Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-α-based regimens.

Pegylated interferon-α (PEG-IFN-α or PEG-IFN 2a and 2b)- and ribavirin (RBV)-based regimens are the mainstay for treatment of hepatitis C virus (HCV) genotype 1. IFNL3 (IL28B) genotype is the strongest baseline predictor of response to PEG-IFN-α and RBV therapy in previously untreated patients and can be used by patients and clinicians as part of the shared decision-making process for initiating treatment for HCV infection. We provide information regarding the clinical use of PEG-IFN-α- and RBV-containing regimens based on IFNL3 genotype.

Inosine triphosphatase deficiency helps predict anaemia, anaemia management and response in chronic hepatitis C therapy.

Anaemia frequently complicates peginterferon/ribavirin therapy for chronic hepatitis C infection. Better prediction of anaemia, ribavirin dose reduction or erythropoietin (EPO) need, may enhance patient management. Inosine triphosphatase (ITPA) genetic variants are associated with ribavirin-induced anaemia and dose reduction; however, their impact in real-life clinic patient cohorts remains to be defined. We studied 193 clinic patients with chronic hepatitis C infection of mixed viral genotype (genotype 1/4 n = 123, genotype 2/3, n = 70) treated with peginterferon/ribavirin. Patients were genotyped for ITPA polymorphisms rs1127354 and rs7270101 using Taqman primers. Hardy-Weinberg equilibrium was present. Estimated ITPA deficiency was graded on severity (0-3, no deficiency/mild/moderate/severe, n = 126/40/24/3, respectively). Multivariable models tested the association with anaemia at 4 weeks of treatment [including decline in haemoglobin (g/dL); haemoglobin <10 g/dL and haemoglobin decline >3 g/dL]; ribavirin dose reduction and EPO use and explored sustained viral response (SVR) to peginterferon/ribavirin. More severe ITPA deficiency was associated with less reduction in haemoglobin level (P <0.001; R(2) = 0.34), less ribavirin dose reduction (OR 0.42; (95% CI = 0.23-0.77); P = 0.005) and less EPO use [OR 0.53; (0.30-0.94); P = 0.029]. ITPA deficiency was associated with SVR [OR: 1.70; (1.02-2.83); P = 0.041] independently of clinical covariates (adjusted R(2) = 0.31). In this clinical cohort, ITPA deficiency helped predict the risk of on-treatment anaemia, ribavirin dose reduction, need for EPO support and was associated with SVR. For patients on HCV regimens including peginterferon/ribavirin, testing for ITPA deficiency may have clinical utility.

Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response.

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.

Hepatitis C treatment among racial and ethnic groups in the IDEAL trial.

Previous studies of chronic hepatitis C virus (HCV) treatment have demonstrated variations in response among racial and ethnic groups including poorer efficacy rates among African American and Hispanic patients. The individualized dosing efficacy vs flat dosing to assess optimaL pegylated interferon therapy (IDEAL) trial enrolled 3070 patients from 118 United States centres to compare treatment with peginterferon (PEG-IFN) alfa-2a and ribavirin (RBV) and two doses of PEG-IFN alfa-2b and RBV. This analysis examines treatment response among the major racial and ethnic groups in the trial. Overall, sustained virologic response (SVR) rates were 44% for white, 22% for African American, 38% for Hispanic and 59% for Asian American patients. For patients with undetectable HCV RNA at treatment week 4, the positive predictive value of SVR was 86% for white, 92% for African American, 83% for Hispanic and 89% for Asian American patients. The positive predictive values of SVR in those with undetectable HCV RNA at treatment week 12 ranged from 72% to 81%. Multivariate regression analysis using baseline characteristics demonstrated that treatment regimen was not a predictor of SVR. Despite wide-ranging SVR rates among the different racial and ethnic groups, white and Hispanic patients had similar SVR rates. In all groups, treatment response was largely determined by antiviral activity in the first 12 weeks of treatment. Therefore, decisions regarding HCV treatment should consider the predictive value of the early on-treatment response, not just baseline characteristics, such as race and ethnicity.

Gastroesophageal reflux and altered motility in lung transplant rejection.

BACKGROUND: Lung transplantation has become an effective therapeutic option for selected patients with end stage lung disease. Long-term survival is limited by chronic rejection manifest as bronchiolitis obliterans syndrome (BOS). The aspiration of gastric contents has been implicated as a causative or additive factor leading to BOS. Gastroesophageal reflux (GER) and altered foregut motility are common both before and after lung transplantation. Further, the normal defense mechanisms against reflux are impaired in the allograft. Recent studies using biomarkers of aspiration have added to previous association studies to provide a growing body of evidence supporting the link between rejection and GER. Further, the addition of high-resolution manometry (HRM) and impedance technology to characterize bolus transit and the presence and extent of reflux regardless of pH might better identify at-risk patients. Although additional prospective studies are needed, fundoplication appears useful in the prevention or treatment of post-transplant BOS. PURPOSE: This review will highlight the existing literature on the relationship of gastroesophageal reflux and altered motility to lung transplant rejection, particularly BOS. The article will conclude with a discussion of the evaluation and management of patients undergoing lung transplantation at our center.

Severity of Clostridium difficile-associated diarrhea in solid organ transplant patients.

Clostridium difficile-associated diarrhea (CDAD) has a wide spectrum of disease severity. Studies have implicated immunosuppressants as a risk factor for severe disease. We hypothesized that solid organ transplant (SOT) patients with CDAD would be at greater risk for severe disease because of their profound immunosuppression. Adult SOT patients with CDAD seen at Duke University Medical Center between 1999 and 2003 were compared with a reference group of non-transplant patients with CDAD. The primary outcome was the development of complicated colitis defined as death, intensive care unit admission, or urgent colectomy within 30 days of diagnosis. A secondary outcome was relapse within 60 days. Eighty transplant and 86 non-transplant cases were reviewed. There was no significant difference in the development of complicated colitis (13.8% vs. 7.0%) or relapse rates (6.2% vs. 7.0%) between the 2 groups. In the entire sample, 18.5% of patients receiving corticosteroids unrelated to transplantation relapsed as compared with 4.5% not receiving corticosteroids (risk ratio 4.3, P=0.02). In conclusion, no significant difference was found in severity of CDAD between SOT patients and non-transplant patients. Exposure to corticosteroids was significantly associated with an increased risk of relapse and may warrant a longer treatment course.

Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection.

Given that the complications of hepatitis C are due to fibrosis, we hypothesized that the antifibrotic effects of interferon gamma on stellate cells would lead to beneficial effects in patients with hepatitis C. Thus, we evaluated the safety and efficacy of interferon gamma-1b in patients with hepatitis C. A cohort of 20 patients with chronic hepatitis C who failed or were intolerant to previous interferon-alpha-based regimens received 200 mug of interferon gamma-1b subcutaneously three times weekly for 24 weeks. Liver biopsy was performed prior to and at the end of treatment. Biopsies were evaluated by a single blinded pathologist using the Knodell system modified by Ishak, and fibrosis was also quantitated by morphometric analysis. The study population was 75% male and 70% Caucasian. Mean age was 47.9 +/- 7.5 years. Eighteen of 20 patients completed therapy. One patient discontinued therapy because of constitutional symptoms. One patient discontinued therapy because of elevated aminotransferases greater than twice baseline. No serious adverse events occurred. Morphometric analysis revealed that six patients (30%) had >1% absolute reduction in fibrosis score. Four of 20 (20%) patients had improvement in Ishak fibrosis scores after treatment. In conclusion, interferon gamma therapy is safe and well tolerated in patients with chronic hepatitis C. Although we did not detect an overall reduction in fibrosis, interferon gamma-1b treatment led to a reduction in fibrosis in selected patients. These data provide a basis for further study of interferon gamma-1b in patients with chronic fibrosing liver disease.

A case of electrical storm in a liver transplant patient.

Electrical storm has not been well described in liver transplant patients. We present a case of sympathetically mediated recurrent ventricular fibrillation in a young patient transplanted for acute Wilson's disease. This case highlights the role of the sympathetic nervous system in causing electrical storm and it demonstrates the ability of beta-blocking agents to terminate the event. In young liver transplant patients, beta-blocking agents should be considered for therapy of perioperative electrical storm if there is no known structural or coronary heart disease and when there are no risk factors for, or evidences of, torsades de pointes.

Localization of cell wall polysaccharides in nonarticulated laticifers of Asclepias speciosa Torr.

Asclepias speciosa Torr. has latex-containing cells known as nonarticulated laticifers. In stem sections of this species, we have analyzed the cell walls of nonarticulated laticifers and surrounding cells with various stains, lectins, and monoclonal antibodies. These analyses revealed that laticifer walls are rich in (1-->4) beta-D-glucans and pectin polymers. Immunolocalization of pectic epitopes with the antihomogalacturonan antibodies JIM5 and JIM7 produced distinct labeling patterns. JIM7 labeled all cells including laticifers, while JIM5 only labeled mature epidermal cells and xylem elements. Two antibodies, LM5 and LM6, which recognize rhamnogalacturonan I epitopes distinctly labeled laticifer walls. LM6, which binds to a (1-->5) alpha-arabinan epitope, labeled laticifer walls more intensely than walls of other cells. LM5, which recognizes a (1-->4) beta-D-galactan epitope, did not label laticifer segments at the shoot apex but labeled more mature portions of laticifers. Also the LM5 antibody did not label cells at the shoot apical meristem, but as cells grew and matured the LM5 epitope was expressed in all cells. LM2, a monoclonal antibody that binds to beta-D-glucuronic acid residues in arabinogalactan proteins, did not label laticifers but specifically labeled sieve tubes. Sieve tubes were also specifically labeled by Ricinus communis agglutinin, a lectin that binds to terminal beta-D-galactosyl residues. Taken together, the analyses conducted showed that laticifer walls have distinctive cytochemical properties and that these properties change along the length of laticifers. In addition, this study revealed differences in the expression of pectin and arabinogalactan protein epitopes during shoot development or among different cell types.

A prospective evaluation of health-related quality of life after ileal pouch anal anastomosis for ulcerative colitis.

OBJECTIVES: The ileal pouch anal anastomosis is a safe and effective procedure but is also associated with pouchitis, small bowel obstruction, and incontinence. We prospectively evaluated the health-related quality of life using generic and disease-specific measures in a cohort of patients with ulcerative colitis undergoing ileal pouch anal anastomosis. METHODS: Health-related quality of life measures included the Time Trade-off, Rating Form of IBD Patient Concerns, and the Short-Form 36. Assessments occurred preoperatively and 1, 6, and 12 months postoperatively. RESULTS: Time Trade-off scores had significantly improved at the 1-month postoperative assessment and approached perfect health at the 12-month postoperative assessment. The Rating Form of IBD Patient Concerns revealed a significant reduction in patient concerns at 1 month, and this difference persisted at 6 and 12 months. Seven of the eight subscales of the Short-Form 36 revealed improved health-related quality of life postoperatively. CONCLUSIONS: Health-related quality of life improved after ileal pouch anal anastomosis when assessed with both generic and disease-specific measures. Improvements were observed as early as 1 month postoperatively. These results may guide patients and physicians as they consider and prepare for the impact of ileal pouch anal anastomosis.

Reducing medication regimen complexity: a controlled trial.

OBJECTIVE: To determine if a visual intervention (medication grid) delivered to physicians can reduce medication regimen complexity. DESIGN: Nonrandomized, controlled trial. SETTING: Veterans Affairs medical center. PATIENTS/PARTICIPANTS: Eight hundred thirty-six patients taking at least 5 medications at the time of admission and the 48 teams of physicians and students on the general medicine inpatient service. INTERVENTION: For intervention patients, a medication grid was created that displayed all of the patients' medicines and the times of administration for 1 week. This grid was delivered to the admitting resident soon after admission. MEASUREMENTS AND MAIN RESULTS: For the patients of each team of physicians, we calculated the change in the average number of medications and doses from admission to discharge. The number of medications in the intervention group decreased by 0.92 per patient, and increased by 1.65 in the control group (P <.001). The mean number of doses per day in the intervention group decreased by 2.47 per patient and increased by 3.83 in the control group (P <.001). CONCLUSIONS: This simple intervention had a significant impact on medication regimen complexity in this population. Apparently, physicians were able to address polypharmacy when the issue was brought to their attention.

The natural history of hepatitis C viral infection.

Although early data suggested that chronic hepatitis C virus infection carried little risk, studies with longer duration of infection have reported concerning results. Of patients with acute infection, approximately 80% will develop chronic infection. The greatest risk of morbidity comes with cirrhosis and the resulting increased risk of hepatocellular carcinoma. The true risk of progression to cirrhosis, however, has emerged as an area of controversy. Both host and viral factors seem to impact susceptibility to chronic infection, cirrhosis, and hepatocellular carcinoma. Hepatitis C virus has become the most common indication for liver transplantation, but the infection routinely recurs and may have a more aggressive course after transplantation. Given that current treatment options for hepatitis C virus infection are clearly not optimal, informed decisions regarding treatment require an in depth understanding of the natural history.

The V3 domain of SIVmac251 gp120 contains a linear neutralizing epitope.

Antisera to 21 synthetic peptides containing hydrophilic sequences of simian immunodeficiency virus strain mac251 (SIVmac251) gp120 and gp32 were tested for the ability to neutralize SIVmac251. Goat antisera raised to peptides SP-1 and SP-1V containing the carboxy-terminal portion of the V3 domain of SIVmac251 gp120 between amino acids 327 and 339 inhibited syncytium formation (90% inhibition at a 1/1024 dilution) and cell killing of CEMx174 cells by SIVmac251 (50%) inhibition of cell killing at a dilution of 1/5832), SIVDeltaB670 (1/568), and SIVsmH4 (1/740). Neutralizing antibodies to SIVmac251, SIVDeltaB670, and SIVsmH4 could be adsorbed by peptides containing a neutralizing V3 sequence of SIVmac251 gp120 (GLVFHSQPIND, amino acids 329-339) but not by peptides lacking this sequence. This V3 neutralizing region corresponds to a homologous V3 neutralizing site within HIV-2 gp120 reported by Björling et al. 1991, Proc. Natl. Acad. Sci. USA 88, 6082-6086, 1994, J. Immunol. 152, 1952-1959). Antibodies in 20 of 31 sera obtained from rhesus macaques infected with SIVmac251 reacted with a peptide containing the entire V3 sequence of SIVmac251 gp120, whereas no sera contained antibodies reacting with the V3 neutralizing site between amino acids 329 and 339. Low levels of antibody-mediated recognition and subsequent lack of selective pressure against this linear V3 neutralizing site might in part explain why this region is not a dominant neutralizing site and also why sequences within V3 do not vary during the course of SIV infection.

Mapping of homologous, amino-terminal neutralizing regions of human T-cell lymphotropic virus type I and II gp46 envelope glycoproteins.

Twelve synthetic peptides containing hydrophilic amino acid sequences of human T-cell lymphotropic virus type I (HTLV-I) envelope glycoprotein were coupled to tetanus toxoid and used to raise epitope-specific antisera in goats and rabbits. Low neutralizing antibody titers (1:10 to 1:20) raised in rabbits to peptides SP-2 (envelope amino acids [aa] 86 to 107), SP-3 (aa 176 to 189), and SP-4A (aa 190 to 209) as well as to combined peptide SP-3/4A (aa 176 to 209) were detected in the vesicular stomatitis virus-HTLV-I pseudotype assay. Higher-titered neutralizing antibody responses to HTLV-I (1:10 to 1:640) were detected with pseudotype and syncytium inhibition assays in four goats immunized with a combined inoculum containing peptides SP-2, SP-3, and SP-4A linked to tetanus toxoid. These neutralizing anti-HTLV-I antibodies were type specific in that they did not inhibit HTLV-II syncytium formation. Neutralizing antibodies in sera from three goats could be absorbed with peptide SP-2 (aa 86 to 107) as well as truncated peptides containing envelope aa 90 to 98, but not with equimolar amounts of peptides lacking envelope aa 90 to 98. To map critical amino acids that contributed to HTLV-I neutralization within aa 88 to 98, peptides in which each amino acid was sequentially replaced by alanine were synthesized. The resulting 11 synthetic peptides with single alanine substitutions were then used to absorb three neutralizing goat antipeptide antisera. Both asparagines at positions 93 and 95 were required for adsorption of neutralizing anti-HTLV-I antibodies from all three sera. Peptide DP-90, containing the homologous region of HTLV-II envelope glycoprotein (aa 82 to 97), elicited antipeptide neutralizing antibodies to HTLV-II in goats that were type specific. In further adsorption experiments, it was determined that amino acid differences between homologous HTLV-I and HTLV-II envelope sequences at HTLV-I aa 95 (N to Q) and 97 (G to L) determined the type specificity of these neutralizing sites. Thus, the amino-terminal regions of HTLV-I and -II gp46 contain homologous, linear, neutralizing determinants that are type specific.