Bay Area Reporter - September 7, 2000
Jeff Gustavson, Survive AIDS Writers Pool

It is in this third category that Redfield recently spoke about at length. In order for HIV to reverse transcribe, that is, take the information that it has in the form of RNA when it enters a target cell and put it in the form of DNA, the viral enzyme reverse transcriptase must use the existing nucleotides of the cell it has infected. These four nucleotides: Adenine (A) and Guanine (G) - the purines, along with Cytosine (C) and Thymine (T) - the pyrimidines, are what makes up the genetic triplet code of our genes. Each of our cells must produce these nucleotides in sufficient quantity for a cell to divide and make copies of itself. At the same time, HIV subverts this intent and uses the nucleotides to put its genes into the cell's chromosomes.

Strengthen your inhibitions

"In 1995, Franco Lori and Bob Gallo demonstrated that purine [A and G] biosynthesis could be inhibited by interfering with anuclear reductase using hydroxyurea and ddI," Redfield said. It was on this basis, that the now famous "Berlin patient" was treated. "In that regard, we postulated that other targets could be investigated. Another pathway of purine, specifically, guanine biosynthesis was inosine monophosphate dehydrogenase (IMPDH). Since abacavir [brand name Ziagen] was being used in the treatment of HIV as a guanine analog, we postulated that some synergy might be obtained if we reduced the pool of naturally occurring guanine available and increasing the likelihood of reverse transcriptase using the abacavir. This led to our in vitro experiments and subsequent clinical investigation of mycophenolate mofetil.

"Our reasons were several fold. In the reticular cell system [including monocytes and lymphocytes - T and B cells], the IMPDH pathway is the only way cells make guanine [other cells would still be able to make needed guanine] so there is a possibility of less toxicity. Additionally, these molecules affect cell cycle [their ability to divide], which has in turn multiple effects on the viral life cycle with their target."

Do not enter

Cells are both more susceptible to infection as well as viral production when dividing. Hoffman La Roche's Web site states "Mycophenolate mofetil did not inhibit early events in the activation of human peripheral blood mononuclear cells, such as the production of interleukin-1 [IL-1] and interleukin-2 [IL-2], but did block the coupling of these events to DNA synthesis and proliferation."

Redfield continued, "Last December, we published a paper showing that multiply drug resistant virus cultured with mycophenolate and abacavir in the test tube reverted to wild type. We theorize that this is a result of nucleotide pool depletion by mycophenalate."

Finding out more

In human phase I trials of the abacavir/mycophenalate combination they were able to show a statistically significant initial drop in viral load, but the durability of that response seems to have been lost at weeks 24 and 36 at a dose of 250 milligrams twice a day. Higher doses blocked cellular immunity and exacerbated herpes infections. Redfield was led to "look more broadly. Could mycophenalate be used to enhance durability? Would it be superior in an initial regimen?"

An Aids Clinical Trials Group trial currently in development but which should be enrolling later this year, A5051, will be using mycophenalate in a salvage regimen and will further elaborate on its possible utility there. A planned trial using mycophenalate as an initial regimen was scrapped by the leadership of the ACTG. Redfield was disappointed. "I am interested in doing what I can to avert the ever widening gap between healthcare in the U.S. and the rest of the world. I am interested in developing sustainable therapies for worldwide application. The push for such therapies is unlikely to come from the pharmaceutical industry - most likely it will come from government and community groups. I believe that cell cycle agents work much better and are worthwhile research endeavors," he said.

New organs

Mycophenolate Mofetil (manufactured by Hoffman-LaRoche, brand name CellCept, see http://www.rocheusa.com/products/cellcept/pi.html) is currently an approved immune suppressive anti-rejection drug used for solid organ transplant. This is the drug that will be used in the liver transplant program for HIV-positive people that was recently funded by the National Institutes of Health. San Francisco General Hospital is one of the five initially funded sites nationwide.

Redfield commented, "I view the solid organ transplant program as a positive thing. Clearly, the demand for livers will only accelerate when considering the number of HIV and HCV [hepatitis C virus] coinfections. Our clinic has 300 African American patients on dialysis in need of kidneys."

Don't try this at home

This column would be remiss if it did not restate the company's warning from its Web site: "WARNING: Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of renal or cardiac transplant patients should use CellCept."

Considering the underlying risk for lymphoma already in persons with HIV, it is with caution that these trials are proceeding. It is not recommended that the community try this on their own at this stage.
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