Efficacy and Safety of Two-Drug Regimens with Dolutegravir plus Rilpivirine or Lamivudine in HIV-1 Virologically Suppressed People Living with HIV.

BACKGROUND: The high effectiveness and safety of the two-drug (2DRs) strategy using dolutegravir (DTG) plus lamivudine (3TC) have led to international guidelines recommending their use for treatment-naive HIV patients. In virologically suppressed patients, de-escalating from 3DRs to DTG plus either rilpivirine (RPV) or 3TC has shown high rates of virological suppression. OBJECTIVES: This study aimed to compare the real-life data of two multicenter Spanish cohorts of PLWHIV treated with DTG plus 3TC (SPADE-3) or RPV (DORIPEX) as a switch strategy, not only in terms of virological suppression, safety, and durability but also in terms of immune restoration. The primary endpoint was the percentage of patients with virological suppression on DTG plus 3TC and DTG plus RPV at weeks 24 and 48. The secondary outcomes included the proportion of patients who experienced the protocol-defined loss of virological control by week 48; changes in immune status in terms of CD4+ and CD8+ T lymphocyte counts and the CD4+/CD8+ ratio; the rate, incidence, and reasons for discontinuation of treatment over the 48-week study period; and safety profiles at weeks 24 and 48. METHODS: We conducted a retrospective, observational, multicenter study of 638 and 943 virologically suppressed HIV-1-infected patients in two cohorts who switched to 2DRs with DTG plus RPV or DTG plus 3TC. RESULTS: The most frequent reasons for starting DTG-based 2DRs were treatment simplification/pill burden or drug decrease. The virological suppression rates were 96.9%, 97.4%, and 99.1% at weeks 24, 48, and 96, respectively. The proportion of patients with virological failure over the 48-week study period was 0.01%. Adverse drug reactions were uncommon. Patients treated with DTG+3TC increased CD4, CD8, and CD4/CD8 parameters at 24 and 48 weeks. CONCLUSIONS: We conclude that DTG-based 2DRs (combined with 3TC or RPV) in clinical practice were effective and safe as a switching strategy, with a low VF and high viral suppression rates. Both regimens were well tolerated, and ADR rates were low, including neurotoxicity and induced treatment discontinuations.

Dolutegravir Plus 3TC in Virologically Suppressed PLWHIV: Immunological Outcomes in a Multicenter Retrospective Cohort in Spain during the COVID-19 Pandemic.

Dolutegravir (DTG) based dual therapies for treating PLWHIV are a standard of care nowadays. Switching to DTG and lamivudine (3TC) safety and efficacy were proven in TANGO randomized clinical trial. This multicenter retrospective study included 1032 HIV virologically suppressed patients switching to DTG+3TC from 13 Spanish hospitals. DTG+3TC provided high rates of undetectable viral load over 96%, corresponding to 96.6% (889/921) at 24 weeks, 97.5% (743/763) at 48 weeks, and 98.3% (417/425) at 96 weeks. No significant differences are evident when comparing the total population according to sex, presence of comorbidity, or presence of AIDS. The analysis for paired data showed an increase in CD4+ cell count. A statistically significant increase in CD4+ lymphocyte count was found in those without comorbidities in the three-time series analyzed [average increase at 24 weeks: 48.7 (SD: 215.3) vs. 25.8 (SD: 215.5), p-value = 0.050; a mean increase at 48 weeks: 75.1 (SD: 232.9) vs. 42.3 (SD: 255.6), p-value = 0.003; a mean increase at 96 weeks: 120.1 (SD: 205.0) vs. 63.8 (SD:275.3), p-value = 0.003]. In conclusion, our cohort demonstrates that DTG+3TC is an effective treatment strategy for virologically-suppressed PLWHIV independent of age, sex, and HIV stage, as well as a safe and durable strategy.

Methicillin-susceptible staphylococcus aureus in community-acquired pneumonia: Risk factors and outcomes.

OBJECTIVES: We aimed to describe the prevalence, risk factors and outcomes of Methicillin-susceptible S. aureus (MSSA) community-acquired pneumonia (CAP) and compare them with those associated with CAP due to Streptococcus pneumoniae, the most frequent causative microorganism, in a large cohort of patients. METHODS: This was an observational study of prospectively collected data of consecutive adults with CAP and a definitive etiology enrolled between 2004 and 2018. Patients were divided into MSSA CAP and pneumococcal CAP groups for analysis. RESULTS: A microbial etiology was established in 1,548 (33%) cases: S. aureus caused 6% of microbiologically-confirmed CAP cases. In the latter, 52 were due to MSSA (60% of S. aureus CAP cases, and 3% of microbiologically-confirmed CAP cases) and 34 were due to MRSA (40% of S. aureus CAP cases, and 2% of microbiologically-confirmed CAP cases). S. pneumoniae was identified in 734 (47%) microbiologically-confirmed CAP cases. The presence of fever was independently associated with a lower risk of MSSA CAP (OR 0.53; 95% CI, 0.28-0.99). Patients with MSSA CAP had higher 30-day mortality than patients with pneumococcal CAP, both before and after adjustment for potential confounders (21% vs 7%, p = 0.002). MSSA was independently associated with 30-day mortality in the overall population. CONCLUSION: MSSA CAP was associated with worse outcomes than pneumococcal CAP in our cohort. MSSA was an independent factor of mortality.

Changing epidemiology of bloodstream infection in a 25-years hematopoietic stem cell transplant program: current challenges and pitfalls on empiric antibiotic treatment impacting outcomes.

We aimed to describe epidemiology changes in bloodstream infections (BSI) episodes in hematopoietic stem cell transplant (HSCT) recipients throughout a 25-year period (1993-2017), comparing five-year time spans, and we evaluate their impact on inappropriate empirical antibiotic treatment (IEAT) and mortality. During the study period, 1164 BSI episodes were documented in patients undergoing HSCT (71.6% allogenic and 29% autologous). A significant decrease in gram-positive cocci (GPC) and increase in gram-negative bacilli (GNB) were observed (p < 0.001). Among GP, coagulase-negative staphylococci (CoNS) significantly decreased whereas rising E. faecium BSI was documented. Among GNB, E. coli, Pseudomonas aeruginosa and K. pneumoniae rates increased. Multidrug-resistant (MDR) GNB, especially ESBL-E. coli and MDR-P. aeruginosa, emerged in 2008 and has gradually increased. IEAT against MDR-P. aeruginosa, but not in other MDR-GNB, augmented throughout the study period. Overall, 30-day and related mortality rates were 12.7% and 7.7% respectively, both increasing over time (p < 0.001 and p = 0.025). In GNB, 30-day and related mortality were 18.5% and 12.8%, respectively, increasing over time (p < 0.001 and p = 0.004). To conclude, important BSI epidemiological changes were described in a 25-year period. Concerning increase in IEAT for P. aeruginosa infections and rising 30-day mortality rate were documented.

Olive oil aromatization with saffron by liquid-liquid extraction.

A new aromatization method for olive oils with saffron aqueous extracts rich in safranal has been developed using liquid-liquid extraction. Four flavoured olive oils were obtained (SO1-SO4). SO1 showed the highest safranal concentration (145.89 mg L-1), followed by SO2 (79.33 mg L-1), SO3 (0.30 mg L-1) and SO4 (0.01 mg L-1). Although flavouring originated a decrease in the quality parameters and the oxidative stability of the oils, even after 7 months of storage, at room and refrigeration temperatures, the oil parameters evaluated were still comparable to those of extra virgin olive oil. Flavored olive oils with less safranal (SO3, SO4) are preferred by consumers.

Effect of roasting conditions on the composition and antioxidant properties of defatted walnut flour.

BACKGROUND: Walnut oil extraction by pressure systems produces a press cake as a by-product, with many of the beneficial walnut properties. The objective of this work was to evaluate the composition and antioxidant properties of walnut flours submitted to different roasting protocols (50, 100 and 150 °C during 30, 60 and 120 min). RESULTS: All walnut flours had about 42% protein and a significant amount of dietary fibre (17%), not being affected by the roasting process. Nonetheless, the fat content increased around 50% in walnuts flours subjected to longer and higher roasting temperatures (150 °C). The lipid fraction showed a good nutritional quality with a high vitamin E content (mainly γ-tocopherol) and fatty acid profile rich in linoleic and linolenic acids. The high phenolic content also provides great antioxidant capacity to the flours. CONCLUSION: Mild roasting of walnuts did not affect the quality of the flours that could be used as a functional ingredient in the food industry. © 2017 Society of Chemical Industry.

Cost-effectiveness analysis of azacitidine in the treatment of high-risk myelodysplastic syndromes in Spain.

BACKGROUND: The objective of the study was to analyse whether azacitidine is a cost-effective option for the treatment of myelodysplastic syndrome in the Spanish setting compared with conventional care regimens, including best supportive care, low dose chemotherapy and standard dose chemotherapy. METHODS: A life-time Markov model was constructed to evaluate the cost-effectiveness of azacitidine compared with conventional care regimens. The health states modelled were: myelodysplastic syndrome, acute myeloid leukemia and death. Variables measured included survival rates, progression probabilities and quality of life indicators. Resource use and cost data reflect the Spanish context. The analysis was performed from the Spanish National Health System perspective, discounting both costs (in 2012 euros) and future effects at 3%. The time horizon considered was end-of-life. Results were expressed in cost per quality-adjusted life-year gained and cost per life-year gained and compared with cost-effectiveness thresholds. RESULTS: According to the current use of each conventional care regimens options in Spain, azacitidine resulted in €34,673 per quality-adjusted life-year gained (€28,891 per life-year gained) with an increase of 1.89 in quality-adjusted life-years (2.26 in life-years). Azacitidine was superior to best supportive care and low dose chemotherapy in terms of quality-adjusted life-years gained, 1.82 and 2.03, respectively (life-years 2.16 vs. best supportive care, 2.39 vs. low dose chemotherapy). Treatment with azacitidine resulted in longer survival time and thus longer treatment time and lifetime costs. The incremental cost-effectiveness ratio was €39,610 per quality-adjusted life-year gained vs. best supportive care and €30,531 per quality-adjusted life-year gained vs. low dose chemotherapy (€33,111 per life-year gained vs. best supportive care and €25,953 per life-year gained vs. low dose chemotherapy). CONCLUSIONS: The analysis showed that the use of azacitidine in the treatment of high-risk myelodysplastic syndrome is a cost-effective option compared with conventional care regimen options used in the Spanish setting and had an incremental cost-effectiveness ratio within the range of the thresholds accepted by health authorities.

Study of kidney function impairment after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. A single-center experience.

Acute renal failure (ARF) is a life-threatening complication after allogeneic stem cell transplantation (Allo-HSCT). Identification of ARF risk factors could be useful to develop preventive strategies for patients at high risk. The goal of this study was to evaluate the incidence and risk factors of ARF after reduced intensity conditioning Allo-HSCT (Allo-RIC). We included 188 consecutive patients who underwent Allo-RIC in our center between January 1999 and December 2006. ARF was defined as a decrease of at least 25% in baseline estimated glomerular filtration rate (GFR) calculated by modification of diet in renal disease (MDRD) equation. Conditioning consisted of fludarabine (Flu) 150 mg/m(2) in combination with busulfan (Bu) 8-10 mg/kg (n = 61), melphalan (Mel) 140 mg/m(2) (n = 115), cyclophosphamide (Cy) 120 mg/kg (n = 7) or low-dose total-body irradiation (TBI) 2 Gy (n = 5). Graft-versus-host disease (GVHD) prophylaxis consisted of cyclosporine A (CsA) alone (n = 3) or in addition to methotrexate (MTX; n = 132) or mycophenolate mofetil (MMF; n = 51). The cumulative incidence of ARF at 1 year was 52% (n = 97 patients) after Allo-RIC. Most cases (86%) occurred within the first 3 months, and the main cause was the administration of CsA (71%). The risk factors associated with ARF in multivariate analysis were: administration of MTX (hazard ratio [HR] 1.9, P =.02), more than 3 lines of therapy prior to Allo-RIC (HR 1.8, P = .01), diabetes mellitus (HR 2.1, P < .01), and GVHD grade III-IV (HR 2.1, P = .015). In multivariate analysis, ARF was an independent risk factor for 1-year nonrelapse mortality (NRM) (HR 3, 95% confidence interval [CI]: 1.5-6, P = .002). Patients who experienced ARF had lower 1-year overall survival (OS; 53% versus 74%, P < .05). ARF is a frequent complication in patients after Allo-RIC, and it has a negative impact on outcome. Identification of ARF risk factors could help to avoid exposure to nephrotoxic drugs during the follow-up in patients at high risk.

Efficacy and toxicity of intermediate-dose amphotericin B lipid complex as a primary or salvage treatment of fungal infections in patients with hematological malignancies.

We treated 74 adults with a hematological malignancy and documented or suspected invasive fungal infection (IFI) with amphotericin B lipid complex (ABLC) at 3 mg/kg/day. Forty-five patients (61%) received upfront therapy and 29 patients (39%) received salvage therapy for their IFI. Forty-eight of 71 evaluable patients responded [complete responses in 40 (56%) and partial responses in 8 (11%)] and 15 (21%) died as a consequence of the IFI. Response rates in invasive aspergillosis were 33 out of 49 (67%) for probable/definite cases and 6 out of 11 (55%) for invasive candidiasis. In 40 patients with neutropenia-associated IFI, rapid neutropenic recovery ( < 10 days from study entry) was essential for response to therapy (90% vs. 32%, P < 0.01). Treatment was well tolerated, with 15% infusions followed by infusion-related adverse events, nephrotoxicity in 7% of patients and 11% of withdrawals due to toxicity. These data suggest that intermediate-doses of ABLC may be of similar efficacy than higher doses with less toxicity, making it a cost-effective alternative worthy of study in future trials.

Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning.

We prospectively compared outcomes after a fludarabine (Flu) plus oral busulfan (Bu)-containing reduced-intensity conditioning regimen (150 mg/m2 Flu and 10 mg/kg oral Bu), with (n = 32; Flu- T Bu group) or without (n = 30; Flu-Bu group) therapeutic dose monitoring and dose adjustment of Bu. All patients received peripheral blood stem cells from a genoidentical sibling, and study cohorts had similar patient characteristics. Dose adjustments of Bu were required in 20 (63%) patients in the Flu- T Bu group (median final dose, 8.89 mg/kg; range, 6.3-13.34 mg/kg). Donor T-cell and granulocyte engraftments were similar, and early conditioning-related toxicities were mild and similar in both study groups. With a median follow-up of 45 months (51 months in the 37 survivors), posttransplantation outcomes did not differ between cohorts. The strongest predictor of 2-year overall survival and leukemia-free survival was the presence of chronic graft-versus-host disease (77% versus 34% for overall survival and 74% versus 34% for leukemia-free survival; P < .001 for both outcomes). In conclusion, therapeutic dose monitoring of oral Bu in a reduced-intensity conditioning setting does not seem to affect outcome, although further studies may identify very-high-risk patients who benefit from this strategy.