Zidovudine was first described in 1964.It was approved in the United States in 1987 and was the first treatment for HIV.
It is on the World Health Organization’s (WHO) list of Essential Medicines, the safest and most effective medicines needed in a health system. It is available as a generic medication.
Zidovudine: It is athymidine analogue (azidothymidine, AZT), the prototype Nucleoside Reverse Transcriptase Inhibitors (NRTIs). After phosphorylation in the host cell – zidovudine triphosphate selectively inhibits viral reverse transcriptase in preference to cellular DNA polymerase.
On the template of single-stranded RNA genome of HIV, a double-stranded DNA copy is produced by viral reverse transcriptase. This pro-viral DNA translocates to the nucleus and is integrated with chromosomal DNA of the host cell (by viral integrase enzyme) which then starts transcribing viral genomic RNA as well as viral mRNA.
Under the direction of viral mRNA, viral regulatory and structural proteins are produced in the form of a polyprotein. Finally, viral particles are assembled and matured after fractionation of the polyprotein by viral protease. Zidovudine thus prevents infection of new cells by HIV, but has no effect on pro-viral DNA that has already integrated into the host chromosomes.
Zidovudine itself gets incorporated into the pro-viral DNA and terminates chain elongation. Resistance to AZT occurs by point mutations which alter reverse transcriptase enzyme. In the past, when AZT was used alone,> 50% patients became nonresponsive to AZT within 1-2 years therapy due to growth of resistant mutants.
Toxicity is mainly due to partial inhibition of cellular mitochondrial DNA polymerase gamma which has higher affinity for zidovudine triphosphate than chromosomal DNA polymerase. Anemia and neutropenia are the most important and dose-related adverse effects.
Nausea, anorexia, abdominal pain, headache, insomnia and mylgiaare common at the start of therapy, but diminish leter. Myopathy, pigmentation of nails, lactic acidocis, hepatomegaly, convulsions and encephalopathy are infrequent.
Paracetamol increases AZT toxicity, probably by competing for glucuronidation. Azole antifangals also inhibit AZT metabolism.
Other nephrotoxic and myelosuppressive drugs and probenecid enhance toxicity. Stavudine and zidovudine exhibit mutual antagonism by competing for the same activation pathway.
Medicinal uses of Zidovudine:
Zidovudine is used in HIV infected patients only in combination with at least 2 other ARV drugs. It is one of the two optional NRTIs used by National AIDS Control programme for its first line triple drug ARV regimen.
Its efficacy as monotherapy in AIDS was confirmed in the past. HIV-RNA titer is reduced to undetectable levels and CD4 count increases progressively. Immune status is improved and opportunistic infections become less common.
There is a sense of well-being and patients gain weight. AZT also reduces neurological manifestations of AIDS and new Kaposi’s lesions do not appear. Mortality among AIDS patients is reduced. However, beneficial effects are limited from few months to a couple of years after which progressively non-responsiveness develops.
AZT, along with two other ARV drugs is the standard choice for post-exposure prophylaxis of HIV, as well as for mother to offspring transmission.
|First-line antiretroviral regimens
1. Lamivudine+Zidovudine+ Efavirenz