Understanding treatment goals and their application in clinical trial design for patients with Alzheimer disease and caregivers.

Background: As research continues towards improved treatments for Alzheimer disease (AD), there is growing interest in the views and needs from patients and caregivers on AD treatments. Methods: In this study, we surveyed patients with AD and caregivers to determine the treatment goals that are most important to them. Patients with AD and caregivers were independently recruited in Europe and North America to complete a web-based survey. Eligible participants were ≥18 years old and diagnosed with mild cognitive impairment or mild-to-moderate AD (patient-reported group) or persons involved in the care of patients with AD (caregiver-reported group). A total of 322 patients and 614 caregivers completed the survey. Results: The demographic characteristics of patients in the patient-reported and the caregiver-reported groups were similar. Disease severity of patients was greater in the caregiver-reported group compared with the patient-reported group (72.1% versus 46.9% moderate AD). The most important goal of AD treatment in both groups was maintenance of quality of life (QoL) (patient-reported group 31.1% and caregiver-reported group 38.8%; p=0.01). This was consistent across disease stages or symptom severity except for patients with mild cognitive impairment in the caregiver-reported group where slowing the progression of memory loss was the most important treatment goal. Conclusions: Patient QoL was consistently the most relevant treatment goal for patients with AD and caregivers. In AD clinical trials, patient-relevant outcomes, for example, QoL, should be given high priority to reflect the needs and demands of patients with AD and their caregivers.A preliminary report of this work was presented at the 14th Clinical Trials on Alzheimer's Disease meeting (November 9-12, 2021).

Application of a Novel Endpoint Staging Framework: Proof of Concept in the AMBAR Study.

Background: A theoretical endpoint staging framework was previously developed and published, aligning outcomes (i.e., memory) to the stage of Alzheimer's disease (AD) in which a given outcome is most relevant (i.e., has the greatest risk of degradation). The framework guides the selection of endpoints measuring outcomes relevant within a target AD population. Here, a proof of concept is presented via post-hoc analyses of the Alzheimer Management by Albumin Replacement (AMBAR) Phase 2b clinical trial in patients with AD (NCT01561053, 2012). Objective: To evaluate whether aligning endpoints measuring cognition, function, and quality of life to hypothesized 'target' stages of AD yields magnitudes of treatment efficacy greater than those reported in the AMBAR full analysis set (FAS). Methods: Three endpoints were tested: ADAS-Cog 12, ADCS-ADL, and QoL-AD. The magnitude of treatment efficacy was hypothesized to be maximized in the target stages of mild, mild-to-moderate, and very mild AD, respectively, compared to the full analysis set (FAS) and non-target stages. Results: For ADAS-Cog 12, the magnitude of treatment efficacy was largest in the non-target stage (-4.0, p = 0.0760) compared to target stage and FAS. For ADCS-ADL and QoL-AD, the magnitude of treatment efficacy was largest in the target stage (14.2, p = 0.0003; 2.4, p < 0.0001, respectively) compared to non-target stage and FAS. Conclusions: Findings indicated that evaluating endpoints in the most relevant AD stage can increase the magnitude of the observed treatment efficacy. Evidence provides preliminary proof of concept for the endpoint staging framework.

Early Albumin Infusion Is Associated With Greater Survival to Discharge Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury Among Patients With Sepsis/Septic Shock Who Develop Severe Acute Kidney Injury.

Adults hospitalized with sepsis/septic shock commonly develop acute kidney injury (AKI) which imposes a significant burden on the healthcare system. The administration of early human albumin in this patient population may yield more efficient healthcare resource utilization. Objectives: To examine the association between early use of albumin and time to discharge in adults who develop severe AKI while hospitalized with sepsis/septic shock. Design: Retrospective cohort study using de-identified electronic health records from a national database (Cerner Health Facts; Cerner Corp., Kansas City, MO). Setting and Participants: Patients (n = 2,829) hospitalized between January 2013 and April 2018 with a diagnosis of sepsis/septic shock (identified using International Classification of Diseases, 9th Revision and 10th Revision codes) who developed severe AKI (stage 3 according to Kidney Disease Improving Global Outcomes criteria) during hospitalization (n = 2,845 unique encounters). Main Outcomes and Measures: Patients were grouped according to timing of albumin exposure: within less than or equal to 24 hours of admission ("early albumin") or unexposed/exposed late ("nonearly albumin"). A cause-specific hazard model, censoring for death/discharge to hospice, was used to examine the association between "early albumin" and the rate of hospital discharge with clinical stability. Results: Albumin was administered early in 8.6% of cases. Cases with early albumin administration had a median time to discharge of 13.2 days compared with 17.0 in the nonearly group (Log-rank p < 0.0001). An adjusted analysis showed that the rate of hospital discharge with clinical stability increased by 83% in the early albumin group compared with the nonearly group (hazard ratio, 1.832; 95% CI, 1.564-2.146; p < 0.001 nonearly group. Conclusions and Relevance: The use of albumin within 24 hours of hospital admission was associated with a shorter time to discharge and a higher rate of discharge with clinical stability, suggesting an improvement in healthcare resource utilization among patients with sepsis/septic shock who developed stage 3 AKI during hospitalization.

Cool Temperatures Favor Growth of Oregon Isolates of Calonectria pseudonaviculata and Increase Severity of Boxwood Blight on Two Buxus Cultivars.

Controlled environment experiments were conducted to evaluate the effects of temperature on Calonectria pseudonaviculata mycelial growth and the effects of temperature and infection period on boxwood blight severity. In experiment 1, 15 Oregon isolates (representing five genotypes) were grown on potato dextrose agar (PDA) and malt extract agar (MEA) at six temperatures from 5 to 30°C. Growth (culture diameter) was measured after 2 weeks. Optimal growth occurred at 25°C on PDA and 20°C on MEA. Isolates of genotype G1 also grew faster than genotype G2, but only on MEA at 25°C. In experiment 2, Buxus cultivars Green Velvet (GV, more susceptible) and Winter Gem (WG, more resistant) were inoculated and incubated in moist chambers for 9 or 24 h at 22°C (infection period), then moved into growth chambers at 15 or 25°C. After 4 weeks, chamber temperatures were switched, and plants were incubated for 4 more weeks. Disease severity was evaluated weekly. During the first 4 weeks, disease was generally more severe on GV than WG, on plants with a 24-h versus a 9-h infection period, and on plants incubated at 15°C versus 25°C. However, disease was just as severe on WG as GV when the 24-h infection period was followed by incubation at 15°C. After the temperatures were switched, disease increased only on WG that were cooled from 25 to 15°C. Results show that Oregon isolates of C. pseudonaviculata are capable of growing faster and causing more severe disease at temperatures cooler than those reported previously.

Is Disease Induced by Flooding Representative of Nursery Conditions in Rhododendrons Infected with Phytophthora cinnamomi or P. plurivora?

The degree of flooding commonly used to induce disease in Phytophthora root rot studies rarely occurs in container nurseries. Instead, over-irrigation and poor drainage result in plants periodically sitting in shallow pools of water. Rhododendron plants were grown in a noninfested substrate or substrate infested with Phytophthora cinnamomi or P. plurivora to determine whether root rot induced by flooding represents disease that occurs under simulated nursery conditions when plants are in a shallow pool of water (saucers), or are allowed to freely drain and maintained at ∼75% container capacity (CC). Generally P. cinnamomi caused more disease than P. plurivora, and all water treatments were conducive to root rot. In experiment 1, the amount of disease caused by flooding was similar to that in the saucer treatment (75% CC not tested) while in experiment 2, flooding often caused more rapid and severe disease than the saucer or 75% CC treatment. Pathogens differed in their response to water treatments. P. cinnamomi caused more disease in treatments with >90% substrate moisture for either a short (flood) or long duration (saucer), while P. plurivora was less capable of causing disease when soil moisture was maintained >90% than when substrate moisture was maintained at a more moderate level (flood, 75% CC). Our results indicate that it is not necessary to flood plants to induce disease under experimental conditions and that disease induced by flooding can represent disease in container nurseries when containers are in pools of water or maintained at ∼75% CC. In addition, our results suggest that P. cinnamomi is a more aggressive pathogen than P. plurivora in nursery conditions where drainage is poor; however, both species are capable of causing a similar amount of disease under more typical irrigation management.

Optimizing Inoculum Production Methods for Infesting Soil with Phytophthora Species.

Inoculum production is an important part of conducting research with soilborne Phytophthora species. One common method is to incubate Phytophthora cultures in nutrient-amended vermiculite. However, inoculum levels often vary among batches of inoculum, even when production methods remain the same, and incubation typically takes ≥6 weeks, increasing risks for delayed experiments if the resulting inoculum level is too low. A more reliable and rapid method is needed for future studies. Experiments were conducted to determine inoculum levels of Phytophthora cinnamomi and Phytophthora plurivora after incubation in V8 juice-amended vermiculite (standard method); evaluate how inoculum viability was affected by air-drying; develop a modified method that takes less time to produce a vermiculite-based inoculum; and evaluate the effect of storage on inoculum viability. Results showed that the standard method produced inoculum levels from 716 to 1,808 colony forming units (CFUs)/g and that drying to <78% moisture content significantly reduced viability. The modified method used 2-week-old Phytophthora cultures to infest vermiculite at 80% moisture content and produced inoculum levels from 214 to 525 CFU/g. Storage for >1 day generally reduced inoculum viability. Although inoculum levels from the modified method were lower than the standard method, inoculum levels for each isolate were more consistent between trials, and the modified method was 6 to 8 weeks faster. Production with the modified method can also be easily scaled up by infesting a greater volume of vermiculite with additional cultures of Phytophthora. These results are important because they help explain variability in soilborne Phytophthora inoculum production and storage and provide a new method for producing inoculum more quickly.

Virulence of Five Phytophthora Species Causing Rhododendron Root Rot in Oregon.

Phytophthora root rot is a destructive disease of rhododendron that causes substantial losses of this nursery crop in infested field and container production areas. Historically, Phytophthora cinnamomi was considered the main causal agent of the disease. However, a recent survey of soilborne Phytophthora species from symptomatic rhododendrons in Oregon revealed that P. plurivora is more common than P. cinnamomi, and that several other Phytophthora species may be involved. We investigated the ability of the five most abundant species from the survey to cause root rot: P. plurivora, P. cinnamomi, P. pini, P. pseudocryptogea, and P. cambivora. Three to four isolates were selected for each species from across six Oregon nurseries. Media of containerized Rhododendron catawbiense 'Boursault' was infested with single isolates in a randomized complete block design in a greenhouse. Phytophthora cinnamomi, P. pini, and P. plurivora rapidly caused ≥90% of severe root rot, whereas P. pseudocryptogea caused more moderate disease (46% of severe root rot). Phytophthora cambivora failed to produce enough inoculum and was used at a lower inoculum density than the other four species; however, occasionally, it caused severe root rot (5% incidence). No differences in virulence were observed among isolates of the same species, except for one isolate of P. plurivora that caused less disease than other P. plurivora isolates. This study demonstrates that all five Phytophthora species, which were representative of 94% of the survey isolates, are capable of causing severe root rot and plant death, but that not all species are equally virulent.

Phytophthora Species Differ in Response to Phosphorous Acid and Mefenoxam for the Management of Phytophthora Root Rot in Rhododendron.

Phytophthora root rot, caused by many soilborne Phytophthora spp., is a significant disease affecting the $42 million rhododendron nursery industry. Rhododendron growers have increasingly reported failure by two systemic fungicides, phosphorous acid and mefenoxam, to adequately control root rot. Both fungicides may be applied as a foliar spray or soil drench but it is unknown how application method, fungicide chemistry, or pathogen diversity affects disease control. Therefore, two experiments were conducted to (i) determine whether differences in application method or fungicide chemistry affect control of root rot caused by P. cinnamomi and P. plurivora and (ii) evaluate the sensitivity of Phytophthora spp. and isolates from the rhododendron industry to each fungicide. Results demonstrated that soil drenches of either fungicide were more effective than foliar sprays for control of P. cinnamomi but were ineffective for P. plurivora. Furthermore, Phytophthora spp. and isolates varied in sensitivity to phosphorous acid and mefenoxam, and there were multiple fungicide-insensitive isolates, especially within P. plurivora. Differences in sensitivity were also observed among isolates from different nurseries and production systems, with some nurseries having less sensitive isolates than others and with container systems generally having less sensitive isolates than field systems. Our results provide three potential reasons for why fungicide control of Phytophthora root rot might fail: (i) the fungicide can be applied to the wrong portion of the plant for optimal control, (ii) there are differences in fungicide sensitivity among soilborne Phytophthora spp. and isolates infecting rhododendron, and (iii) fungicide-insensitive isolates are present in the rhododendron nursery industry.

Soilborne Phytophthora and Pythium Diversity From Rhododendron in Propagation, Container, and Field Production Systems of the Pacific Northwest.

Rhododendron root rot is a severe disease that causes significant mortality in rhododendrons. Information is needed about the incidence and identity of soilborne Phytophthora and Pythium species causing root rot in Pacific Northwest nurseries in order to better understand the disease etiology and to optimize disease control strategies. The last survey focusing solely on soilborne oomycete pathogens in rhododendron production was conducted in 1974. Since then, advances in pathogen identification have occurred, new species may have been introduced, pathogen communities may have shifted, and little is known about Pythium species affecting this crop. Therefore, a survey of root-infecting Phytophthora and Pythium species was conducted at seven nurseries from 2013 to 2017 to (i) document the incidence of root rot damage at each nursery and stage of production, (ii) identify soilborne oomycetes infecting rhododendron, and (iii) determine whether there are differences in pathogen diversity among nurseries and production systems. Rhododendrons from propagation, container, and field systems were sampled and Phytophthora and Pythium species were isolated from the roots and collar region. Root rot was rarely evident in propagation systems, which were dominated by Pythium species. However, severe root rot was much more common in container and field systems where the genus Phytophthora was also more prevalent, suggesting that Phytophthora species are the primary cause of severe root rot and that most contamination by these pathogens comes in after the propagation stage. In total, 20 Pythium species and 11 Phytophthora species were identified. Pythium cryptoirregulare, Pythium aff. macrosporum, Phytophthora plurivora, and Phytophthora cinnamomi were the most frequently isolated species and the results showed that Phytophthora plurivora has become much more common than in the past. Phytophthora diversity was also greater in field systems than in propagation or container systems. Risks for Phytophthora contamination were commonly observed during the survey and included placement of potting media in direct contact with field soil, the presence of dead plants that could serve as continuous sources of inoculum, and the presence of excess water as a result of poor drainage, overirrigation, or malfunctioning irrigation equipment. In the past, research on disease development and root rot disease control in rhododendron focused almost exclusively on Phytophthora cinnamomi. More research is needed on both of these topics for the other root-infecting species identified in this survey.

Variation in Disease Severity Caused by Phytophthora cinnamomi, P. plurivora, and Pythium cryptoirregulare on Two Rhododendron Cultivars.

Rhododendrons are an important crop in the ornamental nursery industry, but are prone to Phytophthora root rot. Phytophthora root rot is a continuing issue on rhododendrons despite decades of research. Several Phytophthora species are known to cause root rot, but most research has focused on P. cinnamomi, and comparative information on pathogenicity is limited for other commonly encountered oomycetes, including Phytophthora plurivora and Pythium cryptoirregulare. In this study, three isolates each of P. cinnamomi, P. plurivora, and Py. cryptoirregulare were used to inoculate rhododendron cultivars Cunningham's White and Yaku Princess at two different inoculum levels. All three species caused disease, especially at the higher inoculum level. P. cinnamomi and P. plurivora were the most aggressive pathogens, causing severe root rot, whereas Py. cryptoirregulare was a weak pathogen that only caused mild disease. Within each pathogen species, isolate had no influence on disease. Both P. cinnamomi and P. plurivora caused more severe disease on Cunningham's White than on Yaku Princess, suggesting that the relative resistance and susceptibility among rhododendron cultivars might be similar for both pathogens. Reisolation of P. cinnamomi and P. plurivora was also greater from plants exhibiting aboveground symptoms of wilting and plant death and belowground symptoms of root rot than from those without symptoms. Results show that both P. cinnamomi and P. plurivora, but not Py. cryptoirregulare, are important pathogens causing severe root rot in rhododendron. This study establishes the risks for disease resulting from low and high levels of inoculum for each pathogen. Further research is needed to evaluate longer term risks associated with low inoculum levels on rhododendron health and to explore whether differences among pathogen species affect disease control.

Spillover adherence effects of fixed-dose combination HIV therapy.

The impact of fixed-dose combination (FDC) products on adherence to other, non-fixed regimen components has not been examined. We compared adherence to a third antiretroviral (ART) component among patients receiving a nucleoside reverse transcriptase inhibitor (NRTI) backbone consisting of the FDC Epzicom(®), GlaxoSmithKline Inc, Research Triangle Park, NC (abacavir sulfate 600 mg + lamivudine 300 mg; FDC group) versus NRTI combinations taken as two separate pills (NRTI Combo group) using data from a national sample of 30 health plans covering approximately 38 million lives from 1997 to 2005. Adherence was measured as the medication possession ratio (MPR). Multivariate logistic regression compared treatment groups based on the likelihood of achieving ≥95% adherence, with sensitivity analyses using alternative thresholds. MPR was assessed as a continuous variable using multivariate linear regression. Covariates included age, gender, insurance payer type, year of study drug initiation, presence of mental health and substance abuse disorders, and third agent class. The study sample consisted of 650 FDC and 1947 NRTI Combo patients. Unadjusted mean adherence to the third agent was higher in the FDC group than the NRTI Combo group (0.92 vs 0.85; P < 0.0001). In regression analyses, FDC patients were 48% and 39% more likely to achieve 95% and 90% third agent adherence, respectively (P ≤ 0.03). None of the other MPR specifications achieved comparable results. Among managed care patients, use of an FDC appears to substantially improve adherence to a third regimen component and thus the likelihood of achieving the accepted standard for adherence to HIV therapy of 95%.

Dutasteride vs finasteride: assessment of differences in acute urinary retention rates and surgical risk outcomes in an elderly population aged > or =65 years.

OBJECTIVE: To determine comparative differences on rates of acute urinary retention (AUR) and prostate-related surgeries among patients aged > or =65 years treated with dutasteride or finasteride. METHODS: For this retrospective analysis, medical/pharmacy claims data from July 1, 2003, to June 30, 2006, were analyzed for enlarged prostate patients aged > or =65 years treated with 5-alpha reductase inhibitors (5ARIs) regardless of alpha-blocker use. Charlson Comorbidity Index, Thomson Medstat Disease Staging, and propensity score matching techniques were used for comparative analysis. RESULTS: A total of 5090 patients met selection criteria. After 1 year of 5ARI therapy, the AUR rate was lower for dutasteride (12%) when compared with finasteride (14.7%) (odds ratio [OR], 0.79; P = .0042). Risks for prostate-related surgeries were also lower among dutasteride-treated patients (3.9% vs 5.1%, respectively; OR, 0.77; P = .03). CONCLUSION: Important therapeutic outcome differences exist between dutasteride and finasteride. Patients treated with dutasteride were significantly less likely to experience AUR and prostate-related surgeries than finasteride patients.

Comparative analysis of alpha-blocker utilization in combination with 5-alpha reductase inhibitors for enlarged prostate in a managed care setting among Medicare-aged men.

OBJECTIVE: To evaluate the likelihood of alpha-adrenergic antagonist (alpha-blocker) discontinuation in combination with dutasteride or finasteride among patients aged > or =65 years with enlarged prostate. METHOD: This retrospective analysis used 2003-2006 data representing more than 30 million managed care members. Medical/pharmacy claims were used to select patients, matched 1:1 using propensity scoring. The proportion remaining on alpha-blocker therapy more than 12 months and time to discontinuation were compared between groups, controlling for covariates using survival analysis. RESULTS: The matched sample included 1674 patients. Alpha-blocker therapy discontinuation was observed at 90 days (86.9% dutasteride patients and 91.8% finasteride patients remained on alpha-blocker therapy). After 12 months, more dutasteride patients discontinued (38.1% remained) alpha-blocker therapy than finasteride patients (56.3% remained). CONCLUSIONS: Patients discontinued alpha-blocker therapy as early as 3 months. Those taking dutasteride were 64% more likely to discontinue alpha-blocker therapy than patients taking finasteride. Dutasteride's impact on discontinuation may have important implications and should be examined further.

A predictive model of health state utilities for HIV patients in the modern era of highly active antiretroviral therapy.

OBJECTIVE: Existing estimates of human immunodeficiency virus (HIV)-related health state utilities are inadequate for comparing alternative treatments on the basis of regimen-specific attributes such as dosing requirements or tolerability. The objective of this study was to examine the marginal impact of dosing, adverse events (AEs), and other factors on patients' health state utilities. METHODS: Treatment naive and experienced HIV patients participating in five open-label trials of highly active antiretroviral therapy (HAART) completed the 36-Item Short Form Health Survey (SF-36) instrument at various time points. SF-36 responses were converted to utilities using a previously reported algorithm. Expected utilities were estimated as a function of patient demographics, regimen attributes, disease status, and AEs using a mixed-effects maximum likelihood model. Mean utilities for five HIV health states were derived from predicted patient utilities. RESULTS: Negative predictors of utility included greater age (-0.001), prior acquired immune deficiency syndrome-defining events (-0.036), female gender (-0.038), and injection drug use (-0.056; P < 0.01 for all). Utility also depended on CD4+ cell count (P < 0.01), but not the presence of undetectable viral load. Regimen attributes were marginally associated with changes in utility. Depression was associated with the largest decrease in utility (-0.054, P < 0.001) among the AEs examined. Using the model to generate predicted utilities from the sample provided mean estimates ranging from 0.742 (SD 0.058) to 0.798 (0.052) for CD4+ counts between 0 and 99 and > or =500 cells/mm(3), respectively. CONCLUSIONS: HIV patients' health-related quality of life may be substantially affected by clinically relevant patient-, disease-, and treatment-related factors, such as injection drug use, disease status, food/drink restrictions, and AEs.

Suppressive valacyclovir therapy: impact on the population spread of HSV-2 infection.

OBJECTIVES: Recent trial results demonstrate that the transmission probability of HSV-2 in monogamous couples is nearly halved by the use of valacyclovir as suppressive therapy. GOAL: The goal of this study is to understand the potential impact of suppressive valacyclovir therapy on the transmission of HSV-2 within a population. STUDY DESIGN: A mathematical model of HSV-2 epidemiology was developed which included suppressive therapy with the efficacy observed in the clinical trial. The model represented HSV-2 spread in an age and sexual activity stratified population where rates of viral shedding declined based on time since infection. The model tested the impact of a range of suppression coverage levels. RESULTS: Suppressive therapy reduces the population incidence of HSV-2. With coverage rates of 3.2%, the incidence of HSV-2 would be reduced by between 1.8% and 2.8%. Higher coverage rates were estimated to reduce the incidence of new cases up to 13%. Starting suppression closer to the time of infection also reduces the incidence of new cases. CONCLUSION: The impact of suppressive therapy on the HSV-2 epidemic is modest at current coverage levels but could be substantially increased with higher rates of diagnosis and a focus on coverage soon after infection.

An examination of treatment patterns and costs of care among patients with benign prostatic hyperplasia.

OBJECTIVE: To examine utilization and costs of care for benign prostatic hyperplasia (BPH)-related services in a large cohort of commercially insured persons. METHODS: Pharmacy and medical claims data were obtained from 61 US healthcare plans. Men aged > or = 45 years who were newly diagnosed with BPH between January 2000 and March 2001 were identified. Each patient was followed for 12 months after diagnosis; utilization and costs were calculated for common procedures and disease-related events. Costs were estimated based on health plan payments. Univariate statistics were provided for relevant measures. RESULTS: A total of 77 040 patients were selected (mean age, 58.1 years). Thirty-six percent of patients had 1 or more urologist visits in the year after diagnosis. Two thirds of patients had a prostate-specific antigen test, whereas 7% had a prostate biopsy. A total of 14 392 patients (18.7%) received an alpha blocker during follow-up; 1860 patients (2.4%) received a 5-alpha reductase inhibitor. Approximately 2% of patients had a surgical procedure (either invasive or minimally invasive); transurethral prostatectomy costs averaged approximately dollar 5600, consisting of mean (standard deviation) costs of dollar 794 (dollar 470) for the procedure and dollar 4810 (dollar 8487) in associated inpatient costs. Re-treatment was common (18.7%) among patients with a surgical procedure, at a mean cost of dollar 1888 (dollar 1636). CONCLUSION: Most patients newly diagnosed with BPH appear to undergo watchful waiting in the year after diagnosis. Although rates of surgical intervention and adverse events at 1 year are low, these events are costly. Strategies to prevent or delay the need for surgery, such as regular examinations, testing, and use of pharmacotherapy where indicated, may further reduce the need for surgical intervention.

Minimizing resistance consequences after virologic failure on initial combination therapy: a systematic overview.

OBJECTIVE: To identify optimal first-line therapies based on the rate of virologic success (VS) and the preservation of future treatment options in antiretroviral therapy (ART)-naive subjects. DESIGN: Systematic overview of genotypic resistance mutations from clinical trials of combination ART. METHODS: Various sources were searched for studies in ART-naive subjects providing virologic response rates and genotypes from subjects with virologic failure. The International AIDS Society-USA genotypic resistance guidelines were used to calculate regimen resistance cost (RCreg) and number of active drug (AD) scores for each regimen and to rank the regimens. RESULTS: Intra- and interstudy comparisons showed higher VS rates for nonnucleoside reverse transcriptase inhibitor (NNRTI) regimens (range: 51%-76%) and boosted protease inhibitor (boosted PI) regimens (range: 55%-79%). Boosted PI failures had the lowest RCreg (range: 0.12-0.21) and the highest AD (range: 19.80-20.18) scores. NNRTI failures had higher RCreg (range: 0.00-1.22) and lower AD (range: 16.83-21) scores. CONCLUSIONS: NNRTI and boosted PI regimens provide the highest rates of VS in treatment-naive HIV-infected persons. Treatment option scores were higher in subjects who failed boosted PI- containing regimens versus NNRTI-containing regimens, however.

Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV-1-infected patients.

BACKGROUND: The ESS40013 study tested 4-drug induction followed by 3-drug maintenance as initial antiretroviral therapy (ART) to reduce HIV RNA rapidly and then to simplify to an effective yet more convenient and tolerable regimen. METHODS: Four hundred forty-eight antiretroviral-naive adults were treated with abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) and efavirenz (EFV) for the 48-week induction phase. Two hundred eighty-two patients were randomized in a 1:1 ratio to continue ABC/3TC/ZDV+EFV or to simplify to ABC/3TC/ZDV for the 48-week maintenance phase. RESULTS: The baseline median HIV RNA level and CD4 cell count were 5.08 log10 copies/mL (56%>or=100,000 copies/mL) and 210 cells/mm (48% <200 cells/mm), respectively. No significant differences were noted between ABC/3TC/ZDV+EFV and ABC/3TC/ZDV for an HIV RNA level <50 copies/mL (79% vs. 77% [intent to treat (ITT), missing=failure]; P=0.697) or time to treatment failure (P=0.75) at week 96. Drug-related adverse events were more commonly reported for ABC/3TC/ZDV+EFV than for ABC/3TC/ZDV (15% vs. 6%). Improvements in total cholesterol, low-density lipoprotein cholesterol, and triglycerides were observed in the ABC/3TC/ZDV group. Virologic failure occurred in 22 patients during induction and in 24 patients (16 in ABC/3TC/ZDV group and 8 in ABC/3TC/ZDV+EFV group; P=0.134) during maintenance. A greater proportion of patients receiving ABC/3TC/ZDV than ABC/3TC/ZDV+EFV reported perfect adherence at week 96 (88.8% vs. 79.6%; P=0.057). CONCLUSIONS: After induction with ABC/3TC/ZDV+EFV, simplification to ABC/3TC/ZDV alone maintained virologic control and immunologic response, reduced fasting lipids and ART-associated adverse events, and improved adherence.

Impact of HCV 3.0 EIA relative to HCV 2.0 EIA on blood-donor screening.

BACKGROUND: In 1996, the Ortho HCV Version 3.0 ELISA Test System (HCV 3.0 EIA) was licensed in the United States for donor screening but was neither mandated nor universally implemented. Data from two studies comparing the differential performance of HCV 3.0 EIA and HCV 2.0 EIA are presented. The first study evaluated the differential performance in a cross-section of screened whole-blood donors after implementation of HCV 3.0 EIA; the second study evaluated the differential performance of HCV 3.0 EIA in plasma donors acutely infected with HCV, identified during routine Abbott HCV 2.0 EIA and HCV NAT (using Roche Ampliscreen plate assay) donor screening. STUDY DESIGN AND METHODS: The first study evaluated HCV 3.0 EIA repeat-reactive donations from four US blood centers, identified during the first 5 months of HCV 3.0 EIA implementation. HCV EIA repeat-reactive donations confirmed by RIBA HCV 3.0 SIA were retested using both Ortho HCV Version 2.0 ELISA Test System and Abbott HCV 2.0 EIA. All EIA-discordant donations were tested by polymerase chain reaction (PCR). In the second study, Abbott HCV 2.0 EIA-nonreactive, HCV PCR-positive donors were enrolled in a follow-up study in which the index and follow-up samples were re-evaluated by HCV 3.0 EIA. RESULTS: In the first study, of 292,459 donations, 501 (0.17%) confirmed HCV 3.0 EIA-reactive donations were identified; 15 (0.005%) were nonreactive by Ortho HCV 2.0 EIA and were all HCV RNA negative. In the second study, Ortho HCV 3.0 EIA retesting of Abbott HCV 2.0 EIA-nonreactive, RNA-positive index donations identified 16 (23%) as 3.0 EIA reactive. In 42 panels with a discordant time of seroconversion, HCV 3.0 EIA sero-conversion preceded HCV 2.0 EIA in all cases (p < 0.001). Two donors with HCV 3.0 EIA-reactive index donations never seroconverted by HCV 2.0 EIA during 160 to 180 days of follow-up. CONCLUSION: These studies demonstrate that HCV 3.0 EIA compared to HCV 2.0 EIA can better detect 1) remote nonviremic HCV infections, 2) acute infection, and 3) HCV antibodies in cases of atypical seroconversion.

Economic impact of asthma therapy with fluticasone propionate, montelukast, or zafirlukast in a managed care population.

STUDY OBJECTIVE: To compare asthma-related health care expenditures among patients newly prescribed fluticasone propionate 44 or 110 microg, montelukast 5 or 10 mg, or zafirlukast 20 mg. DESIGN: Retrospective cohort analysis of medical and pharmacy claims. SETTING: University-affiliated health outcomes research center. PATIENTS: Seven hundred eighty-one patients (aged > or = 4 yrs) with asthma treated with controller therapy for 9 months (postindex period), with no claim for an inhaled corticosteroid or leukotriene modifier in the previous 9 months (preindex period). INTERVENTION: Asthma-related medical and pharmacy data from insurance claims of four managed care plans (two Northeastern, one Midwestern, and one Western) were tabulated over the pre- and postindex periods. MEASUREMENTS AND MAIN RESULTS: Numbers of patients identified were 284 beginning fluticasone propionate; 302, montelukast; and 195, zafirlukast. Fluticasone propionate treatment was associated with significantly (p<0.001) lower risk-adjusted asthma-related charges compared with montelukast and zafirlukast treatment: $528, $967, and $1359, respectively In this cohort, fluticasone propionate also was associated with fewer hospitalizations, less need for additional controller agents, and longer maintenance on the index drug compared with montelukast and zafirlukast. CONCLUSIONS: Based on these real-world data, as well as established national and international asthma guidelines, consideration should be given to inhaled corticosteroid therapy, particularly fluticasone propionate, for first-line, long-term effective management of asthma.