Clinical

Triple drug antiviral combination synergistic against HIV

Last Updated: 2003-05-02 9:49:55 -0400 (Reuters Health)

By Will Boggs, MD

NEW YORK (Reuters Health) - The combination of didanosine (ddI), interferon-alfa (IFN-a), and ribavirin is highly synergistic in inhibiting HIV replication in vitro, according to a report in the May 2nd issue of AIDS.

"Interferon-alpha and ribavirin are currently being given to many co-infected patients for the treatment of hepatitis C virus (HCV), both with and without concomitant antiretroviral therapy," Dr. Marina Klein from McGill University Health Center in Montreal, Quebec, Canada told Reuters Health. "Our study highlights the fact that interferon-alpha and ribavirin may potentially greatly enhance the anti-HIV activity of such therapy in certain circumstances."

Because of the accepted use of IFN-a and ribavirin in treating HCV and the frequent occurrence of HCV and HIV coinfection, Dr. Klein and colleagues evaluated the anti-HCV drugs in combination with the antiretroviral drug ddI for potential synergy in inhibiting HIV-1 replication in vitro.

The combination of ribavirin with ddI decreased the average 50% inhibitory concentration (IC50) of ddI against HIV 10- to 20-fold and reduced the IC50 of ribavirin from greater than 50 (mol/L to 4.43 (mol/L without increasing cytotoxicity, the authors report.

Similarly, the report indicates, the combination of ddI and IFN-a reduced the IC50 of ddI by more than two-thirds (from 6.58 to 1.90 (mol/L) and the IC50 of IFN-a by more than 95% (from 6.85 to 0.174 (mol/L).

The activity against HIV was further enhanced when the three drugs were combined, the researchers note, and no increase in cytotoxicity was observed with the triple drug combination. Most of the synergy could be attributed to the addition of ribavirin.

"The choice of agents to be used concomitantly with IFN- and ribavirin is limited by overlapping toxicities and drug interactions," Dr. Klein said. "The use of medications such as interferon and ribavirin that are not traditionally considered 'anti-HIV agents' in combination therapy could represent an important strategy to permit the eradication of HCV prior to institution of potentially hepatotoxic NNRTI or protease inhibitor-based treatment, while allowing sufficient control of HIV to permit immune recovery necessary for HCV control."

Dr. Klein added: "We are currently investigating the combination of ddI/3TC/ribavirin/interferon for the treatment of co-infection in a small pilot study. Because of the recent FDA warning that co-administration of ddI and ribavirin are not recommended due to concerns over excess mitochondrial toxicity, we have decided to amend the trial and replace ddI with an alternative agent which may share similar synergistic properties with ribavirin but is safer."

"The concept however remains that simultaneous control of two viral infections may be possible using novel anti-viral regimens," Dr. Klein concluded.

AIDS 2003;17:1001-1008.