METHODS: We did a cohort analysis of TB cases in SECOND-LINE. TB cases included any clinical or laboratory-confirmed diagnoses and/or commencement of treatment for TB after randomization. Baseline factors associated with TB were analyzed using Cox regression stratified by site.
RESULTS: TB cases occurred at sites in Argentina, India, Malaysia, Nigeria, South Africa, and Thailand, in a cohort of 355 of the 541 SECOND-LINE participants. Overall, 20 cases of TB occurred, an incidence rate of 3.4 per 100 person-years (95% CI: 2.1 to 5.1). Increased TB risk was associated with a low CD4+-cell count (≤200 cells/μL), high viral load (>200 copies/mL), low platelet count (<150 ×109/L), and low total serum cholesterol (≤4.5 mmol/L) at baseline. An increased risk of death was associated with TB, adjusted for CD4, platelets, and cholesterol. A low CD4+-cell count was significantly associated with incident TB, mortality, other AIDS diagnoses, and virologic failure.
DISCUSSION: The risk of TB remains elevated in PLHIV in the setting of second-line HIV therapy in TB endemic regions. TB was associated with a greater risk of death. Finding that low CD4+ T-cell count was significantly associated with poor outcomes in this population supports the value of CD4+ monitoring in HIV clinical management.
METHODS: This was a cross-sectional prospective study conducted from September 2007 to September 2013. Consecutive patients who were detected to have anti-HCV antibodies in the University of Malaya Medical Centre were included and tested for the presence of HCV RNA using Roche Cobas Amplicor Analyzer and HCV genotype using Roche single Linear Array HCV Genotyping strip.
RESULTS: Five hundred and ninety-six subjects were found to have positive anti-HCV antibodies during this period of time. However, only 396 (66.4%) were HCV RNA positive and included in the final analysis. Our results showed that HCV genotype 3 was the predominant genotype with overall frequency of 61.9% followed by genotypes 1 (35.9%), 2 (1.8%) and 6 (0.5%). There was a slightly higher prevalence of HCV genotype 3 among the Malays when compared to the Chinese (P=0.043). No other statistical significant differences were observed in the distribution of HCV genotypes among the major ethnic groups. There was also no association between the predominant genotypes and basic demographic variables.
CONCLUSIONS: In a multi-ethnic Asian society in Malaysia, genotype 3 is the predominant genotype among all the major ethnic groups with genotype 1 as the second commonest genotype. Both genotypes 2 and 6 are uncommon. Neither genotype 4 nor 5 was detected. There is no identification of HCV genotype according to ethnic origin, age and gender.
METHODS: Treatment modification was defined as a change of two antiretrovirals, a drug class change or treatment interruption (TI), all for >14 days. We assessed factors associated with CD4 changes and undetectable viral load (UVL <1,000 copies/ml) at 1 year after second-line failure using linear and logistic regression, respectively. Survival time was analysed using competing risk regression.
RESULTS: Of the 328 patients who failed second-line ART in our cohorts, 208 (63%) had a subsequent treatment modification. Compared with those who continued the failing regimen, the average CD4 cell increase was higher in patients who had a modification without TI (difference =77.5, 95% CI 35.3, 119.7) while no difference was observed among those with TI (difference =-5.3, 95% CI -67.3, 56.8). Compared with those who continued the failing regimen, the odds of achieving UVL was lower in patients with TI (OR=0.18, 95% CI 0.06, 0.60) and similar among those who had a modification without TI (OR=1.97, 95% CI 0.95, 4.10), with proportions of UVL 60%, 22% and 75%, respectively. Survival time was not affected by treatment modifications.
CONCLUSIONS: CD4 cell improvements were observed in those who had treatment modification without TI compared with those on the failing regimen. When no other options are available, maintaining the same failing ART combination provided better VL control than interrupting treatment.
METHODS: Patients initiating cART between 2006 and 2013 were included. TI was defined as stopping cART for >1 day. Treatment failure was defined as confirmed virological, immunological or clinical failure. Time to treatment failure during cART was analysed using Cox regression, not including periods off treatment. Covariables with P < 0.10 in univariable analyses were included in multivariable analyses, where P < 0.05 was considered statistically significant.
RESULTS: Of 4549 patients from 13 countries in Asia, 3176 (69.8%) were male and the median age was 34 years. A total of 111 (2.4%) had TIs due to AEs and 135 (3.0%) had TIs for other reasons. Median interruption times were 22 days for AE and 148 days for non-AE TIs. In multivariable analyses, interruptions >30 days were associated with failure (31-180 days HR = 2.66, 95%CI (1.70-4.16); 181-365 days HR = 6.22, 95%CI (3.26-11.86); and >365 days HR = 9.10, 95% CI (4.27-19.38), all P < 0.001, compared to 0-14 days). Reasons for previous TI were not statistically significant (P = 0.158).
CONCLUSIONS: Duration of interruptions of more than 30 days was the key factor associated with large increases in subsequent risk of treatment failure. If TI is unavoidable, its duration should be minimised to reduce the risk of failure after treatment resumption.
METHODS: The study population consisted of HIV-infected patients enrolled in the TREAT Asia HIV Observational Database (TAHOD). Individuals were included in this analysis if they started combination antiretroviral treatment (cART) after 2002, were being treated at a centre that documented a median rate of viral load monitoring ≥0.8 tests/patient/year among TAHOD enrolees, and experienced a minor or major treatment substitution while on virally suppressive cART. The primary endpoint to evaluate outcomes was clinical or virological failure (VF), followed by an ART class change. Clinical failure was defined as death or an AIDS diagnosis. VF was defined as confirmed viral load measurements ≥400 copies/mL followed by an ART class change within six months. Minor regimen substitutions were defined as within-class changes and major regimen substitutions were defined as changes to a drug class. The patterns of substitutions and rate of clinical or VF after substitutions were analyzed.
RESULTS: Of 3994 adults who started ART after 2002, 3119 (78.1%) had at least one period of virological suppression. Among these, 1170 (37.5%) underwent a minor regimen substitution, and 296 (9.5%) underwent a major regimen substitution during suppression. The rates of clinical or VF were 1.48/100 person years (95% CI 1.14 to 1.91) in the minor substitution group, 2.85/100 person years (95% CI 1.88 to 4.33) in the major substitution group and 2.53/100 person years (95% CI 2.20 to 2.92) among patients that did not undergo a treatment substitution.
CONCLUSIONS: The rate of clinical or VF was low in both major and minor substitution groups, showing that regimen substitution is generally effective in non-clinical trial settings in Asian countries.
METHODS: Blips were defined as detectable VL (≥ 50 copies/mL) preceded and followed by undetectable VL (<50 copies/mL). Virological failure (VF) was defined as two consecutive VL ≥50 copies/ml. Cox proportional hazard models of time to first VF after entry, were developed.
RESULTS: 5040 patients (AHOD n = 2597 and TAHOD n = 2521) were included; 910 (18%) of patients experienced blips. 744 (21%) and 166 (11%) of high- and middle/low-income participants, respectively, experienced blips ever. 711 (14%) experienced blips prior to virological failure. 559 (16%) and 152 (10%) of high- and middle/low-income participants, respectively, experienced blips prior to virological failure. VL testing occurred at a median frequency of 175 and 91 days in middle/low- and high-income sites, respectively. Longer time to VF occurred in middle/low income sites, compared with high-income sites (adjusted hazards ratio (AHR) 0.41; p<0.001), adjusted for year of first cART, Hepatitis C co-infection, cART regimen, and prior blips. Prior blips were not a significant predictor of VF in univariate analysis (AHR 0.97, p = 0.82). Differing magnitudes of blips were not significant in univariate analyses as predictors of virological failure (p = 0.360 for blip 50-≤1000, p = 0.309 for blip 50-≤400 and p = 0.300 for blip 50-≤200). 209 of 866 (24%) patients were switched to an alternate regimen in the setting of a blip.
CONCLUSION: Despite a lower proportion of blips occurring in low/middle-income settings, no significant difference was found between settings. Nonetheless, a substantial number of participants were switched to alternative regimens in the setting of blips.
METHODS: We used Cox regression to analyze data of a cohort of Asian children.
RESULTS: A total of 2608 children were included; median age at cART was 5.7 years. Time-updated weight for age z score < -3 was associated with mortality (P < 0.001) independent of CD4% and < -2 was associated with immunological failure (P ≤ 0.03) independent of age at cART.
CONCLUSIONS: Weight monitoring provides useful data to inform clinical management of children on cART in resource-limited settings.
METHODS: HIV-infected adults enrolled in the TREAT Asia HIV Observational Database were eligible if they had an HIV RNA measurement documented at the time of ART initiation. The dataset was randomly split into a derivation data set (75% of patients) and a validation data set (25%). Factors associated with pre-treatment HIV RNA <100,000 copies/mL were evaluated by logistic regression adjusted for study site. A prediction model and prediction scores were created.
RESULTS: A total of 2592 patients were enrolled for the analysis. Median [interquartile range (IQR)] age was 35.8 (29.9-42.5) years; CD4 count was 147 (50-248) cells/mm3; and pre-treatment HIV RNA was 100,000 (34,045-301,075) copies/mL. Factors associated with pre-treatment HIV RNA <100,000 copies/mL were age <30 years [OR 1.40 vs. 41-50 years; 95% confidence interval (CI) 1.10-1.80, p = 0.01], body mass index >30 kg/m2(OR 2.4 vs. <18.5 kg/m2; 95% CI 1.1-5.1, p = 0.02), anemia (OR 1.70; 95% CI 1.40-2.10, p 350 cells/mm3(OR 3.9 vs. <100 cells/mm3; 95% CI 2.0-4.1, p 2000 cells/mm3(OR 1.7 vs. <1000 cells/mm3; 95% CI 1.3-2.3, p 25 yielded the sensitivity of 46.7%, specificity of 79.1%, positive predictive value of 67.7%, and negative predictive value of 61.2% for prediction of pre-treatment HIV RNA <100,000 copies/mL among derivation patients.
CONCLUSION: A model prediction for pre-treatment HIV RNA <100,000 copies/mL produced an area under the ROC curve of 0.70. A larger sample size for prediction model development as well as for model validation is warranted.
Methods: Study end points were as follows: (1) a CD4 count <200 cells/mm3 followed by a CD4 count ≥200 cells/mm3 (transient CD4 <200); (2) CD4 count <200 cells/mm3 confirmed within 6 months (confirmed CD4 <200); and (3) a new or recurrent World Health Organization (WHO) stage 3 or 4 illness (clinical failure). Kaplan-Meier curves and Cox regression were used to evaluate rates and predictors of transient CD4 <200, confirmed CD4 <200, and clinical failure among virally suppressed children aged 5-15 years who were enrolled in the TREAT Asia Pediatric HIV Observational Database.
Results: Data from 967 children were included in the analysis. At the time of confirmed viral suppression, median age was 10.2 years, 50.4% of children were female, and 95.4% were perinatally infected with HIV. Median CD4 cell count was 837 cells/mm3, and 54.8% of children were classified as having WHO stage 3 or 4 disease. In total, 18 transient CD4 <200 events, 2 confirmed CD4 <200 events, and10 clinical failures occurred at rates of 0.73 (95% confidence interval [95% CI], 0.46-1.16), 0.08 (95% CI, 0.02-0.32), and 0.40 (95% CI, 0.22-0.75) events per 100 patient-years, respectively. CD4 <500 cells/mm3 at the time of viral suppression confirmation was associated with higher rates of both CD4 outcomes.
Conclusions: Regular CD4 testing may be unnecessary for virally suppressed children aged 5-15 years with CD4 ≥500 cells/mm3.
RESULTS: The depletion of IgM+ cells and infiltration of macrophages were observed to be higher in bursa infected with AF2240 as compared to IBS002. In line with the increment of the macrophage population, higher nitric oxide (NO) and malondialdehyde (MDA) contents which indicated higher oxidative stress were also detected in bursa infected with NDV AF2240. In addition, higher pro-inflammatory cytokines and chemokine gene expression such as chicken CXCLi2, IL-18 and IFN-γ were observed in AF2240 infected bursa. Depletion of IgM+ cells was further confirmed with increased cell death and apoptosis of the cells in AF2240 infected bursa as compared to IBS002. However, it was found that the viral load for NDV strain IBS002 was comparatively higher than AF2240 although the magnitude of the pro- inflammatory cytokines expression and cell apoptosis was lower than AF2240.
CONCLUSION: The results of our study demonstrated that infection of NDV strains AF2240 and IBS002 caused apoptosis in bursa IgM+ cells and its severity was associated with increased expression of pro-inflammatory cytokines/chemokine, macrophage infiltration and oxidative stress as the infection duration was prolonged. However, of the two viruses, we observed that NDV AF2240 induced a greater magnitude of apoptosis in chicken bursa IgM+ cells in comparison to IBS002. This might be due to the high level of oxidative stress and inflammatory cytokines/chemokine as well as lower IL10 expression which subsequently led to a high rate of apoptosis in the chicken bursa of Fabricius although the detected viral load of AF2240 was lower than IBS002.
METHODS: Adults living with HIV enrolled in a regional observational cohort in Asia who had initiated combination antiretroviral therapy (cART) were included in the analysis. Factors associated with new TB diagnoses after cohort entry and survival after cART initiation were analysed using Cox regression, stratified by site.
RESULTS: A total of 7355 patients from 12 countries enrolled into the cohort between 2003 and 2016 were included in the study. There were 368 reported cases of TB after cohort entry with an incidence rate of 0.99 per 100 person-years (/100 pys). Multivariate analyses adjusted for viral load (VL), CD4 count, body mass index (BMI) and cART duration showed that CTX reduced the hazard for new TB infection by 28% (HR 0.72, 95% CI l 0.56, 0.93). Mortality after cART initiation was 0.85/100 pys, with a median follow-up time of 4.63 years. Predictors of survival included age, female sex, hepatitis C co-infection, TB diagnosis, HIV VL, CD4 count and BMI.
CONCLUSIONS: CTX was associated with a reduction in the hazard for new TB infection but did not impact survival in our Asian cohort. The potential preventive effect of CTX against TB during periods of severe immunosuppression should be further explored.
METHODOLOGY: Parallel virology was used to investigate the phenotypes of duck and mosquito-derived isolates of TMUV. Molecular biology and bioinformatics methods were employed to investigate the genetic characteristics and evolution of TMUV.
PRINCIPAL FINDINGS: The plaque diameter of duck-derived isolates of TMUV was larger than that of mosquito-derived isolates. The cytopathic effect (CPE) in mammalian cells occurred more rapidly induced by duck-derived isolates than by mosquito-derived isolates. Furthermore, duck-derived isolates required less time to reach maximum titer, and exhibited higher viral titer. These findings suggested that poultry-derived TMUV isolates were more invasive and had greater expansion capability than the mosquito-derived isolates in mammalian cells. Variations in amino acid loci in TMUV E gene sequence revealed two mutated amino acid loci in strains isolated from Malaysia, Thailand, and Chinese mainland compared with the prototypical strain of the virus (MM1775). Furthermore, TMUV isolates from the Chinese mainland had six common variations in the E gene loci that differed from the Southeast Asian strains. Phylogenetic analysis indicated that TMUV did not exhibit a species barrier in avian species and consisted of two lineages: the Southeast Asian and the Chinese mainland lineages. Molecular traceability studies revealed that the recent common evolutionary ancestor of TMUV might have appeared before 1934 and that Malaysia, Thailand and Shandong Province of China represent the three main sources related to TMUV spread.
CONCLUSIONS: The current broad distribution of TMUV strains in Southeast Asia and Chinese mainland exhibited longer-range diffusion and larger-scale propagation. Therefore, in addition to China, other Asian and European countries linked to Asia have used improved measures to detect and monitor TMUV related diseases to prevent epidemics in poultry.