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Tables 1 and 2 show the advantages and disadvantages of phenotypic and genotypic resistance analyses order top avana 80 mg mastercard. Table 1: Advantages and disadvantages of phenotypic resistance analysis Phenotypic resistance analysis Advantages Disadvantages • Direct measure of drug susceptibility • Detection of viral mutants only possible when • Measure of drug susceptibility feasible comprising ≥20% of the total virus population irrespective of the presence of unknown • Clinical cut-offs not available for all drugs resistance mutations • Costly (reimbursement by health insurance often • Measure of drug susceptibility feasible not guaranteed) irrespective of the complexity of resistance • Time-consuming (several weeks) patterns and the presence of resensitizing • HIV-1 subtyping not possible mutations • Interactions between antiviral drugs are not reflected in the test results • Test results are not affected by amino acid exchanges discount top avana 80mg on line, which are only an intermediate step to resistance Basic principles of phenotyping Phenotypic resistance tests involve direct quantification of drug sensitivity best top avana 80mg. Viral replication is measured in cell culture under the selective pressure of increasing concentrations of antiretroviral drugs and is compared to viral replication of wild- type virus. Drug concentrations are expressed as IC50 values (50% inhibitory con- 302 ART centration), the concentration of drug required to inhibit viral replication in cell cul- tures by 50%. The sensitivity of the virus is expressed as the IC50 divided by the IC50 of a wild-type reference virus (fold-change, FC, also known as resistance factor) and compared to the so-called cut-off value. The cut-off value indicates by how much the IC50 of an HIV isolate can be increased in comparison to that of the wild-type and still be classified as sensitive. The determination of the cut-off is crucial for the interpretation of the results. Cut-offs: technical, biological and clinical Three different cut-offs are currently being used. The technical cut-off is a measure of the methodological variability of the assay. The biological cut-off involves the inter-individual variability of wild-type virus iso- lates from ART-naïve HIV-positive patients. If the IC50 is below the biological cut-off, virological success is very likely. However, an IC50 above the biological cut-off does not allow prediction of the virologic response to a drug. In contrast, the clinical cut-off indicates up to what levels of IC50 virologic effective- ness can still be expected. In general, lower and upper clinical cut-offs are defined. The lower clinical cut-off is the fold-change in IC50 (FC) which indicates slightly reduced virological response. An FC above the upper clinical cut-off indicates resistance, and an FC between the two cut-offs indicates partial resistance. Due to limited clinical experience, cut-off data is often lacking for recently approved drugs. In these cases, interpretations are based on biological cut-offs. In the phenotypic analysis, mutations that do not confer resistance by themselves but provide evidence for transmitted, emerging or reverting resistance have no influence on the measure of resistance. Basic principles of genotyping The HIV genome consists of two RNA (ribonucleic acid) strands containing the genetic information of the virus. Within the nucleotide sequence of the HIV genome, a group of three nucleotides, called a codon, code for a particular amino acid in the protein sequence. Resistance mutations are described using a number for each gene, showing the position of the relevant codon, and two letters, the letter preceding the number corresponding to the amino acid specified by the codon at this position in the wild-type virus, while the letter after the number describes the amino acid that is produced from the mutated codon. A change in the nucleotide sequence of a codon is called a mutation. Only those mutations that code for a different amino acid that leads to a change in the protein structure are clinically relevant. This affects protein function and can contribute to the develop- ment of resistance to antiretroviral agents. M184V indicates a mutation in codon 184 of the reverse transcriptase gene leading to a valine for methionine substitution in the reverse transcriptase enzyme and rendering the virus resistant to 3TC and FTC. Genotypic assays are based on the analysis of mutations associated with resistance. These are determined by the direct sequencing of the amplified HIV genome or by specific hybridization techniques with wild-type or mutant oligonucleotides. For therapeutic decision making, sequencing of the pol region, which encodes for the viral enzymes protease, reverse transcriptase and integrase, and sequencing of the env region, which encodes for the glycoproteins of the viral envelope, gp41 and HIV Resistance and Viral Tropism Testing 303 gp120, are of relevance. Other gene regions, in particular RNase H and gag, are reported to be associated with phenotypic drug resistance. However, sequencing of these regions has only been performed in the context of research and is not part of routine diagnostics. The interpretation of genotypic resistance patterns is based on the correlation between genotype, phenotype and clinical response. There is data available from in vitro studies, clinical studies, clinical observations and duplicate testing, in which genotypically localized mutations have been investigated for phenotypic resistance. Table 2: Pros and cons of genotypic resistance analysis (population-based sequencing) Genotypic resistance analysis Advantages Disadvantages • Quick analysis (results within days) • Indirect measurement of resistance • Widely used (no specific safety requirements • Detection of viral mutants only possible when for laboratory) comprising ≥20 of the total virus population • Listing of all changes in the nucleotide sequence • Complex resistance patterns are often • Detection of any mutation – with either evidence difficult to interpret of resistance, emerging resistance or reverting • Unknown mutations are not considered for resistance interpretation • HIV-1 subtyping possible • Interpretation systems must be updated • In general, reimbursement by health insurance regularly (i. Expert panels have developed algorithms based on the literature and clinical outcomes that are updated on an annual or bi- annual basis (Table 3). Interpretation of RAMs in Germany primarily uses the algo- rithm developed by HIV-GRADE e. The Stanford HIV Drug Resistance Database also provides a database with explanations and statistical analy- sis of RAMs aside from the algorithm. Most commercial providers of resistance assays have integrated interpretation guidelines into their systems. Table 3: Genotypic resistance interpretation systems: an overview Interpretation system Interpretation Available Internet address: free of charge http:// HIV-GRADE (12/2013), Rules-based Yes www. The virtual phenotype is characterized by phenotypic information derived from genotype without performing a phenotypic resistance test in the laboratory. Phenotypic estimates derive from large databases of paired genotypic and phenotypic information. Methods of tropism testing To enter the target cell, HIV binds to the CD4 receptor and so-called chemokine co- receptors, of which CCR5 and CXCR4 are most important. Dependent on the use of coreceptors (“tropism”) the virus is classified as CCR5-(“R5”-) tropic or CXCR4- (“X4”-) tropic. Viral strains using both coreceptors are called dual-tropic. Since tropism tests cannot distinguish between dual-tropic viral isolates and a mixture of R5- and X4-tropic viral isolates, the term dual/mixed (D/M) tropic is used. Analogous to resistance testing, tropism testing can be performed genotypically or phenotypically (Braun 2007). European guidelines recommend both the enhanced sensitivity Trofile assay and V3 loop population sequencing (Vandekerckhove 2011). Table 4 outlines the advantages and disadvantages of both methods. Phenotypic tropism testing Due to its use in clinical trials, TrofileTM is the best-known phenotypic tropism test. TrofileTM ES (TrofileTM with enhanced sensitivity) detects minor viral populations down to a 1% sensitivity. This test has further become available for the use of provi- ral DNA when viral load is <1000 HIV RNA copies/ml. Another commercially avail- able phenotypic test is Phenoscript ENV (EuroFins/VIRalliance).

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In a larger trial (N=256) of ziprasidone and aripiprazole cheap 80 mg top avana amex, time to onset of efficacy was evaluated by comparing 125 response at specific time points buy generic top avana 80 mg online. At 4 weeks ziprasidone was found to have superior improvement in the BPRS and the PANSS cheap top avana 80 mg otc, but not on the CGI or at any other time point. Pooling data from the RODOS studies resulted in an onset of initial response 7. The imprecision around the estimate of the weighted mean difference for time-to-onset of olanzapine compared with risperidone was reflected in the wide 95% confidence intervals. A sensitivity analysis examining the influence of individual studies revealed the Snaterse study to contribute to the between-study heterogeneity. Excluding this study gave a pooled weighted mean difference of 4. The mean onset of efficacy in patients admitted to a state psychiatric hospital was approximately 6 days shorter with risperidone than olanzapine, however the data for olanzapine were less 140 complete and the standard deviations were not reported. Discontinuation of treatment No significant difference was found in rates of discontinuation of drug for any reason or switching medications overall, based on 1 trial and 3 observational studies. The risk of discontinuing assigned drug due to lack of efficacy was higher in the olanzapine groups (number needed to treat, 44), while the risk of discontinuing due to adverse events was higher in the risperidone groups (number needed to treat, 59). A trial involving aripiprazole, olanzapine, risperidone, and ziprasidone atypical antipsychotics found ziprasidone to have the highest withdrawal rate due to adverse events, but the difference across the groups was not statistically 62 significant. One of these studies, conducted in Canada, followed patients for 12 months and reported a significant difference in the re-admission rate over this time period (31. Atypical antipsychotic drugs Page 55 of 230 Final Report Update 3 Drug Effectiveness Review Project Discharge rates A small (N=20), 10-week, open-label trial compared clozapine with risperidone in treatment- resistant patients during hospitalization for an acute episode and reported discharge rates (60% 84 with clozapine, 78% with risperidone; P=0. There were significantly more women than men in the risperidone group, but other baseline characteristics were similar. The mean dose of clozapine was 385 mg daily (midrange) compared with 7. A study of olanzapine and risperidone found that the proportion of patients discharged on their assigned drug was not statistically significantly different between the drugs 136 when prior failures on one or the other was taken into account. In a study of ziprasidone and aripiprazole, discharge-readiness was assessed by the 125 Outcome Resource Discharge Questionnaire, rather than actual discharge rates. Nursing burden in inpatient setting A single fair-quality study comparing olanzapine plus lorazepam with haloperidol plus 256 lorazepam evaluated the effects in acutely agitated patients with schizophrenia. The outcome measure was based on the use of restraints, seclusion, or special nursing watch procedures. The proportions of patients needing these were similar in both groups (16. This was a small study (N=100) in a narrowly defined population, so generalizability to other populations was low. Since no other trial used these outcome measures, indirect comparisons were not possible. Atypical antipsychotic drugs Page 56 of 230 Final Report Update 3 Drug Effectiveness Review Project Table 6. Olanzapine compared with risperidone in the inpatient setting Study Olanzapine Risperidone Olanzapine compared with risperidone Length of inpatient stay N Mean days N Mean days Kraus 45 8 40 8 Mladsi 153 11 120 12 Weighted mean difference Advocat 46 332 36 376 a 5. Efficacy Intermediate outcome measures, such as improvement on symptom scales, typically are useful in determining efficacy of a drug. But they are not the ultimate goal of treatment; long-term effectiveness outcomes are. In the chain of evidence, there is a presumed link between the intermediate efficacy measure and a long-term effectiveness outcome, but these links are not always proven. An example of an intermediate outcome measure and an effectiveness outcome is improvement in negative symptoms leading to improvements in social functioning. Previous versions of this report have conducted detailed analyses of intermediate outcome measures; however, with the body of evidence now available for the atypical antipsychotics, we have a large group of studies contributing direct evidence on comparative effectiveness outcomes for most of these drugs. When the direct link between treatment and long-term effectiveness outcomes exists, reviewing the evidence on intermediate outcomes does not confer additional information about medication benefits. In many cases, a large body of evidence would be reviewed to result in the same conclusions as the higher-level evidence. In cases where the intermediate evidence conflicts with the long-term effectiveness Atypical antipsychotic drugs Page 57 of 230 Final Report Update 3 Drug Effectiveness Review Project evidence, the fact that a definite link between the outcomes has not been established may be the cause. One such outcome that has not been addressed above is response or remission rates. Intermediate outcomes that are no longer necessary to be reviewed except in special circumstances are the schizophrenia symptomatology scales (PANSS, BPRS, SANS, and Clinical Global Impression-Improvement [CGI-I]), neuropsychiatric cognitive tests, and symptom scales for aggression and depression as a part of the symptoms of schizophrenia. Below we present the data on response and remission for all atypical antipsychotics and intermediate outcomes for only those drugs without long-term effectiveness evidence. Currently the drugs without effectiveness evidence are asenapine, iloperidone, extended-release paliperidone and paliperidone long-acting injection, the injectable formulations of olanzapine, risperidone, and ziprasidone, the orally disintegrating tablet formulations of clozapine, olanzapine, and risperidone, and the extended release tablet formulation of immediate-release quetiapine. Response rates Response rates across the atypical antipsychotics ranged widely across trials due to variations in patient populations, duration of follow-up, and definition of response. Many trials reported response based on ≥ 20% improvement on the PANSS, but it was clear that this definition did 257, 258 not work well for all populations. Other definitions included the Kane criteria 259 (improvement of ≥ 20% on BPRS and either CGI-S ≤ 3 or BPRS ≤ 35), 30%, 40%, and 50% improvements in PANSS or BPRS, and, more recently, ≤ 3 on all PANSS items and ≤ 3 on the CGI-S. Across the trials, statistically significant differences in response rates were very rare, with these differences occurring only when data were analyzed according to multiple definitions of response (see comparison of clozapine and olanzapine below). In these cases, however, other analyses or other trials have not confirmed findings of a difference. Each of these trials reported response rates of >20% on the PANSS (Table 7), but only 1 study found a 47 statistically significant difference on this measure (olanzapine 75%, risperidone 47%, P=0. Pooled analysis resulted in no significant difference between the drugs. Three studies also reported response rates defined as >40% improvement on the PANSS. Pooling these data did not result in a significant difference (P=1. A significant difference favoring olanzapine was found using >50% improvement on the PANSS in the only study using 80 this threshold. An additional small trial (N=78) was poor quality due to inadequate description of methods for randomization, allocation concealment, and lack of an intention-to-treat 121 analysis. Four studies comparing clozapine with risperidone reported response rate. Three defined 36, 84, 260 26 response as a 20% improvement in the total PANSS score and 1 used the Kane criteria. None of the studies found a significant difference between the drugs based on this criterion (Table 7).

ADD-H Comprehensive Teacher Rating Scale (ACTeRS) contains both parent and teacher forms 80 mg top avana with mastercard. Both versions are used to assess attention buy discount top avana 80mg line, hyperactivity cheap 80mg top avana mastercard, social skills, and oppositional behavior in children and adolescents ages 6-14. Each form contains 24 items and takes 5-10 minutes to complete, and measures 4 areas of behaviors. This scale can be used for screening or to measure 6 response to treatments. Attention deficit hyperactivity disorder 164 of 200 Final Update 4 Report Drug Effectiveness Review Project The ADHD Investigator Symptom Rating Scale (AISRS) is an 18-item scale that helps assess the impact and severity of ADHD among adults. It is clinician-administered scale that assesses each of the 18 individual criteria symptoms of ADHD in DSM-IV on a scale from 0 to 3 (0 =not present; 3= severe). The total score ranges from a minimum of 0 to a maximum of 54. The Adult Self-Report Scale (ASRS) is a checklist of 18 questions about symptoms that are based on the diagnostic criteria of DSM-IV (Diagnostic and Statistical Manual –IV). The scales are rated on a range from 0 to 4 with o being never and 4 being very often. Higher scores on this scale indicate greater symptom severity. This scale has been shown to be valid for assessing 7 ADHD symptom severity. The Alabama Parenting Questionnaire (APQ) is used to assess the five areas of parenting practices that are commonly associated with conduct disorders. The APQ has four components and contains formats for parent and child to respond to questions about “typical” parenting practices used in the home and rate them on a Likert-type scale with 1(Never) to 5 (Always). The APQ also includes a phone interview where the informant is requested to estimate the frequency of parenting behavior over the past 3 days. This questionnaire has been shown to be valid and 8 reliable in assessing parental practices. Barkley’s Attention Deficit Hyperactivity Disorder Checklist and Scale is a self-report rating system that measures the occurrence of symptoms. The range of the scale is 0=never or rarely, 1=sometimes, 2=often, and 3=very often. The checklist is used as a measurement to define 9 symptoms of the disorder. Barkley’s Stimulants Side Effects Rating Scale is a 17-item questionnaire that evaluates the severity and the frequency of common side affects in individuals taking stimulant medications. The side effects scale ranges from 0 (absent) to 9 10 (severe). Barratt Impulsiveness Scale (BIS-10) is a 34-item scale that covers three types of impulsiveness: motor, cognitive, and non-planning. It consists of a four-point scale ranging (“rarely/never”, “occasionally”, “often”, and “almost always/always”). These three factors are considered reliable under a study with an alpha coefficient range from 0. Beck Anxiety Inventory (BAI) quickly assesses the severity of patient anxiety. It was specifically designed to reduce the overlap between depression and anxiety scales by measuring anxiety symptoms shared minimally with those of depression. Both physiological and cognitive components of anxiety are addressed in the 21 items describing subjective, somatic, or panic- related symptoms. In the assessment, the respondent is asked to rate how much he or she has been bothered by each symptom over the past week on a 4-point scale ranging from 0 to 3, and takes about 5 to 10 minutes to complete. The scale obtained high internal consistency and item- 12, 13 total correlations ranging from 0. Brown ADD scale is a 40-item self report scale for assessing the executive function aspects associated with ADHD. The scale has been proved with good internal consistency and good test- Attention deficit hyperactivity disorder 165 of 200 Final Update 4 Report Drug Effectiveness Review Project retest reliability. Child Behavior Checklist (CBCL) originally had three axes, the parent report form, teacher report 15 form, and self-report form for children over 11 years of age. But it had been added to have two more axes, which are cognitive assessment and physical assessment from observations and 16 interviews. It was demonstrated to have high reliability and validity through various studies. Child Autism Rating Scale or Childhood Autism Rating Scale (CARS) is a 15 item behavioral rating scale developed to identify children ages 2 years and older with autism, and to distinguish them from developmentally handicapped children without the autism syndrome. It provides quantifiable ratings based on direct behavior observation. The CARS is especially effective in discriminating between autistic children and those children who are considered trainable mentally retarded; it distinguishes children with autism in the mild to moderate range from children with autism in the moderate to severe range. It can also be used to evaluate adolescents or adults who have never received a diagnosis of autism. The CARS includes items drawn from five of the most widely used systems for diagnosing autism. Each item covers a distinct 17 characteristic, ability, or behavior. CDRS-R total scores range from 17 to 113 and Fourteen of the 17 items are rated on a scale from 1 to 7, with an item score of 3 suggestive of mild, 4 or 5 moderate, and 6 or 7 severe symptoms. Both children and their parents provide input into the first 14 items of the scale. A CDRS-R ≥ 40 suggests the presence of 18 depressive disorder. CDRS-R was administered to determine the convergent validity of BDI. Children’s Global Assessment Scale (CGAS) is an adaptation of the Global Assessment Scale (GAS). This scale is designed to measure the lowest level of functioning during a specific time period for children aged 4 to 16. Children are rated on a scale of 1 (needs constant supervision) to 100 (superior functioning) with anchor points in between. The CGAS has demonstrated discriminate validity (P=0. The CGAS has also demonstrated concurrent validity with the Conners’ ten-item Abbreviated Parent Checklist; the correlation was –0. Child Health and Illness Profile – Child Edition (CHIP-CE) is a self-report health status instrument for children 6 to 11 years old that is designed to assess the health and well-being of children. It includes 5 domains: Satisfaction (with self and health), Comfort (emotional and physical symptoms and limitations), Resilience (positive activities that promote health), Risk Avoidance (risky behaviors that influence future health), and Achievement (of social expectations in school and with peers). Validity is supported through criterion and construct validity tests and structural analyses.

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The Kyushu Lipid No (randomization Not reported; No; pravastatin group tended Yes No-study became No-open-label Intervention Study failed) sealed envelopes to have patients with more open-label Group were sent to severe disease order top avana 80mg amex. Koh K buy top avana 80 mg amex, 2005 Method not reported Not reported Cross-over population Yes Study states "double- Study states "double- blinded" but no details blinded" but no details given given McKenney J purchase top avana 80mg on line, 2007 Method not reported Not reported Yes Yes No-open-label No-open-label (COMPELL) Calza L, 2003 Yes, computer- Not reported Unable to determine but Yes No-open-label No-open-label generated list authors report that they were comparable (data not shown) Mohiuddin S, 2009 Method not reported Not reported Yes Yes Study states "double- Study states "double- blinded" but no details blinded" but no details Randomization ratio given given. Internal validity of controlled clinical trials Patient Different or overall high Study or Author unaware of Intention-to-treat Maintained Reported attrition, crossovers, loss to follow- Year treatment? The Kyushu Lipid Unclear No (patients with TC>300 Unlikely Unclear Unable to determine Intervention Study mg/dL were excluded as NR Group well as those who were Yes contaminated). Yes Koh K, 2005 Study states "double- Not reported Cross-over population Yes No blinded" but no details NR No given NR NR McKenney J, 2007 No-open-label Efficacy- No (92. Internal validity of controlled clinical trials Study or Author Score Year (good/ fair/ poor) The Kyushu Lipid Poor Intervention Study Group Koh K, 2005 Fair McKenney J, 2007 Fair-Poor (COMPELL) Calza L, 2003 Poor to fair Mohiuddin S, 2009 Fair Moura L, 2007 Statins Page 340 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 6. Internal validity of controlled clinical trials Study or Author Randomization Allocation Eligibility criteria Outcome assessors Care provider Year adequate? Shah H, 2007 Method not reported Not reported Differing proportions of Yes No-open-label No-open-label patients with 1-3 vessels involved (PCTA/ACS) More diabetics in Simva/fenofibrate group (48%) than other groups (24- 36%) More HTNsive in Simva group (52%) than other groups (28-40%) Verri V, 2004 Randomization stated, NR Yes Yes "Double-blind" stated "Double-blind" stated but methods NR Mallon P, 2006 Yes, study statistician Likely, central Yes Yes Study states "double- Study states "double- prepared pharmacy (not blinded" but no details blinded" but no details randomization involved in direct given given schedule and central care) were used pharmacy executed the randomization. Statins Page 341 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 6. Internal validity of controlled clinical trials Patient Different or overall high Study or Author unaware of Intention-to-treat Maintained Reported attrition, crossovers, loss to follow- Year treatment? Internal validity of controlled clinical trials Study or Author Score Year (good/ fair/ poor) Shah H, 2007 Poor Verri V, 2004 Fair-Poor Mallon P, 2006 Fair-Poor Statins Page 343 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Author, year Setting Study design Duration Eligibility criteria Bonnet F, et al 2007 Not reported Randomized, placebo-controlled, 3 months Adults with positive anti-HIV antibodies; had double-blind trial been receiving stable antiretroviral therapy including at least one PI for ≥3 months; had a plasma HIV RNA level of <50 copies/mL for ≥3 months before randomization; a TC ≥5. Calza L, et al 2008 Single-center, university Open-label, randomized, 12 months Adults on stable PI-based antiretroviral hospital; outpatient prospective, single-center therapy since at least 12 months, with HIV setting viral load <50 copies/mL for at least 6 months and presenting hypercholesterolemia ± hypertriglyceridemia and lipodystrophy of at least 3 months and unresponsive to diet/exercise Statins Page 344 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Bonnet F, et al 2007 Had current AIDS event or infectious disease; Pravastatin 40 mg QHS 31 1 tumoral, inflammatory, or muscle diseases; Placebo 21 1 kidney or hepatic failure; psychiatric conditions; 20 20 biological elevated muscular enzymes; chronic alcohol consumption; or if pregnant or displayed no evidence of use of effective contraception. Statins Page 345 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Bonnet F, et al 2007 42 yrs All patients using at least 1 protease inhibitor Specific adverse events were graded in severity 1-4 78-92% Male HIV stage C: 67-71% and lab measurements were taken. NR CD4 count: 465-484 cells/mm3 IVDU: 58-37% Baseline lipids (median) TC 239 mg/dL LDL 154 mg/dL HDL 39 mg/dL Calza L, et al 2008 37 yrs AIDS: 3% Specifics on how adverse events were assessed were 56-74% Males Mean CD4 count: 383 cells/mm3 not reported, however, authors did report that adverse NR All patients were using PI, ~88% were using events were carefully checked on monthly outpatient regimens that included ritonavir visits in addition to lab measurements. Baseline lipid panel (mean) TC 282 mg/dL TG 274 mg/dL LDL 177 mg/dL HDL 51 mg/dL Statins Page 346 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Author, year Adverse events reported Comments Funding source Bonnet F, et al 2007 There were a total of 12 adverse events Center Hospital of Prava: 7 Bordeaux; Roche labs Placebo: 5 Grade 2 myalgias: Prava, 3 (1 patient had a 2x increase of CPK); Placebo, 1 Digestive symptoms: Prava, 4; Placebo, 3 Depressive symptoms: Prava, 1; Placebo, 0 Headache: Prava, 1; Placebo, 0 2-fold increase in CPK at week 4: Prava, 2; Placebo, 1 (CPK levels were normal at week 8) Others: Prava, 3; Placebo, 1 1 patient in the Prava group prematurely discontinued the study because of seizure and hospitalization not related to study treatment and another patient in the Prava group temporarily stopped treatment because of diarrhea between week 4-12. There was no significant change of AST, ALT, Bili, glucose, CPK, and myoglobin in both groups. Calza L, et al 2008 No reports of myalgia or myositis across all groups Not reported No significant increases in CPK (>250) or ALT (>200) across all groups For Rosuva, Prava, Atorva Nausea: 7. Studies on harms Author, year Setting Study design Duration Eligibility criteria Franceschini G, 2007 University hospital in Italy Randomized, double-blind trial, 8 weeks Italian and French patients with low HDL-C parallel (<40 mg/dl) and moderate elevations of both LDL-C (<160 mg/dl) and triglycerides (150–500 mg/dl) Mallon P, et al 2006 Single-center, university Randomized, placebo-controlled, 3 months HIV-infected men on stable PI therapy (min 12 hospital (Sydney, double-blind trial weeks before screening and minimal changes Australia); outpatient to ART regimen during the study) setting Statins Page 348 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Franceschini G, 2007 NR Fenofibrate 160 mg/day NR/NR/52 NR/NR/52 Simvastatin 40 mg/day Mallon P, et al 2006 HTN, congestive cardiac failure, malabsorption or Pravastatin 40 mg QHS 34 2 other serious illness, active AIDS illness, serum Placebo 33 0 lactate >2. Statins Page 349 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Franceschini G, 2007 Mean age Fenofibrate vs Simvastatin Laboratory tests and self report Fenofibrate: 56 years; Height (cm): 171. Studies on harms Author, year Adverse events reported Comments Funding source Franceschini G, 2007 NR Fournier Pharma Spa Mallon P, et al 2006 There were no significant changes in Scr, Bili, ALT, AST in either treatment group. Partial funding provided Safety data were not shown in the publication. Studies on harms Author, year Setting Study design Duration Eligibility criteria Milazzol L, et al 2007 Outpatient setting Retrospective chart review Not reported Adults with HIV/HCV co-infection using statins (exploratory) at least 6 months after diagnosis of hepatitis C special group-co- and patients who were HIV-positive but infection group HCV/Hep B negative using statins Rahman A, 2008 Single-center, VA North Retrospective chart review Minimum 6 Adults with HIV infection who received Texas Health Care months efavirenz-based HAART and simvastatin 20 System mg/day. Patients had to be receiving stable HAART regimen (no changes to NRTI backbone or any other concurrent antiretroviral) for a minimum of 4 weeks before and after starting simvastatin. Lipid profiles w/in a 6 month period before simvastatin were required. Adults without HIV infection who received 20 mg/day were randomly selected as controls. These patients had to have been simvastatin naive for 6 months before starting treatment. Statins Page 352 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Milazzol L, et al 2007 Alcohol abuse; concomitant hepatotoxic Statins in HCV+ versus Statins in NR NA (exploratory) medications other than antiretrovirals and HCV/Hep B-negative patients NR NA special group-co- patients on anti-HCV treatment 80 80 infection group Most frequently prescribed statins: Atorvastatin 64% Pravastatin 29% Rosuvastatin 5% Simvastatin 2. NR NA agents while receiving simvastatin; had simvastatin 20 mg/day 32 32 significant changes in DM control; new diagnosis of thyroid disorder; uncontrolled thyroid disorder; had additions or dosage modifications of progestins, glucosteroids, isotretinoin, estrogens, azole antifungals, anabolic steroids, sevelamer, red yeast rice, and TZDs; any evidence of significant changes in dietary/exercise patterns. Statins Page 353 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Age Gender Other population characteristics Author, year Ethnicity (diagnosis, etc) How adverse events assessed Milazzol L, et al 2007 45. Studies on harms Author, year Adverse events reported Comments Funding source Milazzol L, et al 2007 There was no significant difference in the fold change of LFTs in both groups. There were statistically significant differences Not reported (exploratory) between treatment groups in baseline age, sex, special group-co- There was no significant difference in the percentage of patients with increased AST, and LFTs. Patients with HIV/HCV were younger infection group ALT, or GGT ≥1. The higher increase in GGT was in age and a larger proportion were male. None of the patients discontinued statins because of liver toxicity or modified theory antiretroviral regimens because of drug interactions. There was no significant difference between groups and no correlation with cholesterol reduction. Rahman A, 2008 No adverse events including myopathy were documented and no changes were Not reported noted in CK, AST, or ALT levels Statins Page 355 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Author, year Setting Study design Duration Eligibility criteria Verri V, 2004 2 centers, Brazilian Prospective, randomized, double- 6 months Adults with coronary artery disease, serum National Institute of blind, placebo-controlled total cholesterol levels of >200 mg/dl and/or Cardiology and LDL-C of >100 mg/dl, taking cardiovascular the Antonio Pedro medication and with more than 2 risk factors University Hospital for MI. Statins Page 356 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7. Studies on harms Number screened Total withdrawals Eligible Withdrawals due to AE Author, year Exclusion criteria Interventions Enrolled Number analyzed Verri V, 2004 Patients who presented any of the following Simvastatin + AHA Step 1 diet, 844 charts reviewed 2 deaths; 1 from non-cardiac cause factors: 1) history of MI in the previous 3 months; begun at 10mg/day, increased to 28 and 1 from sudden death 2) symptoms of unstable angina or heart failure; a max of 20mg/day 25 3) EKG alterations that would hinder analysis of Placebo + AHA Step 1 diet changes in the tracing; 4) patients taking lipid- lowering medication; and 5) those with chronic debilitating diseases, such as cancer, renal or liver failure, or hypo- or hyperthyroidism. Statins Page 357 of 395 Final Report Update 5 Drug Effectiveness Review Project Evidence Table 7.

Domain V also contains a positively charged specific aAbs responsible for LAC activity are anti- 2GPI and lysine-rich region generic 80 mg top avana overnight delivery, in close proximity to a hydrophobic loop region buy 80mg top avana free shipping, anti-PT top avana 80 mg low cost. The 2GPI molecule, screening assay be performed, with silica as the activator, and low when in the closed circular conformation, hides a cryptic epitope on phospholipid content to increase the sensitivity of the assay. In contrast, Ellagic acid as an activator is not advised due to its insensitivity for when 2GPI is immobilized on a negatively charged phospholipid LAC. SCT has the above a certain antigen density threshold, emphasizing the critical 322 American Society of Hematology APS patients who are negative on the anti- 2GPI and aCL ELISAs. Shown is the autoantibody (Y) binding negatively charged ( ) (or one fetal death after 10 weeks gestation) and negative for aPL phospholipid. Shown is the Abs and 279 women carrying a genetic thrombophilia polymor- phism. Being LAC cant interlaboratory variability with the performance of the anti- positive was the main predictor for unprovoked proximal or distal 2GPI ELISA may reside in the inconsistent exposure of residues 40 DVT and superficial vein thrombosis. The pretest probability of the diagno- other placenta-mediated complications. A significant increased percentage (obstetric and/or thrombotic) and/or systemic lupus erythematosus of LAC or anti- 2GPI ELISA positivity in premenopausal women at the time of entry into the study and healthy controls. Patients with a history of individuals have higher titers of anti- 2GPI aAbs compared with thrombosis or pregnancy complications consistent with APS were individuals who are only positive on the anti- GPI and/or aCL excluded from the study. There was no control arm in this LAC positive have anti- 2GPI aAbs that specifically bind to the 19, prospective study. Summary of commonalities and contrasts between recent ISTH, BCSH, and CLSI guidelines for LAC detection Area of recommendation ISTH 2009 BCSH 2012 CLSI 2014 Sample preparation Double centrifugation Double centrifugation Double centrifugation Assays to use dRVVT and aPTT dRVVT and aPTT and/or others dRVVT and aPTT and/or others Testing order Screen-mix-confirm Screen-mix-confirm Screen-confirm-mix Ratio derivation NPP denominator NPP denominator RI mean denominator RI/cutoffs 99th percentile 97. CLSI that discuss preanalytical, analytical, and postanalytical vari- (2014) recommends deriving the reference interval using the ables. Likewise, guidelines for laboratories to follow have been published ing validating cutoffs that have been previously established either by for the performance of the APS ELISAs that are part of the the reagent manufacturer or from a different analyzer using just 20-60 24,45 healthy donors regardless of whether the 97. The corollary of this is that anionic phospholipid expressed on the platelet surface. It is using the 99th percentile may lead to more false negatives and a failure recommended that plasma be rendered platelet poor via a process of to detect clinically meaningful LAC-positive patients. Previously, filtration of the plasma The sequence of tests performed by laboratories to determine LAC sample through 0. This procedure may cause loss of VWF and ing test, then the mixing studies, and, if the mixing studies consequently factor VIII, leading to artificial prolongation of demonstrate lack of correction, to then proceed to a confirmatory coagulation tests responsive to factor VIII, namely aPTT. Concerns have been raised at having the mixing reason, plasma filtration is no longer recommended. The reasoning is that mixing Testing for LAC during an acute illness is discouraged because studies may dilute out the in vitro effect of clinically relevant aPL factor VIII or C-reactive protein levels may be elevated; the former aAbs and thus may systematically bias results toward false-negative can mask the LAC-screening test, leading to a false-negative result, readings for LAC if a decision to proceed to the confirmatory test is and the latter may lead to a false-positive screening test result. It has been reasoned that, in the context that other types of coagulation disturbances have been excluded by Reference intervals and cutoffs undertaking routine coagulation screening, including PT time, The ISTH 2009 guidelines recommend that the cutoff for consider- thrombin time, and aPTT using a LAC-unresponsive aPTT reagent, ing a LAC screening assay to be positive be based on determining that testing positive at the screening and confirmatory test stages, locally the reference intervals specific to the reagent–analyzer even if the mixing studies are negative, is adequate to consider the pairings in use and using the 99th percentile. As discussed by Moore,15 this is a to screening, confirmatory testing, and then mixing studies. Summary of recommendations for aCL and anti- 2GPI testing Assay characteristic Recommendations Specimen requirements Serum: heat inactivation at 56°C for 30 minutes should be avoided. Use of nonhemolyzed, nonlipemic samples is recommended. Plasma: manufacturers must specify the specimen type, including the anticoagulant used. Use of plasma should take into consideration the dilution factor that may be produced because of the anticoagulant. Isotype of aCL and anti- 2GPI IgG and IgM isotypes are recommended for both aCL and anti- 2GPI. Anti- 2GPI: 2GPI of human origin should be used on a negatively charged (“high” binding or gamma-irradiated) plate. Quantitation of results The test signal is converted into antibody units derived from the calibration curve. Anti- 2GPI are expressed in arbitrary units; universal units of measurement are not available. Development/establishment of international/universal units of measurement is recommended. Standards Manufacturers and test users are strongly encouraged to select a reliable standard to prepare secondary calibrators (polyclonal or monoclonal). The proposed secondary calibrators should be compared and validated against the primary standard using published and accepted procedures. Selected groups of actual patient sera should be used if possible to further establish the extent of agreement in the assay/test system. Most importantly, the production and the quality control of the standards should be subjected to FDA Good Manufacturing Practices guidelines or an equivalent quality assurance program. A record of traceability from the recommended standards to any secondary calibrators is required. Calibration curves Multipoint calibration and use of statistically correct fitting and calculation methods are required. The calibration curve should be rejected if the correlation coefficient between assay readings and expected values of the calibrators is 0. Precision CV of manually performed ELISAs should be 20%, preferably 15%. Positive/negative controls Incorporation of at least 1 “external” positive control in every run to monitor interassay variation is recommended. Similarly, a “negative” control with values below the cutoff of the assay should be used in each run. A run should be rejected if the result with either the positive or the negative control falls out of the established range. Singlet/duplicate It is recommended to do duplicate testing, especially when inter-run and intra-run imprecision determined for a quality measurements control sample is 10%. If this is not feasible, manufacturers’cutoffs may be acceptable if local measurements on 20 or more healthy subjects yields similar results. Reporting of results Given the variability in assay methods, semiquantitative reporting is difficult to define. Each test result above the 99th percentile cutoff should be regarded as positive and reported quantitatively. Imprecision of the method should be considered, especially for results around the cutoff. Manufacturers should disclose information based on evidence derived from clinical studies that may assist with the interpretation of results. As a point of contrast, CLSI (2014) advises arise either when there is an undiagnosed coagulopathy or if the aPL to normalize against the reference interval mean clotting time rather aAbs are sufficiently potent to fully prevent the reagent and excess than the NPP value. Mixing the patient’s plasma at a 1:1 ratio with type, which can systematically bias readings toward false-positive normal pooled plasma (NPP) and then undertaking the screen and or false-negative results if an NPP value is at the extreme of the confirmatory tests may allow the detection of LAC by diluting the reference interval. NPP The index of circulating anticoagulant is one option for assessing samples can be used as normal controls to identify sudden analytical mixing study results; the other is to determine a mixing-study-specific difficulties. The concept is to use the framework of the Reporting screening test but, in addition, to add a higher concentration of It is encouraged by the various guidelines that a definitive summary phospholipid, which can take the form of either bilayer or hexagonal statement be given when reporting the results of the LAC assay (II) phase phospholipid.

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In other words cheap 80mg top avana amex, one must consider what needs to be done in relation to The mosaic of these data reveals a spectrum of HIV disease discount top avana 80mg amex. On one the HIV disease and then decide whether that has any impact on end of the spectrum are those who are quite healthy in terms of HIV cancer management purchase top avana 80 mg on-line. To address these issues, HIV infection should and would be expected to live a normal life span were it not for the cancer. There is a spectrum of comorbid disease that modulates therapeutic decision making in any patients who are highly likely to succumb to the HIV disease even if given case and one assesses whether the impact is nearly negligible the current tumor had never developed. The lowest risk is between 350 and 500 CD4 cells/mm3 and does not change appreciably as the CD4 cells increase beyond that level. The risk increases substantially below 200 CD4 cells/mm3. Preserving CD4 cells with cART thus decreases the incidence of lymphoma and shifts toward the favorable subtypes to the left in the diagram. AIDS complications risk can also be ameliorated with cART. Note that within CD4 cell strata, the ARL incidence has not changed comparing the cART and pre-cART eras. Adapted with permission from Besson et al,1 Little et al,2 and Dunleavy et al. Figure 1 provides a graphic representation of this recommend during polychemotherapy for hematologic cancer). Our concerns about adherence to cART during chemotherapy have In general, patients with CD4 counts 200 cells/mm3 are at low not been borne out. However, be based on experience from the HIV-unrelated population. Those if cART is administered with chemotherapy, we strongly recom- with lower CD4 cells (100-200 CD4 cells/mm3) also do well with mend meticulous attention to toxicity. If early-cycle dose reductions standard therapy but may require more supportive care. In patients are needed, one should consider the possibility of drug-drug with 50 CD4 cells/mm3, there is without question a higher risk interactions as the cause of enhanced toxicity and suspend cART. However, this high-risk group is not therapy dose reductions rather than removing the pharmacokinetic homogenous, and prior HIV treatment status modifies the risk offender may adversely affect cancer cure. Consultation with experts in HIV infec- tive cART suspension may be best. For example, the very real risk tion management may be key to understanding the prospects for of drug-induced pancreatitis from asparaginase is likely to be successful long-term HIV management, and this can be invaluable compounded by effects of many antiretroviral drugs that are also toward planning best cancer therapy. A first reflex may be to assign the advanced CD4 -depleted group to DLBCL and BL the end-stage AIDS end of the spectrum. Before cART, this would In the cART era, the outcome for patients with aggressive lympho- have been correct. However, those who are treatment naive are very mas who receive optimal therapy is equivalent to that of the different from those who have a long history of complicated AIDS background population, and this should be kept in mind when and highly treatment-resistant HIV. Increasingly, patients with selecting up-front treatment. In the pre-cART era, in an attempt to advanced CD4 cell depletion are treatment naive. The AIDS reduce toxicity, approaches such as the use of CHOP (cyclophospha- epidemic is shifting demographically to communities with disadvan- mide, hydroxydaunorubicin, vincristine, prednisone/prednisolone)– taged medical access or high HIV stigma that creates a barrier to like regimens for BL were widely practiced and resulted in dismal HIV testing and care. Estimates suggest that up to 25% of people in outcomes. Such approaches are now recognized as inadequate and 10 should not be practiced. It is critical that these patients are these communities have unknown HIV infection. For patients with approached in the same way as those with HIV-unrelated lymphoma newly diagnosed advanced HIV disease, long-term cancer-free and treated with curative intent. In addition, nearly 40 whether the patient has previously known or newly diagnosed HIV anti-HIV drugs or combinations are Food and Drug Administration infection, just as it would with any other patient. This evaluation (FDA) approved, making HIV salvage therapy more feasible. If a should include assessment of the HIV disease parameters including decision is made to recommend palliative-only cancer care, in most CD4 cell count and HIV viral load. In addition to routine tests cases, it should be based on the cancer outcome prospects rather (including assessment of hepatitis B and C coinfection), thorough than on HIV. Having observed relatively high rates of isolated CNS progression and Another important concern specific to patients with HIV is what to relapse in our HIV-infected patients, more than a decade ago, we do about cART during chemotherapy. Our strategy is to suspend implemented CNS prophylaxis for all patients with aggressive cART before BL and DLBCL chemotherapy and resume after all B-cell lymphomas. It is important not to use a repeated stop-and-start strategy because this promotes HIV drug resistance. The preferred regimen in our judgment for HIV-DLBCL is Our strategy avoids overlapping toxicity, pharmacokinetic interac- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, tions, and possible adherence problems associated with chemo- doxorubicin, rituximab) infusional chemotherapy, as described therapy-related toxicity that could promote HIV drug resistance. However, there are single-institution and would lead to the loss of 50 CD4 cells/mm3 during the time it multicenter phase 2 data, as well as analyses combining trial data takes to complete treatment. Interest in performing the chemotherapy does not appear to protect against CD4 cell depletion. Extrapolation of complete remission was achieved in 74% of patients and, at 53 these data to cancer patients is problematic on at least 2 counts: months median follow-up, disease-free and overall survival were (1) cancer patients were not eligible for the SMART study and (2) it 92% and 60%, respectively. Subsequently, 33 384 American Society of Hematology Second, HIV-associated DLBCL is frequently characterized by high tumor proliferation, a feature that appears to confer resistance to CHOP but not to EPOCH. This holds for studies in which cases were restricted to favorable-risk ARL and yet 31% died of lymphoma with R-CHOP,16 unlike the case with EPOCH-R, in which the progression-free survival exceeds 80% (Figure 2A). In addition, the risk profiles of combining chemotherapy with rituximab in HIV strongly favors the EPOCH regimen, for which excess toxicity has not been reported. At a non-germinal center B-cell-like DLBCL patients treated with short- median follow-up of 73 months, the progression-free and overall course (SC)-EPOCH-RR. Only 16% of the cycles administered were associated with fever and neutropenia. This compelling data was reviewed by the NCI Lymphoma Steering subjects treated with the short-course EPOCH-RR (etoposide, Committee, which recommended funding a national multicenter, prednisone, vincristine, cyclophosphamide, doxorubicin - double single-arm phase 2 study aimed at providing a strong level of dose rituximab) regimen had a progression-free and overall survival 3 evidence for this approach. The study is now being conducted and is of 84% and 68%, respectively, at 5 years median follow-up Tumor available to all AMC, Southwest Oncology Group (SWOG), histogenesis was the only characteristic associated with lymphoma- specific outcome. The progression-free survival at 5 years was 95% Alliance for Clinical Trials in Oncology, and Eastern Cooperative Oncology Group (ECOG) members to enroll BL and cMYC for those with germinal center B-cell-like DLBCL and 44% for non-germinal center B-cell-like DLBCL (Figure 2). Until the outcome of this analysis of 150 patients treated on AIDS Malignancy Consortium study is known, it is highly recommended to refer patients for (AMC) studies of either R-CHOP or EPOCH-R shows the hazard participation in the study.

Here purchase 80mg top avana visa, binding means with sufficient affinity to stimulate a CTL response effective 80 mg top avana. The specificity of MHC binding influences which parasite epitopes dominate an immune response order top avana 80 mg with mastercard. Current understanding of MHC bind- ing is rather crude. Prediction of which parasite sequences would bind strongly to MHC molecules might helpinvaccine design and in under- standing the different patterns in immune response between different individuals. Given this widespread interest, the field is moving rapidly. Many of the MHC molecules have been characterized by a specific binding motif—the amino acid sequence pattern to which they typically bind (Marsh et al. Buus (1999) reviews the different methods to estimate binding motif and alternative techniques for prediction of binding. Details vary for the different alleles, but often an MHC class I molecule has two anchor posi- tions near the ends of the peptide among the 9 or so amino acids of the peptide. Each anchor position has a favored amino acid or sometimes alimited set of alternatives. However, prediction based on anchor posi- tions is only moderately successful;about30% of peptides carrying the predicted motif actually bind, and sequences lacking anchor residues can bind. More complex statistical approaches have improved predic- tion above 70%. Class II molecules also bind a region of about 10 amino acids. How- ever, by contrast to class I molecules, the class II molecules have open- ended binding grooves, allowing class II molecules to bind peptides of varying lengths in which differing numbers of amino acids hang out of each end of the groove (Marsh et al. These varying peptide lengths have made it difficult to establish binding motifs; thus relatively less is known about class II binding. Class II molecules appear to be less specific (more degenerate) in their binding compared with class I molecules (Marsh et al. A few detailed studies of class II binding have been developed (e. It may be that class II’s relatively less specific binding has to do with its role in stimulating helper T cells that regulate the immune response rather than in directly killing parasites, but there is little evidence for this at present. The class I and class II molecules bind only to peptides. Recent work has shown that the CD1 MHC system presents lipids and glycolipids to T cells, providing an opportunity for T cell response to nonprotein antigens (Porcelli and Modlin 1999; Prigozy et al. No doubt this system plays some role in immunity, but its relative importance is not clear at present. SPECIFICITY AND CROSS-REACTIVITY 49 T CELL RECEPTOR BINDING TO PEPTIDE-MHC COMPLEXES The immune system can generate highly specific memory responses against particular antigens. For example, first infection by a measles virus typically leads to symptomatic infection and eventual clearance. Second infection rapidly induces specific antibody and T cell responses based on a pool of memory cells from prior infection. This type of ob- served memory response naturally led to the belief that TCR recognition is highly specific for particular epitopes. However, recent work demon- strated that the TCR binds in a highlydegenerate way, each TCR binding on the order of 104–107 different epitopes (Mason 1999). In addition, limited data suggest that asinglepeptidestimulates several different T cell clones (Maryanski et al. However, different stud- ies and different methods have given variable estimates for the number of clones stimulated by a single peptide (Yewdell and Bennink 1999). How can the TCR binding be so degenerate, yet the immune response be so specific? Most of the details are not understood at present, but some reasonable hypotheses are beginning to take shape. The TCR on CTLs (CD8+ Tcells)bindstopeptide-MHC class I complexes presented on the surface of most cell types. TheTCRonthehelper (CD4+)Tcellsbindsto peptide-MHC class II complexes presented on the surface of specialized antigen-presenting cells. Bindingandsignalstrengthare quantitative factors, butagainIusebinding qualitatively to mean sufficient signal strength to stimulate a T cell response against an epitope. Now consider some magnitudes with regard to the problem of rec- ognition (Mason 1999). Define T as the number of T cell clones with different TCRs in the naive T cell repertoire, T(p) as the number of T cell clones that respond to the same peptide, N as the number of pos- sible peptides to be recognized, and P(t) as the number of different peptide-MHC complexes recognized by a particular TCR. Immune response probably depends more on the frequencies of T cell clones that respond to particular peptides, F(p) = T(p)/T,ratherthan total numbers of clones in the body, so it is also 50 CHAPTER 4 useful to write F(p)= P(t)/N, (4. If we assume that, in the naive T cell repertoire, each clone with a unique TCR has about the same number of cells, then F(p) is also the frequency of individual Tcells that respond to a particu- lar peptide. The number of possible specificities, N,forpeptides with n amino acids, is 20n×S,whereS is the fraction of peptides that can be presented by MHC alleles. Considering nonamers with n = 9, and setting S ≈ 10−2 as discussed above for MHC binding, we have N ≈ 209 × 10−2 = 5 × 109. The lower bound for F(p),thefrequency of T cell clones that respond to a peptide, occurs when every T cell is unique and each peptide stim- ulates only a single T cell. Mice have about 108 Tcells, so the minimum value of F(p) is 10−8,andthus, from equation (4. This is cer- tainly a gross underestimate, because each TCR clone has more than one cell on average, and each peptide likely stimulates more than one clone. Nonetheless, this extreme case shows that the magnitude of the recognition problem demands some degeneracy in TCR binding in mice. Mason (1999) suggests that a more realistic description follows if one accepts the experimental estimate by Butz and Bevan (1998) that, in the naive repertoire, three different viral epitopes each stimulated a fre- quency F(p) ≈ 10−4 of mouse CTL cells. In a mouse with 107–108 naive CTLs, this gives an estimate of 103–104 CTLs potentially responding to each epitope. The estimated frequency F(p) ≈ 10−4 based on Butz and Bevan (1998) refers to the frequency of individual T cells responding to a peptide. It was not clear from that study how many different T cell clones were involved. It is challenging to estimate the number of different clones SPECIFICITY AND CROSS-REACTIVITY 51 from the naive repertoire that respondtoaparticular peptide, although recent technical breakthroughs may soon provide more data (Yewdell and Bennink 1999). Among the better studies available, Maryanski et al. The response in this case may have been limited because the human MHC molecule is similar to mouse MHC molecules, causing the tested peptide to be seen as similar to a self-peptide of the mouse. In another study by the same research group, the clonal diversity of CTLs responding to a Plasmodium berghei peptide was much higher than against HLA-CW3, but the methods did not permit a comparable estimate for the number of clones (Jaulin et al. Humans have about 1011 Tcells compared with about 108 Tcells in mice.

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