Efficacy and safety of GST-HG171 in adult patients with mild to moderate COVID-19: a randomised, double-blind, placebo-controlled phase 2/3 trial.

Background: GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C like protease inhibitor that has demonstrated greater potency and efficacy compared to Nirmatrelvir in pre-clinical studies. We aimed to evaluate the efficacy and safety of orally administered GST-HG171 plus Ritonavir in patients with coronavirus disease 2019 (COVID-19) infected with emerging XBB and non-XBB variants. Methods: This randomised, double-blind, placebo-controlled phase 2/3 trial was conducted in 47 sites in China among adult patients with mild-to-moderate COVID-19 with symptoms onset ≤72 h. Eligible patients were randomised 1:1 to receive GST-HG171 (150 mg) plus Ritonavir (100 mg) or corresponding placebo tablets twice daily for 5 days, with stratification factors including the risk level of disease progression and vaccination status. The primary efficacy endpoint was time to sustained recovery of clinical symptoms within 28 days, defined as a score of 0 for 11 COVID-19-related target symptoms for 2 consecutive days, assessed in the modified intention-to-treat (mITT) population. This trial was registered at ClinicalTrials.gov (NCT05656443) and Chinese Clinical Trial Registry (ChiCTR2200067088). Findings: Between Dec 19, 2022, and May 4, 2023, 1525 patients were screened. Among 1246 patients who underwent randomisation, most completed basic (21.2%) or booster (74.9%) COVID-19 immunization, and most had a low risk of disease progression at baseline. 610 of 617 who received GST-HG171 plus Ritonavir and 603 of 610 who received placebo were included in the mITT population. Patients who received GST-HG171 plus Ritonavir showed shortened median time to sustained recovery of clinical symptoms compared to the placebo group (13.0 days [95.45% confidence interval 12.0-15.0] vs. 15.0 days [14.0-15.0], P = 0.031). Consistent results were observed in both SARS-CoV-2 XBB (45.7%, 481/1053 of mITT population) and non-XBB variants (54.3%, 572/1053 of mITT population) subgroups. Incidence of adverse events was similar in the GST-HG171 plus Ritonavir (320/617, 51.9%) and placebo group (298/610, 48.9%). The most common adverse events in both placebo and treatment groups were hypertriglyceridaemia (10.0% vs. 14.7%). No deaths occurred. Interpretation: Treatment with GST-HG171 plus Ritonavir has demonstrated benefits in symptom recovery and viral clearance among low-risk vaccinated adult patients with COVID-19, without apparent safety concerns. As most patients were treated within 2 days after symptom onset in our study, confirming the potential benefits of symptom recovery for patients with a longer duration between symptom onset and treatment initiation will require real-world studies. Funding: Fujian Akeylink Biotechnology Co., Ltd.

[Effects of polymorphisms in XRCC1 and APE1 on vinyl chloride-induced chromosome damage].

OBJECTIVE: To evaluate the effects of polymorphisms in XRCC1 and APE1 genes on vinyl chloride (VC)-induced chromosomal damage in peripheral lymphocytes. METHODS: In this study, 317 workers occupationally exposed to VC were recruited from a factory in Shandong Province, China. The micronucleus (MN) frequency in peripheral lymphocytes was used as an indicator of chromosomal damage. Polymerase chain reaction-restriction fragment length polymorphism and created restriction site combined with restriction fragment length polymorphism were used to determine the five single nucleotide polymorphisms in XRCC1 and APE1 genes in the base excision repair pathway. The association of chromosomal damage with these polymorphisms and the haplotype of XRCC1 was analyzed using Poisson regression and PHASE 2.0.2. RESULTS: It was found that among the VC-exposed workers, individuals with XRCC1 polymorphisms (-77C/T, Arg194Trp, Arg280His, and Arg399Gln) had a significantly higher MN frequency than those with homozygous wild-type genotypes, with frequency ratios (FR) as follows, respectively: FR = 1.21, 95%CI: 1.05∼1.39 (P < 0.05); FR = 1.14, 95%CI: 1.00∼1.38 (P < 0.05); FR = 1.26, 95%CI: 1.11∼1.44 (P < 0.05); FR = 1.23, 95%CI: 1.08∼1.46 (P < 0.05). APE1 Asp148Glu was found of no significant relationship with MN frequency. Haplotype analysis of XRCC1 demonstrated that the MN frequencies in subjects with CTAA/CTAA and CCAA/CTAA were significantly higher than that in those with TCGG/TCGG (FR = 1.19, 95%CI: 1.02∼1.32, P < 0.05; FR = 1.41, 95%CI: 1.02∼1.87, P < 0.05). Furthermore, association was found between accumulated exposure to VC and XRCC1 polymorphisms (-77C/T, Arg194Trp, Arg280His, and Arg399Gln) after adjustment for age, sex, drinking, and smoking. CONCLUSION: VC can induce chromosomal damage even when the exposure level is lower than the national occupational health standard of China (PC-TWA: 10 mg/m(3)); the polymorphisms in XRCC1 and APE1 are associated with chromosomal damage induced by VC.

Polymorphisms in BER and NER pathway genes: effects on micronucleus frequencies among vinyl chloride-exposed workers in Northern China.

In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65)‰ showed higher micronucleus frequency than the unexposed workers (2.51±1.96)‰ (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A, XPG Exon15 G-C, ERCC13'-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 -77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13'-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05-1.39; P<0.01); (FR=1.14, 95% CI: 1.00-1.38; P<0.05) and (FR=1.26, 95% CI: 1.11-1.44; P<0.01); (FR=1.23, 95% CI: 1.08-1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene-MN association changed with exposure for XRCC1 (-77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5'-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.

Estimation of benchmark dose for micronucleus occurrence in Chinese vinyl chloride-exposed workers.

In this study, we estimated the possibility of using benchmark dose (BMD) to assess the dose-response relationship between vinyl chloride monomer (VCM) exposure and chromosome damage. A group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed control in Shandong Province northern China were examined for chromosomal damage in peripheral blood lymphocytes (PBL) using the cytokinesis-blocked micronucleus (CB-MN) assay of DNA damage. The exposed group (3.47 ± 2.65)‰ showed higher micronucleus frequency than the control (1.60 ± 1.30)‰ (P < 0.01). Occupational exposure level based on micronucleus occurrence in all individuals was analyzed with benchmark dose (BMD) methods. The benchmark dose lower limit of a one-sided 95% confidence interval (BMDL) for 10% excess risk was also determined. Results showed a dose-response relationship between cumulative exposure and MN frequency, and a BMDL of 0.54 mg/m3 and 0.23 mg/m3 for males and females, respectively. Female workers were more susceptible to MN damage than male workers.

Estimation of a safe level for occupational exposure to vinyl chloride using a benchmark dose method in central China.

OBJECTIVES: The aim of this study was to estimate a benchmark dose (BMD) for chromosome damage induced by vinyl chloride monomer (VCM) in VCM-exposed workers in central China and validate the published results in Shanghai. METHODS: VCM-exposed workers who had been exposed to VCM for at least one year (n=463) and matched subjects not exposed to VCM or other toxins (n=273) were asked to participate in this study. Micronucleus (MN) frequency based on the cytokinesis-block micronucleus assay (CBMN) was used as a biomarker for chromosome damage induced by VCM exposure. RESULTS: The MN frequency in the VCM-exposed workers was significantly higher than that in the control group, and multivariate Poisson regression suggested that gender, smoking status and VCM exposure were the significant factors influencing the risk of increased MN frequency. When subjects were further stratified according to gender and smoking status, the results showed that female VCM-exposed workers were more susceptible than the males to the risk of increased MN frequency. The MN frequency of smokers was significantly higher than that of nonsmokers in the control group. Our study also suggested that there was a strong dose-response relationship between VCM CED and the increased risk of MN frequency in the total group, males and females. The BMDL(10) was found to be 630.6, 670.2 and 273.7 mg-year for all VCM-exposed workers, males and females, respectively. CONCLUSIONS: These results invite further scrutiny of the current VCM occupational exposure limits and warrant further study of the risk of VCM genotoxicity and carcinogenicity.

Influence of GSTs, CYP2E1 and mEH polymorphisms on 1, 3-butadiene-induced micronucleus frequency in Chinese workers.

1,3-butadiene (BD) has been classified as a human carcinogen, however, the relationship between chromosomal damage and its metabolic polymorphisms is not clear. The present study used the CBMN assay to detect chromosomal damage in the peripheral lymphocytes of 166 exposed workers and 41 non-exposed healthy individuals. PCR and PCR-RFLP were applied to detect GSTT1, GSTM1, CYP2E1 c1c2 and mEH Tyr113His, His139Arg polymorphisms. The results demonstrated that the micronucleus (MN) frequency of the exposed workers was significantly higher than controls (P<0.01). Among the exposed workers, the individuals with high BD exposures are more susceptible to chromosomal damage than those with low exposures (FR=1.30, 95% CI 1.14-1.53; P<0.05). Gender-difference was also found in our study: males got lower micronucleus frequency than females. Workers who carried the genotypes of GSTM1 (+), CYP2E1 (c1c2/c2c2) and mEH intermediate (I) group had significantly higher MN frequency than those carrying the genotypes of GSTM1 (-) (FR=1.29, 95% CI 1.05-1.59; P<0.05), CYP2E1 (c1c1) (FR=1.55, 95% CI 1.24-1.93; P<0.01) or mEH high (H) group (FR=1.57, 95% CI 1.08-2.34; P<0.05), respectively. Our data indicated that the current BD exposure level could cause significantly higher MN frequency in workers than controls. Polymorphisms of GSTM1, CYP2E1 and mEH are susceptible to altered chromosome damage.

Genetic polymorphisms of DNA repair genes and chromosomal damage in workers exposed to 1,3-butadiene.

The base excision repair (BER) pathway is important in repairing DNA damage incurred from occupational exposure to 1,3-butadiene (BD). This study examines the relationship between inherited polymorphisms of the BER pathway (x-ray repair cross-complementing group 1 (XRCC1) Arg194Trp, Arg280His, Arg399Gln, T-77C, ADPRT Val762Ala, MGMT Leu84Phe and APE1 Asp148Glu) and chromosomal damage in BD-exposed workers, using the cytokinesis-blocked (CB) micronucleus (MN) assay in peripheral lymphocytes of 166 workers occupationally exposed to BD and 41 non-exposed healthy individuals. The MN frequency of exposed workers (3.39 +/- 2.42) per thousand was higher than that of the non-exposed groups (1.48 +/- 1.26) per thousand (P < 0.01). Workers receiving greater than median annual BD exposures had higher MN values than lower exposed workers: frequency ratio (FR) of 1.30, 95% confidence interval (CI) 1.14-1.53; P < 0.05. Workers who carried the following genotypes were associated with greater frequency of MN (P < 0.05 for each comparison, unless specified): XRCC1 -77 C/T genotype (FR = 1.28, 95% CI: 1.04-1.57; reference C/C), ADPRT 762 Ala/Ala (FR = 1.54, 95% CI: 1.17-2.03; P < 0.01), XRCC1 194 Arg/Trp (FR = 1.13, 95% CI: 0.87-1.27; reference, Arg/Arg), XRCC1 280 Arg/His (FR = 1.67, 95% CI: 1.10-2.42; reference, Arg/Arg), XRCC1 399 Arg/Gln and Gln/Gln genotypes (FR = 1.26, 95% CI: 1.03-1.53 and FR = 1.24, 95% CI 1.03-1.49; reference Arg/Arg, respectively). As XRCC1 polymorphisms were linked, workers carrying the XRCC1 (-77)-(194)-(280)-(399) diplotype, TCGA/TCGA, had a higher MN frequency compared with individuals carrying the wild-type CCGG/CCGG (FR = 1.57, 95% CI: 1.02-2.41; P < 0.05). In conclusion, CB-MN is a sensitive index of early damage among BD-exposed workers. In workers exposed to BD, multiple BER polymorphisms and a XRCC1 haplotype were associated with differential levels of chromosome damage.

[Genetic polymorphism of XRCC1 associated with susceptibility of chromosomal damage in workers exposed by 1,3-butadiene].

OBJECTIVE: To explore the relationship between genetic polymorphism of XRCC1 194, 280, 399 and susceptibility of chromosomal damage induced by 1,3-butadiene (BD). METHODS: 138 workers occupationally exposed to BD and 41 normal individuals were involved. Cytokinesis-block micronucleus (CB-MN) assay was used to detect chromosome damage in peripheral lymphocyte. PCR-RFLP technique was applied to detect polymorphisms in XRCC1 194, 280 and 399. RESULTS: The MN frequencies (3.39 +/- 2.42) per thousand of workers exposed to BD were more higher than those of the non-exposed groups (1.48 +/- 1.26) per thousand (P < 0.01). Workers receiving mere exposures had higher MN values than those of lower-exposed workers: frequency ratios (FR) = 1.30 (95% CI 1.14 - 1.53, P < 0.05). Workers with XRCC1 194 Arg/Trp genotype had more susceptibility for chromosome damage, FR = 1.13 (95% CI 1.07 - 1.27). Workers with XRCC1 280 Arg/His genotype had more susceptibility for chromosome damage, FR = 1.67 (95% CI 1.10 - 2.42). XRCC1 399 Arg/Gln and combined group of Arg/Gln and Gln/Gln genotype carrier had higher MN frequency, FR = 1.26 (95% CI 1.03 - 1.53) and 1.24 (95% CI 1.03 - 1.49) respectively. The haplotypes CAG/TGG could associate with the decreased frequencies of total micronucleus (P < 0.05). CONCLUSION: Genotype of XRCC1 could associated with the chromosome damage induced by BD.