AZT

AZT, drug used to slow the progression of HIV infection and delay the development of AIDS. AZT belongs to a group of drugs known as nucleoside reverse transcriptase inhibitors (NRTIs). In 1987 AZT became the first of these drugs to be approved by the U.S. Food and Drug Administration for the purpose of prolonging the lives of AIDS patients.

Detectable increases in plasma levels of HIV RNA (ribonucleic acid) are used as the basis for initiation of AZT therapy. The ability of AZT to slow the progression of HIV infection and suppress viral load (the concentration of virus in the blood) also makes it particularly effective in preventing mother-to-child transmission of HIV during pregnancy.

Mechanism of action

HIV uses its own enzyme, reverse transcriptase, to replicate viral single-stranded RNA into proviral double-stranded DNA (viral DNA synthesized prior to integration into host DNA) after infecting human cells (primarily certain types of T cells and macrophages). This step is crucial because it allows the virus to integrate its genetic material into host cell DNA, where it hijacks replication machinery to produce new virus particles, thereby ensuring viral survival and propagation. AZT is only active against HIV when the virus is replicating into proviral DNA. This is because the active compound of AZT, known as zidovudine 5-triphosphate, has a high affinity (attraction) for reverse transcriptase.

Zidovudine 5-triphosphate is similar in structure to thymidine triphosphate, which is normally produced by cells and is one of several nucleoside compounds (structural units of nucleic acids) needed to synthesize DNA. However, zidovudine 5-triphosphate has a greater affinity for reverse transcriptase than thymidine triphosphate, and it contains a nitrogen group (an azide; N₃) in place of the usual nucleoside hydroxyl group (―OH). As a result, reverse transcriptase incorporates zidovudine 5-triphosphate into growing strands of HIV proviral DNA, and DNA synthesis and replication are terminated, since subsequent nucleosides cannot bind to the nitrogen group of zidovudine 5-triphosphate.

Side effects

Although AZT is selective for HIV reverse transcriptase, it does partially block the activity of certain human polymerase enzymes (enzymes that add free nucleotides to new strands of DNA), including a mitochondrial DNA polymerase. Muscle cells have very high numbers of mitochondria, and AZT therapy can lead to the damage of muscle tissues, including the heart. AZT also suppresses the production of red blood cells, neutrophils, and other cells in the bone marrow, causing symptoms such as fatigue, malaise, and anemia, and many patients taking AZT experience mild gastrointestinal intolerance, which may cause nausea and vomiting. Rare side effects of AZT include potentially life-threatening lactic acidosis (accumulation of lactic acid in body fluids) and hepatic steatosis (accumulation of fat in liver cells), which stem from dysfunctional glucose metabolism by mitochondria in the liver.

Resistance

While AZT is effective in inhibiting viral replication, HIV is capable of mutating and thus of developing resistance to the drug. As a result, it is often given, either orally or intravenously, in combination with at least two or three other drugs in order to overcome drug resistance. Patients receiving combination therapy with AZT or with other NRTIs are closely monitored to determine when the efficacy of the drugs decreases. Such monitoring is often done by periodic measurements of plasma HIV RNA concentrations.