Ranibizumab and Bevacizumab for Treatment of Neovascular Age-related Macular Degeneration: Two-Year Results.

OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES: Mean change in visual acuity. RESULTS: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). CONCLUSIONS: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results.

OBJECTIVE: To describe effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years and to describe the impact of switching to as-needed treatment after 1 year of monthly treatment. DESIGN: Multicenter, randomized clinical trial. PARTICIPANTS: Patients (n = 1107) who were followed up during year 2 among 1185 patients with neovascular age-related macular degeneration who were enrolled in the clinical trial. INTERVENTIONS: At enrollment, patients were assigned to 4 treatment groups defined by drug (ranibizumab or bevacizumab) and dosing regimen (monthly or as needed). At 1 year, patients initially assigned to monthly treatment were reassigned randomly to monthly or as-needed treatment, without changing the drug assignment. MAIN OUTCOME MEASURES: Mean change in visual acuity. RESULTS: Among patients following the same regimen for 2 years, mean gain in visual acuity was similar for both drugs (bevacizumab-ranibizumab difference, -1.4 letters; 95% confidence interval [CI], -3.7 to 0.8; P = 0.21). Mean gain was greater for monthly than for as-needed treatment (difference, -2.4 letters; 95% CI, -4.8 to -0.1; P = 0.046). The proportion without fluid ranged from 13.9% in the bevacizumab-as-needed group to 45.5% in the ranibizumab monthly group (drug, P = 0.0003; regimen, P < 0.0001). Switching from monthly to as-needed treatment resulted in greater mean decrease in vision during year 2 (-2.2 letters; P = 0.03) and a lower proportion without fluid (-19%; P < 0.0001). Rates of death and arteriothrombotic events were similar for both drugs (P > 0.60). The proportion of patients with 1 or more systemic serious adverse events was higher with bevacizumab than ranibizumab (39.9% vs. 31.7%; adjusted risk ratio, 1.30; 95% CI, 1.07-1.57; P = 0.009). Most of the excess events have not been associated previously with systemic therapy targeting vascular endothelial growth factor (VEGF). CONCLUSIONS: Ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period. Treatment as needed resulted in less gain in visual acuity, whether instituted at enrollment or after 1 year of monthly treatment. There were no differences between drugs in rates of death or arteriothrombotic events. The interpretation of the persistence of higher rates of serious adverse events with bevacizumab is uncertain because of the lack of specificity to conditions associated with inhibition of VEGF.

Systemic and mucosal differences in HIV burden, immune, and therapeutic responses.

BACKGROUND: Mucosal tissues represent major targets for HIV transmission but differ in susceptibility and reservoir function by unknown mechanisms. METHODS: In a cross-sectional study, HIV RNA and infectious virus were compared between oral and genital compartments and blood in HIV-infected women, in association with clinical parameters, copathogens, and putative innate and adaptive HIV inhibitors. RESULTS: HIV RNA was detectable in 24.5% of women from all 3 compartments, whereas 45% had RNA in only 1 or 2 sites. By comparison, infectious HIV, present in blood of the majority, was rare in mucosal sites. Innate mediators, secretory leukocyte protease inhibitor and thrombospondin, were highest in mucosae. Highly active antiretroviral therapy was associated with an 80% decreased probability of shedding. Multivariate logistic regression models revealed that mucosal HIV RNA was associated with higher plasma RNA, infectious virus, and total mucosal IgA, but not IgG. There was a 37-fold increased probability of detecting RNA in both genital and oral specimens (P = 0.008; P = 0.02, respectively) among women in highest versus lowest IgA tertiles. CONCLUSIONS: Mucosal sites exhibit distinct characteristics of infectious HIV, viral shedding, and responses to therapy, dependent upon both systemic and local factors. Of the putative innate and adaptive mucosal defense factors examined, only IgA was associated with HIV RNA shedding. However, rather than being protective, there was a striking increase in probability of detectable HIV RNA shedding in women with highest total IgA.

Final visual acuity results in the early treatment for retinopathy of prematurity study.

OBJECTIVE: To compare visual acuity at 6 years of age in eyes that received early treatment for high-risk prethreshold retinopathy of prematurity (ROP) with conventionally managed eyes. METHODS: Infants with symmetrical, high-risk prethreshold ROP (n = 317) had one eye randomized to earlier treatment at high-risk prethreshold disease and the other eye managed conventionally, treated if ROP progressed to threshold severity. For asymmetric cases (n = 84), the high-risk prethreshold eye was randomized to either early treatment or conventional management. The main outcome measure was ETDRS visual acuity measured at 6 years of age by masked testers. Retinal structure was assessed as a secondary outcome. RESULTS: Analysis of all subjects with high-risk prethreshold ROP showed no statistically significant benefit for early treatment (24.3% vs 28.6% [corrected] unfavorable outcome; P = .15). Analysis of 6-year visual acuity results according to the Type 1 and 2 clinical algorithm showed a benefit for Type 1 eyes (25.1% vs 32.8%; P = .02) treated early but not Type 2 eyes (23.6% vs 19.4%; P = .37). Early-treated eyes showed a significantly better structural outcome compared with conventionally managed eyes (8.9% vs 15.2% unfavorable outcome; P < .001), with no greater risk of ocular complications. CONCLUSIONS: Early treatment for Type 1 high-risk prethreshold eyes improved visual acuity outcomes at 6 years of age. Early treatment for Type 2 high-risk prethreshold eyes did not. Application to Clinical Practice Type 1 eyes, not Type 2 eyes, should be treated early. These results are particularly important considering that 52% of Type 2 high-risk prethreshold eyes underwent regression of ROP without requiring treatment. Trial Registration clinicaltrials.gov Identifier: NCT00027222.

Surgical removal vs observation for subfoveal choroidal neovascularization, either associated with the ocular histoplasmosis syndrome or idiopathic: I. Ophthalmic findings from a randomized clinical trial: Submacular Surgery Trials (SST) Group H Trial: SST Report No. 9.

OBJECTIVE: To present visual acuity findings and related outcomes from eyes of patients enrolled in a randomized trial conducted by the Submacular Surgery Trials (SST) Research Group (SST Group H Trial) to compare surgical removal vs observation of subfoveal choroidal neovascular lesions that were either idiopathic or associated with ocular histoplasmosis. METHODS: Eligible patients 18 years or older had subfoveal choroidal neovascularization (new or recurrent) that included a classic component on fluorescein angiography and best-corrected visual acuity of 20/50 to 20/800 in 1 eye ("study eye"). Patients were examined 3, 6, 12, and 24 months after enrollment to assess study outcomes and adverse events. Best-corrected visual acuity was measured by a masked examiner at the 24-month examination. A successful outcome was defined a priori as 24-month visual acuity better or no more than 1 line (7 letters) worse than at baseline. RESULTS: Among 225 patients enrolled (median visual acuity 20/100), 113 study eyes were assigned to observation and 112 to surgery. Forty-six percent of the eyes in the observation arm and 55% in the surgery arm had a successful outcome (success ratio, 1.18; 95% confidence interval, 0.89-1.56). Median visual acuity at the 24-month examination was 20/250 among eyes in the observation arm and 20/160 for eyes in the surgery arm. The prespecified subgroup of eyes with visual acuity worse than 20/100 at baseline (n = 92) had more successes with surgery; 31 (76%) of 41 eyes in the surgery arm vs 20 (50%) of 40 eyes in the observation arm examined at 24 months (success ratio, 1.53; 95% confidence interval, 1.08-2.16). Five (4%) of 111 eyes in the surgery arm subsequently had a rhegmatogenous retinal detachment. Twenty-seven (24%) of 112 initially phakic eyes in the surgery arm (none in the observation arm) had cataract surgery during follow-up, all among patients older than 50 years. Recurrent choroidal neovascularization developed by the 24-month examination in 58% of surgically treated eyes. CONCLUSIONS: Overall, findings supported no benefit or a smaller benefit to surgery than the trial was designed to detect. Findings support consideration of surgery for eyes with subfoveal choroidal neovascularization and best-corrected visual acuity worse than 20/100 that meet other eligibility criteria for the SST Group H Trial. Other factors that may influence the treatment decision include the risks of retinal detachment, cataract among older patients, and recurrent choroidal neovascularization and the possibility that additional treatment will be required after submacular surgery.

Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11.

PURPOSE: To present visual acuity (VA) and related findings from patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of subfoveal choroidal neovascularization secondary to age-related macular degeneration (SST Group N Trial). DESIGN: Randomized clinical trial. PARTICIPANTS: Eligible patients had age-related macular degeneration with subfoveal choroidal neovascularization, some with a classic pattern on fluorescein angiography, and best-corrected VA (BCVA) of 20/100 to 20/800 in one eye (study eye) that had received no treatment in the macula. Any contiguous blood had to account for <50% of the total area occupied by the subfoveal lesion (maximum size, 9.0 disc areas [22.9 mm2]). METHODS: Randomization was stratified by VA and by clinical center. All patients were scheduled for study examinations at 3, 6, 12, and 24 months after enrollment for assessment of study outcomes. MAIN OUTCOME MEASURE: A successful outcome was defined a priori to be either improvement of BCVA or VA no more than 1 line (7 letters) worse than baseline at the 24-month examination. RESULTS: Of 454 patients enrolled, 228 study eyes were assigned to observation and 226 to surgery. The percentages of eyes that had successful outcomes were similar in the 2 arms: 44% assigned to observation and 41% assigned to surgery. Median VA losses from baseline to the 24-month examination were 2.1 lines (10.5 letters) in the observation arm and 2.0 lines (10 letters) in the surgery arm. Median VA declined from 20/100 at baseline to 20/400 at 24 months in both arms. No subgroup of patients was identified in which submacular surgery led to better VA outcomes. In the surgery arm, 55 (39%) of 142 initially phakic eyes had cataract surgery by the 24-month examination, compared with 6 (5%) of 133 eyes in the observation arm. Rhegmatogenous retinal detachment occurred in 12 surgery eyes (5%) and 1 observation eye. CONCLUSIONS: Submacular surgery, as performed in this clinical trial, did not improve or preserve VA for 24 months in more eyes than observation and is not recommended for patients with similar lesions. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Surgery for hemorrhagic choroidal neovascular lesions of age-related macular degeneration: ophthalmic findings: SST report no. 13.

PURPOSE: To present best-corrected visual acuity (BCVA) findings and other clinical outcomes from eyes of patients enrolled in one of the Submacular Surgery Trials (SST) evaluating surgical removal versus observation of predominantly hemorrhagic subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration. DESIGN: Randomized clinical trial (SST Group B Trial). PARTICIPANTS: Eligible patients had subfoveal choroidal neovascular lesions greater than 3.5 disk areas (8.9 mm2) composed of at least 50% blood (either blood or CNV underlying the center of the foveal avascular zone) and BCVA of 20/100 to light perception in the study eye. INTERVENTION: Patients were assigned randomly at time of enrollment to observation or surgical removal of blood and any associated CNV. MAIN OUTCOME MEASURE: A successful outcome was defined a priori as either improvement in visual acuity (VA), no change in VA, or a decline in VA of no more than 1 line (7 letters) from baseline to the 24-month examination based on an intent-to-treat analysis. RESULTS: Of 336 patients enrolled, 168 were assigned to each treatment arm; treatment arms were balanced by baseline characteristics. Of 1501 expected examinations 3 months through 36 months after baseline, 1370 (91%) were performed. Loss of > or =2 lines (> or =8 letters) of VA occurred in 56% of surgery eyes, versus 59% of observation eyes examined at 24 months. Although severe loss of VA was not the primary outcome of interest, surgery more often prevented such loss: 36% in the observation arm versus 21% in the surgery arm at the 24-month examination (chi2 P = 0.004). Of initially phakic eyes, the cumulative percentage that had undergone cataract surgery by 24 months was 44% in the surgery arm, compared with 6% in the observation arm. Twenty-seven eyes (16%) in the surgical arm, compared with 3 eyes (2%) in the observation arm, had a rhegmatogenous retinal detachment (RD). CONCLUSIONS: Submacular surgery as performed in the SST Group B Trial did not increase the chance of stable or improved VA (the primary outcome of interest) and was associated with a high risk of rhegmatogenous RD, but did reduce the risk of severe VA loss in comparison with observation. This article contains additional online-only material available at http://www.ophsource.com/periodicals/ophtha.

Baseline characteristics of participants in the oral health component of the Women's Interagency HIV Study.

OBJECTIVES: This study described baseline sociodemographic and oral health characteristics of a subset of HIV sero-positive and sero-negative women who participated in the oral health component of the Women's Interagency HIV Study (WIHS). METHODS: In 1995-96, 584 HIV sero-positive and 151 sero-negative women from five WIHS core sites were enrolled in the oral study. Data on oral mucosa, salivary glands, dentition and periodontium, along with demographics, socioeconomics, and behavioral characteristics, were used to characterize this population. RESULTS: Mean (SD) age was 37 (8) years for HIV sero-positive and 36 (8) years for sero-negative women; 27% of sero-positive women had CD4 counts < or =200 and 34% had viral loads >50,000 copies/ml. Sero-positive and sero-negative women were similar demographically, as well as on plaque index, gingival bleeding, linear gingival banding, and numbers of DMF teeth and surfaces, but sero-positive women had more abnormal gingival papilla (P = 0.004) and fewer teeth (P = 0.01). Among sero-positive women, those with <200 CD4 counts had more DMF teeth (P = 0.007), and the number of DMF surfaces increased with decreasing CD4 counts (P = 0.04). Sero-positive women who fit the Center for Disease Control (CDC) AIDS criteria were also more likely to have more DMF teeth (P = 0.004), DMF surfaces (P = 0.003), and decayed and/or filled (DF) root surfaces (P = 0.0002) compared to sero-positive women without AIDS. CONCLUSIONS: Dental and periodontal variables showed little difference between HIV sero-positive and sero-negative women. Among sero-positive women, there were significant differences in coronal and root caries by AIDS diagnostic criteria, but no periodontal indicators by either AIDS diagnostic criteria or CD4 status, were observed.

Comparison of preschool vision screening tests as administered by licensed eye care professionals in the Vision In Preschoolers Study.

PURPOSE: To compare 11 preschool vision screening tests administered by licensed eye care professionals (LEPs; optometrists and pediatric ophthalmologists). DESIGN: Multicenter, cross-sectional study. PARTICIPANTS: A sample (N = 2588) of 3- to 5-year-old children enrolled in Head Start was selected to over-represent children with vision problems. METHODS: Certified LEPs administered 11 commonly used or commercially available screening tests. Results from a standardized comprehensive eye examination were used to classify children with respect to 4 targeted conditions: amblyopia, strabismus, significant refractive error, and unexplained reduced visual acuity (VA). MAIN OUTCOME MEASURES: Sensitivity for detecting children with > or =1 targeted conditions at selected levels of specificity was the primary outcome measure. Sensitivity also was calculated for detecting conditions grouped into 3 levels of importance. RESULTS: At 90% specificity, sensitivities of noncycloplegic retinoscopy (NCR) (64%), the Retinomax Autorefractor (63%), SureSight Vision Screener (63%), and Lea Symbols test (61%) were similar. Sensitivities of the Power Refractor II (54%) and HOTV VA test (54%) were similar to each other. Sensitivities of the Random Dot E stereoacuity (42%) and Stereo Smile II (44%) tests were similar to each other and lower (P<0.0001) than the sensitivities of NCR, the 2 autorefractors, and the Lea Symbols test. The cover-uncover test had very low sensitivity (16%) but very high specificity (98%). Sensitivity for conditions considered the most important to detect was 80% to 90% for the 2 autorefractors and NCR. Central interpretations for the MTI and iScreen photoscreeners each yielded 94% specificity and 37% sensitivity. At 94% specificity, the sensitivities were significantly better for NCR, the 2 autorefractors, and the Lea Symbols VA test than for the 2 photoscreeners for detecting > or =1 targeted conditions and for detecting the most important conditions. CONCLUSIONS: Screening tests administered by LEPs vary widely in performance. With 90% specificity, the best tests detected only two thirds of children having > or =1 targeted conditions, but nearly 90% of children with the most important conditions. The 2 tests that use static photorefractive technology were less accurate than 3 tests that assess refractive error in other ways. These results have important implications for screening preschool-aged children.

A 4-year longitudinal evaluation of xerostomia and salivary gland hypofunction in the Women's Interagency HIV Study participants.

OBJECTIVES: Our purpose was to conduct a longitudinal investigation of xerostomia and salivary gland hypofunction in a national cohort of HIV-positive and at-risk HIV-negative participants in the Women's Interagency HIV Study. Study design. Data included responses to a dry mouth questionnaire, clinical evaluations of major salivary glands, and unstimulated and chewing-stimulated whole salivary flow rates. Repeated measures regression models were used to determine factors associated with xerostomia and salivary gland hypofunction. RESULTS: Significant univariate associations were found between HIV status and reports of "too little saliva" (P <.0001), < or = 0.1 mL/min, unstimulated saliva (P =.01), and lack of saliva upon palpation of parotid (P =.02) and submandibular/sublingual salivary glands (P =.03). Adjusted odds of reports of "too little saliva" were significantly higher for HIV-positive participants (odds ratio [OR] = 2.44; 95% CI, 1.49 - 3.97; P =.0004) than for HIV-negative participants. Among HIV-positive women, adjusted odds of reports of "too little saliva" and of < or = 0.7 mL/min chewing-stimulated saliva were significantly higher for those with CD4 < 200 (OR = 1.58; 95% CI, 1.07-2.34; P =.022; and OR = 1.53; 95% CI, 1.05-2.23; P =.027, respectively) and for those with CD4 200-500 (OR = 1.47; 95%CI, 1.07-2.02; P = 0.016; and OR = 1.37; 95% CI, 1.01-2.31; P =.001, respectively) than for those with CD4 > 500. Also, adjusted odds of < or = 0.1mL/min unstimulated saliva and < or = 0.7 mL/min chewing-stimulated saliva were significantly higher in women on highly active antiretroviral therapy (HAART) (OR = 1.25; 95% CI, 1.05 - 1.50; P =.014) than in women not on HAART (OR = 1.34; 95% CI, 1.01 - 1.79; P =.044). CONCLUSIONS: HIV-positive women are at a significantly higher risk for xerostomia and salivary gland hypofunction than HIV-negative women, and low CD4 cell counts and HAART use are significant risk factors for these conditions.

Differences in risk factors among clinical types of oral candidiasis in the Women's Interagency HIV Study.

OBJECTIVES: The purpose of this study was to determine the prevalence and concurrence/associations of oral candidiasis types and multiple risk factors in women. STUDY DESIGN: A cross-sectional analysis of baseline data for 577 human immunodeficiency virus (HIV)-seropositive and 152 HIV-seronegative women from the Women's Interagency HIV Study was conducted. Pseudomembranous candidiasis (PC) and erythematous (EC) candidiasis, angular cheilitis (AC), and denture stomatitis (DS) were studied, and bivariate and multivariate regression analyses were performed. RESULTS: Prevalences were 8% for PC, 7% for EC, 18% for DS, and 3% for AC; all except AC usually occurred alone. HIV seropositivity was associated with PC, EC, and DS, but not AC. Among HIV-seropositive women, low CD4 cell counts were associated with PC, but not with EC or DS. Heroin/methadone use was associated with PC and EC; salivary hypofunction was associated with PC; high viral load was associated with EC, and poor oral hygiene, with EC and DS. CONCLUSIONS: Risk factors varied among candidiasis types, suggesting differences in pathogenic mechanisms and usefulness as markers of HIV infection/progression.