Medscape Awards in Infectious Diseases: Most Important Antiviral Agent

John G. Bartlett, MD

Disclosures

June 12, 2013

The Most Important Antiviral Agent

My pick, based on global importance of the target and the total impact of the drug: AZT.

HIV infection is generally considered the most important contemporary viral pathogen in terms of global numbers of infected individuals, continuing high transmission rates (7000 per day), a morbid natural history, near-certain death without treatment, and the pharmacologic challenge of HIV as a retrovirus that is inculcated into the host CD4 genome so that any treatment required an unprecedented mechanism of action.

AZT was discovered by Jerome Horwitz in 1964 as a potential drug for cancer, a nucleoside intended to reduce tumor growth. It did not work for cancer, so he put this agent, along with his related discoveries didanosine (DDI) and stavudine (D4T), on the shelf. He later described these as "a very interesting set of compounds that were waiting for the right disease"[7] (Figure 1).

Figure 1. A salt crystal of AZT, viewed under polarized light. Source: Wikipedia. http://en.wikipedia.org/wiki/Zidovudine

The mechanism of action of AZT against HIV is intracellular phosphorylation to AZT triphosphate, which acts as a competitive inhibitor for binding to HIV reverse transcriptase, leading to premature chain termination. These and others in the nucleoside class (DDI, D4T, 3TC, and ABC [abacavir]) are active against multiple retroviruses, including HIV-1, HIV-2 and HTLV-1. Thus, AZT opened the door to an important category of drugs with vast current global use.

Of greater importance, AZT was the first drug to demonstrate clinical benefit for HIV infection. Consequently, the drug had an enormous impact on the subsequent development of HIV drugs by countering the argument that treatment of retroviral infections was impossible, given the unique biology of the virus.

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