Include Mycophenolate in Abacavir-Containing Salvage Regimen?

Steven G. Deeks, MD

Disclosures

January 16, 2000

Question

I have a patient with advanced immunosuppression (CD4 40, HIV RNA = 276,000) who requires a salvage regimen, having failed on multiple treatments in the past. On the basis of genotypic resistance testing, I plan to include abacavir in his future regimen. What are the relative merits of adding mycophenolate to the regimen? Do the potential benefits outweigh the side effects of mycophenolate related to immunosuppression? If it is to be added, what dose should I use?

Mark Pakianathan, MB, ChB, MRCP

Response from Steven G. Deeks, MD

Despite the lack of clinical data, there is growing interest in the use of mycophenolate mofetil (MMF; CellCept) for the treatment of HIV infection. I suspect this interest reflects desperation over what to do for patients currently failing antiretroviral therapy.

Response from Steven G. Deeks, MD

MMF is a specific inhibitor of inosine monophosphate dehydrogenase, a cellular enzyme responsible for the conversion of inosine monophosphate to guanosine monophosphate. MMF therefore reduces the intracellular concentration of guanosine nucleotides. Theoretically, with reduced guanosine levels, the anti-HIV activity of a guanosine analogue is enhanced.[1] Abacavir is the only guanosine analogue available, therefore leading to interest regarding abacavir/MMF combination therapy.

The theoretical rationale for this combination is similar to that for hydroxyurea/didanosine. Hydroxyurea reduces intracellular concentration of adenosine nucleotides, thus increasing the activity of adenosine analogues (didanosine). Unfortunately, hydroxyurea may also increase the toxicity of didanosine, most notably peripheral neuropathy and pancreatitis, raising concerns that MMF will enhance the toxicity of abacavir.

MMF was developed as an immunosuppressive agent for use in organ transplantation and has a strong antiproliferative effect on lymphocytes. Since activated T cells are the primary targets for HIV, the ability of MMF to prevent lymphocyte production/activation may indirectly prevent virus replication. Thus, like hydroxyurea, MMF has at least two potential mechanisms of anti-HIV activity.[2]

Response from Steven G. Deeks, MD

Are there any data to support the use of MMF in HIV disease? Not really. Most of the data reported to date are based on in vitro experiments. In particular, Margolis and colleagues[3] recently published a series of elegant in vitro studies. These data indicated that:

  1. Abacavir inhibits HIV in a dose-dependent nature

  2. MMF enhances abacavir activity in a synergistic manner

  3. The M184V mutation confers some resistance to abacavir

  4. MMF restores virus susceptibility to low-level abacavir resistance

  5. MMF has some antiproliferative effects on lymphocytes

  6. MMF had an antagonistic effect on stavudine and zidovudine

This important study clearly supports further investigation of MMF in HIV disease. There are, however, no clinical trial data currently available. Phase I/II studies designed to identify a safe and effective dose of MMF are in development.

Response from Steven G. Deeks, MD

MMF is marketed by Hoffmann-La Roche and is available in the United States as CellCept. The "black box" warning found on the package insert clearly illustrates the major concern in development of this drug for HIV disease:

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. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

This warning applies to the standard doses used in transplantation (1 to 1.5 g twice daily). In the setting of renal transplantation, in which patients received other immunosuppressive agents, approximately 1% of patients developed lymphoma and other lymphoproliferative disorders. CMV viremia and HSV outbreaks were commonly observed. PCP and invasive fungal disease occurred as well, but were relatively rare, occurring in < 1% of patients. Anemia, leukopenia, and thrombocytopenia were very common, affecting 25% to 50% of patients. Abdominal pain, malaise, diarrhea, fatigue, headache, peripheral edema, nausea, etc. were also all common (10% to 25%).

Notably, most clinical studies compared mycophenolate mofetil with azathioprine, and dosed MMF with corticosteroids and/or cyclosporin.[4] The lack of placebo-controlled studies makes it difficult to determine the safety of this agent.

Response from Steven G. Deeks, MD

As is common in HIV disease, there has been little delay between the development of a hypothesis and its application in the clinic. Clinicians who choose to use MMF and abacavir in their patients must understand that there are no clinical data and that MMF can have profound side effects.

The dosage required to prevent transplant rejection (2 to 3 g daily) may be more than that required to enhance the anti-HIV activity of abacavir. An MMF dose of 250 to 500 mg twice daily is being studied in combination with abacavir in clinical trials. Presumably, this dose will be better tolerated than standard doses. Clinicians choosing to use MMF in practice should probably use these lower doses and warn patients about the potential side effects of immunosuppression and lymphoproliferative disorders.

Finally, it is important to note the in vitro data suggesting an antagonistic relationship between mycophenolic acid and either zidovudine or stavudine.[4] Since these are commonly prescribed agents, the widespread use of MMF may be limited.

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