Induction-concurrent chemoradiotherapy with or without sintilimab in patients with locoregionally advanced nasopharyngeal carcinoma in China (CONTINUUM): a multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial.

BACKGROUND: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population. METHODS: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing. FINDINGS: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group. INTERPRETATION: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma. FUNDING: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Entecavir Combined With Adefovir Ameliorates Patients With Chronic Hepatitis B Who Fail to Respond to Nucleotide (Acid) Analog Monotherapy.

The aim of this study was to evaluate the efficacy and safety of entecavir (ETV) combined treatment with adefovir (ADV) on chronic hepatitic B (CHB) patients who failed to respond to nucleotide (acid) analog (NA) treatment. On this basis, the possible factors in the combined treatment of these patients will be analyzed. The safety, biochemical index, and the possible factors that might affect the ETV and ADV combined treatment at different points in time were retrospectively analyzed. The biochemical index included the following: virological response, hepatitis B virus (HBV) DNA decline, primary nonresponse, biochemical response, and the hepatitis B virus E antigen/hepatitis B virus E antibody seroconversion rate. There were 94 CHB patients and compensated liver cirrhosis patients who received ETV plus ADV treatment for over 12 weeks after failure of treatment with NAs. The authors have also investigated 76 CHB patients (80.9%) and 18 hepatitis B cirrhosis patients (19.1%) in this study. The HBV DNA baseline was 4.4 ± 1.4 log10 IU/mL, and the positive rate of HBeAg before salvage treatment was 78.7% (74/94). The sample sizes were 94, 78, 42, 10, 6, and 1 for follow-up of 24, 48, 96, 144, 192, and 240 weeks, respectively. The virological responses (HBV DNA < 2 log10 IU/mL) and biochemical responses were 52.1%, 74.3%, and 90.4% and 63.1%, 61.6%, and 81.1%, respectively, at 24, 48, and 96 weeks, which showed significant differences (P < 0.001 and P < 0.005, respectively). The HBV DNA decline was presented as mean ± SEM, which were 1.53 ± 1.23, 1.75 ± 1.37, 2.07 ± 1.54, and 2.39 ± 1.77 log10 IU/mL at 12, 24, 48, and 96 weeks, respectively. They showed significant differences compared with the baseline (χ = 8.084, P < 0.05). The rate of primary nonresponse was 30.9% (29/94), and the primary treatment failure rates were 26.6% (25/94), 24.4% (19/78), and 4.8% (2/42) at 24, 48, and 96 weeks, respectively. They all have statistical difference (P = 0.011 < 0.05). There were 23 patients who experienced virological breakthrough after the HBV DNA levels were undetectable, whereas after follow-up for 12-24 weeks, the HBV DNA levels were back to undetectable again. ETV plus ADV treatment is an efficient and safe treatment for CHB and compensated liver cirrhosis patients who experienced NA treatment failure. The high quantity of baseline HBV DNA level is a risk factor for poor efficacy of salvage treatment.

Serum HBsAg level and its clinical significance in lamivudine treatment for patients with HBeAg-negative acute-on-chronic liver failure.

OBJECTIVES: To investigate the dynamics and clinical significance of hepatitis B surface antigen (HBsAg) levels in hepatitis B e antigen (HBeAg)-negative acute-on-chronic liver failure (ACLF) patients receiving lamivudine. METHODS: Fifty-nine nucleoside-naïve patients with HBeAg-negative ACLF were enrolled and treated with 100mg of lamivudine daily. The dynamics of serum levels of HBsAg and HBV DNA were analyzed at baseline and at week 12, or before death if the patient died within 12 weeks. RESULTS: Twenty-eight cases died within 12 weeks and 31 cases survived after treatment. HBsAg levels of patients who survived were significantly higher than those of patients who died both pre- and post-treatment (all p<0.05). There were 33 patients with pretreatment HBsAg levels above 4000 COI and 26 cases with levels below this value. The 12-week survival rate of those with levels ≥4000 COI was significantly higher than that of patients with levels <4000 COI (66.7% (22/33) vs. 34.5% (9/26), Chi-square = 5.991, p=0.014). Regardless of the pretreatment HBsAg level, there was no significant difference in HBV DNA levels between survivors and those who died, and no correlation was observed between HBV DNA and HBsAg (all P>0.05). CONCLUSIONS: Changes in HBsAg level could be a useful parameter for predicting the short-term outcome of lamivudine monotherapy in HBeAg-negative ACLF.

[Short-term efficacy of adefovir dipivoxil as an add-on therapy in the pegylated IFNalpha-2a treatment for HBeAg positive chronic hepatitis B patients].

OBJECTIVE: To investigate whether the combination therapy of pegylated IFNalpha-2a plus adefovir dipivoxil (ADV) improve the efficacy of the treatment in CHB patients with HBeAg positive or not. METHODS: 57 CHB patients with HBeAg positive received 48-week pegylated IFNalpha-2a therapy were enrolled into this study. If serum HBV DNA levels exceeded 1000 copies/ml at week 24, the patients were assigned to group A (pegylated IFN-alpha2a plus ADV, 21 cases) or group B (pegylated IFNalpha-2a only, 14 cases); otherwise, they received the unceasing monotherapy of pegylated IFNalpha-2a (group C, 22 cases). RESULTS: At week 48, HBeAg seroconversion rates were 23.8%, 28.6% and 63.6% (A vs C,P = 0.014), but rates of aminotransferases normalization and HBV DNA suppression (< 1000 copies/ml) were not statistically significant among three groups. But during week 24 to week 48, rates of HBeAg seroconversion, aminotransferases normalization and HBV DNA suppression were also not statistically significant between group A and B. But amplitude of DNA drop in group A was much more than that in group B (2.60 +/- 1.37 vs 0.86 +/- 2.09, P = 0.005). CONCLUSION: An ADV add-on therapy in pegylated IFNalpha-2a treatment seems able to improve the inhibition of HBV DNA in chronic hepatitis B patients with HBeAg positive. It requires a large, double-blind, randomized clinical trial to further provent.

[The effect of antiviral therapy for patients with HBeAg-negative cirrhosis].

OBJECTIVE: To investigate the efficacy of nucleot(s)ide analogues therapy in patients with HBeAg-negative cirrhosis in China. METHODS: 111 patiens with HBeAg-negative cirrhosis were divided into antiviral group (58 cases, 25 entecavir, 19 adefovir dipivoxil, 13 lamivudine, 1 telbivudine) and control group (53 cases, supportive and symptomatic treatment). These two groups were matched for demography, liver function and Child-Pugh score. RESULTS: At the 96th week, the rate of ALT normalization and HBV DNA drop (1g copies/ml) in antiviral group were higher than those in control group (P < 0.05). The rates of HBV DNA negative (< 500 copies/ml) were 88.7% (47/53) and 32. 5% (13/40), respectively (P < 0.05 ). There were no differences in the rates of developing HCC and undergoing variceal bleeding between antiviral group and control group (P > 0.5). 15.4% patients with lamivudine treatment emerged YMDD mutations. 10.5% patients with adefovir dipivoxil treatment emerged virologic breakthrough and hepatitis flare during the second year. 2 patients (3.5%) in treatment group and 6 patients (11.5%) in control group died of liver failure or variceal bleeding or HCC ( P > 0.05 ). CONCLUSIONS: Neucleot(s)ide analogues are effective in suppressing HBV replication in patients with HBeAg-negative cirrhosis, but the impact of which on the mortality and complications of cirrhosis should be prolongly observed. For continuing treatment, the neucleot(s)ide analogues with strong effective and low resistance are the first choices to prevent viral mutation and drug resistance.

[Relationship of fatty liver with HBV infection, hyperlipidemia and abnormal alanine aminotransferase].

OBJECTIVE: To investigate the prevalence of fatty liver in Guangzhou and its relation to hepatitis B virus (HBV) infection, hyperlipidemia and abnormal alanine aminotransferase (ALT). METHODS: A retrospective analysis was made on clinical data of 4365 participants who received health check-up in our hospital. RESULTS: The prevalence of fatty liver was 18.2%, 19.2% in males and 17.1% in females, respectively. There was no significant difference between males and females (P = 0.07). Among 793 subjects with fatty liver, 440 were males and 353 were females. The prevalence of fatty liver was 16.7% in HBV infection group and 18.3% in the group without HBV infection, no significant difference was seen between these two groups (P = 0.45). The prevalence of fatty liver was 42.1% in hyperlipidemia group, and 11.6% in the group with normal serum triglyceride (TG) and total cholesterol (TC), respectively, there was a significant difference between these two groups (P < 0.05). The abnormal ALT was seen in 32.5% of the fattty liver group, which was significantly higher than that (8.6%) in the group without fatty liver (P < 0.05). CONCLUSIONS: The prevalence of fatty liver was not significantly different between males and females in Guangzhou. Fatty liver was not related with HBV infection but closely related with age and hyperlipidemia. Fatty liver was a common cause of abnormal ALT.

[The antiviral treatment impacts on clinical outcomes of renal transplantation recipients with hepatitis B virus infection].

UNLABELLED: OBJECTIVE; To investigate the clinic outcomes and the efficacy of antiviral treatment in renal transplantation recipients with hepatitis B viral serum markers positive. METHODS: 32 renal transplantation recipients with hepatitis B viral serum markers positive were enrolled. 23 patients in antiviral treatment group have received the lamivudine (19 cases), enticavir (2 cases) and adefovir (1 case). Another 9 patients have not received the antiviral treatment and were as the control group. RESULTS: The biochemical response rate in antiviral treatment group and control group is 82.60% and 22.22%, respectively. 19 of 23 (82.60%) patients in treatment group survived and 1 of 9 (11.11%) patients in control group survived (P < 0.05). 20 of 23 (86.95%) patients in treatment group have the reduction of HBV DNA more than 2 log copies/ml or maintain less than 5 log copies/ml, while 1 of 9 (11.11%) patients in control group has the HBV DNA maintain less than 5 log copies/ml (P < 0.05). The virology rebound was observed in 6 of 19 (31.58%) patients with lamivudine treatment. 2 of them shift to enticavir treatment and 1 of them add adefovir treatment. The three patients survived. Other 3 patients die of liver function failure. CONCLUSION: The antiviral could improve the survival in renal transplantation recipients with hepatitis B viral serum markers positive. When the virology rebound occurs, the add-on with adefovir or the shift to enticavir could be a rescue treatment.

[The relationship between the levels of HBV DNA loads and both the clinical characteristics and 48-week prognosis in patients with decompensated cirrhosis due to hepatitis B].

OBJECTIVE: To evaluate the relationship between the levels of HBV DNA loads and both the clinical characteristics and 48-week prognosis in patients with decompensated cirrhosis due to hepatitis B. METHODS: One hundred and forty-three patients with decompensated cirrhosis of hepatitis B virus infection were divided into low level HBV DNA group [HBV DNA < 10(5) copies/ml = (46 cases) and high-level HBV-DNA group (HBV DNA > or = 10(5) copies/ml) (97 cases)]. 21 cases in low-level group and 52 cases in high-level group treated with nucleoside analog. RESULTS: There was no significant difference between the two groups on the demography and the baseline in ALT, ALB, TBil, CHE before treatment, while in AST and HBeAg were statistically different. At 48-week, there was no significant difference between the two groups on the liver function. The mortality rate in low-level group was similar to that in high level group. In the low-level HBV DNA patients, hepatocellular carcinoma, spontaneous peritonitis and gastrointestinal hemorrhage were higer than that in the high-level HBV DNA patients. CONCLUSION: In patients with decompensated cirrhosis due to hepatitis B, those who were in low-level HBV DNA had not got better than that in high-level HBV DNA, which indicated that earlier treatment was also needed in low-level HBV DNA patients.