A Randomized Trial to Assess Anti-HIV Activity in Female Genital Tract Secretions and Soluble Mucosal Immunity Following Application of 1% Tenofovir Gel

Preclinical and early phase clinical microbicide studies have not consistently predicted the outcome of efficacy trials. To address this gap, candidate biomarkers of microbicide pharmacodynamics and safety were evaluated in a double-blind, placebo-controlled trial of tenofovir gel, the first microbicide to demonstrate significant protection against HIV acquisition.30 women were randomized to apply a single daily dose of tenofovir or placebo gel for 14 consecutive days. Anti-HIV activity was measured in cervicovaginal lavage (CVL) on Days 0, 3, 7, 14 and 21 by luciferase assay as a surrogate marker of pharmacodynamics. Endogenous activity against E. coli and HSV-2 and concentrations of immune mediators were quantified in CVL as candidate biomarkers of safety. Tenofovir levels were measured in CVL and blood.A significant increase in anti-HIV activity was detected in CVL from women who applied tenofovir gel compared to their endogenous anti-HIV activity in genital tract secretions on Day 0 and compared to activity in CVL from women in the placebo group. The activity correlated significantly with CVL concentration of tenofovir (r = 0.6, p<0.001) and fit a sigmoid E(max) pharmacodynamic model. Anti-HIV activity in CVL from women who applied tenofovir persisted when virus was introduced in semen, whereas endogenous anti-HIV activity decreased. Tenofovir did not trigger an inflammatory response or induce sustained loss in endogenous antimicrobial activity or immune mediators.Tenofovir gel had no deleterious impact on soluble mucosal immunity. The increased anti-HIV activity in CVL, which persisted in the presence of semen and correlated with tenofovir concentration, is consistent with the efficacy observed in a recent clinical trial. These results promote quantified CVL anti-HIV activity as a surrogate of tissue pharmacodynamics and as a potential biomarker of adherence to product. This simple, feasible and inexpensive bioassay may promote the development of models more predictive of microbicide efficacy.ClinicalTrials.gov NCT00594373

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Importance: Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. // Objective: To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. // Design, Setting, and Participants: The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. // Exposures: SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. // Main Outcomes and Measures: The primary end point was all-cause mortality within the primary hospitalization. // Results: Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19–related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). // Conclusions and Relevance: The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed

Treatment patterns and cost-effectiveness of therapeutic sequences among advanced colorectal cancer patients

Background: Colorectal cancer (CRC) ranks third among the most common cancers and one in four CRC patients are diagnosed at metastatic stage. Metastatic colorectal cancer (mCRC) has a poor prognosis, with an overall survival of 5% to 13% at five years. Over the last decade multiple chemotherapies and targeted biologics have been approved for mCRC and patients may receive these chemotherapies and targeted biologics in different sequences. Limited evidence exists with regards to the current usage patterns, comparative effectiveness and cost-effectiveness of treatment sequences for elderly mCRC patients. Objective: The first aim was to describe the usage patterns of treatments (chemotherapy and targeted biologics) and treatment sequences administered to mCRC patients and the factors associated with the receipt of common treatment sequences. The common treatment sequences of interest were: 1) first-line oxaliplatin/irinotecan followed by second-line oxaliplatin/irinotecan + bevacizumab (OI-OIB), 2) first-line oxaliplatin/irinotecan + bevacizumab followed by second-line oxaliplatin/irinotecan + bevacizumab (OIB-OIB), 3) OI-OIB followed by a third-line targeted biologic (OI-OIB-TB), and 4) OIB-OIB followed by a third-line targeted biologic (OIB-OIB-TB). The second and third aims of the study were to determine the comparative effectiveness and cost-effectiveness, respectively for the above mentioned sequence. Methods: A retrospective cohort study was conducted in patients diagnosed with mCRC from January 2004 through December 2009 using the Surveillance, Epidemiology and End Results-Medicare linked database. The treatment continuum administered to elderly mCRC patients was empirically identified. Comparative effectiveness of the treatment sequences was evaluated using fixed time and time dependent (immortal time adjusted) Cox-proportional hazard regression for all-cause mortality. A probabilistic discrete event simulation model assuming Weibull distribution was developed to evaluate the cost-effectiveness of common treatment sequences. A probabilistic sensitivity analysis was performed to account for parameter uncertainty. Costs (2014 U.S. dollars) and effectiveness were discounted at an annual rate of 3%. Results: Of 4,418 mCRC patients who received treatment, 1,370 (31%) received first-, second-, and third-line, 1,164 (26%) received first-, and second-line, and 1,884 (43%) received only first-line. The most common first-line of treatment for mCRC patients were 5-fluorouracil/leucovorin + oxaliplatin (FOLFOX) + bevacizumab (23%) and FOLFOX (23%). The most common treatment sequence was first-line oxaliplatin or irinotecan followed by second-line oxaliplatin or irinotecan + bevacizumab followed by a third-line targeted biologic. Forty seven percent of patients who received first-line therapy also received a targeted biologic and the factors associated were age, comorbidity score, cancer site, geographic location and year of diagnosis. Fixed time model Cox-proportional hazard regression showed that as compared to OI-OIB, statistically significantly lower hazard ratios for all-cause mortality were observed for patients receiving treatment sequences OIB-OIB (0.60, 95% CI: 0.46-0.77), OI-OIB-TB (0.53, 95% CI: 0.42-0.67), and OIB-OIB-TB(0.40, 95% CI: 0.31-0.52). In the base case cost-effectiveness analyses, at the willingness-to-pay (WTP) threshold of $100,000/QALY gained, the treatment sequence OIB-OIB (versus OI-OIB) was not cost-effective with an incremental cost-effectiveness ratio (ICER) per patient of$119,007/QALY, OI-OIB-TB (versus OIB-OIB) was dominated and OIB-OIB-TB (versus OIB-OIB) was not cost-effective with an ICER of $405,857/QALY. Conclusion: Elderly mCRC patients receive a multitude of treatments and in various sequences. Sequences with bevacizumab + oxaliplatin/irinotecan based regimens in first-line and second-line were the most effective for elderly mCRC patients. Moreover, adding a targeted biologic based regimen at third-line may provide additional survival advantage but at substantial costs. Treatment sequences with bevacizumab at first-line and targeted biologics at third-line may not be cost-effective at the commonly used threshold of$100,000/QALY gained but a marginal decrease in the cost of bevacizumab may make treatment sequences with first-line bevacizumab cost-effective

Cost-Effectiveness of Chemotherapy for Breast Cancer and Age Effect in Older Women

AbstractBackgroundPrevious economic evaluations compared specific chemotherapy agents using input parameters from clinical trials and resource utilization costs. Cost-effectiveness of treatment groups (drug classes) using community-level effectiveness and cost data, however, has not been assessed for elderly patients with breast cancer.ObjectiveTo assess the cost-effectiveness of chemotherapy regimens by age and disease stage under “real-world” conditions for patients with breast cancer.MethodsThe Surveillance Epidemiology and End Results-Medicare data were used to identify patients with breast cancer with American Joint Committee on Cancer stage I/II/IIIa, hormone receptor–negative (estrogen receptor–negative and progesterone receptor–negative) patients from 1992 to 2009. Patients were categorized into three adjuvant treatment groups: 1) no chemotherapy, 2) anthracycline, and 3) non–anthracycline-based chemotherapy. Median life-years and quality-adjusted life-years (QALYs) were measured using Kaplan-Meier analysis and were evaluated against average total health care costs (2013 US dollars).ResultsA total of 4575 patients (propensity score–matched) were included for the primary analysis. The anthracycline group experienced 12.05 QALYs and mean total health care costs of $119,055, resulting in an incremental cost-effectiveness ratio of$7,688 per QALY gained as compared with the no chemotherapy group (QALYs 7.81; average health care cost $86,383). The non–anthracycline-based group was dominated by the anthracycline group with lower QALYs (9.56) and higher health care costs ($122,791). Base-case results were found to be consistent with the best-case and worst-case scenarios for utility assignments. Incremental cost-effectiveness ratios varied by age group (range $3,790–$90,405 per QALY gained).ConclusionsAnthracycline-based chemotherapy was found cost-effective for elderly patients with early stage (stage I, II, IIIa) breast cancer considering the US threshold of $100,000 per QALY. Further research may be needed to characterize differential effects across age groups

Development and Evaluation of Nanoparticles-in-Film Technology to Achieve Extended In Vivo Exposure of MK-2048 for HIV Prevention

MK-2048 is a second-generation integrase inhibitor active against HIV, which has been applied vaginally using ring formulations. In this work, a nanoparticle-in-film technology was developed as a discrete pre-exposure prophylactic product option against HIV for an extended duration of use. A film platform loaded with poly (lactic-co-glycolic acid) nanoparticles (PNP) encapsulating MK-2048 was engineered. MK-2048 PNPs were loaded into films that were manufactured via the solvent casting method. Physicochemical and mechanical properties, in vitro efficacy, Lactobacillus compatibility, in vitro and ex vivo permeability, and in vivo pharmacokinetics in macaques were evaluated. PNPs with a mean diameter of 382.2 nm and −15.2 mV zeta potential were obtained with 95.2% drug encapsulation efficiency. PNP films showed comparable in vitro efficacy to free MK-2048 (IC50 0.46 vs. 0.54 nM) and were found to have no impact on Lactobacillus. MK-2048 encapsulated in PNPs showed an increase in permeability (>4-fold) compared to the free MK-2048 in MDCKII cell lines. Furthermore, PNPs had higher ectocervical tissue permeability (1.7-fold) compared to free MK-2048. PNP films showed sustained drug levels for at least 3 weeks in the macaque vaginal fluid. This work demonstrates the synergy of integrating nanomedicine and polymeric film technology to achieve sustained vaginal drug delivery

Chronologic Age at Hospitalization for Respiratory Syncytial Virus Among Preterm and Term Infants in the United States

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