Atom- and step-economic 1,3-thiosulfonylation of activated allenes with thiosulfonates to access vinyl sulfones/sulfides.

A new type of organocatalyzed 1,3-thiosulfonylation has been developed to straightforwardly access highly functionalized vinyl sulfones, which features mild conditions, atom- and step-economy, practicability, conciseness, and environmental friendliness. Moreover, these valuable products can be transformed to vinyl sulfides via a base-promoted isomerization. The versatile route can efficiently and rapidly introduce SCD3 groups with excellent levels of deuterium content (>99% D) by utilizing our newly developed SCD3 reagents. Gram-scale operations and further transformations are smoothly carried out, providing promising applications for drug discovery.

Robust, scalable construction of an electrophilic deuterated methylthiolating reagent: facile access to SCD3-containing scaffolds.

We have established a practical and concise method for the straightforward access of a universal deuterated methylthiolating reagent through a one-pot gram-scale operation under mild conditions. This odourless electrophilic SCD3 reagent was widely applied to react with numerous representative nucleophiles and approached various valuable SCD3 analogues with excellent levels of deuterium content (>99% D). The divergent further transformations were smoothly carried out to obtain the significant derivatives with different oxidative states in high efficiency.

No Statistically Apparent Difference in Antifungal Effectiveness Observed Among Trimethoprim/Sulfamethoxazole Plus Clindamycin or Caspofungin, and Trimethoprim/Sulfamethoxazole Monotherapy in HIV-Infected Patients with Moderate to Severe Pneumocystis Pneumonia: Results of an Observational Multicenter Cohort Study.

INTRODUCTION: Pneumocystis pneumonia is a common opportunistic infection in patients with HIV/AIDS, and is a leading cause of death in this population. Early selection of effective treatment is therefore critical to reduce mortality. We conducted a clinical trial to compare the effectiveness and safety of three different antifungal treatment regimens in HIV-infected patients with moderate to severe PCP. METHODS: Our study was a multicenter, observational prospective clinical trial. We recruited 320 HIV-infected patients with moderate to severe PCP, and stratified these subjects into a trimethoprim/sulfamethoxazole (TMP-SMX) monotherapy group, a TMP-SMX plus clindamycin group, and a TMP-SMX plus caspofungin group. Patients were invited to participate in 12 weeks of follow-up. Outcomes included the difference in overall mortality and the proportion of overall positive response to treatment in the three groups at weeks 4 and 12, the difference in treatment duration, and the proportion of adverse events among the three groups during the study period. RESULTS: The probability of survival not statistically different among three treatment groups. Mortality in the TMP-SMX monotherapy group (group 1) was 15/115 (13.04%) vs. 20/83 (24.10%) in the TMP-SMX plus clindamycin group (group 2) vs. 24/107 (22.43%) in the TMP-SMX plus caspofungin group (group 3) at week 12 (p = 0.092). The overall positive response rate to treatment in the three groups was 24.14%, 34.94%, and 38.32%, respectively, at week 4, and 33.91%, 38.55%, and 44.86%, respectively, at week 12. No significant difference in the overall positive response rate to treatment at either week 4 or week 12 was noted (p = 0.061, p = 0.246). Rates of changes to therapy were 6.50% (8/123) in group 1, 3.40% (3/87) in group 2, and 2.70% (3/110) in group 3, and did not differ significantly among the three groups (p = 0.376). There were also no significant differences in adverse events among the three treatment groups of patients with moderate to severe PCP. CONCLUSIONS: Our results indicate that there are no significant statistical differences among the three studied treatment regimens in terms of antifungal effectiveness in HIV-infected patients with moderate to severe PCP. TMP-SMX monotherapy is a convenient, cheap, and effective therapeutic drug regimen to treat HIV-infected patients with moderate to severe PCP, and is an appropriate treatment strategy in resource-limited settings. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov , ID: ChiCTR1900021195. Registered on February 1, 2019.

Copper-Catalyzed Ullmann-Type Coupling and Decarboxylation Cascade of Arylhalides with Malonates to Access α-Aryl Esters.

We have developed a high-efficiency and practical Cu-catalyzed cross-coupling to directly construct versatile α-aryl-esters by utilizing readily available aryl bromides (or chlorides) and malonates. These gram-scale approaches occur with turnovers of up to 1560 and are smoothly conducted by the usage of a low catalyst loading, a new available ligand, and a green solvent. A variety of functional groups are tolerated, and the application occurs with α-aryl-esters to access nonsteroidal anti-inflammatory drugs (NSAIDs) on the gram scale.

Timing of antiretroviral therapy for HIV-infected patients with cytomegalovirus retinitis: study protocol of a multi-center prospective randomized controlled trial.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is an important opportunistic infection (OI) occurring mainly in patients with acquired immunodeficiency syndrome (AIDS) and has the potential to cause severe visual impairment and blindness among AIDS patients. Subsequent to the adoption and implementation of widespread antiretroviral therapy (ART), the prognosis of AIDS-associated CMVR has been substantially improved. Nevertheless, the equivocal clinical evidence as regards the optimal timing for ART initiation in patients with an established CMVR diagnosis is required. We therefore designed the present study in order to investigate the optimal timing for ART initiation in AIDS/CMVR patients. METHODS: This will be a prospective, randomized controlled trial to be performed at 17 hospitals in mainland China. A total of 300 participants with CMVR will be randomly assigned to an early ART initiation group (ART initiation within 2 weeks after anti-CMV therapy), or a deferred ART initiation group (initiation of ART more than 2 weeks after anti-CMV therapy) at a 1:1 ratio. All participants will receive 48 weeks of follow-up after anti-CMV therapy initiation. Our primary outcome will be the incidence of visual loss (to a visual acuity worse than 20/40 or 20/200) in the two groups during the 48-week follow-up period. Secondary outcomes will include changes in HIV virological suppression and serum CD4+ T-cell counts, the incidence of mortality, retinitis progression (movement of the peripheral border of a CMV lesion ≥ ½ disc diameter, or occurrence of a new CMV lesion), retinal detachment, immune recovery uveitis (IRU), and other OIs and adverse events between the two study groups during the 48 weeks of follow-up. DISCUSSION: The study aims to investigate the optimal timing for ART initiation in AIDS/CMVR patients. We hope to be able to extract robust clinical evidence for use in optimal AIDS/CMVR management should our trial be successful. TRIAL REGISTRATION: This research was registered as one of the twelve clinical trials under the name of a general project "A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections", ChiCTR1900021195. Registered on 1 February 2019, http://www.chictr.org.cn/showproj.aspx?proj=35362 .

No Statistically Apparent Difference in Antiviral Effectiveness Observed Among Ribavirin Plus Interferon-Alpha, Lopinavir/Ritonavir Plus Interferon-Alpha, and Ribavirin Plus Lopinavir/Ritonavir Plus Interferon-Alpha in Patients With Mild to Moderate Coronavirus Disease 2019: Results of a Randomized, Open-Labeled Prospective Study.

BACKGROUND: Currently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread globally, causing an unprecedented pandemic. However, there is no specific antiviral therapy for coronavirus disease 2019 (COVID-19). We conducted a clinical trial to compare the effectiveness of three antiviral treatment regimens in patients with mild to moderate COVID-19. METHODS: This was a single-center, randomized, open-labeled, prospective clinical trial. Eligible patients with mild to moderate COVID-19 were randomized into three groups: ribavirin (RBV) plus interferon-α (IFN-α), lopinavir/ritonavir (LPV/r) plus IFN-α, and RBV plus LPV/r plus IFN-α at a 1:1:1 ratio. Each patient was invited to participate in a 28-d follow-up after initiation of an antiviral regimen. The outcomes include the difference in median interval to SARS-CoV-2 nucleic acid negativity, the proportion of patients with SARS-CoV-2 nucleic acid negativity at day 14, the mortality at day 28, the proportion of patients re-classified as severe cases, and adverse events during the study period. RESULTS: In total, we enrolled 101 patients in this study. Baseline clinical and laboratory characteristics of patients were comparable among the three groups. In the analysis of intention-to-treat data, the median interval from baseline to SARS-CoV-2 nucleic acid negativity was 12 d in the LPV/r+IFN-α-treated group, as compared with 13 and 15 d in the RBV+IFN-α-treated group and in the RBV+LPV/r+ IFN-α-treated group, respectively (p=0.23). The proportion of patients with SARS-CoV-2 nucleic acid negativity in the LPV/r+IFN-α-treated group (61.1%) was higher than the RBV+ IFN-α-treated group (51.5%) and the RBV+LPV/r+IFN-α-treated group (46.9%) at day 14; however, the difference between these groups was calculated to be statistically insignificant. The RBV+LPV/r+IFN-α-treated group developed a significantly higher incidence of gastrointestinal adverse events than the LPV/r+ IFN-α-treated group and the RBV+ IFN-α-treated group. CONCLUSIONS: Our results indicate that there are no significant differences among the three regimens in terms of antiviral effectiveness in patients with mild to moderate COVID-19. Furthermore, the combination of RBV and LPV/r is associated with a significant increase in gastrointestinal adverse events, suggesting that RBV and LPV/r should not be co-administered to COVID-19 patients simultaneously. CLINICAL TRIAL REGISTRATION: www.ClinicalTrials.gov, ID: ChiCTR2000029387. Registered on January 28, 2019.

A study for precision diagnosing and treatment strategies in difficult-to-treat AIDS cases and HIV-infected patients with highly fatal or highly disabling opportunistic infections: Study protocol for antiretroviral therapy timing in AIDS patients with toxoplasma encephalitis.

BACKGROUND: Toxoplasma encephalitis (TE) is one of the main opportunistic infections in acquired immunodeficiency syndrome (AIDS) patients, and represents a social burden due to its high prevalence and morbidity. Concomitant antiretroviral therapy (ART), together with effective anti- toxoplasma combination therapy, is an effective strategy to treat AIDS-associated TE (AIDS/TE) patients. However, the timing for the initiation of ART after diagnosis of TE remains controversial. We therefore designed the present study to determine the optimal timing for ART initiation in AIDS/TE patients. METHODS/DESIGN: This trial is a 17-center, randomized, prospective clinical study with 2 parallel arms. A total of 200 participants will be randomized at a 1:1 ratio into the 2 arms: the early ART initiation (≤14 days after TE diagnosis) arm and the deferred ART (>14 days after TE diagnosis) arm. The primary outcome will be the difference of mortality between the 2 arms at 48 weeks. The secondary outcomes will be the differences between the 2 arms in the changes of CD4+ counts from baseline to week 48, the rate of virologic suppression (HIV ribonucleic acid <50 copies/mL) from baseline to week 48, the incidence of TE-associated immune reconstitution inflammatory syndrome during the study period, and the incidence of adverse effects during the study period. DISCUSSION: This present trial aims to evaluate the optimal timing for ART initiation in AIDS/TE patients, and will provide strong evidence for AIDS/TE treatment should it be successful. TRIAL REGISTRATION: This trial was registered as one of the 12 trials under the name of a general project at the chictr.gov (http://www.chictr.org.cn/showproj.aspx?proj=35362) on February 1, 2019, and the registration number of the general project is ChiCTR1900021195.

Efficacy and Safety of Raltegravir-Based Dual Therapy in AIDS Patients: A Meta-Analysis of Randomized Controlled Trials.

Background: The life expectancy for HIV-infected individuals has improved dramatically because of improvements in antiretroviral therapy (ART). Today, a simplified two-drug regimen enhances adherence and treatment satisfaction by reducing adverse effects. Therefore, we need more evidence to show the benefits and risks of simplified ART regimens from randomized controlled trials (RCTs). We compared the efficacy and safety of raltegravir-based simplified dual therapy (DT) and of traditional triple therapy (TT) for people living with HIV/AIDS (PLWHA). Methods: We carried out a systematic review of RCTs. After using a combination of the key words "HIV," "raltegravir," and "protease inhibitor" to search the English-language electronic databases from January 1, 2004, to September 11, 2019, we pooled data across eligible studies and estimated the summary effect sizes with Review Manager (version 5.3). Results: We included eight RCTs involving 4420 PLWHA: 2187 (49.5%) received raltegravir-based simplified DT, and 2144 (48.5%) received traditional TT. The proportion of viral suppression was 79% at 48 weeks and 74% at 96 weeks in the simplified regimen, and the proportion of viral suppression was 78% at 48 weeks and 71% at 96 weeks in the traditional TT group. Furthermore, the proportion of viral suppression in the simplified DT group was greater than that in the TT group at 24 weeks (risk ratio 1.11, 95% confidence interval 1.02-1.21; p = 0.01). The CD4 cell counts in the simplified DT group were significantly higher at 48 weeks and 96 weeks than those in the group that received the traditional TT. Regarding adverse events and mortality rates, the DT and TT groups were similar. However, there was better adherence in the DT group than in the TT group. Conclusion: We found that the simplified regimen was noninferior to TT regimen in regard to viral suppression. Furthermore, the simplified DT regimen had a better CD4 cell count and lower adverse events than the TT regimen.

Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens: A meta-analysis of randomized controlled trials.

BACKGROUND: To investigate whether TDF-containing regimens significantly benefited efficacy, safety, and tolerability in TAF-containing regimens in virologically suppressed HIV-infected patients. METHODS: PubMed, Embase, Web of Science, and the Cochrane Trial Registry were systematically searched for eligible studies. We extracted and evaluated the pooled data from available randomized controlled trials (RCTs). RESULTS: Eight eligible RCTs were included. In the intention-to-treat (ITT) analysis, patients who switched to TAF-containing regimens had significantly better viral suppression than those continuing TDF-containing regimens at weeks 48 and 96 (RR, 1.02; 95CI, 1.00-1.03; p<0.05), but no significant difference in the per-protocol (PP) analysis (RR, 1.00; 95CI, 0.99-1.01; p>0.05). Compared with those receiving the TDF-containing regimens, virologically suppressed HIV-infected patients on the TAF-containing regimens had significant increases in CD4 cell counts (SMD, 0.12; 95CI, 0.08 to 0.17; p<0.05), renal and bone parameters at the hip (RR, 2.86; 95CI, 2.24-3.64; p<0.05) and the spine (RR, 2.43; 95 CI, 2.03-2.90; p<0.05) between weeks 48 and 96. CONCLUSIONS: Virologically suppressed HIV-infected patients on TDF-containing regimens significantly benefit from switching to TAF-containing regimens, resulting in better viral suppression, better immune reconstruction, and less bone and renal problems.

Assessing the Efficacy of Lopinavir/Ritonavir-Based Preferred and Alternative Second-Line Regimens in HIV-Infected Patients: A Meta-Analysis of Key Evidence to Support WHO Recommendations.

Background: Nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs (NNRTIs) with boosted protease inhibitors are included in standardized first-line and second-line regimens. Recent World Health Organization (WHO) guidelines recommend a boosted protease inhibitor (PI) combined with 2 NRTIs or raltegravir as a second-line regimen. Objective: Ritonavir-boosted lopinavir (LPV/r) is known as a key second-line antiretroviral therapy (ART) in resource-limited settings. We carried out a meta-analysis to analyze virologic suppression and effectiveness of LPV/r-based second-line therapy in HIV-infected patients. Methods: In this meta-analysis, we searched randomized controlled trials and observational cohort studies to evaluate outcomes of second-line ART for patients with HIV who failed first-line therapy. A systematic search was conducted in Pubmed, Cochrane Library, and Embase from inception to January 2018. Outcomes included viral suppression, CD4 cell counts, drug resistance, adverse events, and self-reported adherence. We assessed comparative efficacy and safety in a meta-analysis. Data analysis was performed using RevMan 5.3 and Stata12.0. Results: Nine studies comprising 3,923 patients were included in the meta-analysis. The overall successful virologic suppression rate of the second-line regimen was 77% (ITT) and 87% (PP) at 48 weeks with a plasma HIV RNA load of <400 copies/mL. No statistical significance was found in CD4 cell count recoveries between LPV/r plus 2-3 NRTIs and simplified regimens (LPV/r plus raltegravir) at 48 weeks (P = 0.09), 96 weeks (P = 0.05), and 144 weeks (P = 0.73). Four studies indicated that the virus had low-level resistance to LPV/r, and the most common clinically significant PI-resistance mutations were 46I, 54V, 82A/82F, and 76V; however, no virologic failure due to LPV/r resistance was detected. In addition, no statistical significance was found between the two groups in self-reported adherence [relative risks (RR) = 1.03,95% confidence interval (CI) 1.00, 1.07, P = 0.06], grade 3 or 4 adverse events (RR = 0.84, 95% CI 0.64, 1.10, P = 0.20) or serious events (RR = 0.85, 95% CI 0.77, 1.17, P = 0.62). Conclusions: These results suggest that the LPV/r-based regimen demonstrates efficacious and low resistance as second-line antiretroviral therapy.Both LPV/r plus 2-3 NRTIs and LPV/r plus RAL regimens improved CD4 cell counts. There was no evidence of superiority of simplified regimens over LPV/r plus 2-3 NRTIs.

The protective effects of compatibility of Aconiti Lateralis Radix Praeparata and Zingiberis Rhizoma on rats with heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1α pathway.

Aconiti Lateralis Radix Praeparata ("Fuzi" in Chinese) in combination with Zingiberis Rhizoma ("Ganjiang" in Chinese) is commonly applied for the treatment of heart failure for thousands of years in China. However, its therapeutic mechanism is still poorly defined. This study aimed to investigate whether the compatibility of Fuzi and Ganjiang can protect rats with acute heart failure by enhancing mitochondrial biogenesis via Sirt1/PGC-1α signaling pathway. Hemodynamic parameters, including heart rate and left ventricular maximal rate of pressure rise and decline, were recorded in rats with acute heart failure induced by Propafenone hydrochloride. The serum levels of cardiac enzymes, including creatine kinase, lactate dehydrogenase, brain natriuretic peptide and cardiac troponin T, were also determined. The gene and protein levels of Sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and their downstream transcription factors were measured as well. The results indicated that Fuzi-Ganjiang herbal couple provided more significant benefits by restoring the left ventricular function and cardiac enzyme activities in comparison with their single use. Moreover, this herbal couple possessed a significant cardio-protection by increasing both gene and protein levels of Sirt1 and PGC-1α. In conclusion, the compatibility of Fuzi and Ganjiang had better therapeutic effect than their single use against failing heart, and the underlying mechanisms were partially through increasing mitochondrial biogenesis via Sirt1/PGC-1α pathway.

Paeoniflorin attenuates ANIT-induced cholestasis by inhibiting apoptosis in vivo via mitochondria-dependent pathway.

Apoptosis induced by the bile acids in the liver is considered to play a pivotal role in the pathogenesis of cholestatic disease. Increasing evidence has demonstrated that Paeoniflorin (PF) exerts therapeutic effect on severe cholestatic liver diseases. However, whether PF could protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis by inhibiting apoptosis remains unclear. In this study, we mainly investigated the effect and anti-apoptosis mechanism of PF on cholestasis. Experimental results indicated that PF pretreatment could attenuate liver damage and cholestasis by ANIT in rats, lift the biliary excretion in addition to decrease serum indices (ALT, AST, DBIL, TBIL, TBA, ALP and ϒ-GT) and conspicuous neutrophil infiltration and cell apoptosis in liver evidenced by TUNEL staining. Furthermore, the pro-apoptosis genes expression of Bax, Caspase-9 and Caspase-3 increased by ANIT were prominently reduced after PF treatment. The increase of anti-apoptosis gene and main regulator Bcl-2 in mitochondria by ANIT was largely reversed by PF pre-treatment. In summary, our study demonstrated that PF pre-treatment not only significantly attenuated ANIT-induced cholestasis and liver injury, but also largely reduced cell apoptosis in liver, thus may act as a potential therapeutic agent for cholestasis disease.

Inhibition of Sophocarpine on Poly I: C/D-GalN-Induced Immunological Liver Injury in Mice.

Increasing evidence has suggested that natural killer (NK) cells contribute to the pathogenesis of human immunological liver injury (ILI). Previous studies have demonstrated that Sophocarpine exerts activity in immune modulation. It also has a therapeutic effect on liver protection in that it can alleviate liver fibrosis by suppressing both the activation of hepatic stellate cells and the proliferation of the activated hepatic stellate cells. However, whether Sophocarpine protects the liver by regulating NK cell activity remains unclear. In this study, the modulating effect of Sophocarpine on NK cells in the liver was investigated. The results showed that Sophocarpine dramatically decreased the production of pro-inflammatory cytokines and attenuated the liver injury induced by Poly I: C/D-GalN in C57BL/6- mice. More importantly, Sophocarpine pre-treatment significantly suppressed NK cell activation and downregulated the expression of NKG2D, a receptor responsible for NK cell activation. Moreover, the protein levels of DAP12, ZAP76 and Syk decreased, as did their corresponding mRNA levels. Overall, our study demonstrates that Sophocarpine inhibits NK cell activity, thus making it a promising therapy for ILI.

Therapeutic Efficacy and Safety of Paeoniae Radix Rubra Formulae in Relieving Hyperbilirubinemia Induced by Viral Hepatitis: A Meta-Analysis.

OBJECTIVE: Hyperbilirubinemia is one of the most devastating pathologies induced by various liver diseases. Formulae related to Paeoniae Radix Rubra (PRR) at high doses have been applied to treat hyperbilirubinemia in traditional Chinese medicine (TCM). The aim of this systematic review and meta-analysis is to assess the efficacy and safety of formulae relevant to high-dose PRR in patients suffering from hyperbilirubinemia induced by viral hepatitis. METHODS: We performed a meta-analysis of randomized-controlled clinical trials to evaluate the efficacy and safety of formulae that apply a high dose of PRR for hyperbilirubinemia. Seven databases were searched until April, 2015. All studies were included according to detailed criteria and assessed for methodological quality. The outcome measurements were recorded for further analysis using the RevMan 5.2.11 software. RESULTS: Fifteen articles involving 1323 patients with hyperbilirubinemia were included. Formulae with high-dose PRR might promote the efficacy of either a combined application ([OR: 3.98, 95% CI (2.91, 5.43)]; P < 0.01) or a single application ([OR: 4.00, 95% CI (1.50, 10.68)]; P < 0.01) for hyperbilirubinemia. The indices of TBIL, ALT, and AST significantly decreased ([MD: -75.57, 95% CI (-94.88, -56.26)], [MD: -26.54, 95% CI (-36.19, -16.88)], and ([MD: -28.94, 95% CI (-46.26, -11.61)]; P < 0.01), respectively. In addition, formulae with high-dose PRR could enhance the treatment efficacy of hyperbilirubinemia triggered by hepatitis B ([OR: 2.98, 95% CI (1.75, 5.05)]; P < 0.01). Furthermore, the efficacy was enhanced with an increasing dosage of PRR. Two articles reported that no side effects occurred in clinical trials, and three studies noted that patients presented light digestive tract symptoms. CONCLUSION: Formulae relevant to high-dose PRR ameliorate hyperbilirubinemia and might constitute a promising therapeutic approach. For widespread acceptance by practitioners, more rigorously designed multicenter, double-blind, randomized, and large-scale controlled trials are required.

The Therapeutic Efficacy and Safety of Compound Kushen Injection Combined with Transarterial Chemoembolization in Unresectable Hepatocellular Carcinoma: An Update Systematic Review and Meta-Analysis.

BACKGROUND: Compound Kushen Injection (CKI) is a Chinese patent medicine approved by the China Food and Drug Administration for the treatment of various types of solid tumors. CKI, combined with transarterial chemoembolization (TACE), is believed to increase the therapeutic efficacy of unresectable hepatocellular carcinoma (HCC). We report an updated and extended meta-analysis with detailed outcomes of both the efficacy and adverse events (AEs) of CKI combined with TACE therapy. MATERIALS AND METHODS: Electronic databases, including PubMed, Embase, the Cochrane Library, the Chinese Biomedical Database (CBM), Wanfang, the VIP medicine information system (VMIS) and the China National Knowledge Infrastructure (CNKI), were examined for relevant articles before November 13, 2015. An odds ratio (OR) was used to estimate tumor response (TR), Karnofsky Performance Scale (KPS) improvement, Child-Pugh (CP) improvement, survival rate (SR) and AEs. A publication bias and a subgroup analysis were also assessed. RESULTS: Eighteen studies, with a total of 1,338 HCC patients who met the criteria for the meta-analysis, were included. TR, KPS improvement and CP improvement were significantly enhanced for the combination therapy compared to TACE alone (OR = 1.84, 95% CI: [1.46, 2.33], P < 0.00001; OR = 2.37, 95% CI: [1.76, 3.18], P < 0.00001; OR = 1.81, 95% CI: [1.08, 3.03], P = 0.02, respectively). The combination therapy was associated with an improvement in 1-year and 2-year SRs but not an improved 3-year SR (OR = 2.40; 95% CI: [1.59, 3.62], P < 0.0001; OR = 2.49, 95% CI: [1.24, 5.00], P = 0.01; OR = 2.49, 95% CI: [0.94, 6.61], P = 0.07, respectively). A safety analysis indicated that AEs (including nausea/vomiting, fever, hepatalgia, increased transaminase, increased bilirubin and leukopenia) were reduced for the combination treatment compared to TACE alone. CONCLUSION: The combination treatment of TACE and CKI was associated with improved TR, KPS and CP improvement and improved 1- and 2-year SRs in patients with unresectable HCC. The 3-year SR was not improved. The combination therapy resulted in a reduction in AEs. The findings of this study should be interpreted with caution because of the small sample size and study limitations.