- Purpose
- Typical Antiviral
AZT
Twenty years ago, an AIDS diagnosis was equivalent to a death sentence. The introduction of the first AIDS drug, AZT, in 1987 offered patients hope for the first time. A flurry of drug development followed, and although no cure has emerged, AIDS is now considered a treatable disease. Now the backbone of most combination therapies, AZT remains one of the most prescribed AIDS drugs.
AIDS, which stands for acquired immunodeficiency syndrome, is caused by infection with human immunodeficiency virus. HIV is spread from person to person during unprotected sex, through use of contaminated needles, through transfusion of contaminated blood, or from mother to child during birth. The virus eventually destroys the body's ability to fight off infections and certain cancers by disabling immune system cells. Without immune protection, AIDS patients often succumb to bacterial or viral infections that would simply sicken healthy people.
Although it's now thought to have been around much longer, AIDS emerged as a global health threat in the early 1980s. For years, doctors watched helplessly as those infected died of this then-mysterious disease. Then, in 1983, French and American teams independently fingered HIV as the cause of AIDS. Incapable of replicating itself, HIV cleverly tricks the cell it infects into doing the job: The virus first converts its RNA genome into DNA and then inserts this DNA version of its genome into the cell's genome. As a consequence, the cell unwittingly replicates the virus.
Scientists at the National Institutes of Health's National Cancer Institute quickly set about testing candidate molecules for those that might block replication of HIV in cell culture. By early 1985, Samuel Broder and Hiroaki Mitsuya had demonstrated that AZT, a molecule first synthesized in 1964 by chemist Jerome P. Horwitz of the Michigan Cancer Foundation, prevented HIV from multiplying in cultured human cells.
AZT is an azido analog of thymidine, one of the four building blocks that make up DNA. After being activated by phosphorylation in vivo, AZT inhibits HIV replication by blocking a critical HIV enzyme called reverse transcriptase. This enzyme uses the virus's RNA genome as a template to build a DNA version that can be inserted into the host's genome. Reverse transcriptase incorporates AZT into the growing DNA chain in place of thymine. But because AZT has a 39 azido group instead of a 39 hydroxyl group, it can't make the necessary phosphate bond with the next nucleotide. This terminates the synthesis of the DNA copy of the virus's RNA genome, preventing integration into the host and blocking viral replication.
Clinical trials of AZT's efficacy in late-stage AIDS patients were sufficiently promising to cause the Food & Drug Administration to approve AZT in record time. The agency approved AZT for use against AIDS in early 1987, and Burroughs Wellcome (now GlaxoSmithKline) began marketing the drug under the trade name Retrovir.
The approval of AZT inspired a flurry of interest among drugmakers. Other reverse transcriptase inhibitors soon hit the market, followed by drugs that inhibit HIV protease enzymes required for host cell invasion. Combining AZT with another reverse transcriptase inhibitor and a protease inhibitor proved far superior to AZT alone, and AZT-based combination therapy soon turned AIDS from a death sentence into a chronic disease. Today, AZT remains the backbone of many of the most commonly prescribed AIDS cocktails. Such AZT-containing cocktails are also used to dramatically reduce the chance of mother-to-child transmission of HIV.
Although AZT's initial approval was met with widespread enthusiasm, controversy over its pricing wasn't far behind. Initially, the drug was staggeringly expensive--a year's supply cost around $10,000, and patients were faced with taking the drug (and suffering its side effects) for the rest of their lives. AIDS activists demonized Burroughs Wellcome for making AZT unaffordable, particularly for those in the developing world, where the AIDS crisis was growing increasingly dire. In response to growing public outcry and stiff competition from cheap generic versions of AZT-based therapies, GlaxoSmithKline eventually began offering its AZT-based therapies to poor nations at significant discounts. Still, critics charge, AZT-based therapies remain too expensive for most of the estimated 39 million people who now live with HIV worldwide.—
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