Qualitative Development of the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ) Instrument, a Patient-Reported Outcome Measure in Glaucoma and Ocular Hypertension.

INTRODUCTION: Sustained-release intraocular implants provide a therapeutic option for open-angle glaucoma (OAG) and ocular hypertension (OHT) patients who are non-compliant with eyedrops. Currently, there are no published patient-reported outcome (PRO) measures that assess treatment satisfaction with intraocular implants. To address this gap, a new PRO instrument, the Allergan Satisfaction with Treatment Experience Questionnaire (ASTEQ), has been developed in accordance with Food and Drug Administration guidance. METHODS: Qualitative research interviews were conducted among patients with OAG/OHT who had received three intraocular injections of a sustained-release bimatoprost (10 or 15 µg) implant within the clinical trial setting. A preliminary conceptual framework capturing treatment satisfaction concepts in glaucoma, as identified from the literature, was used to develop a semi-structured interview guide. A concept elicitation (CE) interview to identify aspects of the glaucoma treatment experience pertinent to intraocular implants provided content for a draft instrument. A cognitive debriefing (CD) interview to test the instrument's interpretability, relevance, and validity informed its subsequent refinement. Interview analysis followed a grounded theory approach to identify data patterns and relationships. RESULTS: CE interviews (n = 19) indicated that participants' main considerations in rating satisfaction with implant treatment were physical comfort during preparation for the implant and implant administration, anxiety about the procedure, frequency of implant administration, possible side effects, convenience and accessibility of the implant, relationship with the clinician, and lifestyle fit. Draft ASTEQ revision based on CD interviews (n = 20) and readability tests yielded a nine-item ASTEQ instrument comprising satisfaction with overall implant experience and frequency of administration, occurrence/bother of immediate and long-term side effects, worry about implant administration and possible risks/side effects, and physical discomfort during preparation for the implant and implant administration. CONCLUSION: The ASTEQ instrument has demonstrated content validity in patients with OAG/OHT treated with a sustained-release bimatoprost implant. Further research is necessary to evaluate its psychometric properties.

Safety of Fixed-Combination Bimatoprost 0.03%/Timolol 0.5% Ophthalmic Solution at 6 Months in Chinese Patients with Open-Angle Glaucoma or Ocular Hypertension.

INTRODUCTION: Fixed-combination bimatoprost 0.03%/timolol 0.5% ophthalmic solution (FCBT; Ganfort®, Allergan, an AbbVie company) effectively reduces intraocular pressure (IOP) via complementary mechanisms of action of the agents, but long-term (> 12 weeks) safety evaluations of FCBT remain limited. FCBT safety is evaluated herein, with particular focus on hyperemia and eyelash growth, at 24 weeks in Chinese patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: In this multicenter, open-label, noncomparative, phase 4 study conducted in China, patients diagnosed with OAG or OHT having insufficient response to ß-blocker- or prostaglandin analogue/prostamide (PGA)-based IOP-lowering monotherapy in one or both eyes were switched from their current IOP-lowering treatment to FCBT (one drop per eye every evening) without prior washout. Assessment visits were scheduled at baseline and weeks 4, 12, and 24 (or study exit). The primary outcome measure was adverse event (AE) incidence through 24 weeks. RESULTS: Of 725 patients enrolled, 632 (87.2%) completed the study; 93 (12.8%) patients discontinued, including 29 (4.0%) due to AEs. Of 1326 FCBT-treated eyes (total), 594 (44.8%) experienced ≥ 1 ocular treatment-related AE during the study. Conjunctival hyperemia (the most common AE overall) and eyelash growth were reported in 269 (20.3%) and 54 (4.1%) FCBT-treated eyes, respectively. The incidence of other known PGA-related AEs (including blepharal pigmentation and erythema of eyelid) was < 10% each. Most conjunctival hyperemia reports were mild in severity (214/259; 82.6%) and only 1/259 (0.4%) was severe. Similarly, most cases of eyelash growth were mild (46/52; 88.5%); none were severe. One (< 0.1%) FCBT-treated eye had a serious ocular AE (OAG) considered FCBT-related. CONCLUSIONS: The frequency and severity of FCBT-related AEs, including conjunctival hyperemia and eyelash growth, are consistent with previously published findings. No new safety concerns were raised. This prospective study reaffirms that once-daily FCBT is a safe and well-tolerated therapy for OAG and OHT. GOV IDENTIFIER: NCT02571712.

Triple Fixed-Combination Bimatoprost/Brimonidine/Timolol in Glaucoma and Ocular Hypertension in India: A Multicenter, Open-Label, Phase 3 Study.

Introduction: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a triple fixed-combination of bimatoprost, brimonidine, and timolol (TFC) in patients with glaucoma or ocular hypertension (OHT) treated with fixed-combination or unfixed brimonidine and timolol therapy (dual-combination therapy). Methods: In this multicenter, open-label, phase 3 study, patients who received 4-8 weeks of dual-combination therapy twice daily and had an IOP >18 and <34 mmHg in at least one eye were switched (at baseline) to treatment with TFC twice daily for 12 weeks. At Weeks 4, 8, and 12 on TFC, IOP was assessed at Hours 0, 2, and 8. Primary efficacy variable: mean diurnal IOP change from baseline in the study eye at Week 12 (modified intent-to-treat [mITT] population). Sensitivity (per-protocol [PP] population) and subgroup (≤65 vs >65 years) analyses were performed. Safety, including adverse events (AEs), was assessed at each visit. Results: Of 126 patients enrolled, 121 and 103 formed the mITT/safety and PP populations, including 109 (90.1%) and 94 (91.3%) who completed the study, respectively. In the mITT/safety population, mean age was 58.6 years. Patients had open-angle glaucoma (51.2%), angle-closure glaucoma with patent iridotomy (36.4%), and/or OHT (13.2%). At Week 12, the mean diurnal change in IOP from dual combination-treated baseline was statistically significant (P<0.001) with TFC in the mITT (-3.98 mmHg) and PP (-4.22 mmHg) populations. Results were similar at all visits, regardless of the age subgroup. The most frequent treatment-related AEs were conjunctival hyperemia (14.0%) and dry eye (4.1%); 5.8% of the patients discontinued treatment due to ocular AEs. Conclusion: TFC offers a beneficial therapeutic alternative for patients with glaucoma or OHT whose IOP is not sufficiently controlled with dual-combination therapy. Safety and efficacy findings support those of published studies of TFC in primary open-angle glaucoma and OHT, despite differences in study designs.

Intraocular Pressure-Lowering Efficacy of a Sustained-Release Bimatoprost Implant in Dog Eyes Pretreated with Selective Laser Trabeculoplasty.

Purpose: To assess the intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost implant following selective laser trabeculoplasty (SLT) in a canine model. Methods: Unilateral SLT was performed in 11 normotensive, treatment-naive beagle dogs. IOP was measured at baseline (pre-SLT) and weekly post-SLT (≤10 weeks). After IOP returned to baseline or at 10 weeks (whichever occurred first), a sustained-release bimatoprost implant was administered bilaterally in the anterior chamber of each animal. IOP was measured weekly for 4 weeks and then every 2 weeks up to week 42. Results: The main outcomes included the IOP change (%) from baseline, calculated in both eyes in the overall population, SLT responder subgroup (defined by peak IOP reduction from baseline ≥3 mmHg or ≥15% for >1 week post-SLT), and SLT nonresponder subgroup (defined by peak IOP reduction from baseline <3 mmHg or <15%). The bimatoprost implant lowered IOP similarly in both the SLT-treated and fellow SLT-naive eyes. Following bimatoprost implant administration, the mean (standard deviation [SD]) peak IOP reduction from baseline was 34.4% (8.5%) in SLT-treated eyes and 35.7% (5.9%) in fellow SLT-naive eyes. The bimatoprost implant lowered IOP comparably (P > 0.17) in eyes that responded to SLT (mean [SD] peak IOP reduction, 34.6% [10.7%]; n = 6) and those that did not (mean [SD] peak IOP reduction, 34.1% [6.1%]; n = 5). Conclusion: The bimatoprost implant effectively lowered IOP in eyes pretreated with SLT, regardless of response to SLT. The current data suggest that eyes previously treated with SLT can still benefit from the intracameral bimatoprost implant.

Phase 3, Randomized, 20-Month Study of the Efficacy and Safety of Bimatoprost Implant in Patients with Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 2).

OBJECTIVE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10 and 15 µg bimatoprost implant in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: This randomized, 20-month, multicenter, masked, parallel-group, phase 3 trial enrolled 528 patients with OAG or OHT and an open iridocorneal angle inferiorly in the study eye. Study eyes were administered 10 or 15 µg bimatoprost implant on day 1, week 16, and week 32, or twice-daily topical timolol maleate 0.5%. Primary endpoints were IOP and IOP change from baseline through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both 10 and 15 µg bimatoprost implant met the primary endpoint of noninferiority to timolol in IOP lowering through 12 weeks. Mean IOP reductions from baseline ranged from 6.2-7.4, 6.5-7.8, and 6.1-6.7 mmHg through week 12 in the 10 µg implant, 15 µg implant, and timolol groups, respectively. IOP lowering was similar after the second and third implant administrations. Probabilities of requiring no IOP-lowering treatment for 1 year after the third administration were 77.5% (10 µg implant) and 79.0% (15 µg implant). The most common TEAE was conjunctival hyperemia, typically temporally associated with the administration procedure. Corneal TEAEs of interest (primarily corneal endothelial cell loss, corneal edema, and corneal touch) were more frequent with the 15 than the 10 µg implant and generally were reported after repeated administrations. Loss in mean CECD from baseline to month 20 was ~ 5% in 10 µg implant-treated eyes and ~ 1% in topical timolol-treated eyes. Visual field progression (change in the mean deviation from baseline) was reduced in the 10 µg implant group compared with the timolol group. CONCLUSIONS: The results corroborated the previous phase 3 study of the bimatoprost implant. The bimatoprost implant met the primary endpoint and effectively lowered IOP. The majority of patients required no additional treatment for 12 months after the third administration. The benefit-risk assessment favored the 10 over the 15 µg implant. Studies evaluating other administration regimens with reduced risk of corneal events are ongoing. The bimatoprost implant has the potential to improve adherence and reduce treatment burden in glaucoma. CLINICALTRIALS. GOV IDENTIFIER: NCT02250651.

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-µg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. DESIGN: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. PARTICIPANTS: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. METHODS: Study eyes received bimatoprost implant 10 µg (n = 198) or 15 µg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. MAIN OUTCOME MEASURES: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-µg implant, 15-µg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-µg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-µg implant) and 21.8% (15-µg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. CONCLUSIONS: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-µg implant over the 15-µg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.

Fixed-combination Bimatoprost/Brimonidine/Timolol in Glaucoma: A Randomized, Masked, Controlled, Phase III Study Conducted in Brazil☆.

PURPOSE: Many patients with open-angle glaucoma eventually require >2 medications to lower their intraocular pressure (IOP). Fixed-combination ophthalmic solutions can be advantageous in patients who require multiple medications, but the number of fixed combinations combining 3 complementary IOP-lowering agents remains limited. This study assessed the efficacy and safety of a triple fixed combination (TFC) of bimatoprost 0.01%/brimonidine 0.15%/timolol 0.5% ophthalmic solution in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT), compared with a dual fixed combination (DFC) of brimonidine 0.2%/timolol 0.5%. METHODS: Patients with a baseline IOP of 23-34 mm Hg in both eyes and no history of IOP-lowering procedures were eligible for participation in this multicenter, double-masked, randomized, Phase III study. After washout of previous treatment (if applicable), patients were randomized to receive TFC or DFC twice daily in each eye for 3 months. The primary efficacy variable was the change from baseline in mean IOP in the worse eye at week 12 in the modified intent-to-treat (mITT) population. TFC was superior to DFC if the treatment difference (TFC - DFC) favored TFC at week 12 (P ≤ 0.05; 2-sample t test). Secondary and sensitivity analyses were also performed. Safety, including adverse events, was assessed at all visits. FINDINGS: The mITT/safety population included 185 patients (TFC, n = 90; DFC, n = 95). TFC superiority was demonstrated at all postbaseline visits (all, P < 0.001) through week 12 (week 12 treatment difference: ─2.17 mm Hg; 95% CI, ─3.12 to ─1.22). While treatment-related conjunctival hyperemia was more frequent with TFC than with DFC (47.8% vs 23.2%; P < 0.001), consistent with the additional presence of bimatoprost in TFC, most cases were mild and the numbers of patient discontinuations at week 12 were similar between the TFC and DFC groups (11 [12.2%] vs 7 [7.4%] patients; P = 0.266). No unexpected adverse events were reported. IMPLICATIONS: Compared with DFC, TFC provided superior IOP lowering throughout the primary efficacy period. An acceptable tolerability profile was observed through 12 months of use of TFC, offering an effective therapeutic option in patients with POAG or OHT who require multiple medications to control their IOP. Additional studies are required for the assessment of the long-term effects of TFC. ClinicalTrials.gov identifier: NCT01217606.

24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in Glaucoma Patients.

OBJECTIVE: The objective of this study was to evaluate the safety and intraocular pressure (IOP)-lowering effects over 24 months of biodegradable bimatoprost sustained-release implant (Bimatoprost SR) administration versus topical bimatoprost 0.03% in patients with open-angle glaucoma (OAG). METHODS: This was a phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, adult patients with OAG (N = 75) received Bimatoprost SR (6, 10, 15, or 20 µg) intracamerally in the study eye; the fellow eye received topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or single repeat administration with implant was permitted. The primary endpoint was IOP change from baseline. Safety measures included adverse events (AEs). RESULTS: At month 24, mean IOP reduction from baseline was 7.5, 7.3, 7.3, and 8.9 mmHg in eyes treated with Bimatoprost SR 6, 10, 15, and 20 µg, respectively, versus 8.2 mmHg in pooled fellow eyes; 68, 40, and 28% of pooled study eyes had not been rescued/retreated at months 6, 12, and 24, respectively. AEs in study eyes that occurred ≤ 2 days post-procedure typically were transient. After 2 days post-procedure, overall AE incidence was similar between study and fellow eyes, with some events typically associated with topical prostaglandin analogs having lower incidence in study eyes. CONCLUSIONS: Bimatoprost SR showed favorable efficacy and safety profiles up to 24 months, with all evaluated dose strengths demonstrating overall IOP-reducing effects comparable to those of topical bimatoprost. Targeted and sustained delivery of bimatoprost resulted in protracted IOP lowering, suggesting that Bimatoprost SR may represent a transformational new approach to glaucoma therapy. Clinicaltrials.gov identifier: NCT01157364.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications.

PURPOSE: Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. METHODS: New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. RESULTS: Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6-8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. CONCLUSION: Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties), formulations of bimatoprost 0.01% can be administered once or twice daily. These findings support development of bimatoprost 0.01%-based fixed-dose combination therapies administered twice daily for patients who require multiple adjunctive medications to control their IOP.

Bimatoprost Sustained-Release Implants for Glaucoma Therapy: 6-Month Results From a Phase I/II Clinical Trial.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost sustained-release implant (Bimatoprost SR). DESIGN: Phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. METHODS: At baseline following washout, open-angle glaucoma patients (n = 75) were administered Bimatoprost SR (6 µg, 10 µg, 15 µg, or 20 µg) intracamerally in the study eye; the fellow eye began topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or a single repeat treatment with implant was allowed. The primary endpoint was IOP change from baseline. The main safety measure was adverse events. Results through month 6 are reported. RESULTS: Bimatoprost SR provided rapid, sustained IOP lowering. Overall mean IOP reduction from baseline through week 16 in study eyes was 7.2, 7.4, 8.1, and 9.5 mm Hg with the 6-µg, 10-µg, 15-µg, and 20-µg dose strengths of implant, respectively, vs 8.4 mm Hg in topical bimatoprost-treated pooled fellow eyes (data censored at rescue/retreatment). Rescue/retreatment was not required in 91% and 71% of study eyes up to week 16 and month 6, respectively. Adverse events in study eyes usually occurred within 2 days after the injection procedure and were transient. Conjunctival hyperemia with onset later than 2 days after the injection procedure was more common with topical bimatoprost than Bimatoprost SR (17.3% vs 6.7% of eyes). CONCLUSIONS: Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months.

Reversal of retinal ganglion cell dysfunction after surgical reduction of intraocular pressure.

PURPOSE: The pattern electroretinogram optimized for glaucoma screening (PERGLA) is a noninvasive method of objectively measuring retinal ganglion cell (RGC) function. This study was undertaken to quantify the RGC response to intraocular pressure (IOP) reduction after glaucoma surgery. DESIGN: Prospective cohort study. PARTICIPANTS: Forty-seven eyes of 47 patients with uncontrolled IOP or progressive glaucomatous optic neuropathy receiving maximal medical therapy requiring trabeculectomy or aqueous drainage device implantation who met eligibility criteria. METHODS: Eyes with visual acuity less than 20/30, corneal or retinal pathologic features, or unreliable standard automated perimetry (SAP) results were excluded. All patients underwent complete ocular examination, arterial blood pressure, SAP, and PERGLA at 2 sessions before surgery and at 3 months after surgery. Mean ocular perfusion pressure (MOPP) was calculated. Each measure of PERGLA amplitude and phase was an average of 600 artifact-free signal registrations. MAIN OUTCOME MEASURES: Intraocular pressure and PERGLA amplitude and phase. RESULTS: Forty-seven eyes of 47 patients (mean age ± standard deviation [SD], 69.9 ± 11.3 years) were enrolled. Thirty-four eyes (72%) underwent trabeculectomy with antifibrosis therapy; 13 eyes (28%) underwent glaucoma drainage implant surgery. Mean ± SD postoperative IOP (10.4 ± 4.6 mmHg) was significantly (P< 0.001) reduced compared with that before surgery (19.7 ± 8.6 mmHg). Mean ± SD postoperative PERGLA amplitude (0.46 ± 0.22 µV) was significantly (P = 0.001) increased compared with preoperative PERGLA amplitude (0.37 ± 0.18 µV). Mean ± SD postoperative PERGLA phase (1.72 ± 0.20 π-radian) was significantly (P = 0.01) reduced compared with preoperative PERGLA phase (1.81 ± 0.22 π-radian). Mean ± SD postoperative MOPP (53.1 ± 6.4 mmHg) was significantly (P < 0.001) increased compared with mean ± SD preoperative MOPP (45.8 ± 10.1 mmHg). No correlation (P > 0.05) was identified between change in PERGLA amplitude and change in IOP or MOPP. CONCLUSIONS: Reversal of RGC dysfunction occurs after surgical reduction of IOP and may be quantified using PERGLA.

Three-dimensional high-speed optical coherence tomography for diagnosis of hypotony maculopathy after glaucoma filtration surgery.

PURPOSE: To describe the clinical findings of hypotony maculopathy using 3-dimensional (3D) topography maps reconstructed from spectral domain optical coherence tomography (SD-OCT) imaging, and compare SD-OCT with time domain OCT (TD-OCT) for hypotony maculopathy diagnosis. METHODS: This was an observational noncomparative case series comprising 7 patients with hypotony maculopathy after trabeculectomy with mitomycin-C. All patients underwent consecutive imaging with TD-OCT (Stratus OCT) and SD-OCT using various high-resolution instruments. 3-D surface maps obtained using SD-OCT were compared with linear scans obtained using TD-OCT. RESULTS: Two of 7 eyes had minimally detectable folds with TD-OCT imaging in the vertical axis. Five eyes did not show folds on TD-OCT. 3-D topographic maps using SD-OCT demonstrated advanced retinal and subretinal folds throughout the macular region in all 7 patients. All eyes (4 cases) with no topographically detectable folds using SD-OCT within the foveal avascular zone had visual acuity of 20/25 or better. Three eyes with obvious contour disruption within the foveal pit had visual acuity ranging from 20/30 to 20/70. CONCLUSIONS: SD-OCT using 3-D surface topography mapping provides greater sensitivity for hypotony maculopathy diagnosis and monitoring as compared with TD-OCT. Disruption of the foveal pit as detected using SD-OCT is associated with reduced visual acuity.

Nuclear translocation of NF-kappaB precedes apoptotic poly(ADP-ribose) polymerase cleavage during productive HSV-1 replication in corneal epithelial cells.

PURPOSE: Herpes simplex virus (HSV)-1 infections of the human cornea range in severity from uncomplicated episodes that readily resolve to severe, recurring disease that invades the stroma, having a devastating permanent effect on vision. Recent published data implicate an apoptotic component to stromal HSV-1 infection. In a prior study, it was found that wild type (wt) HSV-1 infection induces, then blocks, apoptosis in epithelial cells derived from skin and that this block requires infected cell proteins (ICPs) synthesized between 3 and 6 hours post infection (hpi). This inhibition of apoptosis is in part dependent on the activation of inducible nuclear transcription factor kappaB (NF-kappaB). METHODS: HSV-1-dependent apoptosis in rabbit corneal epithelial (SIRC) cells was compared with that in infected human epithelial (HEp-2) cells. RESULTS: SIRC cells were sensitive to apoptotic cell death induced by environmental treatment with tumor necrosis factor (TNF)-alpha plus cycloheximide (CHX). HSV-1 stimulated the degradation of regulatory IkappaBalpha protein, resulting in nuclear translocation of NF-kappaB. This phenomenon was dependent on ICP synthesis. Neither wt nor apoptotic HSV-1 infection resulted in apoptosis in these cells. However, wt HSV-1-infected cells produced detectable levels of cleaved poly(ADP-ribose) (PARP). Inhibition of SIRC cell protein synthesis with CHX during wt HSV-1 infection led to a reduction in the amount of PARP cleavage. Whereas PARP cleavage defined cell death in most other cell types, its processing in SIRC cells was a reproducible characteristic of wt HSV-1 infection. CONCLUSIONS: This is the first report of such an effect, and it suggests that in corneal epithelial cells, activation of apoptotic pathways may be necessary for productive viral replication. Thus, efficient replication of HSV-1 in the corneal milieu proceeds via a different mechanism than it does in skin. However, it appears that NF-kappaB participates in inhibiting apoptosis during HSV-1 infection in both systems.

Herpes simplex virus infection and apoptosis.

Consequences of human herpes simplex virus (HSV) infection include the induction of apoptosis and the concomitant synthesis of proteins which act to block this process from killing the infected cell. Recent data has clarified our current understanding of the mechanisms of induction and prevention of apoptosis by HSV. These findings emphasize the fact that modulation of apoptosis by HSV during infection is a multicomponent phenomenon. We review recent evidence showing how this important human pathogen modulates the fundamental cell death process.

NF-kappaB is required for apoptosis prevention during herpes simplex virus type 1 infection.

Wild-type herpes simplex virus type 1 (HSV-1) infection triggers apoptosis in human cells. The subsequent synthesis of infected cell proteins between 3 and 6 h postinfection (hpi) acts to block this process from killing the cells. The factors produced during this window also prevent cell death induced by environmental staurosporine or sorbitol (M. Aubert, J. O'Toole, and J. A. Blaho, J. Virol. 73:10359-10370, 1999). We now report that (i) during the prevention window, HSV-1(F) also inhibited apoptosis induced by tumor necrosis factor alpha (TNF-alpha) plus cycloheximide (CHX) treatment. While deciphering the mechanism of this inhibition, we observed that (ii) the transcription factor NF-kappaB translocated from the cytoplasm into the nuclei of infected cells, and (iii) this migration initiated at 3 hpi. (iv) The complete inhibition of protein synthesis at 3 hpi by the addition of CHX precluded NF-kappaB translocation, while CHX additions at 6 hpi or later did not elicit this effect. This result confirms that infected cell protein synthesis is required for the nuclear import of NF-kappaB. (v) The detection of NF-kappaB in nuclei correlated with the ability of HSV-1(F), HSV-1(KOS1.1), or HSV-1(R7032), a replication-competent recombinant virus containing a deletion in the gene encoding the gE glycoprotein, to prevent apoptosis. (vi) NF-kappaB did not bind its kappaB DNA recognition site and remained cytoplasmic in cells actively undergoing apoptosis following infection with HSV-1(vBSdelta27), a virus with the key regulatory protein ICP27 deleted. (vii) Prestimulation of NF-kappaB by the addition of a phorbol ester prevented HSV-1(vBSdelta27)-induced apoptosis. (viii) Retention of NF-kappaB in the cytoplasm by the addition of a pharmacological antagonist of its release from IkappaBalpha led to an increase in death factor processing during HSV-1(F) infection. (ix) A novel HEp-2 clonal cell line, termed IkappaBalphaDN, was generated which expresses a dominant-negative form of IkappaBalpha. Treatment of IkappaBalphaDN cells with TNF-alpha in the absence of CHX resulted in apoptotic death due to the inability of NF-kappaB to become activated in these cells. Finally, (x) infection of IkappaBalphaDN cells with HSV-1(F) or HSV-1(KOS1.1) resulted in apoptosis, demonstrating that (xi) the nuclear translocation of NF-kappaB between 3 and 6 hpi (the prevention window) is necessary to prevent apoptosis in wild-type HSV-1-infected human HEp-2 cells.