Zidovudine (ZDV), also known as azidothymidine (AZT), was the first antiretroviral medication used to prevent and treat HIV/AIDS. It is generally recommended for use in combination with other antiretrovirals. It may be used to prevent mother-to-child spread during birth or after a needlestick injury or other potential exposure. It is sold both by itself and together as lamivudine/zidovudine and abacavir/lamivudine/zidovudine. It can be used by mouth or by slow injection into a vein.[5]
Common side effects include headaches, fever, and nausea.[5] Serious side effects include liver problems, muscle damage, and high blood lactate levels.[5] It is commonly used in pregnancy and appears to be safe for the fetus.[5] ZDV is of the nucleoside analog reverse-transcriptase inhibitor (NRTI) class.[5] It works by inhibiting the enzyme reverse transcriptase that HIV uses to make DNA and therefore decreases replication of the virus.[5]
Zidovudine was first described in 1964.[6] It was resynthesized from a public-domain formula by Burroughs Wellcome.[7] It was approved in the United States in 1987 and was the first treatment for HIV.[5][8] It is on the World Health Organization's List of Essential Medicines.[9] It is available as a generic medication.[5]
Medical uses
HIV treatment
AZT was usually dosed twice a day in combination with other antiretroviral therapies. This approach is referred to as Highly Active Antiretroviral Therapy (HAART) and is used to prevent the likelihood of HIV resistance.[10][11] As of 2019, the standard is a three-drug once-daily oral treatment that can include AZT.[12]
HIV prevention
AZT has been used for post-exposure prophylaxis (PEP) in combination with another antiretroviral drug called lamivudine. Together they work to substantially reduce the risk of HIV infection following the first single exposure to the virus.[13]
Side effects
Most common side effects include nausea, vomiting, acid reflux (heartburn), headache, cosmetic reduction in abdominal body fat, trouble sleeping, and loss of appetite. Less common side effects include faint discoloration of fingernails and toenails, mood elevation, occasional tingling or transient numbness of the hands or feet, and minor skin discoloration. Allergic reactions are rare.[26]
Early long-term higher-dose therapy with AZT was initially associated with side effects that sometimes limited therapy, including anemia, neutropenia, hepatotoxicity, cardiomyopathy, and myopathy. All of these conditions were generally found to be reversible upon reduction of AZT dosages. They have been attributed to several possible causes, including transient depletion of mitochondrial DNA, sensitivity of the γ-DNA polymerase in some cell mitochondria,[27] the depletion of thymidine triphosphate, oxidative stress, reduction of intracellular L -carnitine or apoptosis of the muscle cells.[28] Anemia due to AZT was successfully treated using erythropoetin
Mechanism of action
AZT is a thymidine analogue. AZT works by selectively inhibiting HIV's reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA. Reverse transcription is necessary for production of HIV's double-stranded DNA, which would be subsequently integrated into the genetic material of the infected cell (where it is called a provirus).[37]
Cellular enzymes convert AZT into the effective 5'-triphosphate form. Some studies have shown that terminating synthesis of HIV's DNA chains is the specific inhibitory mechanism.[38]
At very high doses, AZT's triphosphate form may also inhibit DNA polymerase used by human cells to undergo cell division, but regardless of dosage AZT has an approximately 100-fold greater affinity for HIV's reverse transcriptase.[39] The selectivity has been suggested to be due to the cell's ability to quickly repair its own DNA chain if it is disrupted by AZT during its formation, whereas the HIV virus lacks that ability.[40]
Chemistry
Enantiopure AZT crystallizes in the monoclinic space group P21. The primary intermolecular bonding motif is a hydrogen bonded dimeric ring formed from two N-H...O interactions.[45][46]
History
Initial cancer research
In the 1960s, the theory that most cancers were caused by environmental retroviruses gained clinical support and funding. It had recently become known, due to the work of Nobel laureates Howard Temin and David Baltimore,[47] that nearly all avian cancers were caused by bird retroviruses, but corresponding human retroviruses had not yet been found.
In parallel work, other compounds that successfully blocked the synthesis of nucleic acids had been proven to be both antibacterial, antiviral, and anticancer agents, the leading work being done at the laboratory of Nobel laureates George H. Hitchings and Gertrude Elion, leading to the development of the antitumor agent 6-mercaptopurine.[48]
Richard E. Beltz first synthesized AZT in 1961, but did not publish his research.[49][50]
Society and culture
Until 1991, 80% of the $420 million allocated to the National Institute of Health's AIDS Clinical Trials Group went toward studies of AZT. Aside from two similarly designed chemotherapies, ddI and ddC, from approval of AZT in 1987 until 1993, no other drugs against AIDS were approved, leading to criticism that research preoccupation with AZT and its close relatives, and the massive diverting of funds to such, had delayed the development of more efficacious drugs.[7] In 1991, the advocacy group Public Citizen filed a lawsuit claiming that the patents were invalid. Subsequently, Barr Laboratories and Novopharm Ltd. also challenged the patent, in part based on the assertion that NCI scientists Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan should have been named as inventors, and those two companies applied to the FDA to sell AZT as a generic drug. In response, Burroughs Wellcome Co. filed a lawsuit against the two companies. The United States Court of Appeals for the Federal Circuit ruled in 1992 in favor of Burroughs Wellcome, ruling that even though they had never tested it against HIV, they had conceived of it working before they sent it to the NCI scientists. This suit was appealed up to the Supreme Court of the US, but in 1996 the Court declined to formally review it.[69] The case, Burroughs Wellcome Co. v. Barr Laboratories, was a landmark in US law of inventorship.[70]
External links
References
- Retrovir 100mg Capsules – Summary of Product Characteristics (SmPC) (emc), December 14, 2018, retrieved January 23, 2021^
- Retrovir – zidovudine capsule Retrovir – zidovudine solution Retrovir – zidovudine injection, solution DailyMed, retrieved January 23, 2021^
- Active substance: Zidovudine