Onset and Progression of Persistent Choroidal Hypertransmission Defects in Intermediate Age-Related Macular Degeneration: A Novel Clinical Trial Endpoint.

PURPOSE: The appearance and growth of persistent choroidal hypertransmission defects (hyperTDs) detected on en face swept-source optical coherence tomography (SS-OCT) images from eyes with intermediate age-related macular degeneration (iAMD) were studied to determine if they could serve as novel clinical trial endpoints. DESIGN: Post hoc subgroup analysis of a prospective study. METHODS: Subjects with iAMD underwent 6 × 6 mm SS-OCT angiography imaging at their baseline and follow-up visits. The drusen volumes were obtained using a validated SS-OCT algorithm. Two graders independently evaluated all en face structural images for the presence of persistent hyperTDs. The number and area of all hyperTDs along with drusen volume were obtained from all SS-OCT angiography scans. Eyes were censored from further follow-up once exudative AMD developed. RESULTS: A total of 171 eyes from 121 patients with iAMD were included. Sixty-eight eyes developed at least 1 hyperTD. Within 1 year after developing a hyperTD, 25% of eyes developed new hyperTDs for an average of 0.44 additional hyperTDs. Over 2 years, as hyperTDs appeared, enlarged, and merged, the average area growth rate was 0.220 mm/yr using the square-root transformation strategy. A clinical trial design using the onset and enlargement of these hyperTDs for the study of disease progression in eyes with iAMD is proposed. CONCLUSIONS: The appearance and growth of persistent choroidal hyperTDs in eyes with iAMD can be easily detected and measured using en face OCT imaging and can serve as novel clinical trial endpoints for the study of therapies that may slow disease progression from iAMD to late AMD.

Control of myopia using diffusion optics spectacle lenses: 12-month results of a randomised controlled, efficacy and safety study (CYPRESS).

BACKGROUND: Mutations in the L/M cone opsin gene array cause abnormally high perceived retinal contrast and the development of myopia. Environmental factors may also lead to high visual contrast and cause myopia. Diffusion optics technology (DOT) lenses are designed to reduce contrast signalling in the retina and slow myopia progression. METHODS: The Control of Myopia Using Peripheral Diffusion Lenses Efficacy and Safety Study (CYPRESS, NCT03623074) is a 36-month, multicentre, randomised, controlled, double-masked trial evaluating two investigational spectacle lenses versus control lenses in myopic children aged 6-10, with a planned interim analysis at 12 months. The primary endpoints are change from baseline in axial length (AL) and spherical equivalent refraction (SER). RESULTS: 256 children (58% female; mean age at screening, 8.1 years) were dispensed spectacles. Across all groups, baseline averages were AL 24.02 mm (SD±0.77 mm), SER -2.01 D (SD±0.9 D) using manifest refraction, and SER -1.94 D (SD±1.0 D) using cycloplegic autorefraction. At 12 months, mean difference in SER progression for test 1 versus control was -0.40 D (p<0.0001), representing a 74% reduction and -0.32 D for Test 2 (p<0.0001), representing a 59% reduction. The difference in AL progression for test 1 versus control was 0.15 mm (p<0.0001) and test 2 versus control was 0.10 mm (p=0.0018). CONCLUSION: 12-month results from this ongoing trial demonstrate the safety and effectiveness of DOT spectacles for reducing myopic progression.

Development of Learning Curves for Bronchoscopy: Results of a Multicenter Study of Pulmonary Trainees.

BACKGROUND: There are currently no reference standards for the development of competence in bronchoscopy. RESEARCH QUESTION: The aims of this study were to (1) develop learning curves for bronchoscopy skill development and (2) estimate the number of bronchoscopies required to achieve competence. STUDY DESIGN AND METHODS: Trainees from seven North American academic centers were enrolled at the beginning of their pulmonology training. Performance during clinical bronchoscopies was assessed by supervising physicians using the Ontario Bronchoscopy Assessment Tool (OBAT). Group-level learning curves were modeled using a quantile regression growth model, where the dependent variable was the mean OBAT score and the independent variable was the number of bronchoscopies performed at the time the OBAT was completed. RESULTS: A total of 591 OBAT assessments were collected from 31 trainees. The estimated regression quantiles illustrate significantly different learning curves based on trainees' performance percentiles. When competence was defined as the mean OBAT score for all bronchoscopies rated as being completed without need for supervision, the mean OBAT score associated with competence was 4.54 (95% CI, 4.47-4.58). Using this metric, the number of bronchoscopies required to achieve this score varied from seven to 10 for the 90th percentile of trainees and from 109 to 126 for the lowest 10th percentile of trainees. When competence was defined as the mean OBAT score for the first independent bronchoscopy, the mean was 4.40 (95% CI, 4.20-4.60). On the basis of this metric, the number of bronchoscopies required varied from one to 11 for the 90th percentile of trainees and from 83 to 129 for the lowest 10th percentile of trainees. INTERPRETATION: We were able to generate learning curves for bronchoscopy across a range of trainees and centers. Furthermore, we established the average number of bronchoscopies required for the attainment of competence. This information can be used for purposes of curriculum planning and allows a trainee's progress to be compared with an established norm.

Complement C3 Inhibitor Pegcetacoplan for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Phase 2 Trial.

PURPOSE: Geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), is a major cause of blindness. Even while central visual acuity remains relatively well preserved, GA often causes considerable compromise of visual function and quality of life. No treatment currently exists. We evaluated the safety and efficacy of pegcetacoplan, a complement C3 inhibitor, for treatment of GA. DESIGN: Prospective, multicenter, randomized, sham-controlled phase 2 study. PARTICIPANTS: Two hundred forty-six patients with GA. METHODS: Patients with GA were assigned randomly in a 2:2:1:1 ratio to receive intravitreal injections of 15 mg pegcetacoplan monthly or every other month (EOM) or sham intravitreal injections monthly or EOM for 12 months with follow-up at months 15 and 18. Area and growth of GA were measured using fundus autofluorescence imaging. MAIN OUTCOME MEASURES: The primary efficacy end point was mean change in square root GA lesion area from baseline to month 12. Secondary outcome measures included mean change from baseline in GA lesion area without the square root transformation, distance of GA lesion from the fovea, best-corrected visual acuity (BCVA), low-luminance BCVA, and low-luminance visual acuity deficit. The primary safety end point was the number and severity of treatment-emergent adverse events. RESULTS: In patients receiving pegcetacoplan monthly or EOM, the GA growth rate was reduced by 29% (95% confidence interval [CI], 9-49; P = 0.008) and 20% (95% CI, 0-40; P = 0.067) compared with the sham treatment group. Post hoc analysis showed that the effect was greater in the second 6 months of treatment, with observed reductions of 45% (P = 0.0004) and 33% (P = 0.009) for pegcetacoplan monthly and EOM, respectively. Two cases of culture-positive endophthalmitis and 1 case of culture-negative endophthalmitis occurred in the pegcetacoplan monthly group. New-onset investigator-determined exudative AMD was reported more frequently in pegcetacoplan-treated eyes (18/86 eyes [20.9%] and 7/79 eyes [8.9%] in monthly and EOM groups, respectively) than in sham-treated eyes (1/81 eyes [1.2%]). CONCLUSIONS: Local C3 inhibition with pegcetacoplan resulted in statistically significant reductions in the growth of GA compared with sham treatment. Phase 3 studies will define the efficacy and safety profile further.

Short-term cardiovascular and autonomic effects of inhaled salbutamol.

Asthma independently increases the risk of developing cardiovascular disease. As inhaled ß-agonists have systemic cardiovascular effects, and elevations in arterial stiffness and sympathetic nerve activity are associated with increased cardiovascular morbidity/mortality, this study examines the effect of salbutamol use on pulse wave velocity (PWV) and muscle sympathetic nervous activity (MSNA). Healthy men and women (26.2±1.5years) were recruited for: Day 1: 4 inhalations of placebo followed by 4 inhalations of salbutamol (4×100µg); Day 2: placebo only; Day 3: carotid-femoral PWV measurements before/after placebo/salbutamol. Heart rate (HR), mean arterial pressure (MAP), and carotid-radial PWV were obtained on Day 1 and 2. MSNA was obtained on Day 1. Salbutamol increased HR and total MSNA (Baseline1: 2.8±2.8au; Placebo: 2.4±2.1au; Baseline2: 2.7±3.0au; Salbutamol: 3.3±2.9au; p=0.05), with no changes in MAP or PWV. There were no effects of placebo on HR, MSNA, or PWV. Acute salbutamol use increases sympathetic activity suggesting that salbutamol could contribute to cardiovascular morbidity/mortality in individuals using inhaled ß-agonists.

Safety of infusing rituximab at a more rapid rate in patients with rheumatoid arthritis: results from the RATE-RA study.

BACKGROUND: As recommended in the current prescribing information, rituximab infusions in patients with rheumatoid arthritis (RA) take 4.25 hours for the first infusion and 3.25 hours for subsequent infusions, which is a burden on patients and the health care system. We therefore evaluated the safety of infusing rituximab at a faster rate for an infusion period of 2 hours in patients with RA. METHODS: Patients with an inadequate response to anti-TNF who were rituximab-naive or -experienced received 2 courses of rituximab: Infusion 1 (Day 1) was administered over the standard 4.25 hours, and Infusions 2 (Day 15), 3 (Day 168) and 4 (Day 182) were administered over a faster 2-hour period. The primary endpoint was incidence of infusion-related reactions (IRRs) associated with Infusion 2. RESULTS: Of the 351 patients enrolled, 87% and 13% were rituximab-naive and -experienced, respectively. The incidence (95% CI) of IRRs associated with Infusion 1 was 16.2% (12.5%, 20.5%) and consistent with weighted historical incidence of 20.7% (19.4%, 22.1%). The incidence (95% CI) of IRRs associated with Infusions 2, 3, and 4 compared with respective weighted historical incidences at the standard infusion rate was 6.5% (4.1%, 9.7%) vs 8.1% (7.2%, 9.1%); 5.9% (3.5%, 9.3%) vs 11.5% (10.3%, 12.8%); and 0.7 (0.1%, 2.6%) vs 5.0% (4.2%, 6.0%), respectively. All IRRs were grade 1 or 2, except for 3 grade 3 IRRs associated with Infusion 1 and 2 grade 3 IRRs associated with Infusion 2. Four patients experienced a total of 5 grade 3 IRRs; 3 of these patients continued on to received subsequent infusions at the faster rate. There were no serious IRRs. CONCLUSION: This study demonstrated that rituximab can be administered at the faster infusion rate at the second and subsequent infusions without increasing the rate or severity of IRRs.

Composite Indices Using 3 or 4 Components of the Core Data Set Have Similar Predictive Ability to Measure Disease Activity in RA: Evidence from the DANCER and REFLEX Studies.

Background. Understanding how disease-assessment indices perform in rheumatoid arthritis (RA) clinical trials can inform their use in routine practice. The study objective was to assess the capacity of combinations of RA Core Data Set measures to distinguish rituximab from control treatment. Methods. Post hoc analysis of two randomised clinical trials was used. Composite Efficacy Indices were derived by combining three or four RA Core Data Set measures from three possible sources: physician, patient, and laboratory. Results. All 105 Composite Efficacy Indices evaluated significantly distinguished rituximab from control treatment (P < 10(-7)). Generally, indices containing measures from three different sources had a greater capacity to distinguish rituximab from control treatment than indices containing three measures from one source. Composite Efficacy Indices performed as well as validated indices such as DAS28, RAPID3, and CDAI. Conclusions. All indices composed of three or four RA Core Data Set measures have a similar capacity to detect treatment differences. These results suggest that the precise measurement used is less important than whether any measurement is performed, although selection should be consistent for each patient. Therefore, the choice of assessment tool should not be limited to a prescribed list and should instead be left to the clinician's discretion.

Multiple courses of rituximab produce sustained clinical and radiographic efficacy and safety in patients with rheumatoid arthritis and an inadequate response to 1 or more tumor necrosis factor inhibitors: 5-year data from the REFLEX study.

OBJECTIVE: This 5-year observational posthoc analysis of the REFLEX study and its open-label extension assessed clinical efficacy, radiographic response, and safety of rituximab (RTX) in patients with rheumatoid arthritis (RA) who had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: Patients in REFLEX were originally randomized to placebo (PBO) + methotrexate (MTX; PBO-randomized) or RTX + MTX (RTX-randomized). PBO-randomized patients were rescued with RTX as appropriate. Patients responding to initial RTX treatment could receive further RTX courses. For clinical efficacy and safety analyses, PBO-randomized patients were re-baselined prior to first RTX treatment and the data were pooled with RTX-randomized patient data. Efficacy outcomes 24 weeks after each course were calculated relative to first RTX pretreatment baseline. Radiographic outcomes were assessed relative to randomization baseline for both PBO-randomized and RTX-randomized groups. RESULTS: A total of 480 patients received ≥ 1 RTX course. At 24 weeks, American College of Rheumatology 20/50/70 responses were 62.0%, 30.8%, and 13.0%, respectively at course 1 (n = 400) and 70.3%, 41.8%, and 22.0% at course 5 (n = 91). European League Against Rheumatism good/moderate responses were 77.2% and 84.4% at courses 1 (n = 390) and 5 (n = 90). Rates of adverse events (AE), serious AE, and infections generally remained stable. Rate of progressive joint damage (PJD; change in mean Total Sharp Score) decreased over time in both PBO-randomized (n = 79) and RTX-randomized (n = 105) groups. Mean change from baseline in PJD over 5 years was greater in PBO-randomized versus RTX-randomized patients (5.51 vs 3.21). CONCLUSION: RTX re-treatment over 5 years is associated with maintained or improved efficacy, continued inhibition of PJD, and a safety profile consistent with that previously reported. A delay in initiating RTX treatment may result in increased PJD.

Sleep disturbance among older adults in assisted living facilities.

OBJECTIVES: To evaluate whether objectively and subjectively measured sleep disturbances persist among older adults in assisted living facilities (ALFs) and to identify predictors of sleep disturbance in this setting. DESIGN: Prospective, observational cohort study. SETTING AND PARTICIPANTS: A total of 121 residents, age ≥ 65 years, in 18 ALFs in the Los Angeles area. MEASUREMENTS: Objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index) sleep measures were collected at baseline and 3- and 6-month follow-up. Predictors of baseline sleep disturbance tested in bivariate analyses and multiple regression models included demographics, Mini-Mental State Examination score, number of comorbidities, nighttime sedating medication use, functional status (activities of daily living; instrumental activities of daily living), restless legs syndrome, and sleep apnea risk. RESULTS: Objective and subjective sleep measures were similar at baseline and 3- and 6-month follow-up (objective nighttime total sleep [hours] 6.3, 6.5, and 6.4; objective nighttime percent sleep 77.2, 77.7, and 78.3; and Pittsburgh Sleep Quality Index total score 8.0, 7.8, and 7.7, respectively). The mean baseline nighttime percent sleep decreased by 2% for each additional unit increase in baseline comorbid conditions (measured as the number of conditions), and increased by 4.5% for each additional unit increase in baseline activities of daily living (measured as the number of activities of daily living), in a multiple regression model. CONCLUSIONS: In this study, we found that objectively and subjectively measured sleep disturbances are persistent among ALF residents and are related to a greater number of comorbidities and poorer functional status at baseline. Interventions are needed to improve sleep in this setting.

Psychosocial care for adolescent and young adult hematopoietic cell transplant patients.

Psychological issues following hematopoietic cell transplantation (HCT) are unfortunately common. Literature specific to the transplant experience for the needs of adolescents and young adults (AYA) is lacking. The purpose of this article is to (1) describe the allogeneic transplant experience for AYA transplant patients during the first year following transplantation including demographic and treatment characteristics, (2) present AYA data obtained during and following a six-part posttransplant discharge study, (3) illustrate typical AYA experiences using case studies, and (4) propose AYA intervention strategies within Erickson's stages of psychosocial development. A quality of life model provided the research conceptual framework, and the content analysis framework for the qualitative research. Themes that emerged within each domain were the following: sexuality/fertility, fatigue, depression/poor coping/habits,adherence issues, use of technology, dependency issues, changes in roles/relationships, issues with school/education, financial issues, family problems/issues, miscellaneous, religion/spirituality, fear of future, uncertainty, life, death, more life appreciation. These data guide us for providing targeted interventions for the needs of this AYA population. This paper has presented literature and developmental theory, qualitative and qualitative data from an intervention study, and clinical cases in order to propose a developmental treatment model for AYA transplant patients. A coordinated and multidisciplinary approach is needed for the HCT patient who is an AYA.

Incidence of retinal pigment epithelial tears after intravitreal ranibizumab injection for neovascular age-related macular degeneration.

OBJECTIVE: To explore the association between treatment for neovascular age-related macular degeneration (AMD) and incidence and timing of retinal pigment epithelium (RPE) tears in ranibizumab-treated patients versus control treatment. DESIGN: Results from 3 phase III clinical trials (ANti-VEGF antibody for the treatment of predominantly classic CHORoidal neovascularization in age-related macular degeneration [ANCHOR], Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular Age-related macular degeneration [MARINA], and A Phase IIIb, Multicenter, Randomized, Double-Masked, Sham Injection-Controlled Study of the Efficacy and Safety of Ranibizumab in Subjects with Subfoveal Choroidal Neovascularization [CNV] with or without Classic CNV Secondary to Age-Related Macular Degeneration [PIER]) were retrospectively reviewed to identify patients who developed RPE tears during the study period, detected on fluorescein angiography performed at prespecified intervals. PARTICIPANTS: Patients with baseline and post-baseline angiographic assessments. METHODS: Patients received intravitreal ranibizumab (0.3 or 0.5 mg) or control treatment (verteporfin photodynamic therapy [PDT] in ANCHOR and sham intravitreal injections in ANCHOR, MARINA, and PIER). MAIN OUTCOME MEASURES: Incidence and timing of RPE tears during the treatment period. RESULTS: Data from 1298 patients were analyzed. No statistically significant differences in RPE tear incidence were observed. The pooled rate of RPE tears was 1.8% with 0.5 mg ranibizumab, 3.0% with 0.3 mg ranibizumab, and 1.6% in the control group. Most (76%; 16/21) RPE tears in ranibizumab-treated patients were identified within 3 months of initiating treatment, whereas the majority (80%; 4/5) of late-onset RPE tears occurred in control patients. In patients who developed RPE tears, better visual acuity (VA) outcomes were observed in those treated with ranibizumab versus control treatment. CONCLUSIONS: As studied in these trials, no statistically significant differences in the incidence of RPE tears within a 2-year treatment period were observed in patients who received ranibizumab (0.5 or 0.3 mg) versus control treatment, although most RPE tears with ranibizumab occurred within 3 months of initiating treatment. Mean VA was better in patients who developed RPE tears while receiving ranibizumab than in those who received control treatment, suggesting a potential benefit of continued ranibizumab therapy in patients with neovascular AMD who developed RPE tears. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration (FOCUS): year 2 results.

PURPOSE: To assess the efficacy and adverse-events profile of combined treatment with ranibizumab and verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization (CNV) secondary to neovascular age-related macular degeneration. DESIGN: Two-year, multicenter, randomized, single-masked, controlled study. METHODS: Patients received monthly intravitreal injections of ranibizumab 0.5 mg (n = 106) or sham injections (n = 56). All patients received PDT on day zero, then quarterly as needed. Efficacy assessment included changes in visual acuity (VA) and lesion characteristics and PDT frequency. Adverse events were summarized by incidence and severity. RESULTS: At month 24, 88% of ranibizumab + PDT patients had lost <15 letters from baseline VA (vs 75% for PDT alone), 25% had gained >or=15 letters (vs 7% for PDT alone), and the two treatment arms differed by 12.4 letters in mean VA change (P < .05 for all between-group differences). The VA benefit of adding ranibizumab to PDT in year one persisted through year two. On average, ranibizumab + PDT patients exhibited less lesion growth and greater reduction of CNV leakage and subretinal fluid accumulation, and required fewer PDT retreatments, than PDT-alone patients (mean = 0.4 vs 3.0 PDT retreatments). Endophthalmitis and serious intraocular inflammation occurred, respectively, in 2.9% and 12.4% of ranibizumab + PDT patients and 0% of PDT-alone patients. Incidences of serious nonocular adverse events were similar in the two treatment groups. CONCLUSIONS: Through two years, ranibizumab + PDT was more effective than PDT alone and had a low rate of associated adverse events.

Ranibizumab combined with verteporfin photodynamic therapy in neovascular age-related macular degeneration: year 1 results of the FOCUS Study.

OBJECTIVE: To investigate the safety and efficacy of intravitreal ranibizumab treatment combined with verteporfin photodynamic therapy (PDT) in patients with predominantly classic choroidal neovascularization secondary to age-related macular degeneration. METHODS: In this 2-year, phase I/II, multicenter, randomized, single-masked, controlled study, patients received monthly ranibizumab (0.5 mg) (n = 106) or sham (n = 56) injections. The PDT was performed 7 days before initial ranibizumab or sham treatment and then quarterly as needed. MAIN OUTCOMES MEASURES: Proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months (primary efficacy outcome) and the incidence and severity of adverse events. RESULTS: At 12 months, 90.5% of the ranibizumab-treated patients and 67.9% of the control patients had lost fewer than 15 letters (P<.001). The most frequent ranibizumab-associated serious ocular adverse events were intraocular inflammation (11.4%) and endophthalmitis (1.9%; 4.8% if including presumed cases). On average, patients with serious inflammation had better visual acuity outcomes at 12 months than did controls. Key serious nonocular adverse events included myocardial infarctions in the PDT-alone group (3.6%) and cerebrovascular accidents in the ranibizumab-treated group (3.8%). CONCLUSION/APPLICATION TO CLINICAL PRACTICE: Ranibizumab + PDT was more efficacious than PDT alone for treating neovascular age-related macular degeneration. Although ranibizumab treatment increased the risk of serious intraocular inflammation, affected patients, on average, still experienced visual acuity benefit.

Ranibizumab for neovascular age-related macular degeneration.

BACKGROUND: Ranibizumab--a recombinant, humanized, monoclonal antibody Fab that neutralizes all active forms of vascular endothelial growth factor A--has been evaluated for the treatment of neovascular age-related macular degeneration. METHODS: In this multicenter, 2-year, double-blind, sham-controlled study, we randomly assigned patients with age-related macular degeneration with either minimally classic or occult (with no classic lesions) choroidal neovascularization to receive 24 monthly intravitreal injections of ranibizumab (either 0.3 mg or 0.5 mg) or sham injections. The primary end point was the proportion of patients losing fewer than 15 letters from baseline visual acuity at 12 months. RESULTS: We enrolled 716 patients in the study. At 12 months, 94.5% of the group given 0.3 mg of ranibizumab and 94.6% of those given 0.5 mg lost fewer than 15 letters, as compared with 62.2% of patients receiving sham injections (P<0.001 for both comparisons). Visual acuity improved by 15 or more letters in 24.8% of the 0.3-mg group and 33.8% of the 0.5-mg group, as compared with 5.0% of the sham-injection group (P<0.001 for both doses). Mean increases in visual acuity were 6.5 letters in the 0.3-mg group and 7.2 letters in the 0.5-mg group, as compared with a decrease of 10.4 letters in the sham-injection group (P<0.001 for both comparisons). The benefit in visual acuity was maintained at 24 months. During 24 months, presumed endophthalmitis was identified in five patients (1.0%) and serious uveitis in six patients (1.3%) given ranibizumab. CONCLUSIONS: Intravitreal administration of ranibizumab for 2 years prevented vision loss and improved mean visual acuity, with low rates of serious adverse events, in patients with minimally classic or occult (with no classic lesions) choroidal neovascularization secondary to age-related macular degeneration. (ClinicalTrials.gov number, NCT00056836 [ClinicalTrials.gov].).

Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models.

BACKGROUND: Combination therapy of ribavirin with interferon alfa-2b and pegylated interferon alfa-2b is currently approved for the treatment of chronic hepatitis C. Approved ribavirin dosages vary from a fixed dosage of 800 mg/d to as much as 1200 mg/d on the basis of body weight. OBJECTIVE: Our objective was to evaluate ribavirin dosing strategies by comparison of their relative efficacy and toxicity profiles. METHODS: Three models were developed on the basis of data collected from a large phase III trial. A population pharmacokinetic model was used to describe the ribavirin dose-concentration relationship and the influence of covariates. Logistic regression models were developed for both sustained virologic response and hematologic toxicity. Ribavirin concentration was an important explanatory variable for both response and toxicity. Simulations of these models were developed for different ribavirin doses to obtain efficacy and toxicity profiles across the various dosing strategies. These strategies included a fixed 800-mg/d dose, empiric weight-adjusted doses (ie, 1000 mg/d for patients who weighed < or =75 kg and 1200 mg/d for patients who weighed >75 kg [1000/1200 mg/d on the basis of body weights < or =75/>75 kg] and 800 mg/d for patients who weighed <65 kg, 1000 mg/d for patients who weighed from 65 to 85 kg, and 1200 mg/d for patients who weighed >85 kg [800/1000/1200 mg/d on the basis of body weights <65/65-85/>85 kg]), a dose of 13 mg/kg per day, and other per-body weight doses between 9 and 16 mg/kg per day. RESULTS: Simulation results showed that both efficacy and toxicity increased as the milligrams-per-kilogram dose of ribavirin increased. The body weight-based 800/1000/1200-mg/d dose had overall response and toxicity rates that were 6.3% and 2.5% higher than those of the fixed 800-mg/d dose. In particular, patients with genotype-1 disease had a 7.4% increase in response rate. There were no differences in response and toxicity rates between the 800/1000/1200-mg/d and 13-mg/kg per day dose groups. CONCLUSIONS: This simulation suggests that ribavirin dosage (in combination with pegylated interferon alfa-2b) for patients with chronic hepatitis C should be based on body weight.