectious disease specialist Dr. Diego Miralles, principal investigator of a clinical trial funded by the National Institutes of Health using cyclophosphamide in AIDS patients.
"If we can demonstrate that this drug can actively reduce the lymphoid cells in which the virus is hiding, we can conceivably impact the effectiveness of current drugs by reducing the numbers of infected cells, some of which may harbor drug-resistant virus," Miralles said in an interview. "We are not going after a cure for AIDS with the current protocol, but we hope this will lay the foundation for strategies that will eventually lead to a cure by completely eliminating all infected cells."
Lymphoid tissues are involved in the production and "education" of immune system cells -- specifically T cells, the major target of HIV.
When HIV invades its target cells, it takes over the genetic machinery of the cell and uses it to produce more copies of itself, Miralles said. In the process, the genetic material integrates itself into the cell and actually becomes part of it.
"The combinations of drugs we use now to treat AIDS are quite effective in stopping viral replication in the bloodstream, but they seem to have little power against virus hiding in cells of the lymphoid tissue," Miralles continued. "The virus will be there as long as these cells live. Although initial estimates suggested that these cells will be eliminated within two to three years, current estimates place that time at least five to 10 years; therefore, we propose to expedite the elimination of these cells.
"We know that cyclophosphamide can kill lymphoid cells in cancer patients, so the key question is whether using this agent can kill those cells harboring the virus," he said. "If it can, that opens up new avenues for more protocols involving other agent and dosing schedules."
While it is expected that the drug will kill the cells harboring the virus, Miralles said that new immune system cells should be reproduced within three to four weeks after the drug is stopped because the doses of chemotherapy are not strong enough to attack the body's complex storehouse of stem cells, which produce immune system cells.
Cyclophosphamide has been used in a small number of HIV-infected patients with lymphoma who also received bone marrow transplants. While a decrease in HIV was detected in lymphoid tissue, the current trial will be the first to test the effects of chemotherapy in combination with complete suppression of virus in the bloodstream.
The trial protocol will enroll 10 patients, all of whom will receive combination anti-retroviral and protease inhibitor therapy to virtually eliminate the virus circulating in the bloodstream. Two to four months later, when the virus is no longer detectable, five of the patients will receive the cyclophosphamide treatment.
These patients will receive three increasingly higher doses of cyclophosphamide over an 18-week period, and then will be followed for one year. Biopsies of lymph nodes and other lymphoid tissue will be taken throughout the trial to track levels of HIV genetic material in those cells.
In order to be considered for the trial, patients must be asymptomatic and healthy, with CD4 T cell counts greater than 300 per cubic milliliter of blood, and must not have taken protease inhibitors.