An Experimental Study on Micro-Milling of a Medical Grade Co-Cr-Mo Alloy Produced by Selective Laser Melting.

Cobalt-chromium-molybdenum (Co-Cr-Mo) alloys are very promising materials, in particular, in the biomedical field where their unique properties of biocompatibility and wear resistance can be exploited for surgery applications, prostheses, and many other medical devices. While Additive Manufacturing is a key technology in this field, micro-milling can be used for the creation of micro-scale details on the printed parts, not obtainable with Additive Manufacturing techniques. In particular, there is a lack of scientific research in the field of the fundamental material removal mechanisms involving micro-milling of Co-Cr-Mo alloys. Therefore, this paper presents a micro-milling characterization of Co-Cr-Mo samples produced by Additive Manufacturing with the Selective Laser Melting (SLM) technique. In particular, microchannels with different depths were made in order to evaluate the material behavior, including the chip formation mechanism, in micro-milling. In addition, the resulting surface roughness (Ra and Sa) and hardness were analyzed. Finally, the cutting forces were acquired and analyzed in order to ascertain the minimum uncut chip thickness for the material. The results of the characterization studies can be used as a basis for the identification of a machining window for micro-milling of biomedical grade cobalt-chromium-molybdenum (Co-Cr-Mo) alloys.

Cost effectiveness of darunavir/ritonavir 600/100 mg bid in protease inhibitor-experienced, HIV-1-infected adults in Belgium, Italy, Sweden and the UK.

BACKGROUND: Two phase II trials (POWER 1 and 2) have demonstrated that darunavir co-administered with low-dose ritonavir (DRV/r) provides significant clinical benefit compared with control protease inhibitors (PIs) in highly treatment-experienced, HIV-1-infected adults, when co-administered with optimized background therapy (OBR). OBJECTIVE: To determine whether DRV/r is cost effective compared with control PIs, from the perspective of Belgian, Italian, Swedish and UK reimbursement authorities, when used in treatment-experienced patients similar to those included in the POWER 1 and 2 trials. METHODS: 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 death was adapted for use in four European healthcare settings. Baseline demographics, CD4 cell count distribution and antiretroviral drug usage reflected those reported in the POWER 1 and 2 trials. Virological/immunological response rates and matching transition probabilities over the patient's lifetime were based on results from the POWER trials and published data. After treatment failure, patients were assumed to switch to a tipranavir-containing regimen plus OBR. For each CD4 cell count range, utility values and HIV-related mortality rates were obtained from the published literature. National all-cause mortality data and published data on the increased risk of non HIV-related mortality in HIV-infected individuals were taken into account in the model. Data from observational studies conducted in each healthcare setting 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 selected based on local guidelines. RESULTS: In the base-case analysis, quality-adjusted life-year (QALY) gains of up to 1.397 in Belgium, over 1.171 in Italy, 1.142 in Sweden and 1.091 in the UK were predicted when DRV/r-based therapy was used instead of control PI-based treatment. The base-case analyses predicted an incremental cost-effectiveness ratio (ICER) of €11,438/QALY in Belgium, €12,122/QALY in Italy,€10,942/QALY in Sweden and €16,438/QALY in the UK. Assuming an acceptability threshold of €30,000/QALY, DRV/r-based therapy remained cost effective over all parameter ranges tested in extensive one-way sensitivity analyses. Probabilistic sensitivity analysis revealed a 95% (Belgium), 97% (Italy), 92% (Sweden) or 78% (UK) probability of attaining an ICER below this threshold. CONCLUSION: From four European payer perspectives, DRV/r-based antiretroviral therapy is predicted to be cost effective compared with currently available control PIs, when both are used with an OBR in treatment-experienced, HIV-1-infected adults who failed to respond to more than one PI-containing regimen.

Cost effectiveness of darunavir/ritonavir 600/100 mg bid in treatment-experienced, lopinavir-naive, protease inhibitor-resistant, HIV-infected adults in Belgium, Italy, Sweden and the UK.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Predicting direct costs of HIV care during the first year of darunavir-based highly active antiretroviral therapy using CD4 cell counts: evidence from POWER.

BACKGROUND: Given the association between CD4 cell counts and HIV-related morbidity/mortality, new antiretroviral therapies could potentially lower the direct costs of HIV care by raising CD4 cell counts. OBJECTIVES: To predict the effects of the ritonavir-boosted, HIV protease inhibitor (PI) darunavir on the direct costs of care, while accounting for CD4 cell counts, during the first year of therapy in highly treatment-experienced, HIV-infected adults in different healthcare settings. METHODS: The mean annual per-patient cost of darunavir/ritonavir (DRV/r) and control PI-based highly active antiretroviral therapy (HAART) was calculated from the proportional use of antiretroviral agents in the DRV/r and control PI arms of the pooled POWER 1 and 2 trials, applying drug-acquisition costs for five healthcare settings. Non-antiretroviral-related costs by CD4 cell count, derived from non-interventional studies in the same settings, were applied to the POWER data (proportion of patients with CD4 cell counts in different strata at week 48) to estimate mean annual non-antiretroviral-related costs per patient in patients receiving DRV/r or control PI-based HAART during year 1. RESULTS: Across all settings, the mean annual per-patient cost of DRV/r-based treatment was 2-19% higher than that of control PI-based therapy during the first year of therapy. By raising CD4 cell counts, however, DRV/r-based regimens were predicted to lower mean annual non-antiretroviral-related costs by 16-38% compared with control PI-based therapy. When combined, the total annual per-patient cost of HIV care during the first year of therapy was estimated to be 7% lower in the DRV/r compared with the control PI arm using US data, 8% lower using Swedish data, budget neutral using UK and Belgian data and 5% higher using Italian data. CONCLUSIONS: Darunavir-based HAART may lower non-antiretroviral-related costs compared with control PI-based therapy in highly treatment-experienced, HIV-infected patients during the first year of therapy by improving patients' CD4 cell counts. These costs could partly/fully offset the increased acquisition cost of DRV/r in this patient population over the same period.