Efficacy of Repeat Selective Laser Trabeculoplasty in Medication-Naïve Open Angle Glaucoma and Ocular Hypertension during the LiGHT Trial

PURPOSE: To determine the efficacy of repeat selective laser trabeculoplasty (SLT) in medication-naïve open angle glaucoma (OAG) and ocular hypertensive (OHT) patients requiring repeat treatment for early to medium-term failure during the Laser in Glaucoma and Ocular Hypertension (LiGHT) trial. // DESIGN: Post-hoc analysis of SLT treatment arm of a multicentre prospective randomised-controlled-trial. // PARTICIPANTS: Treatment-naïve OAG or OHT requiring repeat 360-degree SLT within 18 months. Re-treatment was triggered by pre-defined IOP and disease-progression criteria (using objective individualised target IOPs) // METHODS: After SLT at baseline, patients were followed for a minimum of 18 months after second (‘repeat’) SLT. A mixed model analysis was performed with the eye as the unit of analysis, with crossed random-effects to adjust for correlation between fellow eyes and repeated measures within eyes. Kaplan-Meier curves plot the duration of effect. // OUTCOME MEASURES: Initial (‘early’) IOP lowering at 2-months and duration of effect following initial and Repeat SLT. // RESULTS: 115 eyes of 90 patients received Repeat SLT during first 18 months of the trial. Pre-treatment IOP prior to Initial SLT was significantly higher than that prior to pre-retreatment IOP of Repeat SLT (mean difference: 3.4, 95% confidence interval (CI) 2.6 to 4.3, mmHg; p<0.001). Absolute IOP reduction at 2-months was greater following Initial, compared to Repeat, SLT (mean difference: 1.0, 95% CI 0.2 to 1.8, mmHg; p=0.02). Adjusted absolute IOP reduction at 2-months (adjusting for IOP prior to initial or repeat laser) was greater following Repeat SLT (adjusted mean difference: -1.1, 95% CI -1.7 to -0.5, mmHg; p=0.001). 34 eyes were ‘early failures’ (retreated 2-months after Initial SLT) vs 81 ‘later failures’ (retreatment beyond 2-months following Initial SLT). No significant difference in early absolute IOP reduction at 2-months following Repeat SLT was noted between ‘early’ vs ‘later’ failures’ (mean difference: 0.3, 95% CI, -1.1 to 1.8,mmHg; p=0.655). Repeat SLT maintained drop-free IOP control in 67% of 115 eyes at 18 months, with no clinically-relevant adverse events. // CONCLUSION: These exploratory analyses demonstrate Repeat SLT can maintain IOP at or below Target IOP in medication-naive OAG and OHT eyes requiring retreatment with atleast an equivalent duration of effect to initial laser

Changes in Cardiovascular Disease Risk Factors With Immediate Versus Deferred Antiretroviral Therapy Initiation Among HIV-Positive Participants in the START (Strategic Timing of Antiretroviral Treatment) Trial

Introduction-HIV infection and certain antiretroviral therapy (ART) medications increase atherosclerotic cardiovascular disease risk, mediated, in part, through traditional cardiovascular disease risk factors. Methods and Results-We studied cardiovascular disease risk factor changes in the START (Strategic Timing of Antiretroviral Treatment) trial, a randomized study of immediate versus deferred ART initiation among HIV-positive persons with CD4+ cell counts >500 cells/mm(3). Mean change from baseline in risk factors and the incidence of comorbid conditions were compared between groups. The characteristics among 4685 HIV-positive START trial participants include a median age of 36 years, a CD4 cell count of 651 cells/mm(3), an HIV viral load of 12 759 copies/mL, a current smoking status of 32%, a median systolic/diastolic blood pressure of 120/76 mm Hg, and median levels of total cholesterol of 168 mg/dL, low-density lipoprotein cholesterol of 102 mg/dL, and high-density lipoprotein cholesterol of 41 mg/dL. Mean follow-up was 3.0 years. The immediate and deferred ART groups spent 94% and 28% of follow-up time taking ART, respectively. Compared with patients in the deferral group, patients in the immediate ART group had increased total cholesterol and low-density lipoprotein cholesterol and higher use of lipid-lowering therapy (1.2%;95% CI, 0.1-2.2). Concurrent increases in high-density lipoprotein cholesterol with immediate ART resulted in a 0.1 lower total cholesterol to high-density lipoprotein cholesterol ratio (95% CI, 0.1-0.2). Immediate ART resulted in 2.3% less BP-lowering therapy use (95% CI, 0.9-3.6), but there were no differences in new-onset hypertension or diabetes mellitus. Conclusions-Among HIV-positive persons with preserved immunity, immediate ART led to increases in total cholesterol and lowdensity lipoprotein cholesterol but also concurrent increases in high-density lipoprotein cholesterol and decreased use of blood pressure medications. These opposing effects suggest that, in the short term, the net effect of early ART on traditional cardiovascular disease risk factors may be clinically insignificant.

CD4 cell count and the risk of AIDS or death in HIV-Infected adults on combination antiretroviral therapy with a suppressed viral load: a longitudinal cohort study from COHERE.

BACKGROUND: Most adults infected with HIV achieve viral suppression within a year of starting combination antiretroviral therapy (cART). It is important to understand the risk of AIDS events or death for patients with a suppressed viral load. METHODS AND FINDINGS: Using data from the Collaboration of Observational HIV Epidemiological Research Europe (2010 merger), we assessed the risk of a new AIDS-defining event or death in successfully treated patients. We accumulated episodes of viral suppression for each patient while on cART, each episode beginning with the second of two consecutive plasma viral load measurements 500 copies/µl, the first of two consecutive measurements between 50-500 copies/µl, cART interruption or administrative censoring. We used stratified multivariate Cox models to estimate the association between time updated CD4 cell count and a new AIDS event or death or death alone. 75,336 patients contributed 104,265 suppression episodes and were suppressed while on cART for a median 2.7 years. The mortality rate was 4.8 per 1,000 years of viral suppression. A higher CD4 cell count was always associated with a reduced risk of a new AIDS event or death; with a hazard ratio per 100 cells/µl (95% CI) of: 0.35 (0.30-0.40) for counts <200 cells/µl, 0.81 (0.71-0.92) for counts 200 to <350 cells/µl, 0.74 (0.66-0.83) for counts 350 to <500 cells/µl, and 0.96 (0.92-0.99) for counts ≥500 cells/µl. A higher CD4 cell count became even more beneficial over time for patients with CD4 cell counts <200 cells/µl. CONCLUSIONS: Despite the low mortality rate, the risk of a new AIDS event or death follows a CD4 cell count gradient in patients with viral suppression. A higher CD4 cell count was associated with the greatest benefit for patients with a CD4 cell count <200 cells/µl but still some slight benefit for those with a CD4 cell count ≥500 cells/µl

Selective laser trabeculoplasty versus drops for newly diagnosed ocular hypertension and glaucoma: the LiGHT RCT

BACKGROUND: Newly diagnosed open-angle glaucoma (OAG) and ocular hypertension (OHT) are habitually treated with intraocular pressure (IOP)-lowering eyedrops. Selective laser trabeculoplasty (SLT) is a safe alternative to drops and is rarely used as first-line treatment. OBJECTIVES: To compare health-related quality of life (HRQoL) in newly diagnosed, treatment-naive patients with OAG or OHT, treated with two treatment pathways: topical IOP-lowering medication from the outset (Medicine-1st) or primary SLT followed by topical medications as required (Laser-1st). We also compared the clinical effectiveness and cost-effectiveness of the two pathways. DESIGN: A 36-month pragmatic, unmasked, multicentre randomised controlled trial. SETTINGS: Six collaborating specialist glaucoma clinics across the UK. PARTICIPANTS: Newly diagnosed patients with OAG or OHT in one or both eyes who were aged ≥ 18 years and able to provide informed consent and read and understand English. Patients needed to qualify for treatment, be able to perform a reliable visual field (VF) test and have visual acuity of at least 6 out of 36 in the study eye. Patients with VF loss mean deviation worse than -12 dB in the better eye or -15 dB in the worse eye were excluded. Patients were also excluded if they had congenital, early childhood or secondary glaucoma or ocular comorbidities; if they had any previous ocular surgery except phacoemulsification, at least 1 year prior to recruitment or any active treatment for ophthalmic conditions; if they were pregnant; or if they were unable to use topical medical therapy or had contraindications to SLT. INTERVENTIONS: SLT according to a predefined protocol compared with IOP-lowering eyedrops, as per national guidelines. MAIN OUTCOME MEASURES: The primary outcome was HRQoL at 3 years [as measured using the EuroQol-5 Dimensions, five-level version (EQ-5D-5L) questionnaire]. Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness and safety. RESULTS: Of the 718 patients enrolled, 356 were randomised to Laser-1st (initial SLT followed by routine medical treatment) and 362 to Medicine-1st (routine medical treatment only). A total of 652 (91%) patients returned the primary outcome questionnaire at 36 months. The EQ-5D-5L score was not significantly different between the two arms [adjusted mean difference (Laser-1st - Medicine-1st) 0.01, 95% confidence interval (CI) -0.01 to 0.03; p = 0.23] at 36 months. Over 36 months, the proportion of visits at which IOP was within the target range was higher in the Laser-1st arm (93.0%, 95% CI 91.9% to 94.0%) than in the Medicine-1st arm (91.3%, 95% CI 89.9% to 92.5%), with IOP-lowering glaucoma surgery required in 0 and 11 patients, respectively. There was a 97% probability of Laser-1st being more cost-effective than Medicine-1st for the NHS, at a willingness to pay for a quality-adjusted life-year of £20,000, with a reduction in ophthalmology costs of £458 per patient (95% of bootstrap iterations between -£585 and -£345). LIMITATION: An unmasked design, although a limitation, was essential to capture any treatment effects on patients' perception. The EQ-5D-5L questionnaire is a generic tool used in multiple settings and may not have been the most sensitive tool to investigate HRQoL. CONCLUSIONS: Compared with medication, SLT provided a stable, drop-free IOP control to 74.2% of patients for at least 3 years, with a reduced need for surgery, lower cost and comparable HRQoL. Based on the evidence, SLT seems to be the most cost-effective first-line treatment option for OAG and OHT, also providing better clinical outcomes. FUTURE WORK: Longitudinal research into the clinical efficacy of SLT as a first-line treatment will specify the long-term differences of disease progression, treatment intensity and ocular surgery rates between the two pathways. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32038223. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 31. See the NIHR Journals Library website for further project information

Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial

BACKGROUND: Primary open angle glaucoma and ocular hypertension are habitually treated with eye drops that lower intraocular pressure. Selective laser trabeculoplasty is a safe alternative but is rarely used as first-line treatment. We compared the two. METHODS: In this observer-masked, randomised controlled trial treatment-naive patients with open angle glaucoma or ocular hypertension and no ocular comorbidities were recruited between 2012 and 2014 at six UK hospitals. They were randomly allocated (web-based randomisation) to initial selective laser trabeculoplasty or to eye drops. An objective target intraocular pressure was set according to glaucoma severity. The primary outcome was health-related quality of life (HRQoL) at 3 years (assessed by EQ-5D). Secondary outcomes were cost and cost-effectiveness, disease-specific HRQoL, clinical effectiveness, and safety. Analysis was by intention to treat. This study is registered at controlled-trials.com (ISRCTN32038223). FINDINGS: Of 718 patients enrolled, 356 were randomised to the selective laser trabeculoplasty and 362 to the eye drops group. 652 (91%) returned the primary outcome questionnaire at 36 months. Average EQ-5D score was 0·89 (SD 0·18) in the selective laser trabeculoplasty group versus 0·90 (SD 0·16) in the eye drops group, with no significant difference (difference 0·01, 95% CI -0·01 to 0·03; p=0·23). At 36 months, 74·2% (95% CI 69·3-78·6) of patients in the selective laser trabeculoplasty group required no drops to maintain intraocular pressure at target. Eyes of patients in the selective laser trabeculoplasty group were within target intracoluar pressure at more visits (93·0%) than in the eye drops group (91·3%), with glaucoma surgery to lower intraocular pressure required in none versus 11 patients. Over 36 months, from an ophthalmology cost perspective, there was a 97% probability of selective laser trabeculoplasty as first treatment being more cost-effective than eye drops first at a willingness to pay of £20 000 per quality-adjusted life-year gained. INTERPRETATION: Selective laser trabeculoplasty should be offered as a first-line treatment for open angle glaucoma and ocular hypertension, supporting a change in clinical practice. FUNDING: National Institute for Health Research, Health and Technology Assessment Programme

Surveillance of Transmitted Antiretroviral Drug Resistance among HIV-1 Infected Women Attending Antenatal Clinics in Chitungwiza, Zimbabwe

The rapid scale-up of highly active antiretroviral therapy (HAART) and use of single dose Nevirapine (SD NVP) for prevention of mother-to-child transmission (pMTCT) have raised fears about the emergence of resistance to the first line antiretroviral drug regimens. A cross-sectional study was conducted to determine the prevalence of primary drug resistance (PDR) in a cohort of young (<25 yrs) HAART-naïve HIV pregnant women attending antenatal clinics in Chitungwiza, Zimbabwe. Whole blood was collected in EDTA for CD4 counts, viral load, serological estimation of duration of infection using the BED Calypte assay and genotyping for drug resistance. Four hundred and seventy-one women, mean age 21 years; SD: 2.1 were enrolled into the study between 2006 and 2007. Their median CD4 count was 371cells/µL; IQR: 255–511 cells/µL. Two hundred and thirty-six samples were genotyped for drug resistance. Based on the BED assay, 27% were recently infected (RI) whilst 73% had long-term infection (LTI). Median CD4 count was higher (p<0.05) in RI than in women with LTI. Only 2 women had drug resistance mutations; protease I85V and reverse transcriptase Y181C. Prevalence of PDR in Chitungwiza, 4 years after commencement of the national ART program remained below WHO threshold limit (5%). Frequency of recent infection BED testing is consistent with high HIV acquisition during pregnancy. With the scale-up of long-term ART programs, maintenance of proper prescribing practices, continuous monitoring of patients and reinforcement of adherence may prevent the acquisition and transmission of PDR

Feasibility and effectiveness of indicator condition-guided testing for HIV: results from HIDES I (HIV indicator diseases across Europe study)

Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009- February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% [95% CI: 1.42-2.34]; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe