Resistance

As with all other anti-HIV drugs, strains of HIV that are resistant to AZT (zidovudine, 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 AZT 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 AZT in combination with 3TC (lamivudine, Epivir) may make it more difficult for HIV to develop resistance to AZT.

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

The pattern of mutations are caused by the thymidine analogues, including AZT and d4T (stavudine, 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 AZT, 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] AZT-resistant strains persist in the body long after a person stops taking AZT.

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 AZT as part of their first antiretroviral regimen have a better chance of viral suppression when they switch to a regimen containing d4T, compared with people who start with d4T and then switch to AZT. Conversely, HIV that is resistant to 3TC may still be susceptible to AZT, while virus that is resistant to AZT may subsequently become sensitive to the drug again once 3TC resistance has emerged. Although the application of these observations remains to be established in clinical trials, these findings suggest that AZT may be used successfully after failure of a 3TC-containing regimen, even if AZT resistance has occurred in a previous drug combination.

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

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