August 09, 2006; Updated
October 08, 2015|
|Susa Coffey, MD|
| 1. ||Katlama
T; the POWER 1 study group.|
Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS. 2007 Feb;21(4):395-402
[PubMed ID: 17301557]
BACKGROUND: The ongoing phase IIb POWER 1 (TMC114-C213) trial is designed to assess efficacy and safety of the protease inhibitor (PI) TMC114 (darunavir) in treatment-experienced HIV-1-infected patients. DESIGN: This randomized, partially blinded, 24-week dose-finding study compared efficacy and safety of four doses of TMC114 plus low-dose ritonavir (TMC114/r) with investigator-selected control PI(s) (CPI[s]). METHODS: Patients with one or more primary PI mutation and HIV RNA > 1000 copies/ml received optimized background therapy, plus TMC114/r 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily or 600/100 mg twice daily, or CPI(s). The primary endpoint (intent-to-treat) compared proportions of patients achieving viral load reduction >or= 1.0 log10 copies/ml from baseline. RESULTS: In total, 318 patients were treated. Baseline mean viral load was 4.48 log10 copies/ml; median CD4 cell count was 179 cells/microl. In the CPI arm 62% of patients discontinued (virological failure: 54%); 10% of TMC114/r patients discontinued. More TMC114/r (69-77%) than CPI patients (25%) reached the primary endpoint (P < 0.001); 43-53% of TMC114/r patients and 18% of the CPI arm achieved viral load < 50 copies/ml (P < 0.001). TMC114/r demonstrated greater mean CD4 cell count increases versus CPI(s) (68-124 versus 20 cells/microl; P < 0.05). TMC114/r 600/100 mg twice daily demonstrated the highest virological and immunological responses. Adverse event incidence was similar between treatments; headache and diarrhoea were more common with CPI(s). CONCLUSIONS: TMC114/r demonstrated statistically higher 24-week virological response rates and CD4 cell count increases than CPI(s). TMC114/r 600/100 mg twice daily has received regulatory approval in treatment-experienced patients.
| 2. ||Haubrich
M, van Baelen
E; POWER 2 Study Group.|
Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS. 2007 Mar;21(6):F11-8
[PubMed ID: 17413685]
BACKGROUND: Agents for the treatment of HIV-1-infected patients with resistance to current antiretroviral (ART) drugs are needed. METHODS: TMC114-C202 was a randomized, partially blinded, dose-finding study in treatment-experienced HIV-1-infected patients with one or more primary protease inhibitor (PI) mutations and HIV-1 RNA > 1000 copies/ml. Patients were randomized to receive one of four TMC114 doses given with ritonavir (TMC114/r) or investigator-selected control PI drug(s) (CPI); all received an optimized background regimen. The primary intent-to-treat analysis compared the proportion of patients achieving a >or= 1 log10 copies/ml HIV-1 RNA reduction at week 24 between the treatment arms using the time-to-loss of virological response algorithm. RESULTS: For 278 patients at baseline, mean HIV-1 RNA was 4.7 log10 copies/ml, median CD4 cell count was 106 cells/mul; HIV-1 isolates had a median of three primary PI mutations and a median fold change in lopinavir susceptibility of 80. Discontinuation rates were 23% for TMC114/r versus 64% for CPI. More patients in each TMC114/r dose group achieved >or= 1.0 log10 copies/ml reduction in HIV-1 RNA than in the CPI group (45-62% versus 14%; P <or= 0.003): patients taking TMC114/r twice daily had the greatest responses. HIV-1 RNA was < 50 copies/ml in 18-39% of TMC114/r patients versus 7% CPI (P < 0.001 for highest dose). Mean CD4 cell count increased by 59-75 versus 12 cells/mul (TMC114/r versus CPI: P <or= 0.005). Overall adverse event rates were similar in both arms, without significant differences among TMC114/r groups. CONCLUSIONS: TMC114/r treatment resulted in greater virological and immunological responses in ART-experienced patients compared with CPI at 24 weeks.
| 6. ||Clotet
E; POWER 1 and 2 study groups.|
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. 2007 Apr;369(9568):1169-78
[PubMed ID: 17416261]
BACKGROUND: The continuing, randomised, multinational, phase IIB POWER 1 and 2 studies aim to evaluate efficacy and safety of darunavir in combination with low-dose ritonavir in treatment-experienced HIV-1-infected patients. We did a pooled subgroup analysis to update results at week 48 for patients receiving the recommended dose of darunavir-ritonavir compared with those receiving other protease inhibitors (PIs). METHODS: After 24-week dose-finding phases and primary efficacy analyses, patients randomised to receive darunavir-ritonavir were given 600/100 mg twice daily, and patients receiving control PIs continued on assigned treatment into the longer-term, open-label phase; all patients continued on optimised background regimen. We assessed patients who had reached week 48 or discontinued earlier at the time of analysis; for the darunavir-ritonavir group, only patients who received 600/100 mg twice daily from baseline were included. Analyses were intention-to-treat. The POWER 2 study (TMC114-C202) is registered with ClinicalTrials.gov (NCT00071097). FINDINGS: At week 48, 67 of 110 (61%) darunavir-ritonavir patients compared with 18 of 120 (15%) of control PI patients had viral load reductions of 1 log10 copies per mL or greater from baseline (primary endpoint; difference in response rates 46%, 95% CI 35%-57%, p<0.0001). Based on a logistic regression model including stratification factors (baseline number of primary PI mutations, use of enfuvirtide, baseline viral load) and study as covariates, the difference in response was 50% (odds ratio 11.72, 95% CI 5.75-23.89). In the darunavir-ritonavir group, rates of adverse events were mostly lower than or similar to those in the control group when corrected for treatment exposure. No unexpected safety concerns were identified. INTERPRETATION: Efficacy responses with darunavir-ritonavir 600/100 mg twice daily plus optimised background regimen were greater than those with control PI and were sustained to at least week 48, with favourable safety and tolerability in treatment-experienced patients. This regimen could expand the treatment options available for such patients.
| 8. ||Madruga
E, de Béthune
F, De Pauw
S; TITAN study group.|
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. 2007 Jul;370(9581):49-58
[PubMed ID: 17617272]
BACKGROUND: The protease inhibitor darunavir has been shown to be efficacious in highly treatment-experienced patients with HIV infection, but needs to be assessed in patients with a broader range of treatment experience. We did a randomised, controlled, phase III trial (TITAN) to compare 48-week efficacy and safety of darunavir-ritonavir with that of lopinavir-ritonavir in treatment-experienced, lopinavir-naive patients. METHODS: Patients received optimised background regimen plus non-blinded treatment with darunavir-ritonavir 600/100 mg twice daily or lopinavir-ritonavir 400/100 mg twice daily. The primary endpoint was non-inferiority (95% CI lower limit for the difference in treatment response -12% or greater) for HIV RNA of less than 400 copies per mL in plasma at week 48 (per-protocol analysis). TITAN (TMC114-C214) is registered with ClinicalTrials.gov, number NCT00110877. FINDINGS: Of 595 patients randomised and treated, 187 (31%) were protease inhibitor naive; 476 of 582 (82%) were susceptible to four or more protease inhibitors. At week 48, significantly more darunavir-ritonavir than lopinavir-ritonavir patients had HIV RNA of less than 400 copies per mL (77% [220 of 286] vs 68% [199 of 293]; estimated difference 9%, 95% CI 2-16). Fewer virological failures treated with darunavir-ritonavir than with lopinavir-ritonavir developed primary protease inhibitor mutations (21% [n=6] vs 36% [n=20]) and nucleoside analogue-associated mutations (14% [n=4] vs 27% [n=15]). Safety data were generally similar between the groups; grade 3 or 4 adverse events occurred in 80 (27%) darunavir-ritonavir and 89 (30%) lopinavir-ritonavir patients. INTERPRETATION: In lopinavir-naive, treatment-experienced patients, darunavir-ritonavir was non-inferior to lopinavir-ritonavir treatment in terms of our virological endpoint, and should therefore be considered as a treatment option for this population.
|10. ||Darunavir [package insert]. East Bridgewater, NJ: Tibotec Therapeutics.|