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Resistance Testing (resistance + testing)
Kinds of Resistance Testing Selected AbstractsNaturally occurring dominant resistance mutations to hepatitis C virus protease and polymerase inhibitors in treatment-naïve patients,,§HEPATOLOGY, Issue 6 2008Thomas Kuntzen Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo. Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin. (HEPATOLOGY 2008;48:1769,1778.) [source] PENTA 2009 guidelines for the use of antiretroviral therapy in paediatric HIV-1 infectionHIV MEDICINE, Issue 10 2009PENTA Steering Committee PENTA Guidelines aim to provide practical recommendations for treating children with HIV infection in Europe. Changes to guidance since 2004 have been informed by new evidence and by expectations of better outcomes following the ongoing success of antiretroviral therapy (ART). Participation in PENTA trials of simplifying treatment is encouraged. The main changes are in the following sections: ,When to start ART': Treatment is recommended for all infants, and at higher CD4 cell counts and percentages in older children, in line with changes to adult guidelines. The number of age bands has been reduced to simplify and harmonize with other paediatric guidelines. Greater emphasis is placed on CD4 cell count in children over 5 years, and guidance is provided where CD4% and CD4 criteria differ. ,What to start with': A three-drug regimen of two nucleoside reverse transcriptase inhibitors (NRTIs) with either a nonnucleoside reverse transcriptase inhibitor (NNRTI) or a boosted protease inhibitor (PI) remains the first choice combination. Lamivudine and abacavir are the NRTI backbone of choice for most children, based on long-term follow-up in the PENTA 5 trial. Stavudine is no longer recommended. Whether to start with an NNRTI or PI remains unclear, but PENPACT 1 trial results in 2009 may help to inform this. All PIs should be ritonavir boosted. Recommendations on use of resistance testing, therapeutic drug monitoring and HLA testing draw from data in adults and from European paediatric cohort studies. Recently updated US and WHO paediatric guidelines provide more detailed review of the evidence base. Differences between guidelines are highlighted and explained. [source] Genotypic antiretroviral drug resistance testing at low viral loads in the UKHIV MEDICINE, Issue 8 2008PA Cane Background Antiretroviral drug resistance testing is recommended in HIV-1 infected patients failing therapy in order to inform treatment selection. Although guidelines and test manufacturers recommend a viral load of at least 500,1000 HIV-1 RNA copies/mL for genotypic resistance testing to be performed, prompt management of virological failure could benefit from testing at lower viral load levels. Methods Laboratories undertaking genotypic resistance testing were asked to provide figures for the number of resistance tests undertaken at viral loads <2000 copies/mL, the success rates of such tests and the extent of resistance detected, all stratified for viral load levels. Results Of the replies received, most laboratories were attempting resistance testing at viral loads below the recommended guidelines, with variable success and outcomes. Conclusions This audit of current practice in the UK for undertaking genotypic resistance tests at viral loads <1000 copies/mL highlights the widespread use of such testing outside the British HIV Association guidelines. [source] Factors associated with virological response in HIV-infected patients failing antiretroviral therapy: a prospective cohort studyHIV MEDICINE, Issue 2 2005S Fournier Objectives To assess the antiviral response to optimized therapy following genotypic resistance testing and to identify factors associated with virological response in HIV-1-infected patients failing antiretroviral therapy. Methods A prospective cohort study was conducted in 344 HIV-1-infected patients who underwent genotypic resistance testing because of virological failure. Virological response was defined as a plasma HIV RNA level below 200 HIV-1 RNA copies/mL or a drop of plasma viral load from baseline of more than 1 log10. A multivariate logistic regression analysis was performed to identify factors associated with virological response. Results The median age of the patients was 40 years, with a male to female ratio of 4:1. Fifty-one per cent of patients had received the three major classes of antiretrovirals and the median duration of previous antiretroviral therapy was 4.6 years. At baseline, the median plasma HIV RNA level was 4.4 log10 copies/mL and the median CD4 cell count was 274 cells/,L. At 3 months, 55% of patients (188 of 344) had a virological response, which was sustained at 6 months (53%). Predictors of virological response were exposure to two or fewer protease inhibitors [odds ratio (OR) 1.8; P=0.046], and use in optimized therapy of a new class of antiretrovirals (OR 2.9; P=0.006), of more than two new drugs (OR 3.0; P<0.0001), of abacavir (OR 1.9; P=0.03), or of lopinavir/ritonavir (OR 3.7; P=0.0002). Conclusions A high proportion of patients achieved a short-term virological response in this cohort study. Patients with the least experience of protease inhibitor treatment and in whom a new class of antiretroviral, more than two new drugs, abacavir or lopinavir/ritonavir was used in optimized therapy had the best virological outcome. [source] European guidelines on resistance testing: why are they needed?HIV MEDICINE, Issue 3 2000V. Miller No abstract is available for this article. [source] Detection of drug resistance mutations as a predictor of subsequent virological failure in patients with HIV-1 viral rebounds of less than 1,000 RNA copies/mlJOURNAL OF MEDICAL VIROLOGY, Issue 9 2007Chris Verhofstede Abstract In order to evaluate the usefulness of resistance testing after a viral rebound with plasma HIV RNA levels of less than 1,000 copies (c)/ml, genotyping was performed on 39 samples from patients on highly active antiretroviral therapy (HAART) showing a viremia of over 50 c/ml up to a maximum of 1,000 c/ml after at least one undetectable viral load result. Protease and reverse transcriptase (RT) sequences were obtained for all 39 samples. In 10 (25.6%) of the samples, mutations not seen before the initiation of the regimen were observed. The M184V/I mutation was the most prevalent but in several patients a combination of multiple mutations was detected. Follow-up samples were available for 34 patients. In six (85.71%) out of seven patients with new mutations, the viral load on the follow-up visit remained detectable, indicating true failure, compared to 6 (31.6%) true failures out of 19 patients in whom only wild type virus was detected (P,=,0.02) and three (37.5%) out of eight patients in whom only the mutations already present at the initiation of HAART were seen (P,=,0.08). The results indicate that reliable resistance testing can be performed on samples with a viral burden of less than 1,000 c/ml and demonstrate that multiple drug resistance mutations can be selected at low viral load rebounds. Most importantly, detection of resistance mutations in viral rebound samples was predictive of subsequent virological failure. J. Med. Virol. 79:1254,1260, 2007. © Wiley-Liss, Inc. [source] Prevalence and risk factors associated with antiretroviral resistance in HIV-1-infected childrenJOURNAL OF MEDICAL VIROLOGY, Issue 9 2007Constance Delaugerre Abstract In the USA and West Europe, nearly 80% of HIV-1-infected adults, experiencing virologic failure, harbored virus strain resistant to at least one antiretroviral drug. Limited data are available on antiretroviral drug resistance in pediatric HIV infection. The aims of this study were to analyze prevalence of HIV-1 drug resistance and to identify risk factors associated with resistance in this population. Prevalence of genotypic resistance was estimated retrospectively in treated children who experienced virologic failure (with HIV-1-RNA,>,500 copies/ml) followed in Necker hospital between 2001 and 2003. Among 119 children with resistance testing, prevalence of resistance to any drug was 82.4%. Resistance ranged from 76.5% to nucleoside reverse transcriptase inhibitor (NRTI), to 48.7% to non-nucleoside reverse transcriptase inhibitor (NNRTI) and 42.9% to protease inhibitor (PI). Resistance to at least one drug of two classes and three classes (triple resistance) was 31.9 and 26.9%, respectively. Resistance was not associated with geographic origin, HIV-1 subtype, and CDC status. In multivariate analysis, resistance to any drug remained associated independently with current low viral load and high lifetime number of past PI. Triple resistance was independently associated with the high lifetime number of past PI and with gender, particularly among children aged 11 years old or more with a prevalence seven times higher in boys than in girls. In conclusion, antiretroviral resistance is common among treated HIV-1-infected children and prevalence was similar with those observed in adult population in the same year period. However, adolescent boys seem to be at greater risk. J. Med. Virol. 79:1261,1269, 2007. © Wiley-Liss, Inc. [source] Effect of Auxiliary Grooves on Molar Crown Preparations Lacking Resistance Form: A Laboratory StudyJOURNAL OF PROSTHODONTICS, Issue 2 2008DClinDent, GradDipClinDent, Po-Ching Lu BDSc(Hons) Abstract Purpose: To investigate the effect of auxiliary grooves on resistance to dislodgment of crowns on compromised molar preparations lacking resistance form. Materials and Methods: Thirty human molar teeth were randomly assigned to three groups of ten, and prepared to a height-to-width ratio of 0.3 with a total convergence of 50°, and 1-mm shoulder margin. Base metal alloy copings were constructed with a 45° loading platform and cemented with zinc phosphate cement under a 50 N load. Initially, resistance testing was conducted using a Universal Testing Machine (Instron) at 1 mm/min for all 30 specimens. Following crown dislodgment, Group 1 copings were recemented and retested, Group 2 had one axial groove added, and Group 3 had two axial grooves added. New copings for Groups 2 and 3 were made, cemented, and again tested for resistance. Standardized radiographs were taken prior to initial cementation and scanned into digital images. The percentage of area occupied by the pulpal chamber above the acrylic mounting (PS), and the closest distance to pulp from the preparation surface (CD) were measured. Results: Recementation or the addition of one groove did not affect the dislodgment values (p > 0.05), but addition of two grooves caused a highly significant increase in resistance (p < 0.001). Regression analysis showed an inverse relationship between initial resistance values and pulpal space area. Lower resistance values were observed when the pulpal space area was large (p= 0.004). Conclusions: Crowns can be recemented without affecting resistance to dislodgment. Two grooves should be incorporated into compromised molar crown preparations to increase resistance form. Teeth with large pulps and therefore less coronal dentine have poorer resistance form, and therefore would benefit from placement of auxiliary grooves. [source] Kinetics of host immune responses and cytomegalovirus resistance in a liver transplant patientLIVER TRANSPLANTATION, Issue 10 2009Kirsten Schaffer Among solid organ transplant (SOT) recipients, donor-seropositive/recipient-seronegative (D+/R,) cytomegalovirus (CMV) status is associated with the highest risk of ganciclovir-resistant CMV disease, which has been reported for patients receiving oral ganciclovir but not valganciclovir prophylaxis. We report a case of CMV breakthrough infection in a D+/R, liver transplant patient while he was receiving oral valganciclovir. Forty samples collected over 6 months were analyzed for the CMV viral load, lymphocyte counts, cytokine levels, and lymphocyte differentiation status. Genotypic resistance testing of the viral UL97 gene was performed when the patient failed to respond. CMV viremia occurred on day 50 post-transplant, and 5 samples taken between days 50 and 85 showed the wild-type UL97 genotype. The appearance of deletion 594-595 was observed from day 114 post-transplant. Viral loads declined when foscarnet was commenced and remained below 10,000 copies/mL when the lymphocyte count was greater than 1000/,L (P = 0.02). T cell responses revealed significant expansion of CD8+ terminal effector memory cells. CD4+ cells were largely populations of naïve and central memory cells. Circulating interleukin 10 (IL-10) levels correlated with the viral load (P < 0.0001). Seroconversion occurred on day 230. The CMV viral load in combination with lymphocyte counts and IL-10 may be a predictive marker for the risk of development of resistant CMV disease in D+/R, SOT patients. Liver Transpl 15:1199,1203, 2009. © 2009 AASLD. [source] How to diagnose and treat hepatitis B virus antiviral drug resistance in the liver transplant settingLIVER TRANSPLANTATION, Issue S2 2008Anna S. F. Lok Key Points 1Hepatitis B virus variants with antiviral drug,resistant mutations and/or hepatitis B immune globulin,resistant mutations are the main cause of hepatitis B virus reinfections post,liver transplant. 2Early diagnosis of antiviral drug resistance and prompt initiation of rescue therapy are important in preventing hepatitis flares and hepatic decompensation. 3Virologic breakthrough is the first indication of antiviral drug resistance. 4Genotypic resistance testing should be performed when possible to avoid unnecessary modification of treatment in patients who do not have confirmed antiviral drug resistance and to permit appropriate selection of rescue therapy in those who have confirmed antiviral drug resistance. 5Choice of rescue therapy requires knowledge of the past history of hepatitis B virus treatments and virologic response to those treatments, patterns of mutations detected at the time of virologic breakthrough, and in vitro cross-resistance data. 6Occurrence of antiviral drug resistance can be reduced by the use of the most potent nucleos(t)ide analogue(s) with the highest genetic barrier to resistance, emphasis of medication compliance, and close monitoring of virologic response. Liver Transpl 14:S8,S14, 2008. © 2008 AASLD. [source] Characterization of grooves in scratch resistance testingPOLYMER ENGINEERING & SCIENCE, Issue 10 2008Witold Brostow For a number of polymers with different chemical structures and different properties we have determined scratch resistance and sliding wear (15 scratches along the same groove). We have measured cross section areas after scratching, namely the groove and side top-ridge areas. Nanohardness after scratching was determined using nanoindentation testing both inside and outside the scratching and sliding wear grooves. Three modes of sliding wear are seen: plowing, cutting with debris formation, and densification. The dominating mode depends on the material and is reflected in nanohardness. In polycarbonate (PC) the nanohardness inside and outside the groove are practically the same; the indenter just plows the material aside without debris formation or densification. Thus, the old measure of wear as the weight of the debris formed is not usable for PC; grooves are present but there is no loosened material. By contrast, in brittle materials such as polystyrene there is debris formation and nanohardness inside the groove decreases after 15 scratching runs. A third type of behavior is seen in polyethylene and polypropylene, namely densification caused by scratching; as a result, nanohardness inside the groove increases after 15 passes of the indenter. POLYM. ENG. SCI., 2008. © 2008 Society of Plastics Engineers [source] The use of human immunodeficiency virus resistance tests in clinical practiceCLINICAL MICROBIOLOGY AND INFECTION, Issue 10 2010F. Ceccherini-Silberstein Clin Microbiol Infect 2010; 16: 1511,1517 Abstract Important progress has been made in recent years in the development and clinical use of drugs for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Nevertheless, when antiretroviral therapy fails to be fully suppressive, new viral variants emerge, thus allowing HIV-1 to escape from drug pressure by accumulating mutations. Between 50% and 70% of treated patients with virological rebound harbour some form of drug-resistant virus; transmitted drug resistance in drug-naïve populations has reached 5,20% in areas of the world with access to treatment. The emergence of drug-resistant viruses remains the limiting factor in HIV-1 management, being a major cause of treatment failure, and being associated with clinical progression and death. All international guidelines focus on the importance of tailoring antiretroviral therapy to the individual patient, on the basis onf HIV-1 genetic data, integrated with clinical, laboratory and therapeutic information. The aim of this review is to provide useful information to clinicians and virologists about how and when to use genotypic resistance testing in clinical practice, especially in the management of the first stages of HIV-1 patient care and treatment decisions. [source] Prevalence of drug resistance and newly recognised treatment-related substitutions in the HIV-1 reverse transcriptase and protease genes from HIV-positive patients naïve for anti-retroviralsCLINICAL MICROBIOLOGY AND INFECTION, Issue 9 2004C. Torti Abstract The aim of this study was to assess the prevalence of genetic changes in either the HIV reverse transcriptase (RT) or protease (Pro) genes in a cohort of patients naïve for anti-retroviral therapy. Of 61 patients, 43 (70.5%) were infected with HIV strains harbouring at least one resistance-related mutation, with 41 (67.2%) harbouring newly recognised treatment-related mutations. Among the 61 patients, the prevalence of specific mutations in the RT gene was as follows: 39A, 1.6%; 43E, 1.6%; and 228H, 1.6%. The prevalence of specific mutations in the Pro gene was as follows: 11I, 1.6%; 13V, 26.2%; 35D, 19.6%; 45R, 1.6%; 58E, 1.6%; 62V, 31%; 72V, 11.4%; 72M, 6.5%; 72T, 3.2%; 75I, 1.6%; and 89M, 13%. A higher prevalence of newly recognised mutations was found in strains from patients infected through sexual practices (30/36 = 83.4% vs. 11/25 = 44%; p 0.0023; OR 10.91; 95% CI 3.14,40.39). These findings support the use of resistance testing in patients naïve for anti-retroviral therapy, and suggest that the possible impact of newly recognised treatment-related mutations on clinical outcome requires further investigation. [source] | ||||||||||