Evaluating the in vitro wettability and coefficient of friction of a novel and contemporary reusable silicone hydrogel contact lens materials using an in vitro blink model.

PURPOSE: To evaluate the in vitro wettability and coefficient of friction of a novel amphiphilic polymeric surfactant (APS), poly(oxyethylene)-co-poly(oxybutylene) (PEO-PBO) releasing silicone hydrogel (SiHy) contact lens material (serafilcon A), compared to other reusable SiHy lens materials. METHODS: The release of fluorescently-labelled nitrobenzoxadiazole (NBD)-PEO-PBO was evaluated from serafilcon A over 7 days in a vial. The wettability and coefficient of friction of serafilcon A and three contemporary SiHy contact lens materials (senofilcon A; samfilcon A; comfilcon A) were evaluated using an in vitro blink model over their recommended wearing period; t = 0, 1, 7, 14 days for all lens types and t = 30 days for samfilcon A and comfilcon A (n = 4). Sessile drop contact angles were determined and in vitro non-invasive keratographic break-up time (NIKBUT) measurements were assessed on a blink model via the OCULUS Keratograph 5 M. The coefficient of friction was measured using a nano tribometer. RESULTS: The relative fluorescence of NBD-PEO-PBO decreased in serafilcon A by approximately 18 % after 7 days. The amount of NBD-PEO-PBO released on day 7 was 50 % less than the amount released on day 1 (6.5±1.0 vs 3.4±0.5 µg/lens). The reduction in PEO-PBO in the lens also coincided with an increase in contact angles for serafilcon A after 7 days (p < 0.05), although there were no changes in NIKBUT or coefficient of friction (p > 0.05). The other contact lens materials had stable contact angles and NIKBUT over their recommended wearing period (p > 0.05), with the exception of samfilcon A, which had an increase in contact angle after 14 days as compared to t = 0 (p < 0.05). Senofilcon A and samfilcon A also showed an increase in coefficient of friction at 14 and 30 days, respectively, compared to their blister pack values (p < 0.05). CONCLUSION: The results indicate that serafilcon A gradually depletes its reserve of PEO-PBO over 1 week, but this decrease did not significantly change the lens performance in vitro during this time frame.

The activity of antimicrobial peptoids against multidrug-resistant ocular pathogens.

BACKGROUND: Ocular infections caused by antibiotic-resistant pathogens can result in partial or complete vision loss. The development of pan-resistant microbial strains poses a significant challenge for clinicians as there are limited antimicrobial options available. Synthetic peptoids, which are sequence-specific oligo-N-substituted glycines, offer potential as alternative antimicrobial agents to target multidrug-resistant bacteria. METHODS: The antimicrobial activity of synthesised peptoids against multidrug-resistant (MDR) ocular pathogens was evaluated using the microbroth dilution method. Hemolytic propensity was assessed using mammalian erythrocytes. Peptoids were also incubated with proteolytic enzymes, after which their minimum inhibitory activity against bacteria was re-evaluated. RESULTS: Several alkylated and brominated peptoids showed good inhibitory activity against multidrug-resistant Pseudomonas aeruginosa strains at concentrations of ≤15 µg mL-1 (≤12 µM). Similarly, most brominated compounds inhibited the growth of methicillin-resistant Staphylococcus aureus at 1.9 to 15 µg mL-1 (12 µM). The N-terminally alkylated peptoids caused less toxicity to erythrocytes. The peptoid denoted as TM5 had a high therapeutic index, being non-toxic to either erythrocytes or corneal epithelial cells, even at 15 to 22 times its MIC. Additionally, the peptoids were resistant to protease activity. CONCLUSIONS: Peptoids studied here demonstrated potent activity against various multidrug-resistant ocular pathogens. Their properties make them promising candidates for controlling vision-related morbidity associated with eye infections by antibiotic-resistant strains.

Impact of in vitro lens deposition and removal on bacterial adhesion to orthokeratology contact lenses.

PURPOSE: The purpose of this study was to explore the impact of several contact lens (CL) care solutions on the removal of proteins and lipids, and how deposit removal impacts bacterial adhesion and solution disinfection. METHODS: Lysozyme and lipid deposition on three ortho-k (rigid) and two soft CL materials were evaluated using an ELISA kit and gas chromatography respectively. Bacterial adhesion to a fluorosilicone acrylate material using Pseudomonas aeruginosa with various compositions of artificial tear solutions (ATS), including with denatured proteins, was also investigated. The impact of deposition of the different formulations of ATS on biofilm formation was explored using cover slips. Finally, the lysozyme and lipid cleaning efficacy and disinfection efficacy against P. aeruginosa and Staphylococcus aureus of four different contact lens care solutions were studied using qualitative analysis. RESULTS: While maximum lysozyme deposition was observed with the fluorosilicone acrylate material (327.25 ± 54.25 µg/lens), the highest amount of lipid deposition was recorded with a fluoro-siloxanyl styrene material (134.71 ± 19.87 µg/lens). Adhesion of P. aeruginosa to fluorosilicone acrylate lenses and biofilm formation on cover slips were significantly greater with the addition of denatured proteins and lipids. Of the four contact lens care solutions investigated, the solution based on povidone-iodine removed both denatured lysozyme and lipid deposits and could effectively disinfect against P. aeruginosa and S. aureus when contaminated with denatured proteins and lipids. In contrast, the peroxide-based solution was able to inhibit P. aeruginosa growth only, while the two multipurpose solutions were unable to disinfect lenses contaminated with denatured proteins and lipids. CONCLUSION: Bacterial adhesion and biofilm formation is influenced by components within artificial tear solutions depositing on lenses, including denatured proteins and lipids, which also affects disinfection. The ability of different solutions to remove these deposits should be considered when selecting systems to clean and disinfect ortho-k lenses.

A review of using Traditional Chinese Medicine in the management of glaucoma and cataract.

Traditional Chinese Medicine has a long history in ophthalmology in China. Over 250 kinds of Traditional Chinese Medicine have been recorded in ancient books for the management of eye diseases, which may provide an alternative or supplement to current ocular therapies. However, the core holistic philosophy of Traditional Chinese Medicine that makes it attractive can also hinder its understanding from a scientific perspective - in particular, determining true cause and effect. This review focused on how Traditional Chinese Medicine could be applied to two prevalent ocular diseases, glaucoma, and cataract. The literature on preclinical and clinical studies in both English and Chinese on the use of Traditional Chinese Medicine to treat these two diseases was reviewed. The pharmacological effects, safety profile, and drug-herb interaction of selected herbal formulas were also investigated. Finally, key considerations for conducting future Traditional Chinese Medicine studies are discussed.

Common systemic medications that every optometrist should know.

Healthcare in the twenty-first century has witnessed an increased use of prescription drugs. As a member of a patient's health care team, optometrists should be aware of the pharmaceuticals taken by patients and their potential ocular complications. This paper will discuss the most prescribed medications in Australia today and their effects on the visual system. The paper will review the agents used to treat six common systemic conditions, their frequency of use, mechanism of action, clinical indications, and potential ocular manifestations. Literature has documented both positive and negative associations of systemic medications on the eye's health. Many associations documented here have shown conflicting evidence, thus warranting further investigation. Based on the frequency and severity of the ocular manifestations in the literature, recommendations for clinical care are given. Being familiar with the most common ocular side effects associated with common systemic medications aids in the correct and timely diagnosis of ocular complications to prevent permanent sequelae.

CLEAR - Contact lens technologies of the future.

Contact lenses in the future will likely have functions other than correction of refractive error. Lenses designed to control the development of myopia are already commercially available. Contact lenses as drug delivery devices and powered through advancements in nanotechnology will open up further opportunities for unique uses of contact lenses. This review examines the use, or potential use, of contact lenses aside from their role to correct refractive error. Contact lenses can be used to detect systemic and ocular surface diseases, treat and manage various ocular conditions and as devices that can correct presbyopia, control the development of myopia or be used for augmented vision. There is also discussion of new developments in contact lens packaging and storage cases. The use of contact lenses as devices to detect systemic disease has mostly focussed on detecting changes to glucose levels in tears for monitoring diabetic control. Glucose can be detected using changes in colour, fluorescence or generation of electric signals by embedded sensors such as boronic acid, concanavalin A or glucose oxidase. Contact lenses that have gained regulatory approval can measure changes in intraocular pressure to monitor glaucoma by measuring small changes in corneal shape. Challenges include integrating sensors into contact lenses and detecting the signals generated. Various techniques are used to optimise uptake and release of the drugs to the ocular surface to treat diseases such as dry eye, glaucoma, infection and allergy. Contact lenses that either mechanically or electronically change their shape are being investigated for the management of presbyopia. Contact lenses that slow the development of myopia are based upon incorporating concentric rings of plus power, peripheral optical zone(s) with add power or non-monotonic variations in power. Various forms of these lenses have shown a reduction in myopia in clinical trials and are available in various markets.

Povidone iodine for the treatment of adenoviral conjunctivitis.

Adenoviral conjunctivitis is the most common cause of ocular viral infection in the world, but currently has no approved therapeutic treatments. The antiseptic povidone-iodine (PVP-I) has been used as an off-label treatment for the condition, but high-quality evidence for its use is limited. This paper aims to review the literature surrounding the use of PVP-I in the management of adenoviral conjunctivitis. Unfortunately, treatment regimens, inclusion criteria, outcome measures, and review periods vary widely between studies, making direct comparisons between outcomes difficult. The majority of studies investigate daily instillation of 0.4 to 2.0% PVP-I rather than one-time instillation of PVP-I as has been used anecdotally in practice. In addition, only one treatment arm investigates daily PVP-I alone, with no significant difference in the duration of disease or clinical outcome compared to placebo. All other treatment arms investigate PVP-I in combination with dexamethasone which generally improve outcomes. Tolerability of PVP-I is generally good for low concentrations <1.0%, but efficacy of treatment is generally reported to be concentration dependent. Future research should investigate the optimal concentration, dosing regimen and role of each agent in combination treatment and aim to use laboratory techniques to improve diagnosis and provide quantifiable outcomes.

Current understanding and therapeutic management of contact lens associated sterile corneal infiltrates and microbial keratitis.

Contact lenses are widely prescribed in clinical practice with multiple applications and advantages. However, contact lenses can be associated with various complications which range from innocuous to severe. Clinicians thus not only need to possess the ability to prescribe the most appropriate contact lenses for each individual patient but also be able to recognise and manage any associated complications. This review examines the existing literature on the management of corneal infiltrative events associated with soft contact lenses, including microbial keratitis, particularly in the context of practising in Australia. The definitions and diagnosis of corneal infiltrative events, as well as the current understanding of their aetiologies, will be explored. The various aspects of a successful management will be discussed, including the applications of therapeutic agents such as antimicrobial and anti-inflammatory agents, the role of microbiological investigations, and strategies to improve long-term prognosis. The currently available evidence supporting management options will be presented, highlighting the relative abundance of high-level evidence on management protocols, antimicrobial selection and treatment duration for microbial keratitis; and the relative paucity of studies and trials for sterile corneal infiltrative events, despite this condition being much more commonly encountered in clinical practice.

Emerging targets of inflammation and tear secretion in dry eye disease.

The underlying mechanisms of dry eye are thought to be part of a vicious circle involving a hyperosmolarity-triggered inflammatory cascade, resulting in loss of goblet cells and glycocalyx mucin and observed corneal and conjunctival epithelial cell damage. This damage leads to increased tear film instability, further hyperosmolarity and hence perpetuating of a vicious circle. The aim of dry eye management is to restore the homeostasis of the tear film and break the perpetuation of this vicious circle. Despite the plethora of treatment options available, many of these are largely palliative, short-lived and require repeated instillations. Two emerging areas in dry eye therapy aim to promote tear secretion and to safely manage dry eye-associated inflammation and are the focus of this review.

In vitro release of two anti-muscarinic drugs from soft contact lenses.

The purpose of this study was to investigate the release of the anti-myopia drugs atropine sulfate and pirenzepine dihydrochloride from commercially available soft contact lenses. Standard ultraviolet (UV) absorbance-concentration curves were generated for atropine and pirenzepine. Ten commercially available contact lenses, including four multifocal lenses, were loaded by soaking in atropine or pirenzepine solutions at two different concentrations (10 mg/mL and 1 mg/mL). The release of the drugs into phosphate-buffered saline was determined over the course of 24 hours at 34°C using UV absorbance. Materials with surface charge released the greatest amount of atropine when loaded with either concentration when compared to the other lens types (p<0.05), releasing upward of 1.026±0.035 mg/lens and 0.979±0.024 mg/lens from etafilcon A and ocufilcon A, respectively. There were no significant differences in the amount of atropine or pirenzepine released from the multifocal and non-multifocal lenses made from the same lens materials. Narafilcon A material demonstrated prolonged release of up to 8 hours when loaded with pirenzepine, although the overall dose delivered from the lens into the solution was among the lowest of the materials investigated. The rest of the lenses reached a plateau within 2 hours of release, suggesting that they were unable to sustain drug release into the solution for long periods of time. Given that no single method of myopia control has yet shown itself to be completely effective in preventing myopia progression, a combination of optical and pharmaceutical devices comprising a drug delivering contact lens presents a novel solution that warrants further investigation.

Contact lenses for ophthalmic drug delivery.

Contact lenses as a means to deliver pharmaceuticals to the eye have seen a significant increase in research interest in the past few years. This review will detail the in vitro experiments which have investigated use of these contact lenses in the context of the desired pharmacological treatment goals in the management of infectious, inflammatory, allergic and glaucomatous diseases of the eye. The techniques researchers have employed to modify and tailor drug release rates from these materials, including the use of vitamin E diffusion barriers, modified ionicity, molecular imprinting and incorporation of drug reservoirs, will be discussed, as well as their impact on drug release kinetics. Finally, the demonstration of the feasibility of these materials when applied in vivo in animal models as well as in humans with and without disease will be presented and their results discussed relating to their implications for the future of the field.

In Vivo Studies Evaluating the Use of Contact Lenses for Drug Delivery.

This review highlights the current state of knowledge of in vivo testing of drug-delivering contact lenses. There has been a significant increase in interest in alternative means to deliver ocular pharmaceuticals, and within the past few decades, contact lenses have emerged as a vehicle of interest because of their biocompatibility and acceptance by both eye care professionals and the public. Using techniques such as molecular imprinting, vitamin E diffusion barriers, ionic reservoirs, and drug-impregnated films, significantly improved drug release kinetics have been observed in vitro. Extension of these results into in vivo studies has thus far been limited but has led to evidence of the viability of this drug delivery platform by demonstrating improved drug residence time, drug penetration, and clinical outcomes when compared with conventional therapy such as eye drops. The evidence supporting these improvements has occurred in both animal models and small human trials and is presented within this review.

In vitro and in vivo evaluation of novel ciprofloxacin-releasing silicone hydrogel contact lenses.

PURPOSE: The purpose of this study was to evaluate ciprofloxacin-releasing silicone hydrogel contact lens materials in vitro and in vivo for the treatment of microbial keratitis. METHODS: Model silicone hydrogel contact lens materials were manufactured using a molecular imprinting technique to modify ciprofloxacin release kinetics. Various contact lens properties, including light transmission and surface wettability, were determined, and the in vitro ciprofloxacin release kinetics elucidated using fluorescence spectrophotometry. The materials then were evaluated for their ability to inhibit Pseudomonas aeruginosa growth in vitro and in an in vivo rabbit model of microbial keratitis. RESULTS: Synthesized lenses had similar material properties to commercial contact lens materials. There was a decrease in light transmission in the shorter wavelengths due to incorporation of the antibiotic, but over 80% light transmission between 400 and 700 nm. Modified materials released for more than 8 hours, significantly longer than unmodified controls (P < 0.05). In vivo, there was no statistically significant difference between the number of colony-forming units (CFU) recovered from corneas treated with eye drops and those treated with one of two modified contact lenses (P > 0.05), which is significantly less than corneas treated with unmodified control lenses or those that received no treatment at all (P < 0.05). CONCLUSIONS: These novel contact lenses designed for the extended release of ciprofloxacin may be beneficial to supplement or augment future treatments of sight-threatening microbial keratitis.

Targeted hepatitis C screening among ex-injection drug users in the community.

BACKGROUND AND AIM: Chronic hepatitis C virus (HCV) infection is one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide. It is highly prevalent among injection drug users (IDUs) but is often undiagnosed because they represent an underprivileged group that faces multiple barriers to medical care. Here, we report the results of the New Life New Liver Project, which provides targeted HCV screening and education for ex-IDUs in the community. METHODS: Patients were recruited through the social worker networks and referrals by fellow ex-IDUs, and rapid diagnosis was based on point-of-care anti-HCV testing at rehabilitation centers. RESULTS: From 2009 to 2012, we served 234 subjects. One hundred thirty (56%) subjects were anti-HCV positive. The number needed to screen to detect one patient with positive anti-HCV was 1.8 (95% confidence interval, 1.6-2.0). However, only 69 (53%) HCV patients attended subsequent follow-up at regional hospitals, and 26 (20%) received antiviral therapy. Patients who attended follow-up were older, had higher education level and more active disease as evidenced by higher alanine aminotransferase, HCV RNA, and liver stiffness measurement by transient elastography. CONCLUSIONS: Targeted screening in ex-IDUs is effective in identifying patients with HCV infection in the community. Improvement in the referral system and introduction of interferon-free regimens are needed to increase treatment uptake.

Delivery of ketotifen fumarate by commercial contact lens materials.

PURPOSE: To investigate the uptake and delivery of the anti-allergy drug ketotifen fumarate (KF) by commercially available contact lenses. METHODS: A total of 14 different commercially available contact lenses were investigated, including five frequent-replacement silicone hydrogels, three conventional hydrogels, and six daily disposable lenses. Lenses were soaked in a 0.025% KF loading solution for 24 h, and the concentration of KF in solution over time was determined by ultraviolet absorbance at 297 nm. After the 24-h loading period, lenses were placed in fresh vials containing borate buffered saline, and the release of drug into solution at 34°C was monitored for 24 h. RESULTS: All the lenses studied demonstrated significant uptake and release of KF into the borate buffered saline (p < 0.05 compared with initial time point). Lenses with charged surfaces [balafilcon A, etafilcon A, and etafilcon A (daily disposable)] demonstrated the greatest uptake and release of KF. Etafilcon A released 284.5 ± 29.8 µg/lens, whereas balafilcon A released 227.6 ± 14.7 µg/lens, which was substantially more (p < 0.05) than the lowest releasing lenses [nelfilcon A (40.4 ± 4.1 µg/lens) and comfilcon A (110.4 ± 8.9 µg/lens)]. The majority of lenses were able to match or exceed the total amount of KF commonly administered to the eye using twice-daily dosing of commercially available (0.025%) eye drop formulations. Most of the lenses surveyed reached a plateau concentration of KF relatively quickly, and no lens was able to release KF for longer than 4 h. CONCLUSIONS: Commercially available lenses demonstrated the ability to release a clinically relevant amount of KF compared with conventional eye drops. The use of commercially available contact lenses as a KF delivery system in a daily wear scenario may be feasible.

Release of Ciprofloxacin-HCl and Dexamethasone Phosphate by Hyaluronic Acid Containing Silicone Polymers.

The purpose of this study was to determine the effect of the covalent incorporation of hyaluronic acid (HA) into conventional hydrogel and hydrogels containing silicone as models for contact lens materials on the uptake and release of the fluoroquinolone antibiotic ciprofloxacin and the anti-inflammatory steroid dexamethasone phosphate. A 3 mg/mL ciprofloxacin solution (0.3% w/v) and a 1 mg/mL dexamethasone phosphate solution (0.1%) was prepared in borate buffered saline. Three hydrogel material samples (pHEMA; pHEMA TRIS; DMAA TRIS) were prepared with and without the covalent incorporation of HA of molecular weight (MW) 35 or 132 kDa. Hydrogel discs were punched from a sheet of material with a uniform diameter of 5 mm. Uptake kinetics were evaluated at room temperature by soaking the discs for 24 h. Release kinetics were evaluated by placing the drug-loaded discs in saline at 34 °C in a shaking water bath. At various time points over 6-7 days, aliquots of the release medium were assayed for drug amounts. The majority of the materials tested released sufficient drug to be clinically relevant in an ophthalmic application, reaching desired concentrations for antibiotic or anti-inflammatory activity in solution. Overall, the silicone-based hydrogels (pHEMA TRIS and DMAA TRIS), released lower amounts of drug than the conventional pHEMA material (p < 0.001). Materials with HA MW132 released more ciprofloxacin compared to materials with HA MW35 and lenses without HA (p < 0.02). Some HA-based materials were still releasing the drug after 6 days.

Acetic and Acrylic Acid Molecular Imprinted Model Silicone Hydrogel Materials for Ciprofloxacin-HCl Delivery.

Contact lenses, as an alternative drug delivery vehicle for the eye compared to eye drops, are desirable due to potential advantages in dosing regimen, bioavailability and patient tolerance/compliance. The challenge has been to engineer and develop these materials to sustain drug delivery to the eye for a long period of time. In this study, model silicone hydrogel materials were created using a molecular imprinting strategy to deliver the antibiotic ciprofloxacin. Acetic and acrylic acid were used as the functional monomers, to interact with the ciprofloxacin template to efficiently create recognition cavities within the final polymerized material. Synthesized materials were loaded with 9.06 mM, 0.10 mM and 0.025 mM solutions of ciprofloxacin, and the release of ciprofloxacin into an artificial tear solution was monitored over time. The materials were shown to release for periods varying from 3 to 14 days, dependent on the loading solution, functional monomer concentration and functional monomer:template ratio, with materials with greater monomer:template ratio (8:1 and 16:1 imprinted) tending to release for longer periods of time. Materials with a lower monomer:template ratio (4:1 imprinted) tended to release comparatively greater amounts of ciprofloxacin into solution, but the release was somewhat shorter. The total amount of drug released from the imprinted materials was sufficient to reach levels relevant to inhibit the growth of common ocular isolates of bacteria. This work is one of the first to demonstrate the feasibility of molecular imprinting in model silicone hydrogel-type materials.

Uptake and release of dexamethasone phosphate from silicone hydrogel and group I, II, and IV hydrogel contact lenses.

OBJECTIVES: To investigate the uptake and release kinetics of the synthetic glucocorticoid anti-inflammatory drug dexamethasone into various conventional and silicone hydrogel contact lens materials. METHODS: Three conventional and six silicone hydrogel lenses were used in this study. A 0.1% dexamethasone solution was formulated and used to dope the various contact lens materials. The uptake and release of the drug was measured using a UV-visible light spectrophotometer at various time points during a period of 24 hr for each phase. RESULTS: Statistical analysis showed that all lenses took up a significant amount of dexamethasone. Alphafilcon A and lotrafilcon A showed the greatest uptake of dexamethasone, at 118 +/- 10 microg/lens and 102 +/- 11 microg/lens, respectively, and galyfilcon took up the least amount of drug at 34 +/- 6 microg/lens. The release of the drug from the lens materials was also statistically significant. The majority of the lenses released between 20 and 30 microg/lens, except for alphafilcon A and lotrafilcon A, which released a statistically different amount of drug when compared with the other lens materials. Alphafilcon A released 65 +/- 1.3 microg/lens, whereas lotrafilcon A slowly released only 11 +/- 0.2 microg/lens. CONCLUSIONS: Although most of the lenses released enough drug to have anti-inflammatory action, none of the materials released drug for a long enough period of time to be clinically useful as a drug delivery device.

Surrogate end points and long-term outcome in patients with chronic hepatitis B.

BACKGROUND & AIMS: It is unclear whether surrogate end points reported in clinical trials correlate with long-term outcome of patients with chronic hepatitis B. METHODS: Patients with chronic hepatitis B who participated in any of 4 randomized controlled trials were followed prospectively for liver-related events (hepatocellular carcinoma, ascites, spontaneous bacterial peritonitis, variceal bleeding, liver transplantation, and death). Biochemical (normal ALT levels), virologic (levels of hepatitis B virus DNA below 10,000 copies/mL), and histologic (reduction of necroinflammation grading by 2 points or more with no increase in fibrosis staging) responses were evaluated at the end of each trial. RESULTS: One hundred ninety-five patients with adequate pretreatment and post-treatment liver biopsies (15 mm long and 6 portal tracts) were followed for 86 months (interquartile range, 77-98). Liver-related events occurred in 12 patients (6%). The risk of liver-related events was lower in patients with biochemical (hazard ratio, 0.21; 95% confidence interval, 0.068-0.68) and histologic (hazard ratio, 0.095; 95% confidence interval, 0.012-0.74) responses. Only 1 patient with a histologic response and 1 patient with an ALT level below Prati's cutoffs (30 IU/L in men and 19 IU/L in women) developed liver-related events. Fifteen of 25 patients (60%) with cirrhosis at baseline had regression of cirrhosis, and none of these patients died or developed liver-related events. In contrast, 3 of these patients still developed liver-related events, despite an initial virologic response, and 2 had virologic breakthrough. CONCLUSIONS: Biochemical and histologic responses, particularly regression of cirrhosis, in patients with chronic hepatitis B are associated with decreased liver-related complications.