Darunavir was licensed for treatment-experienced patients on the basis of the POWER 1 and 2, phase IIb study results. In these studies, two different doses of boosted darunavir (DRV/r) were compared with the effects of other protease inhibitors in treatment-experienced patients. After a 24-week analysis, 600mg darunavir and 100mg ritonavir was selected as the optimal dose and all participants in the DRV/r arm used that dosage.
Participants took darunavir along with an optimised background regimen of two nucleoside reverse transcriptase inhibitors (NRTIs). About half of the patients in both arms also took T-20 (enfuvirtide, Fuzeon). In a pooled 48-week analysis:
- 61% of the patients randomised to the darunavir arm had a minimum 10-fold viral load decrease as compared to 15% in the comparator PI arm.
- 46% of the patients taking darunavir had viral loads <50 copies/ml, compared to 10% of the control patients.
- The mean increase in CD4 cell count was 102 cells/mm3 in the DRV/r arm and 19 cells/mm3 in the comparator arm.
- 62% of participants with 2 DRV-associated mutations who used T-20 for the first time achieved an undetectable load as compared to 40% who did not use T-20.
- 43% of participants with ≥3 DRV-associated mutations who used T-20 for the first time achieved undetectable load as compared to 14% who did not use T-20.
Use of darunavir was approved at a dose of DRV 600mg/RTV 100mg.1
2 Originally, darunavir's use in the EU was limited to highly-treated adult patients who had failed more than one regimen containing a protease inhibitor. In 2008, its licensing was expanded to include any antiretroviral-experienced person.
In 2008, the US FDA 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 patients with previous ARV experience. This approval was based on data from the ARTEMIS study.
In that study, results showed that patients randomised to receive DRV/r had a non-inferior virological response after 48 weeks as compared to those randomised to receive LPV/r (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 DRV/r. At 96-weeks, results showed the following:
- DRV/r dosed at 800/100mg once daily was non-inferior to LPV/r dosed at either 800mg/200mg once daily or 400mg/100 mg twice daily.
- 79% of patients in the DRV/r arm reached undetectable viral load (<50copies/ml) vs 71% in the LPV/r arm.
- In patients with a baseline viral load ≥100,000 copies/ml, 76% in the DRV/r arm reached undetectable viral load vs 63% in the LPV/r arm.
- In patients with a baseline viral load <100,000 copies/ml, 81% in the DRV/r arm reached undetectable viral load vs 75% in the LPV/r arm (not a significant difference).
- In patients with baseline CD4 cell count < 200 cells/mm3, 79% in the DRV/r arm reached an undetectable viral load (<50 copies/ml) vs 65% in the LPV/r.
- In patients with baseline CD4 cell count > 200 cells/mm3, 79% in the DRV/r arm reached an undetectable viral load (<50 copies/ml) vs 75% in the LPV/r (not a significant dfference).3
Darunavir was licensed in the US for use in treatment-naive patients 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 DRV 800mg/r 100mg, for a first-line regimen.
For ARV-experienced patients, the TITAN study compared twice daily darunavir/ritonavir (600/100mg) with twice daily lopinavir/ritonavir capsules (at the previous 400/100mg 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 lopinavir/ritonavir. This was statistically significant and DRV/r was seen as having superiority over LPV/r in virologic suppression. A similar difference emerged when the proportion of patients with viral load below 50 copies/ml at week 48 was compared.4 On the basis of this study, the drug was licensed for use in the EU for all ARV-experienced patients.
Subgroup analysis of the BENCHMRK study of the new integrase inhibitor raltegravir also showed that 90% of patients who received raltegravir with darunavir or enfuvirtide achieved a viral load below 400 copies/ml after 16 weeks, compared with 74% who received neither darunavir nor enfuvirtide (T-20).5
A small study has also found that ritonavir-boosted darunavir may be effective in patients with substantial treatment experience, including T-20 and tipranavir (Aptivus).6
that once-daily, 800mg/100mg DRV/r dosing could also be suitable for some treatment-experienced
patients. 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 patients 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 patients taking darunavir/ritonavir during its clinical development were diagnosed with drug-induced hepatitis. Please see the Side-effects section for more information on this topic.