IAS: Virological failure rare in patients taking saquinavir / ritonavir

HIV-positive patients taking ritonavir (Norvir)-boosted saquinavir (Invirase) as part of their first antiretroviral regimen develop protease inhibitor resistance mutations very rarely. This finding resulted from a genetic analysis of patients enrolled in the Staccato trial, presented this week at the Third International AIDS Society Conference on HIV Pathogenesis and Treatment in Rio de Janeiro.

The study’s investigators argue that this supports the use of saquinavir / ritonavir in first-line therapy, since patients experiencing failure of saquinavir are likely to be able to benefit from other protease inhibitors in subsequent drug regimens.

The Staccato trial examined the anti-HIV activity of a combination of saquinavir / ritonavir at a dose of 1600 / 100mg once daily in combination with nucleoside or nucleotide reverse transcriptase inhibitors. It recruited 258 treatment-naïve Thai patients, with a median CD4 cell count of 269 cells/mm³ and viral load of 50,100 copies/ml at the start of the trial.

After a median follow-up of 29.6 weeks, only ten (4%) of the patients had experienced virological failure of their treatment, which was defined as two viral load measurements above 500 copies/ml after at least twelve weeks of treatment.

However, none of these ten patients had any major protease inhibitor resistance mutations, which would be expected to bring about a reduction in the activity of protease inhibitors by tenfold or more.

This is similar to the situation for other ritonavir-boosted protease inhibitors, such as lopinavir / ritonavir (Kaletra), in treatment-naïve patients. Although the mechanisms for drug resistance in the absence of major resistance mutations remain unclear, they may be linked to effects such as the body developing the ability to pump the drug out of its cells or alterations in the way the body breaks the drug down.

Seven of the patients experiencing virological failure had evidence of other minor protease inhibitor resistance mutations. However, analysis of the samples of the HIV taken from the patients at baseline revealed that in four of these patients, the mutations were present before therapy began.

Conversely, three patients had minor protease inhibitor resistance mutations before therapy, but these had disappeared by the time of virological failure, suggesting that they have a very weak influence on the risks of saquinavir failure.

The investigators measured blood levels of saquinavir in eight of the patients with virological failure. Five of these had blood levels that were above 100ng/ml, the minimum level necessary for the drug to be active. In the three patients with inadequate drug levels, there was no common pattern of resistance mutations.

Consequently, the researchers argue that low blood levels of saquinavir are not linked to the development of protease inhibitor resistance mutations.

They conclude, “these results support the use of saquinavir / ritonavir in first-line therapy and indicate that in these patients virological failure following saquinavir / ritonavir treatment occurs with relatively low frequency and may not compromise future treatment options.”