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.