Sandra De Meyer

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.

TMC114, a novel human immunodeficiency virus type 1 protease inhibitor active against protease inhibitor-resistant viruses, including a broad range of clinical isolates

ABSTRACT The purpose of this study was to characterize the antiviral activity, cytotoxicity, and mechanism of action of TMC114, a novel human immunodeficiency virus type 1 (HIV-1) protease inhibitor (PI). TMC114 exhibited potent anti-HIV activity with a 50% effective concentration (EC50) of 1 to 5 nM and a 90% effective concentration of 2.7 to 13 nM. TMC114 exhibited no cytotoxicity at concentrations up to 100 μM (selectivity index, >20,000). All viruses in a panel of 19 recombinant clinical isolates carrying multiple protease mutations and demonstrating resistance to an average of five other PIs, were susceptible to TMC114, defined as a fold change in EC50 of <4. TMC114 was also effective against the majority of 1,501 PI-resistant recombinant viruses derived from recent clinical samples, with EC50s of <10 nM for 75% of the samples. In sequential passage experiments using HIV-1 LAI, two mutations (R41T and K70E) were selected. One selected virus showed a 10-fold reduction in susceptibility to TMC114, but <10-fold reductions in susceptibility to the current PIs (atazanavir was not assessed), except saquinavir. However, when the selected mutations were introduced into a laboratory strain by site-directed mutagenesis, they had no effect on susceptibility to TMC114 or other PIs. There was no evidence of antagonism between TMC114 and any currently available PIs or reverse transcriptase inhibitors. Combinations with ritonavir, nelfinavir, and amprenavir showed some evidence of synergy. These results suggest that TMC114 is a potential candidate for the treatment of both naïve and PI-experienced patients with HIV.

Hepatitis C Virus Variants with Decreased Sensitivity to Direct-Acting Antivirals (DAAs) Were Rarely Observed in DAA-Naive Patients prior to Treatment

ABSTRACT The prevalence of naturally occurring hepatitis C virus (HCV) variants that are less sensitive to direct-acting antiviral (DAA) inhibitors has not been fully characterized. We used population sequence analysis to assess the frequency of such variants in plasma samples from 3,447 DAA-naive patients with genotype 1 HCV. In general, HCV variants with lower-level resistance (3- to 25-fold increased 50% inhibitor concentration [IC50]) to telaprevir were observed as the dominant species in 0 to 3% of patients, depending on the specific variant, whereas higher-level resistant variants (>25-fold-increased IC50) were not observed. Specific variants resistant to NS5A inhibitors were predominant in up to 6% of patients. Most variants resistant to nucleo(s/t)ide active-site NS5B polymerase inhibitors were not observed, whereas variants resistant to non-nucleoside allosteric inhibitors were observed in up to 18% of patients. The presence of DAA-resistant variants in NS5A, NS5B, or NS3 (including telaprevir-resistant variants), in baseline samples of treatment-naive patients receiving a telaprevir-based regimen in phase 3 studies did not affect the sustained viral response (SVR). Treatment-naive patients with viral populations containing the telaprevir-resistant variants NS3 V36M, T54S, or R155K at baseline achieved a 74% SVR rate, whereas patients with no resistant variants detected prior to treatment achieved a 76% SVR rate. The effect of specific resistant variant frequency on response to various DAA treatments in different patient populations, including interferon nonresponders, should be further studied.

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.

Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96

BACKGROUND Long-term (96-week) efficacy and safety of the protease inhibitor (PI) darunavir coadministered with low-dose ritonavir (DRV/r) was evaluated in HIV type-1 (HIV-1)-infected patients with extensive prior treatment experience in the POWER 1, 2 and 3 trials. METHODS Patients with HIV-1 RNA>or=1,000 copies/ml and >or=1 primary PI mutation were randomized to receive either DRV/r 600/100 mg twice daily plus an optimized background regimen (OBR), or an investigator-selected control PI (CPI) plus OBR (POWER 3 was a DRV/r 600/100 mg twice daily single-arm study). The proportion of patients with HIV-1 RNA<50 copies/ml at week 96 was assessed (intent-to-treat [ITT], time-to-loss of virological response algorithm). RESULTS In total, 467 patients received DRV/r 600/100 mg twice daily; 124 patients received CPI(s). At week 96, 39% of DRV/r patients in POWER 1 and 2 (pooled analysis) versus 9% of CPI patients achieved HIV-1 RNA<50 copies/ml (ITT, time-to-loss of virological response algorithm; P<0.001). A similar proportion of DRV/r patients (42%) in POWER 3 achieved HIV-1 RNA<50 copies/ml at week 96. Mean absolute CD4(+) T-cell count increase for DRV/r at 96 weeks was 133 cells/mm(3) in POWER 1 and 2 and 103 cells/mm(3) in POWER 3. Grade 2-4 treatment-emergent adverse events at least possibly related to DRV/r (>or=2% incidence, excluding laboratory abnormalities) were diarrhoea (3%), vomiting (3%), nausea (2%) and headache (2%). CONCLUSIONS Treatment with DRV/r 600/100 mg twice daily was well tolerated and led to sustained virological and immunological responses in treatment-experienced HIV-1-infected patients over 96 weeks.

TMC114/ritonavir substitution for protease inhibitor(s) in a non-suppressive antiretroviral regimen : a 14-day proof-of-principle trial

Objective:To evaluate antiviral activity, tolerability, and safety of the protease inhibitor (PI) TMC114 boosted with low-dose ritonavir (RTV). Design:A randomized, open-label, controlled, phase IIA clinical trial in 15 sites in Europe with 50 HIV-1-infected patients who had taken multiple PIs. Methods:At entry, PIs in non-suppressive regimens were replaced with TMC114/RTV (300/100 or 600/100 mg twice daily, or 900/100 mg once daily) or left unchanged for 14 days. The time-averaged difference (DAVG) in HIV-1 RNA from baseline, change in HIV-1 RNA from baseline, proportions achieving plasma HIV-1 RNA < 400 copies/ml and ≥ 0.5 and ≥ 1.0 log10 copies/ml reductions in HIV-1 RNA, and safety were assessed. Results:DAVG responses in all TMC114/RTV groups (range, −0.56 to −0.81 log10 copies/ml) were significantly greater (P < 0.001) than in the controls (−0.03 log10 copies/ml). Median change at day 14 was −1.38 and +0.02 log10 copies/ml for all TMC114/RTV groups and the control group, respectively. A reduction of ≥ 0.5 and ≥ 1.0 log10 copies/ml was attained by 97% and 76% of patients, respectively, in all TMC114/RTV groups and by 25% and 17%, respectively, in the control group. HIV-1 RNA < 400 copies/ml at any time during treatment was achieved by 40% in the TMC114/RTV groups and 8% in the control group. Most common reported adverse events were gastrointestinal and central nervous system disorders (mild to moderate severity). No dose relationship was observed. Biochemical, haematological and electrocardiographic parameters showed no significant changes. Conclusions:TMC114/RTV demonstrated a potent antiretroviral effect over 14 days in multiple-PI–experienced patients and was generally well tolerated.

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.

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.

Week 96 efficacy, virology and safety of darunavir/r versus lopinavir/r in treatment-experienced patients in TITAN.

Long-term potent activity of antiretrovirals is essential for HIV-1-infected, treatment-experienced patients. TITAN (TMC114/r In Treatment-experienced pAtients Naive to lopinavir) compared Week-96 efficacy and safety of darunavir/ritonavir (DRV/r) versus lopinavir/ritonavir (LPV/r). Treatment-experienced, LPV-naive, HIV-1-infected patients were randomised to DRV/r 600/100 mg bid or LPV/r 400/100 mg bid plus optimised background regimen (≥ 2 NRTIs/NNRTIs). 595 patients were enrolled (mean baseline HIV-1 RNA: 4.30 log10 copies/mL; median CD4 count: 232 cells/mm3). At Week 96, more DRV/r than LPV/r patients achieved HIV-1 RNA < 400 copies/mL (66.8% versus 58.9% [intent-to-treat (ITT)/time-to-loss of virological response (TLOVR)], estimated difference 8.7%, 95% confidence interval [CI]: 0.7-16.7), demonstrating the primary endpoint of non-inferiority of DRV/r (p < 0.001); the difference in response was statistically significant (p = 0.034). For the secondary efficacy parameter (HIV-1 RNA < 50 copies/mL) at Week 96, response to DRV/r was 60.4% versus 55.2% for LPV/r (ITT-TLOVR), estimated difference 5.8%, 95% CI: -2.3-13.9. Virological failure (VF; HIV-1 RNA > 400 copies/mL) with DRV/r (13.8%) was nearly half that with LPV/r (25.6%). Discontinuations due to adverse events were 8.1% for both DRV/r and LPV/r. Treatment-related grade 2-4 diarrhoea was 8.1% (DRV/r) versus 15.2% (LPV/r). Increases in triglycerides and total cholesterol were less pronounced with DRV/r. At 96 weeks, noninferiority (HIV-1 RNA < 400 copies/mL) of DRV/r over LPV/r was maintained; the difference in response was statistically significant. VF rate and treatment-related grade 2-4 diarrhoea were lower with DRV/r versus LPV/r.