Past treatment with amprenavir/fosamprenavir associated with presence of resistance that can reduce susceptibility to darunavir

Resistance mutations reducing susceptibility to the boosted protease inhibitor darunavir (Prezista) are rare in both treatment-naïve and treatment-experienced patients, according to a study published in the October 15^th edition of theJournal of Infectious Diseases.

The study showed that prior use of amprenavir/fosamprenavir was associated with an increased risk of having a mutation associated with darunavir resistance. However, the investigators calculated that even if a patient had up to three mutations conferring resistance to darunavir, they still had a 50% chance of achieving an undetectable viral load after six months of treatment with the drug.

Darunavir, boosted by ritonavir, was recently licensed for use by heavily treatment-experienced patients. The POWER studies showed that such patients who took boosted darunavir with optimised background therapy were significantly more likely to achieve an undetectable viral load than patients who took optimised background therapy with a comparator boosted protease inhibitor.

Darunavir has been shown to achieve good results in patients who have previously been treated with protease inhibitors and have resistance to this class of drugs. However, a subanalysis of the POWER studies identified eleven resistance mutations that reduce the effectiveness of darunavir.

No studies have looked at the prevalence of these resistance mutations, or their risk factors. Therefore investigators in the United States conducted an analysis to see how often the mutations occur in two populations: a cohort of patients receiving their HIV care at 16 Kaiser-Permanente Medical Care Program clinics in Northern California and in the Stamford HIV Drug Resistance Database.

The clinic population included 1,847 patients of whom 1,175 had received a protease inhibitor. The database included 11,697 patients, of whom 2,744 had received a protease inhibitor.

The eleven mutations that confer resistance to darunavir were extremely uncommon in treatment-naïve patients. The mutations rarely had a prevalence of greater than 0.5% in any of eight major HIV subtypes examined. The V11I mutation did, however, occur with a frequency of between 0.6 – 2.3% in patients infected with the CRF01_AE, CRF02_AE, D and G subtypes.

As expected, the eleven darunavir-associated resistance mutations occurred more frequently in treatment -experienced patients. Of the clinic populations, 30% had at least one of the resistance mutations, with 4% of patients having between three and six. In the database patients, darunavir resistance mutations were found in 24% of patients, with 1% having between three and six of the mutations present.

Analysis was then undertaken to see if a relationship between past antiretroviral use and the presence of darunavir-associated resistance could be established. In both the clinic and database populations, the number of protease inhibitors previously taken had an independent positive association with the presence of mutations conferring resistance to darunavir (p 10). Previous treatment with amprenavir/fosamprenavir was also positively associated with the presence of one or more of the eleven mutations (p 16).

A further 16 mutations were also identified by the researchers that might reduce susceptibility to darunavir.

“Our results show that 96% of PI-treated persons in a…clinic population and 99% of PI-treated persons listed on a database have fewer than three darunavir-associated mutations and would therefore be expected to have a favourable response to darunavir, with an [approximately] 50% chance of achieving a plasma HIV-1 RNA level below 50 copies/ml by week 24”, comment the investigators.

They note the relationship between previous amprenavir/fosamprenavir use and the presence of darunavir-associated resistance mutations. They believe that this is because amprenavir/fosamprenavir and darunavir have a similar molecular structure.