Background: Herpes simplex virus 1 (HSV-1) affects a large part of the adult population. Anti-HSV-1 drugs, such as acyclovir, target thymidine kinase and viral DNA polymerase. However, the emerging of resistance of HSV-1 alerts for the urgency in developing new antivirals with other therapeutic targets. Thus, this study evaluated a series of 1,4-disubstituted-1,2,3-triazole derivatives against HSV-1 acute infection and provided deeper insights into the possible mechanisms of action.
Methods: Human fibroblast cells (HFL-1) were infected with HSV-1 17syn+ and treated with the triazole compounds at 50 μM for 24 h. The 50% effective drug concentration (EC50) was determined for the active compounds. Their cytotoxicity was also evaluated in HFL-1 with the 50% cytotoxic concentration (CC50) determined using CellTiter-Glo® solution. The most promising compounds were evaluated by virucidal activity and influence on virus egress, DNA replication and transcription, and effect on an acyclovir-resistant HSV-1 strain.
Results: Compounds 3 ((E)-4-methyl-N'-(2-(4-(phenoxymethyl)-1H-1,2,3-triazol1yl)benzylidene)benzenesulfonohydrazide) and 4 (2,2'-(4,4'-((1,3-phenylenebis(oxy))bis(methylene))bis(1H-1,2,3-triazole-4,1 diyl)) dibenzaldehyde) were the most promising, with an EC50 of 16 and 21 μM and CC50 of 285 and 2,593 μM, respectively. Compound 3 was able to inhibit acyclovir-resistant strain replication and to interfere with virus egress. Both compounds did not affect viral DNA replication, but inhibited significantly the expression of ICP0, ICP4 and gC. Compound 4 also affected the transcription of UL30 and ICP34.5.
Conclusions: Our findings demonstrated that these compounds are promising antiviral candidates with different mechanisms of action from acyclovir and further studies are merited.
Background: Telbivudine (LdT) and tenofovir (TDF) are widely used in pregnant women to prevent vertical transmission; however, limited data are available on the differences in clinical efficacy and safety between the two drugs.
Methods: A total of 307 hepatitis B e antigen (HBeAg)-positive pregnant women with complete follow-up data were enrolled, the patients with alanine aminotransferase (ALT) levels <1×ULN at baseline were enrolled to cohort 1 for treatment from 28 ±4 weeks gestation to delivery, while ALT levels >1×ULN at baseline were enrolled to cohort 2 for treatment from 28 ±4 weeks gestation and continued after delivery. The clinical efficacy and safety was compared in LdT- and TDF-treated patients. In addition, 32 patients in cohort 1 were analysed for nucleoside analogue (NA)-related resistance mutations at baseline and after delivery.
Results: The results showed that HBV DNA levels were significantly lower at delivery than at baseline (P<0.001), but the decreases in HBV DNA, ALT, total bilirubin and total bile acid levels did not differ between the LdT- and TDF-treated patients at different time points (P>0.05) in the two cohorts. However, gastrointestinal adverse effects (vomiting) occurred more frequently in TDF-treated than LdT-treated patients (6.6% versus 0.0%; P=0.001). The results of NA-related resistance mutations analysis in cohort 1 revealed that short-term LdT or TDF treatment did not significantly change the NA-related resistance mutations (P>0.05).
Conclusions: This study revealed that the clinical efficacy in LdT- or TDF-treated HBeAg-positive Chinese pregnant women is similar, and gastrointestinal adverse effects occurred more frequently in TDF-treated patients.
Background: Cofactors associated with persistently abnormal CD4+:CD8+ T-cell ratio in people with HIV (PWH) on antiretroviral treatment (ART) might change over time as the population of people with HIV ages or as new ART drugs become available. The main objective of our study was to determine the long-term associations of baseline factors, including the CD4+ T-cell count and ratio, with ratio normalization (≥1). In addition to this, we explored whether the ratio remained associated with the risk of both AIDS and non-AIDS events among individuals on suppressive ART.
Methods: Clinic-based study in a tertiary, university hospital in Madrid. People with HIV starting a first-line ART regimen (January 2006-June 2017) were included in a prospective national multicentre cohort (CoRIS). People with controlled HIV-infection within the first year of ART initiation and complete CD4+ and CD8+ T-cell records were selected. Cox proportional hazard (PH) regression models were used to estimate the cumulative incidence of ratio normalization and to examine associations with socio-demographic and clinical variables. To investigate factors independently associated with the development of AIDS and non-AIDS events we used a time updated Poisson regression model.
Results: The study included 557 subjects. During follow-up (median 5.24 years), 44% of participants achieved a ratio of 1 within a median of 1.49 years. In a multivariate PH model, pre-ART factors negatively associated with ratio normalization were the pre-ART CD4+:CD8+ T-cell ratio and mode of HIV acquisition. For the secondary analysis, 1.3 events/100 person years of follow-up were observed. After adjustment, older age, HIV RNA >200 copies/ml and CD4+:CD8+ T-cell ratios over follow-up, remained significantly associated with the development of AIDS and non-AIDS events. In contrast, pre-ART ratio was not associated with the risk of AIDS and non-AIDS events.
Conclusions: In summary, our study showed that higher pre-ART CD4+:CD8+ T-cell ratio is associated with rates of ratio normalization ≥1. In addition, the risk of AIDS and non-AIDS events seems to be predicted by the time updated CD4+:CD8+ T-cell ratio not by the pre-ART CD4+:CD8+ T-cell ratio. Therefore, CD4+:CD8+ T-cell ratio should be considered as a dynamic marker for translation into clinical practice.
Background: This study investigated survival in people living with HIV being followed-up from 5 and 10 years after antiretroviral therapy (ART) initiation in a multi-country Asian cohort.
Methods: We included patients in follow-up >5 years after ART initiation. Factors associated with mortality beyond 5 and 10 years on ART were analysed using competing risk regression with time-updated variables.
Results: Of 13,495 patients retained after 5 years on ART, 279 subsequently died (0.56/100 person-years). Increased mortality was associated with age >50 years (sub-hazard ratio [sHR] 2.24, 95% CI 1.58, 3.15, compared with ≤40 years), HIV exposure through injecting drug use (sHR 2.17, 95% CI 1.32, 3.56), HIV viral load ≥1,000 copies/ml: sHR 1.52, 95% CI 1.05, 2.21, compared with <400), regimen (second-line regimen: sHR 2.11, 95% CI 1.52, 2.94, and third-line regimen: sHR 2.82, 95% CI 2.00, 3.98, compared with first-line regimen), HBV coinfection (sHR 2.23, 95% CI 1.49, 3.33), fasting plasma glucose ≥126 mg/dl (sHR 1.98, 95% CI 1.22, 3.21, compared with <100 mg/dl) and estimated glomerular filtration rate <60 ml/min/1.73 m2 (sHR 2.57, 95% CI 1.56, 4.22). Decreased mortality was associated with transmission through male-to-male sexual contact (sHR 0.44, 95% CI 0.22, 0.88, compared with heterosexual transmission) and higher CD4+ T-cell count (200-349 cells/µl: sHR 0.27, 95% CI 0.20, 0.38, 350-499 cells/µl: sHR 0.10, 95% CI 0.07, 0.16 and ≥500 cells/µl: sHR 0.09, 95% CI 0.06, 0.13, compared with <200 cells/µl). Results after 10 years were similar, but most associations were weaker due to limited power.
Conclusions: Next to preventing ART failure, HIV programmes should carefully monitor and treat comorbidities, including hepatitis, kidney disease and diabetes, to optimize survival after long-term ART exposure.
Background: For patients with HBV infection who have decompensated cirrhosis (DC), a higher dose (1.0 mg/day) of entecavir is recommended than that used for those with compensated disease (0.5 mg/day), though with very little supporting data. We therefore compared the viral suppression achieved with 0.5 mg/day and 1.0 mg/day of entecavir in patients with HBV-related DC (NCT03345498).
Methods: Treatment-naive patients with HBV-related DC and serum HBV DNA titre exceeding 100,000 IU/ml received either dose of entecavir for 24 weeks. HBV DNA concentration was measured in blood specimens collected at baseline and after 2, 4, 8, 12 and 24 weeks of entecavir treatment.
Results: Participants in the 0.5 mg/day (n=13) and 1.0 mg/day (n=16) groups had similar baseline hepatitis B e antigen (HBeAg) positivity rates (12/13 and 12/16; P=0.34) and median (range) log10 serum HBV DNA levels (6.81 [5.01-8.12] and 7.45 [5.24-8.65]; P=0.17). The two doses led to similar reductions in serum HBV DNA levels after 2, 4, 8, 12 and 24 weeks of entecavir administration. At 24 weeks, 3 of the 13 patients receiving 0.5 mg/day and 1 of the 16 patients receiving 1.0 mg/day of entecavir had undetectable serum HBV DNA. Serum albumin level showed significant and similar improvement at the end of 24 weeks in the two groups.
Conclusions: Treatment-naive patients with HBV-related DC can be treated with entecavir in a 0.5 mg/day dose instead of the higher 1.0 mg/day dose, without compromising the degree of virological suppression. ClincialTrials.gov number NCT03345498.
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