1,721,183 research outputs found
Pharmacogenetics of First-Line Antitubercular Drugs: An Update
No full textBackground:Tuberculosis (TB) treatment relies on a prolonged first-line antibiotic regimen, including isoniazid, rifampicin (RF), ethambutol (EMB), and pyrazinamide.Pharmacogenetics plays a crucial role in optimizing TB treatment by addressing individual variability in drug metabolism and responses. Genetic polymorphisms can significantly affect pharmacokinetics and therapeutic outcomes. The aim of this review was to explore the role of pharmacogenetics in first-line antibiotics used to treat TB.Methods:We reviewed the literature using PubMed, Scopus, Web of Science, and the Cochrane Library, focusing on articles published in the last 10 years (from December 2014 to December 2024) on the pharmacogenetics of first-line anti-TB drugs. Only English-language studies involving human subjects were included, prioritizing those investigating genetic variants that affect drug bioavailability.Results:In this study, 33 manuscripts were included.N-acetyltransferase 2 Single-nucleotide polymorphisms were associated with different isoniazid acetylation rates, which affect toxicity and efficacy. Genetic variations in CYP2E1, GSTM1, and MnSOD also contribute to hepatotoxicity.For RF, variants in SLCO1B1, ABCB1, PXR, CAR, CES1, and CES2 genes were related to variability in drug absorption, metabolism, and clearance, highlighting the need for personalized dosing strategies. Notably, SLCO1B1 rs4149056 polymorphism is associated with decreased OATP1B1 RF transport activity, potentially leading to increased plasma exposure, whereas other polymorphisms modulate drug exposure and clearance rates. In addition, sex, body weight, and genotype influenced RF pharmacokinetics, suggesting the need for tailored dosing recommendations based on patient characteristics.Similarly, variability in EMB pharmacokinetics is associated with CYP1A2 2159, which is related to a 50% reduction in bioavailability, necessitating dose adjustments in patients coinfected with TB and HIV. Some variants of ABCB1, OATP1B1, PXR, VDR, CYP24A1, and CYP27B1 may further modulate the plasma and intracellular concentrations of EMB, thereby influencing drug efficacy.Conclusions:This review highlights the importance of integrating pharmacogenetic insights into clinical practice to enhance the efficacy of TB treatment, minimize toxicity, and prevent drug resistance. Despite promising evidence, further research and clinical validation are required to implement pharmacogenetics in routine TB management. Future advancements in therapeutic drug monitoring and omics technologies will pave the way for precision medicine in TB therapy
Role of IL28B genotype in the liver stiffness increase in untreated patients with chronic hepatitis C
No full textThe role of interleukin (IL)28B has been deepened in the treatment response to pegylated-interferon in patients affected by chronic hepatitis C (CHC). However, recently the IL28B genotypes were also related to hepatic fibrosis progression in untreated patients, using the liver biopsy. The aim of this prospective and longitudinal study was to assess the role of different IL28B genotypes in the liver stiffness progression in a cohort of untreated subjects affected by CHC. We included in this analysis all untreated patients affected by CHC and followed for at least 5years with the annual evaluation of liver stiffness using Fibroscan®. All enrolled subjects were genotyped for rs8099917 and rs12979860 IL28B polymorphisms. In the study period, 266 patients were considered. After 5years we observed the following median stiffness increases: 6.7kPa [5.1-7.8] in TT/CC, 4.9kPa [4.1-5.0] in TT/TC, 3.4kPa [3.2-3.8] in TG/TC and 1.7kPa [1.2-1.9] in GG/TT. These values were statistically significant in all groups (p<0.001). In the multivariate analysis resulted as predictive factors of liver stiffness progression the following: IL28B TT/CC genotype (OR=4.571; 95%IC=2.381-12.994; p<0.001) and IL28B GG/TT genotype (OR=0.510; 95%IC=0.289-0.712; p=0.007). In this study we evidenced that IL28B genotypes were associated with a different level of liver stiffness increase after 5years and could be used to select the patients who should be treated with priority
Ruolo della riduzione precoce di HBsAg per individuare i pazienti con infezione precoce da HBV, HBeAg-negativi e genotipo E ad alta probabilità di risposta sostenuta con 48 settimane di trattamento con PEG-INF ALFA-2A
No full textRole of HBsAg decline in patients with chronic hepatitis B HBeAg-negative and E genotype treated with pegylated-interferon
No full textTreatment options for patients with chronic hepatitis B (CHB) and hepatitis B e antigen (HBeAg)-negative are pegylated interferon alfa-2a (PEG-IFN) for 48 weeks or nucleos(t)ide analogues (NAs). The choice of patients with higher chance of sustained response (SR) to PEG-IFN can be made with pre-treatment and on-treatment factors; recent studies evidenced the role of early drop of serum hepatitis B surface antigen (HBsAg) as predictor of SR. The aim of this study was the evaluation of early decrease of HBsAg on the SR in HBeAg-negative patients with E genotype. A retrospective analysis was performed on 72 patients affected by HBeAg-negative CHB with E genotype, treated for 48 weeks with PEG-IFN. HBsAg and HBV-DNA kinetics were evaluated. Decline of HBsAg (>0.5 logIU/mL) and HBV-DNA (≥2 logIU/mL) at 12 weeks was described according to observed chance of SR. After 96 weeks of follow-up, SR was observed in 10 patients (13.9%); HBsAg loss 6 (8.3%), HBsAg seroconversion in 3 (4.2%). No patients with HBsAg decline ≤0.5 log IU/mL and HBV-DNA<2 logIU/mL achieved SR (negative predictive value, NPV 100%). In multivariate analysis were significantly associated with SR the combined decline of HBsAg and HBV-DNA at 12 weeks (OR = 35.336; 95% CI: 4.668-112.226; p < 0.001) and the HBsAg≤7500 IU/mL at 24 weeks (OR = 51.824; 95% CI: 9.692-134.144; p < 0.001). Combining the HBsAg and HBV-DNA decline at 12 weeks we can identify patients without chance of SR who may stop PEG-IFN treatment. Stopping rule at 24 weeks using HBsAg≤7500 IU/mL is strong predictor of SR in HBeAg-negative patients with E genotype
Entecavir plasma concentrations are inversely related to HBV-DNA decrease in a cohort of treatment-naïve patients with chronic hepatitis B
No full textSignificant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir
No full textThe new standard of care for treatment for infection with genotype 1a/b of HCV now is the combination of telaprevir (TLV) with ribavirin (RBV) and pegylated interferon (Peg-IFN). Although this new therapy gives a higher response rate than the Peg-IFNα plus RBV treatment, a greatly higher rate of anaemia onset has been reported in all clinical trials. Because haemolysis is a typical concentration-dependent side effect of RBV, modulated by ITPA gene polymorphisms, we aimed to compare the early RBV plasma exposure of nine patients after 2 weeks of treatment with triple therapy with RBV concentrations of 187 patients treated with RBV and Peg-IFNα over the same time scale; this comparison was performed also stratifying patients according to ITPA polymorphism genotype and anaemia onset after 1 month of treatment. All TLV-treated patients had unfavourable ITPA genetic profile and developed anaemia. Moreover, both the rate of anaemia onset and the haemoglobin loss at 1 month were significantly higher in patients treated with TLV. This observation has been confirmed also in patients with the same ITPA genetic profile in double therapy. Strikingly, also early RBV plasma concentrations were significantly higher in patients treated with TLV. These unbiased results confirm the observations recently reported and suggest that the high rate of anaemia onset could be mainly due to the increased RBV exposure, probably caused by a 'boosting effect' by TLV. These data highlight the great importance of early therapeutic drug monitoring of RBV in the management of anaemia in the triple therapy
Role of IL28B genotyping in patients with hepatitis C virus-associated mixed cryoglobulinemia and response to PEG-IFN and ribavirin treatment
No full textThe role of interleukin (IL) 28B in the treatment of chronic hepatitis C (CHC) has recently been examined in many studies, while a possible relationship between IL28B and the presence of mixed cryoglobulinemia (MC) remains to be clarified. In this study, we analyzed the influence of IL28B rs8099917/rs12979860 on the presence of MC and the role in treatment with PEG-IFN. We retrospectively examined 541 patients affected by CHC who were treated with pegylated interferon (PEG-IFN) and ribavirin from 2003 to 2012. We included all treatment-naïve patients without other viral co-infections or major contraindications to the PEG-IFN and ribavirin standard of care. One hundred seventy-five patients (32.3 %) had MC; 49 of these (33.3 %) had symptomatic MC. The IL28B rs8099917/rs12979860 TT/CC genotype was the most frequent in MC-positive patients with sustained virological response (SVR) (p < 0.001), while the TG/TC genotype was most frequent in non-SVR (p < 0.001). The TT/CC genotype was found to be the main positive predictive factor of MC in HCV patients (OR = 11.914; IQR = 7.092-18.776; p < 0.001); HCV genotype 2/3 was the strongest positive predictive factor of SVR (OR = 10.448; IQR = 8.352-21.561; p < 0.001); IL28B rs8099917/rs12979860 TT/CC was a better predictive factor than rs12979860 CC alone (OR = 9.829 vs. 2.663). Negative predictive factors were Metavir score F3-F4 (OR = 0.625; IQR = 0.416-0.779; p = 0.008), insulin-resistance (OR = 0.315; IQR = 0.224-0.585; p < 0.001) and presence of symptoms (OR = 0.716; IQR = 0.492-0.855; p < 0.001). IL28B rs8099917/rs12979860 is useful in the treatment of MC-positive HCV patients with PEG-IFN and ribavirin; the TT/CC genotype is associated with SVR, the TG/TC with non-SVR; TT/CC is also predictive of MC in HCV patients
VDR gene polymorphisms impact on anemia at 2 week of anti-HCV therapy: a possible mechanism for early RBV-induced anemia
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