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Praveen J Patel,1 Focke Ziemssen,2 Eugene Ng,3 Anushini Muthutantri,4 David Silverman,5 Elizabeth A Tschosik,6 Ronald A Cantrell6 1NIHR Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust, and University College London Institute of Ophthalmology, London, UK; 2University of Tuebingen, Tuebingen, Germany; 3Institute of Eye Surgery, UPMC Whitfield and Waterford Institute of Technology, Waterford, Ireland; 4IQVIA, London, UK; 5Roche Products Limited, Welwyn Garden City, Hertfordshire, UK; 6Genentech, Inc., A Member of the Roche Group, South San Francisco, CA, USACorrespondence: David SilvermanOphthalmology, Roche Products Limited, 6 Falcon Way, Shire Park, Welwyn Garden City AL7 1TW, UKTel +44 1707 36 6394Email david.silverman@roche.comPurpose: 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

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. [ABSTRACT FROM AUTHOR]

Context: The Zambian Ministry of Health provides pediatric antiretroviral therapy (ART) at primary care clinics in Lusaka, where, despite scale-up of perinatal prevention efforts, many children are already infected with the human immunodeficiency virus (HIV).Objective: To report early clinical and immunologic outcomes of children enrolled in the pediatric treatment program.Design, Setting, and Patients: Open cohort assessment using routinely collected clinical and outcome data from an electronic medical record system in use at 18 government primary health facilities in Lusaka, Zambia. Care was provided primarily by nurses and clinical officers ("physician extenders" akin to physician assistants in the United States). Patients were children (<16 years of age) presenting for HIV care between May 1, 2004, and June 29, 2007.Intervention: Three-drug ART (zidovudine or stavudine plus lamivudine plus nevirapine or efavirenz) for children who met national treatment criteria.Main Outcome Measures: Survival, weight gain, CD4 cell count, and hemoglobin response.Results: After enrollment of 4975 children into HIV care, 2938 (59.1%) started ART. Of those initiating ART, the median age was 81 months (interquartile range, 36-125), 1531 (52.1%) were female, and 2087 (72.4%) with World Health Organization stage information were in stage III or IV. At the time of analysis, 158 children (5.4%) had withdrawn from care and 382 (13.0%) were at least 30 days late for follow-up. Of the remaining 2398 children receiving ART, 198 (8.3%) died over 3018 child-years of follow-up (mortality rate, 6.6 deaths per 100 child-years; 95% confidence interval [CI], 5.7-7.5); of these deaths, 112 (56.6%) occurred within 90 days of therapy initiation (early mortality rate, 17.4/100 child-years; post-90-day mortality rate, 2.9/100 child-years). Mortality was associated with CD4 cell depletion, lower weight-for-age, younger age, and anemia in multivariate analysis. The mean CD4 cell percentage at ART initiation among the 1561 children who had at least 1 repeat measurement was 12.9% (95% CI, 12.5%-13.3%) and increased to 23.7% (95% CI, 23.1%-24.3%) at 6 months, 27.0% (95% CI, 26.3%-27.6%) at 12 months, 28.0% (95% CI, 27.2%-28.8%) at 18 months, and 28.4% (95% CI, 27.4%-29.4%) at 24 months.Conclusions: Care provided by clinicians such as nurses and clinical officers can result in good outcomes for HIV-infected children in primary health care settings in sub-Saharan Africa. Mortality during the first 90 days of therapy is high, pointing to a need for earlier intervention. [ABSTRACT FROM AUTHOR]

Context: The Zambian Ministry of Health has scaled-up human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care and treatment services at primary care clinics in Lusaka, using predominately nonphysician clinicians.Objective: To report on the feasibility and early outcomes of the program.Design, Setting, and Patients: Open cohort evaluation of antiretroviral-naive adults treated at 18 primary care facilities between April 26, 2004, and November 5, 2005. Data were entered in real time into an electronic patient tracking system.Intervention: Those meeting criteria for antiretroviral therapy (ART) received drugs according to Zambian national guidelines.Main Outcome Measures: Survival, regimen failure rates, and CD4 cell response.Results: We enrolled 21,755 adults into HIV care, and 16,198 (75%) started ART. Among those starting ART, 9864 (61%) were women. Of 15,866 patients with documented World Health Organization (WHO) staging, 11,573 (73%) were stage III or IV, and the mean (SD) entry CD4 cell count among the 15,336 patients with a baseline result was 143/microL (123/microL). Of 1142 patients receiving ART who died, 1120 had a reliable date of death. Of these patients, 792 (71%) died within 90 days of starting therapy (early mortality rate: 26 per 100 patient-years), and 328 (29%) died after 90 days (post-90-day mortality rate: 5.0 per 100 patient-years). In multivariable analysis, mortality was strongly associated with CD4 cell count between 50/microL and 199/microL (adjusted hazard ratio [AHR], 1.4; 95% confidence interval [CI], 1.0-2.0), CD4 cell count less than 50/microL (AHR, 2.2; 95% CI, 1.5-3.1), WHO stage III disease (AHR, 1.8; 95% CI, 1.3-2.4), WHO stage IV disease (AHR, 2.9; 95% CI, 2.0-4.3), low body mass index (<16; AHR,2.4; 95% CI, 1.8-3.2), severe anemia (<8.0 g/dL; AHR, 3.1; 95% CI, 2.3-4.0), and poor adherence to therapy (AHR, 2.9; 95% CI, 2.2-3.9). Of 11,714 patients at risk, 861 failed therapy by clinical criteria (rate, 13 per 100 patient-years). The mean (SD) CD4 cell count increase was 175/microL (174/microL) in 1361 of 1519 patients (90%) receiving treatment long enough to have a 12-month repeat.Conclusion: Massive scale-up of HIV and AIDS treatment services with good clinical outcomes is feasible in primary care settings in sub-Saharan Africa. Most mortality occurs early, suggesting that earlier diagnosis and treatment may improve outcomes. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether the types and rates of post-surgical complications associated with the Port Delivery System with ranibizumab (PDS) are comparable with those reported for other ocular implants that cross the sclera., Methods: Systematic literature reviews were conducted to determine the long-term (≥ 18-month) safety of ocular implants that cross the sclera in clinical trials and real-world studies. Complication types and rates were compared with those reported for the PDS in phase III clinical trials (Archway, Pagoda, and Pavilion)., Results: Sixteen clinical trials (24 publications) and 43 real-world studies were identified reporting 30 complications in eyes with 15 implant types and 8 ocular diseases. Implants were associated with an acceptable, well-characterized safety profile, with most complications resolving spontaneously or with treatment. Device-related complications were reported in 0.7% (0.0-5.0%) of study eyes in clinical trials and 1.3% (0.0-14.5%) of eyes in real-world studies. Rates of conjunctival complications were 2.1% (0.0-22.8%) and 2.2% (0.9-4.6%), respectively. The overall types and rates of adverse events of special interest reported for the PDS in phase III trials (cataract, conjunctival bleb, vitreous hemorrhage, conjunctival erosion, conjunctival retraction, endophthalmitis, implant dislocation, retinal detachment, and hyphema) were within the ranges reported for other ocular implants., Conclusions: The rates of complications reported in phase III clinical trials for the PDS were within the ranges reported for other ocular implants that cross the sclera. This suggests that the long-term safety of the PDS is consistent with other ocular devices established in ophthalmology clinical practice., Trial Registration: PROSPERO international prospective register of systematic reviews: CRD5202234129, CRD42022343129., (© 2024. The Author(s).)

Competing Interests: Disclosure: The authors disclose no financial or other conflicts of interest.

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., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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) mm 2 in participants with bilateral GA (Proxima A), 3.55 (0.16) mm 2 in the fellow eye CNV cohort (Proxima B), and 2.96 (0.25) mm 2 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., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

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.

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., (Copyright © 2017 American Academy of Ophthalmology. All rights reserved.)

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., (Copyright © 2016 American Academy of Ophthalmology. All rights reserved.)

We apply multiscale methods to describe the strained growth of multiple layers of C60 on a thin film of pentacene. We study this growth in the presence of a monolayer pentacene step to compare our simulations to recent experimental studies by Breuer and Witte of submonolayer growth in the presence of monolayer steps. The molecular-level details of this organic semiconductor interface have ramifications on the macroscale structural and electronic behavior of this system and allow us to describe several unexplained experimental observations for this system. The growth of a C60 thin film on a pentacene surface is complicated by the differing crystal habits of the two component species, leading to heteroepitactical growth. In order to probe this growth, we use three computational methods that offer different approaches to coarse-graining the system and differing degrees of computational efficiency. We present a new, efficient reaction-diffusion continuum model for 2D systems whose results compare well with mesoscale kinetic Monte Carlo (KMC) results for submonolayer growth. KMC extends our ability to simulate multiple layers but requires a library of predefined rates for event transitions. Coarse-grained molecular dynamics (CGMD) circumvents KMC's need for predefined lattices, allowing defects and grain boundaries to provide a more realistic thin film morphology. For multilayer growth, in this particularly suitable candidate for coarse-graining, CGMD is a preferable approach to KMC. Combining the results from these three methods, we show that the lattice strain induced by heteroepitactical growth promotes 3D growth and the creation of defects in the first monolayer. The CGMD results are consistent with experimental results on the same system by Conrad et al. and by Breuer and Witte in which C60 aggregates change from a 2D structure at low temperature to 3D clusters along the pentacene step edges at higher temperatures.

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.

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., (© 2012 Wiley Periodicals, Inc.)

A novel multilattice kinetic Monte Carlo algorithm is developed for heteroepitactical growth of a hexagonal lattice material (C60) on an oblique lattice material (pentacene). This algorithm captures the behavior of single molecule and small clusters of C60 molecules diffusing, clustering, and reorganizing as monolayers on the surface and switching lattices depending on their local environment. An extensive catalog of jump rates and energy barriers created from molecular dynamics simulations and molecular mechanics is used as the sole input to the method in order to follow the evolution of C60 growth on pentacene for time scales approaching a millisecond that are unattainable using molecular dynamics alone.

The tendency for C(60) nanowires to persist on two monolayers of recumbent pentacene is studied using molecular dynamics (MD) simulations. A review of existing experimental literature for the tilt angle adopted by pentacene on noble metal surfaces shows that studies cover a limited range from 55° to 90°, motivating simulation studies of essentially the entire range of tilt angles (10°-90°) to predict the optimum surface tilt angle for C(60) nanowire formation. The persistence of a 1D nanowire depends sensitively on this tilt angle, the amount of initial tensile strain, and the presence of surface step edges. At room temperature, C(60) nanowires oriented along the pentacene short axes persist for several nanoseconds and are more likely to occur if they reside between, or within, pentacene rows for ϕ ≤ ∼60°. The likelihood of this persistence increases the smaller the tilt angle. Nanowires oriented along the long axes of pentacene molecules are unlikely to form. The limit of stability of nanowires was tested by raising the temperature to 400 K. Nanowires located between pentacene rows survived this temperature rise, but those located initially within pentacene rows are only stable in the range ϕ(1) = 30°-50°. Flatter pentacene surfaces, that is, tilt angles above about 60°, are subject to disorder caused by C(60) molecules "burrowing" into the pentacene surface. An initial strain of 5% applied to the C(60) nanowires significantly decreases the likelihood of nanowire persistence. In contrast, any appreciable surface roughness, even by half a monolayer in height of a third pentacene monolayer, strongly enhances the likelihood of nanowire formation due to the strong binding energy of C(60) molecules to step edges.

Aim: To assess and present the current body of evidence regarding composite measures associated with differential treatment response or outcome as a result of patient heterogeneity and to evaluate their consistency across disease areas., Methods: A comprehensive review of the literature from the last 10 years was performed using three databases (PubMed, Embase and Cochrane). All articles that met the inclusion/exclusion criteria were selected, abstracted and assessed using the NICE level-of-evidence criteria., Results: Forty-nine studies were identified in the data abstraction. Approximately one-third focused on existing composite measures, and the rest investigated emerging composite factors. The majority of studies targeted patients with cancer, cardiovascular disease or psychological disorders. As a whole, the composite measures were found to be disease-specific, but some composite elements, including age, gender, comorbidities and health status, showed consistency across disease areas. To complement these findings, common individual factors found in five previous independent disease-specific literature assessments were also summarised, including age, gender, treatment adherence and satisfaction, healthcare resource utilisation and health status., Conclusions: Composite measures can play an important role in characterising heterogeneity of treatment response and outcome in patients suffering from various medical conditions. These measures can help clinicians to better distinguish between patients with high likelihood to respond well to treatment and patients with minimal chances of positive therapeutic outcomes. Herein, the individual factors identified can be used to develop novel predictive or prognostic composite measures that can be applicable across disease areas. Reflecting these cross-disease measures in clinical and public health decisions has the distinctive appeal to enable targeted treatment for patients suffering from multiple medical conditions, which may ultimately yield significant gains in individual outcomes, population health and cost-effective resource allocation., (© 2011 Blackwell Publishing Ltd.)

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.

The response to treatment for type 2 diabetes typically varies among individuals within a study population. This variation is known as heterogeneity of treatment response. We conducted a comprehensive literature review to identify factors that account for heterogeneity of treatment response in patients treated for type 2 diabetes. Three databases (PubMed, EMBASE and Cochrane Library) were searched for articles published in the last 10 years describing investigations of factors associated with treatment response and outcomes among people with type 2 diabetes receiving pharmacological treatment. Of the 43 articles extracted and summarized, 35 (81%) discussed clinical factors, 31 (72%) described sociodemographic factors and 17 (40%) reported on comorbidity or behavioural factors. Clinical factors identified included baseline glycated hemoglobin A1c or fasting plasma glucose (FPG) levels, insulin response or sensitivity, C-peptide, body composition, adipose tissue proteins, lipid profile, plasma albumin levels and duration of disease or insulin treatment. Other factors identified included age, sex, race, socioeconomic status and comorbidities. This review identified the following research gaps: use of multiple definitions for response, few patient-reported measures and lack of evidence regarding whether factors were associated with treatment response for only specific medications or across pharmacological therapies. Furthermore, identification of factors associated with type 2 diabetes treatment response was generally a secondary objective in the research reviewed. Understanding which patient subgroups are more likely to respond to treatment and identifying factors associated with response may result in targeted treatment decisions and alter the interpretation of efficacy or effectiveness of results. In conclusion, accounting for these factors in clinical trials and when making clinical treatment decisions may improve therapy selection and individual patient outcomes., (© 2010 Eli Lilly and Company.)

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.

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.

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.

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.

Background: The provision of food supplementation to food-insecure patients initiating antiretroviral therapy (ART) may improve adherence to medications., Methods: A home-based adherence support program at 8 government clinics assessed patients for food insecurity. Four clinics provided food supplementation, and 4 acted as controls. The analysis compared adherence (assessed by medication possession ratio), CD4, and weight gain outcomes among food-insecure patients enrolled at the food clinics with those enrolled at the control clinics., Results: Between May 1, 2004, and March 31, 2005, 636 food- insecure adults were enrolled. Food supplementation was associated with better adherence to therapy. Two hundred fifty-eight of 366 (70%) patients in the food group achieved a medication possession ratio of 95% or greater versus 79 of 166 (48%) among controls (relative risk = 1.5; 95% confidence interval: 1.2 to 1.8). This finding was unchanged after adjustment for sex, age, baseline CD4 count, baseline World Health Organization stage, and baseline hemoglobin. We did not observe a significant effect of food supplementation on weight gain or CD4 cell response., Conclusions: This analysis suggests that providing food to food-insecure patients initiating ART is feasible and may improve adherence to medication. A large randomized study of the clinical benefits of food supplementation to ART patients is urgently needed to inform international policy.

Objective: To examine the association between baseline renal insufficiency and mortality among adults initiating antiretroviral therapy (ART) in an urban African setting., Design: Open cohort evaluation., Methods: We examined mortality according to baseline renal function among adults initiating ART in Lusaka, Zambia. Renal function was assessed by the Cockcroft-Gault method, the Modification of Diet in Renal Disease equation, and serum creatinine., Results: From April 2004 to September 2007, 25 779 individuals started ART with an available creatinine measurement at baseline. When creatinine clearance was calculated by the Cockcroft-Gault method, 8456 (33.5%) had renal insufficiency: 73.5% were mild (60-89 ml/min), 23.4% moderate (30-59 ml/min), and 3.1% severe (<30 ml/min). Risk for mortality at or before 90 days was elevated for those with mildly [adjusted hazard ratio (AHR)(1/4)1.7; 95% confidence interval (95% CI)(1/4)1.5-1.9], moderately (AHR(1/4)2.3; 95% CI(1/4)2.0-2.7), and severely (AHR(1/4)4.3; 95% CI(1/4)3.1-5.5) reduced creatinine clearance. Mild (AHR(1/4)1.4; 95% CI(1/4)1.2-1.6), moderate (AHR(1/4)1.9; 95% CI(1/4)1.5-2.3), and severe (AHR(1/4)3.6; 95% CI(1/4) 2.4-5.5) insufficiency were also associated with increased mortality after 90 days, when compared with those with normal renal function. Trends were similar when renal function was estimated with Modification of Diet in Renal Disease or serum creatinine., Conclusion: Renal insufficiency at time of ART initiation was prevalent and associated with increased mortality risk among adults in this population. These results have particular relevance for settings like Zambia, where tenofovir--a drug with known nephrotoxicity--has been adopted as part of first-line therapy. This emphasizes the need for resource-appropriate screening algorithms for renal disease, both as part of ART eligibility and pretreatment assessment.

We evaluated the association between two antiretroviral therapy (ART) adherence measurements--the medication possession ratio (MPR) and patient self-report--and detectable HIV viremia in the setting of rapid service scale-up in Lusaka, Zambia. Drug adherence and outcomes were assessed in a subset of patients suspected of treatment failure based on discordant clinical and immunologic responses to ART. A total of 913 patients were included in this analysis, with a median time of 744 days (Q1, Q3: 511, 919 days) from ART initiation to viral load (VL) measurement. On aggregate over the period of follow-up, 531 (58%) had optimal adherence (MPR > or =95%), 306 (34%) had suboptimal adherence (MPR 80-94%), and 76 (8%) had poor adherence (MPR <80%). Of the 913 patients, 238 (26%) had VL > or =400 copies/ml when tested. When compared to individuals with optimal adherence, there was increasing risk for virologic failure in those with suboptimal adherence [adjusted relative risk (ARR): 1.3; 95% confidence interval (CI): 1.0, 1.6] and those with poor adherence (ARR: 1.7; 95% CI: 1.3, 2.4) based on MPR. During the antiretroviral treatment course, 676 patients (74%) reported no missed doses. The proportion of patients with virologic failure did not differ significantly among those reporting any missed dose from those reporting perfect adherence (26% vs. 26%, p = 0.97). Among patients with suspected treatment failure, a lower MPR was associated with higher rates of detectable viremia. However, the suboptimal sensitivity and specificity of MPR limit its utility as a sole predictor of virologic failure.

Background: Zambia faces overlapping tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics; however, care for co-infected patients often occurs through separate, vertical programs., Objective: To establish a program to integrate TB and HIV services in Lusaka primary care centers., Methods: In collaboration with the Zambian Ministry of Health, TB-HIV integration activities began in December 2005 and were expanded to seven health centers by March 2007. Principal activities included developing staff capacity to manage co-infected patients, implementing HIV testing within TB departments and establishing referral systems between departments., Results: Using a provider-initiated approach, 2053 TB patients were offered HIV testing. Seventy-seven per cent agreed to be tested; 69% of those tested were HIV-infected. Of these, 59% were enrolled in HIV care. The proportion of antiretroviral treatment (ART) program enrollees who were TB-HIV co-infected increased by 38% after program implementation. The median CD4 count among co-infected patients was 161 cells/microl, with 88% eligible for ART., Conclusion: Integration of HIV testing and referral services into urban primary care centers identified many co-infected patients and significantly increased the proportion of TB patients among people accessing HIV care. Ongoing challenges include maximizing the number of patients accepting HIV testing and overcoming barriers to enrollment into HIV care.

Objective: To determine the impact of adjuvant single-dose peripartum tenofovir/emtricitabine (TDF/FTC) on intrapartum/early postpartum HIV transmission., Methods: In the setting of routine short-course zidovudine (ZDV) and peripartum nevirapine (NVP) for perinatal HIV prevention, participants were randomized to single-dose TDF (300 mg)/FTC (200 mg) or to no intervention in labor. Six-week infant HIV infection was compared according to actual-use drug regimens., Results: Of 397 women randomized, 355 (89%) had infants who were alive and active at 6 weeks postpartum. Of these, 18 (5.1%) were infected in utero and 6 (1.8%) were infected intrapartum/early postpartum. Among the 243 who used ZDV and NVP, intrapartum/early postpartum transmission was not reduced among infants whose mothers received TDF/FTC compared with those who did not (2 of 123 [1.6%] vs. 3 of 109 [2.8%]; P = 0.67). Among the 49 infants whose mothers did not receive antenatal ZDV but who had confirmed NVP ingestion, transmission similarly did not differ (0 of 19 [0%] vs. 1 of 26 [3.4%]). TDF/FTC was not significantly associated with reduced overall transmission (odds ratio [OR] = 0.7, 95% confidence interval [CI]: 0.3 to 1.6), even when other antiretroviral drugs were considered (adjusted OR = 0.8, 95% CI: 0.3 to 1.8)., Conclusions: Adjuvant peripartum single-dose TDF/FTC did not reduce perinatal transmission. Whether a higher dose might be effective remains unknown but should be studied in settings in which NVP is used without antenatal ZDV.

Timely adherence to clinical and pharmacy appointments is well correlated with favourable patient outcomes among HIV-infected individuals on antiretroviral therapy. To date, however, there is little work exploring reasons behind missed visits or evaluating programmatic strategies to recall patients. For this study we implemented community-based follow-up of late patients as part of a large-scale programme for HIV care and treatment in Lusaka, Zambia. Through a network of local home-based care organizations, we attempted home visits to recall patients using locator information provided at time of enrolment. Between May and September 2005, home-based caregivers were dispatched to trace 1,343 patients with missed appointments. Of these, 554 (41%) were untraceable because the provided address was invalid, the patient had moved or no one was at the home. Of the remaining 789, 359 (46%) were reported to have died. Only 430 (54% of those traced, 32% overall) were contacted directly and encouraged to return for care. The likelihood of patient return was higher among traced patients in crude analysis (relative risk [RR] = 2.5; 95%CI = 1.9-3.2) and in multivariable analysis controlling for baseline body mass index, sex and CD4 + count < or = 50/microL (adjusted RR = 2.3; 95%CI = 1.7-3.2). However, the process was inefficient: one late patient returned for every 18 home visits that were made. Reasons for missed visits were provided in 271 of 430 (63%) of the patients who were successfully traced. Common reasons included feeling too sick to come to the clinic, travelling away from home and being too busy. Despite the availability of free ART in Lusaka, patients face significant barriers to attending scheduled clinical visits. Cost-effective and feasible strategies are urgently needed to improve timely patient follow-up.

Objective: To determine whether prior exposure to single-dose nevirapine (NVP) for prevention of mother-to-child HIV transmission (PMTCT) is associated with attenuated CD4 cell response, death, or clinical treatment failure in women starting antiretroviral therapy (ART) containing non-nucleoside reverse transcriptase inhibitors (NNRTI)., Methods: Open cohort evaluation of outcomes for women in program sites across Zambia. HIV treatment was provided according to Zambian/World Health Organization guidelines., Results: Peripartum NVP exposure status was known for 6740 women initiating NNRTI-containing ART, of whom 751 (11%) reported prior use of NVP for PMTCT. There was no significant difference in mean CD4 cell change between those exposed or unexposed to NVP at 6 (+202 versus +182 cells/microl; P = 0.20) or 12 (+201 versus +211 cells/microl; P = 0.60) months. Multivariable analyses showed no significant differences in mortality [adjusted hazard ratio (HR), 1.2; 95% confidence interval (CI), 0.8-1.8] or clinical treatment failure (adjusted HR, 1.1; 95% CI, 0.8-1.5). Comparison of recent NVP exposure with remote exposure suggested a less favorable CD4 cell response at 6 (+150 versus +219 cells/microl; P = 0.06) and 12 (+149 versus +215 cells/microl; P = 0.39) months. Women with recent NVP exposure also had a trend towards elevated risk for clinical treatment failure (adjusted HR, 1.6; 95% CI, 0.9-2.7)., Conclusion: Exposure to maternal single-dose NVP was not associated with substantially different short-term treatment outcomes. However, evidence was suggestive that exposure within 6 months of ART initiation may be a risk factor for poor treatment outcomes, highlighting the importance of ART screening and initiation early in pregnancy.