Zidovudine

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reduce the risk of HIV infection following the first single exposure to the virus.[13] More recently, AZT has been replaced by other antiretrovirals such as tenofovir to provide PEP.[14] Before tenofovir, a principal part of the clinical pathway for both pre-exposure prophylaxis and post-exposure treatment of mother-to-child transmission of HIV during pregnancy, labor, and delivery and has been proven to be integral to uninfected siblings' perinatal and neonatal development.[15][16] AZT has been shown to reduce this risk to 8% when given in a three-part regimen post-conception, delivery, and six weeks post-delivery. Consistent and proactive precautionary measures, such as the rigorous use of antiretroviral medications, cesarean section, face masks, heavy-duty rubber gloves, clinically segregated disposable diapers, and avoidance of mouth contact will further reduce child-attendant transmission of HIV to as little as 1–2%.[17][18][19]

During 1994 to 1999, AZT was the primary form of prevention of mother-to-child HIV transmission. AZT prophylaxis prevented more than 1000 parental and infant deaths from AIDS in the United States.[20] In the U.S. at that time, the accepted standard of care for HIV-positive mothers was known as the 076 regimen and involved five daily doses of AZT from the second trimester onwards, as well as AZT intravenously administered during labour.[21] As this treatment was lengthy and expensive, it was deemed unfeasible in the Global South, where mother-to-child transmission was a significant problem. A number of studies were initiated in the late 1990s that sought to test the efficacy of a shorter, simpler regimen for use in 'resource-poor' countries.[22] This AZT short course was an inferior standard of care and would have been considered malpractice if trialed in the US; however, it was nonetheless a treatment that would improve the care and survival of impoverished subjects.[22]

Antibacterial properties

Zidovudine also has antibacterial properties,[23] though not routinely used in clinical settings. It acts on bacteria with a mechanism of action still not fully explained. Promising results from in vitro and in vivo studies showed the efficacy of AZT also against multidrug-resistant gram-negative bacteria (including mcr-1 carrying and metallo-β-lactamase producing isolates), especially in combination with other active agents (e.g., fosfomycin, colistin, tigecycline).[24][25]

Viral resistance

Even at the highest doses that can be tolerated in patients, AZT is not potent enough to prevent all HIV replication and may only slow the replication of the virus and progression of the disease. Prolonged AZT treatment can lead to HIV developing resistance to AZT by mutation of its reverse transcriptase.[35][36] To slow the development of resistance, physicians generally recommend that AZT be given in combination with another reverse-transcriptase inhibitor and an antiretroviral from another group, such as a protease inhibitor, non-nucleoside reverse-transcriptase inhibitor, or integrase inhibitor; this type of therapy is known as HAART (Highly Active Anti Retroviral Therapy).

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]Jerome Horwitz of the Barbara Ann Karmanos Cancer Institute and Wayne State University School of Medicine synthesized AZT in 1964 under a US National Institutes of Health (NIH) grant.[51][52][53] Development was shelved after it proved biologically inert in mice.[51][54] In 1974, Wolfram Ostertag of the Max Planck Institute for Experimental Medicine in Göttingen, Germany, reported that AZT specifically targeted Friend virus (strain of murine leukemia virus).[40]

This report attracted little interest from other researchers as the Friend leukemia virus is a retrovirus, and at the time, there were no known human diseases caused by retroviruses.[55]

HIV/AIDS research

In 1983, researchers at the Institut Pasteur in Paris identified the retrovirus now known as the Human Immunodeficiency Virus (HIV) as the cause of acquired immunodeficiency syndrome (AIDS) in humans.[56][57] Shortly thereafter, Samuel Broder, Hiroaki Mitsuya, and Robert Yarchoan of the United States National Cancer Institute (NCI) initiated a program to develop therapies for HIV/AIDS.[58] Using a line of CD4+ T cells that they had made, they developed an assay to screen drugs for their ability to protect CD4+ T cells from being killed by HIV. To expedite the process of discovering a drug, the NCI researchers actively sought collaborations with pharmaceutical companies having access to libraries of compounds with potential antiviral activity.[59] This assay could simultaneously test both the anti-HIV effect of the compounds and their toxicity against infected T cells.

In June 1984, Burroughs-Wellcome virologist Marty St. Clair set up a program to discover drugs with the potential to inhibit HIV replication. Burroughs-Wellcome had expertise in nucleoside analogs and viral diseases, led by researchers including George Hitchings, Gertrude Elion, David Barry, Paul (Chip) McGuirt Jr., Philip Furman, Martha St. Clair, Janet Rideout, Sandra Lehrman and others. Their research efforts were focused in part on the viral enzyme reverse transcriptase. Reverse transcriptase is an enzyme that retroviruses, including HIV, use to replicate themselves. Secondary testing was performed in mouse cells infected with the retroviruses Friend virus or Harvey sarcoma virus, as the Wellcome group did not have a viable in-house HIV antiviral assay in place at that time, and these other retroviruses were believed to represent reasonable surrogates. AZT proved to be a remarkably potent inhibitor of both Friend virus and Harvey sarcoma virus, and a search of the company's records showed that it had demonstrated low toxicity when tested for its antibacterial activity in rats many years earlier. Based in part on these results, AZT was selected by nucleoside chemist Janet Rideout as one of 11 compounds to send to the NCI for testing in that organization's HIV antiviral assay.[55]

In February 1985, NCI scientists found that AZT had potent efficacy in vitro.[59][51] Several months later, a Phase I clinical trial of AZT was initiated at the NCI and Duke University.[60][61][62] The Phase I study was informed by prior clinical work involving suramin, another compound that had shown in vitro efficacy against HIV. The early clinical studies demonstrated that AZT was generally well tolerated in people with HIV infection and was associated with immunologic improvements, including increases in CD4+ lymphocyte counts and partial restoration of T cell function as assessed by delayed-type hypersensitivity skin testing. Participants also showed signs of clinical benefit such as weight gain in some advanced AIDS cases. In addition, these trials confirmed that anti-HIV concentrations demonstrated in vitro could be achieved in humans through systemic administration, and that AZT was capable of reaching the central nervous system.[62]

Patent filed and FDA approval

A double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome and found that AZT prolonged the lives of people with HIV.[63] This study was halted early due to ethical concerns of continuing to provide participants with a placebo in the face of such striking results.[64] Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee of the United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.[65] The FDA approved the drug for use against HIV, AIDS, and AIDS Related Complex (ARC, a now-obsolete medical term for pre-AIDS illness) on March 20, 1987.[66] The time between the first demonstration that AZT was active against HIV in the laboratory and its approval was 25 months. Criticism of the clinical trial and subsequent approval of AZT resurfaced in the early 2020s in a series of internet memes likely intended to discredit immunologist Dr. Anthony Fauci.[64]

AZT was subsequently approved unanimously for infants and children in 1990.[67] AZT was initially administered in significantly higher dosages than today, typically 400 mg every four hours, day and night, compared to modern dosage of 300 mg twice daily.[68]