Baseline Genotype Research Articles

Symtuza® (DRV/c/FTC/TAF) en el tratamiento de inicio

The management of HIV infection is based on the administration of lifelong antiretroviral therapy (ART). Single-tablet regimens (STR) reduce pill burden and maximise long-term adherence. Cobicistat-boosted darunavir with emtricitabine and tenofovir alafenamide co-formulation (DRV/c/FTC/TAF), with trade name Symtuza®, is the first STR based on a protease inhibitor (PI). Symtuza® exhibits the efficacy, potency and high genetic barrier of DRV/c, positioning it as the drug of choice even in patients at risk of developing resistance mutations, in addition to the good safety profile of TAF and the advantages of an STR. Early ART initiation is also possible as baseline genotype and HLA-B5701 are not needed. It therefore represents a very good regimen for naive patients, in particular those at risk of poor adherence, and those with low potential risk for drug-drug interactions. Supplement information: This article is part of a supplement entitled “Co-formulated cobicistat-boosted darunavir, emtricitabine, and tenofovir alafenamide for the treatment of HIV infection”, which is sponsored by Janssen.

Long-term outcome of entecavir treatment of nucleos(t)ide analogue-naïve chronic hepatitis B patients in Japan.

We determined the antiviral potency and viral breakthrough rate after 10years of continuous entecavir treatment in patients with chronic hepatitis B (CHB) infection. The cumulative rates of undetectable hepatitis B virus DNA (HBV-DNA, < 2.1logcopies/mL), alanine aminotransferase (ALT) normalization, hepatitis B e antigen (HBeAg) seroclearance, hepatitis B surface antigen (HBsAg) seroclearance, and viral breakthrough of 1094 nucleos(t)ide analogue-naïve CHB patients (HBeAg-positive: 47%) who were on continuous entecavir treatment for 10years were calculated. The median age was 50years and follow-up period was 5.5years, with 999, 804, 591, 390, 182 and 87 patients followed up for at least 1, 3, 5, 7, 9 and 10years, respectively. Incremental increases were noted in the rates of undetectable HBV-DNA, ALT normalization, HBeAg seroclearance, and HBsAg seroclearance, reaching 96, 79, 38 and 3.7%, respectively, by the tenth year. The mean decline in HBsAg level from baseline was - 0.08logIU/mL/year. Multivariate analysis identified HBsAg level and genotype (A) as independent predictors of HBsAg seroclearance. Sixteen patients experienced viral breakthrough. The cumulative percentages of patients with viral breakthrough analyzed by the Kaplan-Meier test were 1.5 and 2.5% at years 5 and 10, respectively. There were no serious adverse events during treatment. Long-term entecavir treatment of nucleos(t)ide analogue-naïve CHB patients was associated with an excellent viral response and a low rate of entecavir-resistant mutations at 10years. Baseline HBsAg levels and genotype were predictors of HBsAg seroclearance during entecavir treatment.

High Cure Rates With Grazoprevir-Elbasvir With or Without Ribavirin Guided by Genotypic Resistance Testing Among Human Immunodeficiency Virus/Hepatitis C Virus-coinfected Men Who Have Sex With Men.

This study was performed to investigate the efficacy and safety of grazoprevir-elbasvir guided by baseline resistance-associated substitutions (RASs) in the Swiss HCVree Trial. We performed hepatitis C virus (HCV) RNA screening among all men who have sex with men (MSM) enrolled in the Swiss HIV Cohort Study. Individuals with replicating HCV genotype 1 or 4 infection were eligible for grazoprevir-elbasvir treatment. Genotype 1a-infected individuals with baseline RASs and genotype 4-infected individuals with prior failure of HCV treatment received 16 weeks of grazoprevir-elbasvir combined with ribavirin. All other individuals received 12 weeks of grazoprevir-elbasvir alone. Patients reporting unprotected sex with occasional partners were offered a HCV risk reduction-oriented behavioral intervention. We screened 3722 MSM and identified 177 (4.8%) with replicating infection. A total of 122 individuals (3.3%) were eligible for study treatment. Six of 76 patients infected with genotype 1a (7.3%) harbored baseline RASs. Sustained virological response after 12 weeks of follow-up was achieved in 121 patients (99%), including all with genotype 1a infection. Overall, 8 serious adverse events occurred, none of which was related to the study drug. Seventy-five percent of eligible MSM participated in the risk counseling program. Grazoprevir-elbasvir for 12 or 16 weeks, with or without ribavirin, achieved high cure rates and had an excellent safety profile. Unique to other studies, the treatment duration was guided by the presence of baseline RASs among genotype 1a-infected individuals, and the treatment phase was accompanied by an HCV risk reduction-oriented behavioral intervention. This successful population-wide treatment approach lays the groundwork to achieve HCV elimination in coinfected MSM. NCT02785666.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults

Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). To use genetic variants in the CETP gene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Five CETP variants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL. CETP variants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL per rs2303790-G allele; P = 9.4 × 10-47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, the CETP genetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly, rs2303790 was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases with rs2303790 (4090 events; OR, 1.43; 95% CI, 1.13-1.80; P = .003). CETP variants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.

Q192R polymorphism in the PON1 gene and familial hypercholesterolemia in a Saudi population.

BACKGROUNDFamilial hypercholesterolemia (FH) is an autosomal dominant condition characterized by abnormal levels of low-density lipoprotein (LDL) in the blood. FH is a risk factor for atherosclerosis and cardiovascular disease. The relationship between the paraoxonase 1 (PON1) gene, atherosclerosis and coronary artery disease has not been studied in Saudi patients.OBJECTIVETo investigate the genetic associations of the Q192R polymorphism in the PON1 gene with FH in Saudi patients.DESIGNCase-control study.SETTINGTertiary care center, Riyadh.METHODSTwo hundred Saudi patients were enrolled in this study, including 100 patients with FH and 100 healthy controls, during the period from January 2012 to March 2013. Serum was separated from coagulated blood (3 mL) and used for analysis of lipid profiles. Genomic DNA was isolated from anticoagulant-treated blood (2 mL). Genotyping for the Q192R polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism analysis, followed by 3% agarose gel electrophoresis.MAIN OUTCOME MEASUREThe strength of association between the Q192R polymorphism and FH in the Saudi population.RESULTSWe confirmed that QR versus QQ (odds ratio [OR]: 1.55; 95% confidence interval [CI]: 1.05–3.43; P=.03), QR+RR versus QQ (OR: 1.98; 95% CI: 1.13–3.49; P=.01), and R versus Q (OR: 1.68; 95% CI: 1.09–2.59; P=.01) in the Q192R polymorphism were associated with FH in the Saudi population.CONCLUSIONIn conclusion, the Q192R polymorphism in the PON1 gene is associated with FH in the Saudi population. Our results confirmed that the R allele, QR, and dominant model genotypes were associated with FH.LIMITATIONOnly a single variant (Q192R) was analyzed, and the medical and family histories of the patients were not known.

Prevalence and trends in transmitted and acquired antiretroviral drug resistance, Washington, DC, 1999\u20132014

BackgroundDrug resistance limits options for antiretroviral therapy (ART) and results in poorer health outcomes among HIV-infected persons. We sought to characterize resistance patterns and to identify predictors of resistance in Washington, DC.MethodsWe analyzed resistance in the DC Cohort, a longitudinal study of HIV-infected persons in care in Washington, DC. We measured cumulative drug resistance (CDR) among participants with any genotype between 1999 and 2014 (n = 3411), transmitted drug resistance (TDR) in ART-naïve persons (n = 1503), and acquired drug resistance (ADR) in persons with genotypes before and after ART initiation (n = 309). Using logistic regression, we assessed associations between patient characteristics and transmitted resistance to any antiretroviral.ResultsPrevalence of TDR was 20.5%, of ADR 40.5%, and of CDR 45.1% in the respective analysis groups. From 2004 to 2013, TDR prevalence decreased for nucleoside and nucleotide analogue reverse transcriptase inhibitors (15.0 to 5.5%; p = 0.0003) and increased for integrase strand transfer inhibitors (INSTIs) (0.0–1.4%; p = 0.04). In multivariable analysis, TDR was not associated with age, race/ethnicity, HIV risk group, or years from HIV diagnosis.ConclusionsIn this urban cohort of HIV-infected persons, almost half of participants tested had evidence of CDR; and resistance to INSTIs was increasing. If this trend continues, inclusion of the integrase-encoding region in baseline genotype testing should be strongly considered.

Direct-Acting Antiviral Therapy for Chronic HCV Infection Results in Liver Stiffness Regression Over 12Months Post-treatment.

Liver fibrosis stage determines risk of morbidity and mortality from chronic hepatitis C virus (HCV) infection. Prior data have shown long-term reversal of liver fibrosis, measured by vibration-controlled transient elastography (VCTE), in patients successfully treated with interferon-based therapies. Our study sought to determine the effect of treatment with modern HCV direct-acting antiviral (DAA) therapy on noninvasive liver fibrosis measurements. A total of 70 patients had VCTE-based liver stiffness measurement (LSM) taken before treatment, directly after treatment completion, and at least 12months after completion of DAA therapy. Our primary outcome was a >30% improvement in VCTE score at the end of follow-up, relative to baseline. The sustained virologic response rate in our cohort was 95.7%. In our cohort, 34 (48.6%) met the primary outcome. Those who had baseline elevated alanine aminotransferase (OR 3.27; 95% CI 1.13-9.47) and genotype 1 (OR 14.63; 95% CI 1.70-125.83) had higher odds of meeting that outcome, and this remained significant after adjusting for age, baseline body mass index, gender, baseline elevated alkaline phosphatase levels, treatment experience, liver transplant status, smoking, and baseline liver stiffness. Treatment of chronic HCV with modern DAA therapy was associated with a significant improvement in LSM by VCTE measurement, suggesting possible early improvement in liver fibrosis along with resolution of inflammation over the first year after treatment completion.

ASSOCIATION OF HDL SUBSPECIES WITH OR WITHOUT APOLIPOPROTEIN E WITH ALZHEIMER’S DISEASE NEUROPATHOLOGY: THE GINKGO EVALUATION OF MEMORY STUDY

High-density lipoprotein (HDL) cholesterol concentrations have been inconsistently associated with cognitive decline and Alzheimer's disease (AD). While the APOE genotype is one of the strongest risk factors for AD, it has yet to be examined whether the association of HDL and AD reflect the extent to which HDL contains apolipoprotein E (apoE) that may mediate the functional importance of HDL. Thus, we investigated whether the association of HDL and AD neuropathology differs by the presence and absence of apoE on HDL. Among 170 participants (42% women, age 84–96 years) of the Ginkgo Evaluation of Memory Study (2000–2008) who remained free of dementia throughout the trial and had amyloid ß (Aß) brain burden measured by Pittsburgh Compound B-positron emission tomography in 2009, plasma total HDL (by apoA-I) and HDL containing or lacking apoE and total apoE were measured by ELISA. We evaluated the cross-sectional associations of apoE and HDL, and HDL with or without apoE (per SD increments) with high Aß deposition (standardized uptake value ratio ≥ 1.57) in Poisson regression models with robust error variance adjusted for age, sex, education, race/ethnicity, alcohol intake, smoking status, BMI, history of heart disease or type 2 diabetes, systolic blood pressure, and intake of antihypertensive and lipid lowering medications. Approximately 7.6% of the HDL contained apoE and high Aß deposition was detected in 94 participants (55%). The prevalence ratio (PR) for high Aß deposition per SD increase in HDL was 1.08 (95% CI: 0.95,1.24). The HDL subspecies were differentially associated with high Aß deposition (p for heterogeneity = 0.03). The PR per SD increment of HDL with apoE was 0.86 (95% CI: 0.69,1.06) and 1.16 for HDL without apoE (95% CI: 1.01,1.33). No evidence for effect modification by sex, lipid lowering medication intake, mild cognitive impairment at baseline or APOE genotype was observed (all p>0.05). Total plasma apoE and apoE in HDL were not associated with high Aß deposition (PR: 0.92; 95% CI: 0.79,1.08 and 0.91; 95% CI: 0.78,1.07; respectively). The association of HDL and AD neuropathology differs by the presence and absence of apoE.

Clinical, Biochemical, and Genetic Characterization of North American Patients With Erythropoietic Protoporphyria and X-linked Protoporphyria

ImportanceAutosomal recessive erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are rare photodermatoses presenting with variable degrees of painful phototoxicity that markedly affects quality of life. The clinical variability, determinants of severity, and genotype/phenotype correlations of these diseases are not well characterized.ObjectiveTo describe the baseline clinical characteristics, genotypes, and determinants of disease severity in a large patient cohort with EPP or XLP.Design, Setting, and ParticipantsA prospective observational study was conducted among patients with confirmed diagnoses of EPP or XLP from November 1, 2010, to December 6, 2015, at 6 academic medical centers of the Porphyrias Consortium of the National Institutes of Health Rare Diseases Clinical Research Network. Detailed medical histories, including history of phototoxicity and treatment, were collected on standardized case report forms. Patients underwent baseline laboratory testing, total erythrocyte protoporphyrin (ePPIX) testing, and molecular genetic testing. Data were entered into a centralized database.Main Outcomes and MeasuresResults of biochemical and genetic tests were explored for association with clinical phenotype in patients with EPP or XLP.ResultsOf the 226 patients in the study (113 female and 113 male patients; mean [SD] age, 36.7 [17.0] years), 186 (82.3%) had EPP with a FECH (OMIM 612386) mutation and the common low-expression FECH allele IVS3–48T>C, and only 1 patient had 2 FECH mutations. Twenty-two patients had XLP (9.7%; 10 male and 12 female patients), and 9 patients (4.0%) had elevated ePPIX levels and symptoms consistent with protoporphyria but no detectable mutation in the FECH or ALAS2 (OMIM 301300) gene. Samples of DNA could not be obtained from 8 patients. Patients’ mean (SD) age at symptom onset was 4.4 (4.4) years. Anemia (107 [47.3%]), history of liver dysfunction (62 [27.4%]), and gallstones (53 [23.5%]) were commonly reported. Higher ePPIX levels were associated with earlier age of symptom onset (median ePPIX levels for those who developed symptoms before vs after 1 year of age, 1744 vs 1567 µg/dL; P = .02), less sun tolerance (median ePPIX levels for those reporting symptoms before vs after 10 minutes of sun exposure, 2233 vs 1524 µg/dL; P ≤ .001), and increased risk of liver dysfunction (median ePPIX levels for those with liver dysfunction vs normal liver function, 2016 vs 1510 µg/dL; P = .003). Patients with EPP and FECH missense mutations had significantly lower ePPIX levels than those with other mutations (1462 vs 1702 µg/dL; P = .01). Male patients with XLP had significantly higher ePPIX levels, on average, than did patients with EPP (3574 vs 1669 µg/dL; P < .001). Marked clinical variability was seen in female patients with XLP owing to random X-chromosomal inactivation.Conclusions and RelevanceThese data suggest that higher ePPIX levels are a major determinant of disease severity and risk of liver dysfunction in patients with EPP or XLP. These findings provide a framework for clinical monitoring and management of these disorders.

Use of standard laboratory methods to obviate routine dithiothreitol treatment of blood samples with daratumumab interference

Daratumumab is an antibody currently used in the treatment of patients with refractory multiple myeloma. Blood samples from patients being treated with daratumumab may show panreactivity during pre-transfusion testing. To facilitate the provision of blood components for such patients, it is recommended that a baseline phenotype or genotype be established prior to starting treatment with daratumumab. If patient red blood cells (RBCs) require phenotyping after the start of daratumumab treatment, dithiothreitol (DTT) treatment of the patient's RBCs should be performed. The medical charts of four patients treated with daratumumab were reviewed. The individual number of doses ranged from 1 to 14; patient age ranged from 55 to 78 years; two men and two women were included in the review. Type and screen data were obtained from samples collected over 33 encounters with a range of 1 to 13 encounters per patient. All samples were tested initially by automated solid-phase testing. Any reactivity with solid phase led to tube testing with either low-ionic-strength saline, polyethylene glycol, or both. If incubation failed to eliminate the reactivity, the sample was sent to a reference laboratory for DTT treatment and phenotyping. Of the 33 samples tested, 23 (69.7%) samples had reactivity in solid-phase testing. In 8 of the 10 samples that did not react in solid-phase, testing was conducted more than four half-lives after the last dose of daratumumab. Of the 23 that had reactivity in solid-phase, 16 (69.6%) samples demonstrated loss of reactivity using common laboratory methods. For the seven patients whose sample reactivity was not initially eliminated, six were provided with phenotypically matched blood based on prior molecular testing. Only one sample was sent out for DTT treatment. These results suggest that daratumumab interference with pre-transfusion testing can be addressed using common laboratory methods. This finding could save time and money for laboratories that do not have DTT available.

HIV-1 drug resistance mutations emerging on darunavir therapy in PI-naive and -experienced patients in the UK.

BackgroundDarunavir is considered to have a high genetic barrier to resistance. Most darunavir-associated drug resistance mutations (DRMs) have been identified through correlation of baseline genotype with virological response in clinical trials. However, there is little information on DRMs that are directly selected by darunavir in clinical settings.ObjectivesWe examined darunavir DRMs emerging in clinical practice in the UK.Patients and methodsBaseline and post-exposure protease genotypes were compared for individuals in the UK Collaborative HIV Cohort Study who had received darunavir; analyses were stratified for PI history. A selection analysis was used to compare the evolution of subtype B proteases in darunavir recipients and matched PI-naive controls.ResultsOf 6918 people who had received darunavir, 386 had resistance tests pre- and post-exposure. Overall, 2.8% (11/386) of these participants developed emergent darunavir DRMs. The prevalence of baseline DRMs was 1.0% (2/198) among PI-naive participants and 13.8% (26/188) among PI-experienced participants. Emergent DRMs developed in 2.0% of the PI-naive group (4 mutations) and 3.7% of the PI-experienced group (12 mutations). Codon 77 was positively selected in the PI-naive darunavir cases, but not in the control group.ConclusionsOur findings suggest that although emergent darunavir resistance is rare, it may be more common among PI-experienced patients than those who are PI-naive. Further investigation is required to explore whether codon 77 is a novel site involved in darunavir susceptibility.

α-Fetoprotein level-dependent early hepatitis B surface antigen decline during entecavir therapy in chronic hepatitis B with hepatitis flare.

Hepatitis B surface antigen (HBsAg) reduction during nucleos(t)ide analogue therapy is related to ALT level. ALT reflects hepatocytolysis while α-fetoprotein (AFP) ≥100 ng/mL during hepatitis flare reflects more extensive hepatocytolysis (bridging hepatic necrosis). The impact of AFP levels on early HBsAg kinetics during entecavir therapy was investigated. HBsAg level was measured at baseline and months 6 and 12 of entecavir therapy in 149 chronic hepatitis B patients with hepatitis flare, defined as ALT ≥5× upper limit of normal (ULN), and 58 patients with ALT <5× ULN. There was a significantly greater HBsAg reduction in an ALT (<5, 5-10, 10-20 and ≥20× ULN, P = 0.001) and AFP (<20, 20-99 and ≥100 ng/mL, P = 0.000) level-dependent manner. In hepatitis flares with a peak AFP level ≥20 ng/mL, the differences in HBsAg reduction across all ALT levels became non-significant. HBsAg reduction was greater in genotype B- than genotype C-infected patients with baseline ALT ≥20× ULN, but the difference became non-significant in those with peak AFP ≥100 ng/mL. Multivariate linear regression analysis showed that AFP level ≥100 ng/mL, baseline HBsAg level and genotype B were independent significant factors for greater HBsAg decline at month 6 of entecavir therapy. During entecavir therapy, early HBsAg reduction increased in an AFP and ALT level-dependent manner, suggesting the impact of hepatocytolysis rather than nucleos(t)ide analogue per se. Notably, a higher AFP level during hepatitis flare, reflecting more extensive hepatic necrosis, was a more powerful factor than ALT and genotype for greater HBsAg decline.

Abstract MP60: Coronary Artery Calcium and Dementia Risk in the Multi-Ethnic Study of Atherosclerosis

Introduction: Vascular risk factors (VRFs) predict incident dementia. Coronary artery calcium (CAC), capturing cumulative VRFs exposure, may predict dementia beyond VRFs. Hypothesis: In a community-based sample, baseline CAC is associated with incident dementia independent of VRFs assessed at baseline and APOE -ε 4 genotype. Methods: Among 6,814 participants of the Multi-Ethnic Study of Atherosclerosis (MESA), aged 45-84 years at baseline (2000-2002), we first identified candidate cases for incident all-cause dementia using hospital and death certificate ICD codes. For the analyses, we limited to cases whose diagnosis was validated using following criteria: 1) verifiable medical records available, 2) unlikely alternative diagnosis (e.g. delirium), and 3) written dementia diagnosis. Baseline CAC was categorized according to Agatston score (0, &gt; 0 to &lt;50, 50 to &lt;100, 100 to &lt;400, and ≥400). Cox models were used to obtain hazard ratios (HRs) adjusted for demographics, VRFs, APOE -ε 4, and incident stroke prior to dementia diagnosis. Results: We had complete data on 6,295 individuals for analysis with a mean follow-up of 11.1 years (208 validated cases). Crude rates of dementia were greater with higher baseline CAC categories. Adjusted HR of dementia per one higher CAC category was 1.14 (95%CI 1.03, 1.26) (see Table). The associations were similar when excluding interim incident coronary heart disease, or cardiovascular diseases, or using a model that accounted for competing risk of death with no dementia diagnosis. Conclusion: Higher CAC score measured at baseline was independently and significantly associated with increased risk of dementia. This finding is consistent with an important role for vascular injury in development of dementia.

Evaluation of Dual Therapy in Real Life Setting in Treatment-Naïve Turkish Patients with HCV Infection: A Multicenter, Retrospective Study.

Before the introduction of direct-acting antivirals in the treatment of chronic hepatitis C patients, the combination of peginterferon alpha and ribavirin was the standard therapy. Observational studies that investigated sustained virological response (SVR) rates by these drugs yielded different outcomes. The goal of the study was to demonstrate real life data concerning SVR rate achieved by peginterferon alpha plus ribavirin in patients who were treatment-naïve. A multicenter, retrospective observational study. The study was conducted retrospectively on 1214 treatment naïve-patients, being treated with peginterferon alpha-2a or 2b plus ribavirin in respect of the current guidelines between 2005 and 2013. The patients' data were collected from 22 centers via a standard form, which has been prepared for this study. The data included demographic and clinical characteristics (gender, age, body weight, initial Hepatitis C virus RNA (HCV RNA) level, disease staging) as well as course of treatment (duration of treatment, outcomes, discontinuations and adverse events). Renal insufficiency, decompensated liver disease, history of transplantation, immunosuppressive therapy or autoimmune liver disease were exclusion criteria for the study. Treatment efficacy was assessed according to the patient's demographic characteristics, baseline viral load, genotype, and fibrosis scores. The mean age of the patients was 50.74 (±0.64) years. Most of them were infected with genotype 1 (91.8%). SVR was achieved in 761 (62.7%) patients. SVR rate was 59.1% in genotype 1, 89.4% in genotype 2, 93.8% in genotype 3, and 33.3% in genotype 4 patients. Patients with lower viral load yielded higher SVR (65.8% vs. 58.4%, p=0.09). SVR rates according to histologic severity were found to be 69.3%, 66.3%, 59.9%, 47.3%, and 45.5% in patients with fibrosis stage 0, 1, 2, 3 and 4, respectively. The predictors of SVR were male gender, genotype 2/3, age less than 45 years, low fibrosis stage, low baseline viral load and presence of early virological response. SVR rates to each peginterferon were found to be similar in genotype 1/4 although SVR rates were found to be higher for peginterferon alpha-2b in patients with genotype 2/3. The number of patients who failed to complete treatment due to adverse effects was 33 (2.7%). The number of patients failed to complete treatment due to adverse effects was 33 (2.7%). Our findings showed that the rate of SVR to dual therapy was higher in treatment-naïve Turkish patients than that reported in randomized controlled trials. Also peginterferon alpha-2a and alpha-2b were found to be similar in terms of SVR in genotype 1 patients.

Five Laboratory Tests Predict Patient Risk and Treatment Response in Hepatitis C: Veterans Affairs Data from 1999-2010

Background and Aims: New Hepatitis C [HCV] drugs are expensive but highly effective but have created an overwhelming ‘cash flow’ problem for payers facing a large bolus of infected patients. Health plans are developing ‘watchful waiting’ strategies to safely defer treatment for low risk patients. This study identifies five laboratory tests which predict increasing risk of liver related events and documents that delaying treatment until after an abnormal lab test diminished effectiveness of treatment with interferon alpha plus ribavirin. Methods: Patients from the Veterans Administration’s clinical registry of HCV patients [1999-2010] were screened for a detectable viral load at baseline and a recorded baseline genotype. The primary outcomes were time to death and time to time to a composite clinical event. Cox proportional hazards models were estimated with time dependent independent variables for initial treatment and first abnormal laboratory test. Results: 128,769 patients met all inclusion criteria. Abnormal values for five laboratory were associated with increased risk for the composite outcome/death: 1.35/1.84 for the AST/ALT ratio > 1; 2.35/5.01 for albumin 195 IU/L; 3.85/1.55 for platelet count 144 ng/mL. Delaying drug therapy until after an abnormal lab test significantly reduced treatment effectiveness. Discussion: Five tests predict liver complications for HCV patients which can be used to develop “watchful waiting” protocols which monitor untreated HCV patients over time and defer access to expensive new drug regimens to those patients most at risk adverse liver-related events.

Genotypic Tannin Levels in Populus tremula Impact the Way Nitrogen Enrichment Affects Growth and Allocation Responses for Some Traits and Not for Others.

Plant intraspecific variability has been proposed as a key mechanism by which plants adapt to environmental change. In boreal forests where nitrogen availability is strongly limited, nitrogen addition happens indirectly through atmospheric N deposition and directly through industrial forest fertilization. These anthropogenic inputs of N have numerous environmental consequences, including shifts in plant species composition and reductions in plant species diversity. However, we know less about how genetic differences within plant populations determine how species respond to eutrophication in boreal forests. According to plant defense theories, nitrogen addition will cause plants to shift carbon allocation more towards growth and less to chemical defense, potentially enhancing vulnerability to antagonists. Aspens are keystone species in boreal forests that produce condensed tannins to serve as chemical defense. We conducted an experiment using ten Populus tremula genotypes from the Swedish Aspen Collection that express extreme levels of baseline investment into foliar condensed tannins. We investigated whether investment into growth and phenolic defense compounds in young plants varied in response to two nitrogen addition levels, corresponding to atmospheric N deposition and industrial forest fertilization. Nitrogen addition generally caused growth to increase, and tannin levels to decrease; however, individualistic responses among genotypes were found for height growth, biomass of specific tissues, root:shoot ratios, and tissue lignin and N concentrations. A genotype’s baseline ability to produce and store condensed tannins also influenced plant responses to N, although this effect was relatively minor. High-tannin genotypes tended to grow less biomass under low nitrogen levels and more at the highest fertilization level. Thus, the ability in aspen to produce foliar tannins is likely associated with a steeper reaction norm of growth responses, which suggests a higher plasticity to nitrogen addition, and potentially an advantage when adapting to higher concentrations of soil nitrogen.

HCV viral load at baseline and at week 4 of telaprevir/boceprevir based triple therapies are associated with virological outcome in HIV/hepatitis C co-infected patients

BackgroundAs first generation HCV-specific protease inhibitors, boceprevir (BOC) or telaprevir (TVR) can achieve 60% to 70% sustained virological response (SVR) for HCV infected patients with genotype 1 infections, they could remain temporary a therapeutic option in patients living in resources limited countries with limited access to the new anti-HCV direct acting antiviral (DAA) drugs, such as sofosbuvir. Objectives and Study designHere we evaluated in a routine practice setting, the treatment responses, tolerance and factors associated with SVR of a triple therapy with BOC or TVR, combined with pegylated interferon and ribavirin (PegIFN/RBV) in HIV/HCV co-infected patients, included in a large cohort of HIV/HCV coinfected patients (ANRS CO13-HEPAVIH). ResultsAmong the 89 HIV/HCV coinfected patients treated, 65% of whom were previous non-responders to PegIFN/RBV therapy, 65%, 55% and 41% had at baseline genotype 1a, a high baseline HCV-RNA (≥800,000IU/ml) and a cirrhosis, respectively. The SVR12 rate was 63% overall, 53% for BOC-based regimen and 66% for TVR-based regimen. In multivariate analysis, two factors were significantly associated with HCV SVR: HCV viral load <800,000IU/mL at treatment initiation versus ≥800,000IU/mL (OR 4.403, 95% CI 1.29–15.04; p=0.018) and virological response at W4 (HCV-RNA undetectable after 4 weeks of triple therapy) (OR 3.35, 95% CI 1.07–10.48; p=0.038). ConclusionsOverall SVR12 was 63% and our results suggest that HIV/HCV coinfected patients with low HCV viral load (<800,000IU/mL) and undetectable HCV-RNA after 4 weeks of triple therapy with TVR or BOC-based regimen have a higher probability of treatment success.

Asymmetric Evolutionary Games.

Evolutionary game theory is a powerful framework for studying evolution in populations of interacting individuals. A common assumption in evolutionary game theory is that interactions are symmetric, which means that the players are distinguished by only their strategies. In nature, however, the microscopic interactions between players are nearly always asymmetric due to environmental effects, differing baseline characteristics, and other possible sources of heterogeneity. To model these phenomena, we introduce into evolutionary game theory two broad classes of asymmetric interactions: ecological and genotypic. Ecological asymmetry results from variation in the environments of the players, while genotypic asymmetry is a consequence of the players having differing baseline genotypes. We develop a theory of these forms of asymmetry for games in structured populations and use the classical social dilemmas, the Prisoner’s Dilemma and the Snowdrift Game, for illustrations. Interestingly, asymmetric games reveal essential differences between models of genetic evolution based on reproduction and models of cultural evolution based on imitation that are not apparent in symmetric games.

Factors Associated with Recurrence of Age-Related Macular Degeneration after Anti-Vascular Endothelial Growth Factor Treatment: A Retrospective Cohort Study

To investigate the predictive factors associated with recurrence after anti-vascular endothelial growth factor (VEGF) treatment for neovascular age-related macular degeneration (AMD). Retrospective cohort study. A total of 343 eyes of 326 patients with subfoveal neovascular AMD who were treated with an as-needed regimen after 3 monthly loading doses of intravitreal ranibizumab. Patients were followed up by an as-needed regimen for more than 1 year after the first injection. Baseline data and CFH I62V and ARMS2 A69S polymorphisms were analyzed for their association with recurrence after anti-VEGF treatment. Regression analysis was used to identify independent predictors of visual acuity (VA) prognosis. The primary end point was the presence or absence of recurrence. The secondary end point was VA improvement. In total, 236 eyes (68.8%) showed complete resolution of retinal exudative change after the 3 loading injections, and 81 eyes (34.3%) experienced no recurrence during the first year. Of the 236 eyes, 139 (58.9%) were followed for more than 2 years and 35 (25.2%) showed no recurrent retinal exudation during 24 months. Visual acuity improvement was significantly better in eyes without recurrence than in eyes with recurrence during the 2-year period. Baseline characteristics and genotypes had no influence on response to ranibizumab loading treatment. Stepwise analysis revealed that age (P<0.001), subtype of AMD (P=0.041), and VA at baseline (P<0.001) were associated with VA at 24 months. Older patients (P=0.006) and male patients (P=0.018) tended to require re-treatment for recurrence during the first year, yet the statistical significance disappeared when evaluated in 2 years. The subtypes of neovascular AMD were solely associated with the interval to the recurrence, which was shorter in eyes with polypoidal choroidal vasculopathy (PCV) than in eyes with typical AMD (P=0.015). Older age and male sex may predict recurrence after 3 monthly ranibizumab injections, and PCV may be associated with shorter interval to recurrence. Predicting the risk of recurrence would help us to choose the most appropriate follow-up treatment strategy for patients with AMD.

Characteristics and genotype profiles of antiretroviral-naïve patients entering a Southern US HIV outpatient clinic 2009–2012

The US city of New Orleans was ranked second in the nation for estimated HIV case rates in 2011. Opt-out testing was established at the Interim Louisiana Hospital in New Orleans in 2013. The majority of new diagnoses were referred to the HIV outpatient program. We conducted a retrospective chart review of newly referred antiretroviral-naïve patients establishing HIV care between January 2009 and June 2013 to characterise demographic and genotype profiles to assist in clinical management and needed services. Of the eligible 226 patients, 68% were men, and 88% were African American. Nearly half of the study patients were younger than 35 years of age. Forty-six percent had an initial CD4 count <200 cells/mm(3), and 39% had a HIV viral load >100,000 copies/mL. The antiretroviral class with the most common major mutation was the non-nucleoside reverse transcriptase inhibitors (NNRTIs) where K103N was the most common major NNRTI mutation at presentation. We observed that male patients showed more advanced disease with later presentation to care, confirming the need for earlier HIV diagnosis. When considering initial antiretroviral therapy, baseline genotype information is encouraged, particularly if considering a NNRTI-based regimen.