Report 4 -  4th International Workshop on HIV Drug Resistance and Treatment Strategies
Written by Jules Levin
Sitges, Spain, June 12-16 2000

Mycophenolic Acid + Abacavir+DDI+Amprenavir+Ritonavir Salvage Therapy

Addendum: Information in the abstract in Sitges has been corrected: In the Mycophenolic Acid (MA) regimen, DDI was dosed 400 miligrams QD: No benefit to MA was proven: MPA levels were too low - below IC90 for lymphocyte proliferation: Future MA dosing plans appear to be 500 mg bid.

Mycophenolic Acid (MA) is a selective inhibitor of de novo synthesis of guanosine monophosphate and lymphocyte proliferation, exhibits synergy in vitro with guanosine analalugue NRTI abacavir and DDI against wild-type and NRTI resistant HIV. The hypothesis is similar to combining hydroxyurea with ddI.

JJ Coull and co-investigators, including Randy Lanier at Glaxo Wellcome and David Margolis, performed a 6-week open-label pilot study in 7 late stage AIDS patients who had failed 10 or mor ARTs („4 NRTIs, „2 protease inhibitors,„1 NNRTI). Genotypes prior to enrollment show mean 3.3 NRTI, 4.6 PI, and 2.1 NNRTI mutations. Subjects received 300 mg abacavir twice daily, 250 mg MA twice daily, 400 mg ddI 4 times daily, 600 mg amprenavir twice daily and ritonavir 200 mg twice daily. One patient without K103N (EFV resistance mutation) also received 600 mg efavirenz 4 times daily. Therapy was well tolerated, reportedly in this group with symptomatic AIDS. No significant decline in lymphocyte or other blood count was observed. Mean CD4s were 30 at entry, 43 at 4 weeks of therapy, and 46 at 16 weeks of therapy. Mean HIV RNA was 5.3 log 200,000 copies/ml at entry, 3.6 log (3980 copies/ml) at 4 weeks, and 4.8 log (63,000 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 to 2.6 log of HIV RNA during the first 4 weeks of therapy. HIV RNA declined 2.15 log during the first month in 4 subjects deemed adherent. Mean CD4 in these subjects rose from 21 to 47 although mean HIV RNA decreased from 5.5 log (316,000 copies/ml) to 4.5 log (31,600 copies/ml).  

Minimal changes in HIV reverse transcriptase or protease genotypic mutations were noted at viral nadir (lowest point of viral load) and following viral rebound. Phenotypic testing and limited PK studies are in progress. Five patients continue to receive MA. As MA may induce apoptosis (cell death) in lymohocytes (CD4s, CD3 cells were analyzed for markers of apoptosis and activation. Annexin V and CD69 staining declined 50% at week 2. Three to 4-fold decreases in these markers continued in 4 of 5 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 CD4s. The use of low dose MA appears to be well toerated in this advanced group. MA may have contributed to the transient antiviral effect or the modest immunological benefit observed in this group with resistant HIV.

It seems to me that the affect of MA in this study is difficult or impossible to ferret out. The population studied is very advanced and may not be the best place to conduct a pilot study of this nature. The ACTG is considering a few studies with MA but is also having trouble agreeing on a study design that will yield the answers we need.