A pilot study of the use of mycophenolate mofetil as a component of therapy for multidrug-resistant HIV-1 infection.
Mycophenolic acid (MPA) increases the activity of both abacavir (ABC) and didanosine (ddI) in vitro against wild-type and multinucleoside-resistant HIV. We treated 7 patients with diagnosed AIDS who did not respond to eight or more antiretroviral therapies in an open label pilot study with mycophenolate mofetil (MMF), ABC, ddI, amprenavir (APV), and ritonavir (RTV), with or without efavirenz (EFV). Therapy was well tolerated despite the patients' advanced disease states. No significant decline in lymphocyte or other blood counts was observed. Median HIV RNA was 5.26 log10 copies/ml at entry, 4.53 log10 copies/ml at 4 weeks, and 5.13 log10 copies/ml at 16 weeks. Median CD4+ count was 34 cells/microl at entry and 39 cells/microl at 16 weeks of therapy. CD4+ counts increased further in five study subjects on extended therapy to 25 weeks (median 27 cells/microl at entry, 66 cells/microl at close), despite loss of virologic suppression in 4 of 5 cases. MPA can induce apoptosis in lymphocytes in vitro. However despite viral rebound, cell surface markers of apoptosis and activation declined in total CD3+ cells and CD3+/CD4+ cells twofold to fourfold in 4 of 5 adherent study subjects at 16 weeks, reaching levels comparable with those found in seronegative donors. Although low-dose MMF appears safe in late-stage HIV disease, this study did not demonstrate virologic efficacy. Higher doses of MMF may be more effective. With careful monitoring of toxicities and pharmacokinetics, MMF deserves further testing in HIV therapy.
Coull
J J
JJ
Division of Infectious Diseases, University of Texas Southwestern Medical Center at Dallas, 75390-9113, USA.
Turner
D
D
Melby
T
T
Betts
M R
MR
Lanier
R
R
Margolis
D M
DM
D000328:Adult; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D004352:Drug Resistance, Microbial / Q000235:genetics; D018432:Drug Resistance, Multiple / Q000235:genetics; D004359:Drug Therapy, Combination; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D010865:Pilot Projects; D012367:RNA, Viral / Q000097:blood; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016879:Salvage Therapy; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D012367:RNA, Viral; D018894:Reverse Transcriptase Inhibitors; D009173:Mycophenolic Acid