In clinical studies, darunavir is administered together with low-dose ritonavir (darunavir/ritonavir). Published results from one phase IIa clinical study and two phase IIb studies indicate that darunavir/ritonavir has potent antiviral activity in PI-experienced patients75–77
. In the 24-week dose-finding portion of two large, randomized and controlled 144-week phase IIb studies (POWER 1 [TMC114-C213] and POWER 2 [TMC114-C202]), patients were nucleoside reverse transcriptase inhibitor (NRTI)-, nonnucleoside reverse transcriptase inhibitor (NNRTI)- and PI-experienced, had at least one primary PI mutation (according to the IAS-USA guidelines) and had viral load ≥ 1000 copies/ml at screening76,77
. Both studies were of similar design. Patients were randomized to receive either investigator-selected PI(s) or one of four darunavir/ritonavir doses: 400/100 mg 1/d, 800/100 mg 1/d, 400/100 mg 2/d or 600/100 mg 2/d; all regimens were given in combination with an optimized background regimen (OBR; at least two NRTI with or without enfuvirtide). Patients were stratified by the number of primary PI mutations, by the use of enfuvirtide and by screening viral load. The primary endpoint was the proportion of patients with a decrease in viral load of ≥ 1 log10
HIV-RNA copies/ml at week 24. Secondary endpoints included the decrease in viral load from baseline, the proportion of patients with HIV-RNA < 50 copies/ml, and the mean change in CD4 cell count at week 24.
The baseline characteristics showed that patients in the POWER 2 study had somewhat more advanced disease (longer duration of infection, lower baseline CD4 and higher viral load), more patients had virus resistant to all commercially available PIs (71 vs. 63%) and a greater percentage of patients had three or more primary PI mutations (66 vs. 56%) than in the POWER 1 study77
. In both studies, darunavir/ritonavir plus OBR was shown to be significantly more effective than investigator-selected PI(s) plus OBR for both suppression of HIV-1 RNA and increase in CD4 cell count.
In the POWER 1 study, 77% of patients receiving darunavir/ritonavir 600/100 mg 2/d (the dose selected for further development in treatment-experienced patients) achieved at least a 1.0 log10
reduction in viral load relative to baseline, compared with only 25% of control patients (p < 0.001)76
. Similarly, significantly more darunavir/ritonavir patients had viral load < 50 copies/ml at week 24 compared with control patients (53 vs. 18%; p < 0.001). Increases in mean CD4 cell count were substantially greater at week 24 versus baseline for darunavir/ritonavir compared with the control group (124 vs. 20 cells/mm3
; p < 0.001).
Similar results were observed in the POWER 2 study, which recruited more advanced patients: significantly more patients on darunavir/ritonavir 600/100 mg 2/d achieved at least a 1.0 log10
reduction in viral load relative to baseline compared with control patients (62 vs. 14%; p < 0.001)77
. Patients on the recommended dose of darunavir/ritonavir were also more likely to achieve a viral load < 50 copies/ml than control patients (39 vs. 7%; p < 0.001). The mean increase in CD4 cell count at week 24 versus baseline was significantly greater for patients on darunavir/ritonavir 600/100 mg compared with control patients (59 vs. 12 cells/mm3
; p < 0.01).
At week 24, the overall mean changes versus baseline in log10
viral load (NC = F) for the darunavir/ritonavir 600/100 mg 2/d treatment groups of the POWER 1 and 2 studies were −2.03 and −1.71 copies/ml, respectively76,77
. In the control groups, the mean changes versus baseline in log10
viral load were −0.63 and −0.29 copies/ml, respectively76,77
. Importantly, the magnitude of the differences in change in viral load between the darunavir/ritonavir 600/100 mg 2/d groups and the control groups of the POWER 1 and 2 studies were comparable: a difference of 1.35 and 1.37 copies/ml, respectively76,77
Subgroup analyses demonstrated that the inclusion of a greater number of active ARV (including NRTI and enfuvirtide) in the OBR was associated with better virologic outcomes in all treatment groups. In the POWER 1 study, 63% of patients receiving darunavir/ritonavir 600/100 mg 2/d and using enfuvirtide for the first time achieved suppression < 50 copies/ml at week 24 compared to 56% of patients who did not receive enfuvirtide (for control: 22 and 19%, respectively)76
. In the POWER 2 study, this was 64 and 30% of patients, respectively (for control: 7 and 4%, respectively)77
. This apparent difference was likely related to the number of other viable agents in their OBR. On the recommended dose, the population evaluated in the POWER 1 study had a greater proportion of patients with one or more susceptible NRTI than POWER 2 (77 vs. 62%)76,77
. Taken together, these findings underscore the value of using at least two potent ARV agents in heavily treatment-experienced patients. Similar results were obtained with a comparable patient population receiving the darunavir/ritonavir 600/100 mg 2/d dose, in a nonrandomized integrated analysis of two trials (POWER 3 [TMC114-C215 and C208])78
The pooled POWER 1 and 2 48-week analysis showed darunavir/ritonavir provided durable efficacy in this highly treatment-experienced population79
. More recently, treatment with darunavir/ritonavir 600/100 mg 2/d was shown to be statistically non-inferior and superior to lopinavir/ritonavir 400/100 mg 2/d for the endpoint of viral load < 400 copies/ml in early treatment-experienced patients at 48 weeks in the phase III TITAN trial80
. Treatment with darunavir/ritonavir 800/100 mg 1/d in treatment-naive patients was also shown to be non-inferior to lopinavir/ritonavir 800/200 mg (either 1/d or 400/100 mg 2/d) for the endpoint of viral load < 50 copies/ml in the phase III ARTEMIS trial at 48 weeks, and was more effective in patients with baseline HIV-1 RNA above 100,000 copies/ml81
In terms of safety, darunavir showed no cytotoxicity at concentrations of up to 100 µM in in vitro studies51
. In patients, darunavir/ ritonavir has been shown to be well tolerated in a phase IIa clinical study and the phase IIb POWER 1 and POWER 2 controlled studies75–77
. In a combined analysis of all darunavir/ritonavir dose groups from POWER 1 and POWER 2, the most common adverse events (AE) (occurring in ≥10% of patients, regardless of severity and causality) were similar in darunavir/ritonavir-treated patients and in the control arms; in decreasing order of incidence, these were: diarrhea, headache, nausea, fatigue, nasopharyngitis, upper respiratory tract infection, insomnia, cough, herpes simplex, and pyrexia82
. The combined safety analysis revealed that there were more discontinuations in the control group (81% total: 67% for virologic failure, 5% for AEs) than in the darunavir/ritonavir groups (25% total: 12% for virologic failure, 8% for AEs) resulting in a shorter treatment duration for control patients. Finally, the safety results of the POWER 1 and POWER 2 studies showed no apparent relationship between darunavir dose and AE incidence, and no overall difference compared to PIs used in the control groups. The safety results of POWER 3 were similar to those of POWER 1 and POWER 278
. The pooled 48-week analysis of POWER 1 and 2 safety and tolerability results79
, along with the more recent 48-week data from the two phase III TITAN80
trials, confirmed the favourable tolerability of darunavir/ritonavir treatment.
The similarity between the POWER trials and the phase III RESIST trials (which evaluated tipranavir/r), in terms of study design, inclusion criteria, selection of control treatment and primary efficacy endpoint, formed the basis of a recent non-randomized comparison between the 24-week results of the studies83
. Although darunavir/r and tipranavir/r showed statistically significant benefits over the control treatments in the respective trials, the size of the treatment benefit over control PIs was found to be greater for darunavir/r than tipranavir/r in treatment-experienced patients83
. As certain differences exist in baseline characteristics in the two trials, including enfuvirtide use, hepatitis co-infection and advanced HIV infection, such a comparison may not allow for robust conclusions84,85
; however, in the absence of randomized comparative trials in treatment-experienced patients, this remains one of the only ways to compare antiviral efficacy83
. Both of these most recently approved PIs are considered to be effective in treatment-experienced patients, do not generally show signs of cross-resistance, and can be selected individually on the basis of their resistance profiles85