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Quality assessments of randomized controlled trials of beta blockers for hypertension Loss to Author Maintenance of Reporting of attrition discount cialis super active 20 mg with amex, follow-up: Year Intention-to-treat (ITT) comparable crossovers, adherence, differential Country analysis groups and contamination /high Score Funding Head-to-head controlled trials Walle No Unclear Yes No Fair NR 1994 13 (21. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Control group Length of Country standard of care follow-up Head-to-head controlled trials Walle Yes 6 weeks 1994 Sundar Yes 4 weeks 1991 Steiner Yes 4 weeks 1990 Beta blockers Page 34 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Allocation Similarity to target Country Randomization described concealed Groups similar at baseline population Number recruited Head-to-head controlled trials Dahlof NR NR n/a-crossover Mean age=54. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Head-to-head controlled trials Dahlof 1. The patient had not followed the instructions to fill in and Yes Yes Yes Yes 1988 return the questionnaire on 3 occasions during the run-in period 2. Any serious concomitant illness or drug abuse which can interfere with the treatment 10. Unwillingness to participate in the study Blumenthal NR Yes Yes Yes Yes 1988 Buhler Patients were on other antihypertensive drugs, had Yes Yes Yes Yes 1986 contraindications for beta-blocker therapy, severe disease, or who were known for their poor compliance. Beta blockers Page 36 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Loss to Author Maintenance of Reporting of attrition, follow-up: Year Intention-to-treat (ITT) comparable crossovers, adherence, differential Country analysis groups and contamination /high Score Funding Head-to-head controlled trials Dahlof No; excluded 3 patients n/a - crossover Yes No Fair NR 1988 (3. No MacArthur No Foundation, National Institutes of Health greants HL30675, HS31514, and AG04238, and a grant (RO7233) from the US Public Health Services Buhler No Yes No Fair NR 1986 30 (22. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Control group Length of Country standard of care follow-up Head-to-head controlled trials Dahlof Yes 6 weeks 1988 Blumenthal Yes 2 weeks 1988 Buhler Yes 8 weeks 1986 Beta blockers Page 38 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Allocation Similarity to target Country Randomization described concealed Groups similar at baseline population Number recruited Placebo-controlled trials Oberman 1990 NR NR NR Mean age=49 878 randomized Wassertheil-Smoller 1991 56% male 697 analyzed Wassertheil-Smoller 1992 United States Trial of Antihypertensive Interventions and Management (TAIM) Perez-Stable 2000 Adequate: computer- NR No; statistically significant Fair 312 generated list of random differences between the two Mean age=45. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Placebo-controlled trials Oberman 1990 History of myocardial infarction, stroke, or asthma, or a serum Yes NR Yes Yes Wassertheil-Smoller 1991 creatinine level of 177 mmol/d or greater, insulin-dependent Wassertheil-Smoller 1992 diabetes, allergy to thiazides or beta-blockers, pregnancy, or United States likelihood of difficulty in complying with the interventions Trial of Antihypertensive Interventions and Management (TAIM) Perez-Stable 2000 Concomitant use of insulin, bronchodilators, antidepressants Yes NR Yes Yes or antihypertensive medications within 1 month of screening; coronary artery disease, vascular heart disease, renal insufficiency, cerebrovascular disease, and secondary causes of hypertension Anonymous 1977 Secondary hypertension; already on antihypertensive Yes Yes; assessed Yes Yes Greenberg 1984 treatment; cardiac failure; MI or stroke within previous 3 by an Anonymous 1985 months, angina; intermittent claudication; diabetes; gout; arbitrator Miall 1987 asthma; other serious disease; pregnancy ignorant of the Anonymous 1988a treatment Anonymous 1988b regimen Anonymous 1992 Lever 1993 Medical Research Council (MRC) UK Beta blockers Page 40 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Loss to Author Maintenance of Reporting of attrition, follow-up: Year Intention-to-treat (ITT) comparable crossovers, adherence, differential Country analysis groups and contamination /high Score Funding Placebo-controlled trials Oberman 1990 No NR Attrition: 181(20. H Robins; National Wassertheil-Smoller 1992 taking > 80% of the pills): Heart, Lung and United States 92%; others NR Blood Institute Trial of Antihypertensive Interventions and Management (TAIM) Perez-Stable 2000 No NR 45% attrition; others NR NR Fair Public Health Services Grants Anonymous 1977 Yes NR Attrition due to primary and NR Fair Duncan, Flockhart Greenberg 1984 adverse events reported; and Co Ltd; Imperial Anonymous 1985 others NR Chemical Industries Miall 1987 Ltd; CIBA Anonymous 1988a Laboratories; Merck Anonymous 1988b Sharp and Dohme Ltd Anonymous 1992 Lever 1993 Medical Research Council (MRC) UK Beta blockers Page 41 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Control group Length of Country standard of care follow-up Placebo-controlled trials Oberman 1990 Yes 6 months Wassertheil-Smoller 1991 Wassertheil-Smoller 1992 United States Trial of Antihypertensive Interventions and Management (TAIM) Perez-Stable 2000 Yes 12 months Anonymous 1977 Yes 5 years Greenberg 1984 Anonymous 1985 Miall 1987 Anonymous 1988a Anonymous 1988b Anonymous 1992 Lever 1993 Medical Research Council (MRC) UK Beta blockers Page 42 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Allocation Similarity to target Country Randomization described concealed Groups similar at baseline population Number recruited Head-to-head trials Brixius computer generated NR Yes mean age: group A 48. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Head-to-head trials Brixius Yes Yes NR NR NR (stated 2007 (stated double- (stated double-blind, blind, no double- no details details given) blind, no given) details given) Yilmaz Yes Yes No No No 2008 Turkey Beta blockers Page 44 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Loss to Author Maintenance of Reporting of attrition, follow-up: Year Intention-to-treat (ITT) comparable crossovers, adherence, differential Country analysis groups and contamination /high Score Funding Head-to-head trials Brixius Yes Yes No NR fair NR 2007 No Yes No Yilmaz No, 3 patients were Yes Yes No Fair Ulagay-Menarini 2008 excluded from analysis No Group, Istanbul, Turkey Yes Turkey No Menarini International, Florence Italy Beta blockers Page 45 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 2. Quality assessments of randomized controlled trials of beta blockers for hypertension Author Year Control group Length of Country standard of care follow-up Head-to-head trials Brixius yes 28 weeks 2007 Yilmaz Yes 6 weeks 2008 Turkey Beta blockers Page 46 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 3. Randomized controlled trials of beta blockers for angina Author Year Country Interventions (drug, regimen, Study Design Eligibility criteria Exclusion criteria duration) Head-to-head trials Chieffo Patients with comorbid essential hypertension Severe bradycardia (< 50 beats per minute); congestive Labetalol 200 mg + chlorthalidone 1986 (WHO Classes I-II) and stable angina pectoris heart failure; myocardial infarction less than three 20 mg (lab+chl) daily (n=5) Italy months before the start of the trial; asthma and renal Atenolol 100 mg + chlorthalidone insufficiency 25 mg (ate+chl) (n=5) x 8 weeks Fair quality RCT Dorow Outpatients aged between 41 and 67 years, Unstable angina or angina at rest; myocardial infarction Atenolol (ate) 50 mg daily 1990 suffering from angina pectoris due to coronary within the last 6 months; heart failure with or without Bisoprolol (bis) 5 mg daily x 6 artery disease and concomitant reversible, digitalis treatment; arterial hypertension with supine months Fair quality chronic obstructive bronchitis; three angina diastolic blood pressure values under a thiazide diuretic RCT Crossover attacks per week over the last three months (with of >/= 105 mm Hg; cardiac arrhythmias requiring or without therapy) treatment; bronchial asthma; restrictive airway disease; pulmonary hypertension; diseases that could impair the implementations of bicycle ergometry Beta blockers Page 47 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 3. Randomized controlled trials of beta blockers for angina Author Year Allowed other Method of outcome Age Other population Country medications/ assessment and timing of Gender characteristics Study Design interventions assessment Ethnicity (diagnosis, etc) Head-to-head trials Chieffo sl ntg Patient daily record Mean age=56. Randomized controlled trials of beta blockers for angina Author Year Number screened/ Country eligible/ Number withdrawn/lost to fu/ Method of adverse Study Design enrolled analyzed Outcomes effects assessment? Randomized controlled trials of beta blockers for angina Author Year Withdrawals due to adverse Country events (%, adverse Study Design Adverse Effects Reported n/enrolled n) Comments Head-to-head trials Chieffo NR NR Comorbid HTN 1986 Italy Fair quality RCT Dorow NR NR 1990 Fair quality RCT Crossover Beta blockers Page 50 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 3. Randomized controlled trials of beta blockers for angina Author Year Country Interventions (drug, regimen, Study Design Eligibility criteria Exclusion criteria duration) Frishman Patients with angina pectoris due to ischemic Co-existent valvular heart disease, congestive heart Pindolol (pin) 10-40 mg daily 1979 coronary artery disease as documented by failure, hypertension, bronchial asthma requiring (n=23) United States coronary angiography or previous MI; positive continued treatment with bronchodilators, severe Propranolol (pro) 40-240 mg daily treadmill exercise test showing at least a 1 mm bradycardia, intermittent claudication, and either (n=18) x 8 weeks Fair quality ECG ST segment depression of the ischemic myocardial infarction or a coronary artery bypass within RCT type in association with typical angina pectoris 3 months pain; at least 5 attacks of angina pectoris/2 weeks for three months with no evidence for an accelerated course Beta blockers Page 51 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 3. Randomized controlled trials of beta blockers for angina Author Year Allowed other Method of outcome Age Other population Country medications/ assessment and timing of Gender characteristics Study Design interventions assessment Ethnicity (diagnosis, etc) Frishman Nitroglycerin Patient daily record Mean age: 55 Diagnosis of coronary artery disease 1979 Treadmill (protocol nr) 85. Randomized controlled trials of beta blockers for angina Author Year Number screened/ Country eligible/ Number withdrawn/lost to fu/ Method of adverse Study Design enrolled analyzed Outcomes effects assessment? Frishman NR/NR/40 NR/NR/40 analyzed Angina attacks/2 weeks(% reduction):pin=(- NR 1979 41. Randomized controlled trials of beta blockers for angina Author Year Withdrawals due to adverse Country events (%, adverse Study Design Adverse Effects Reported n/enrolled n) Comments Frishman Overall incidence: pin=4/23(17. Randomized controlled trials of beta blockers for angina Author Year Country Interventions (drug, regimen, Study Design Eligibility criteria Exclusion criteria duration) van der Does Male or female (postmenopausal or using Contraindications to study drugs/exercise testing; other Carvedilol (car) 100 mg daily 1999 reliable contraceptive methods) treated or forms of angina pectoris (vasospastic, unstable); (n=247) Europe untreated patients (70% narrowing of a major phlebothrombosis; disorders of impulse coronary vessel) or MI (electrocardiogram or formation/conduction (resting heart rate <45 beats/min, cardiac enzymes), or a previous positive bundle brach block, pacemaker); obstructive airways exercise test with occurrence of angina and ST- disease; insulin-dependent DM; relevant hepatic segment depression; capable of performing impairment; gross obesity; alcohol/drug abuse; epilepsy; upright bicycle ergometric exercise tests; not to concomitant drugs interfering with study objectives (e. Randomized controlled trials of beta blockers for angina Author Year Allowed other Method of outcome Age Other population Country medications/ assessment and timing of Gender characteristics Study Design interventions assessment Ethnicity (diagnosis, etc) van der Does Nitrates Erect bicycle ergometric exercise Mean age: car=62; met=61 %smokers: car=14; met=19 1999 %male: car=72; met=71 %systemic hypertension: car=38; met=33 Europe Race nr %diabetes mellitus: car=15; met=13 %dyslipidemia: car=32; met=31 Fair quality %anterior MI: car=9; met=11 RCT %posterior MI: car=18; met=17 %positive angiography: car=23; met=22 %1-vessel disease: car=13; met=10 %2-vessel disease: car=5; met=8 %3-vessel disease: car=5; met=3 Beta blockers Page 56 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 3. Randomized controlled trials of beta blockers for angina Author Year Number screened/ Country eligible/ Number withdrawn/lost to fu/ Method of adverse Study Design enrolled analyzed Outcomes effects assessment? Randomized controlled trials of beta blockers for angina Author Year Allowed other Method of outcome Age Other population Country medications/ assessment and timing of Gender characteristics Study Design interventions assessment Ethnicity (diagnosis, etc) Narahara Sublingual Patient diary used to measure (1) Mean age=61 History of prior MI = 42% 1990 nitroglycerin angina frequency; and (2) 21. Randomized controlled trials of beta blockers for angina Author Year Number screened/ Country eligible/ Number withdrawn/lost to fu/ Method of adverse Study Design enrolled analyzed Outcomes effects assessment?

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The most advantageous changes of metabolic parameters have been observed by replacement of the PI with nevirapine or abacavir generic cialis super active 20 mg overnight delivery. This option is, however, not always suitable, and the clinical benefit of effective viral suppression and improved immune function needs to be considered in view of drug history, current viral load, and resist- 294 ART ance mutations. When options are limited, antiretroviral drugs that may lead to ele- vation of lipid levels should not be withheld for fear of further exacerbating lipid disorders. Lipid-lowering agents should be considered for the treatment of severe hyper- triglyceridemia, elevated LDL or a combination of both. The clinical benefit, however, of lipid lowering or insulin-sensitizing therapy in HIV+ patients with lipodystrophy remains to be demonstrated. In light of the potentially increased cardiovascular risk to recipients of antiretroviral therapy, the AIDS Clinical Trials Group (ACTG) pub- lished recommendations based on the National Cholesterol Education Program (NCEP) for primary and secondary prevention of coronary artery disease in seroneg- ative patients. In addition, more detailed recommendations by the European AIDS Clinical Society have been published to provide guidelines for physicians actively involved in HIV care that will be regularly updated (www. However, these recommendations should be considered as being rather pre- liminary, given the limited numbers, size and duration so far of the clinical studies they are based on. It appears reasonable to measure fasting lipid levels annually before and 3-6 months after ART is initiated or changed. Whenever possible, the ART least likely to worsen lipid levels should be selected for patients with dyslipidemia. Metformin has been evaluated for the treatment of lipodystrophy syndrome. Some studies have revealed a positive effect on the parameters of insulin resistance and the potential reduction of intra-abdominal (and subcutaneous) fat, although not clinically significant. Together with exercise training, metformin has been described to reverse the muscular adiposity in HIV+ patients (Driscoll 2004). Metformin, like all biguanides, can theoretically precipitate lactic acidosis and should thus be used with caution. Use of metformin should be avoided in patients with creatinine levels above 1. Surgical intervention (liposuction) for the treatment of local fat hypertrophy has been successfully performed, but appears to be associated with an increased risk of secondary infection (Guaraldi 2011), and recurrence of fat accumulation is possible. For the treatment of facial lipoatrophy, repeated subcutaneous injection of agents such as poly-L-lactic acid (Sculptra, New-Fill), a resorbable molecule that promotes collagen formation, has been effectively used in HIV+ patients (Casavantes 2004, Mest 2004, Behrens 2008). In 2004, Sculptra was approved by the FDA as an injectable filler to correct facial fat loss in people with HIV. We recommend consul- tation with experienced specialists for surgical treatments and injection therapy. Further evaluation in long-term follow-up studies is necessary to fully assess the value of these methods. We do not recommend the following drugs for HIV-related lipodystrophy: • The therapeutic intervention of recombinant human growth hormone (rHGH) (Serostim); the role of rHGH for HIV-associated fat accumulation has not been clearly defined. This therapy is very expensive and its only at best moderate effects disappear after stopping the treatment; there was rapid rebound of visceral fat to levels above baseline after treatment discontinuation (Grunfeld 2007, Lo 2008, Lo 2010). Management of Side Effects 295 Lifestyle changes Dietary interventions are commonly accepted as the first therapeutic option for hyperlipidemia, especially hypertriglyceridemia. Use of NCEP guidelines may reduce total cholesterol and triglycerides by 11 and 21%, respectively. Whenever possible, dietary restriction of total fat to 25–35% of the total caloric intake should be a part of any treatment in conjunction with lipid-lowering drugs. Consultation with pro- fessional and experienced dieticians should be considered for HIV+ patients and their partners. Patients with excessive hypertriglyceridemia (>1,000 mg/dl) may benefit from a very low fat diet and alcohol abstinence to reduce the risk of pancreatitis, especially if there is a positive family history or concurrent medications that may harbor a risk of developing pancreatitis. Regular exercise may have beneficial effects, not only on triglycerides and insulin resistance, but probably also on fat redistribu- tion (reduction in truncal fat and intramyocellular fat) and should be considered in all HIV+ patients (Driscoll 2004). All patients should be advised and supported to give up smoking in order to reduce cardiovascular risk. Cessation of smoking is more likely to reduce cardiovascular risk than any choice or change of ART or use of any lipid-lowering drug (Petoumenos 2010). Metabolic effects of darunavir/ritonavir versus atazanavir/ritonavir in treat- ment-naive, HIV type 1-infected subjects over 48 weeks AIDS Res Hum Retroviruses 2012, 28:1184-95. A randomized, pilot trial to evaluate glomerular filtration rate by creatinine or cystatin C in naïve HIV-infected patients after tenofovir/emtricitabine in combination with atazanavir/riton- avir or efavirenz. Barrios A, Garcia-Benayas T, Gonzalez-Lahoz J, et al. Treatment option for lipodystrophy in HIV-positive patients. Suspected drug-induced liver fatalities reported to the WHO database.

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Applicability to general populations with type 2 diabetes No included trial evaluated the effects of pramlintide in patients whose type 2 diabetes was inadequately managed on combination prandial and basal insulin therapy with or without oral agents buy cialis super active 20mg amex. Two studies evaluated pramlintide in patients using fixed-dose insulin. One trial used flexible dosing for insulin glargine only. Hence, results have limited applicability to the broader population using more commonly prescribed insulin regimens. FDA-approved dosage of pramlintide for type 2 diabetes includes initial therapy of 60 mcg/meal and maintenance therapy of 120 mcg/meal. The third included trial was a dose-ranging study that did not use a 120 mcg dose but 17 did include a 75 mcg dose which may be used in clinical practice. Overall, patients included in these 3 trials represent a highly selected population: mainly white, middle-aged men and women with mean baseline A1c between 8. None of the patients had significant pulmonary, cardiovascular, renal, neurologic, or hematologic diseases or problems with gastrointestinal motility. The study populations probably included highly motivated subjects who desired to achieve optimal glycemic control through the additional 2-4 injections added to their usual regimens of insulin and oral hypoglycemic agent over 16-52 weeks of participation in a trial. Study setting also was not reported in any of the included trials; subjects likely were evaluated in outpatient clinics. Diabetes Page 30 of 99 Final Report Drug Effectiveness Review Project Table 9. Summary evidence table Type 1 diabetes Type 1 Diabetes Quality of evidence Conclusion Key Question 1. For children and adults with type 1 diabetes, does pramlintide differ in efficacy, Evidence in children is lacking. Effectiveness No available data -No studies assessed long-term health outcomes and none were > 52 weeks in duration. Pramlintide with titratable insulin -Evidence on FPG and time to treatment failure is lacking. Pramlintide with fixed or stable insulin -Pramlintide produced small reductions in A1c (placebo-corrected: 0. For both groups: -Studies beyond 52 weeks in duration -Fair-Poor evaluating harms are lacking. Harms -More pramlintide-treated patients withdrew due to adverse effects than Diabetes Page 31 of 99 Final Report Drug Effectiveness Review Project Type 1 Diabetes Quality of evidence Conclusion insulin-treated patients (5-20% compared with 2-8%). In one trial where patients were allowed to decrease prandial insulin by 30- 50%, rates of severe hypoglycemia were still slightly higher for those on pramlintide+insulin than compared with those receiving placebo+insulin. Two trials mentioned that most of these events occurred within 4 weeks of therapy, however, no actual data were available to verify the statement. Are there A1c <8% exhibited similar reductions in subgroups of patients for which -Poor (post hoc analyses and A1c than the total population. Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; PPG, postprandial glucose; RCT, randomized controlled trial. Type 2 Diabetes Type 2 Diabetes Quality of evidence Conclusions Key Question 1. For children and adults with type 2 diabetes, does pramlintide differ in efficacy, effectiveness, and in harms for No evidence in children. Effectiveness No available data -No studies assessed long-term health outcomes and none were > 52 weeks in duration. Efficacy Pramlintide added to titratable Added to titratable insulin glargine doses of insulin glargine with or with or without oral agents) without oral agents -Addition of pramlintide to a glargine- Diabetes Page 32 of 99 Final Report Drug Effectiveness Review Project Type 2 Diabetes Quality of evidence Conclusions -Fair, 1 RCT only regimen lowered A1c by 0. There was no significant differences between the groups at the end of 16 weeks (change from baseline: +11. One trial reported data that showed most events occurring within 4 weeks of therapy. It is unknown whether these events were associated with hypoglycemia. Are there -The incidence of nausea had no subgroups of patients for which -Poor (post hoc analyses with impact on observed weight loss with pramlintide is more or less suitable selective outcome reporting) pramlintide. Abbreviations: BMI, body mass index; FPG, fasting plasma glucose; PPG, postprandial glucose; RCT, randomized controlled trial. Diabetes Page 34 of 99 Final Report Drug Effectiveness Review Project Exenatide We identified 4 RCTs that compared exenatide with conventional insulin therapy, with both 26-30 groups receiving oral diabetes agents (Table 10 and Evidence Table 1-3). In addition we 31-34 identified 4 placebo-controlled trials (Table 11 and Evidence Table 1-3), 5 single-arm open- 35-39 40 label extension studies of exenatide, one single-arm retrospective cohort study (Table 12 41, 42 and Evidence Tables 1-4), and two relevant systematic reviews (Evidence Tables 5-6). No studies that met our inclusion criteria compared exenatide to oral diabetes agents used as either monotherapy or combined therapy in adults. The literature search results are provided in Figure 2, and studies excluded upon review of the full text are listed in Appendix D. Diabetes Page 35 of 99 Final Report Drug Effectiveness Review Project Figure 2. Literature search results for exenatide Citations identified through searches (Medline, Cochrane, FDA, pharmaceutical dossiers, and peer review): 324 Citations excluded at the title/abstract-level: 281 Full-text articles retrieved for more detailed evaluation: 43 Articles excluded at full-text level: 27 Wrong drug: 1 Wrong population: 1 Wrong publication: 10 Wrong study design: 15 Included studies: 16 Active-control trials: 4 Placebo-controlled trials: 4 Observational studies: 6 (5 open-label extension studies) Systematic reviews: 2 Systematic Reviews 41,42 Two systematic reviews of exenatide met our inclusion criteria.

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If one suspects that the distinction between equilibrium affinity and kinetic on-rates matters in an essential way for immunodominance discount 20 mg cialis super active with amex, then an extended mathematical model would pro- vide testable predictions about that aspect of the system. Iemphasizetheseissues here because the dynamics of immune cells andparasite populations within each infected host provide one of the few subjects that has been developed mathematically (Nowak and May 2000). The simple principles from those models do seem to be impor- tant, if only because the rules of population dynamics must play a key role in shaping how populations of immune cells and parasites interact. One can, of course, make more specific mathematical models to pre- dict the dynamics ofparticularparasites or the role of particular mo- lecular mechanisms. Those specific models require empirical study of their specialized predictions. And that is exactly what we want: tests of clearly and logically formulated quantitative predictions. Helper T cells pro- vide an important stimulus in the development of an antibody response. As B cells bind antigen to their BCR, they often pull the antigen into the 92 CHAPTER 6 cell. The B cells process protein antigens into small peptides, bind those peptides to MHC class II molecules, and present the peptide-MHC com- plexes on their cell surfaces. Helper T cells with matching specificity in their TCRs bind the peptide-MHC complexes and stimulate the B cells. Thus, an antigen must have two epitopes to stimulate a robust B cell response with affinity maturation. One epitope binds the BCR, and a second must survive digestion and be presented on the B cell surface bound to a class II molecule for the TCR of a helper T cell. Several factors likely affect the degree to which helper T cell epitopes modulate the immunodominance of B cellepitopes. These factors in- clude the proximity of the two epitopes, the binding kinetics of the T cell epitope to the TCR, the nature of the helper T cell signal that pro- vides stimulation to the B cell, and the population dynamics of the helper Tcelllineages with different TCR specificities. In particular, ahelperTcellepitope near the hypervariable region of thehepatitis C virus envelope gene aids in generation of antibodies to the hypervariable region. Antibody attack favors antigenic variation in parasites’ surface molecules. By contrast, CTLs favor varia- tion in any parasite molecule that can be presented by the host’s MHC system. The balance of antibody versus CTL defense affects the popula- tion dynamics of the parasites within the host, the time before clearance, and the memory properties of host immunity against reinfection (Seder and Hill 2000). The factors that tip an immune response toward anti- body, CTL, or a mixture ofthetwoarenot fully understood (Constant and Bottomly 1997; Power 2000). Studies of model systems sometimes show a sharp dichotomy between CTL and antibody response controlled by a simple variable such as antigen dosage (Menon and Bretscher 1998). But the immune response to many viruses includes robust antibody and CTLattack (Knipe and Howley 2001). As more parasite genomes are sequenced, it may be useful to look at which potential antigenic sites do in fact show significant variation. Those highly variable sites can be studied to determine if they are CTL or antibody epitopes, providing clues about which type of immunity imposes the strongest selective pressure on the parasite. Parasite Escape within Hosts 7 Specific immunity favors parasites that change their epitopes and escape recognition. In this chapter, I summarize examples of parasite escape and the consequences for antigenic diversity within hosts. The first section presents HIV and hepatitis C virus (HCV) as two pathogens that evolve within hosts to escape specific immunity. HIV variants escape recognition by CTLs, whereas HCV variants escape rec- ognition by specific antibodies. HIV also diversifies its surface molecules in order to attack different cell types. Changing tissue tropisms over the course of an infection provide an additional force to drive the evolu- tion of parasite diversification within hosts. HIV and HCV are both RNA viruses, which mutate frequently and evolve rapidly. The importance of within-host immune escape by random mutations in DNA-encoded pathogens remains to be studied. The second section describes how parasites interfere with host immu- nity. For example, viruses may disrupt MHC presentation of antigens, send misleading signals to natural killer cells, block programmed cell death (apoptosis) of infected cells, orexpress cytokines that alter im- mune regulation. In some cases, parasite antigens may lack variation because the parasite repels immune attack by interfering with host im- munity rather than altering the specificity of its epitopes.

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