Safety and effectiveness of switching to Abacavir/Lamivudine plus rilpivirine for maintenance therapy in virologically suppressed HIV-1 individuals in Singapore (SEALS).

BACKGROUND: The efficacy and tolerability of an antiretroviral regimen are important considerations for selection of HIV-1 infection maintenance therapy. Abacavir/lamivudine plus rilpivirine (ABC/3TC + RPV) has been shown in international studies to be effective and well-tolerated in virologically suppressed individuals. This study evaluated the effectiveness and safety of switching to ABC/3TC + RPV as maintenance therapy in virologically suppressed HIV-1 infected individuals in Singapore. METHODS: In this retrospective, single-centre study, we included individuals who were prescribed ABC/3TC + RPV, had HIV-1 viral load (VL) < 50 copies/ml immediately pre-switch, and had no documented history of resistance mutations or virologic failure to any of the components. The follow-up period was 48 ± 12 weeks. The primary outcome was the proportion of individuals who maintained virologic suppression of HIV-1 VL < 50 copies/ml at the end of follow-up period based on on-treatment analysis. The secondary outcomes were the resistance profiles associated with virologic failure, changes in immunologic and metabolic parameters, and the safety profile of ABC/3TC + RPV. RESULTS: A total of 222 individuals were included in the study. The primary outcome was achieved in 197 individuals [88.8%, 95% confidence interval: 83.7-92.4%]. There were 21 individuals (9.5%) who discontinued treatment for non-virologic reasons. The remaining 4 individuals experienced virologic failure, of whom, 3 of these individuals had developed emergent antiretroviral resistance and had HIV-1 VL > 500 copies/ml at the end of the 48 ± 12 weeks follow-up period. The remaining individual experienced sustained low level viremia and subsequently achieved viral suppression without undergoing resistance testing. A total of 49 adverse events were observed in 31 out of 222 individuals (14.0%), which led to 13 individuals discontinuing therapy. Neuropsychiatric adverse events were most commonly observed (53.1%). A statistically significant increase in CD4 was observed (p < 0.01), with a median absolute change of 31 cells/uL (interquartile range: - 31.50 to 140.75). No significant changes in lipid profiles were detected. CONCLUSION: ABC/3TC + RPV is a safe and effective switch option for maintenance therapy in virologically suppressed HIV-1 individuals with in Singapore.

Olfactory taste disorder as a presenting symptom of COVID-19: a large single-center Singapore study.

PURPOSE: To investigate the prevalence and epidemiological risk factors of olfactory and/or taste disorder (OTD), in particular isolated OTD, in patients with laboratory-confirmed COVID-19 infection. METHODS: We conducted a retrospective and cross-sectional study. Patients with laboratory-confirmed COVID-19 infection were recruited from the National Centre for Infectious Diseases (NCID) Singapore between 24 March 2020 and 16 April 2020. The electronic health records of these patients were accessed, and demographic data and symptoms reported (respiratory, self-reported OTD and other symptoms such as headache, myalgia and lethargy) were collected. RESULTS: A total of 1065 patients with laboratory-confirmed COVID-19 were recruited. Overall, the prevalence of OTD was 12.6%. Twelve patients (1.1%) had isolated OTD. The top three symptoms associated with OTD were cough, fever and sore throat. The symptoms of runny nose and blocked nose were experienced by only 29.8 and 19.3% of patients, respectively. Multivariate analysis demonstrated that the female gender, presence of blocked nose and absence of fever were significantly associated with OTD (adjusted relative risks 1.77, 3.31, 0.42, respectively). All these factors were statistically significant. CONCLUSION: Patients with COVID-19 infection can present with OTD, either in isolation or in combination with other general symptoms. Certain demographic profile, such as being female, and symptomatology such as the presence of blocked nose and absence of fever, were more likely to have OTD when infected by COVID-19. Further studies to elucidate the pathophysiology of OTD in these patients will be beneficial.

Does incubation period of COVID-19 vary with age? A study of epidemiologically linked cases in Singapore.

This study estimates the incubation period of COVID-19 among locally transmitted cases, and its association with age to better inform public health measures in containing COVID-19. Epidemiological data of all PCR-confirmed COVID-19 cases from all restructured hospitals in Singapore were collected between 23 January 2020 and 2 April 2020. Activity mapping and detailed epidemiological investigation were conducted by trained personnel. Positive cases without clear exposure to another positive case were excluded from the analysis. One hundred and sixty-four cases (15.6% of patients) met the inclusion criteria during the defined period. The crude median incubation period was 5 days (range 1-12 days) and median age was 42 years (range 5-79 years). The median incubation period among those 70 years and older was significantly longer than those younger than 70 years (8 vis-à-vis 5 days, P = 0.040). Incubation period was negatively correlated with day of illness in both groups. These findings support current policies of 14-day quarantine periods for close contacts of confirmed cases and 28 days for monitoring infections in known clusters. An elderly person who may have a longer incubation period than a younger counterpart may benefit from earlier and proactive testing, especially after exposure to a positive case.

Methicillin-resistant Staphylococcus aureus colonisation: epidemiological and molecular characteristics in an acute-care tertiary hospital in Singapore.

Current knowledge of methicillin-resistant Staphylococcus aureus (MRSA) colonisation in relation to epidemiological characteristics is incomplete. We conducted a cross-sectional study at an acute-care tertiary infectious diseases hospital of MRSA isolates identified through routine surveillance from January 2009 to December 2011. We randomly selected 205 MRSA isolates (119 inpatients) from 798 isolates (427 inpatients) for molecular profiling using multilocus sequence typing. Multilevel multinomial logistic regression was used to estimate odds ratio (OR) assessing the predilection of MRSA strains for anatomic sites, and associations of strains with human immunodeficiency virus (HIV) infection. The most frequent sequence types (STs) were 239, 22 and 45. The proportion of ST22 increased over the sampling period, replacing ST239 as the dominant lineage. However, ST239 remained the most prevalent among HIV-seropositive individuals who were six times more likely to be colonised with this strain than non-HIV patients (adjusted OR (aOR) 6.44, 95% confidence interval (CI) 1.94-21.36). ST45 was >24 times more likely to be associated with perianal colonisation than in the nares, axillae and groin sites (aOR 24.20, 95% CI 1.45-403.26). This study underlines the clonal replacement of MRSA in Singapore as previously reported but revealed, in addition, key strain differences between HIV-infected and non-infected individuals hospitalised in the same environment.

Risk assessment and laboratory investigation of respiratory illness in travellers returning to Singapore 2012-2015: experience from the MERS-CoV Surveillance Programme.

Since the emergence of Middle East respiratory syndrome coronavirus (MERS-CoV), Singapore has enhanced its national surveillance system to detect the potential importation of this novel pathogen. Using the guidelines from the Singapore Ministry of Health, a suspect case was defined as a person with clinical signs and symptoms suggestive of pneumonia or severe respiratory infection with breathlessness, and with an epidemiological link to countries where MERS-CoV cases had been reported within the preceding 14 days. This report describes a retrospective review of 851 suspected MERS-CoV cases assessed at the adult tertiary-care hospital in Singapore between September 2012 and December 2015. In total, 262 patients (31%) were hospitalized. All had MERS-CoV infection ruled out by RT-PCR or clinical assessment. Two hundred and thirty (88%) of the hospitalized patients were also investigated for influenza virus by RT-PCR. Of these, 62 (27%) tested positive for seasonal influenza. None of the patients with positive influenza results had been vaccinated in the year prior to hospital admission. Ninety-three (36%) out of the 262 hospitalized patients had clinical and/or radiological evidence of pneumonia. This study demonstrates the potential benefits of pre-travel vaccination against influenza and pneumococcal disease.

Contacts of healthcare workers, patients and visitors in general wards in Singapore.

To characterize contacts in general wards, a prospective survey of healthcare workers (HCWs), patients and visitors was conducted using self-reported diary, direct observation and telephone interviews. Nurses, doctors and assorted HCWs reported a median of 14, 18 and 15 contact persons over one work shift, respectively. Within 1 h, we observed 3·5 episodes with 25·6 min of cumulative contact time for nurses, 2·9 episodes and 22·1 min for doctors and 5·0 episodes with 44·3 min for assorted-HCWs. In interactions with patients, nurses had multiple brief episodes of contact; doctors had fewer episodes and less cumulative contact time; assorted-HCWs had fewer contact episodes of longer durations (than for nurses and doctors). Assortative mixing occurred amongst HCWs: those of the same HCW type were the next most frequent class of contact after patients. Over 24-h, patients contacted 14 persons with 23 episodes and 314·5 min of contact time. Patient-to-patient contact episodes were rare, but a maximum of five were documented from one patient participant. 22·9% of visitors reported contact with patients other than the one they visited. Our study revealed differences in the characteristics of contacts among different HCW types and potential transmission routes from patients to others within the ward environment.

Performance of case definitions for influenza surveillance.

Influenza-like illness (ILI) case definitions, such as those from the European Centre for Disease Control and Prevention, World Health Organization (WHO) and United States Centers for Disease Control and Prevention, are commonly used for influenza surveillance. We assessed how various case definitions performed during the initial wave of influenza A(H1N1) pdm09 infections in Singapore on a cohort of 727 patients with two to three blood samples and whose symptoms were reviewed fortnightly from June to October 2009. Using seroconversion (≥ 4-fold rise) to A/California/7/2009 (H1N1), we identified 36 presumptive influenza A(H1N1)pdm09 episodes and 664 episodes unrelated to influenza A(H1N1)pdm09. Cough, fever and headache occurred more commonly in presumptive influenza A(H1N1)pdm09. Although the sensitivity was low (36%), the recently revised WHO ILI case definition gave a higher positive predictive value (42%) and positive likelihood ratio (13.3) than the other case definitions. Results including only episodes with primary care consultations were similar. Individuals who worked or had episodes with fever, cough or sore throat were more likely to consult a physician, while episodes with Saturday onset were less likely, with some consultations skipped or postponed. Our analysis supports the use of the revised WHO ILI case definition, which includes only cough in the presence of fever defined as body temperature ≥ 38 °C for influenza surveillance.

Dengue myocarditis in Singapore: two case reports.

The authors report two cases of complicated dengue viral infection with acute myocarditis involving young male adults, of which one was fatal. The first case presented with typical signs of myocardial disease: chest pain and diaphoresis with myocardial depression in the electrocardiograph. The second case deteriorated rapidly and demised within the first day of admission. Histology of the heart muscles showed multiple small foci of myocyte necrosis surrounded by lymphocytes, in keeping with viral myocarditis. Both cases fulfilled the World Health Organization (WHO) diagnosis of probable dengue: the first case had positive dengue serology, both IgM and IgG at day six of illness, and the second case was polymerase chain reaction (PCR) positive for dengue and identified as serotype 2. Despite the severe outcome, both cases did not completely fulfil the criteria for dengue haemorrhagic fever (DHF). Although severe cardiac impairment is not commonly reported in dengue infection, it can be life threatening.

Primary drug resistance and transmission analysis of HIV-1 in acute and recent drug-naïve seroconverters in Singapore.

OBJECTIVES: The aim of the study was to elucidate primary drug resistance and transmission of HIV-1 in acute and recent drug-naïve seroconverters in Singapore. METHODS: Acute and recent HIV-1 seroconverters were enrolled in the study. The HIV-1 polymerase (pol) gene was sequenced and used for genotypic drug resistance analysis and phylogenetic analysis. HIV-1 transmission clusters were inferred from phylogenetic clustering analysis. RESULTS: Of the 60 subjects analysed, 95% were men, and 73.3% were men who have sex with men (MSM). Six HIV-1 subtypes were identified, including CRF01_AE (46.7%), subtypes B (30%), B' (15%) and G (1.7%), CRF33_01B (1.7%) and CRF34_01B (5%). Primary genotypic resistance was detected in only one (1.7%) subtype B variant. Thirty-one patients (51.7%) were phylogenetically clustered, of whom 90% reported having local risk exposure, compared with 59% of the patients who were not phylogenetically clustered [odds ratio (OR) 6.35, 95% confidence interval (CI) 1.65-23.95]. MSM (OR 5.63, 95% CI 1.17-27.15), high viral load (OR 4.28, 95% CI 1.37-13.36) and young age (OR 0.92, 95% CI 0.85-0.99) were independently associated with clustered individuals. CONCLUSIONS: In Singapore, HIV-1 primary resistance is insignificant; individuals with seroconversion account for about half of onward transmission among recently infected seroconverters. MSM, high viral load and young age are factors that facilitate transmission. Early detection of these individuals is of paramount importance for the prevention of HIV-1 transmission.

Decision tree algorithm in deciding hospitalization for adult patients with dengue haemorrhagic fever in Singapore.

OBJECTIVES: To develop a simple decision tree for clinicians to decide between hospitalization and outpatient monitoring of adult dengue patients. METHOD: Retrospective cohort study on all laboratory-diagnosed dengue patients admitted in 2004 to Tan Tock Seng Hospital, Singapore. Demographic, clinical, laboratory and radiological data were collected, and cases classified as dengue fever (DF) or dengue haemorrhagic fever (DHF) using World Health Organization criteria. To develop the decision tree, we used chi-squared automatic interaction detector (CHAID) with bi-way and multi-way splitting. The resulting trees were pruned to achieve the highest sensitivity with the shortest tree. RESULTS: In 2004, 1973 probable and confirmed adult dengue patients were admitted; DF comprised 1855 (94.0%) and DHF 118 (6.0%) of the cases. The best decision tree prediction had three branches, consisting of a history of clinical bleeding, serum urea, and serum total protein. This decision tree had a sensitivity of 1.00, specificity of 0.46, positive predictive value of 7.5%, and negative predictive value of 100%. The overall accuracy of the decision tree was 48.1%. The test sensitivity and specificity compared favourably with other predictive probability equations and sophisticated laboratory tests, and would prevent 43.9% of mild DF cases from hospitalization. CONCLUSIONS: A simple decision tree is effective in predicting DHF in the clinical setting for adult dengue infection.

Fulminant hepatitis in dengue haemorrhagic fever.

Dengue virus is estimated to cause over 100 million infections throughout the world annually. While dengue infections can have a wide range of infections, atypical manifestations have been described. These involve the central nervous system, cardiac alterations and hepatitis. Here, we highlight a case of dengue haemorrhagic fever (DHF) with fulminant hepatitis. A 55-year-old male was admitted for 16 days, developing severe thrombocytopenia as low as 6x10(9)/L, haematocrit of 48% with transaminitis: ALT: 3,515 U/L, AST: 12,541 U/L, GGT: 1,094 U/L. Subsequent investigations excluded any occult liver lesions, hepatitis A, B and C, Wilson's disease, Epstein-Barr virus and Cytomegalo virus as possible causes. His dengue PCR was positive. His condition subsequently improved with supportive treatment. Liver injury from dengue virus is mediated by its direct infection of hepatocytes and kupffer cells. While mild to moderate elevations of serum aminotransferases (ALT and AST<5X normal) are common in dengue virus infection, liver failure rarely dominate the clinical picture. Liver dysfunction was commoner in DHF, with case reports indicating that severe hepatic dysfunction (ALT and AST>10X normal) was seen with DHF associated with spontaneous bleeding tendencies. Overall prognosis depends on age and other concomitant co-morbidities. We seek to review the literature on dengue infections with hepatitis and discuss issues pertaining to pathophysiology of liver impairment in dengue, the frequency of transaminitis associated with DHF and the overall prognosis.

Serodiagnosis of dengue virus infection using commercially available antibody and NS1 antigen ELISAs.

Accuracy of the InBios DENV Detect IgM, IgG and NS1 antigen (Ag) ELISAs (Seattle, WA) for detection of dengue virus (DENV) infection were evaluated using 100 retrospectively selected sera from acutely febrile patients presenting to a Singapore hospital. The InBios DENV NS1, IgM and IgG ELISAs had an overall sensitivity of 83.6%, 40% and 58.2% and an overall specificity of 97.8%, 97.8% and 55.6%, respectively. Simultaneous testing for NS1 and IgM-antibodies yielded a sensitivity and specificity of 85.5% and 95.5%, respectively, which did not significantly differ from testing for NS1 Ag alone. Using sera positive for IgM- or IgG-class antibodies to six common arboviruses, the InBios IgM and IgG ELISAs showed an overall analytic specificity of 89.2% and 66.4%, respectively. This study suggests that recent DENV infection can reliably be detected by the InBios NS1 Ag ELISA alone and that InBios DENV IgG reactivity should be interpreted with caution.

Influenza and the pandemic threat.

With the increasing concern of an imminent influenza pandemic, Singapore and many other countries have been developing preparedness plans. Influenza affects an estimated 20 percent of the population of Singapore annually, and local outbreaks can last for more than 12 weeks and occur at different periods of the year. The 1968 pandemic in Singapore had a clinical attack rate of about 20 percent and resulted in infections with fever that lasted up to five days. However, absenteeism from work due to seasonal influenza-like illnesses was estimated to be less than one day per person in Singapore. The next pandemic in Singapore is predicted to cause an average of 1,105 deaths and 3,338 hospitalisations, while a severe pandemic will cause more healthcare damage. Preventive strategies include national public health initiatives, vaccination, anti-viral therapy, and hygiene measures. To develop effective preparedness plans, it is important for healthcare workers to understand the disease's epidemiology, outcomes, and treatment and prevention strategies available.

Surveillance of severe acute respiratory syndrome (SARS) in the post-outbreak period.

INTRODUCTION: This retrospective one-month survey evaluated the practicality of post-severe acute respiratory syndrome (SARS) surveillance recommendations in previously SARS-affected countries, namely Singapore. These included staff medical sick leave for febrile illness, inpatient fevers, inpatient pneumonia, atypical pneumonia, febrile illnesses with significant travel history and sudden unexplained deaths from pneumonia/ adult respiratory distress syndrome (ARDS). METHODS: Surveillance data on medical sick leave of staff, all inpatient fevers, all febrile (temperature greater than or equal to 38 degrees Celsius) inpatient pneumonia, including atypical pneumonia, and deaths from pneumonia were collected from sick leave reports, ward reports, isolation room rounds and mortuary reports from 1 to 28 September 2003. RESULTS: Baseline results show 167 (1.4/1000 staff-days) observed in staff sick leave for febrile illnesses, and 1798 (71.3/1000 bed-days) observed for inpatient fever. There were 40, 31 and 12 instances, respectively, of staff having temperatures of high fever (greater than or equal to 38 degrees Celsius), prolonged sick leave (3 days or more), and repeated sick leave (within 7 days) for febrile illnesses. An average of 4.6 wards a day potentially fulfilled the World Health Organisation SARS alert criteria. Of 27 cases with fever, pneumonia and a total white count of less than 10,000 cells per cubic mm as per Ministry of Health, Singapore criteria for the diagnosis of atypical pneumonia, only five were identified by clinicians. CONCLUSION: Surveillance is time-consuming and current recommendations are not specific enough to be used practically. Surveillance indicators for inpatients must overcome a high degree of background noise.

Measurable predictive factors for progression to AIDS among HIV-infected patients in Singapore.

INTRODUCTION: This study identifies measurable factors at the time of diagnosis that predict the progression to Acquired Immunodeficiency Syndrome (AIDS) among Human Immunodeficiency Virus (HIV)-infected patients in Singapore. MATERIALS AND METHODS: We carried out a retrospective study of 790 HIV-infected patients from 16 May 1985 to 31 December 2001. The end-point was the onset of AIDS-defining illness listed in the 1987 and 1991 revised Centers for Disease Control and Prevention criteria, but excluded CD4 cell counts as a criterion. Using the Kaplan-Meier method, AIDS-free survival curves were plotted for age groups at diagnosis, baseline CD4 counts and periods for utilisation of antiretroviral treatment. A Cox regression model was constructed to determine independent predictors of disease progression. RESULTS: Univariate analysis showed that patients of older age at diagnosis had a significantly higher risk of progression compared to younger patients, and patients with higher baseline CD4 cell counts had a lower risk of progression to AIDS. Adjusting for the simultaneous influence of several covariates on the rate of HIV progression to AIDS, multivariate analysis using the Cox model showed a significantly higher risk of progression for older patients at diagnosis, and the progressive lowering of risk with increasing baseline CD4 cell counts. CONCLUSIONS: This study found older age at diagnosis and baseline CD4 cell counts to be measurable predictors for HIV progression to AIDS at time of diagnosis. Identification of these risk factors enables physicians to provide counselling and advice, and to start appropriate treatment early. This could lower the risk of progression and improve survival.

Severe acute respiratory syndrome and pulmonary tuberculosis.

In Singapore, of 236 patients with probable severe acute respiratory syndrome (SARS), 2 were coinfected with tuberculosis, a phenomenon not previously reported. The patients' tuberculosis episodes only came to light after full recovery from SARS, when they presented with persistent respiratory symptoms and/or worsening chest radiography findings.

The severe acute respiratory syndrome coronavirus in tears.

BACKGROUND: Severe acute respiratory syndrome (SARS) is a new infectious disease that caused a global outbreak in 2003. Research has shown that it is caused by a novel coronavirus. A series of cases is reported where polymerase chain reaction (PCR) testing on tears had demonstrated the presence of the virus. Detection of ocular infection from tears using the PCR technique has been widely used by ophthalmologists to diagnose infections for other viruses. METHODS: This is a case series report from cases classified as probable or suspect SARS cases. Tear samples were collected from 36 consecutive patients who were suspected of having SARS in Singapore over a period of 12 days (7-18 April 2003), and analysed by PCR using protocols developed by the WHO network of laboratories. RESULTS: Three patients with probable SARS (one female and two male patients) had positive results from their tear samples. Tear samples were used to confirm SARS in the female patient, who was positive only from her tears. The positive specimens were found in cases sampled early in their course of infection. CONCLUSIONS: This is the first case series reported with the detection of the SARS coronavirus from tears, and has important implications for the practice of ophthalmology and medicine. The ability to detect and isolate the virus in the early phase of the disease may be an important diagnostic tool for future patients and tear sampling is both simple and easily repeatable. Many healthcare workers are in close proximity to the eyes of patients and this may be a source of spread among healthcare workers and inoculating patients. Ophthalmic practices may need to change as more stringent barrier methods, appropriate quarantine, and isolation measures are vital when managing patients with SARS.

Understanding HIV disease.

The world is now facing the second decade of global epidemic of HIV infection. Most of the Asian countries including Singapore are seeing a trend of rapid increase of HIV infected cases each year. It is now known that the HIV disease has a prolonged asymptomatic period of several years before the onset of AIDS defining illness. A HIV-infected person may present to a physician at any point of the entire course of HIV infection. Hence, this article aims to give an overview of HIV disease and to provide information for doctors today to equip themselves with adequate knowledge to deal with this deadly infection.

Nucleoside analogue-induced fatal lactic acidosis in two HIV-infected patients in Singapore.

The introduction of antiretroviral therapy has led to a significant decrease in the mortality and morbidity associated with human immunodeficiency virus (HIV) infection. Nucleoside reverse transcriptase inhibitors (NRTI) have been widely used as part of the antiretroviral therapy against HIV. However, one recently recognised serious complication of NRTI is the development of lactic acidosis. We report two cases of fatal NRTI-induced lactic acidosis, which occurred within five months of each other. Both were being treated with didanosine (ddI) and stavudine (d4T). Physicians involved in the care of HIV patients should recognise and be alert to the possibility of this highly fatal complication.