Drugs that inhibit hepatic glucuronidation, such as indomethacin, nordazepam, acetylsalicylic acid (aspirin) and trimethoprim decreased the elimination rate and increased the therapeutic strength of the medication. Today, side-effects are much less common with the use of lower doses of AZT. According to IARC, there is sufficient evidence in experimental animals for the carcinogenicity of zidovudine; it is possibly carcinogenic to humans (Group 2B). In 2009, the State of California added zidovudine to its list of chemicals "known to the state of California to cause cancer and other reproductive harm." 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. 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). Mechanism of action
AZT is a thymidine analogue. AZT works by selectively inhibiting HIVs reverse transcriptase, the enzyme that the virus uses to make a DNA copy of its RNA.
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 organizations HIV antiviral assay.In February 1985, the NCI scientists found that AZT had potent efficacy in vitro. Several months later, a phase 1 clinical trial of AZT at the NCI was initiated at the NCI and Duke University,. In doing this Phase I trial, they built on their experience in doing an earlier trial, with suramin, another drug that had shown effective anti-HIV activity in the laboratory. This initial trial of AZT proved that the drug could be safely administered to patients with HIV, that it increased their CD4 counts, restored T cell immunity as measured by skin testing, and that it showed strong evidence of clinical effectiveness, such as inducing weight gain in AIDS patients. It also showed that levels of AZT that worked in vitro could be injected into patients in serum and suppository form, and that the drug penetrated deeply only into infected brains. Patent filed and FDA approval
A rigorous double-blind, placebo-controlled randomized trial of AZT was subsequently conducted by Burroughs-Wellcome and proved that AZT safely prolongs the lives of people with HIV. Burroughs-Wellcome filed for a patent for AZT in 1985. The Anti-Infective Advisory Committee to United States Food and Drug Administration (FDA) voted ten to one to recommend the approval of AZT.