Efficacy and safety of celgosivir in patients with dengue fever (CELADEN): a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Dengue infection is the most common mosquito-borne viral disease worldwide, but no suitable antiviral drugs are available. We tested the α-glucosidase inhibitor celgosivir as a treatment for acute dengue fever. METHODS: To establish eligibility for inclusion in a phase 1b, randomised, double-blind, placebo-controlled, proof-of-concept trial, individuals aged 21-65 years who had had a fever (≥38°C) for less than 48 h, met at least two criteria indicating probable dengue infection, and had a positive result on a dengue point-of-care test kit or PCR assay were referred for screening at a centre in Singapore between July 30, 2012, and March 4, 2013. Using a web-based system, we randomly assigned patients who met full inclusion criteria after screening (1:1; random permuted block length four) to celgosivir (initial 400 mg loading dose within 6 h of randomisation, followed by 200 mg every 12 h for a total of nine doses) or matched placebo. Patients and the entire study team were masked to group assignment. The primary endpoints were mean virological log reduction (VLR) from baseline for days 2, 3, and 4, and area under the fever curve (AUC) for a temperature above 37°C from 0 h to 96 h. Efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01619969. FINDINGS: We screened 69 patients and randomly assigned 50 (24 to celgosivir, 26 to placebo). Mean VLR was greater in the celgosivir group (-1·86, SD 1·07) than in the placebo group (-1·64, 0·75), but the difference was non-significant (-0·22, 90% CI -0·65 to 0·22; one-sided p=0·203). The mean AUC was also higher in the celgosivir group (54·92, SD 31·04) than in the placebo group (40·72, 18·69), but again the difference was non-significant (14·20, 90% CI 2·16-26·25; one-sided p=0·973). We noted similar incidences of adverse events between groups. INTERPRETATION: Although generally safe and well tolerated, celgosivir does not seem to reduce viral load or fever burden in patients with dengue. FUNDING: STOP Dengue Translational Clinical Research.

Epidemiological surveillance and control of rubella in Singapore, 1991-2007.

INTRODUCTION: We reviewed the epidemiological features of rubella in Singapore and the impact of the national immunisation programme in raising the population herd immunity against rubella, with special reference to females in the reproductive age group, and in the elimination of congenital rubella syndrome (CRS). MATERIALS AND METHODS: Epidemiological data on all reported cases of rubella and CRS were obtained from the Communicable Diseases Division and Central Claims Processing System, respectively, at the Ministry of Health. Coverage of the childhood immunisation programme against rubella was based on the immunisation data maintained by the National Immunisation Registry, Health Promotion Board. To assess the herd immunity of the population against rubella, 4 serological surveys were conducted from 1989 to 1990, in 1993, 1998 and 2004. RESULTS: The incidence of rubella has decreased significantly from the peak of 13.3 per 100,000 population in 1996 to 1.8 per 100,000 in 2007. CRS has virtually disappeared. With more than 92% to 93% of primary school leavers and preschool children annually vaccinated against rubella since 1976 and 1990, respectively, the level of susceptibility to rubella among women in the reproductive age group has gradually decreased from 44% in 1975 to 28% in 1985, and maintained at between 10% and 20% from 1987 to 1998. A considerable proportion (15.8%) of women 18 to 44 years of age remained susceptible to rubella infection in 2004. CONCLUSION: Rubella prevention and control has been successfully implemented. However, the relatively high level of susceptibility to rubella among women in the reproductive age group continues to be of concern. More public awareness and health educational efforts are needed and every opportunity should be taken to ensure that all susceptible women are identified and protected against the infection.

Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007.

INTRODUCTION: We reviewed the epidemiology of hand, foot and mouth disease (HFMD) in Singapore after the 2000 epidemic caused by Enterovirus 71 (EV71), with particular reference to the cyclical pattern, predominant circulating enteroviruses and impact of prevention and control measures in preschool centres. MATERIALS AND METHODS: We analysed the epidemiological data from all clinical cases and deaths of HFMD diagnosed by medical practitioners and notified to the Ministry of Health, as well as laboratory data on enteroviruses detected among HFMD patients maintained by the Department of Pathology, Singapore General Hospital, and the Microbiology Laboratory, KK Women's and Children's Hospital from 2001 to 2007. RESULTS: The incidence rate was highest in the 0 to 4 years old age group, with males being predominant. Three deaths were reported between January and February 2001. Nationwide epidemics occurred periodically; the predominating circulating virus was Coxsackievirus A16 (CA16) in the 2002, 2005 and 2007 epidemics, and EV71 in the 2006 epidemic. During the epidemic years between 2005 and 2007, 2 peaks were observed. The number of institutional outbreaks had increased 10-fold from 167 in 2001 to 1723 in 2007, although most of these outbreaks were rapidly brought under control with an attack rate of less than 10%. CONCLUSION: HFMD remains an important public health problem in Singapore with the annual incidence rate per 100,000 population increasing from 125.5 in 2001 to 435.9 in 2007, despite stringent measures taken in preschool centres to prevent the transmission of infection. A high degree of vigilance should be maintained over the disease situation, in particular, surveillance of EV 71 which continues to cause severe complications and deaths in the region.

A 24-year review on the epidemiology and control of measles in Singapore, 1981-2004.

The objective of our paper is to review the epidemiology of measles in Singapore and the impact of the measles vaccination program on the control of measles. Our review will form the basis for a critical appraisal of our future measles control program. We analyzed the trend of reported measles cases in relationship to measles vaccination coverage from 1981 to 2004 using routine measles notifications and measles vaccination data submitted to the Ministry of Health and the National Immunization Registry, respectively. We determined the measles vaccine efficacy using data from epidemiological investigations of reported institutional measles outbreaks. The herd immunity of the population against measles was accessed through three seroepidemiological surveys that we conducted in 1989/1990, 1993 and 1998. In addition, we collected blood specimens from every clinically diagnosed case of measles notified to the Ministry in 1998/1999 to for measles-specific IgM antibodies in order to evaluate the proportion of clinically diagnosed cases of measles that were laboratory confirmed. The incidence of measles has decreased significantly since 1981 as a result of increased vaccination coverage of 89-93% following implementation of compulsory measles vaccination in 1985. However, resurgences still occurred in 1992/1993 and 1997. With the implementation of the two-dose measles vaccination schedule, the annual number of laboratory confirmed cases of measles to date has been less than 150. Vaccine efficacy of the trivalent MMR vaccine based on institutional outbreak investigations was consistently above 92%. We also found that the overall seroprevalence of the population to measles has decreased from approximately 91.5% in 1989/1990 to 1993 to 77.9% in 1998 (mainly in children < 4 years old) and that only 7% of clinically notified cases of measles were serologically confirmed to be positive for measles. Achieving a vaccination coverage of more than 95%, tightening our MMR vaccine delivery system and strengthening surveillance of measles are essential components which must be addressed in order to interrupt measles transmission in Singapore.