Thiopurine S-methyltransferase polymorphisms and thiopurine toxicity in treatment of inflammatory bowel disease

AIM: To evaluate the relationship between thiopu- rine S-methyltransferase (TPMT) polymorphisms and thiopurine-induced adverse drug reactions (ADRs) in inflammatory bowel disease (IBD). METHODS: Eligible articles that compared the frequency of TPMT polymorphisms among thiopurine-tolerant and-intolerant adult IBD patients were included. Statistical analysis was performed with Review Manager 5.0. Sub-analysis/sensitivity analysis was also performed. RESULTS: Nine studies that investigated a total of 1309 participants met our inclusion criteria. The inci- dence of TPMT gene mutation was increased 2.93-fold (95% CI: 1.68-5.09, P = 0.0001) and 5.93-fold (95% CI: 2.96-11.88, P < 0.00001), respectively, in IBD patients with thiopurine-induced overall ADRs and bone marrow toxicity (BMT), compared with controls. The OR for TPMT gene mutation in IBD patients withthiopurine-induced hepatotoxicity and pancreatitis was 1.51 (95% CI: 0.54-4.19, P = 0.43) and 1.02 (95% CI: 0.26-3.99, P = 0.98) vs controls, respectively. CONCLUSION: This meta-analysis suggests that the TPMT polymorphisms are associated with thiopurine-induced overall ADRs and BMT, but not with hepatotoxicity and pancreatitis.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir

BACKGROUND Entecavir(ETV)is a potent and safe antiviral agent for patients with chronic hepatitis B(CHB);however,some patients may exhibit suboptimal response or resistance to ETV.Tenofovir alafenamide(TAF)is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate.AIM To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV.METHODS A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia[Hepatitis B virus(HBV)DNA≥20 IU/mL]or partial virologic response(HBV DNA<20 IU/mL,but detectable)were enrolled in the study.The patients were randomly assigned to either continue ETV(0.5 mg)daily or switch to TAF(25 mg)daily for 48 wk.The primary endpoint was the proportion of patients who achieved a virologic response(HBV DNA level<20 IU/mL)at week 48.Secondary endpoints included changes in serum alanine aminotransferase(ALT),hepatitis B surface antigen(HBsAg),hepatitis B e antigen(HBeAg),and anti-HBe levels,and renal and bone safety parameters.RESULTS At week 48,the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group(93.3%vs 66.7%,P=0.012).The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group(-3.8 vs-2.4 Log10 IU/mL,P<0.001).The rates of ALT normalization,HBeAg loss,HBeAg seroconversion,and HBsAg loss were not found to significantly differ between the two groups.None of the patients developed genotypic resistance to ETV or TAF.Both drugs were well tolerated,with no serious adverse events or discontinuations caused by adverse events.No significant changes were observed in the estimated glomerular filtration rate,serum creatinine level,or urine protein-to-creatinine ratio in either group.The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group(-0.8%vs-2.1%,P=0.004;-0.6%vs-1.8%,P=0.007,respectively).CONCLUSION Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Assessing taxane-associated adverse events using the FDA adverse event reporting system database

Background:Taxanes are an essential class of antineoplastic agents used to treat various cancers and are a fundamental cause of hypersensitivity reactions.In addition,other adverse events,such as bone marrow toxicity and peripheral neuropathy,can lead to chemotherapy discontinuation.This study aimed to evaluate the safety of taxanes in the real world.Methods:Taxane-associated adverse events were identified by the Medical Dictionary for Regulatory Activities Preferred Terms and analyzed and compared by mining the US Food and Drug Administration Adverse Event Reporting System pharmacovigilance database from January 2004 to December 2019.Reported adverse events,such as hypersensitivity reaction,bone marrow toxicity,and peripheral neuropathy,were analyzed with the following signal detection algorithms:reporting odds ratio(ROR),proportional reporting ratio(PRR),multi-item gamma Poisson shrinker(MGPS),Bayesian confidence propagation neural network(BCPNN),and logistic regression methods.Adverse outcome events and death outcome rates were compared between different taxane groups using Pearson'sχ^(2) test,whereas significance was determined at P<0.05 with a 95%confidence interval(CI).Results:A total of 966 reports of hypersensitivity reactions,1109 reports of bone marrow toxicity,and 1374 reports of peripheral neuropathy were analyzed.Compared with paclitaxel and docetaxel,bone marrow toxicity following the use of nab-paclitaxel had the highest ROR of 6.45(95%two-sided CI,6.05–6.88),PRR of 5.66,(χ^(2)=4342.98),information component of 2.50(95%one-sided CI=2.34),and empirical Bayes geometric mean of 5.64(95%one-sided CI=5.34).Peripheral neuropathy following the use of nab-paclitaxel showed a higher ROR of 12.78(95%two-sided CI,11.55–14.14),PRR of 12.16(χ^(2)=4060.88),information component of 3.59(95%one-sided CI=3.25),and empirical Bayes geometric mean of 12.07(95%one-sided CI=11.09).Conclusions:The results showed that bone marrow toxicity and peripheral neuropathy were the major adverse events induced by taxanes.Nab-paclitaxel exhibited the highest potential for taxane-associated adverse events.Further research in the future is warranted to explain taxane-associated adverse effects in real-world circumstances.