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
Community Consensus Statement on Access to HIV Treatment and its Use for Prevention

Together, we can make it happen

We can end HIV soon if people have equal access to HIV drugs as treatment and as PrEP, and have free choice over whether to take them.

Launched today, the Community Consensus Statement is a basic set of principles aimed at making sure that happens.

The Community Consensus Statement is a joint initiative of AVAC, EATG, MSMGF, GNP+, HIV i-Base, the International HIV/AIDS Alliance, ITPC and NAM/aidsmap
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