Resistance

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

Resistance to indinavir develops within weeks if dosing is sub-optimal. However, resistance seems to take much longer to develop if treatment is begun with a highly effective regimen, using a full dose of indinavir in combination with other anti-HIV drugs, and viral load is rapidly suppressed to below the limit of detection.

A high level of resistance occurs after four or more mutations have emerged in the gene for the protease enzyme. Although the combinations of mutations that give rise to indinavir resistance have not been well established in trials, a recent study has shown that a combination of at least one ‘primary’ mutation plus varying numbers of ‘secondary’ mutations at codons can reduce the efficacy of ritonavir (Norvir)-boosted indinavir.¹ Primary protease mutations include:

• M46I/L/V.
• G48M/S/V.
• V82A/F/S/T.
• I84A/V.
• L90M.

Cross-resistance between the protease inhibitors can be a problem in treatment-experienced individuals. People who develop resistance to one protease inhibitor may be less likely to experience a strong or lasting response after switching to a different protease inhibitor. There is preliminary evidence that people who begin to develop resistance to indinavir may benefit from amprenavir (Agenerase), ritonavir-boosted lopinavir (Kaletra) or saquinavir (Invirase). People who experience treatment failure with indinavir may also benefit from adding low-dose ritonavir, which increases indinavir levels enough to overcome low-level resistance.

HIV that is resistant to saquinavir may not be resistant to indinavir, suggesting that indinavir can be used after saquinavir failure. In contrast, people who develop resistance to full-dose ritonavir are less likely to benefit from a switch to indinavir than those who have begun to show signs of viral rebound on saquinavir or nelfinavir (Viracept).