Tony Vangeneugden

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48

Background:The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. Methods:Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. Results:Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/μl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval −0.1–11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/μl) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2–4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. Conclusion:DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1.

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 ≥ 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/μl. 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/μl; 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.

Resistance profile of darunavir: combined 24-week results from the POWER trials.

The resistance profile of darunavir (TMC114) in treatment-experienced patients was explored using pooled week 24 data from POWER 1, 2, and 3 at the recommended dose of darunavir with low-dose ritonavir (darunavir/r, 600/100 mg bid, N = 458). Baseline darunavir fold change in EC(50) was a strong predictor of virological response at week 24. Preliminary phenotypic clinical cut-offs of 10 and 40 were established. Virological response to darunavir/r was maintained in the presence at baseline of a high number of IAS-USA PI resistance-associated mutations (IAS-USA PI RAMS); a diminished response occurred with >or=14. Eleven protease mutations associated with diminished darunavir/r virological response were identified (V11I, V32I, L33F, I47V, I50V, I54L/M, G73S, L76V, I84V, and L89V). These darunavir resistance-associated mutations (DRV RAMS) occurred in the presence of a high number of IAS-USA PI RAMS. Virological response was diminished with three or more DRV RAMS in the background of a high number of IAS-USA PI RAMS. Incremental numbers of DRV RAMS were more predictive of outcome than were IAS-USA PI RAMS. Mutations developing during darunavir/r virological failure (V32I, L33F, I47V, I54L, and L89V) were also featured in the DRV RAMS list. Site-directed mutants carrying these five mutations, or any one of these mutations either alone or together with one or two IAS-USA PI RAMS, showed no reduced darunavir susceptibility, suggesting that a high number of additional background mutations is required for darunavir resistance. In this population of treatment-experienced patients, darunavir/r demonstrated significantly greater efficacy than investigator-selected control PIs of trials POWER 1 and 2, regardless of baseline viral genotype or phenotype, while exhibiting a high genetic barrier to the development of resistance.

Safety and efficacy of darunavir (TMC114) with low-dose ritonavir in treatment-experienced patients : 24-week results of POWER 3

Objective:In POWER 1 and POWER 2, darunavir (TMC114) with low-dose ritonavir (darunavir/r) demonstrated greater efficacy versus control protease inhibitors (PIs). To examine the efficacy and safety of the selected darunavir/r dose further, additional patients were analyzed. Methods:Treatment-experienced HIV-1-infected patients received darunavir/r at a dose of 600/100 mg twice daily plus an optimized background regimen. The primary intent-to-treat analysis was the proportion of patients with an HIV-1 RNA reduction ≥1 log10 at week 24. Results:Three hundred twenty-seven patients were treated; the baseline mean HIV-1 RNA was 4.6 log10 copies/mL, and the median CD4 count was 115 cells/mm3 (median primary PI mutations = 3, PI resistance-associated mutations = 9). Two hundred forty-six patients reached week 24 by the cutoff date and were included in the efficacy analysis: 65% and 40% achieved HIV-1 RNA reductions of ≥1 log10 and <50 copies/mL, respectively, at week 24. The mean CD4 count increase was 80 cells/mm3. The most common adverse events (AEs) were diarrhea (14%), nasopharyngitis (11%), and nausea (10%). Nine (3%) patients discontinued treatment because of AEs or HIV-1-related events. Six treatment-unrelated deaths (2%) were reported. Conclusions:These results corroborate POWER 1 and POWER 2. In this larger set of treatment-experienced patients, darunavir/r at a dose of 600/100 mg twice daily provided substantial virologic and immunologic responses and was generally safe and well tolerated.

Liarozole-a novel treatment approach for advanced prostate cancer : Results of a large randomized trial versus cyproterone acetate

OBJECTIVESnTo compare the efficacy of oral liarozole, the first retinoic acid metabolism-blocking agent (RAMBA) to be developed as differentiation therapy for human solid tumors, with that of cyproterone acetate (CPA), an antiandrogen for the treatment of metastatic prostate cancer. Liarozole promotes differentiation of cancer cells by increasing the intratumoral levels of retinoic acid.nnnMETHODSnA total of 321 patients with metastatic prostate cancer in relapse after first-line endocrine therapy entered a Phase III international multicenter study (recruitment from February 1992 to August 1994) comparing liarozole (300 mg two times daily) with CPA (100 mg two times daily).nnnRESULTSnAccounting for differences in baseline prognostic factors, the adjusted hazard ratio for survival was 0.74 in favor of liarozole (P = 0.039), indicating a 26% lower risk of death than in patients treated with CPA. Median crude (unadjusted) survival time was the same in the liarozole group as in the CPA group (10.3 months). More patients showed a PSA response (at least 50% reduction in PSA from baseline) when treated with liarozole (20%) than with CPA (4%) (P < 0.001). Prostate-specific antigen (PSA) responders had a median survival benefit of 10 months over nonresponders, irrespective of treatment (hazard ratio 0.43; P = 0.0018). PSA response was apparent within 3 months in approximately 90% of patients who responded. Pain improved more in the liarozole group than in the CPA group (P = 0.03). PSA responders had lower median pain scores than nonresponders (1.7 versus 2.5) and better quality of life (median Functional Living Index-Cancer score 108 versus 98) at end point, ie, treatment discontinuation, as well as throughout the treatment period. Among the most frequently occurring adverse events in the liarozole group were dry skin (51% of patients), pruritus (25%), rash (16%), nail disorders (16%), and hair loss (15%). These adverse events were generally mild to moderate in severity and did not affect the overall quality of life score. There were no detectable effects of either treatment on vital signs such as blood pressure, heart rate, electrocardiogram, and body weight.nnnCONCLUSIONSnLiarozole is superior to CPA in terms of PSA response, PSA progression, and survival, and is capable of maintaining patients quality of life. The observed adverse events were mild to moderate in nature. These results show that liarozole is a possible treatment option after first-line endocrine therapy has failed.

Characterization of virologic failure patients on darunavir/ritonavir in treatment-experienced patients.

Objective:Characterization of resistance development in virologic failure patients on the protease inhibitor darunavir administered with low-dose ritonavir (DRV/r) in the 48-week analysis of TMC114/r In Treatment-experienced pAtients Naive to lopinavir (TITAN). Design:TITAN is a randomized, controlled, open-label, phase III, noninferiority trial comparing the efficacy and safety of DRV/r with that of lopinavir/ritonavir (LPV/r) in HIV-1-infected, treatment-experienced, LPV-naive patients. The primary endpoint was the proportion of patients with HIV-1 RNA less than 400 copies/ml at week 48. Methods:Patients received DRV/r 600/100 mg twice daily (n = 298) or LPV/r 400/100 mg twice daily (n = 297), and an optimized background regimen. Patients who lost or never achieved HIV-1 RNA less than 400 copies/ml after week 16 were considered virologic failure patients. Genotyping and phenotyping were performed. Results:The virologic failure rate in the DRV/r arm (10%, n = 31) was lower than in the LPV/r arm (22%, n = 65). Furthermore, fewer virologic failure patients in the DRV/r arm than in the LPV/r arm developed primary protease inhibitor mutations (6 vs. 20) or nucleoside reverse transcriptase inhibitor resistance-associated mutations (4 vs. 15). In addition, fewer virologic failure patients on DRV/r than on LPV/r lost susceptibility to the protease inhibitor (3 vs. 13) or nucleoside reverse transcriptase inhibitor(s) (3 vs. 14) used in the treatment regimen or to other protease inhibitors. Most DRV/r-treated virologic failure patients retained susceptibility to all protease inhibitors. Conclusion:In treatment-experienced, LPV-naive patients, the overall virologic failure rate in the DRV/r arm was low and was associated with limited resistance development. These findings showed that the use of DRV/r in earlier lines of treatment was less likely to lead to cross-resistance to other protease inhibitors compared with LPV/r.

Pharmacokinetics of darunavir/ritonavir and rifabutin coadministered in HIV-negative healthy volunteers.

ABSTRACT The drug-drug interaction between rifabutin (RFB) and darunavir/ritonavir (DRV/r) was examined in a randomized, three-way crossover study of HIV-negative healthy volunteers who received DRV/r 600/100 mg twice a day (BID) (treatment A), RFB 300 mg once a day (QD) (treatment B), and DRV/r 600/100 mg BID plus RFB 150 mg every other day (QOD) (treatment C). The sequence of treatments was randomized, and each treatment period lasted 12 days. Full pharmacokinetic profiles were determined for DRV, ritonavir, and RFB and its active metabolite, 25-O-desacetylrifabutin (desRFB), on day 13. The DRV and ritonavir areas under the plasma concentration-time curve from zero to 12 h (AUC12h) increased by 57% and 66%, respectively, in the presence of RFB. The RFB exposure was comparable between treatment with RFB QD alone (treatment B) and treatment with DRV/r plus RFB QOD (treatment C); however, based on least-square means ratios, the minimum plasma concentration (Cmin) increased by 64% and the maximum plasma concentration (Cmax) decreased by 28%, respectively. The exposure (AUC within the dosage interval and at steady state [AUCτ]) to desRFB was considerably increased (by 881%) following treatment with DRV/r/RFB. The exposure to the parent drug plus the metabolite increased 1.6-fold in the presence of DRV/r. Adverse events (AEs) were more commonly reported during combined treatment (83% versus 44% for RFB and 28% for DRV/r); similarly, grade 3-4 AEs occurred in 17% versus 11% and 0%, respectively, of volunteers. Eighteen of 27 volunteers (66.7%) prematurely discontinued the trial; all volunteers discontinuing for safety reasons (n = 9) did so during RFB treatment phases. These results suggest that DRV/r may be coadministered with RFB with a dose adjustment of RFB to 150 mg QOD and increased monitoring for RFB-related AEs. Based on the overall safety profile of DRV/r, no dose adjustment of DRV/r is considered to be warranted. Given the safety profile seen with the combination of RFB with a boosted protease inhibitor in this and other studies, it is not recommended to conduct further studies with this combination in healthy volunteers.

Efficacy of once-daily darunavir/ritonavir 800/100 mg in HIV-infected, treatment-experienced patients with no baseline resistance-associated mutations to darunavir.

Objective:The objective of this study was to examine the potential of once-daily dosing with darunavir/ritonavir 800/100 mg in a HIV-infected, treatment-experienced patient population with no baseline darunavir resistance-associated mutations (RAMs). Methods:Patients in the randomized controlled POWER 1 and 2 trials were treatment experienced, with ≥1 International AIDS Society-USA primary protease inhibitor (PI) mutation. The virological and immunological responses in patients with no baseline darunavir RAMs receiving darunavir/r 800/100 mg once daily (n = 23), darunavir/r 600/100 mg twice daily (n = 29), or currently available PI(s) (n = 28) plus an optimized background regimen were compared. Results:The proportion of patients achieving HIV RNA <50 copies per milliliter at week 24 was 67% for the group receiving darunavir/r 800/100 mg once daily and 62% for the group receiving darunavir/r 600/100 mg twice daily (P = 0.774); both were superior to control PI(s) (11%; P < 0.0001). Mean HIV RNA change from baseline was 22.39 and 22.35 log10 copies per milliliter for the group receiving darunavir/r 800/100 mg once daily and for the group receiving 600/100 mg twice daily, respectively (P = 0.895); mean CD4 increases were 88 and 111 cells per milliliter, respectively (P = 0.526). Conclusions:Treatment-experienced, HIV-infected patients with no baseline darunavir RAMs achieved similar high responses with darunavir/r 800/100 mg once daily and 600/100 mg twice daily. This suggests that once-daily darunavir/r 800/100 mg therapy, which has been shown effective in treatment-naive patients and is currently being studied in treatment-experienced patients, shows potential in patients with no darunavir RAMs.

Pharmacokinetic Interaction Between Darunavir and Saquinavir in Hiv-negative Volunteers

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n = 14, panel 1; n = 12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.

Validation of a longitudinally measured surrogate marker for a time-to-event endpoint

The objective of this paper is to extend the surrogate endpoint validation methodology proposed by Buyse et al. (2000) to the case of a longitudinally measured surrogate marker when the endpoint of interest is time to some key clinical event. A joint model for longitudinal and event time data is required. To this end, the model formulation of Henderson et al. (2000) is adopted. The methodology is applied to a set of two randomized clinical trials in advanced prostate cancer to evaluate the usefulness of prostate-specific antigen (PSA) level as a surrogate for survival.