TITAN Trial Research Articles

Cost Effectiveness of Darunavir/Ritonavir 600/100mg bid in Treatment-Experienced, Lopinavir-Naive, Protease Inhibitor-Resistant, HIV-Infected Adults in Belgium, Italy, Sweden and the UK

Using data from the phase IIb POWER trials, darunavir boosted with low-dose ritonavir (DRV/r; 600/100 mg twice daily; bid)-based highly active antiretroviral therapy (HAART) was shown to be significantly more efficacious and cost effective than other protease inhibitor (PI)-based therapy in highly treatment-experienced, HIV-1-infected adults. Furthermore, in the phase III TITAN trial (TMC114-C214), DRV/r 600/100 mg bid-based HAART generated a superior 48-week virological response rate compared with standard-of-care lopinavir/ritonavir (LPV/r; 400/100 mg bid)-based therapy in treatment-experienced, lopinavir-naive patients, and in particular those with one or more International AIDS Society - USA (IAS-USA) primary PI resistance-associated mutations at baseline. These patients had a broader degree of previous PI use/failure (0 - ≥ 2) than the POWER patients. To determine whether DRV/r 600/100 mg bid-based HAART is cost effective compared with LPV/r-based therapy, from the perspective of Belgian, Italian, Swedish and UK reimbursement authorities, when used in treatment-experienced patients similar to TITAN patients with one or more IAS-USA primary PI mutations at baseline. An existing Markov model containing health states defined by CD4 cell count ranges (>500, 351-500, 201-350, 101-200, 51-100 and 0-50 cells/mm³) and an absorbing state of death was adapted for use in the above-mentioned healthcare settings. Baseline demographics, CD4 cell count distribution, antiretroviral drug usage, virological/immunological response rates and matching transition probabilities were based on data collected during the first 48 weeks of therapy in the modelled subgroup of TITAN patients and the published literature. After treatment failure, patients were assumed to switch to a follow-on combination regimen. For each health state, utility values and mortality rates were obtained from the published literature. Data from local observational studies (Belgium, Sweden and Italy) or the published literature (UK) were used to determine resource-use patterns and costs associated with each CD4 cell count range. Unit costs were derived from official local sources; a lifetime horizon was taken and discount rates were chosen based on local guidelines. The base-case analysis predicted quality-adjusted life year (QALY) gains of 0.785 in Belgium, 0.608 in Italy, 0.584 in Sweden and 0.550 in the UK when DRV/r-based therapy was used instead of LPV/r-based treatment. The estimated base-case incremental cost-effectiveness ratios (ICERs) were €6964/QALY gained in Belgium, €9277/QALY gained in Italy, €6868 (SEK69,687)/QALY gained in Sweden and €14,778 (£12 612)/QALY gained in the UK. Assuming a threshold of €30,000/QALY gained, DRV/r-based therapy remained cost effective over most parameter ranges tested in extensive one-way sensitivity analyses. The variation of immunological response rates and the time horizon were identified as important drivers of cost effectiveness. Probabilistic sensitivity analysis revealed a greater than 70% probability of achieving an ICER below this threshold in all four healthcare settings. From the perspective of Belgian, Italian, Swedish and UK payers, DRV/r 600/100 mg bid-based HAART is predicted to be cost effective compared with LPV/r 400/100 mg bid-based therapy, when used to manage treatment experienced, lopinavir-naive, PI-resistant, HIV-infected adults with a broad range of previous PI use/failure.

TCT-505: Subgroup Analysis of Hemodynamic and Clinical Response to Percutaneous Mitral Annuloplasty for Functional Mitral Regurgitation in the TITAN Trial

TCT-505: Subgroup Analysis of Hemodynamic and Clinical Response to Percutaneous Mitral Annuloplasty for Functional Mitral Regurgitation in the TITAN Trial

Identification of new genotypic cut-off levels to predict the efficacy of lopinavir/ritonavir and darunavir/ritonavir in the TITAN trial

Genotypic algorithms used to predict the clinical efficacy of lopinavir/ritonavir (LPV/r) have included a range of mutation lists and efficacy endpoints. Normally, HIV clinical trials are powered to detect a difference between treatment arms of 10-12% for the endpoint of viral load suppression <50 HIV-1 RNA copies/mL. The TITAN trial evaluated LPV/r vs. darunavir/ritonavir (DRV/r) in treatment-experienced patients with viral load >1000 copies/mL. This analysis aimed to re-evaluate resistance algorithms for LPV/r in the TITAN trial. Baseline genotype data were classified using seven genotypic resistance algorithms: International AIDS Society USA (IAS-USA) LPV mutations (current cut-off=6), Abbott 2007 mutation list (cut-off=3), ANRS mutations (cut-off=4), FDA mutations (cut-off=3), Stanford, REGA and IAS-USA major protease inhibitor (PI) mutations. Efficacy in the TITAN trial (HIV-1 RNA <50 copies/mL at week 48) was correlated with the number of mutations from each list, to show the 'efficacy advantage cut-off level': the number of mutations from each list associated with a difference in efficacy between treatment arms of at least 12%. Multivariate logistic regression analysis identified lower genotypic cut-off levels than previously reported where there was at least 12% lower efficacy for LPV/r vs. DRV/r. These efficacy advantage cut-off levels were: IAS-USA LPV mutations, cut-off=3; Abbott 2007, cut-off=2; ANRS LPV, cut-off=3; FDA LPV mutations, cut-off=2; major IAS-USA PI mutations, cut-off=1; Stanford algorithm, cut-off=low-level LPV resistance; REGA algorithm, cut-off=intermediate-level LPV resistance. There were linear falls in HIV-1 RNA suppression rates with rising mutation counts in the TITAN, French LPV ATU, BMS-045 and RESIST trials. The analysis identified more sensitive cut-off levels for LPV genotypic algorithms, below those currently used.

Influence of Baseline Protease Inhibitor Resistance on the Efficacy of Darunavir/Ritonavir or Lopinavir/Ritonavir in the TITAN Trial

Influence of Baseline Protease Inhibitor Resistance on the Efficacy of Darunavir/Ritonavir or Lopinavir/Ritonavir in the TITAN Trial

Lipid elevations in the ARTEMIS and TITAN trials: effects of demographics, HIV disease stage, treatment arm and lipid-lowering drugs

Methods Lipid parameters included total cholesterol, LDL (calculated, for samples with triglycerides below 4.52 mmol/L), HDL, triglycerides, apolipoprotein A1, Apo B, glucose and insulin. Analysis of covariance was used to correlate changes in each lipid parameter with baseline lipid levels, age, gender, and race, baseline CD4 count, HIV-RNA, treatment arm (LPV/r vs. DRV/r), and use of NNRTI (TITAN trial only) and lipid-lowering drugs (fibrates/statins). Numbers in brackets show the size of effects of factors on lipid elevations at week 48 – these effects were all statistically significant (p < 0.01).

Re-evaluation of resistance algorithms for lopinavir/ritonavir in the TITAN trial

Re-evaluation of resistance algorithms for lopinavir/ritonavir in the TITAN trial

O424 Resistance development in virological failures with DRV/r or LPV/r: 96-week analysis of the Phase III TITAN trial in treatment-experienced patients

Purpose of the study In the randomised, controlled, Phase III TITAN trial, at week 96, significantly more patients on darunavir coadministered with low-dose ritonavir (DRV/r) than on lopinavir/r (LPV/r) achieved HIV-1 RNA <400 copies/mL (67.5% vs. 59.5%; difference 8%, 95% CI 0.1–15.8), confirming non-inferiority (p < 0.001) and superiority of DRV/r over LPV/r (p = 0.034). A detailed resistance characterisation of virological failures (VFs) was performed.