Progression from Early/Intermediate to Advanced Forms of Age-Related Macular Degeneration in a Large UK Cohort: Rates and Risk Factors.

PURPOSE: To estimate rates and risk factors for progression to geographic atrophy (GA) or choroidal neovascularization (CNV) among eyes diagnosed with early or intermediate age-related macular degeneration (AMD) in clinical practice. DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database from the United Kingdom. PARTICIPANTS: Patients aged 50 years or more with diagnosis of early/intermediate AMD in at least 1 eye (the study eye) and no evidence of CNV or GA in the study eye, from 10 clinical sites using the EMR. METHODS: Anonymized data for 40 543 patients with a diagnosis of early/intermediate AMD were extracted between October 2000 and February 2016 from EMR database records held in the 10 sites. A sample of records randomly selected from each center was used to validate disease definitions. Records were analyzed by subgroup, based on the AMD status of the fellow eye. Multivariate Cox regression models identified other predictors of disease progression. MAIN OUTCOME MEASURES: Progression rate (per 100 person-years) to GA or CNV in study eyes with early/intermediate AMD by fellow eye status and identified risk factors for progression. RESULTS: Study eyes with early/intermediate AMD and a diagnosis of CNV in the fellow eye progressed to CNV fastest (at a rate of 15.2 per 100 person-years), and those with a diagnosis of GA in the fellow eye progressed to GA fastest (11.2 per 100 person-years), compared with the rates per 100 person-years of progression to CNV (3.2-11.9) or GA (2.0-7.8) in the other subgroups. In individuals with bilateral early/intermediate AMD, rates of progression to GA or CNV were 2.0 and 3.2 per 100 person-years, respectively. In the multivariate model, age, female sex, and cardiovascular disease were associated with an increased risk for progression to advanced AMD, whereas diabetes and glaucoma were associated with a decreased rate of progression (hazard ratios, 0.45 and 0.64, respectively). CONCLUSIONS: Progression to GA or CNV was observed frequently in eyes with early/intermediate AMD, with the status of the fellow eye affecting the rate of progression. Novel associations with risk factors were observed and require replication in other cohorts.

Natural History of Geographic Atrophy Secondary to Age-Related Macular Degeneration: Results from the Prospective Proxima A and B Clinical Trials.

PURPOSE: To better characterize visual function decline and geographic atrophy (GA) progression secondary to age-related macular degeneration (AMD). DESIGN: Proxima A (NCT02479386)/Proxima B (NCT02399072) were global, prospective, noninterventional, observational clinical trials. PARTICIPANTS: Eligible patients were aged ≥50 years. Patients in Proxima A had bilateral GA without choroidal neovascularization (CNV) in either eye (N = 295). Patients in Proxima B had GA without CNV in the study eye and CNV±GA in the fellow eye (fellow eye CNV cohort, n = 168) or GA without CNV in the study eye, no CNV/GA in the fellow eye (fellow eye intermediate AMD cohort, n = 32). METHODS: Changes in visual function and imaging/anatomic parameters were evaluated over time using a mixed model for repeated measurement accounting for key baseline characteristics. MAIN OUTCOME MEASURES: Prespecified end points included change in GA area from baseline, best-corrected visual acuity (BCVA) score assessed by Early Treatment Diabetic Retinopathy Study (ETDRS), and visual acuity under low-luminance (LLVA). RESULTS: At 24 months, adjusted mean (standard error) change in GA lesion area from baseline was 3.87 (0.15) mm2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm2 in the fellow eye intermediate AMD cohort (Proxima B). Progression of GA was greater in patients with baseline nonsubfoveal (vs. subfoveal) GA lesions and tended to increase as baseline low-luminance deficit increased (all patients). Conversion to GA or CNV in the fellow eye occurred in 30% and 6.7% of participants, respectively, in the Proxima B intermediate AMD cohort at month 12. Adjusted mean (standard error) changes in BCVA and LLVA (ETDRS letters) in the study eye from baseline to 24 months were -13.88 (1.40) and -7.64 (1.20) in Proxima A, -9.49 (1.29) and -7.57 (1.26) in Proxima B fellow eye CNV cohort, and -11.48 (3.39) and -8.37 (3.02) in Proxima B fellow eye intermediate AMD cohort, respectively. CONCLUSIONS: The prospective Proxima A and B studies highlight the severe functional impact of GA and the rapid rate of GA lesion progression over a 2-year period, including in patients with unilateral GA at baseline.

Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use.

PURPOSE: To gain comprehensive information on the burden of illness due to geographic atrophy (GA). METHODS: This cross-sectional study with a retrospective chart review involved patients aged ≥70 years with physician-confirmed bilateral symptomatic GA due to age-related macular degeneration (GA group), as well as patients of similar age with no ophthalmic condition that in the opinion of the investigator affected visual function (non-GA group). Data relating to patients' current disease status and sociodemographics were self-reported on patient questionnaires at study entry and extracted from patient charts. Historical data on health care resource utilization (HCRU) were also collected via patient questionnaires and retrospective chart review (GA group only). Overall vision-related functioning and quality of life (QoL) were compared between the GA and non-GA groups using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) composite and subscales, and change in vision over the past year was assessed using the Global Rating of Change Scale. RESULTS: Vision-related functioning and QoL were poorer in patients with vs without GA (n=137 vs 52), as demonstrated by significantly lower NEI-VFQ-25 composite score (mean, 53.1 vs 84.5 points, respectively; P<0.001), as well as lower subscale scores for near activities, distance activities, dependency, driving, social functioning, mental health, role difficulties, color vision, and peripheral vision. Substantially more patients with GA than without GA reported worsening in vision over the past year (82% vs 25%, respectively; odds ratio, 13.55; P<0.001). In the GA group, associated mean annual costs for direct ophthalmological resource use per patient amounted to €1772 (mostly for tests/procedures), and for indirect ophthalmological resource use, €410 (mostly for general practitioner visits). CONCLUSION: Patients with GA experience a poorer level of vision-related function and QoL than their peers, especially in relation to driving. GA is also associated with notable HCRU/associated costs, mostly direct costs attributed to diagnostic tests/procedures.

Direct Ophthalmic Healthcare Resource Use among Patients with Geographic Atrophy in a Large Cohort from the United Kingdom.

PURPOSE: To estimate the direct ophthalmic healthcare resource use in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective analysis of anonymized data derived from electronic medical records (EMRs) acquired at 10 clinical sites in the United Kingdom. PARTICIPANTS: Patients aged ≥50 years with ≥1 eye with a clinical record of GA or, for comparison, bilateral early/intermediate AMD. Four subgroups were identified: GA in both eyes (GA:GA); GA in 1 eye, choroidal neovascularization (CNV) in the fellow eye (GA:CNV); GA in 1 eye with early or intermediate AMD in the fellow eye (GA:E); and early/intermediate AMD in both eyes (E:E). METHODS: The EMRs were analyzed to derive the median number of visits over the first 2 years after diagnosis of GA or early/intermediate AMD. Clinical tests recorded at visits were used to calculate estimated costs (payer perspective) of monitoring. Analyses were restricted to patients with an initial diagnosis on or after January 1, 2011, to represent present day monitoring and costs associated with AMD. MAIN OUTCOME MEASURES: Median number of visits and estimated monitoring costs per patient (in £) over the first 2 years among patients with ≥2 years of follow-up and in the individual subgroups. Intravitreal treatment costs in the GA:CNV group were excluded. RESULTS: For all 3 GA subgroups (n = 1080), the median number of visits over the first 2 years was 5, and monitoring costs were £460.80 per patient. The GA:CNV subgroup (n = 355) had the highest number of visits (median, 15), with a cost of £1581, compared with the GA:E subgroup (n = 283; median 4 visits; cost ∼£369) and the GA:GA subgroup (n = 442; median 3 visits; cost ∼£277). Ophthalmic tests were conducted most frequently in the GA:CNV subgroup. Visits and costs in the E:E subgroup (n = 6079) were lower. CONCLUSIONS: Resource use in patients with GA varies considerably and is strongly influenced by the concomitant presence of CNV and lack of monitoring strategies for GA.

Self-reported healthcare utilization by adults with diabetic retinopathy in the United States.

PURPOSE: To assess healthcare utilization patterns across diabetic retinopathy (DR) severity levels in the United States (US). DESIGN: Cross-sectional study of 699 adults, participating in the 2005-2008 National Health and Nutritional Examination Surveys. METHODS: Diagnosis of DR was based on fundus photographs and categorized as: (1) no DR; (2) mild/moderate nonproliferative DR (NPDR); and (3) severe NPDR/proliferative DR (PDR). Healthcare utilization patterns were assessed during a household questionnaire where survey participants self-reported: (1) awareness that diabetes had affected their eyes; (2) pupil-dilation during the past year; and (3) visits to a diabetes education/nutrition specialist during the past year. RESULTS: Among adults with self-reported diabetes, the proportion of those that were aware that diabetes had affected their eye was 15.3% [95% confidence interval (C.I.)] 10.9-19.6%), 21.7% (95% C.I. 14.6-28.7%), and 81.5% (95% C.I. 66.5-96.5%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p < 0.01). The utilization of a diabetic education/nutrition specialist during the past year was 30.4% (95% C.I. 24.8-36.0%), 31.8% (95% C.I 23.4-40.2%), and 55.9% (95% C.I. 32.3-79.6%) across those with no retinopathy, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.13). Pupil dilation within the past year was 62.2% (95% C.I. 56.3-68.1%), 62.1% (95% C.I. 53.4-70.8%), and 93.8% (95% C.I. 87.3-100.0%) across those with no DR, mild/moderate NPDR, and severe NPDR/PDR, respectively (p = 0.01). CONCLUSIONS: Adults with diabetes in the United States, even those with the most severe forms of DR, do not fully utilize healthcare services for diabetic eye disease. Future studies should aim to address barriers to appropriate diabetes care.

Characterizing Disease Burden and Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration.

PURPOSE: To understand levels of disease burden and progression in a real-world setting among patients from the United Kingdom with bilateral geographic atrophy (GA) secondary to age-related macular degeneration (AMD). DESIGN: Retrospective cohort analysis of a multicenter electronic medical record (EMR) database. PARTICIPANTS: Patients who were aged ≥50 years with bilateral GA and no history of choroidal neovascularization (CNV) and who attended 1 of 10 clinical sites using the EMR. METHODS: A deidentified data set was constructed from the records held at the 10 sites. An algorithm was used to extract cases with a GA diagnosis, of which 1901 had bilateral GA and form the basis of this report. A sample of records randomly selected from each center was used to validate disease definitions. MAIN OUTCOME MEASURES: Progression to blindness (visual acuity [VA] <20 letters or Snellen 3/60 in the better-seeing eye), driving ineligibility (VA ≤70 letters or Snellen 6/12 in the better-seeing eye), progression to CNV, loss of 10 or more letters, and mean change in VA over time. RESULTS: At first record of GA, 7.1% had a VA in the better-seeing eye equal to or lower than the cutoff for blindness registration and 71.1% had a VA that would have rendered them ineligible to drive. Over time, 16% became legally blind (median time to outcome, 6.2 years) and 66.7% became ineligible to drive (median time to outcome, 1.6 years). In the worse-seeing eye, 40.1% lost ≥10 letters in 2.4 years. Among patients with baseline and 24-month VA measurements, mean VA decline was 6.1 letters in the worse-seeing eye (n = 413) and 12.4 letters in the better-seeing eye (n = 414). The rate of progression to CNV in either eye was 7.4% per patient-year. CONCLUSIONS: At initial diagnosis, based on VA in the better-seeing eye, a high proportion of patients with bilateral GA were ineligible to drive and approximately 7% were eligible for UK blindness registration. The subsequent reduction in VA that occurred in the better-seeing eye would render a further two-thirds ineligible to drive. These findings emphasize the severity of the visual disability associated with GA secondary to AMD.

The Systemic Safety of Ranibizumab in Patients 85 Years and Older with Neovascular Age-Related Macular Degeneration.

OBJECTIVE: Ranibizumab safety is well established for treatment of neovascular age-related macular degeneration (nAMD), but less is known about the risk of systemic serious adverse events (SAEs), specifically among patients with heightened baseline risk due to age (≥85 years). This analysis examines whether patients ≥85 years of age versus those <85 years experience an increased risk of key systemic SAEs during intravitreal ranibizumab treatment for nAMD. DESIGN: Retrospective, pooled analysis of safety data from 5 phase III/IIIb multicenter randomized clinical trials in patients with nAMD: ANCHOR, MARINA, PIER, SAILOR, and HARBOR. PARTICIPANTS: Patients with nAMD receiving ranibizumab (n = 4347) or control (sham/verteporfin photodynamic therapy, n = 441) treatment included in the safety-evaluable set of the 5 trials. METHODS: The incidence of nonocular SAEs was analyzed stratified by age (<85 years [n = 3795] vs ≥85 years [n = 993]), treatment (control, ranibizumab 0.3 mg, ranibizumab 0.5 mg, ranibizumab 2.0 mg), and injection frequency (monthly, as needed [PRN]). MAIN OUTCOME MEASURES: Incidence of key systemic SAEs, defined as total nonocular SAEs, deaths, cardiovascular events, cerebrovascular (CBV) events, and Antiplatelet Trialists' Collaboration events. RESULTS: The MARINA and ANCHOR trials had greater rates of key SAEs for patients ≥85 years versus those <85 years. Ranibizumab exposure did not increase the risk of most SAEs in elderly patients; for CBV events and death, the effect of ranibizumab versus control treatment for age ≥85 years was not interpretable due to small number of events (CBV: n = 2, 2, 5 for control, ranibizumab 0.3 mg, and ranibizumab 0.5 mg, respectively; death: n = 2, 4, 5, respectively). Across all 5 trials, an increased risk was found for age ≥85 years versus <85 years for the marketed dose of ranibizumab 0.5 mg. In the HARBOR trial, increased rates of key SAEs (excluding total nonocular SAEs) for age ≥85 years versus <85 years were observed with monthly dosing but not with PRN dosing; event rates were similar for 2.0 mg versus 0.5 mg. CONCLUSIONS: Consistent with general trends, the risk of key systemic SAEs was associated with age ≥85 years versus <85 years, but not with ranibizumab drug exposure. The difference between monthly versus PRN was inconclusive. There was no evidence of a dose effect. Interpretation of this retrospective analysis is limited because it was not prospectively powered for statistically definitive conclusions.

Vision-Related Functional Burden of Diabetic Retinopathy Across Severity Levels in the United States.

Importance: Among adults with diabetes in the United States, severe forms of diabetic retinopathy (DR) are significantly associated with a greater vision-related functional burden. Objective: To assess the functional burden of DR across severity levels in the United States. Design, Setting, and Participants: This cross-sectional study was based on 1004 participants 40 years or older with diabetes and valid ocular and sociodemographic outcomes in the National Health and Nutrition Examination Surveys (NHANES) (2005-2006 and 2007-2008). Diabetic retinopathy was based on fundus photograph grading, using the Early Treatment Diabetic Retinopathy Study severity scale. The analysis was performed from October 15, 2016, to June 15, 2017. Main Outcomes and Measures: Functional difficulties secondary to vision were assessed during a household questionnaire in which participants self-reported difficulty with reading, visuospatial tasks (ie, close-up work or finding things on a crowded shelf), mobility (ie, walking down steps, stairs, or curbs), and driving. The main outcome measure was vision-related functional burden, which was defined as present for individuals reporting moderate or greater difficulty in any of the aforementioned tasks. Results: Of the 1004 persons with diabetes analyzed for this study (mean age, 65.7 years [95% CI, 64.0-67.3 years]; 51.1% male [95% CI, 47.1-55.2] and 48.9% female [95% CI, 44.8-52.9]), the prevalence was 72.3% for no retinopathy, 25.4% for mild and moderate nonproliferative diabetic retinopathy (NPDR), and 2.3% for severe NPDR or proliferative diabetic retinopathy (PDR). The prevalence of vision-related functional burden was 20.2% (95% CI, 16.3%-24.1%) for those with no retinopathy, 20.4% (95% CI, 15.3%-27.8%) for those with mild and moderate NPDR, and 48.5% (95% CI, 25.6%-71.5%) for those with severe NPDR or PDR (P = .02). In multivariable analysis, the odds of vision-related functional burden were significantly greater among those with severe NPDR or PDR relative to those with no retinopathy (adjusted odds ratio [aOR], 3.59; 95% CI, 1.29-10.05; P = .02). Those with severe NPDR or PDR did not have a statistically significant greater odds of vision-related functional burden than did those with mild or moderate NPDR (aOR, 2.70; 95% CI, 0.93-7.78; P = .07). Conclusions and Relevance: Among US adults with diabetes, approximately half of those with severe NPDR or PDR had difficulty with at least one visual function task. Moreover, vision-related functional burden was significantly greater among those with severe NPDR or PDR than among those with no retinopathy. These data suggest the importance of preventing severe forms of DR to mitigate the vision-related functional burden among US adults with diabetes. Future studies should complement our study by assessing the association of worsening retinopathy with objectively measured functional outcomes.

Treatment Patterns for Myopic Choroidal Neovascularization in the United States: Analysis of the IRIS Registry.

PURPOSE: To characterize treatment patterns and outcomes in eyes with treatment-naïve myopic choroidal neovascularization (mCNV) in the United States. DESIGN: Retrospective cohort study. PARTICIPANTS: Individuals aged 18 years and older seen in clinics participating in the American Academy of Ophthalmology's IRIS (Intelligent Research in Sight) Registry. METHODS: We analyzed data from the IRIS Registry, from January 1, 2012 to December 31, 2014, to identify cases of treatment-naïve mCNV, which was defined as the presence of myopic refractive error worse than -6.0 diopters with the presence of subretinal/choroidal neovascularization as indicated by International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of "362.16: Retinal Neovascularization NOS." MAIN OUTCOME MEASURES: Type of initial treatment for mCNV was categorized as the administration of 1 of the following within the first 365 days after the diagnosis date: (1) observation (i.e., no treatment); (2) intravitreal anti-VEGF injection; (3) verteporfin photodynamic therapy (vPDT); or (4) laser photocoagulation. We assessed the difference between logarithm of the minimal angle of resolution (logMAR) visual acuity (VA) on the diagnosis date (baseline) and 1 year after the diagnosis date. Anti-VEGF injection frequency per treated eye over a 1-year period was also estimated. RESULTS: We identified 185 patients with treatment-naïve mCNV in 1 or both eyes. Treatment within 1 year of diagnosis was recorded for 73.0% (135/185); the remainder was classified as "observation." Nearly all treatment (134/135; 99.3%) consisted of anti-VEGF injections; 0.7% (1/135) received vPDT. Those treated with anti-VEGF injections showed significant improvement in VA at 1 year (mean logMAR VA improvement of 0.17 units, 95% confidence interval [CI], 0.12-0.20, P < 0.01), whereas those who were not treated showed a significant decline in VA at 1 year (mean logMAR VA decline: 0.03 units, 95% CI, 0.008-0.05, P < 0.01). The mean number of anti-VEGF injections for an eye with mCNV during the first year after diagnosis was 2.8 (standard deviation, 2.5) (median, 2.0; interquartile range, 1.0-4.0). CONCLUSIONS: In the United States, anti-VEGF injection was the most frequently utilized treatment for mCNV. Those treated were observed to gain vision. However, one quarter of patients received no treatment and lost vision. Further studies are needed to understand the sociodemographic and health-systems barriers surrounding the delivery of anti-VEGF injections to patients with mCNV.

The Prevalence of Myopic Choroidal Neovascularization in the United States: Analysis of the IRIS(®) Data Registry and NHANES.

PURPOSE: To determine the prevalence of high myopia (HM), progressive high (degenerative) myopia (PHM), and myopic choroidal neovascularization (mCNV) in the United States. DESIGN: Cross-sectional study. PARTICIPANTS: Individuals aged 18 years and older participating in the National Health and Nutrition Examination Survey (NHANES) and patients aged 18 years and older seen in clinics participating in the American Academy of Ophthalmology's Intelligent Research in Sight (IRIS(®)) Registry. METHODS: We analyzed NHANES data from 2005 to 2008 to determine the prevalence of HM in the United States. This prevalence was then applied to estimates from the US Population Census (2014) to arrive at a population burden of HM at the diopter level in the United States. Data from the IRIS Registry were used to calculate the real-world prevalence rates of PHM and mCNV among patients with HM at the diopter level. This was subsequently applied to this reference population with HM to calculate the diopter-adjusted prevalence and population burden of PHM and mCNV in the United States in 2014. MAIN OUTCOME MEASURES: High myopia was defined as myopic refractive error of ≤6.0 diopters in the right eye. Progressive HM was defined as HM with the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code of "360.21: Progressive High (Degenerative) Myopia." Myopic CNV was defined as HM with the presence of subretinal/choroidal neovascularization indicated by the ICD-9-CM diagnosis of "362.16: Retinal Neovascularization NOS." RESULTS: The estimated diopter-adjusted prevalence of HM, PHM, and mCNV was 3.92% (95% confidence interval [CI], 2.82-5.60), 0.33% (95% CI, 0.21-0.55), and 0.017% (95% CI, 0.010-0.030), respectively, among adults in the United States aged 18 years and older in 2014. This translated into a population burden of approximately 9 614 719 adults with HM, 817 829 adults with PHM, and 41 111 adults with mCNV in the United States in 2014. CONCLUSIONS: Although HM and PHM impose a relatively large burden among adults in the United States, mCNV seems to be a rare disease. Relating data from the IRIS Registry and NHANES could be a novel method for assessing ophthalmic disease prevalence in the United States. Future studies should aim to better assess current treatment patterns and optimal management strategies of this condition.

Pragmatic clinical trials: U.S. payers' views on their value.

BACKGROUND: Randomized controlled trials (RCTs) reflect priorities established by regulators. Recently, pragmatic clinical trials (PCTs) have begun to attract interest. Unlike RCTs, PCTs aim to better inform post-regulatory decision making by using head-to-head comparisons of alternative treatments, diverse patient populations, and outcomes meaningful to patients, prescribers, and payers. OBJECTIVES: To describe how U.S. insurers and public payers perceive the value of PCTs for assessment of new prescription drugs. STUDY DESIGN: Criterion-based sample of U.S. insurers and public payers. METHODS: We gathered qualitative evidence from intensive interviews with formulary decision makers at 15 payers, representing 10 major types of U.S. payers. Prior literature and exploratory interviews informed our question selection. RESULTS: Payers viewed PCTs favorably despite wariness of drug company-sponsored trials. Payers would accept results from PCTs as part of payers' synthesis of multiple sources of evidence. Payers were enthusiastic about 2 PCT features-a diverse population (compared with the more homogeneous populations typical of RCTs) and an active comparator drug (not placebo). Payers did not anticipate that PCTs would displace their own analyses of internal data. Pharmaceutical companies' financial interest in obtaining trial results that favor their own drugs reduces PCTs' perceived value and dampens their appeal to payers; nonetheless, payers would seek PCT results and review them carefully, as they do other evidence. CONCLUSIONS: Recommendations to trial designers based on payers' views include tailoring different types of PCTs to different disease conditions, building in head-to-head comparisons in phase IIIb PCTs, and designing phase IV PCTs to include broader populations.

Comprehensive review of factors implicated in the heterogeneity of response in depression.

BACKGROUND: Heterogeneity in overall response and outcomes to pharmacological treatment has been reported in several depression studies but with few sources that integrate these results. The goal of this study was to review the literature and attempt to identify nongenetic factors potentially predictive of overall response to depression treatments. METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant studies that met the inclusion criteria were selected and scored for their levels of evidence using the NICE scoring method. A subjective assessment of the strength of evidence for each factor was performed using predefined criteria. RESULTS: Our broad search yielded 76 articles relevant to treatment heterogeneity. Sociodemographic factors, disease characteristics, and comorbidities were the most heavily researched areas. Some of the factors associated with more favorable overall response include being married, other social support, and low levels of baseline depressive symptoms. Evidence relating to baseline disease severity as a factor predictive of antidepressant response was particularly convincing among the factors reviewed. The presence of comorbid anxiety and pain contributed to worse antidepressant treatment outcomes. CONCLUSIONS: Several factors either predictive of or associated with overall response to antidepressant treatment have been identified. Inclusion of factors predictive of response in the design of future trials may help tailor treatments to depression patients presenting to the average clinical practice, resulting in improved outcomes.

Review of treatment response in rheumatoid arthritis: assessment of heterogeneity.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic, systemic, progressive, inflammatory disorder. The primary goals of treatment in RA are to reduce the signs and symptoms of disease, prevent progression of joint damage and improve patients' physical function. Patients with different sociodemographic characteristics, varying degrees of severity of illness, and comorbidities tend to exhibit differential response to treatment. The purpose of this review was to identify a broad set of factors that are associated with and/or predictive of RA treatment response and determine those that warrant further research. RESEARCH DESIGN AND METHODS: A comprehensive review of the literature from the last 10 years was performed using three key databases (PubMed, EMBASE, and Cochrane). All relevant articles that met the inclusion/exclusion criteria were selected and scored for their levels of evidence using the National Institute of Clinical Excellence (NICE) scoring method. Data on study design, interventions and treatment outcomes were abstracted using a structured abstraction table. RESULTS: A total of 30 articles were included in the review and data abstraction. Besides gender, baseline clinical variables such as C-reactive protein level, erythrocyte sedimentation rate, measures of disease activity, and Health Assessment Questionnaire scores (based on five patient-centered dimensions) were consistently associated with treatment response over time. CONCLUSIONS: This comprehensive literature review identified several factors associated with treatment response which might be valuable to include as relevant measures in future studies of RA treatment. Inclusion of these factors, particularly those in the clinical and sociodemographic domains, in the design of future trials will further the understanding that ultimately may help clinicians deliver targeted treatment to community practice RA patients, thus resulting in improved patient outcomes.

A cluster randomized trial of routine HIV-1 viral load monitoring in Zambia: study design, implementation, and baseline cohort characteristics.

BACKGROUND: The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree). METHODOLOGY: Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months. PRINCIPAL FINDINGS: From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites. CONCLUSIONS: A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings. TRIAL REGISTRATION: Clinicaltrials.gov NCT00929604.

An empirical approach to defining loss to follow-up among patients enrolled in antiretroviral treatment programs.

In many programs providing antiretroviral therapy (ART), clinicians report substantial patient attrition; however, there are no consensus criteria for defining patient loss to follow-up (LTFU). Data on a multisite human immunodeficiency virus (HIV) treatment cohort in Lusaka, Zambia, were used to determine an empirical "days-late" definition of LTFU among patients on ART. Cohort members were classified as either "in care" or LTFU as of December 31, 2007, according to a range of days-late intervals. The authors then looked forward in the database to determine which patients actually returned to care at any point over the following year. The interval that best minimized LTFU misclassification was described as "best-performing." Overall, 33,704 HIV-infected adults on ART were included. Nearly one-third (n = 10,196) were at least 1 day late for an appointment. The best-performing LTFU definition was 56 days after a missed visit, which had a sensitivity of 84.1% (95% confidence interval (CI): 83.2, 85.0), specificity of 97.5% (95% CI: 97.3, 97.7), and misclassification of 5.1% (95% CI: 4.8, 5.3). The 60-day threshold performed similarly well, with only a marginal difference (<0.1%) in misclassification. This analysis suggests that > or =60 days since the last appointment is a reasonable definition of LTFU. Standardization to empirically derived definitions of LTFU will permit more reliable comparisons within and across programs.

Intrapartum tenofovir and emtricitabine reduces low-concentration drug resistance selected by single-dose nevirapine for perinatal HIV prevention.

A single dose of tenofovir/emtricitabine (TDF/FTC) during labor significantly reduces peripartum nevirapine-associated viral drug resistance when measured by consensus HIV sequencing. It is unknown whether this effect extends to HIV subpopulations of <25-50%. We conducted a randomized trial of single-dose TDF/FTC added to peripartum nevirapine to reduce drug resistance associated with nonnucleoside reverse transcriptase inhibitors (NNRTIs). To detect mutations for NNRTIs comprising > or = 2% of the viral population, we used an oligonucleotide ligation assay (OLA) at codons 103, 106, 181, and 190 of HIV reverse transcriptase. To assess development of drug resistance mutations to our study intervention, OLA was also performed at codons 65 and 184. Among the 328 women included in the 2-week analysis, those receiving TDF/FTC were less likely to have NNRTI resistance by OLA (RR = 0.40, 95% CI = 0.21-0.77). A similar trend was observed among the 315 women included in the 6-week analysis (RR = 0.45, 95% CI = 0.31-0.66). Only two (1%) specimens had detectable K65R by OLA. Both were at 6 weeks postpartum; one was detected in the intervention arm and one in the control arm (p = 0.96). M184V was not detected. The ability of single-dose TDF/FTC to protect against peripartum NVP-induced NNRTI resistance extends to minority populations. This efficacy is achieved without significant selection of TDF- or FTC-resistant viruses.

Adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in Lusaka, Zambia.

BACKGROUND: High-level adherence to antiretroviral therapy (ART) is associated with favourable patient outcomes. In resource-constrained settings, however, there are few validated measures. We examined the correlation between clinical outcomes and the medication possession ratio (MPR), a pharmacy-based measure of adherence. METHODS: We analysed data from a large programmatic cohort across 18 primary care centres providing ART in Lusaka, Zambia. Patients were stratified into three categories based on MPR-calculated adherence over the first 12 months: optimal (> or =95%), suboptimal (80-94%) and poor (<80%). RESULTS: Overall, 27 115 treatment-naïve adults initiated and continued ART for > or =12 months: 17 060 (62.9%) demonstrated optimal adherence, 7682 (28.3%) had suboptimal adherence and 2373 (8.8%) had poor adherence. When compared with those with optimal adherence, post-12-month mortality risk was similar among patients with sub-optimal adherence [adjusted hazard ratio (AHR) = 1.0; 95% CI: 0.9-1.2] but higher in patients with poor adherence (AHR = 1.7; 95% CI: 1.4-2.2). Those <80% MPR also appeared to have an attenuated CD4 response at 18 months (185 cells/microl vs 217 cells/microl; P < 0.001), 24 months (213 cells/microl vs 246 cells/microl; P < 0.001), 30 months (226 cells/microl vs 261 cells/microl; P < 0.001) and 36 months (245 cells/microl vs 275 cells/microl; P < 0.01) when compared with those above this threshold. CONCLUSIONS: MPR was predictive of clinical outcomes and immunologic response in this large public sector antiretroviral treatment program. This marker may have a role in guiding programmatic monitoring and clinical care in resource-constrained settings.

Estimated 10-year stroke risk by region and race in the United States: geographic and racial differences in stroke risk.

OBJECTIVE: Black individuals younger than 75 years have more than twice the risk for stroke death than whites in the United States. Regardless of race, stroke death is approximately 50% greater in the "stroke belt" and "stroke buckle" states of the Southeastern United States. We assessed geographic and racial differences in estimated 10-year stroke risk. METHODS: The Reasons for Geographic and Racial Differences in Stroke study is a population-based cohort of men and women 45 years or older, recruited February 2003 to September 2007 at this report, with oversampling of stroke belt/buckle residents and blacks. Racial and regional differences in the Framingham Stroke Risk Score were studied in 23,940 participants without previous stroke or transient ischemic attack. RESULTS: The mean age-, race-, and sex-adjusted 10-year predicted stroke probability differed slightly across regions: 10.7% in the belt, 10.4% in the buckle, and 10.1% elsewhere (p <0.001). Geographic differences were largest for the score components of diabetes and use of antihypertensive therapy. Blacks had a greater age- and sex-adjusted mean 10-year predicted stroke probability than whites: 12.0 versus 9.2%, respectively (p <0.001). Race differences were largest for the score components of hypertension, systolic blood pressure, diabetes, smoking, and left ventricular hypertrophy. INTERPRETATION: Although blacks had a greater predicted stroke probability than whites, regional differences were small. Results suggest that interventions to reduce racial disparities in stroke risk factors hold promise to reduce the racial disparity in stroke mortality. The same may not be true regarding geographic disparities in stroke mortality.