Frank Tomaka

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

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.

Final 192‐week efficacy and safety of once‐daily darunavir/ritonavir compared with lopinavir/ritonavir in HIV‐1‐infected treatment‐naïve patients in the ARTEMIS trial

This paper presents the final analysis of once‐daily darunavir/ritonavir (DRV/r) vs. lopinavir/ritonavir (LPV/r) in treatment‐naïve HIV‐1‐infected adults.

Week 48 analysis of once-daily vs. twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients

Objective:ODIN (Once-daily Darunavir In treatment-experieNced patients) was a phase III, 48-week, open-label study comparing once-daily vs. twice-daily darunavir/ritonavir (DRV/r) in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Methods:Patients with no DRV RAMs and receiving stable HAART for at least 12 weeks were stratified by HIV-1 RNA (≤ or > 50 000 copies/ml) and randomized to once-daily DRV/r 800/100 mg or twice-daily DRV/r 600/100 mg and an optimized background regimen (≥2 nucleoside reverse transcriptase inhibitors). Primary objective was to demonstrate noninferiority of once-daily vs. twice-daily DRV/r in confirmed virologic response (HIV-1 RNA < 50 copies/ml) at week 48. Results:Five hundred and ninety patients received once-daily (n = 294) or twice-daily (n = 296) DRV/r. Mean baseline HIV-1 RNA was 4.16 log10 copies/ml; median CD4 cell count was 228 cells/μl; and 53.9% had previously used at least one protease inhibitor. At week 48, 72.1% of once-daily and 70.9% of twice-daily patients achieved HIV-1 RNA less than 50 copies/ml (intent-to-treat/time-to-loss of virologic response). The difference in response between once-daily and twice-daily arms was 1.2% (95% confidence interval –6.1 to 8.5%; P < 0.001), establishing noninferiority of once-daily DRV/r versus twice-daily DRV/r. Median CD4 cell count increase was 100 (once-daily) and 94 cells/μl (twice-daily). Virologic failure rate was low and similar for both arms; only one patient (once-daily arm) developed primary protease inhibitor mutations. Once-daily DRV/r had a lower incidence of grade 2–4 triglyceride increases (5.2 vs. 11.0%, P < 0.05). Conclusion:Once-daily DRV/r 800/100 mg was noninferior in virologic response to twice-daily DRV/r 600/100 mg at 48 weeks in treatment-experienced patients with no DRV RAMs, and with a more favorable lipid profile. These findings support use of once-daily DRV/r in this population.

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.

Effects of ritonavir-boosted darunavir vs. ritonavir- boosted atazanavir on lipid and glucose parameters in HIV-negative, healthy volunteers

Darunavir (TMC114) is a new HIV protease inhibitor (PI).

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.

Pharmacokinetic Interactions Between Darunavir/Ritonavir and Opioid Maintenance Therapy Using Methadone or Buprenorphine/Naloxone

271 U substance abuse is a common comorbidity among human immunodeficiency virus (HIV)–infected patients and can result in poor HIV treatment outcomes. The most effective treatment for opioid dependence is opioid maintenance therapy because it reduces opioid craving and helps to prevent the use of illicit drugs. Two of the most common maintenance therapies are methadone (METH) and, more recently, buprenorphine/naloxone (BUP/ NLX). Methadone is a synthetic narcotic analgesic that exists as Rand S-isomers. Only the R-enantiomer is biologically active, acting as an agonist at the opioid μ and δ receptors. Buprenorphine is a partial opioid receptor agonist with excellent sublingual resorption, whereas NLX is an opioid antagonist with very low sublingual resorption. The combination of these 2 agents provides an effective maintenance pharmacotherapy for opioid dependence when taken subligually, with an efficacy that is generally similar to that of METH. Interactions between antiretroviral (ARV) medications and opioid agonist maintenance therapies are of particular importance given the high prevalence of HIV infection among intravenous drug users. Several ARV agents have been shown to have pharmacologic interactions of potential clinical significance. For example, a substantial and clinically relevant decrease in METH concentrations was observed when METH was coadministered with the combination of the ARV lopinavir and low-dose ritonavir (LPV/r). Darunavir (DRV) is an HIV type 1 (HIV-1) protease inhibitor (PI) that is boosted with low-dose RTV (DRV/r) and has proven efficacy and safety in treatmentexperienced and treatment-naïve HIV-1-infected patients. DRV/r in combination with other ARVs is approved in the United States, European Union, and other countries for the treatment of HIV infection in adult and pediatric patients (6-18 years old). Pharmacokinetic drug–drug interactions between DRV/r and METH and between DRV/r and BUP/NLX may be expected based on their hepatic metabolism, because all of these drugs are metabolized by cytochrome P450 (CYP) 3A4. Methadone is primarily metabolized to an inactive metabolite, 2-ethylidene1,5-dimethyl-3,3-diphenylpyrrolidene, and the main (active) metabolite of BUP is norbuprenorphine (norBUP). Ritonavir (RTV) and DRV are inhibitors of CYP3A4 metabolism, with RTV being the more potent of the 2 inhibitors. Additionally, the isoenzyme CYP2B6 has a key role in METH clearance, and this enzyme is induced by RTV. Thus, DRV/r could potentially affect METH and BUP metabolism.

Effect of ritonavir-boosted tipranavir or darunavir on the steady-state pharmacokinetics of elvitegravir.

Objective:Elvitegravir (EVG) is in phase 3 development in combination with ritonavir (RTV)-boosted protease inhibitors in treatment-experienced, HIV-infected patients. Two studies evaluated pharmacokinetic (PK) interactions among EVG and RTV-boosted tipranavir (TPV/r) or darunavir (DRV/r). Methods:Healthy volunteers received EVG/r alone (study 1: 200/100 mg once daily; study 2: 125/100 mg once daily), TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) alone, and EVG (200 or 125 mg as applicable) added to TPV/r (500/200 mg twice daily) or DRV/r (600/100 mg twice daily) in a randomized crossover design, with assessment of steady-state PK for EVG, TPV, DRV, and RTV. Safety was assessed by clinical monitoring. Studies were powered to conclude lack of an interaction if the 90% confidence interval for the geometric mean ratios of the AUCtau and Cmax for EVG, TPV, and DRV were within predefined no-effect boundaries. Trough concentrations were also assessed. Results:No subjects discontinued for adverse events during treatment with EVG/r alone. On coadministration, AUCtau and Cmax of EVG and TPV and EVG and DRV were within prespecified no-effect boundaries versus treatment alone; trough concentrations were also not substantially altered. Conclusions:The PK of EVG and TPV or DRV were not altered after coadministration of EVG with TPV/r or DRV/r. EVG PK was similar with varied RTV doses of 100 mg once daily, 100 mg twice daily, or 200 mg twice daily. EVG can be added to TPV/r or DRV/r regimens without dose adjustment.

Pharmacokinetics of Multiple-Dose Darunavir in Combination with Low-Dose Ritonavir in Individuals with Mild-to-Moderate Hepatic Impairment

Background and ObjectiveThe pharmacokinetics of some HIV protease inhibitors are altered in patients with hepatic impairment. The TMC114-C134 study assessed the pharmacokinetics and safety of darunavir/ritonavir 600 mg/100 mg twice daily in HIV-negative subjects with hepatic impairment (defined according to Child-Pugh classification A [mild] or B [moderate]) compared with matched, HIV-negative, healthy subjects.MethodsAll subjects received darunavir/ritonavir 600 mg/100 mg twice daily for 6 days with a morning dose on day 7. Pharmacokinetic profiles were obtained up to 72 hours post-dose for darunavir and 12 hours post-dose for ritonavir on day 7. Safety and tolerability were also assessed.ResultsDarunavir pharmacokinetics in subjects with mild (n= 8) and moderate (n = 8) hepatic impairment were comparable to those in matched healthy control subjects (n= 16). In those with mild hepatic impairment, the least square mean ratios relative to healthy subjects for darunavir exposure (the area under the plasma concentration-time curve from 0 to 12 hours) and for maximum and minimum plasma concentrations were 0.94 (90% CI 0.75, 1.17), 0.88 (90% CI 0.73, 1.07) and 0.83 (90% CI 0.63, 1.10), respectively. In those with moderate hepatic impairment, these values were 1.20 (90%CI 0.90,1.60), 1.22 (90% CI 0.95,1.56) and 1.27 (90% CI 0.87, 1.85), respectively. Ritonavir pharmacokinetics were comparable between healthy subjects and those with mild hepatic impairment, but mean exposure was 50% higher in subjects with moderate hepatic impairment. Darunavir/ritonavir was generally well tolerated, regardless of hepatic impairment. All adverse events were grade 1–2 in severity, except for a grade 3 increase in alanine aminotransferase reported in one subject with mild hepatic impairment. No adverse events led to discontinuation.ConclusionsThe results of this study show that the pharmacokinetics of darunavir/ritonavir 600 mg/100 mg are not affected by mild or moderate hepatic impairment. Therefore, it is recommended that dose adjustments of darunavir/ritonavir are not required in patients with mild or moderate hepatic impairment.

Phase III TITAN week 96 final analysis: efficacy/safety of darunavir/r (DRV/r) vs. lopinavir/r (LPV/r) in LPV-naïve, treatment-experienced patients

Address: 1Szent László Hospital, Budapest, Hungary, 2Département des Maladies Infectieuses et Tropicales, Hôpital Pitié-Salpêtrière, Paris, France, 3Centro Medico Sao Francisco, Curitiba, Brazil, 4Living Hope Clinical Foundation, Long Beach, California, USA, 5University of Toronto, Toronto, Ontario, Canada, 6Republican Centre for AIDS and Infectious Diseases Prevention, Tatarstan Republic, Russian Federation, 7Ground Zero Medical Centre, Darlinghurst, Australia, 8Tibotec BVBA, Mechelen, Belgium and 9Tibotec Inc., Yardley, Pennsylvania, USA * Corresponding author