Azodicarbonamide (ADA) is a zinc finger inhibitor. ADA is being developed by a Belgian company, Hubriphar, in collaboration with the Rega Institute, Leuven.

HIVs zinc fingers are chains of amino acids found in HIVs nucleocapsid, a core viral protein. They are involved in binding and packaging viral RNA into new virions budding from an infected cell, and may also play a role in the process of reverse transcription. Experiments in which HIVs zinc fingers have been deleted have shown that viruses without zinc fingers are unable to infect new cells, and that any new virus particles that they produce do not incorporate the viral RNA and are thus non-infectious and dysfunctional.

ADA is a chemical product used in the food industry (to make buns spongy). Its cost is minimum, and the pharmaceutical industry is reluctant to develop as a drug a product that is well known for its low manufacturing cost. Patents and protections may be more difficult to defend as well. For this reason, the Belgian company is charge of its development can only dedicate its own resources to investigate its role.

The main difficulty consists of the assessment of ADA activity: it does not act directly on the production of new virus, therefore viral load is not the marker of choice to assess whether or not if it works. The protective effect on CD4 cells is only partial (ADA can not prevent cell to cell infection), therefore it may be difficult to show any impact on the CD4 on the short term.

Dr Frank Goebel of Munich's Ludwig-Maximilians-Universitat showed that ADA treatment in a group of 15 individuals with advanced HIV disease and virological failure on current HAART was associated with a significant viral load reduction when added to failing therapy.

An initial open label phase escalated the dosage monthly, from 1g tid to 3g tid over three months.

The phase I/II study was not specifically designed to test efficacy, and treated a very small number of patients, but a clear relationship between introduction of ADA treatment, withdrawal of treatment, suppression and subsequent rebound of viral load was demonstrated, despite failing background therapy. Declines of 0.5 log to 1.2 log and corresponding rebounds were observed after starting and withdrawing treatment in three of five individuals who received ADA in a subsequent open label phase.

CD4 cell count improvements were also noted in the open label phase of the study. CD4 counts increased by an average of 120 cells after three months.

A number of drawbacks have been identified with this drug:

• Nephrolithiasis: three discontinuations due to renal pain or high levels of creatinine, all caused by the breakdown of ADA into biurea

• Dose related glucose intolerance was observed (only two patients had elevated glucose levels at baseline, but fasting glucose increased significantly in all patients by month three of ADA treatment, and declined after ADA was withdrawn). ADA may interfere with the formation of insulin.

• ADA needs to be re-formulated to improve absorption, so that lower doses may be given, thereby reducing the risk of some of these side effects

References

Goebel FD et al. Phase I/II dose escalation and randomized withdrawal study with add-on azodicarbonamide in patients failing on current antiretroviral therapy. AIDS 15: 33-45, 2000.