Effectiveness

Darunavir/ritonavir is recommended as a preferred third agent for use in combination with tenofovir and emtricitabine in first-line treatment in British HIV Association and US treatment guidelines.

Darunavir was initially licensed for treatment-experienced people on the basis of the POWER 1 and 2, phase IIb study results. In these studies, two different doses of boosted darunavir were compared with the effects of other protease inhibitors in treatment-experienced people. After a 24-week analysis, 600mg darunavir and 100mg ritonavir was selected as the optimal dose and all participants in the darunavir/ritonavir arm used that dosage.

Use of darunavir was approved at a dose of darunavir 600mg/ritonavir 100mg.^{1 2} Originally, darunavir's use in the EU was limited to highly-treated adults who had failed more than one regimen containing a protease inhibitor. In 2008, its licensing was expanded to include any antiretroviral (ARV)-experienced person.

In 2008, the US Food and Drug Administration expanded the indication for darunavir to include its use as first-line therapy, dosed once daily. The protease inhibitor was also given full approval for twice-daily use in all people with previous ARV experience. This approval was based on data from the ARTEMIS study. 

In that study, results showed that people randomised to receive darunavir/ritonavir had a non-inferior virological response after 48 weeks as compared to those randomised to receive lopinavir/ritonavir (Kaletra). However, those who started treatment with a viral load over 100,000 copies/ml were significantly more likely to achieve a sustained undetectable viral load if they received darunavir/ritonavir.³

Darunavir was licensed in the US for use in treatment-naive people dosed as two 400mg tablets once daily with a 100mg boosting dose of ritonavir. In late 2008, once-daily dosing of boosted darunavir was approved in the US, dosed at darunavir 800mg/ritonavir 100mg, for a first-line regimen.

Darunavir/ritonavir has been compared with atazanavir/ritonavir, raltegravir and dolutegravir in two clinical trials in previously untreated people.

In the ACTG 5257 study people treated with raltegravir were significantly more likely to have undetectable viral load after 96 weeks when compared to atazanavir/ritonavir or darunavir/ritonavir, but also more likely to develop resistance after virological failure.⁴

In the FLAMINGO study a significantly higher proportion of people who received dolutegravir plus two nucleoside reverse transcriptase inhibitors (NRTIs) had an undetectable viral load after 96 weeks compared to darunavir/ritonavir (80% vs 68%). The difference between arms was most pronounced in participants with high baseline viral load (> 100,000 copies/ml) (82% vs 52% response through week 96) and in people taking the tenofovir/emtricitabine backbone (79% vs 64%). Virologic non-response to treatment (dolutegravir 8%; darunavir/ritonavir 12%) and non-response due to other reasons (dolutegravir 12%; darunavir/ritonavir 21%) occurred less frequently with dolutegravir.⁵

For ARV-experienced people, the TITAN study compared twice daily darunavir/ritonavir (600mg/100mg) with twice daily lopinavir/ritonavir capsules (at the previous 400mg/100mg formulation), plus an optimised background regimen selected by resistance testing.

After 48 weeks of treatment, intent-to-treat analysis showed that 77% of those randomised to receive darunavir had viral load below 400 copies/ml, compared with 68% of those randomised to receive lopinavir/ritonavir. This was statistically significant and darunavir/ritonavir was seen as having superiority over lopinavir/ritonavir in virologic suppression. A similar difference emerged when the proportion of people with viral load below 50 copies/ml at week 48 was compared.⁶ On the basis of this study, the drug was licensed for use in the EU for all ARV-experienced people.

Once-daily 800mg/100mg darunavir/ritonavir dosing is also suitable for some treatment-experienced people. The randomised, open-label ODIN trial found this once-daily dose to be as effective at suppressing viral load after 48 weeks as a 600mg twice-daily dose in treatment-experienced people who did not have resistance mutations to darunavir at the start of the trial. The once-daily dose was also less likely to cause lipid disturbances.⁷

The open-label GRACE study found that 600/100mg darunavir/ritonavir twice daily, plus optimised background therapy, was equally effective in women and in men after 48 weeks. There was little difference in side-effects, except that women were somewhat more likely to report nausea.⁸

A caution has been issued that 0.5% of people taking darunavir/ritonavir during its clinical development were diagnosed with drug-induced hepatitis. See the Side-effects section for more information on this topic.