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Combivir

By B. Kaelin. Waldorf College. 2018.

In Europe between 1997–2004 cheap 300mg combivir overnight delivery, among 760 cases of so-called “late presenters” who were diagnosed with HIV infection and AIDS at the same time purchase combivir 300mg overnight delivery, PCP (35%) was the most frequent OI (Mussini 2008) 300mg combivir amex. In many cases with known HIV infection buy 300mg combivir with visa, adherence to antiretroviral therapy was poor prior to PCP (Denis 2014). PCP is a life-threatening disease, which should be treated by an HIV specialist. It often requires mechanical ventilation and still continues to have a high fatality rate of up to 10% (Walzer 2008, Llibre 2013). Factors associated with mortality are older age, low hemoglobin level, and low partial pressure of oxygen at hospital admission (Walzer 2008, Miller 2010). Relapses seen frequently in the past have become rare, thanks to ART and prophylaxis. Scar tissue formation may result in susceptibility to recurring pneumothoraces. PCP may rarely occur in relation to immune reconstitu- tion inflammatory syndrome (see below). Extrapulmonary manifestations of pneu- mocystis infections are also considerably rare. They may affect the liver, but many other organs may be involved. Signs and symptoms Every clinician should be familiar with the classic triad of PCP symptoms that include dry cough, subfebrile temperatures, and dyspnea on exertion; should ask patients specifically about their symptoms; and should measure the patients’ respiratory rates. A subacute course that allows differentiation from the productive cough, acutely high fever, pain and less common dyspnea-associated bacterial pneumonia is typical. Oral thrush is a frequent symptom in patients with PCP. Also, substantial weight loss of several kilos in the weeks before PCP diagnosis is common. These and other symp- toms may be more subtle in cases with suboptimal prophylaxis (rare). Weeks and sometimes even months may go by before the diagnosis of PCP is made. It is noteworthy to state that decompensation – as with all interstitial pneumonias – often occurs much faster than expected. It is not rare for a patient to suddenly require ventilation after weeks of antibiotic therapy prescribed by the primary health care provider, especially when even “broad spectrum” antibiotics do not help. A patient with significant exertional dyspnea or even resting dyspnea should be directed immediately to hospital. Diagnosis If there is clinical suspicion of PCP determined by a physical examination with atten- tion given to respiratory rate, oral thrush, and significant findings on auscultation, then a chest x-ray should follow without delay and, if possible, a high resolution Opportunistic Infections (OIs) 335 computed tomography (HRCT) of the lungs. The chest x-ray often shows relatively characteristic findings with a butterfly-shaped (perihilar) interstitial infiltrate. In the early stages, focus is on the mid- and lower fields. Indistinct, diffuse changes are more easily visible on HRCT than on a chest x-ray. A CT scan also allows a fairly certain distinction from other pulmonary infections (Hidalgo 2003). However, in cases where nothing pathological is visible on CT scan to an experienced radiolo- gist, then rapid initiation of treatment is still justified even without a definitive diag- nosis – particularly in the presence of the classic triad of symptoms, low CD4 T cell count and no previous PCP prophylaxis. Almost always present is partial respiratory insufficiency, which should be confirmed by arterial blood gas analysis. Lactate dehydrogenase (LDH) is often elevated and may have limited use as a predictive parameter for the course of disease. A high LDH is an unfavorable sign and may reflect the severity of the PCP. In contrast, CRP is often normal, provided there are no other concurrent infections. Sputum specimens are generally not useful (Review: Cruciani 2002), so that a bronchoalveolar lavage (BAL) is usually necessary. This can lead to detection of pneumocysts even after several days of treatment. Therefore, it is not essential to wait for the BAL to start treatment. The lab should be specifically alerted to possible PCP. The routine test for detecting Pneumocystis in the BAL is direct immunofluo- rescence assay (DFA). A real-time PCR assay also seems to be an accurate diagnosis method and could replace the DFA (Fillaux 2008). Performing the BAL as early as possible also allows for the timely diagnosis of co-infections (CMV, pneumococci). It should be noted that respiratory insufficiency can deteriorate with BAL. Full blood count, transaminases and kidney function must be monitored during treatment and baseline values should be determined at this point. Newer diagnostic approaches include antibody testing (Bishop 2003) and measure- ment of S-adenosylmethionine, an agent that pneumocysts require but cannot produce. S-adenosylmethionine levels are significantly reduced in patients with PCP (Skelly 2008). It is currently not foreseeable, whether these tests, which spare patients the discomfort of bronchoscopy, will be available for routine diagnostic testing in the future. This also applies to other serum markers such as beta-glucan or antibody tests (Desmet 2009, Watanabe 2009, Djawe 2010, Gingo 2011, Sax 2011). Elevated plasma beta-glucan has an especially high predictive value for diagnosing PCP in AIDS patients with respiratory symptoms (Wood 2013). Treatment General Treatment should be initiated immediately if there is clinical suspicion. In cases of mild PCP (PO2 >70–80 mm Hg), ambulatory treatment can be attempted. In very mild cases, even oral medication can be considered. This may well be possible in cooperation with a competent HIV nursing service. If such monitoring is not possi- ble, if respiratory deterioration occurs, and in all cases with resting dyspnea, imme- diate hospitalization is advised. If ventilation becomes necessary, patients have a poor prognosis, even today (Crothers 2005, Walzer 2008). Non-invasive methods (like CPAP) may be beneficial if used from an early stage.

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Randomized controlled study demonstrating failure of LPV/r monother- apy in HIV: the role of compartment and CD4-nadir order 300 mg combivir with amex. Changes in bone turnover and bone loss in HIV-infected patients changing treatment to tenofovir-emtricitabine or abacavir-lamivudine combivir 300 mg generic. Maintenance antiretroviral therapies in HIV infected patients with undetectable plasma HIV RNA after triple-drug therapy buy combivir 300mg low price. Change to abacavir-lamivudine-tenofovir combination treatment in patients with HIV-1 who had complete virological suppression discount 300 mg combivir with mastercard. A lamivudine (3TC)-based backbone in conjunction with a boosted protease inhibitor (PI) is sufficient to achieve virologic suppression in the presence of M184V mutations. Randomized, controlled, 48 week study of switching stavudine and/or pro- tease inhibitors to Combivir/abacavir to prevent or reverse lipoatrophy in HIV-infected patients. Ritonavir boosted indinavir treatment as a simplified maintenance “mono”- therapy for HIV infection. Maraviroc plus raltegravir failed to maintain virological suppression in HIV-infected patients with lipohypertrophy: results from the ROCnRAL ANRS 157 study. TRIZAL study: switching from successful HAART to Trizivir (abacavir lamivu- dine-zidovudine combination tablet): 48 weeks efficacy, safety and adherence results. Switch to efavirenz (EFV) after protease-inhibitor (PI)-failure: explorative analysis of outcome by baseline viral VS tolerability failure. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. Factors associated with virological failure in HIV-1-infected patients receiving darunavir/ritonavir monotherapy. Resistant minority species are rarely observed in patients on darunavir/ritonavir monotherapy. Targeting only reverse transcriptase with zidovudine/lamivudine/abacavir plus tenofovir in HIV-1-infected patients with multidrug-resistant virus: a multicentre pilot study. The safety and efficacy of switching stavudine to tenofovir df in com- bination with lamivudine and efavirenz in hiv-1-infected patients: three-year follow-up after switching therapy. Efficacy and safety of switching from boosted lopinavir to boosted atazanavir in patients with virological suppression receiving a LPV/r-containing HAART: the ATAZIP study. J AIDS 2009, 51:29-36 Marcelin AG, Lambert-Niclot S, Peytavin G, et al. Baseline HIV RNA ultrasensitive assay and viral DNA predict rise in plasma viral load in patients of MONOI-ANRS 136 Trial. Induction with abacavir/lamivudine/zidovudine plus efavirenz for 48 weeks followed by 48-week maintenance with abacavir/lamivudine/zidovudine alone in antiretroviral-naive HIV- 1-infected patients. Simplification of antiretroviral therapy with tenofovir-emtricitabine or abacavir- lamivudine: a randomized, 96-week trial. Bone mineral density in HIV participants randomized to raltegravir and lopinavir/ritonavir compared with standard second line therapy. HIV lipodystrophy in participants randomised to lopinavir/ritonavir (LPV/r) +2-3 nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTI) or LPV/r + raltegravir as second-line anti- retroviral therapy. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. Substitution of nevirapine, efavirenz, or abacavir for protease inhibitors in patients with HIV infection. Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study. Effectiveness of protease inhibitor monotherapy versus combination anti- retroviral maintenance therapy: a meta-analysis. PLoS One 2011, 6:e22003 McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in antiretroviral-naive persons ran- domized to receive abacavir-lamivudine or tenofovir disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: Aids Clinical Trials Group A5224s, a substudy of ACTG A5202. Effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in HIV-infected subjects: a randomized, controlled study. Mitochondrial function, inflammation, fat and bone in HIV lipoat- rophy: randomized study of uridine supplementation or switch to tenofovir. Improvements in lipoatrophy, mitochondrial DNA levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. Improvement in lipoatrophy associated with HAART in HIV- infected patients switched from stavudine to abacavir or zidovudine: the results of the TARHEEL study. Lopinavir/ritonavir monotherapy versus current treatment contin- uation for maintenance therapy of HIV-1 infection: the KALESOLO trial. How to switch ART 221 Milinkovic A, Martinez E, Lopez S, et al. The impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in HIV-infected patients. Reasons for stopping antiretrovirals used in an initial highly active anti- retroviral regimen: increased incidence of stopping due to toxicity or patient/physician choice in patients with hepatitis C coinfection. Simplification therapy with once-daily emtricitabine, didanosine, and efavirenz in HIV-1-infected adults with viral suppression receiving a PI-based regimen: a randomized trial. Dual therapy with etravirine plus raltegravir for virologically suppressed HIV- infected patients: a pilot study. J Antimicrob Chemother 2014, 69:742-8 Moyle G, Baldwin C, Langroudi B, Mandalia S, Gazzard BG. A 48 week, randomized, open label comparison of three abacavir-based substitution approaches in the management of dyslipidemia and peripheral lipoatrophy. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. Early vs deferred HAART switch in heavily pre-treated HIV patients with low viral load level and stable CD4 cell count. Virological, immunological, and clinical impact of switching from protease inhibitors to nevirapine or to efavirenz in patients with HIV infection and long-lasting viral suppression. Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus Darunavir/r in patients with suppressed viral load did not result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial. Viral rebound after switch to maraviroc/raltegravir dual therapy in highly experienced and virologically suppressed patients with HIV-1 infection. Four-year outcome of a PI and NRTI-sparing salvage regimen: maraviroc, ral- tegravir, etravirine. Monotherapy with Lopinavir/Ritonavir as maintenance after HIV-1 viral suppression: results of a 96-week randomized, controlled, open-label, pilot trial (KalMo study). A Switch in Therapy to a Reverse Transcriptase Inhibitor Sparing Combination of Lopinavir/Ritonavir and Raltegravir in Virologically Suppressed HIV-infected Patients: A Pilot Randomized Trial to Assess Efficacy and Safety Profile: The KITE Study. AIDS Res Hum Retroviruses 2012, 28:1196- 2062012 Feb 26. A randomized trial of simplified maintenance therapy with abacavir, lamivudine, and zidovudine in HIV infection. Simplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants.

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This substitution did not significantly reduce binding affinityoftheGP33–41 epitope for the MHC molecule Db 300 mg combivir with visa. Moskophidis and Zinkernagel (1995) concluded that this substitution interfered with stimulation of CTLs by the peptide-MHC complex generic combivir 300mg without a prescription. The V→Lsubstitution at P3 reduced binding affinity to the TCR by a factor of 50 order 300 mg combivir free shipping, even though P3 is buried in the peptide-MHC binding groove (fig purchase combivir 300mg fast delivery. The residue at P4 is exposed and had the strongest effect on binding affinity to the TCR, so movement of P4 could EXPERIMENTAL EVOLUTION: CTL ESCAPE 239 be responsible for the change in affinity. Escape variants with a Y→Fsub- stitution at P4 obtainedduringexperimental evolution in vivo cause a 100-fold decline in affinity for the TCR. Those changed proteins may have altered performance, affecting pathogen fit- ness in ways other than CTL escape. Ideally, experimental studies of escape would provide information about changed functional character- istics of pathogen proteins and the associated fitness consequences. I am not aware of any suchanalysesforCTL escape in experimentally controlled systems. They focused on the Tax protein, a major target of CTLs. Individuals with MHC type HLA-A2 simultaneously recognize at leastfiveepitopes of Tax (Parker et al. By contrast, in subjects without HLA-A2, only one of 116 of these epitopes had a substitution. CTLs appear to be imposing strong selective pressure that favors escape. Ninedifferent substitutions oc- curred across the five Tax epitopes. Each substitution abolished CTL attack of the associated epitope. HTLV-1 is a retrovirus that integrates itself into the host genome. The Tax protein is a trans-acting transcriptional regulator that modulates expression of several viral and cellular genes (Yoshida 2001). Because HTLV-1 typically occurs as an integrated provirus in host cells, viral replication occurs by transmission within the lineages of host cells and by transmission between cells. Tax appears to affect several aspects of the cell cycle, potentially enhancing cell division and reducing cell death. Potencies were comparedwithactivation by a consensus se- quence. Three substitutions had lowered ability to activate the viral promoter, and all nine substitutions caused lowered or no activation of two cellular promoters. The fitness consequences of these substitutions could not be measured directly. In vitro studies introduced mutations 240 CHAPTER 14 into the Tax protein and demonstrated that most mutations abolished Tax function (Smith and Greene 1990; Semmes and Jeang 1992). Thus, Tax appears to be highly constrained, suggesting that substitutions ac- cumulate only under very strong CTL pressure. Asecondstudy analyzed the selective pressure imposed by a drug (Samri et al. This study of human patients with HIV compared the viral reverse transcriptase (RT) protein before and after application of nucleoside inhibitors of RT. Substitutions in RT that escape drug pres- sure also reduce viral fitness (Coffin 1995; Back et al. Amino acid sequences of viral proteins may be shaped by two opposing pressures: contribution to viral function and escape from im- mune recognition. Thus, amino acid substitutions in response to a third force, such as a drug, may be likely to reduce protein performance or enhance recognition by the host immune system. In the case of RT, both reduced performance and enhanced MHC recognition may have occurred. Aparticularviral sequence reflects the balance between functional performance and avoidance of CTL recognition via MHC presentation. Experimentally applied selective pressures such as drugs may provide information about the functional andimmune selective pressures that shaped the wild-type sequence. IMMUNODOMINANCE The first experimentally controlled studies of escape from CTLs used extreme immunodominance (Pircher et al. In that system, ge- netically constructed mice produced the identical TCR on 75–90% of circulating T cells. That extreme, monoclonal TCR distribution creates EXPERIMENTAL EVOLUTION: CTL ESCAPE 241 powerful selection favoring escape mutants for epitopes recognized by the dominant TCR. More realistic polyclonal distributions of TCRs may not favor escape so easily (Borrow and Shaw 1998; Haanen et al. A single viral mutation can abrogate recognition of aparticularepitope, but the virus carrying the mutant will likely expressotherepitopes recognized by dif- ferent CTLs. By this argument, partial escape means partial recognition and death. Thedegree of immunodominance plays an important role. For some pathogens and hosts, a typical response may primarily target a single epitope, with fewer CTLs focusing on subdominant epitopes. In this case, the pressure on the lead epitope favors escape. Other infections may have a broader and more even CTL response against several epi- topes. Escape at one epitope does not alleviate recognition at several other epitopes. However, escape at multiple epitopes may be observed within individual hosts (Evans etal. The role of immunodomi- nance in escape depends on the rate of killing by CTLs relative to the rate of viral transmission between cells (McMichael and Phillips 1997; Nowak and May 2000). RATE OF KILLING VERSUS RATE OF TRANSMISSION Consider a cytopathic virus—one that bursts its host cell when lib- erating progeny virions. A CTL escape mutant gains if it enhances the probability of cellular burst before CTL-mediated death. This probabil- ity depends on the race between the CTLs to kill infected cells and the viruses to liberate progeny. Escapeatadominant epitope provides ben- efit if the aggregate rate of killing via subdominant epitopes allows a higher probability of burst before death. Noncytopathic viruses leak progeny virions from intact host cells. Here the race occurs between, on the one hand, CTL-induced death and, on the other hand, the time before the first viral progeny release and then the subsequent rate of progeny production. CTL escape has no benefit if pressure on other epitopes still kills before initial progeny production. If some infected cells survive to produce new virions, the benefit of escape at one epitope depends on the expected increase in cellular longevity during the productive phase of virion release and the probability that released viruses transmit to new host cells.

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Results of trials of treatment in adults with perennial allergic rhinitis 1 generic 300 mg combivir with visa. Directcomparisons The only evidence suggesting superiority of any 1 nasal corticosteroid over another comes from one 6-week trial of 273 patients with perennial allergic rhinitis in which budesonide aqueous 256 mcg was associated with a significantly greater mean reduction in a combined nasal 12 symptom score relative to fluticasone aqueous 200 mcg (-2 purchase 300mg combivir free shipping. There were no significant differences between nasal corticosteroids in perennial allergic rhinitis 52 combivir 300mg free shipping, symptom reductions when compared at similar dosages in most other trials (Tables 11 and 12) proven 300 mg combivir. The disparity of dosage levels between treatments used in this trial raise questions about how to interpret this finding, however. Reductions in nasal symptom scores in head-to-head trials of perennial allergic rhinitis patients Beclomethasone Budesonide Mometasone AQ AQ AQ Fluticasone p. AQ No 52, 53 Beclomethasone AQ No evidence 56 Mixed differences No Budesonide Budesonide AQ 58 12 differences superior 57 Mometasone AQ No differences Fluticasone p. AQ 51 50 It is unknown how the new or old forms of flunisolide 200 mcg compare directly to the new aqueous form of beclomethasone because both have only been compared to the discontinued aerosol form of beclomethasone 400 mcg in 4-week trials. No other head-to-head trials comparing either form of flunisolide directly to any other nasal corticosteroid in perennial allergic rhinitis patients were identified. The new and old forms of flunisolide were compared directly to each other in one 4-week trial and both were associated with similar reductions in 59 individual symptom scores (sniffing, stuffiness, sneezing, postnasal drainage). No fair- to good-quality trial of the direct comparative efficacy of triamcinolone relative to other nasal corticosteroids was identified. Beclomethasone compared with fluticasone Mixedfindingswerereportedacross2head-to-head trials comparing efficacy of 52, 53 beclomethasone to fluticasone (Table 10). While 1 study comparing standard doses of the 2 52 drugs found no significant differences in total symptom score, the other trial found that an above maximum daily dosage of fluticasone propionate (400 mcg) was superior to a maximum 53 dosage of beclomethasone (400 mcg) in reducing most individual symptoms. TheBritishmulticentertrial compared non-equivalent doses of the drugs (beclomethasone 200 mcg to fluticasone 200 mcg, both twice daily) for up to 1 year in 242 53 patients. The population included adolescents aged 16 and over and adults with perennial NCS Page 25 of 71 Final Report Update 1 Drug Effectiveness Review Project rhinitis based on clinical history, not an allergy test. There was no composite symptom score reported but only individual symptom scores for nasal and non-nasal symptoms. Results showed that fluticasone had significantly better symptom grades for nasal discharge, nasal blockage, and eye watering and irritation than beclomethasone. The other study compared fluticasone 100 mcg either once or twice daily to beclomethasone 168 mcg or placebo twice daily in 466 adults and adolescents as young as 12 52 years for 6 months. The outcome measures were expressed as reduction of total symptom scores using a visual analog scale (0-100 for each of 4 nasal symptoms). The study found no significant differences in efficacy between any of active drugs, both of which showed at least 45% reduction in total symptom score. It was noted that equivalent dosages of beclomethasone (400 mcg) and fluticasone (200 mcg) also had similar efficacy and safety in an unpublished 4- week randomized double-blind placebo-controlled parallel group trial of 286 adult patients with 70 perennial rhinitis that was identified in the dossier provided by the manufacturer of fluticasone. Drop-out rates for beclomethasone, fluticasone 100 and 200 mcg, and placebo (28% compared with 23% compared with 14% compared with 28%) in the published trial were noted to be relatively higher than in other similar trials. Mometasone Mometasone was associated with generally similar reductions in rhinitis symptoms 56 57 relative to beclomethasone and fluticasone across 2 head-to-head trials (Table 10). One double-blind RCT compared beclomethasone 400 mcg twice daily to mometasone 200 mcg once 56 daily in 427 adults and adolescents as young as age 12 with perennial allergic rhinitis. The study population included 45-54% patients with seasonal allergies and 18-24% with concomitant asthma. The primary outcome in this 12-week study was measured with mean percent reduction in total morning and evening symptom scores within the first 15 days. A trial comparing fluticasone to mometasone revealed mixed results for differences in 57 efficacy. One double-blind multicenter RCT compared fluticasone 200 mcg to mometasone 200 mcg in 550 adults and adolescents as young as 12 years with confirmed perennial allergic rhinitis. The primary outcome of mean percent reduction in total nasal symptom score had to be estimated from figures provided in the article. Although mometasone resulted in greater reduction of the total nasal symptom score, this patient-rated outcome was not significantly different between the 2 drugs. There was, however, a significantly greater reduction in the same physician-rated secondary outcomes of nasal congestion, nasal discharge, and overall condition with mometasone. Budesonide One trial found budesonide to be more efficacious in treating combined nasal symptoms 12 than fluticasone (Table 10). This 6-week Canadian/Spanish study investigated budesonide 256 mcg compared with fluticasone 200 mcg compared with placebo in 273 adults with confirmed 12 perennial allergic rhinitis. There was a significantly greater reduction in combined nasal symptoms scores with budesonide (-2. Moreover, they found that budesonide was significantly better than placebo at reducing nasal blockage than was fluticasone, while improvement in all other individual symptom scores was similar for both drugs. The onset of action, measured in hours before significant step-score reductions, was NCS Page 26 of 71 Final Report Update 1 Drug Effectiveness Review Project quicker for budesonide than fluticasone (36 h compared with 60 h). The secondary outcome of percentage of patients who reported substantial or total symptom control did not differ significantly between the 2 drugs. The only head-to-head study investigating budesonide and mometasone for perennial rhinitis found the 2 drugs comparable for nasal symptom scores and overall symptom control. One fair-quality European RCT compared budesonide 256 mcg or 128 mcg to mometasone 200 58 mcg or placebo in 438 adults with confirmed perennial allergic rhinitis. The primary efficacy outcome, nasal symptom score (morning and evening combined), was not significantly different in the 2 medications. Furthermore, there was no statistically significant difference for the secondary outcomes: percentage of patients experiencing no symptom control, consumption of rescue medication, and onset of action. We have identified unpublished quality of life data from this study in the dossier supplied by the manufacturer of budesonide that found no significant differences between treatments except that budesonide is superior to placebo for general health and vitality. Flunisolide: New compared with old formulations The randomized double-blind parallel-group study compared 2 different formulations of flunisolide aqueous in 215 patients with confirmed perennial allergic rhinitis and found similar 59 efficacy in both treatments. Dosages were equivalent in both the old and new formulations, which reduced propylene glycol from 20% to 5%, increased polyethylene glycol from 15% to 20%, and added 2. There were no significant differences in mean reduction of total symptom and individual symptom scores between formulations. Further, patients rated acceptability of nasal burning/stinging on a 100- point visual analog scale. The original formulation had a mean score of 52 while the new formulation was rated as 87 (P<0. Outcomes in head-to-head trials of perennial allergic rhinitis patients Interventions Study (Total Daily Dose) Sample size Duration Outcome Results Reduction in mean symptom (A) -1. The only head-to-head evidence identified for triamcinolone (220 mcg) comes from an open-label randomized parallel group 3-week trial of 175 perennial allergic rhinitis patients in which there were no differences in efficacy or safety 70 endpoints when compared to fluticasone 200 mcg once daily. Indirect comparisons Placebo-controlled trials of triamcinolone were evaluated due to the dearth of head-to- head evidence available for this nasal corticosteroid. There were 4 large (N=178 to 305) fair NCS Page 28 of 71 Final Report Update 1 Drug Effectiveness Review Project quality placebo-controlled trials that assessed triamcinolone in patients with perennial allergic 71-75 rhinitis and 1 very small study of cat allergic patients (N=12). All of the larger studies reported significantly lower nasal symptoms for the active drug in treatment of perennial rhinitis. Another study of 296 patients with mixed allergic rhinitis reported -4.

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Head-to-head trials of beta blockers for heart failure Number Number Author Other population screened/ Author withdrawn/ Year characteristics eligible/ Year lost to fu/ Country (diagnosis effective combivir 300 mg, etc) enrolled Country analyzed Galatius NYHA class III-IV=19 purchase combivir 300mg line. NR/70/70 Lombardo 2/0/70 2006 NYHA function class 2 generic combivir 300 mg overnight delivery. Head-to-head trials of beta blockers for heart failure Author Year Method of adverse effects Adverse effects Country Outcomes assessment? Beta blockers Page 310 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 11 cheap combivir 300mg without a prescription. Head-to-head trials of beta blockers for heart failure Author Withdrawals due to Year adverse events (%, Country adverse n/enrolled n) Galatius 0 2004 Denmark Poor Quality Lombardo 2. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Randomization Allocation Groups similar at Country described? Quality assessments of head-to-head trials of beta blockers for heart failure Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Sanderson Valvular heart disease as the etiology of LV dysfunction, active Yes Yes Yes Yes 1999 myocarditis, unstable angina, a documented history of sustained China ventricular tachycardia or symptomatic nonsustained ventricular tachycardia or second- or third degree atrioventricular block; chronic obstructive lung diseases, asthma, long-term alcohol or drug abuse or chronic renal failure (serum creatine >200 mmol/liter), hepatic hematological, neurological or collagen vascular disease Kukin Obstructive valvular disease, acute myocardial infarction within 6 weeks, Yes N/A - open N/A - open N/A - open 1999 or active angina study study study Metra Unstable angina,acute myoardial infarction, or a coronary Yes Yes Yes Yes 2000 revascularization procedure within 3 months; history of alcohol abuse; primary valve disease; congenital heart disease; systolic blood pressure <90 mm Hg; concomitant disease that might adversely influence prognosis or impair exercise capacity; contraindications to b-blocker therapy; concomitant treatment with other b-blockers, a-antagonists, calcium antagonists or antiarrhythmic agents (except amiodarone) Beta blockers Page 313 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Maintenance of Reporting of attrition, Year Intention-to-treat comparable crossovers, adherence, Loss to follow-up: Country (ITT) analysis groups and contamination differential/high Score Sanderson Unclear Unclear Attrition reported; Others NR Fair 1999 NR China Kukin No NR Attrition reported; Others None Fair 1999 NR Metra No NR Attrition reported; Others None Fair 2000 NR Beta blockers Page 314 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Country Funding Control group standard of care Length of follow-up Sanderson NR Yes 12 weeks 1999 China Kukin SKB Yes 6 months 1999 Metra CARIPLO funds University of Brescia Yes 44 months 2000 Beta blockers Page 315 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Randomization Allocation Groups similar at Country described? Metoprolol European Trial (COMET) Beta blockers Page 316 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Metra Patients with an acute ischemic event or a coronary revascularization Yes Yes Yes Yes 2002 procedure within 3 months; a history of alcohol abuse; primary valve US, Italy disease or congenital heart disease; frequent ventricular premature beats and/or runs of ventricular tachycardia; contraindications to beta-blocker therapy; concomitant treatment with other beta-blockers, a-antagonists, calcium antagonists or antiarrhythmic agents (except amiodarone) Poole-Wilson Recent change in treatment within 2 weeks before randomization; Yes Yes Yes Yes 2003 requirement for intravenous inotropic therapy; current treatment with non- Europe dihydropyridine calcium channel blockers (diltiazem, verapamil); amiodarone (>200 mg per day); class-I antiarrhythmic drugs; unstable Carvedilol Or angina; myocardial infarction; coronary revascularisation or stroke within Metoprolol the previous 2 months; uncontrolled hypertension (SBP >170 mm Hg or European Trial DBP >105 mm Hg); hemodynamically significant valvular disease; (COMET) symptomatic and sustained ventricular arrhythmias within the past 2 months note adequately treatment with antiarrhythmic drugs or implantation of an automatic defibrillator; pregnancy; women with childbrearing potential on inadequate contraception; known drug or alcohol misuse; poor compliance; any other serious systemic disease; contraindication to beta blockers Beta blockers Page 317 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Maintenance of Reporting of attrition, Year Intention-to-treat comparable crossovers, adherence, Loss to follow-up: Country (ITT) analysis groups and contamination differential/high Score Metra No NR Attrition reported; Others None Fair 2002 NR US, Italy Poole-Wilson Yes NR 31. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Country Funding Control group standard of care Length of follow-up Metra NR Yes 9-12 months 2002 US, Italy Poole-Wilson F Hoffman La Roche and GlaxoSmithKline; Yes 58 months 2003 first author has served as a consultant to or Europe received travel expenses, payment for speaking at meetings or funding for Carvedilol Or research from one or more of the major Metoprolol pharmaceutical companies European Trial (COMET) Beta blockers Page 319 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Randomization Allocation Groups similar at Country described? Beta blockers Page 320 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Eligibility Outcome Care Patient Year criteria assessors provider unaware of Country Exclusion criteria for recruitment specified blinded blinded treatment Galatius Patients who had contraindications for BB treatment; and those who had Yes No No No 2004 been admitted, had attended an emergency room, or who had been treated in the heart failure clinic for acute decompensation within 2 weeks prior to randomization. Patients were excluded from data analysis if they died before two months of follow-up. Lombardo SBP <90mm Hg; DBP <60mm Hg; HR <50 bpm; cerebral vascular Yes No No No 2006 accidents w/in previous 6 months; heart or vascular surgery or MI w/in Italy previous 3 months; serious valvular conditions that required surgery; atrioventricular conduction abnormalites; milignancies; serious liver, kidney, connective tissue, respiratory, or hematologic disease; history of allergy; intolerance to ACE inhibitors; unstable angina, DM; digitalis intolerance; BMI >30; excercise tolerance limited by other disorders; pregnancy. Beta blockers Page 321 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Maintenance of Reporting of attrition, Year Intention-to-treat comparable crossovers, adherence, Loss to follow-up: Country (ITT) analysis groups and contamination differential/high Score Galatius No; excluded 3 NR Yes NR Poor 2004 patients that died No prior to completing 2 No months of treatment No Lombardo Yes Yes Yes NR Fair 2006 No Italy No No Beta blockers Page 322 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 12. Quality assessments of head-to-head trials of beta blockers for heart failure Author Year Country Funding Control group standard of care Length of follow-up Galatius Danish Pharmacy Foundation, Merck Sharp Yes 10. Outcomes in head-to-head trials of beta blockers for heart failure Sample Worsening Trial Interventions* size Duration Baseline EF Mortality heart failure Sanderson Carvedilol 51 12 weeks 26% NR NR 1999 Metoprolol Fair Kukin Carvedilol 67 6 months 18-19% NR car=3/37(8. Outcomes in head-to-head trials of beta blockers for heart failure Change in EF following Trial NYHA Class Exercise capacity treatment Sanderson # patients at NYHA class I/II/III/IV Improvement in 6-min walk(feet) Mean EF at Week 12 (% 1999 car car=72(6. Outcomes in head-to-head trials of beta blockers for heart failure Trial Quality of life Sanderson Minnesota QOL mean reduction in symptom 1999 score (%) car=9. Randomized controlled trials of beta blockers for arrhythmia Author Year Study design Country Setting Eligibility criteria Exclusion criteria Head-to-head trials Katritsis RCT Patients subjected to cardioversion of Terminal illness, age > 80 years, left ventricular 2003 multicenter persistent AF (> 7 days) ejection fraction <30, concomitant treatment with class I or III antiarrhythmic drugs, amiodarone use Fair quality within 3 months before randomization, previous treatment with bisoprolol or carvedilol, and contraindications to beta blockade, such as conduction disturbances, asthma, or severe chronic obstructive pulmonary artery disease Beta blockers Page 327 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 14. Randomized controlled trials of beta blockers for arrhythmia Author Allowed other Method of outcome Age Year Interventions (drug, regimen, medications/ assessment and timing of Gender Country duration) interventions assessment Ethnicity Head-to-head trials Katritsis Bisoprolol 10 mg daily (or 5 mg No restrictions, with Clinic visits at months 1, 3, Mean 2003 daily if LVEF < 40%) exception of class I 6 and 12 age=65. Randomized controlled trials of beta blockers for arrhythmia Number Author Number screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Head-to-head trials Katritsis Heart rate=71. Randomized controlled trials of beta blockers for arrhythmia Author Year Method of adverse Adverse effects Withdrawals due to adverse events Country effects assessment? Randomized controlled trials of beta blockers for arrhythmia Author Year Study design Country Setting Eligibility criteria Exclusion criteria Placebo- controlled trials Metoprolol vs placebo Kuhlkamp RCT Patients at 71 centers with persistent atrial Use of Class 1 or 3 antiarrhythmic drug, beta- 2000 multicenter fibrillation of 3 days to 1 year. Must be blockers or calcium channel blockers; chronic Germany converted to sinus rhythm. Sufficient treatment with amiodarone within 6 months; anticoagulation for 1+ months strongly contraindications to beta-adrenergic blocking recommended to providers. Randomized controlled trials of beta blockers for arrhythmia Author Allowed other Method of outcome Age Year Interventions (drug, regimen, medications/ assessment and timing of Gender Country duration) interventions assessment Ethnicity Placebo- controlled trials Metoprolol vs placebo Kuhlkamp n = 403 Digoxin/digitoxin, Primary endpoint: Mean age 2000 metoprolol (met): start 100 mg/day ACE inhibitor, relapse into atrial fibrillation 60. Randomized controlled trials of beta blockers for arrhythmia Number Author Number screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Placebo- controlled trials Metoprolol vs placebo Kuhlkamp Previous cardioversion: Screened = NR Lost for efficacy data (no Death: 2000 met = 18/197 (9%) pla = 22/197 (11%) Eligible = NR followup ECG) = 9/403 met = 3/200 (2%) pla = 0 Germany Hypertension: Enrolled = 403 (2%) met = 96/197 (49%) pla = 91/197 (46%) Lost for safety data = Premature discontinuation due to relapse to Coronary artery disease: 4/403 (1%) atrial fibrillation/flutter: met = 52/197 (26%) pla = 48/197 (24%) met = 96/197 (49%) Heart failure: Analyzed = 394/403 (98%) pla = 118/197 (60%) met = 51/197 (26%) pla = 49/197 (25%) and 399/403 (99%) Stroke/TIA: Total relapse to atrial fibrillation: met = 15/197 (8%) pla = 12/197 (12%) met = 87/197 (44%) Diabetes mellitus: pla = 118/197 (60%) met = 23/197 (12%) pla = 17/197 (9%) NYHA 1: met = 125/197 (64%) pla = 137/197 (70%) NYHA2: met = 64/197 (33%) pla = 54/197 (27%) NYHA3: met = 8/197 (4%) pla = 6/197 (3%) Beta blockers Page 333 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 14. Randomized controlled trials of beta blockers for arrhythmia Author Year Method of adverse Adverse effects Withdrawals due to adverse events Country effects assessment? Randomized controlled trials of beta blockers for arrhythmia Author Year Study design Country Setting Eligibility criteria Exclusion criteria Metoprolol vs placebo Khand RCT Patients with persistent atrial fibrillation (> 1 Heart rate at rest < 60 beats/min, systolic blood 2003 multicenter month) and heart failure (appropriate symptoms pressure < 90 mm Hg, sick sinus synddrome or UK of heart failure for more than two months and complete heart block, current treatment with a beta- echocardiographic evidence of cardiac blocker or HR-lowering calcium channel antagonist Fair quality dysfunction [LVEF < 40% or preserved LV or > 200 mg amiodarone, recent major systolic function, together with LV hypertrophy, cardiovascular event or procedures, asthma or suggesting diastolic dysfunction in the absence reversible obstructive airways disease, serum of an alternative potential cause of symptoms]) creatinine > 250 µmol/l or significant hepatic who were receiving digoxin and diuretics disease, uncorrected significant valvular heart disease, or any life-threatening noncardiac disease Beta blockers Page 335 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 14. Randomized controlled trials of beta blockers for arrhythmia Author Allowed other Method of outcome Age Year Interventions (drug, regimen, medications/ assessment and timing of Gender Country duration) interventions assessment Ethnicity Metoprolol vs placebo Khand Phase I ACE inhibitors 1) LVEF Mean 2003 Open digoxin +placebo Warfarin 2) Ventricular rate control by age=68. Randomized controlled trials of beta blockers for arrhythmia Number Author Number screened/ withdrawn/ Year Other population characteristics eligible/ lost to fu/ Country (diagnosis, etc) enrolled analyzed Outcomes Metoprolol vs placebo Khand IHD etiology=40. Randomized controlled trials of beta blockers for arrhythmia Author Year Method of adverse Adverse effects Withdrawals due to adverse events Country effects assessment? Quality assessments of randomized controlled trials of beta blockers for arrhythmia Author Year Allocation Groups similar Similarity to target Number Country Random assignment concealed at baseline population recruited Head-to- head trials Katritsis NR NR Yes Selected for patients 102 2003 naïve to study drugs Placebo- controlled trials Metoprolol vs placebo Kuhlkamp Adequate, computer NR Yes No - selection for 403 2000 generated healthier population - mean age of sample = 60 years; mean age atrial fibrillation patients = 75 years Beta blockers Page 339 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 15. Quality assessments of randomized controlled trials of beta blockers for arrhythmia Author Eligibility Outcome Care Patient Intention-to- Maintenance of Year criteria assessors provider unaware of treat (ITT) comparable Country Exclusion criteria for recruitment specified blinded blinded treatment analysis groups Head-to- head trials Katritsis Terminal illness, age > 80 years, left ventricular Yes Yes NR NR No NR 2003 ejection fraction <30, concomitant treatment with class I or III antiarrhythmic drugs, amiodarone use within 3 months before randomization, previous treatment with bisoprolol or carvedilol, and contraindications to beta blockade, such as conduction disturbances, asthma, or severe chronic obstructive pulmonary artery disease Placebo- controlled trials Metoprolol vs placebo Kuhlkamp • Use of Class 1 or 3 antiarrhythmic drug, beta- Yes NR Yes Yes No Yes 2000 blockers or calcium channel blockers; chronic treatment with amiodarone within 6 months. Quality assessments of randomized controlled trials of beta blockers for arrhythmia Reporting of attrition, Differential loss to Control Author crossovers, follow-up or Score group Year adherence, and overall high loss to (good/ fair/ standard of Length of Country contamination follow-up poor) Funding care follow-up Head-to- head trials Katritsis Yes No Fair NR Yes 12 months 2003 No No No No Placebo- controlled trials Metoprolol vs placebo Kuhlkamp Attrition=6. Quality assessments of randomized controlled trials of beta blockers for arrhythmia Author Year Allocation Groups similar Similarity to target Number Country Random assignment concealed at baseline population recruited Metoprolol vs placebo Khand NR NR Yes Mean age=68. Quality assessments of randomized controlled trials of beta blockers for arrhythmia Author Eligibility Outcome Care Patient Intention-to- Maintenance of Year criteria assessors provider unaware of treat (ITT) comparable Country Exclusion criteria for recruitment specified blinded blinded treatment analysis groups Metoprolol vs placebo Khand Heart rate at rest < 60 beats/min, systolic blood Yes Yes Yes Yes Yes NR 2003 pressure < 90 mm Hg, sick sinus syndrome or UK complete heart block, current treatment with a beta- blocker or HR-lowering calcium channel antagonist or > 200 mg amiodarone, recent major cardiovascular event or procedures, asthma or reversible obstructive airways disease, serum creatinine > 250 µmol/l or significant hepatic disease, uncorrected significant valvular heart disease, or any life-threatening noncardiac disease Beta blockers Page 343 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 15. Quality assessments of randomized controlled trials of beta blockers for arrhythmia Reporting of attrition, Differential loss to Control Author crossovers, follow-up or Score group Year adherence, and overall high loss to (good/ fair/ standard of Length of Country contamination follow-up poor) Funding care follow-up Metoprolol vs placebo Khand Yes No Fair Roche Yes Phase I=4 2003 No No Pharmaceuticals months; UK No Phase II=6 No months Beta blockers Page 344 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Year Allowed other Country Interventions (drug, medications/ Study Design Eligibility criteria Exclusion criteria regimen, duration) interventions Fair quality Atenolol Forssman History of migraine (Ad Hoc Committee) NR Atenolol (ate) 100 mg daily Common analgesics and 1982 Placebo (pla) x 90 days; then ergotamine Sweden crossover Fair quality RCT Crossover Beta blockers Page 345 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Year Age Other population Number screened/ Country Method of outcome assessment Gender characteristics eligible/ Study Design and timing of assessment Ethnicity (diagnosis, etc) enrolled Fair quality Atenolol Forssman Patient forms: 1) number; 2) intensity Mean age=40 NR NR/NR/24 enrolled 1982 (3-point scale); 3) duration of attacks; 80% female Sweden 4) incapacity for work; 5) medication Race NR Fair quality Integrated headache: score RCT Crossover considering combined effect of intensity and duration Follow-up visits were made after 14, 56, 154, and 254 days Beta blockers Page 346 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment? Placebo controlled trials of beta blockers for migraine Author Withdrawals due Year to adverse events Country (%, adverse Study Design Adverse effects reported n/enrolled n) Comments Fair quality Atenolol Forssman Dizziness of orthostatic ate=1 1982 type(# pts): ate=6; pla=1 pla=0 Sweden Diffuse tiredness: ate=2; pla=0 Fair quality Mood alterations: ate=1; RCT Crossover pla=0 Beta blockers Page 348 of 494 Final Report Update 4 Drug Effectiveness Review Project Evidence Table 16. Placebo controlled trials of beta blockers for migraine Author Year Age Other population Number screened/ Country Method of outcome assessment Gender characteristics eligible/ Study Design and timing of assessment Ethnicity (diagnosis, etc) enrolled Bisoprolol van de Ven Patient diary assessed at 4-wk Mean age: bis Family history of migraine(# NR/NR/226 randomized 1997 intervals 5 mg=38. Placebo controlled trials of beta blockers for migraine Author Number Year withdrawn/ Method of Country lost to fu/ adverse effects Study Design analyzed Outcomes assessment?

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