As with all other anti-HIV drugs, strains of HIV that are resistant to zidovudine (AZT, Retrovir) may emerge after a period of treatment. The emergence of drug-resistant strains coincides with a fall in the effectiveness of the drug .

If zidovudine is taken as a single drug treatment, resistance emerges within a few months. A combination of three or more antiretroviral drugs that can suppress HIV to very low levels in the blood reduces the likelihood of drug resistance developing. Furthermore, using zidovudine in combination with lamivudine (3TC, Epivir) may make it more difficult for HIV to develop resistance to zidovudine.

Zidovudine resistance is particularly unwelcome, since certain resistance mutations appear to be associated with more rapid disease progression.1 However, a person who has zidovudine-resistant virus may continue taking zidovudine because the drug may still be effective against HIV in the brain. Zidovudine-resistant HIV is also less infectious than wild-type virus.2

The pattern of mutations caused by the thymidine analogues, including zidovudine and stavudine (d4T, Zerit), is well characterised, involving the accumulation of up to six mutations at codons 41, 67, 70, 210, 215 and 219 of reverse transcriptase. These are called thymidine analogue mutations (TAMs) and affect sensitivity to all licensed NRTIs. In general, the more mutations that are present, the greater the level of resistance to zidovudine, with the T215Y/F mutation being the most significant.

There is considerable cross-resistance amongst the nucleoside reverse transcriptase inhibitors (NRTIs). This means that once resistance to one NRTI has developed, other NRTIs may have less effect on HIV viral load.3 Zidovudine-resistant strains persist in the body long after a person stops taking zidovudine.

Cross-resistance to the majority of the available NRTIs can severely restrict future treatment options. It can be caused by TAMs, or by one of two other sets of mutations:

  • Mutations in reverse transcriptase at codons 62, 75, 77, 116 and 151.
  • A T69S mutation, plus the insertion of six amino acids at the same position.

There is evidence that people who take zidovudine as part of their first antiretroviral regimen have a better chance of viral suppression when they switch to a regimen containing stavudine, compared with people who start with stavudine and then switch to zidovudine. Conversely, HIV that is resistant to lamivudine may still be susceptible to zidovudine, while virus that is resistant to zidovudine may subsequently become sensitive to the drug again once lamivudine resistance has emerged. Although the application of these observations remains to be established in clinical trials, these findings suggest that zidovudine may be used successfully after failure of a lamivudine-containing regimen, even if zidovudine resistance has occurred in a previous drug combination.

A similar relationship has been observed between didanosine (ddI, Videx / VidexEC) and zidovudine. The L74V mutation, which is selected by didanosine, can re-sensitise HIV with TAMs to zidovudine. Zidovudine may therefore be a suitable option after failure of a didanosine-containing regimen, even if zidovudine resistance has previously occurred.4


  1. d'Aquila RT et al. Zidovudine resistance and HIV-1 disease progression during antiretroviral therapy. Ann Intern Med 122: 401-408, 1995
  2. Tremblay M et al. Short communication: zidovudine-resistant and -sensitive HIV-1 isolates from patients on drug therapy: in vitro studies evaluating level of replication-competent viruses and cytopathogenicity. AIDS 6: 1445-1449, 1992
  3. Mayers DL et al. Dideoxynucleoside resistance emerges with prolonged zidovudine monotherapy. Antimicrobial Agents Chemother 38: 307-314, 1994
  4. Miranda LR et al. The L74V mutation in human immunodeficiency virus type 1 reverse transcriptase counteracts enhanced excision of zidovudine monophosphate associated with thymidine analog resistance mutations. Antimicrob Agents Chemother 49: 2648-2656, 2005
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap

This content was checked for accuracy at the time it was written. It may have been superseded by more recent developments. NAM recommends checking whether this is the most current information when making decisions that may affect your health.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.