Risk factors for short-term all-cause mortality in patients with end stage renal disease: a scoping review.

OBJECTIVES: There is a lack of prognostic information to guide the prediction of short-term all-cause mortality in patients with end-stage renal disease (ESRD). The aim was to review the risk factors that influenced the risk of short-term all-cause mortality in patients with ESRD. METHODS: MEDLINE, Embase, PubMed, CINAHL, the Cochrane Library and Web of Science databases were searched for articles published between 2000 and 2020. Articles describing risk factors predicting short-term mortality (≤ 3 years) in patients with ESRD were included. Four reviewers independently performed title, abstract, full text screening and data extraction. Assessment of risk of bias was assessed using the Quality In Prognosis Studies (QUIPS) tool checklist. RESULTS: 20,840 articles were identified and 113 papers were included for this review. Of the 113 papers, 6.2% included only peritoneal dialysis (PD) patients, 67.3% included only hemodialysis (HD) patients, 20.4% included both PD and HD patients, with the remaining papers featuring patients on conservative management or awaiting renal transplant. Risk factors were categorised into 13 domains: 1)demographics/ lifestyle, 2) comorbidities 3)intradialytic blood pressure, 4)biomarkers, 5)cardiovascular measurements, 6)frailty status, 7)medications, 8)treatment related indicators, 9)renal related parameters, 10)health status, 11)cause of ESRD, 12)access to healthcare care/ information and, 13)proxy measures for poor health. C-reactive protein(CRP), age, and functional status were observed to have higher percentage of instances of being significantly associated with all-cause mortality. CONCLUSION: Commonly examined risk factors observed from this review may be used to build a general prognostic model for patients with ESRD, with specific treatment related risk factors added on to enhance the accuracy of the models.

Prognostic Factors of Mortality in Nonchronic Obstructive Pulmonary Disease Chronic Lung Disease: A Scoping Review.

Introduction: Patients with chronic lung disease (CLD) experience a heavy symptom burden at the end of life, but their uptake of palliative care is notably low. Having an understanding of a patient's prognosis would facilitate shared decision making on treatment options and care planning between patients, families, and their clinicians, and complement clinicians' assessments of patients' unmet palliative needs. While literature on prognostication in patients with chronic obstructive pulmonary disease (COPD) has been established and summarized, information for other CLDs remains less consolidated. Summarizing the mortality risk factors for non-COPD CLDs would be a novel contribution to literature. Hence, we aimed to identify and summarize the prognostic factors associated with non-COPD CLDs from the literature. Methods: We conducted a scoping review following published guidelines. We searched MEDLINE, Embase, PubMed, CINAHL, Cochrane Library, and Web of Science for studies published between 2000 and 2020 that described non-COPD CLD populations with an all-cause mortality risk period of up to three years. Only primary studies which reported associations with mortality adjusted through multivariable analysis were included. Results: Fifty-five studies were reviewed, with 53 based on interstitial lung disease (ILD) or connective tissue disease-associated ILD populations and two in bronchiectasis populations. Prognostic factors were classified into 10 domains, with pulmonary function and disease being the largest. Older age, lower forced vital capacity, and lower carbon monoxide diffusing capacity were most commonly investigated and associated with statistically significant increases in mortality risks. Conclusions: This comprehensive overview of prognostic factors for patients with non-COPD CLDs would facilitate the identification and prioritization of candidate factors to predict short-term mortality, supporting tool development for decision making and to identify high-risk patients for palliative needs assessments. Literature focused on patients with ILDs, and more studies should be conducted on other CLDs to bridge the knowledge gap.

Predicting mortality in patients diagnosed with advanced dementia presenting at an acute care hospital: the PROgnostic Model for Advanced DEmentia (PRO-MADE).

BACKGROUND: Challenges in prognosticating patients diagnosed with advanced dementia (AD) hinders timely referrals to palliative care. We aim to develop and validate a prognostic model to predict one-year all-cause mortality (ACM) in patients with AD presenting at an acute care hospital. METHODS: This retrospective cohort study utilised administrative and clinical data from Tan Tock Seng Hospital (TTSH). Patients admitted to TTSH between 1st July 2016 and 31st October 2017 and identified to have AD were included. The primary outcome was ACM within one-year of AD diagnosis. Multivariable logistic regression was used. The PROgnostic Model for Advanced Dementia (PRO-MADE) was internally validated using a bootstrap resampling of 1000 replications and externally validated on a more recent cohort of AD patients. The model was evaluated for overall predictive accuracy (Nagelkerke's R2 and Brier score), discriminative [area-under-the-curve (AUC)], and calibration [calibration slope and calibration-in-the-large (CITL)] properties. RESULTS: A total of 1,077 patients with a mean age of 85 (SD: 7.7) years old were included, and 318 (29.5%) patients died within one-year of AD diagnosis. Predictors of one-year ACM were age > 85 years (OR:1.87; 95%CI:1.36 to 2.56), male gender (OR:1.62; 95%CI:1.18 to 2.22), presence of pneumonia (OR:1.75; 95%CI:1.25 to 2.45), pressure ulcers (OR:2.60; 95%CI:1.57 to 4.31), dysphagia (OR:1.53; 95%CI:1.11 to 2.11), Charlson Comorbidity Index ≥ 8 (OR:1.39; 95%CI:1.01 to 1.90), functional dependency in ≥ 4 activities of daily living (OR: 1.82; 95%CI:1.32 to 2.53), abnormal urea (OR:2.16; 95%CI:1.58 to 2.95) and abnormal albumin (OR:3.68; 95%CI:2.07 to 6.54) values. Internal validation results for optimism-adjusted Nagelkerke's R2, Brier score, AUC, calibration slope and CITL were 0.25 (95%CI:0.25 to 0.26), 0.17 (95%CI:0.17 to 0.17), 0.76 (95%CI:0.76 to 0.76), 0.95 (95% CI:0.95 to 0.96) and 0 (95%CI:-0.0001 to 0.001) respectively. When externally validated, the model demonstrated an AUC of 0.70 (95%CI:0.69 to 0.71), calibration slope of 0.64 (95%CI:0.63 to 0.66) and CITL of -0.27 (95%CI:-0.28 to -0.26). CONCLUSION: The PRO-MADE attained good discrimination and calibration properties. Used synergistically with a clinician's judgement, this model can identify AD patients who are at high-risk of one-year ACM to facilitate timely referrals to palliative care.

Psychometric Properties of the Patient Activation Measure in Community-Dwelling Adults in Singapore.

INTRODUCTION: Measuring health activation in general population using valid instruments is needed to facilitate the evaluation of health education and behavioral programs in community. The 13-item Patient Activation Measure was well validated in patients with different chronic diseases but rarely validated in general population. The objective of this study was to assess the psychometric properties of the Patient Activation Measure among community-dwelling adults in Singapore. METHODS: Data of participants having valid responses to the English-version measure (N = 824) were analyzed. The psychometric properties were assessed by demonstrating evidence for uni-dimensionality using Rasch Principal Component Analysis of Residuals, known-group validity, convergent and divergent validity, and internal consistency reliability using Cronbach's alpha. RESULTS: The uni-dimensionality of the Patient Activation Measure was supported by the Rasch Principal Component Analysis of Residuals results. Participants having multimorbidity or polypharmacy and being inactive in physical activity had significantly lower activation scores. The activation score was positively and moderately correlated with health confidence measured by the Health Confidence Measure (r = .38, P < .001), and negatively and weakly correlated with depressive symptoms measured by the Patient Health Questionnaire (r = - .13, P < .001). The internal reliability was good with a Cronbach's alpha of .82. CONCLUSION: The 13-item Patient Activation Measure has acceptable construct validity and good internal consistency among community-dwelling adults. It is a potential instrument to measure health activation in this population. Further research is required to investigate the expansion of response options, validate the cut-off scores for the activation levels and examine the test-retest reliability and responsiveness.

Emergency department interventions for frailty (EDIFY): improving functional outcomes in older persons at the emergency department through a multicomponent frailty intervention.

OBJECTIVES: emergency department interventions for frailty (EDIFY) delivers frailty-centric interventions at the emergency department (ED). We evaluated the effectiveness of a multicomponent frailty intervention (MFI) in improving functional outcomes among older persons. DESIGN: a quasi-experimental study. SETTING: a 30-bed ED observation unit within a 1,700-bed acute tertiary hospital. PARTICIPANTS: patients aged ≥65 years, categorised as Clinical Frailty Scale 4-6, and planned for discharge from the unit. METHODS: we compared patients receiving the MFI versus usual-care. Data on demographics, function, frailty, sarcopenia, comorbidities and medications were gathered. Our primary outcome was functional status-Modified Barthel Index (MBI) and Lawton's iADL. Secondary outcomes include hospitalisation, ED re-attendance, mortality, frailty, sarcopenia, polypharmacy and falls. Follow-up assessments were at 3, 6 and 12 months. RESULTS: we recruited 140 participants (mean age 79.7 ± 7.6 years; 47% frail and 73.6% completed the study). Baseline characteristics between groups were comparable (each n = 70). For the intervention group, MBI scores were significantly higher at 6 months (mean: 94.5 ± 11.2 versus 88.5 ± 19.5, P = 0.04), whereas Lawton's iADL scores experienced less decline (change-in-score: 0.0 ± 1.7 versus -1.1 ± 1.8, P = 0.001). Model-based analyses revealed greater odds of maintaining/improving MBI in the intervention group at 6 months [odds ratio (OR) 2.51, 95% confidence interval (CI) 1.04-6.03, P = 0.04] and 12 months (OR 2.98, 95% CI 1.18-7.54, P = 0.02). This was similar for Lawton's iADL at 12 months (OR 4.01, 95% CI 1.70-9.48, P = 0.002). ED re-attendances (rate ratio 0.35, 95% CI 0.13-0.90, P = 0.03) and progression to sarcopenia (OR 0.19, 95% CI 0.04-0.94, P = 0.04) were also lower at 6 months. CONCLUSIONS: the MFI delivered to older persons at the ED can possibly improve functional outcomes and reduce ED re-attendances while attenuating sarcopenia progression.

Medical cost of advanced illnesses in the last-year of life-retrospective database study.

OBJECTIVE: This study aims to quantify medical care utilisation, and to describe the cost trajectories of individuals with advanced illnesses in the last-year of life, differentiated by advanced cancer, end-stage organ failure and progressive neurological disorders. METHODS: This retrospective database study included decedents who had previous inpatient or outpatient encounters at a public hospital in Singapore. Patients with advanced diseases were identified based on diagnostic codes and clinical criteria. Using a look-back approach, the amount of healthcare services utilised and the corresponding mean monthly and annual costs to the healthcare system in the last 12-months of life were quantified. RESULTS: The last 12-months of life among 6,598 decedents was associated with £20,524 (95% confidence interval: £20,013-£21,036) in medical costs, of which 80% was accounted for by inpatient admissions. Costs increased sharply in the last 2-months of life, with a large proportion of monthly costs accounted for by inpatient admissions which rose rapidly from 61% at 12-months prior to death to 94% in the last-month of life. Compared to patients with cancer, individuals diagnosed with non-cancer advanced illnesses accumulated 1.6 times more healthcare costs in the last-year of life with significant differences across patients with end-stage organ failure and progressive neurological disorders. CONCLUSION: Healthcare costs varied across disease conditions at the end-of-life. With advance care planning and close collaboration between the inpatient clinical team and the community providers, it may be possible to re-direct some of the hospitalisation costs to community-based palliative care services.

Psychometric evaluation of the 8-item Altarum Consumer Engagement (ACE) Measure™ in community-dwelling adults in Singapore.

BACKGROUND: A valid and reliable measure is essential to assess patient engagement and its impact on health outcomes. This study aimed to examine the psychometric properties of the 8-item Altarum Consumer Engagement Measure™ (ACE Measure) among English-speaking community-dwelling adults in Singapore. METHODS: This cross-sectional study involved 400 randomly selected community-dwelling adults (mean age: 49.7 years, 50.0% were female, 72.3% were Chinese) who completed the English version of the 8-item ACE Measure independently. The item-level statistics were described. The internal consistency of the measure was measured by Cronbach alpha and item-rest correlations. Validity of the tool was assessed by 1) factorial validity using confirmatory factor analysis (CFA), 2) hypothesis-testing validity by correlating ACE subscales (Commitment and Navigation) with health-related outcomes, and 3) criterion validity against the Patient Activation Measure and Health Confidence Measure. RESULTS: There was no floor or ceiling effect for Commitment and Navigation subscales, and the Cronbach alpha for each subscale was 0.76 and 0.54, respectively. The two-factor structure was confirmed by CFA. In general, Commitment and Navigation subscales were positively correlated with frequency of activity participation (rho = 0.30 - 0.33) and EQ-5D visual analog scale (rho = 0.15 - 0.30). Individuals who perceived better health than peers had higher subscale scores (p < 0.01). Each subscale score had moderate and positive correlations with activation score (rho = 0.48 - 0.55) and health confidence score (rho = 0.35 - 0.47). CONCLUSIONS: The two-subscale ACE Measure demonstrated good construct validity in English-speaking Singapore community-dwelling adults. Evidence in internal consistency was mixed, indicating further investigation.

Emergency Department Interventions for Frailty (EDIFY): Front-Door Geriatric Care Can Reduce Acute Admissions.

OBJECTIVES: The EDIFY program was developed to deliver early geriatric specialist interventions at the emergency department (ED) to reduce the number of acute admissions by identifying patients for safe discharge or transfer to low-acuity care settings. We evaluated the effectiveness of EDIFY in reducing potentially avoidable acute admissions. DESIGN: A quasi-experimental study. SETTING: ED of a 1700-bed tertiary hospital. PARTICIPANTS: ED patients aged ≥85 years. MEASUREMENTS: We compared EDIFY interventions versus standard care. Patients with plans for acute admission were screened and recruited. Data on demographics, premorbid function, frailty status, comorbidities, and acute illness severity were gathered. We examined the primary outcome of "successful acute admission avoidance" among the intervention group, which was defined as no ED attendance within 72 hours of discharge from ED, no transfer to an acute ward from subacute-care units (SCU) within 72-hours, or no transfer to an acute ward from the short-stay unit (SSU). Secondary outcomes were rehospitalization, ED re-attendance, institutionalization, functional decline, mortality, and frailty transitions at 1, 3, and 6 months. RESULTS: We recruited 100 participants (mean age 90.0 ± 4.1 years, 66.0% women). There were no differences in baseline characteristics between intervention (n = 43) and nonintervention (n = 57) groups. Thirty-five (81.4%) participants in the intervention group successfully avoided an acute admission (20.9% home, 23.3% SCU, and 44.2% SSU). All participants in the nonintervention group were hospitalized. There were no differences in rehospitalization, ED re-attendance, institutionalization and mortality over the study period. Additionally, we observed a higher rate of progression to a poorer frailty category at all time points among the nonintervention group (1, 3, and 6 months: all P < .05). CONCLUSIONS AND IMPLICATIONS: Results from our single-center study suggest that early geriatric specialist interventions at the ED can reduce potentially avoidable acute admissions without escalating the risk of rehospitalization, ED re-attendance, or mortality, and with possible benefit in attenuating frailty progression.

Estimating Transmission Parameters for COVID-19 Clusters by Using Symptom Onset Data, Singapore, January-April 2020.

We estimated the generation interval distribution for coronavirus disease on the basis of serial intervals of observed infector-infectee pairs from established clusters in Singapore. The short mean generation interval and consequent high prevalence of presymptomatic transmission requires public health control measures to be responsive to these characteristics of the epidemic.

Deaths in dementia: a scoping review of prognostic variables.

OBJECTIVES: To identify the types of factors included in research examining mortality in patients with dementia, and to stratify the identified factors by care settings. DESIGN: We systematically searched PubMed, Embase, PsycINFO and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, and identified grey literature from the Networked Digital Library of Theses and Dissertations, Open Grey and Grey Literature Report. Two authors independently screened for eligibility of studies. Independent reviewers extracted relevant study information. We conducted a narrative synthesis of the data. RESULTS: We identified 8254 articles, of which 94 met the inclusion criteria. More than half (n=53) were published between 2009 and 2018 with half from Europe. Studies were conducted across hospices/nursing homes (n=25), hospital (n=23), outpatient clinics (n=21), mixed settings (n=15) and in the community (n=10). Nearly 60% adopted a prospective cohort study design with 87% performing multivariable analysis. Overall, 239 variables were identified and classified into six themes-individual factors, health status, functional ability, cognition and mental health, treatments and health system factors. Although a general set of factors were common across all studies, when stratified by care settings, variations were seen in the specific variables included. CONCLUSION: Identifying prognostic variables relevant to the dementia population in each setting is key to facilitate appropriate care plans and to ensure timely access to palliative care options. Future research should also focus on ensuring the replicability of prognostic models and to generate a better understanding of the direct and interacting influence of the identified factors on mortality.

Cost-utility analysis of hearing aid device for older adults in the community: a delayed start study.

BACKGROUND: Hearing aids (HA) is the primary medical intervention aimed to reduce hearing handicap. This study assessed the cost-effectiveness of HA for older adults who were volunteered to be screened for hearing loss in a community-based mobile hearing clinic (MHC). METHODS: Participants with (1) at least moderate hearing loss (≥40 dB HL) in at least one ear, (2) no prior usage of HA, (3) no ear related medical complications, and (4) had a Mini-Mental State Examination score ≥ 18 were eligible for this study. Using a delayed-start study design, participants were randomized into the immediate-start (Fitted) group where HA was fitted immediately or the delayed-start (Not Fitted) group where HA fitting was delayed for three months. Cost utility analysis was used to compare the cost-effectiveness of being fitted with HA combined with short-term, aural rehabilitation with the routine care group who were not fitted with HA. Incremental cost effectiveness ration (ICER) was computed. Health Utility Index (HUI-3) was used to measure utility gain, a component required to derive the quality adjusted life years (QALY). Total costs included direct healthcare costs, direct non-healthcare costs and indirect costs (productivity loss of participant and caregiver). Demographic data was collected during the index visit to MHC. Cost and utility data were collected three months after index visit and projected to five years. RESULTS: There were 264 participants in the Fitted group and 163 participants in the Not Fitted group. No between-group differences in age, gender, ethnicity, housing type and degree of hearing loss were observed at baseline. At 3 months, HA fitting led to a mean utility increase of 0.12 and an ICER gain of S$42,790/QALY (95% CI: S$32, 793/QALY to S$62,221/QALY). At five years, the ICER was estimated to be at S$11,964/QALY (95% CI: S$8996/QALY to S$17,080/QALY) assuming 70% of the participants continued using the HA. As fewer individuals continued using their fitted HA, the ICER increased. CONCLUSIONS: HA fitting can be cost-effective and could improve the quality of life of hearing-impaired older individuals within a brief period of device fitting. Long term cost-effectiveness of HA fitting is dependent on its continued usage.

Effect of multimorbidity on survival of patients diagnosed with heart failure: a retrospective cohort study in Singapore.

OBJECTIVE: Multimorbidity in patients with heart failure (HF) results in poor prognosis and is an increasing public health concern. We aim to examine the effect of multimorbidity focusing on type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) on all-cause and cardiovascular disease (CVD)-specific mortality among patients diagnosed with HF in Singapore. DESIGN: Retrospective cohort study. SETTING: Primary and tertiary care in three (out of six) Regional Health Systems in Singapore. PARTICIPANTS: Patients diagnosed with HF between 2003 and 2016 from three restructured hospitals and nine primary care polyclinics were included in this retrospective cohort study. PRIMARY OUTCOMES: All-cause mortality and CVD-specific mortality. RESULTS: A total of 34 460 patients diagnosed with HF from 2003 to 2016 were included in this study and were followed up until 31 December 2016. The median follow-up time was 2.1 years. Comorbidities prior to HF diagnosis were considered. Patients were categorised as (1) HF only, (2) T2DM+HF, (3) CKD+HF and (4) T2DM+CKD+HF. Cox regression model was used to determine the effect of multimorbidity on (1) all-cause mortality and (2) CVD-specific mortality. Adjusting for demographics, other comorbidities, baseline treatment and duration of T2DM prior to HF diagnosis, 'T2DM+CKD+HF' patients had a 56% higher risk of all-cause mortality (HR: 1.56, 95% CI 1.48 to 1.63) and a 44% higher risk of CVD-specific mortality (HR: 1.44, 95% CI 1.32 to 1.56) compared with patients diagnosed with HF only. CONCLUSION: All-cause and CVD-specific mortality risks increased with increasing multimorbidity. This study highlights the need for a new model of care that focuses on holistic patient management rather than disease management alone to improve survival among patients with HF with multimorbidity.

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites.

HIV subtypes not only predominate in different geographical regions but also differ in key phenotypic characteristics. To determine if genotypic and/or phenotypic differences in the Envelope (Env) glycoprotein can explain subtype related differences, we cloned 37 full length Envs from Subtype B and AE HIV infected individuals from Singapore. Our data demonstrates that CRF01_AE Envs have lower Potential N Glycosylation Sites and higher risk of ×4 development. Phenotypically, CRF01_AE were less infectious than subtype B Envs in cells expressing low levels of CCR5. Moreover, the Maraviroc IC50 was higher for subtype B Envs and correlated with infectivity in low CCR5 expressing cells as well as PNGS. Specifically, the glycosylation site N301 in the V3 loop was seen less frequently in AE subtype and CXCR4 topic viruses. CRF01_AE differs from B subtype in terms of CCR5 usage and Maraviroc susceptibility which may have implications for HIV pathogenesis and virus evolution.

Differences in clinical and psychiatric outcomes between prevalent HIV-1 molecular subtypes in a multiethnic Southeast Asian sample.

OBJECTIVE: In Southeast Asia, subtypes B and CRF01_AE are the prevalent human immunodeficiency virus-1 (HIV-1) subtypes. This study examines the intersubtype differences in clinical indicators and psychiatric symptoms in a multiethnic sample. METHODS: The study site was a national HIV treatment center. Data were extracted from the Molecular Epidemiology Research study and the HIV-Psychiatry Integrated Mental Health Project, and analyzed according to groups defined by viral subtype. RESULTS: Of 177 subjects, 54.8% were infected with subtype CRF01_AE; 42.9% screened positive on the Hospital Anxiety and Depression Scale (HADS). The CRF01_AE group was significantly older (mean 38.29 years vs. 34.62 years, P=.031) and had advanced immunosuppression (CD4 <200) just prior to HADS screening (33.0% vs. 13.5%, P=.003). By multivariate logistic regression, homosexual transmission [odds ratio (OR) 0.388, 95% confidence interval (CI) 0.158-0.951, P=.038], subtype CRF01_AE (OR 2.898, 95% CI 1.199-7.001, P=.018) and positive HADS screening (OR 2.859, 95% CI 1.261-8.484, P=.012) were associated with advanced immunosuppression; and only advanced immunosuppression was associated with screening positive on the HADS (OR 3.270, 95% CI 1.299-8.227, P=.012). CONCLUSION: Subtype CRF01_AE is associated with advanced immunosuppression but not with symptoms of anxiety and depression. The results suggest that psychiatric symptoms are associated with advanced HIV disease regardless of subtype.

Clinical evaluation of a low cost, in-house developed real-time RT-PCR human immunodeficiency virus type 1 (HIV-1) quantitation assay for HIV-1 infected patients.

OBJECTIVES: HIV-1 viral quantitation is essential for treatment monitoring. An in-house assay would decrease financial barriers to access. MATERIALS AND METHODS: A real-time competitive RT-PCR in house assay (Sing-IH) was developed in Singapore. Using HXB2 as reference, the assay's primers and probes were designed to generate a 183-bp product that overlaps a portion of the LTR region and gag region. A competitive internal control (IC) was included in each assay to monitor false negative results due to inhibition or human error. Clinical evaluation was performed on 249 HIV-1 positive patient samples in comparison with the commercially available Generic HIV Viral Load assay. Correlation and agreement of results were assessed for plasma HIV-1 quantification with both assays. RESULTS: The assay has a lower limit of detection equivalent to 126 copies/mL of HIV-1 RNA and a linear range of detection from 100-1000000 copies/mL. Comparative analysis with reference to the Generic assay demonstrated good agreement between both assays with a mean difference of 0.22 log10 copies/mL and 98.8% of values within 1 log10 copies/mL range. Furthermore, the Sing-IH assay can quantify HIV-1 group M subtypes A-H and group N isolates adequately, making it highly suitable for our region, where subtype B and CRF01_AE predominate. CONCLUSIONS: With a significantly lower running cost compared to commercially available assays, the broadly sensitive Sing-IH assay could help to overcome the cost barriers and serve as a useful addition to the currently limited HIV viral load assay options for resource-limited settings.

High prevalence of CXCR4 usage among treatment-naive CRF01_AE and CRF51_01B-infected HIV-1 subjects in Singapore.

BACKGROUND: Recent studies suggest HIV-1 inter-subtype differences in co-receptor usage. We examined the correlation between HIV-1 subtype and co-receptor usage among treatment-naïve HIV-1 subjects in Singapore. Additionally, we investigated whether the subtype co-receptor association was influenced by stage of infection. METHODS: V3 sequences of HIV-1 envelope protein gp120 were obtained from 110 HIV treatment-naïve patients and genotypic co-receptor tropism determination was performed using Geno2pheno. Two false-positive rate (FPR) cut-offs, 10% and 5.75% were selected for tropism testing. RESULTS: Subtype assignment of viral strains from 110 HIV-infected individuals based on partial sequencing of HIV-1 pol, gp120 and gp41 were as follows: 27 subtype B, 64 CRF01_AE, 10 CRF51_01B, and 9 other subtypes. At FPR=10%, 10 (100%) CRF51_01B-infected subjects and 26 (40.6%) CRF01_AE-infected subjects had CXCR4-using virus, compared to 7 (25.9%) subtype B subjects and 1 (11.1%) CRF33_01B-infected subject (P < 0.001). At FPR=5.75%, 10 (100%) CRF51_01B-infected subjects and 20 (31.3%) CRF01_AE-infected subjects had CXCR4-using virus, compared to 4 (14.8%) subtype B and 1 (11.1%) CRF33_01B-infected subjects (P < 0.001). Among those with evidence of seroconversion within 2 years prior to study enrolment, 100% of CRF51_01B-infected subjects had CXCR4-using virus, independent of Geno2pheno FPR. CONCLUSION: CRF51_01B and CRF01_AE-infected individuals have higher prevalence of CXCR4-usage compared to subtype B infected individuals. Further studies examining these differences could help optimise the use of CCR5-antagonist in populations with these subtypes, and increase our understanding of HIV-1 biology.

Clinical evaluation of an in-house human immunodeficiency virus (HIV) genotyping assay for the detection of drug resistance mutations in HIV-1 infected patients in Singapore.

INTRODUCTION: Human immunodeficiency virus type 1 (HIV-1) genotyping resistance test (GRT) is essential for monitoring HIV-1 drug resistance mutations (DRMs). High cost and HIV-1 genetic variability are challenges to assay availability in Singapore. An in-house Sanger sequencing-based GRT method was developed at the Communicable Disease Centre (CDC), Singapore's HIV national treatment reference centre for both subtype B and non-subtype B HIV-1. MATERIALS AND METHODS: The in-house GRT sequenced the fi rst 99 codons of protease (PR) and 244 codons of reverse transcriptase (RT) in the pol gene. The results were compared with the Food and Drug Administration (FDA)-approved ViroSeq™ HIV-1 Genotyping System. RESULTS: Subtype assignment for the 46 samples were as follows: 31 (67.4%) CRF01_AE, 14 (30.5%) subtype B and 1 (2.1%) subtype C. All 46 samples had viral load of ≥500 copies/mL, and were successfully amplified by the in-house primer sets. Compared to the ViroSeq™ test, our in-house assay showed drug-resistance conferring codon concordance of 99.9% at PR and 98.9% at RT, and partial concordance of 0.1% at PR and 1.1% at RT. No discordant result was observed. CONCLUSION: The assay successfully identified DRMs in both subtype AE and B, making it suitable for the efficient treatment monitoring in genetically diverse population. At less than half of the running cost compared to the ViroSeq™ assay, the broadly sensitive in-house assay could serve as a useful addition to the currently limited HIV genotyping assay options for resource-limited settings, thereby enhancing the DRM surveillance and monitoring in the region.