4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

A PILOT STUDY OF THE USE OF MYCOPHENOLATE MOFETIL AS A COMPONENT OF THERAPY FOR MULTIDRUG-RESISTANT HIV-1

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):9 (Abstract 11

JJ Coull¹, M Betts¹, D Turner², T Melby³, ER Lanier³ and DM Margolis^1,2
1University of Texas Southwestern Medical Center at Dallas, Dallas, Tex., USA; ²North Texas Veterans Health Care Systems, Dallas, Tex., USA; and ³Virology Department, Glaxo Wellcome, Research Triangle Park, N.C., USA

Mycophenolic acid (MA), a selective inhibitor of de novo synthesis of guanosine monophosphate and lymphocyte proliferation, exhibits synergy in vitro with guanosine analogue nucleoside reverse transcriptase inhibitor (NRTI) abacavir and didanosine against wild-type and NRTI-resistant HIV. We performed a 16-week, open-label pilot study in seven late-stage AIDS patients who had failed 10 or more antiretrovirals [≥4 NRTIs, ≥2 protease inhibitors (PIs) and ≥1 non-nucleoside RTIs (NNRTIs)]. Genotypes prior to enrolment showed NRTI (mean, 3.3), PI (mean, 4.6), and NNRTI (mean, 2.1) mutations. Subjects received 300 mg abacavir twice daily, 250 mg mycophenolate mofetil (MMF) twice daily, 400 mg didanosine four times daily, 600 mg amprenavir twice daily and 200 mg ritonavir twice daily. One patient without K103N also received 600 mg efavirenz four times daily. Therapy was well tolerated in this cohort with symptomatic AIDS. No significant decline in lymphocyte or other blood counts was observed. Mean CD4 count was 30 cells/mm³ at entry, 43 cells/mm³ at 4 weeks of therapy, and 46 cells/mm³ at 16 weeks of therapy. Mean HIV RNA was 5.3 log₁₀ copies/ml at entry, 3.6 log₁₀ copies/ml at 4 weeks, and 4.8 log₁₀ copies/ml at 16 weeks. Two patients reported non-adherence to the protease arm of therapy; pharmacy records were consistent with non-adherence in a third patient. All patients experienced a decline of 1.1–2.6 log₁₀ of HIV RNA during the first 4 weeks of therapy. HIV RNA declined 2.15 log₁₀ copies/ml during the first month in four subjects deemed adherent. Mean CD4 cell count in these subjects rose from 21 to 47 cells/mm³, although mean HIV RNA only decreased from 5.5 to 4.5 log₁₀ copies/ml. Minimal changes in HIV reverse transcriptase or protease genotype were noted at viral nadir and following viral rebound. Phenotypic testing and limited pharmacokinetic studies are in progress. Five patients continue to receive MMF. As MA may induce apoptosis in lymphocytes, CD3 cells were analysed for markers of apoptosis and activation. Annexin V and CD69 staining declined 50% at week 2. Three- to four-fold decreases in these markers continued in four of five subjects taking MA at 16 weeks, despite suboptimal antiviral effect, reaching levels comparable with normal HIV controls. This finding is intriguing given modest increases in CD4 cell counts. The use of low dose MMF appears to be well tolerated in late stage HIV disease. MMF may have contributed to the transient antiviral effect or the modest immunological benefit observed in this cohort with advanced disease and resistant HIV. Further studies of MMF in antiretroviral therapy are indicated.

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2000-06-12
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