Resistance to darunavir related to pre-existing mutations

Pre-existing resistance may reduce the efficacy of the protease inhibitor darunavir, a study published in the September 12^th edition of AIDS suggests. French investigators found that both baseline protease inhibitor resistance and darunavir treatment which did not fully suppress viral load were associated with the emergence of mutations conferring resistance to darunavir. The authors suggest guidelines to reduce development of darunavir resistance in people who have previously taken protease inhibitors.

Mutations that cause resistance to one protease inhibitor are important since they also often cause resistance to other protease inhibitors. But little is known about such resistance in people taking darunavir (Prezista), boosted with ritonavir. The potent effect of the darunavir/ritonavir combination has been confirmed in patients failing other protease inhibitor combinations in the POWER 1, 2, and 3 studies. These studies also showed the effectiveness of darunavir in patients who were moderately pre-treated and in those who have never received antiretrovirals. From these studies, eleven mutations have been identified that are linked with reduced effect of darunavir in the laboratory. In these studies, the proportion of patients experiencing substantial viral load reductions when darunavir was introduced was inversely related to the number of pre-existing mutations related to darunavir.

A team led by Constance Delaugerre at Hopital Saint-Louis in Paris studied 25 highly protease-inhibitor experienced patients who had treatment failure. Mutations were analysed at baseline and then at virological failure (viral load above 200 copies/ml) after at least three months of a darunavir/ritonavir combination (600/100 mg twice daily). Baseline median HIV load was 100,000 copies/ml and the number of total-protease inhibitor, major-protease inhibitor, and darunavir-associated resistance mutations was 13, four, and three, respectively. New darunavir-associated resistance mutations developed in 72% of patients. The time between starting darunavir and virological failure was a median of 34 weeks.

The risk of darunavir resistance was highly related to the number of pre-existing mutations and the length of time of ongoing viral replication (i.e. when viral load was not fully suppressed). The researchers note that many patients had mutations associated with prior treatment with fosamprenavir (Telzir) or lopinavir (Kaletra).

They suggest that in highly protease-inhibitor experienced patients, initiation of a single boosted protease inhibitor, darunavir/ritonavir, may be insufficient. They recommend that clinicians should consider treatment with darunavir only in those people with two or less pre-existing mutations. They also suggest that if viral replication persists, darunavir should not be used for more than 24 weeks, since this is likely to encourage further mutations.

Pointing to recent studies which have suggested that boosted tipranavir may be the only protease inhibitor with partial susceptibility after darunavir failure, they also recommend that the the efficacy of this strategy needs to be investigated.