Effectiveness

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

It appears 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.   

References

  1. Clotet B et al. Efficacy and safety of darunavir-ritonavir at week 48 in treatment-experienced patients with HIV-1 infection in POWER 1 and 2: a pooled subgroup analysis of data from two randomised trials. Lancet 369: 1169-1178, 2007
  2. Lazzarin A et al. TMC114 provides durable viral load suppression in treatment-experienced patients: POWER 1 and 2 combined 48 week analysis. 16th International AIDS Conference, Toronto, abstract TuAb0104, 2006
  3. Ortiz R et al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1 infected patients at week 48. AIDS 22(12): 1389-1397, 2008
  4. Madruga JV et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. Lancet 370: 49-58, 2007
  5. Steigbigel RT et al. Raltegravir with optimized background therapy for resistant HIV-1 infection. N Engl J Med359(4): 339-54, 2008
  6. Poveda E et al. Successful rescue therapy with darunavir (TMC114) in HIV-infected patients who have failed several ritonavir-boosted protease inhibitors. AIDS 20: 1558-1560, 2006
  7. Cahn P et al. Efficacy and safety at 48 weeks of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-positive patients with no darunavir resistance-associated mutations: the ODIN Trial. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 57, San Francisco, 2010
  8. Currier J et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med, 153: 349-57, 2010