Boosted NRTIs may overcome resistance and toxicity

Nucleoside analogues remain the backbone of anti-HIV treatment, but concerns over nucleoside analogue treatment have grown in the past few years,increasingly focussing on the impact of this class of drugs on mitochondria, small bodies within cells which generate energy. Nucleoside analogues have been shown to damage the DNA of mitochondria to varying degrees, and in the search for new drugs of this class, the avoidance of mitochondrial toxicity will be a key requirement in the selection and licensing of new drugs.

Mitochondrial toxicities include peripheral neuropathy, pancreatitis, muscle wasting and lactic acidosis. Peripheral fat wasting has also been suggested as a mitochondrial toxicity, although this remains a controversial view.

Many of those who need alternatives to the drugs most toxic to mitochondria are also those with extensive nucleoside analogue resistance, in whom mutants with resistance to all the NRTIs have emerged.

At last week's Fifth International Workshop on HIV Drug Resistance, Triangle Pharmacueticals presented data on a new strategy of boosting an NRTI with low mitochondrial toxicity in order to overcome multi-NRTI resistance, using mycophenolic acid.

Mycophenolic acid is a compound which inhibits the creation of guanosine nucleotides. It is used in organ transplantation. Its brand name is Cellcept. There is a competition between nucleoside analogues and guanosine nucleotides (the cellular ones) on the active site of reverse transcriptase, and depletion of the cellular pool facilitates the action of RT inhibitors.

Guanosine nucleotide competitors are abacavir (Ziagen) and amdoxovir (former DAPD). Triangle Pharmaceuticals presented test tube data on the synergistic effect of amdoxovir combined with mycophenolic acid and ribavirin, which is also an inhibitor of guanosine nucleotides. The active form of DAPD is a dioxolane guanine triphosphate, DXG-TP.

The effect is cell line dependent. In MT2 cells, the effective concentration of DXG is decreased by one log (10 fold more potent). In PBMCs, the virus replication is totally inhibited.

More interestingly, HIV-1 isolates harboring multi-nucleoside resistance conferring mutations are inhibited at much lower concentrations of DAPD when combined with mycophenolic acid as compared to those exposed to DAPD alone.

Furthermore, the combination of mycophenolic acid or ribavirin with DAPD seemed to exert very little negative effect on mitochondrial DNA.

The same results were found by Margolis et al. from Dallas using abacavir in vitro and in vivo in five patients treated with 500mg twice daily of mycophenolate mofetil.. After 3 to 6 weeks, HIV1 RNA declined by 1.05 log following addition of mycophenolate to existing abacavir treatment or escalation of the mycophenoltae dose from 250mg to 500mg, with a clear dose response effect. Therapy was well tolerated in all cases.

Thus, such combinations could enhance new NRTI anti-HIV activity. The possible toxicity warrants further study to eliminate the risk of severe toxicity, as was seen with hydroxyurea.