Sofosbuvir and velpatasvir with or without voxilaprevir in direct-acting antiviral-naïve chronic hepatitis C: patient-reported outcomes from POLARIS 2 and 3.

BACKGROUND: Chronic hepatitis C infection leads to impairment of patient-reported outcomes (PROs). Treatment with direct-acting antiviral regimens results in short- and long-term improvement of these outcomes. AIM: To assess PROs in patients treated with a newly developed direct-acting antiviral, a fixed-dose combination of sofosbuvir/velpatasvir (SOF/VEL) with/without voxilaprevir (VOX). METHODS: The PRO data were collected from participants of POLARIS-2 and POLARIS-3 clinical trials (DAA-naïve, all HCV genotypes). Participants self-administered SF-36v2, FACIT-F, CLDQ-HCV and WPAI:SHP instruments at baseline, during treatment, and in follow-up. RESULTS: Of 1160 patients, 611 received SOF/VEL/VOX and 549 received SOF/VEL (52.8 ± 11.0 years, 55.9% male, 75.4% treatment-naïve, 33.9% cirrhotic). The sustained viral response at 12 weeks (SVR12) rates were 95%-98%. During treatment, improvements in most PRO scores were significant (all but one P < .01) and ranged from, on average, +2.3 to +15.0 points (on a 0-100 scale) by the end of treatment. These improvements were similar between SOF/VEL/VOX and SOF/VEL arms (all P > .05). After treatment discontinuation, patients treated with both regimens achieved significant and clinically meaningful PRO gains (+2.7 to +16.7 by post-treatment week 12, +3.9 to +20.1 by post-treatment week 24; all but one P < .001). Multivariate analysis showed that depression, anxiety and cirrhosis were the most consistent independent predictors of PRO impairment while no association of PROs with the treatment regimen choice was found (all P > .05). CONCLUSIONS: The pan-genotypic regimens with SOF/VEL with or without VOX not only have excellent efficacy and safety, but also significantly positively impact patients' experience both during treatment and after achieving sustained virologic response in DAA-naïve patients with HCV.

Evaluation of viral heterogeneity using next-generation sequencing, end-point limiting-dilution and mass spectrometry.

Hepatitis C Virus sequence studies mainly focus on the viral amplicon containing the Hypervariable region 1 (HVR1) to obtain a sample of sequences from which several population genetics parameters can be calculated. Recent advances in sequencing methods allow for analyzing an unprecedented number of viral variants from infected patients and present a novel opportunity for understanding viral evolution, drug resistance and immune escape. In the present paper, we compared three recent technologies for amplicon analysis: (i) Next-Generation Sequencing; (ii) Clonal sequencing using End-point Limiting-dilution for isolation of individual sequence variants followed by Real-Time PCR and sequencing; and (iii) Mass spectrometry of base-specific cleavage reactions of a target sequence. These three technologies were used to assess intra-host diversity and inter-host genetic relatedness in HVR1 amplicons obtained from 38 patients (subgenotypes 1a and 1b). Assessments of intra-host diversity varied greatly between sequence-based and mass-spectrometry-based data. However, assessments of inter-host variability by all three technologies were equally accurate in identification of genetic relatedness among viral strains. These results support the application of all three technologies for molecular epidemiology and population genetics studies. Mass spectrometry is especially promising given its high throughput, low cost and comparable results with sequence-based methods.

Prognosis--the dilemma of modern periodontics.

As periodontics has progressed towards an understanding of the influences of risk factors such as genetics, smoking and stress in the occurrence and severity of periodontal disease, the question of prognosis, so essential to treatment planning, has become even more perplexing to the clinician. A survey of long term clinical practice gives insight into the outcome of therapy relative to initial severity, and modern concepts of bacteria versus host relationships provide directions for greater predictability. However, it is only with observation over time that a more accurate assessment of prognosis can be made, as response to initial therapeutic measures can be determined.

The analgesic efficacy of ibuprofen in periodontal surgery: A multicentre study.

The efficacy of a non-steroidal anti-inflammatory agent, ibuprofen, was evaluated in pain control following periodontal surgery. This type of agent acts peripherally by inhibiting the release of prostaglandins and minimizing the local inflammatory response. Thus there may be an advantage in pre-treatment administration of the drug so as to delay or even prevent postoperative pain. The study was multicentre, involving a Public Hospital Periodontal Unit, two specialist periodontal practices in Sydney, NSW, and two in Canberra, ACT. One hundred and twenty-seven patients who were to undergo periodontal surgery were randomly given either two 200 mg tablets of ibuprofen or two matching placebo tablets at least 30 minutes before administration of local anaesthesia. The procedure was double blind: neither the patient nor the clinician was aware of the tablet identity. Postoperatively, all patients were given labelled ibuprofen for pain relief, but were randomly divided into two groups: As directed who were instructed to take the drug regularly for two days postoperatively, and As required, who were to take the drug only if needed for pain relief. All patients completed a diary recording quantity and time of medication, and regular assessment of pain experience utilizing a visual analogue scale. The As directed group showed no significant difference in pain experience between pre-operative and post-operative only medication, but the As required group experienced significantly less pain and requirement for medication if the ibuprofen was administered pre-operatively.

A mistaken health belief resulting in gingival injury: a case report.

This case report describes extensive ulceration of the gingiva caused by harsh and repetitive toothbrushing. The lesions wee localized to several areas of the mouth. Despite considerable pain, the patient had persisted in the causative toothbrushing pattern. He had absorbed an invalid health belief that when pain or bleeding occurred, he should utilize consistent harsh brushing in the affected areas. Following re-education, this brushing behavior was discarded and healing ensued. The origin of his health belief and its relationship to the behavioral principle of self-efficacy are discussed.

Long-term periodontal care: a comparative retrospective survey.

The maintenance of 172 patients who were treated and then attended a periodontal practice in Sydney, Australia for periods of at least 10 years has been surveyed. The results, expressed as loss of teeth over the maintenance period, have been compared with a 1978 study. Results of the two surveys have been compared for total tooth loss over the maintenance period, loss of individual tooth types, loss of teeth with furca lesions, and tooth loss relative to surgical experience. The comparative analysis is limited by the difference in total number of patients and by the duration of the studies. The proportionate division of patients into three groups according to tooth retention (well maintained, downhill, and extreme downhill) was statistically similar in both surveys. There were very few statistically valid differences in numbers of individual teeth lost between the two studies. Despite these comparable end results of long-term maintenance, the surgical experience was quite different, with the patients in our practice undergoing much more surgical treatment than those in the earlier report. The results appear to support the hypothesis that long-term maintenance is attainable for most periodontal patients, and is consistent with a variety of treatment approaches.

Studies on the prevalence and epidemiology of urinary stone disease in men in Leeds.

A postal survey among 2% of men in Leeds showed that the prevalence of urinary stone disease is 3.8%. The prevalence of upper urinary tract and spontaneously passed stones increases progressively from 0.7% in social class 5 to 5.0% in social class 1 but that of bladder stones (0.7% in the group as a whole) is independent of social class. There is an initial peak of upper urinary tract and spontaneously passed stones commencing at age 20 and having a projected prevalence at age 90 of 5.7% and a second peak of bladder stones, commencing about age 50, with a projected prevalence of 1.9%. The prevalence of stone disease increases according to the order: single less than divorced/separated less than married less than widowed men. A family history of stones tends to be higher amongst relatives of stone-formers than amongst the corresponding relatives of control subjects, the male/female ratio being 2:1. The occurrence of urinary stones is significantly associated with that of gallstones, high blood pressure, backache, arthritis and gout but not with that of peptic ulcer, diabetes, thyroid disease or bronchitis.

Dose-dependent response of FSH, flushes and urinary calcium to oestrogen.

The reduction of gonadotrophin levels, urinary calcium and hot flushes in post-menopausal patients by ethinyl oestradiol is shown to be dose dependent, near maximum response being achieved by a dose of 15 micrograms daily. Equivalent ethinyl oestradiol doses to a number of other gonadal hormone preparations have been assessed using the derived dose-response curve of the reduction in urinary calcium.

Sulfation of lithocholate as a possible modifier of chenodeoxycholic acid-induced elevations of serum transaminase in patients with gallstones.

Chenodeoxycholic acid (CDC), through its metabolite, lithocholic acid (LC), is hepatotoxic in certain species. The cause of elevations of serum transaminase in 25% of humans ingesting CDC, however, is unknown, but also may be due to LC. Because efficient hepatic sulfation of LC may protect against hepatic injury, the aim of this study was to determine if sulfation of LC might modify CDC-induced elevations of transaminase. Pretreatment sulfation fraction (SF) was estimated in 63 randomly selected patients with gallstones in a double-blind randomized trial of CDC, 750 mg/d, 375 mg/d, or placebo; in 27 of these, SF was repeated at 1 or 2 yr. In four other patients, the SF was measured at 2 yr only. Serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase were determined monthly for 3 mo and then every 3 or 4 mo; an elevation of transaminase was defined as > 150% of the normal upper limit in asymptomatic patients. 10 muCi of (3)H-glyco-LC (sp act 84 mCi/mol) was ingested 10-12 h before fasting duodenal biliary drainage. Bile acids in bile were separated by thin-layer chromatography. The SF was estimated as a percentage of total radioactivity (scintillation counting) in sulfated glyco-LC. The standard deviation for replicate SF determinations (n = 311) was 2.1% The pretreatment SF (mean 60.7+/-1.7 SEM) correlated inversely with age (r = 0.336, P < 0.005) and directly with the obesity index (r = 0.495, P > 0.001), but was independent of sex. The SF, remeasured at 1 or 2 yr, did not change significantly with time or CDC. Among CDC-treated patients, elevations of transaminase occurred in 75% of patients with a SF < 45% vs. 11% with a SF > 45% (P < 0.001). In conclusion, a SF < 45% occurred in patients with gallstones who had a high probability of developing elevated serum transaminase when treated with CDC. Thus, sulfation of lithocholate may modify CDC-induced elevations of serum transaminase.

Treatment of choledocholithiasis with oral chenodeoxycholic acid.

The aim of this study was to conduct a controlled trial of oral chenodeoxycholic acid in the management of radiolucent choledocholithiasis. Thirteen patients were randomized in double-blind fashion to receive either 750 mg/day of chenodeoxycholic acid (CDCA) or a placebo. After 4 months, those who had the placebo were administered CDCA; those who had received CDCA and showed a 25% or more decrease in the size of stones (evaluated blindly) received CDCA for an additional 4 months. Five of the 13 patients did not complete the study; four (one initially placebo and three CDCA) because acute biliary symptoms mandated operative intervention and one (initially placebo, then CDCA) because of asymptomatic elevations of the serum transaminase levels. Patients who were withdrawn from the study had significantly larger stones (P less than 0.02) (mean largest diameter, 11.4 mm +/- 1.6 SEM) than those who completed the study (6.5 +/- 0.5). Of the eight patients who completed the study, two of the three who received CDCA initially for 6 to 8 months experienced complete disappearance of stones; all five patients who took the placebo failed to show dissolution, and one of these subsequently had dissolution of stones after 8 months of CDCA. Biliary lipid analyses during treatment showed bile unsaturated with respect to cholesterol in the three patients whose stones dissolved with CDCA therapy. In conclusion, a patient with partial dissolution of stones and unsaturated bile after 4 months of CDCA probably will have complete dissolution of stones after 6 to 8 months of CDCA.

Cholesterol gallstone formation and prevention by chenodeoxycholic and ursodeoxycholic acids. A new hamster model.

Prior animal models of cholesterol gallstone formation have been criticized for their dissimilarity to the conditions of humans with gallstones. We present a new hamster model of cholesterol cholelithiasis that more closely approximates the human situation. Sixty female Golden Syrian hamsters (average weight 83.2 +/- 3.4 g) were allocated to six groups of 10 animals each. Groups were fed standard diet (containing 0.8 gm cholesterol/g of food) or increased cholesterol diet (containing 2.4 mg cholesterol/g of food), with or without ethinyl estradiol, 15 micrograms/kg/d. Two groups receiving both increased cholesterol and ethinyl estradiol also received either chenodeoxycholic acid or ursodeoxycholic acid, 20 mg/kg/d. The animsl were sacrificed at 12 wk. Cholesterol gallstones (78.3 +/- 5.0% cholesterol by weight) formed in 30% of the animals fed ethinyl estradiol, 50% of those fed increased cholesterol, and 90% of those fed the combination of both. Bile was saturated in all three groups, with the saturation index of the combination group (2.08 +/- 0.17) being the highest. In both groups receiving bile acid therapy, no gallstones were found, and the bile remained unsaturated. For the bile acid-fed groups, both hepatic HMG-CoAR and hepatic cholesterol 7 alpha-hydroxylase activities were reduced (P less than 0.01) when compared to the group fed standard diet and to the grou fed the combination. Thus, a new animal model of cholesterol gallstone formation has been developed in which chenodeoxycholic acid and ursodeoxycholic acid therapy prevented gallstone formation through mechanisms similar to those reported in cholesterol gallstone patients.

Gallstone dissolution--a progress report.

Cholesterol gallstone formation occurs in three stages. First, the bile must be saturated with cholesterol, thereby allowing cholesterol crystals to form. Then, nucleation and growth of the gallstone can occur, although little is known about these latter two stages. Therapy for dissolution of gallstones is directed at desaturating the bile. Chenodeoxycholic acid (CDCA), the most extensively tested agent, is successful in dissolving 60 per cent of radiolucent gallstones; however, long-term safety remains to be demonstrated. Ursodeoxycholic acid (UDCA), the 7 beta epimer of CDCA, is a promising agent for cholesterol gallstone dissolution, but it, other potential agents, and dietary manipulations require more extensive study. An important problem, the prevention of recurrence of gallstones after dissolution, also needs resolution. Medical dissolution probably will be applicable as an alternative to cholecystectomy for most patients with radiolucent gallstones, but the specific relative indications remain to be determined. A variety of modalities, both medical and surgical, are being used for the treatment of retained or reformed bile duct stones. These include T-tube infusions, oral CDCA, and extraction either through the T-tube tract or after endoscopic papillotomy. Further studies, including controlled trials, are necessary to determine the relative indications for these methods.

Gallstones. The present and future of medical dissolution.

Adequate concentrations of bile acids and phospholipids are necessary to keep cholesterol in solution in bile. When the amount of cholesterol exceeds the capacity of bile acids and phospholipids to keep the cholesterol in micellar solution, bile becomes supersaturated; then, under appropriate conditions, cholesterol crystals form and gallstones may develop. Current dissolution therapy is aimed at desaturating the bile, thereby shifting the equilibrium of cholesterol from a crystalline phase back toward a micellar state, thus permitting gallstones to dissolve. Chenodeoxycholic acid is the drug being most extensively tested for efficacy in dissolution; at present, it is successful in about 60 per cent of cases. The primary mechanism of action appears to be suppression of biliary secretion of cholesterol. Further experience is needed to confirm the safety of chenodeoxycholic acid, to gain more precision in patient selection, and to determine ideal dose. The role of chenodeoxycholic acid in prophylaxis and in prevention of recurrence needs further study. Other potential agents for dissolution also deserve investigation.