Genetic polymorphisms and opioid therapies

Interindividual variability in pain perception and response to opioids in terms of efficacy and side effects has been long noted. Numerous genes have been proposed as ideal candidate genes for the study of the genetic component of pain and pharmacogenetics of opioids. Despite the inherent complexity in studying pain, it is obvious that several genetic polymorphisms contribute to modulate nociception and the antinociceptive effects of opioids; specifically those involved in pharmacokinetics and the metabolism of opioids (cytochrome P450) and neurotransmitters (catechol-O-methyltransferase), as well as those affecting pharmacodynamics or the drug targets such as the mu-opioid receptor or the unexpected melanocortin 1-receptor.     

脓毒症相关因子基因多态性的研究进展

基因多态性在脓毒症、MODS等炎症反应紊乱相关疾病的病理生理变化中起着重要的作用,基因多态性是决定人体对应激打击和感染的易感性与耐受性、临床表现多样性及药物治疗反应性差异的重要内在因素。近年来的研究发现炎症反应中的一些关键分子的基因多态性在很大程度上确定着患者的命运,现就此方面作一综述     

Single nucleotide polymorphisms near IL28B gene and response to treatment of chronic hepatitis C in hemodialysis patients

Abstract

Background: It has been shown that single nucleotide polymorphisms (SNPs) near the interleukin 28B (IL28B) gene were associated with sustained virological response following standard antivirological treatment of chronic hepatitis C. Objectives: The aim of the study was to evaluate the association between SNPs near the IL28B gene and response to the treatment of chronic hepatitis C in hemodialysis patients. Patients and methods: The study group included 24 hemodialysis patients with chronic hepatitis C routinely treated with pegylated interferon α-2?a. HCV genotype 1 was the cause of chronic hepatitis C in all study participants. Sustained virological response was determined by an assay with a sensitivity of 20?IU/mL, 6 months after completion of the antivirological treatment. The genotyping of the three most widely studied IL28B gene polymorphisms (rs12979860, rs8099917, and rs12980275) was performed in all study participants. Results: Sustained virological response was achieved in 50% of the treated patients. The treatment response was significantly associated with the CC genotype of rs12979860, TT genotype of rs8099917, and AA genotype of rs12980275 (p?=?0.003, p?=?0.009, and p?=?0.012, respectively). Conclusions: The three most widely studied SNPs near the IL28B gene were associated with sustained virological response following antivirological treatment of chronic hepatitis C in hemodialysis patients.     

Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus

BACKGROUND: Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. METHODS: A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. RESULTS: The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. CONCLUSION: Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.     

Toll样受体7和9基因多态性与慢性丙型肝炎病毒感染的相关性

目的 分析慢性丙型肝炎病毒(HCV)感染与Toll样受体7(TLR7)和Toll样受体9(TLR9)单核苷酸多态性(SNP)的相关性.方法 选择2011年1月至2012年5月武汉大学人民医院150例慢性丙型肝炎(CHC)患者及同期体检的168名健康对照者.采用Sanger测序法检测TLR7IVS2-151(rs179009)基因型,应用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测TLR9T-1486C(rs187084)基因型.采用SPSS 15.0软件进行统计学分析,对基因型进行Hardy-Weinberg平衡吻合度检验.结果 TLR7 IVS2-151G频率在男性CHC患者中高于对照组男性(41.4％∶21.6％,x2=7.250,P=0.007,OR=0.389,95％ CI:0.194 ～0.781);TLR7 IVS2-151A的频率在女性CHC患者中显著高于对照组女性(76.9％∶63.1％,x2=7.202,P=0.007, OR=1.942,95％ CI:1.192 ～3.164).TLR9 T-1486C (rs187084)位点不同基因型和等位基因在CHC组和健康对照组间的分布频率差异均无统计学意义(P＞0.05).结论 TLR7 IVS2-151 (rs179009)位点与HCV感染存在相关性,其可能参与了CHC的发病.     

Antibodies to hepatitis C virus in kidney transplantation.

Ninety patients on dialysis, 241 cadaveric kidney donors and 27 cadaveric kidney recipients with a follow-up of 2 years, have been investigated as for anti-HCV positivity by means of 3 tests. As for patients on dialysis and cadaveric donors, the prevalence was 32 and 4%, respectively. As for transplanted patients, it must be noted that 4 negative recipients from positive donors seroconverted, but without any change in hepatic enzymes, while in 2 or 9 anti-HCV-positive recipients, hepatic enzymes increased after transplantation. Seroconversion in patients transplanted from a negative donor was not significantly different. We conclude that, according to their experience, anti-HCV positivity in the donors is not associated with a significant risk of infection in recipients of cadaveric grafts.     

Thyroid and hepatitis C

Autoimmune thyroid diseases are complex diseases that develop as a result of interactions between genetic, epigenetic and environmental factors. IFNa therapy of chronic HCV infection is associated with subclinical or clinical thyroiditis, while the relationship between thyroiditis and virus C infection is still debated.     

Pancreas transplantation from hepatitis C viremic donors to uninfected recipients

Despite utilization of hepatitis C viremic organs for hepatitis C naïve recipients (HCV D+/R-) in other solid organ transplants, HCV viremic pancreata remain an unexplored source of donor organs. This study reports the first series of HCV D+/R- pancreas transplants. HCV D+/R- had shorter waitlist times compared to HCV D-/R-, waiting a mean of 16 days from listing for HCV-positive organs. HCV D+/R- had a lower match allocation sequence than HCV D-/R-, and this correlated with receipt of organs with a lower Pancreas Donor Risk Index (PDRI) score. All HCV D+/R- had excellent graft function with a mean follow-up of 438 days and had undetectable HCV RNA levels by a mean of 23 days after initiation of HCV-directed therapy. The rates of infectious complications, reoperation, readmission, rejection, and length of stay were not impacted by donor HCV status. A national review of potential ideal pancreas donors found that 37% of ideal HCV-negative pancreas allografts were transplanted, compared to only 5% of ideal HCV-positive pancreas allografts. The results of the current study demonstrate the safety of accepting HCV-positive pancreata for HCV-naïve recipients and advocates for increased utilization of ideal HCV-positive pancreas allografts.     

Ultra‐short duration direct acting antiviral prophylaxis to prevent virus transmission from hepatitis C viremic donors to hepatitis C negative kidney transplant recipients

We conducted an adaptive design single‐center pilot trial between October 2017 and November 2018 to determine the safety and efficacy of ultra‐short‐term perioperative pangenotypic direct acting antiviral (DAA) prophylaxis for deceased hepatitis C virus (HCV)‐nucleic acid test (NAT) positive donors to HCV negative kidney recipients (D+/R?). In Group 1, 10 patients received one dose of SOF/VEL (sofusbuvir/velpatasvir) pretransplant and one dose on posttransplant Day 1. In Group 2A (N = 15) and the posttrial validation (Group 2B; N = 25) phase, patients received two additional SOF/VEL doses (total 4) on Days 2 and 3 posttransplant. Development of posttransplant HCV transmission triggered 12‐week DAA therapy. For available donor samples (N = 27), median donor viral load was 1.37E + 06 IU/mL (genotype [GT]1a: 70%; GT2: 7%; GT3: 23%). Overall viral transmission rate was 12% (6/50; Group 1:30% [3/10]; Group 2A:13% [2/15]; Group 2B:4% [1/25]). For the 6 viremic patients, 5 (83%) achieved sustained virologic response (3 with first‐line DAA therapy; and two after retreatment with second‐line DAA). At a median follow‐up of 8 months posttransplant, overall patient and allograft survivals were 98%, respectively. The 4‐day strategy reduced viral transmission to 7.5% (3/40; 95% confidence interval [CI]: 1.8%‐20.5%) and could result in avoidance of prolonged posttransplant DAA therapy for most D+/R ? transplants.     

Liver transplantation and hepatitis C

End-stage liver disease caused by chronic hepatitis C viral infection is one of the major indications for liver transplantation. However, evidence for ongoing viral replication can already be found days after surgery and may lead sequentially to lobular hepatitis, chronic active hepatitis, fibrosis and liver cirrhosis. In some patients, this evolution is remarkably fast, most probably enhanced by the immunosuppressive therapy. A minority of patients develop a clinical picture of progressive cholestatic liver disease with histological signs of chronic rejection, which may necessitate retransplantation. While the 1- and 5-year survival rates for all patients transplanted because of hepatitis C virus (HCV)-induced liver cirrhosis are satisfactory, severe complications of disease recurrence are nonetheless expected during the first and second decade after liver transplantation. Larger and preferably randomized studies are needed to investigate whether combination therapy with interferon and ribavirin, preferably initiated as soon as possible after liver transplantation, prevents the fast evolution to cirrhosis without the appearance of chronic rejection and the expected complications of recurrent end-stage HCV-induced liver disease. The final goal should be the inhibition of viral replication even before liver transplantation, but other antiviral strategies should probably be used to attain this goal in patients with decompensated cirrhosis. Although the recurrence of a hepatitis C infection and concomitant disease in the liver graft may cause substantial morbidity, end-stage liver disease and liver failure caused by a chronic hepatitis C infection remain good indications for liver transplantation.     

Liver transplantation for hepatitis C

Hepatitis C virus (HCV) infection is the leading cause of endstage liver disease in Western and Asian countries. However, after liver transplantation, HCV recurs in virtually all patients, and estimated HCV-related graft cirrhosis at 5-year follow-up is 30%. Although immunosuppression accounts for a major part of the accelerated progression of HCV in the transplant population, the best immunosuppression for recipients with HCV that could avoid such complication remains unknown at present. Combination therapy of interferon and ribavirin is thought to be the most effective for the treatment or prophylaxis of HCV infection. However, who should be treated, when treatment should be initiated, and with what agent should patients with HCV infection be treated are still unknown. The current data on HCV recurrence in patients who have received either living- or deceased-donor liver transplantation are controversial, but they are, presumably, similar. Thus, to avoid HCV recurrence in living-donor liver transplantation, we have to take approaches similar to those used for patients receiving deceased-donor liver transplantation. Based on reports from major transplant centers around the world, we consider the best strategy for liver transplantation-related HCV infection is steroid-free immunosuppression and preemptive low-dose interferon and ribavirin combination therapy. Here we describe our experience with living-donor liver transplantion for patients with hepatitis C at Osaka University. There is a need for standardizing the treatment for HCV infection. This can only be achieved through collaborative work between various liver transplant centers worldwide.     

Treatment for recurrent hepatitis C

Hepatitis C virus (HCV) has become the leading cause for orthotopic liver transplantation (OLT) worldwide. OLT for HCV has been associated with good survival outcomes. HCV recurrence has been universally documented in allograft recipients within the 1st year post-transplantation. Slow but steady progression of recurrent disease has resulted in allograft failure in a small number of patients in the short-term and may cause allograft destruction in a larger number of patients in the long-term. A pressing need has therefore developed to identify antiviral regimens to treat or prevent recurrent disease. Unfortunately, current antiviral therapy has limited efficacy and is associated with multiple adverse events. Therefore, a concerted effort has been directed toward identification of the patient populations who are most susceptible to the deleterious effects of recurrent disease or those who are most likely to benefit from antiviral treatment. These patient populations may therefore be selected for antiviral therapeutic intervention. Unsuccessful antiviral therapy or the development of allograft may be an indication for retransplantation (re-OLT), a procedure that is not widely accepted since it is associated with high morbidity and mortality. Nevertheless, the appropriate and timely utilization of re-OLT may achieve good results in selected patients. This chapter will outline the current understanding and the results of medical and surgical therapeutic options for recurrent HCV following OLT.     

Outbreak of hemodialysis-associated non-A, non-B hepatitis and correlation with antibody to hepatitis C virus.

Between January 1987 and October 1988, 35 (45%) of 77 patients undergoing chronic hemodialysis at one unit developed serum alanine aminotransferase (ALT) elevations suggestive of non-A, non-B hepatitis (NANBH). Patients were grouped by level of ALT elevation and presence of other etiologies for liver injury. All dialysis patients and staff were tested for antibody to hepatitis C virus (anti-HCV) by enzyme immunoassay on three occasions, 9 months apart; anti-HCV repeatedly reactive specimens were tested by the HCV neutralization assay. Household and sexual contacts of patients were tested once for anti-HCV. Case-patients were classified on the basis of clinical case definitions as probable, possible, questionable, and noncases, and by anti-HCV testing. Case-patients who had no history of transfusions or parenteral drug use were compared with noncases for common exposures. A total of 35% (27/77) of patients and none (0/24) of staff were anti-HCV-positive. Anti-HCV was found in 82% of probable cases, compared with 44% of possible cases, 44% of questionable cases, and 12% of noncases (P less than 0.01). Neither a common source nor direct person-to-person transmission could be documented; however, inadequate infection control measures demonstrated by lack of glove use and poor handwashing occurred during the exposure period. The incidence of HCV infection in patients over an 18-month period was 5%. Transmission of HCV to household or sexual contacts of patients did not appear to occur.(ABSTRACT TRUNCATED AT 250 WORDS)