DB921 and DB911 are benzimidazole-biphenyl isomers with terminal charged amidines. DB911 has a central meta-substituted phenyl that gives it a shape similar to those of known minor groove binding compounds. DB921 has a central para-substituted phenyl with a linear conformation that lacks the appropriate radius of curvature to match the groove shape. It is thus expected that DB911, but not DB921, should be an effective minor groove binder, but we find that DB921 not only binds in the groove but also has an unusually high binding constant in SPR experiments (2.9 x 10(8) M(-)(1), vs 2.1 x 10(7) M(-)(1) for DB911). ITC thermodynamic analysis with an AATT sequence shows that the stronger binding of DB921 is due to a more favorable binding enthalpy relative to that of DB911. CD results support minor groove binding for both compounds but do not provide an explanation for the binding of DB921. X-ray crystallographic analysis of DB921 bound to AATT shows that an induced fit structural change in DB921 reduces the twist of the biphenyl to complement the groove, and places the functional groups in position to interact with bases at the floor of the groove. The phenylamidine of DB921 forms indirect contacts with the bases through a bound water. The DB921-water pair forms a curved binding module that matches the shape of the minor groove and provides a number of strong interactions that are not possible with DB911. This result suggests that traditional views of compound curvature required for minor groove complex formation should be reevaluated.
Objectives We evaluated the effect of time intervals between the initiation of antiretroviral therapy (ART) and tuberculosis (TB) treatment on clinical outcomes in HIV-TB co-infected patients in an Asian regional cohort. Methods Adult HIV-TB co-infected patients in an observational HIV cohort database who had a known date of ART initiation and history of TB treatment were eligible for study inclusion. The time intervals between the initiation of ART and TB treatment were categorized as follows: TB diagnosed while on ART, early ART (<90 days after TB treatment), delayed ART (>90 days after TB treatment), and ART not started. Outcomes were assessed using survival analyses. Results A total of 768 HIV-TB co-infected patients were included in this study. Median CD4 T-cell count at TB diagnosis was 100 (IQR 40–208) cells/µL. The treatment outcomes between early ART and delayed ART initiation were not significantly different. Kaplan-Meier analysis indicated that mortality was highest for those diagnosed with TB while on ART (3.77 deaths per 100 person-years), and the prognoses of other groups were not different (in deaths per 100 person-years: 2.12 early ART, 1.46 delayed ART, and 2.94 ART not started). In a multivariate model, the interval between ART initiation and TB therapy did not significantly impact all-cause mortality. Conclusions The negative impact of delayed ART in patients co-infected with TB was not observed in this observational cohort of moderately to severely immunosuppressed patients. The broader impact of earlier ART in actual clinical practice should be monitored more closely.
Objectives With aging of the HIV‐positive population, cardiovascular disease (CVD) increasingly contributes to morbidity and mortality. We investigated CVD‐related and other causes of death (CODs) and factors associated with CVD in a multi‐country Asian HIV‐positive cohort. Methods Patient data from 2003–2017 were obtained from the Therapeutics, Research, Education and AIDS Training in Asia (TREAT Asia) HIV Observational Database (TAHOD). We included patients on antiretroviral therapy (ART) with > 1 day of follow‐up. Cumulative incidences were plotted for CVD‐related, AIDS‐related, non‐AIDS‐related, and unknown CODs, and any CVD (i.e. fatal and nonfatal). Competing risk regression was used to assess risk factors of any CVD. Results Of 8069 patients with a median follow‐up of 7.3 years [interquartile range (IQR) 4.4–10.7 years], 378 patients died [incidence rate (IR) 6.2 per 1000 person‐years (PY)], and this total included 22 CVD‐related deaths (IR 0.36 per 1000 PY). Factors significantly associated with any CVD event (IR 2.2 per 1000 PY) were older age [sub‐hazard ratio (sHR) 2.21; 95% confidence interval (CI) 1.36–3.58 for age 41–50 years; sHR 5.52; 95% CI 3.43–8.91 for ≥ 51 years, compared with < 40 years], high blood pressure (sHR 1.62; 95% CI 1.04–2.52), high total cholesterol (sHR 1.89; 95% CI 1.27–2.82), high triglycerides (sHR 1.55; 95% CI 1.02–2.37) and high body mass index (BMI) (sHR 1.66; 95% CI 1.12–2.46). CVD crude IRs were lower in the later ART initiation period and in lower middle‐ and upper middle‐income countries. Conclusions The development of fatal and nonfatal CVD events in our cohort was associated with older age, and treatable risk factors such as high blood pressure, triglycerides, total cholesterol and BMI. Lower CVD event rates in middle‐income countries may indicate under‐diagnosis of CVD in Asian‐Pacific resource‐limited settings.
Data are limited regarding risk factors for mortality among patients with human immunodeficiency virus (HIV)-associated tuberculosis (TB) in areas with low HIV prevalence and intermediate TB burden, such as the Western Pacific region. This study aimed to assess such risk factors in Hong Kong, which has an intermediate TB burden and low HIV prevalence. Methods: We conducted a retrospective cohort analysis of adult patients reported to the Hong Kong TB-HIV Registry between 2006 and 2015. Baseline characteristics were compared with Kaplan-Meier estimates. Cox proportional hazards regression modelling was used to identify factors associated with mortality. Results: Of 299 patients studied, 21 (7.0%) died within 12 months of anti-TB treatment (median [interquartile range], 7.5 [3.8-10] months). The median age of death was 54 (interquartile range, 40.5-75.0) years. The cause of death was TB in five and unrelated to TB in the remaining 16. Cox proportional hazards regression showed that older age (adjusted hazard ratio=4.5; 95% confidence interval [CI]=1.4-14.9), history of drug addiction (4.6; 95% CI=1.6-13.0), and low baseline CD4 cell count of <50/µL (2.9; 95% CI=1.1-7.7) were independent risk factors for death within 12 months.
Objectives Diabetes is a growing cause of morbidity and mortality in people living with HIV (PLHIV) receiving antiretroviral therapy (ART). We investigated the association between fasting plasma glucose (FPG) levels and mortality, and factors associated with FPG monitoring rates in Asia. Methods Patients from the Therapeutics Research, Education, and AIDS Training in Asia (TREAT Asia) HIV Observational Database Low Intensity Transfer (TAHOD‐LITE) cohort were included in the present study if they had initiated ART. Competing risk and Poisson regression were used to analyse the association between FPG and mortality, and assess risk factors for FPG monitoring rates, respectively. FPG was categorized as diabetes (FPG ≥ 7.0 mmol/L), prediabetes (FPG 5.6–6.9 mmol/L) and normal FPG (FPG < 5.6 mmol/L). Results In total, 33 232 patients were included in the analysis. Throughout follow‐up, 59% had no FPG test available. The incidence rate for diabetes was 13.7 per 1000 person‐years in the 4649 patients with normal FPG at ART initiation. Prediabetes [sub‐hazard ratio (sHR) 1.32; 95% confidence interval (CI) 1.07–1.64] and diabetes (sHR 1.90; 95% CI 1.52–2.38) were associated with mortality compared to those with normal FPG. FPG monitoring increased from 0.34 to 0.78 tests per person‐year from 2012 to 2016 (P < 0.001). Male sex [incidence rate ratio (IRR) 1.08; 95% CI 1.03–1.12], age > 50 years (IRR 1.14; 95% CI 1.09–1.19) compared to ≤ 40 years, and CD4 count ≥ 500 cells/μL (IRR 1.04; 95% CI 1.00–1.09) compared to < 200 cells/μL were associated with increased FPG monitoring. Conclusions Diabetes and prediabetes were associated with mortality. FPG monitoring increased over time; however, less than half of our cohort had been tested. Greater resources should be allocated to FPG monitoring for early diabetic treatment and intervention and to optimize survival.
Summary Objective To assess the prevalence of and characteristics associated with current smoking in an Asian HIV-positive cohort, calculate the predictive risks of cardiovascular disease (CVD), coronary heart disease (CHD), and myocardial infarction (MI), and identify the impact that simulated interventions may have. Methods Logistic regression analysis distinguished associated characteristics. Five-year predictive risks of CVD, CHD, MIs and the impact of simulated interventions were calculated utilizing the Data Collection on Adverse Effects of Anti-HIV Drugs Study (D:A:D) algorithm. Results Smoking status data were collected from 4,274 participants and 1,496 of these had sufficient data for simulated intervention calculations. Current smoking prevalence in these two groups was similar (23.2% vs. 19.9%). Characteristics associated with current smoking included being ≥50 years compared to 30–39 years (OR, 0.65; 95% confidence interval [CI], 0.51–0.83), HIV exposure through injection drug use compared to heterosexual exposure (OR, 3.03; CI, 2.25–4.07), and receiving ART at study sites in Singapore, South Korea, Malaysia, Japan, and Vietnamese sites in comparison to Thailand (all odds ratios >2). Alternatively, females were less likely to smoke than males (OR, 0.11; CI, 0.08–0.14). In simulated interventions smoking cessation demonstrated the greatest impact in reducing CVD and CHD risk and closely approximated the impact of switching from abacavir to an alternate antiretroviral in the reduction of five-year MI risk. Conclusion Multiple interventions could reduce CVD, CHD, and MI risk in Asian HIV-positive patients, with smoking cessation potentially being the most influential.
Objectives We conducted a longitudinal cohort analysis to evaluate the association of pre‐treatment body mass index (BMI) with CD4 recovery, virological failure (VF) and cardiovascular risk disease (CVD) markers among people living with HIV (PLHIV). Methods Participants who were enrolled between January 2003 and March 2019 in a regional Asia HIV cohort with weight and height measurements prior to antiretroviral therapy (ART) initiation were included. Factors associated with mean CD4 increase were analysed using repeated‐measures linear regression. Time to first VF after 6 months on ART and time to first development of CVD risk markers were analysed using Cox regression models. Sensitivity analyses were done adjusting for Asian BMI thresholds. Results Of 4993 PLHIV (66% male), 62% had pre‐treatment BMI in the normal range (18.5–25.0 kg/m2), while 26%, 10% and 2% were underweight (< 18.5 kg/m2), overweight (25–30 kg/m2) and obese (> 30 kg/m2), respectively. Both higher baseline and time‐updated BMI were associated with larger CD4 gains compared with normal BMI. After adjusting for Asian BMI thresholds, higher baseline BMIs of 23–27.5 and > 27.5 kg/m2 were associated with larger CD4 increases of 15.6 cells/µL [95% confidence interval (CI): 2.9–28.3] and 28.8 cells/µL (95% CI: 6.6–50.9), respectively, compared with normal BMI (18.5–23 kg/m2). PLHIV with BMIs of 25–30 and > 30 kg/m2 were 1.27 times (95% CI: 1.10–1.47) and 1.61 times (95% CI: 1.13–2.24) more likely to develop CVD risk factors. No relationship between pre‐treatment BMI and VF was observed. Conclusions High pre‐treatment BMI was associated with better immune reconstitution and CVD risk factor development in an Asian PLHIV cohort.
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