- Reduced Activation and Apoptosis of Peripheral CD3+/CD4+ T Cells Persists After Viral Rebound in AIDS Patients Treated with Mycophenolate Mofetil (MMF) (Poster 56)
Authored by J.J. Coull and D.M. Margolis
View the original abstract
Mycophenolic acid (MA), a selective inhibitor of lymphocyte proliferation, currently in use in organ transplantation, inhibits inosine monophosphate dehydrogenase, blocking the synthesis of guanosine monophosphate. A few years ago there was a lot of excitement over this drug, when everybody was talking about hydoxyurea in combination with ddI. Mycophenolic acid should be used in combination with guanosine analogs like ddI or abacavir, because in theory, this could increase their antiviral activity. The principle behind this is that the depletion of the substrate (guanosine nucleotides) makes the reverse transcriptase of the virus more likely to get the guanosine analog triphosphates when it is replicating the RNA of the virus. Everything seems simple, but one of the main side effects of MA is immunosuppression (which is why it is used in renal transplants). The question is, how safe is it to use a drug like this in a patient infected with a virus that produces immunodeficiency?
That is the question that David Margolis's group in Texas tried to tackle in this poster. We have seen presentations of this cohort of patients before (in last year's resistance meeting in Sitges, Spain, I believe.)
Ten patients with heavy antiretroviral experience and multi-drug resistance as evaluated by genotype, received Abacavir 300mg bid, MA 250mg bid (a low dose by all means), ddI 400mg q day, ampenavir 600mg bid, ritonavir 100mg bid, and efavirenz if they had not used NNRTIs before -- quite a complicated regimen.
Most of the patients had some antiviral effect that was, in most cases, transient (i.e., it only lasted a few weeks), but that should not be unexpected in patients harboring these kind of nasty viruses.
The main question Margolis and his group asked was, how toxic is MA for the CD4 cells? They looked at it using some sophisticated immunologic tests and surface markers. The answer is that MA is not very toxic at all. In fact, some of the data suggest that it might even have a protective effect: there was an increase in CD4 cells, a decrease of CD4 cell apoptosis (programmed death), and also a decrease in CD4 cell activation. These immunologic effects could potentially add an additional benefit to the antiviral activity of this drug.
It is time to do a good, large trial that defines the role of MA in the management of HIV infection. The initial enthusiasm with this drug was tempered because of the hydroxyurea problem, especially with ACTG 5025 and the FDA "Dear Doctor" letters. But strategies increasing the efficacy of our current armamentarium are clearly needed in this era of multi-drug resistance.
The ACTG actually has a couple of ongoing trials attempting to find some answers about the role of myophenolic acid in HIV treatment. They use slightly higher dosages then the that used in this trial (500mg bid), which might be more effective. The results could be available next year.