By Y. Emet. University of Alaska, Fairbanks. 2018.
Applicability: see External Validity Before-after study: A type nonrandomized study where data are collected before and after patients receive an intervention order proscar 5mg fast delivery. Before-after studies can have a single arm or can include a control group cheap 5 mg proscar with amex. Bias: A systematic error or deviation in results or inferences from the truth. Several types of bias can appear in published trials, including selection bias, performance bias, detection bias, and reporting bias. Bioequivalence: Drug products that contain the same compound in the same amount that meet current official standards, that, when administered to the same person in the same dosage regimen result in equivalent concentrations of drug in blood and tissue. Black box warning: A type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects. It is so named for the black border that usually surrounds the text of the warning. A black box warning means that medical studies indicate that the drug carries a significant risk of serious or even life-threatening adverse effects. The US Food and Drug Administration (FDA) can require a pharmaceutical company to place a black box warning on the labeling of a prescription drug, or in literature describing it. Blinding: A way of making sure that the people involved in a research study — participants, clinicians, or researchers —do not know which participants are assigned to each study group. Blinding usually is used in research studies that compare two or more types of treatment for an illness. Newer antiplatelet agents 64 of 98 Final Update 2 Report Drug Effectiveness Review Project Case series: A study reporting observations on a series of patients receiving the same intervention with no control group. Case study: A study reporting observations on a single patient. Case-control study: A study that compares people with a specific disease or outcome of interest (cases) to people from the same population without that disease or outcome (controls). Clinical diversity: Differences between studies in key characteristics of the participants, interventions or outcome measures. Clinically significant: A result that is large enough to affect a patient’s disease state in a manner that is noticeable to the patient and/or a caregiver. Cohort study: An observational study in which a defined group of people (the cohort) is followed over time and compared with a group of people who were exposed or not exposed to a particular intervention or other factor of interest. A prospective cohort study assembles participants and follows them into the future. A retrospective cohort study identifies subjects from past records and follows them from the time of those records to the present. Combination Therapy: The use of two or more therapies and especially drugs to treat a disease or condition. Confidence interval: The range of values calculated from the data such that there is a level of confidence, or certainty, that it contains the true value. The 95% confidence interval is generally used in Drug Effectiveness Review Project reports. If the report were hypothetically repeated on a collection of 100 random samples of studies, the resulting 95% confidence intervals would include the true population value 95% of the time. Confounder: A factor that is associated with both an intervention and an outcome of interest. Controlled clinical trial: A clinical trial that includes a control group but no or inadequate methods of randomization. Control group: In a research study, the group of people who do not receive the treatment being tested. The control group might receive a placebo, a different treatment for the disease, or no treatment at all. Convenience sample: A group of individuals being studied because they are conveniently accessible in some way. Convenience samples may or may not be representative of a population that would normally be receiving an intervention. Crossover trial: A type of clinical trial comparing two or more interventions in which the participants, upon completion of the course of one treatment, are switched to another. Direct analysis: The practice of using data from head-to-head trials to draw conclusions about the comparative effectiveness of drugs within a class or group. Results of direct analysis are the preferred source of data in Drug Effectiveness Review Project reports. Dosage form: The physical form of a dose of medication, such as a capsule, injection, or liquid. The route of administration is dependent on the dosage form of a given drug. Various dosage forms may exist for the same compound, since different medical conditions may warrant different routes of administration. Dose-response relationship: The relationship between the quantity of treatment given and its effect on outcome. In meta-analysis, dose-response relationships can be investigated using meta- regression. Double-blind: The process of preventing those involved in a trial from knowing to which comparison group a particular participant belongs. While double-blind is a frequently used term Newer antiplatelet agents 65 of 98 Final Update 2 Report Drug Effectiveness Review Project in trials, its meaning can vary to include blinding of patients, caregivers, investigators, or other study staff. Double-dummy: The use of two placebos in a trial that match the active interventions when they vary in appearance or method of administrations (for example, when an oral agent is compared with an injectable agent). Effectiveness: The extent to which a specific intervention used under ordinary circumstances does what it is intended to do.
Nevertheless purchase proscar 5 mg with mastercard, the probability of transmission from occupational needlestick injuries after exposure to HCV-contaminated blood is less than 2% buy proscar 5mg with mastercard, possibly even lower; i. In contrast, sexual transmission of HCV occurs significantly less frequently than HBV or HIV (risk of transmission via heterosexual intercourse is <1%). About 4–8% of all HIV+ men who have sex with men (MSM) are also infected with HCV. The first cases of acute hepatitis C among HIV+ MSM were observed in London, Paris, Amsterdam and Berlin but have spread to a worldwide epidemic over the last decade (Boesecke 2015). The risk of transmission depends on concomitant sexually transmitted dis- eases such as syphilis or lymphogranuloma venereum, performance of sexual prac- tices that are prone to injuries of the mucosal membranes like fisting or intensive repetitive anal sex, and intravenous use of recreational drugs (“Chem sex”) (Vogel 2005, GMFA 2013). Perinatal transmission of hepatitis C is rare in immunocompetent individuals (<1%). The transmission rate rises with increasing immunosuppression in HIV+ mothers, and is estimated to be as high as 20%. On the other hand, HIV+ mothers treated effectively with antiretroviral therapy do not appear to have an increased risk for materno-fetal transmission of the hepatitis C virus (<3% with cesarean section) (Pembrey 2005). Cesarean section did not reduce the risk of transmission to the newborn of HCV-monoinfected women putting the role of cesarean section into question (Indolfi 2009). Clinical course and pathogenesis The clinical course of hepatitis C and HIV coinfection is determined by HIV-associ- ated immunosuppression. Progression of immunosuppression accelerates the course of hepatitis C. Conversely, there is no significant influence of hepatitis C on the course of HIV infection (Rockstroh 2005). The latent period until development of liver failure or hepatocellular carcinoma in coinfected patients is estimated to be 10–20 years, whereas it is 30–40 years in HCV-monoinfected patients (Benhamou 1999). Improved treatment options for HIV infection have increased the likelihood of patients actually living to experience the development of liver failure which has become at least in some centers a frequent cause of death (Rosenthal 2007). ART can improve the unfavorable course of hepa- HIV and HBV/HCV Coinfections 455 titis C and delay the development of liver failure. This is particularly true for patients who achieve good immune recovery (Pineda 2007). Therefore and as a result of the START study (see ART chapter) initiation of ART regardless of CD4 T cell count is recommended in HCV-coinfected patients (EACS 2015). On the other hand, hepatitis C infection can aggravate the potential hepatotoxicity of ART regimens. Up to 10% of patients have to discontinue ART due to severe hepa- totoxicity. This risk is associated especially with the so-called “d drugs” (ddI, d4T). These agents should be avoided in coinfected patients. Nevirapine and tipranavir should be used with caution. In some coinfected patients, a temporary increase in transaminases is observed after initiation of ART. This most likely corresponds to an increased inflammatory activity of hepatitis C as a result of improved immune status. Nevertheless, long-term follow-up has shown that ART improves the course of hepatitis C. Diagnosis Diagnostic tests in coinfected patients are no different from those used in HCV monoinfection (see Table 1). Detection of HCV antibodies (anti-HCV) confirms expo- sure to HCV, but does not distinguish between resolved and chronic hepatitis C. Chronic hepatitis C is diagnosed by the detection of HCV viremia (HCV RNA). It should be noted that HCV antibodies might be lost during the course of HIV infec- tion as a result of the underlying immunosuppression, although nowadays this phenomenon has become rare, probably due to improved test kits. It may therefore be useful to determine HCV RNA levels, even if the anti-HCV test is negative, if there is clinical suspicion or advanced immunodeficiency (it can also occur in patients undergoing chemotherapy). Similarly, determination of HCV RNA levels is indicated in cases of suspected acute HCV infection. HCV antibodies usually only become detectable one to five months after infection. In one study, they were still lacking in 37% of patients 3 months after first detecting HCV RNA (Thomson 2009). Patients with HIV/HCV coinfection have significantly higher levels of HCV viremia than patients with HCV monoinfection (about 1 log). Based on current knowledge the level of viremia does not have a prognostic value for the course of hepatitis C. However, it should be noted that some patients might lose HCV RNA in parallel with progression of immune deficiency, but experience a flare up of hepatitis C together with clinical symptoms following immune reconstitution on ART (Kim 2006). Therefore, regular testing around the initiation of ART seems prudent. When considering the treatment of hepatitis C, genotyping is necessary before start- ing. Six genotypes with numerous subtypes are known, and are seen to have differ- ent regional distributions: genotypes 1 and 3 are predominantly found in Europe, whereas genotypes 4 and 5 are found in Africa, and genotype 6 in Asia. Genotypes 2 and 3 in particular have been associated with significantly better responses to inter- feron-containing therapy. Another marker associated with response to interferon-containing treatment is deter- mination of IL28B genotype. This is a T/C dimorphism close to a region coding for human interleukin 28B.
Summary of efficacy trials in adult patients with ulcerative colitis Author Study Secondary Quality Year design N Duration Comparisons Primary outcome outcomes Population Results rating INFLIXIMAB Relative risk of failure to Ford et Infliximab 5 mg/kg to Inducing remission SR and 6 to 12 Adults with achieve remission 0 purchase proscar 5 mg fast delivery. Targeted immune modulators 76 of 195 Final Update 3 Report Drug Effectiveness Review Project Plaque Psoriasis The following drugs are currently approved by the US Food and Drug Administration for the treatment of plaque psoriasis: adalimumab 5 mg proscar mastercard, alefacept, etanercept, infliximab, and ustekinumab. We did not review trials of efalizumab because it was withdrawn from the market. Summary of findings We located one fair-quality, randomized, head-to-head trial of etanercept compared with 234 ustekinumab for the treatment of severe plaque psoriasis. In the trial 903 patients were randomized to 50 mg etanercept twice weekly or two doses of ustekinumab (45 mg or 90 mg) in a 12-week period. Significantly more patients in both ustekinumab groups achieved the primary outcome of a PASI 75 response compared with etanercept. The strength of evidence for this comparison was low. Fair to good evidence from multiple placebo-controlled randomized controlled trials demonstrated the general efficacy of adalimumab, alefacept, etanercept, infliximab, and ustekinumab for achieving a Psoriasis Area and Severity Index 75 response in adults with plaque psoriasis. Specifically, we located 17 placebo-controlled trials that assessed the efficacy of targeted immune modulators for the treatment of plaque psoriasis in adults: five on 235-239 240-242 243-247 248 adalimumab, three on alefacept, five on etanercept, one on infliximab, and 249-251 three on ustekinumab. The studies on alefacept and etanercept were pooled in a meta- 252 analysis. We did not find any studies on other targeted immune modulators. In addition, one 253 study assessed the efficacy of etanercept in children and adolescents. Significantly more children in the etanercept group than in the placebo group experienced a response. Study populations and outcome measures In general, studies enrolled patients who had a history of plaque psoriasis for more than 6 months, with more than 5% to 10% of body surface area involved. Minimum Psoriasis Area and Severity Index scores to meet inclusion criteria ranged from 10 to 12. Most patients had previous systemic treatments for plaque psoriasis or were candidates for systemic treatment. Patients were excluded if they had clinically significant disease flares at screening or enrollment, major concomitant illnesses, immune disorders, malignancies, or organ dysfunction. Prior therapy with biologic agents was an exclusion criterion for some studies. All studies assessed Psoriasis Area and Severity Index 50 or Psoriasis Area and Severity Index 75 as one of the primary outcome measures (see Appendix D). The Physician Global Assessment was also a common outcome measure. In addition, most trials included some measure of health-related quality of life or functional capacity such as the Dermatology Life Quality Index, Dermatology Quality of Life Scale, the itching visual analogue scale, the European Quality of Life – 5 Dimensions, or the Short Form 36 Health Survey. The methodological quality of studies was generally good and some of the “fair” ratings were probably more attributable to inadequate reporting than methodological flaws. Randomization methods and blinding were generally adequate; all studies used a double-dummy design (i. Targeted immune modulators 77 of 195 Final Update 3 Report Drug Effectiveness Review Project Sponsorship All of the included studies were funded by the pharmaceutical industry. Detailed assessment: Direct evidence on the comparative effectiveness Etanercept compared with ustekinumab We located one fair-quality, randomized, head-to-head trial that compared etanercept with 234 ustekinumab in 903 patients with moderate-to-severe plaque psoriasis. The doses of targeted immune modulator in the three arms were: 50 mg etanercept twice weekly, ustekinumab 45 mg at week 0 and week 4, or ustekinumab 90 mg at week 0 and week 4. The trial lasted 12 weeks and patients and study personnel administering the drugs were not blinded to treatment allocation. All other study personnel including assessors and data managers were blinded to treatment allocation. The results of this one trial indicated that ustekinumab is superior to etanercept for treating plaque psoriasis. Significantly more patients in both ustekinumab groups achieved the primary outcome of a Psoriasis Area and Severity Index 75 response compared with etanercept (etanercept 50 mg, 56. Similarly, statistically significantly more patients in both ustekinumab groups demonstrated cleared or minimal disease with the Physician’s Global Assessment (etanercept 50 mg, 49%; ustekinumab 45 mg, 65. Detailed assessment: Indirect evidence on the comparative effectiveness We did not find any indirect evidence on the comparative effectiveness of the targeted immune modulators for plaque psoriasis. Detailed assessment: Evidence on the general efficacy Because of the small number of head-to-head trials, we reviewed placebo-controlled trials. We summarized evidence on the general efficacy of targeted immune modulators in the treatment of plaque psoriasis; however, this did not provide evidence on the comparative efficacy and tolerability of targeted immune modulators. Adalimumab 236,237 235,238,239 Two good and three fair studies provided evidence on the general efficacy of adalimumab for the treatment of moderate to severe plaque psoriasis in adult patients. All five trials had a primary endpoint of PASI 75 or hfPGA between week 12 and 16 and included one arm where patients received an initial dose of 80 mg adalimumab subcutaneously followed by 40 mg adalimumab every other week. Furthermore, one trial included methotrexate as a comparison 236 arm and one trial also included a dose of adalimumab that is higher than the approved dose for 235 plaque psoriasis (80 mg initial dose followed by 40 mg weekly). One trial looked specifically 239 at patients with psoriasis of the hands and/or feet. All results consistently demonstrated that adalimumab is more efficacious than placebo for Psoriasis Area and Severity Index, Physician Global Assessment, Dermatology Life Quality Index and health-related quality of life outcomes. Between 53% and 81% of patients in the adalimumab every other week arms achieved a Psoriasis Area and Severity Index 75 response compared with 4% to 19% of placebo-treated patients. Specifically, in the largest good-quality trial 1212 patients were randomized to 237 adalimumab every other week or placebo for 16 weeks.
Mathematical models would clarify the various relations that may arise between antigenic and phylogenetic classiﬁcations order proscar 5mg free shipping. Those rela- tions depend on the time scales of diﬀerentiation proscar 5 mg discount, the epitopes used for antigenic classiﬁcation, and the antibodies used to discriminate between variant epitopes. Experimental Evolution: Foot-and-Mouth 12 Disease Virus Experimental evolution manipulates the environment of a population and observes the resulting pattern of evolutionary change. This allows one to study the selective forces that shape antigenic diversity. For ex- ample, one could manipulate immune selection by exposing parasites to diﬀerent regimes of monoclonal antibodies. The parasites’ evolutionary response reveals the adaptive potential and the constraints that shape patterns of antigenic variation. In this chapter, I describe experimental evolution studies of foot-and- mouth disease virus (FMDV). I also use this virus as a case study to show how diﬀerent methods combine to provide a deeper understanding of antigenic variation. These approaches include structural analysis of the virion, functional analysis of epitopes with regard to binding cellular re- ceptors, sequence analysis of natural isolates, and experimental analysis of evolving populations. The ﬁrst section introduces the antigenicity and structure of FMDV. Structural studies provide the three-dimensional location of amino ac- ids. This allows one to analyze how particular amino acid substitutions aﬀect shape, charge, and interaction with antibodies. Structural infor- mation also aids functional analysis of substitutions with regard to bind- ing cellular receptors or aﬀecting other components of viral ﬁtness. The second section describes antibody escape mutants of FMDV. Most of these escape mutants were generated by application of monoclonal antibodies in controlled experimental studies. Several laboratory escape mutants occur in an exposed loop on the surface of the virion, which is also the site of a key antigenic region identiﬁed by sequencing natural isolates. This antigenic loop mediates binding to cellular receptors, an essential step for viralentryintohost cells. The pattern of antibody escape mutantsidentiﬁesvarying and unvarying amino acid sites. The unvarying sites play an essential role in binding to host cells. The third section continues discussion of binding to host cells and tro- pism for diﬀerent host receptors. Experimental evolution studies show that in cell culture FMDV can evolve to use alternate cellular receptors. EXPERIMENTAL EVOLUTION: FMDV 189 This switch in receptor tropism relieves the constraint on the previously unvarying amino acid sites in the key antigenic region. Consequently, escape mutants in that conserved region arise readily, demonstrating that the conserved sites play an important role in recognition by anti- bodies. This highlights the dual selective pressures by antibodies and receptor binding that may shape key antigenic sites. The fourth section describes an experimental approach to analyze the ﬁtness consequences of amino acid substitutions. Molecular stud- ies can measure changes in binding aﬃnity for antibodies and cellular receptors associated with changes in amino acid shape and charge. But substitutions ultimately spread or fail based on their consequences for the dynamics of growth and transmission. I describe one study in which pigs were injected with a wild-type virus and various antibody escape mutants. The rela- tive success of parental and mutant viruses provides clues about how particular amino acid substitutions may inﬂuence evolutionary dynam- ics. The ﬁnal section lists problems for future research. General discussions and examples of experimental evolution can be found in Rose (1991), Bennett and Lenski (1999), Landweber (1999), Crill et al. FMDV belongs to the Picornaviridae family of viruses, which includes poliovirus, human hepatitisAvirus, and the human rhinoviruses (Racaniello 2001). FMDV populations maintain antigenic diversity in several rapidly evolving epi- topes(Mateuetal. Seven major serotypes occur across the world (Sobrino et al. Phylogenetic distance between serotypes correlates reasonably well with antigenic distance measured by cross-reactivity to polyclonal antisera— in other words, phylogeny roughly matches serology at a broad scale of sequence divergence (Mateu 1995). By contrast, small-scale phylogenetic divergence does not correspond to patterns of antigenicity. One or a few amino acid substitutions within a serotype can greatly alter antibody recognition (Mateu et al. Each of the three main surface proteins, VP1, VP2, and VP3, ﬁlls a trapezoidal space with eight β chains (arrows) labeled B-I and two α chains (cylinders).
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