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Malegra FXT

2019, Minneapolis College of Art and Design, Koraz's review: "Malegra FXT 140 mg - Trusted Malegra FXT.".

Included interventions were a proton pump inhibitor (omeprazole 140 mg malegra fxt, lansoprazole malegra fxt 140 mg, pantoprazole 140mg malegra fxt, rabeprazole malegra fxt 140mg, or esomeprazole) compared with proton pump inhibitor , other ulcer drug (H2 receptor antagonist , prokinetic agent , or antacid) , placebo , surgery , or antibiotics. For adverse effects, we also included observational studies. Outcomes measured were symptoms, functional outcomes, endoscopic healing, eradication of Helicobacter pylori, quality of life, and adverse effects. We excluded reports that were published as only abstracts (see Appendix C). To evaluate efficacy we included only randomized controlled trials. The validity of controlled trials depends on how they are designed. Randomized, properly blinded clinical trials 1-3 are considered the highest level of evidence for assessing efficacy. Clinical trials that are not randomized or blinded, and those that have other methodological flaws, are less reliable but are also discussed in our report. Trials that compared one proton pump inhibitor with another provided direct evidence of comparative efficacy and adverse event rates. We did not examine in detail placebo-controlled or active-control trials when head-to-head trials were available. In theory, trials that compare proton pump inhibitors with H2 receptor antagonists or placebos also can provide evidence about efficacy. However, the efficacy of proton pump inhibitors in different trials can be difficult to interpret because of differences between patients. To supplement our analyses of published results, we requested and received from the trial 4, 5 6 funders additional data for 2 published trials and 1 trial that was submitted to the US Food and Drug Administration but not published. Proton pump inhibitors Page 11 of 121 Final Report Update 5 Drug Effectiveness Review Project To evaluate adverse events, we included clinical trials and observational cohort studies. Clinical trials are often not designed to assess adverse events and may select only low-risk patients (in order to minimize drop-out rate) or use inadequately rigorous methodology for assessing adverse events. Observational studies designed to assess adverse event rates may include broader populations, carry out observations over a longer period, use higher quality methodological techniques for assessing adverse events, or examine larger sample sizes. Data Abstraction The following data were abstracted from included studies: study design; setting; population characteristics (including sex, age, ethnicity, diagnosis); eligibility and exclusion criteria; interventions (dose and duration); comparisons; numbers screened, eligible, enrolled, and lost to follow-up; method of outcome ascertainment; and results for each outcome. We recorded intention-to-treat results if they were available and the trial did not report high overall loss to follow-up. Data were abstracted by one reviewer and checked for accuracy by a second; disagreements were resolved by consensus. Validity Assessment We assessed the internal validity (quality) of trials based on the predefined criteria listed in Appendix D. These criteria are based on criteria developed by the US Preventive Services Task Force and the National Health Service Centre for Reviews and Dissemination (United Kingdom) 2, 7 for assessing study quality. We rated the internal validity of each trial on the basis of the methods used for randomization, allocation concealment, and blinding; the similarity of compared groups at baseline; maintenance of comparable groups; adequate reporting of dropouts, attrition, crossover, adherence, and contamination; loss to follow-up; and the use of intention-to-treat analysis. Trials that had a fatal flaw in 1 or more categories were rated poor quality. Trials that met all criteria were rated good quality. As the fair-quality category is broad, studies with this rating vary in their strengths and weaknesses: The results of some fair-quality studies are likely to be valid, while others are only probably valid. A poor-quality trial is not valid; the results are at least as likely to reflect flaws in the study design as a true difference between the compared drugs. External validity of trials was assessed based on whether the publication adequately described the study population, whether patients in the study were similar to patients in the target population in whom the intervention will be applied, and whether the treatment received by the control group was reasonably representative of standard practice. We also recorded the funding source and role of the funder. Appendix D also shows the criteria we used to rate observational studies of adverse events. These criteria reflect aspects of the study design that are particularly important for assessing adverse event rates. We rated observational studies as good quality for adverse event assessment if they adequately met 6 or more of the 7 predefined criteria, fair if they met 3 to 5 criteria, and poor if they met 2 or fewer criteria. Overall quality rating for an individual study was based on ratings of internal and external validity of the trial. A particular randomized trial might receive 2 quality ratings, 1 for efficacy and another for adverse events. The overall strength of evidence for a particular key question reflects the quality, consistency, and power of the set of studies relevant to the question. Proton pump inhibitors Page 12 of 121 Final Report Update 5 Drug Effectiveness Review Project Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy-of-evidence approach, in which the best evidence was the focus of our synthesis for each question, population, intervention, and outcome addressed. Differences in healing rates (ulcers and esophagitis) between drugs based on head-to-head trials are expressed as the percent risk difference, defined as the difference between the proportions healed in 2 groups of patients at a specified time-point. For example, if at 4 weeks 80% of patients in group A have only healed lesions and 75% in group B have only healed lesions, then the risk difference between the groups is 5%. A measure of the variance around these estimates, the 95% confidence interval (CI) is also reported. If the 95% CI includes 0, then the difference is not statistically significant. Meta- analysis was done using RevMan software using a random-effects model. To determine healing and symptom resolution rates for individual drugs, we performed a meta-analysis by using a random-effects model controlling for the effect of the study. For example, the healing rate for Drug A might be calculated as 81% based on 7 head-to-head trials, and Drug B might have a rate of 83% based on 4 head-to-head trials.. Similarly, we conducted random-effects logistic meta-regression to estimate rates of healing associated with individual drugs based on studies comparing a proton pump inhibitor with a H2 receptor antagonist. The rate of healing with the proton pump inhibitor was adjusted for healing rate with H2 receptor antagonist within the same study. The model stratified by type of proton pump inhibitor (lansoprazole, omeprazole, pantoprazole, and rabeprazole). Posterior distributions were simulated using WinBUGS software version 1. Peer and Public Review The Original report underwent a review process that involved solicited peer review from clinical experts. Their comments were reviewed and, where possible, incorporated into the final document. The comments received and the author’s proposed actions were reviewed by the representatives of the participating organizations of the Drug Effectiveness Review Project prior to finalization of the report. Names of peer reviewers for Drug Effectiveness Review Project reports are listed at www. Peer reviewers have a maximum of 3 weeks for review and comment. They are asked to submit their comments in a standardized form in order to maintain consistent handling of comments across reports and to allow the Drug Effectiveness Review Project team to address all comments adequately. The Drug Effectiveness Review Project process allows for a 2-week public comment period prior to finalization of the current report. Draft reports are posted on the Drug Effectiveness Review Project web site and interested individuals or organizations have the ability to review the complete draft report and submit comments. For Update 5 of this report, we received comments from 2 pharmaceutical companies. Proton pump inhibitors Page 13 of 121 Final Report Update 5 Drug Effectiveness Review Project RESULTS Overview Our literature searches identified 550 new citations for Update 5: 376 from Medline, 57 from Cochrane Central Register of Controlled Trials, 45 from dossiers submitted by the manufacturers of esomeprazole and rabeprazole, 31 from Cochrane Database of Systematic Reviews, 29 from Database of Abstracts of Reviews of Effects, 7 from public comment on the draft of this report, and 5 from reference lists of included review articles. Of these 68 were ultimately included (see Figure 1). We excluded trials when the study was reported only as an abstract, contained no original data, contained no included outcome measure, did not have an included study design, did not use an included drug or used combined drug therapy where the effect of the proton pump inhibitor could not be distinguished, did not evaluate an included patient population, or was reported in a language other than English. Figure 1 summarizes the flow of study inclusion and exclusion. No study of omeprazole in combination with sodium bicarbonate (Zegerid) met inclusion criteria. There is controversy about the appropriateness of dose comparisons in head-to-head trials comparing esomeprazole with omeprazole. The US Food and Drug Administration’s clinical review of esomeprazole indicates that esomeprazole 40 mg is “pharmacodynamically thrice that of the s-isomer” in omeprazole 20 mg (see US Food and Drug Administration Medical Review, 9 executive summary, page 4). While the doses approved by the US Food and Drug Administration for treatment of erosive esophagitis are 20 to 40 mg daily for esomeprazole, and 20 mg daily for omeprazole (both for 4 to 8 weeks), because of differences in drug chemistry and pharmacology, there is no clear equivalent dose of omeprazole and esomeprazole. Proton pump inhibitors Page 14 of 121 Final Report Update 5 Drug Effectiveness Review Project Figure 1. Results of literature search a 3585 (550) : Total number of citations identified from searches 3065 (449) excluded at title/abstract level 520 (101) articles retrieved for full- text evaluation 243 (33) articles excluded at full- text level: • 23 (11) population not included • 85 (1) publication type not included (letter, editorial, nonsystematic review, etc) • 112 (20) study design not included • 9 (0) outcome not included • 4 (0) intervention not included • 9 (0) foreign language • 1 (1) study not retrievable 277 (68) included studies: • 118 (37) head-to-head trials • 79 (2) active-control trials • 17 (1) placebo-controlled trials • 21 (6) systematic reviews • 26 (15) observational studies • 16 (7) other (pooled analyses, postmarketing surveillance study, retrospective studies etc. Proton pump inhibitors Page 15 of 121 Final Report Update 5 Drug Effectiveness Review Project Key Question 1. What is the comparative efficacy of different proton pump inhibitors in patients with symptoms of gastroesophageal reflux disease? Summary Symptom relief and healing in patients with erosive esophagitis • Among 16 head-to-head trials, those with comparable doses did not find differences in symptom relief or healing of esophagitis. Thirteen head-to-head trials found these 4 proton pump inhibitors to be equally effective in healing at 4 and 8 weeks. The pooled difference in healing rate was significantly greater with esomeprazole at 4 and 8 weeks, risk differences 5% (95% CI 2 to 7) and 3% (95% CI 1 to 5), respectively. Pooled analysis of 3 trials with similar populations finds that esomeprazole was superior to pantoprazole at 4 weeks (risk difference 5%, 95% CI 2 to 8), but not at 8 weeks (risk difference 1%, 95% CI −3 to 5). Healing in moderate to severe erosive esophagitis • Esomeprazole 40 mg was more effective at healing esophagitis at 4 and 8 weeks than omeprazole 20 mg and lansoprazole 30 mg. Proton pump inhibitors Page 16 of 121 Final Report Update 5 Drug Effectiveness Review Project Prevention of relapse in patients with erosive esophagitis • For maintenance of healed esophagitis, there was good evidence that no difference exists between omeprazole, lansoprazole, and rabeprazole. The longest study (over 5 years) compared omeprazole with rabeprazole. Symptom relief in patients with nonerosive gastroesophageal reflux disease or presumptively treated symptoms of gastroesophageal reflux disease • Three head-to-head trials in patients with gastroesophageal reflux disease but without erosive esophagitis on endoscopy found no difference between esomeprazole 20 mg and omeprazole 20 mg, pantoprazole 20 mg, or rabeprazole 10 mg. Evidence in children • There were no direct comparisons of proton pump inhibitors for reflux esophagitis in children. A fair-quality placebo-controlled trial in infants did not find omeprazole to be superior to placebo in controlling symptoms or acid-exposure time. Detailed Assessment Erosive esophagitis We identified 31 randomized controlled trials comparing 2 or more proton pump inhibitors in patients with gastroesophageal reflux disease with endoscopically-proven erosive esophagitis 4-6, 10-38 (Evidence Table 1). Two publications are supplemented with additional data provided by 4, 5 the manufacturer. No study of omeprazole in combination with sodium bicarbonate met inclusion criteria. The scales used to grade esophagitis in these studies are described in Appendix E. In most studies of proton pump inhibitors, patients who have esophagitis before treatment undergo another endoscopy for assessment of healing 4 or 8 weeks after starting treatment. There is no evidence that rate of esophageal healing after 4 or 8 weeks of treatment is associated with risk of stricture or esophageal cancer in the long run. As distinct from symptom relief, the benefit of quicker esophageal healing is also uncertain. The clinical importance of small differences in healing rates at 4 or 8 weeks is not known. In addition, patients who have clinically significant improvements but who are not completely healed (for example, patients whose esophagitis improves from LA classification scale grade D to grade B) are considered unhealed. Studies do not report the esophagitis grade for patients “not healed” at follow-up. Resolution of symptoms Proton pump inhibitors Page 17 of 121 Final Report Update 5 Drug Effectiveness Review Project Five head-to-head comparisons of proton pump inhibitors measured symptom relief as a primary 10, 11, 13, 16, 37 4, 5, 12, 14, 15, 17, 21-26, 30, 32, outcome, and 14 reported symptoms as a secondary outcome. Sixteen head-to-head trials reported the proportion of patients with resolution of 4, 5, 10, 12-14, 16, 17, 20, 23, 24, 26, 27, 29, 33, 36 symptoms at 4 weeks. We performed a random-effects meta- analysis of data from these studies to determine an estimate of the proportion who were symptom-free at 4 weeks for each drug. Proportions ranged from 65% to 77%, and 95% confidence intervals overlapped, indicating the drugs are similarly efficacious for resolution of symptoms at 4 weeks. A systematic review of most of these trials, with search dates through 2004, evaluated the 39 proton pump inhibitors as a group and compared to one another. This meta-analysis found omeprazole 20 mg daily to be inferior to esomeprazole 40 mg or lansoprazole 30 mg daily in heartburn relief at day 1, with relative risks of 0. Lansoprazole and esomeprazole were not found statistically different (relative risk 1. Our analysis includes more recently published trials. Symptom resolution in head-to-head trials in patients with erosive gastroesophageal reflux disease Proton pump inhibitor Resolution of symptoms at 4 Reference number and daily dose weeks (95% CI) 4, 5, 10, 12, 16, 20, 29 Esomeprazole 40 mg 73% (65 to 82) 4, 13-15, 23, 29 Lansoprazole 30 mg 70% (61 to 80) 5, 12, 13, 16, 24, 26, 27 Omeprazole 20 mg 65% (54 to 76) 14, 17 Omeprazole 40 mg 76% (65 to 87) 27 Pantoprazole 20 mg 77% (70 to 84) 10, 13, 17, 20, 23, 26 Pantoprazole 40 mg 72% (62 to 83) 24 Rabeprazole 20 mg 69% (52 to 86) 4, Figure 2 shows risk differences in rates of symptom resolution at 4 weeks in these trials. The pooled data on the comparison of esomeprazole 40 mg with omeprazole 20 mg significantly favored esomeprazole; for every 13 persons treated with esomeprazole 40 mg instead of omeprazole 20 mg, 1 additional patient would be symptom-free at 4 weeks in the esomeprazole group. The pooled data for comparison of esomeprazole 40 mg with either lansoprazole 30 mg or pantoprazole 40 mg did not indicate a significant difference between drugs. Proton pump inhibitors Page 18 of 121 Final Report Update 5 Drug Effectiveness Review Project Figure 2.

Similarly malegra fxt 140 mg, unblinded ratings of the Children’s Global Assessment Scale and Social Skills Rating Scale improved by 5 points (of 100; P<0 140 mg malegra fxt. Children (elementary school age; 6-12 years) Stimulants Comparison of immediate-release and sustained-release formulations Methylphenidate 140mg malegra fxt. We included 13 trials of immediate-release methylphenidate compared with 39-49 methylphenidate SR malegra fxt 140mg. Of these , 4 were poor quality due to either inadequate or undescribed methods of randomization and allocation concealment , combined with lack of description of an intent to treat analysis , lack of information on eligibility criteria , attrition , or post randomization 39 , 40, 44, 46 exclusions (Evidence Table 3). The remaining studies compared immediate-release ® ® methylphenidate to 5 extended-release formulations of methylphenidate (Biphentin , Concerta , ® ® ® 41-43, 45, 47-49 Ritalin SR , Medikinet , or Metadate CD ). No trials comparing the other extended-release formulations of methylphenidate (Ritalin ® ® ® LA , Methylin ER , or Metadate ER ) to immediate-release methylphenidate were found. Table 4, below, presents basic pharmacokinetic information on the methylphenidate products. Five studies have compared immediate-release methylphenidate with methylphenidate OROS once 41, 42, 48-50 daily, enrolling a total of 561 children with ADHD (Table 5). Attention deficit hyperactivity disorder 39 of 200 Final Update 4 Report Drug Effectiveness Review Project a Table 4. Pharmacokinetic profiles of methylphenidate products Time to Duration Daily peak of action Drug doses (hours) (hours) Delivery system Short-acting immediate-release 2-3 1-2 3-4 Immediate-release tablet methylphenidate Intermediate-acting ® Metadate ER 2-3 ~ 4-5 8 Wax-matrix vehicle tablet ® Methylin ER 2-3 ~ 4-5 8 Wax-matrix vehicle tablet ® Ritalin SR 1-2 ~ 3-4 8 Wax-matrix vehicle tablet Focalin® 2 1-1. Attention deficit hyperactivity disorder 40 of 200 Final Update 4 Report Drug Effectiveness Review Project Table 5. Trials of immediate-release methylphenidate compared with ® methylphenidate OROS (Concerta ) Mean change in IOWA Conners’ SNAP-IV Study details Mean dose MPH OROS vs. MPH IR Teacher SNAP-IV: Inattention Teacher ratings: –0. United States ® Concerta 18- Other outcomes compared only to N=64 54 mg daily placebo. Attention deficit hyperactivity disorder 41 of 200 Final Update 4 Report Drug Effectiveness Review Project In the 3 double-blind trials submitted to the US Food and Drug Administration, in which the primary comparison of interest was specified as methylphenidate OROS compared with placebo, methylphenidate OROS and immediate-release methylphenidate did not differ 41, 42, 50 significantly on the majority of direct comparisons. In contrast, the 2 newer, open-label 48, 49 studies did find a significant difference favoring methylphenidate OROS. There is a potential 41 risk of selection bias in that only 1 of the studies reported the proportion of patients taking immediate-release methylphenidate or methylphenidate OROS prior to enrollment. The US Food and Drug Administration Statistical Review of the New Drug Application for methylphenidate 41, 42, 50 OROS includes criticism of the trials submitted for product approve, indicating that an assumption of equivalence should not be made based on these studies alone. In the largest, highest-quality study, there were no significant differences between the formulations on the primary outcome measure (IOWA Conners’ scale) or on 11 secondary 42 measures in a randomized controlled trial of 312 children. Similarly, a much smaller crossover trial (68 children) that was 7 days long and included behavioral treatment, found methylphenidate OROS to have lower scores on the Abbreviated Conners’ Parents scale (total), and on the inattention/overactivity item (out of 16 items), however no differences were found 41 based on assessments made by teachers and counselors. An additional study of 64 children was rated poor quality because it lacked adequate reporting on multiple measures to provide 50 meaningful results. Based on a definition of remission as a score of 0 or 1 (none or just a little) on the 18 items relating to ADHD symptoms only (excluding the items pertaining to oppositional defiant disorder) of the parent assessed SNAP-IV scale, methylphenidate OROS treatment resulted in more patients being classified as in remission at 8 weeks, with a number needed to treat near 4 (see Table 5). Similar results were found using other measures of parental assessment. Because the study was open to patients currently receiving treatment, including immediate-release methylphenidate, and it was unblinded, it is potentially biased against immediate-release methylphenidate. The proportion of patients taking immediate-release methylphenidate, methylphenidate OROS, or who were not taking drug therapy prior to study enrollment was not reported. We undertook an exploratory analysis, pooling the parent ratings of inattention/overactivity subscale items of the IOWA Conners’ scale from these 3 studies, as it was the only item reported across all 3 (see Table 5). While the Wolraich and Pelham studies did not find significant differences in the mean change on this item, the pooled analysis with the Steele study does result in a statistically significant finding, favoring methylphenidate OROS (weighted mean difference, –1. However, we did consider this an exploratory analysis because standard deviations were not provided in the Pelham and Wolraich studies and we made an assumption that the baseline and final scores were moderately correlated 2 (r = 0. A fourth study conducted in Taiwan found methylphenidate OROS superior to immediate-release methylphenidate, assessing the change in Conners’ Teacher Rating Scale Revised Short-Form score by either teacher or parent over 5 time points using a linear mixed model, P<0. The absolute difference in individual scores were not large (Table 4), with the largest difference in teacher ratings being 1. This study had the same potential for bias as the unblinded study by Steele, except that here all patients had previously been taking some form of methylphenidate, but again the proportions taking immediate-release methylphenidate compared with methylphenidate OROS or other formulations prior to enrollment was not reported. In contrast, findings from a retrospective study of 92 children from a “real-life clinical situation” in the United Kingdom suggested that 32% (P<0. The validity and generalizability of these findings were unclear, however, as the study was retrospective in nature, physicians’ use of personal case load to identify patients may have introduced a selection bias, treatment failure was not precisely defined, and it was unclear whether the United Kingdom formulation is comparable to methylphenidate OROS as included in this review. A small 2-week randomized controlled trial (34 children) of immediate-release methylphenidate 43 compared with methylphenidate SR found mixed results. The outcome measures included questionnaires (not validated) completed by a physician, a teacher, and a parent. The teacher questionnaires indicated significant differences in final total score and the “Conduct Problem” scores favored immediate-release methylphenidate. Parent questionnaires indicated a significant difference favoring methylphenidate SR on the “Conduct Problem” item final score, and the physician scores showed no difference. A 3-week study using over-encapsulation for blinding enrolled 327 children, ® comparing immediate-release methylphenidate to Equasym (sold in the United States as ® Metadate CD ). The study analyzed only 87% of patients in the main per-protocol analysis with 47 unclear description of those excluded. The study included a non-inferiority analysis, assuming a difference of ≤ 1. At weeks 1, 2, and 3 immediate-release methylphenidate ® was found equivalent to Equasym. Intent-to-treat analysis as well as subgroup analyses (country, dose, ADHD subtype) was reported in the discussion as supporting these results. Additional analysis examined the effects of the drugs in the morning and afternoon, but a direct comparison was made only to the placebo group as both methylphenidate groups were found similarly superior to placebo at both time points throughout the study. Immediate-release methylphenidate compared with methylphenidate multilayer-release ® (Biphentin ). Two small, fair-quality, crossover studies compared immediate-release ® methylphenidate to methylphenidate multilayer-release (Biphentin , available in Canada, not 53, 54 available in the United States as of September 2011). In the first study, 90 children were randomized to either immediate-release methylphenidate or methylphenidate multilayer-release and had dose titration over 2-3 weeks, with observation by parent, teacher, and investigator over 54 2 weeks. Discontinuations were similar between groups (86% methylphenidate multilayer- release, 89% immediate-release methylphenidate), and mean daily doses were similar between treatments (0. Using the Conners’ scales, “normal” was defined as a final T-score of <65 on each of the 4 subscales. After 5 weeks of treatment, more children taking immediate- release methylphenidate had achieved a normal score on the ADHD Index compared with those taking methylphenidate multilayer-release (90% compared with 79% on the teacher scale and Attention deficit hyperactivity disorder 43 of 200 Final Update 4 Report Drug Effectiveness Review Project 81% compared with 77% on the parent scale). The authors reported that the mean ADHD Index T-scale score was statistically significantly better (lower) with immediate-release methylphenidate based on the teacher scale (mean differences, 3. No other differences were found between treatment groups. The second, smaller study (N=18) reported only single-day measurements after 1 week of 53 immediate-release methylphenidate, methylphenidate multilayer-release, or placebo. This study found no statistically significant differences between drug treatments on the Conners’ IOWA scale, although baseline scores differed across treatment groups such that these findings should be interpreted with caution; the analyses attempted to control for differences in baseline scores, including assessing for carryover effects. Analyses of time-course responses were not able to identify consistent differences among the drugs compared with placebo. Other measures of comparative effectiveness of immediate-release compared with sustained-release formulations Clinical trials of extended-release compared with immediate-release formulations were too short to demonstrate differences in long-term health outcomes. However, the intermediate outcome measure of persistence (the proportion of patients continuing to take or refill prescriptions for a medication after some longer period of time) is thought to be a good proxy for extension of benefits seen in the short-term, or if none were found, evidence of a difference in longer-term, real-life settings. Persistence is an intermediate outcome with unknown validity because direct evidence of a relationship between persistence rates and long-term health outcomes with ADHD drugs is lacking. In 5 observational studies (6 publications), persistence with treatment with long-acting stimulant formulations (methylphenidate OROS or methylphenidate ER) was significantly longer compared with shorter-acting formulations (immediate-release methylphenidate or immediate- 55-58 release mixed amphetamine salts) over periods of 6 months and 12 months following index prescription. One of these studies examined only adults treated with methylphenidate OROS (median duration of treatment 68 days; 95% CI, 65 to 71) compared with immediate-release 59 methylphenidate (39 days; 95% CI, 33 to 52). The findings of these studies should be interpreted with caution, however, until confirmed by a randomized controlled trial that would serve to rule out potential sources of bias, including between-group baseline differences in unmeasured clinical characteristics, physicians’ prescribing preferences, and differences in reasons for discontinuation (e. Data were derived from the Integrated Health Care Information Services National Managed Care Benchmark Database in 2 studies from the same group of researchers, with overlapping data. Using a definition of persistence as less than a 15-day gap in prescription refills, the studies found methylphenidate OROS to be associated with greater persistence rates 56 than immediate-release methylphenidate (12% compared with 1%, P<0. The second study also reported persistence using less than a 30-day gap in refills as the definition and found 33% persistent with methylphenidate OROS and 57, 58 5% with immediate-release methylphenidate. There was uncertainty about how well this study population represented patients in actual practice as ethnicity and comorbidity characteristics were not reported and there were age and diagnosis differences between those receiving methylphenidate OROS compared with immediate-release methylphenidate. Attention deficit hyperactivity disorder 44 of 200 Final Update 4 Report Drug Effectiveness Review Project California Medicaid claims files from a 3-year period were examined to identify youth 55 prescribed methylphenidate (N=11 537). This study population involved a lower than average proportion of White patients (45. Total mean duration (days) of treatment without any 30-day gaps was greater for patients taking extended-release formulations (combined group of methylphenidate OROS = 83%, methylphenidate ER = 8. Subgroup analysis results suggested that persistence duration was greatest for methylphenidate OROS (147. Together, extended-release formulations extended persistence duration regardless of ethnicity. The Texas Medicaid Vendor Drug Program database was used to identify claims for 60 newly started stimulants (2001-2002 school year). Proportion of days of treatment without any 15-day gaps was greater for patients taking methylphenidate OROS than for immediate-release methylphenidate or immediate-release mixed amphetamine salts (0. Within those days of treatment, compliance rates, as measured using the Medication Possession Ratio, were higher in patients taking methylphenidate OROS compared with immediate-release methylphenidate or immediate-release mixed amphetamine salts (0. Comparisons of sustained-release formulations ® ® Methylphenidate OROS (Concerta ) compared with methylphenidate CD (Metadate CD ). Results from the fair-quality COMACS crossover study of 184 children suggested that relative improvements in SKAMP deportment and attention scale scores differed for the comparison of methylphenidate OROS 18-54 mg and methylphenidate CD 20-60 mg (both given once daily) 61, 62 depending on time of assessment. Methylphenidate CD was associated with significantly larger effect sizes than methylphenidate OROS in the morning, while treatment effects were similar in the afternoon, and methylphenidate OROS was superior in the evening. This study presented several problems, however, in that the SKAMP scale has been criticized for lack of sensitivity to change in symptoms, and that ANOVA analysis found the interaction of site x treatment x sequence (the order to randomization within patients) was found to be statistically significant. This finding resulted in the authors conducting additional analyses; however the effect of sequence was not included in these subsequent analyses. Therefore, these findings should be interpreted with caution. Two small crossover studies have found methylphenidate SODAS superior to methylphenidate OROS. A small 1-week crossover study of methylphenidate SODAS 20 mg compared with 63 methylphenidate OROS 18 mg and 36 mg found methylphenidate SODAS superior on the attention or deportment subscores of the SKAMP scale depending on the time-point and dose Attention deficit hyperactivity disorder 45 of 200 Final Update 4 Report Drug Effectiveness Review Project comparison. Secondary outcome assessment also found methylphenidate SODAS superior on 1 measure (proportion correct on math test). These limited differences were mitigated by concerns over the assessment tool (SKAMP) sensitivity, use of a simulated classroom, involvement of study sponsor in authorship, and differences in groups at baseline. A similar second crossover study of methylphenidate OROS (18 and 36 mg) and methylphenidate SODAS (20 and 40 mg) also assessed children in a simulated classroom setting after a single dose of the study 64 medication using the SKAMP scale. Here methylphenidate SODAS 40 mg was found superior to methylphenidate OROS 36 mg at all time points (0-4, 0-8, and 0-12 hours) based on the SKAMP attention subscale score area under the curve analyses, while methylphenidate SODAS 20 mg was not significantly different to either dose of methylphenidate OROS. Here, concerns over the clinical importance of the difference in area under the curve, involvement of study sponsor in authorship, and the impact of sequence of randomized treatment (analysis of treatment sequence was stated to be planned but results not reported) were present. Dexmethylphenidate ER compared with methylphenidate OROS. A single, small (N=84) fair- quality crossover study compared 2 doses of dexmethylphenidate ER with 2 doses of 65 methylphenidate OROS or placebo using a simulated classroom assessment. The primary outcome was the mean change in the SKAMP combined score from zero to 2 hours post dose in the dexmethylphenidate ER 20 mg daily group compared with the methylphenidate OROS 36 mg daily group. Children were given the intervention for 7 days prior to the assessment. The mean change in SKAMP combined scores at 2 hours post dose was statistically significantly greater with dexmethylphenidate ER 20 mg daily compared with methylphenidate OROS 36 mg daily (adjusted mean change –11 compared with –6; P<0. Similar results were found comparing the higher doses (30 mg dexmethylphenidate ER and 54 mg methylphenidate OROS daily) to each other. At other time points, the drugs differed depending on the time of day. For time points up to 6 hours, dexmethylphenidate ER had statistically significantly superior change in SKAMP combined scores comparing either the 2 lower doses or the 2 higher doses to each other (P values ranged from <0. Similarly, a statistically significant difference was seen at the first time point, 0. However, at later time points (10, 11, and 12 hours post dose), methylphenidate OROS had statistically significantly superior change in SKAMP combined scores (P values ranged from <0. At hours 7, 8, and 9 there was no statistically significant difference between the drugs at either dose levels and analysis by Area Under the Curve from 0-6 and 6-12 hours was unable to identify statistically significant differences between the drugs. Analysis of attention and deportment subscale scores showed similar results. Assessments of math scores and problems attempted showed dexmethylphenidate ER superior up to 4 hours post dose and methylphenidate OROS superior at 11 and 12 hours post dose. In comparison to placebo, dexmethylphenidate ER was superior on SKAMP combined scores starting at 0. Methylphenidate OROS was superior to placebo starting at 1 hour (not at 0.

Two in the fosinopril group experienced a potassium level greater than 5 milli-equivalents per liter 140 mg malegra fxt, as compared with only 1 in the irbesartan group malegra fxt 140mg. Combination therapy: Inter-class comparison of effectiveness 140mg malegra fxt, efficacy and harms between AIIRA and ACE-I Proteinuric Chronic Kidney Disease We included 16 trials that compared the combination of an AIIRA and an ACE-I with either or 84-86 malegra fxt 140 mg, 89 , 90 , 93 , 94 , 103-105 , 107-112 both as montherapy . Four trials were rated poor quality and will not be 92, 96, 98, discussed in this analysis, but additional information can be found in Evidence Table 10. The former 113 provided no significant information on adverse events; the latter had a very small sample size 98 (19, nine of whom withdrew). The COOPERATE trial and its sub-study were rated as poor for 92, 96 reasons discussed previously. The majority of trials (11 of 16) provided 6 months or more of 84-86, 89, 90, 93, 104, 105, 109, 110, 112 111 follow-up , the longest of which was 36 months (3 years). Only 4 93, 103, 110, 111 of 16 trials had sample sizes of fifty or greater, the largest of which was 109 111 85, 86, 89, 107 participants. Participants among these 16 trials had a wide range of different types of chronic kidney disease. None of these studies reported a renal survival endpoint. One trial reported a renal 111 outcome endpoint including acute kidney injury and hospitalization for renal-related issues. All trials reported changes in levels of proteinuria with combination compared with monotherapy with AIIRA and ACE-I. Of note, although the reduction of proteinuria among patients with 114-117 chronic kidney disease has been linked to a slowing in disease progression, reduction in proteinuria is a surrogate outcome for renal survival. All trials reported changes in creatinine clearance or estimated glomerular filtration rate with the exception of 2 that reported changes in 107, 111 105 creatinine and 1 that did not report renal function measurement outcomes. DRIs, AIIRAs, and ACE-Is Page 58 of 144 Final Report Drug Effectiveness Review Project These 16 trials have some fundamental differences in design which complicate interpretation for an overall effect of mono compared with combination therapy on proteinuria and renal function. The 2 primary designs were those trials in which ACE-I and AIIRA combination therapy was simultaneously compared with monotherapy with either agent, compared with those trials in which monotherapy of either ACE-I or AIIRA were compared with combination therapy. Those trials comparing monotherapy of 1 agent (ACE-I or AIIRA) to combination therapy typically started with all patients on monotherapy and added a second agent compared with placebo to result in a combination therapy arm. Ten trials compared both ACE-I 84-86, 89, 90, 93, 94, 103-105 and AIIRA monotherapy with combination therapy, and 6 trials compared 107-112 monotherapy of either ACE-I or AIIRA to combination therapy. Among those trials comparing monotherapy of both agents with combination therapy, authors either utilized same dose ACE-I and AIIRA in mono and combination therapy or they utilized half dose ACE-I and AIIRA in combination therapy compared with double that dose in monotherapy. Of those comparing dual monotherapy to combination therapy, 5 used same dose ACE-I and AIIRA in both mono and 86, 89, 93, 103, 105 combo therapy, and 5 used half dose ACE-I and AIIRA in combination therapy 84, 85, 90, 94, 104 compared with double that dose in monotherapy. The trials comparing monotherapy of ACE-I and AIIRA compared with combination therapy were varied in their effects on proteinuria. Nine of these 11 trials noted a significant reduction in proteinuria with combination compared with monotherapy, but only 5 showed that effect as independent of blood pressure. Of the 5 trials using equivalent doses in mono and combo therapy, only 1 of the 5 showed that combination therapy was superior to either 86 monotherapy for reduction in proteinuria independent of blood pressure control. Of the 5 trials that compared half dose combination therapy to double that dose monotherapy, 3 of the 5 showed significant reduction in proteinuria with combination therapy that was independent of 84, 94, 104 blood pressure control. Of the 6 trials designed with all participants on monotherapy with ACE-I or AIIRA followed by the addition of the other type of agent compared with placebo, only 2 of the 6 showed a clear and significantly greater reduction in proteinuria for combination therapy 109, 110 compared with monotherapy. Further, in the trial by Kim and colleagues, subgroup analysis only showed significantly greater reduction in proteinuria with combination therapy among those with IgA nephropathy, and not among those with diabetic nephropathy. Similarly, another trial among these 6 also showed a significant reduction in 1 subgroup of chronic kidney disease patients (IgA nephropathy), but not in another included subgroup (diabetic 112 nephropathy). A fourth trial within this group showed a significantly greater reduction in proteinuria in combination therapy compared with monotherapy, but only with the highest dose of combination therapy (whereas a group with lower dose combination therapy did not reveal a 111 statistically significant decrease in proteinuria compared with monotherapy). In total, only 4 of 16 studies found a statistically significantly greater reduction in proteinuria among those on combination therapy with ACE-I and AIIRA compared with monotherapy with either agent that was independent of blood pressure management. These studies suggest do not provide consistent and convincing data regarding the reduction in proteinuria with combination compared with monotherapy with these agents. DRIs, AIIRAs, and ACE-Is Page 59 of 144 Final Report Drug Effectiveness Review Project Monotherapy with ACE-I and AIIRA compared with combination therapy Losartan Losartan in combination with lisinopril One trial (N=10) compared the effects of combination therapy using losartan and lisinopril to monotherapy with losartan or lisinopril on reduction in proteinuria and changes in creatinine 89 clearance. Participants were randomized to escalating doses of lisinopril or losartan in order to identify the optimal antiproteinuric dose for each participant. Participants were then crossed-over the alternate agent and the same process was repeated. After the optimal antiproteinuric dose of ACE-I and AIIRA was identified for each participant, all participants were placed on combination therapy of both agents at their optimal antiproteinuric dose. This trial showed a 51% reduction in proteinuria for those on losartan alone, a 69% reduction in proteinuria for those on lisinopril alone, and a 78% reduction in proteinuria for those on combination therapy at optimal antiproteinuric doses. Reduction in proteinuria with combination therapy was found to be significantly greater (P<0. Combination therapy was also noted to lower blood pressure significantly more than losartan monotherapy. Changes in creatinine clearance compared with baseline were not statistically significant for either monotherapy, but were statistically significantly lower among those on combination therapy (P<0. This trial reported 1 withdrawal, which was not related to adverse events. Two adverse events were reported for each therapy arm in this trial: the incidence of potassium levels greater than 5. Two participants experienced both elevated potassium and dizziness in the combination therapy group (20% event rate for each adverse event). Losartan monotherapy resulted in a 10% adverse event rate for each adverse event (meaning 1 participant for each), and lisinopril monotherapy resulted in a 20% event rate for hyperkalemia (2 participants) and a 10% event rate for dizziness (1 participant). None of these adverse events resulted in a withdrawal of therapy. Losartan in combination with enalapril Two trials compared the combination of losartan plus enalapril to monotherapy with either 93, 103 losartan or enalapril (N=105). Complete details of both of these trials are discussed previously and can also be seen in Evidence Table 9. Both trials compared monotherapy with losartan 25 mg per day or enalapril 10 mg per day to combination therapy with losartan 25 mg per day plus enalapril 10 mg per day. Despite significant similarities in design, these trials resulted in different outcomes. In the trial with shorter duration of follow-up (N=51), combination therapy resulted in a 66% reduction in proteinuria, as compared with a 25% reduction in proteinuria for 103 losartan monotherapy and a 45% reduction in proteinuria for enalapril monotherapy. Reduction in proteinuria was found to be statistically greater among those on combination therapy when compared with either monotherapy (P=0. No significant changes were found in creatinine clearance. Of note, diastolic blood pressure was lower among those on combination therapy. In the trial with longer duration follow-up (N=54), combination therapy resulted in a 63% and 51% decline in proteinuria at 3 and 9 months respectively. Losartan monotherapy resulted in DRIs, AIIRAs, and ACE-Is Page 60 of 144 Final Report Drug Effectiveness Review Project a 22. A statistically significant difference was seen only between combination therapy and losartan monotherapy (P<0. No statistically significant difference in reduction of proteinuria was seen between groups at 9 months. There was no statistically significant change in creatinine clearance between groups. There were some statistically significant differences in diastolic blood pressure levels between groups (lower among those on losartan but only at 3 months, P=0. The other trial reported 1 allergic reaction to a 103 study medication, but they did not report which medication led to that reaction. Losartan in combination with benazepril Two trials compared the combination of losartan with benazepril to monotherapy with either 94, 104 agent (N=60). Complete details on both of these studies are discussed earlier, and can also be found in Evidence Table 9. Both studies utilized the same doses of each medication: Losartan 50 mg per day, compared with benazepril 10 mg per day, compared with half dose combination therapy (losartan 25 mg per day with benazepril 5 mg per day). These studies resulted in similar results in terms of reduction of proteinuria. In the trial with shorter duration of follow-up (N=30), a significantly greater reduction in proteinuria was seen in those on combination therapy as compared with either 94 monotherapy (P<0. The other trial with longer duration of follow-up (N=30) also showed a 45. Analysis revealed a statistically greater reduction in proteinuria in those on combination therapy compared with losartan monotherapy (P=0. Neither trial found a significant change in creatinine clearance; both trials reported equivalent blood pressure control between groups. Each trial reported a total number of adverse events, but neither trial delineated those events by treatment group. Candesartan Candesartan in combination with lisinopril One randomized controlled trial from Spain (N=46) compared the use combination therapy candesartan and lisinopril to monotherapy of either agent in its effect on proteinuria and 90 creatinine clearance. Details of this trial are discussed earlier in this document. This trial compared lisinopril 10 mg daily or candesartan 8 mg daily to half dose combination therapy (lisinopril 5 mg daily with candesartan 4 mg daily). Percent reductions in proteinuria were reported at 2, 3, and 6 months. At 2 and 6 months, combination therapy resulted in 60 and 70% reduction in proteinuria respectively. This was found to be a statistically greater reduction compared with candesartan monotherapy at both time points (28% reduction with candesartan at 2 months [P=0. Compared with lisinopril monotherapy, however, reduction in proteinuria with combination therapy was only statistically greater at 2 months (33% reduction at 2 months [P=0. This trial reported no significant changes in creatinine clearance and blood pressures were equivalent between groups. The adverse event of potassium level greater than 5. Authors did note that significantly more participants in lisinopril monotherapy and lisinopril with candesartan combination therapy experienced a potassium level greater than 5. Valsartan Valsartan in combination with benazepril Two trials (N=60) compared the use of valsartan and benazepril combination therapy to either 84, 105 agent as monotherapy for its impact on proteinuria and renal function. For complete details of these studies please see discussion above or data presented in Evidence Table 9. Doses of medications differed some between these 2 studies. One trial utilized valsartan 80 mg per day and benazepril 10 mg per day for monotherapy, but used half dose for combination therapy (valsartan 40 mg per day and benazepril 5 mg per day) again dose doubled among all groups 84 after 2 weeks. The other used a benazepril dose based on creatinine clearance (10 mg per day if creatinine clearance was less than 50 ml/min and 20 mg per day if creatinine clearance was greater than 50 ml/min) for ACE-I monotherapy, valsartan 80 mg per day with later dose 105 escalation for AIIRA monotherapy, and maximum dose of each for combination therapy. In the trial using half-dose combination therapy, the authors noted a statistically greater decline in proteinuria among those on combination therapy compared with monotherapy after 32 weeks (–56% for combination compared with –41%; P<0. There was no significant difference in blood pressure control between groups in this study. In the trial using same dose monotherapy compared with combination therapy, combination therapy resulted in a statistically greater decline in proteinuria only when compared with benazepril monotherapy (P<0. Of note, systolic blood pressure in this trial was noted to be lower in the valsartan compared with the benazepril group at 3 and 6 months, so the changes in proteinuria cannot necessarily be considered to be independent of blood pressure. Campbell and colleagues additionally reported slight increase in estimated glomerular filtration rate for those on combination therapy that was statistically greater when compared with either monotherapy (P=0. Segura and colleagues did not report on changes in creatinine 105 clearance. One trial evaluated participants for the adverse event of potassium level greater than 0. DRIs, AIIRAs, and ACE-Is Page 62 of 144 Final Report Drug Effectiveness Review Project Valsartan in combination with ramipril One study (N=18) evaluated the use of valsartan in combination with fosinopril to examine the 85 impact of these therapies on proteinuria reduction. Complete details of this study are discussed previously in this document, and are also available in Evidence Table 9. Participants in this study were randomized to valsartan 160 mg per day or ramipril 10 mg per day for monotherapy, compared with half dose combination therapy (valsartan 80 mg per day with ramipril 5 mg per day). This trial reported changes in the protein to creatinine ratio as well as the 24 hour protein levels. No significant difference in reduction in proteinuria was seen between combination and monotherapy. Creatinine levels were followed and were not found to differ significantly between groups before and after intervention. Blood pressure control between groups was equivalent. As noted previously, a subgroup analysis was done within this trial comparing participants with and without diabetes. Although, as previously noted, no statistically significant difference was seen between groups, there was a trend toward combination therapy leading to a greater reduction in proteinuria compared with monotherapy in diabetics (P=0. Adverse events are mentioned solely in terms of hypotension, and no difference in episodes of symptomatic hypotension was found between treatment groups. Irbesartan Irbesartan in combination with fosinopril One trial compared the use of irbesartan in combination with fosinopril to monotherapy with 86 either agent and examined outcomes of proteinuria reduction and renal function. Details of this study are reviewed previously in this document, but are notable for a very small sample size (N=11). Participants were randomized to irbesartan 150 mg per day or fosinopril 20 mg per day for monotherapy compared with full dose combination therapy (irbesartan 150 mg per day with fosinopril 20 mg per day).

140 mg malegra fxt

Antiviral Therapy 2013a; 18 Suppl 1: A108 (Abstract 85) 140 mg malegra fxt. Analysis and characterization of treatment-emergent resistance in ART- experienced 140mg malegra fxt, integrase inhibitor-naïve subjects with Dolutegravir (DTG) vs Raltegravir (RAL) in SAILING (ING111762) malegra fxt 140mg. Antiviral Therapy 2013b; 18 Suppl 1: A29 (Abstract 21) malegra fxt 140 mg. Impact of HIV genotyping and drug levels on the response to salvage therapy with saquinavir/ritonavir . Vandekerckhove LPR , A M J Wensing AMJ , Kaiser R , et al . European guidelines on the clinical management of HIV-1 tropism testing . Cross-resistance profile determination of two second-generation HIV-1 integrase inhibitors using a panel of recombinant viruses derived from raltegravir-treated clinical isolates. Durable efficacy and limited integrase resistance evolution in subjects receiv- ing Dolutegravir after failing prior integrase inhibitor regimens: Week 48 results from Viking-3. Antiviral Therapy & Infectious Diseases 2014, 2:7-8 (abstract O_5). Integrase genotypic and phenotypic predictors of antiviral response to DTG in subjects with resistance to integrase inhibitors. Antiviral Therapy 2013; 18 Suppl 1: A37 (Abstract 29). CXCR4-using HIV type 1 variants are more commonly found in peripheral blood mononuclear cell DNA than in plasma RNA. J Acquir Immune Defic Syndr 2009; 50(Suppl 2):126-36. TMC125 displays a high genetic barrier to the development of resistance: evidence from in vitro selection experiments. Resistance profile of etravirine: combined analysis of baseline geno- typic and phenotypic data from the randomized, controlled Phase III clinical studies. Leitlinien zur Tropismus-Testung Stand Dezember 2012: Empfehlungen zur Bestimmung des HIV-1- Korezeptor-Gebrauchs (Version Dezember 2012). An update of the list of NNRTI mutations associated with decreased viro- logic response to etravirine (ETR): multivariate analyses on the pooled DUET-1 and DUET-2 clinical trial data. HIV Resistance and Viral Tropism Testing 329 Walter H, Eberle J, Mueller H, et al. Empfehlungen zur Bestimmung des HIV-1-Korezeptor-Gebrauchs (Stand Mai 2014). Diminished replicative fitness of primary human immunodeficiency virus type 1 isolates harboring the K65R mutation. Weinheimer S, Discotto L, Friborg J, Yang H, Colonno R. Atazanavir signature I50L resistance substitution accounts for unique phenotype of increased susceptibility to other protease inhibitors in a variety of HIV type 1 genetic backbones. Reduced maximal inhibition in phenotypic susceptibility assays indi- cates that viral strains resistant to the CCR5 antagonist maraviroc utilize inhibitor-bound receptor for entry. Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates. Longitudinal resistance analyses of the phase 3 EVG/COI/FTC/TDF studies. Antiviral Therapy & Infectious Diseases 2014, 2:15 (Abstract O_12). A combination of decreased NRTI incorporation and decreased excision deter- mines the resistance profile of HIV-1 K65R RT. Primary resistance mutations and polymorphisms in gp41-sequences of HIV- 1 B-and non-B subtypes from Fuzeon-naïve patients. The L76V mutation in HIV-1 protease is potentially associated with hyper- susceptibility to protease inhibitors Atazanavir and Saquinavir: is there a clinical advantage? Update on antiretroviral drug resistance testing: Combining laboratory technology with patient care. Clonal analyses of HIV quasispecies in patients harbouring plasma genotype with K65R mutation associated with thymidine analogue mutations or L74V substitution. Effect of transmitted drug resistance on virological and immunologi- cal response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study. Emergence and evolution of enfuvirtide resistance following long-term therapy involves heptad repeat 2 mutations within gp41. Transmission of integrase strand-transfer inhibitor multi-drug resistant HIV: case report and natural history of response to raltegravir-containing antiretroviral therapy. Opportunistic Infections (OIs) CHRISTIAN HOFFMANN In Western industrialized countries, many opportunistic infections (OIs) that in pre- vious years were considered prevalent are now quite rare. This is particularly true for infections associated with severe immunodeficiency such as CMV and MAC. The incidence of these OIs has been reduced to less than one-tenth of their frequency in the pre-HAART era (Brooks 2009, Buchacz 2010). ART has not only decreased the incidence of OIs, but it has also changed the course of OIs considerably. In the early years of the AIDS epidemic, the life expectancy of individuals diagnosed with their first AIDS-defining illness was at most two to three years. Today, however, many patients live with AIDS for 15 years or longer. In our own clinical study of 144 patients with cerebral toxoplasmosis, data from 1990–1993 indicated a 5-year survival rate of 8%; it climbed to 30% by 1994–1996, and to 80% since 1997 (Hoffmann 2007). Up to 90% of patients who develop AIDS or severe opportunistic infections are unaware of their HIV status. Typically, these patients seek medical attention late, when their overall health condition is serious. Since AIDS remains life-threatening, every HIV clinician should be familiar with the diagnosis of OIs and their respective therapies. Even with recent improvements, many challenges still exist. First, there is still no adequate treatment available for diseases such as PML or cryptosporidio- sis. Second, resistance to treatment has become an increasing problem in OIs such as PCP. Even today, OIs like PML have a mortality rate comparable to that of non-Hodgkin lymphoma (ART-CC 2009). Third, ART does not always lead to immediate improvement. ART may even complicate things, given the atypical course of a variety of diseases with ART (see the separate section on “Immune Reconstitution Inflammatory Syndrome”, IRIS). Fourth, in small HIV centers or regions with low HIV prevalence, diagnostic problems for many OIs may occur, due to a lack of familiarity with and inability to recognize these rarer pathogens. Therefore, it is highly recommended that specimens be sent to specialized reference laboratories. If needed, further advice can be sought from a specialized clinician or a clinical HIV center. The predominant rule for nearly all OIs is that the poorer the immune status of the patient, the earlier the invasive diagnostic procedures should begin. The primary aim should not be to spare patients the unpleasant procedures associated with extensive diagnostic testing. And if the results are inconclusive and nothing is identified the first time, diagnostic tests must be repeated. The second rule is that many OIs can be excluded if the immune status is known. Table 1 indicates the CD4 cut-off values and the rates of certain OIs. The third OI rule is that if ART is not already in place, it should be started as quickly as possible. Immune reconstitution is the best protection against relapses or other OIs. For patients with OIs such as PML or cryptosporidiosis, which have no specific therapy, starting ART is the best hope. Especially in these cases there is no time to waste. ART should also be started rapidly in cases of PCP or toxoplasmosis. Table 1: Important cut-offs for CD4 T cells, above which particular AIDS-related illnesses are unlikely. However, exceptions are always possible No cut-off Kaposi’s sarcoma, pulmonary tuberculosis, HZV, bacterial pneumonia, NHL <250/μl PCP, esophageal candidiasis, PML, HSV <100/μl Cerebral toxoplasmosis, cryptococcosis, miliary tuberculosis, HAND <50/μl CMV retinitis, atypical mycobacteriosis Opportunistic Infections (OIs) 333 Although OI therapy is not without toxicity and there are problems regarding inter- actions, the options of antiretroviral drugs has increased, making it easier to react to these issues. In ACTG A5164, a total of 282 subjects with an acute OI (63% PCP) were randomized to initiate ART immediately or after OI treatment (Zolopa 2009). At 48 weeks significantly less mortality and AIDS-related infections occurred in the group starting ART immediately. The risk of changing ART was slightly higher in the immediate group, although not the number of adverse events, hospitalizations or cases of IRIS. ACTG A5164 provides clear arguments for immediate initiation of ART when PCP is diagnosed. However, this does not necessarly apply to all OIs (Lawn 2011). Two randomized studies in patients with cryptococcal meningitis (Makadzange 2010) and tuberculous menin- gitis (Torok 2011) showed unfavorable effects when starting ART too early (see chapter on Late Presenters). The next chapter is intended to be a practical overview and does not include clinical rarities. The literature cited refers to interesting reviews and almost exclusively to controlled studies, and when applicable, randomized studies. For more information on OIs see the detailed (more than 400 pages) US Guidelines https://aidsinfo. Variable impact on mortality of AIDS-defining events diagnosed during combination antiretroviral therapy: not all AIDS-defining conditions are created equal. Clin Infect Dis 2009, 48:1138-51 Brodt HR, Kamps BS, Gute P, Knupp B, Staszewski S, Helm EB. Changing incidence of AIDS-defining illnesses in the era of antiretroviral combination therapy. HIV-associated opportunistic infections—going, going, but not gone: the continued need for prevention and treatment guidelines. Clin Inf Dis 2009, 48:609–611 Buchacz K, Baker RK, Palella FJ Jr, et al. AIDS-defining opportunistic illnesses in US patients, 1994-2007: a cohort study. Evolving characteristics of toxoplasmosis in patients infected with human immunodeficiency virus-1: clinical course and Toxoplasma gondii-specific immune responses. Safe interruption of maintenance therapy against previous infection with four common HIV-associated opportunistic pathogens during potent antiretroviral therapy. Optimum time to start antiretroviral therapy during HIV-associated opportunistic infections. AIDS-related opportunistic illnesses occurring after initiation of potent anti- retroviral therapy: the Swiss HIV Cohort Study. Early versus delayed initiation of antiretroviral therapy for con- current HIV infection and cryptococcal meningitis in sub-saharan Africa. McNaghten AD, Hanson DL, Jones JL, Dworkin MS, Ward JW. Effects of antiretroviral therapy and opportunistic illness primary chemoprophylaxis on survival after AIDS diagnosis. Effect of HAART on natural history of AIDS-related opportunistic disorders. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)–associated tuberculous meningitis. Early antiretroviral therapy reduces AIDS progression/death in individ- uals with acute opportun-istic infections: a multicenter randomized strategy trial. In the last 20 years, there has been significant progress made in understanding this organism, especially through DNA analysis (Review: Thomas 2004). Although pneumocystis was previously classified as a protozoan, it was estab- lished in 1988 that it is in fact an unusual type of fungus (Edman 1988). In the 1990s, it was recognized that every host, whether rat, mouse, monkey or human, has its own specific pneumocysts. The Pneumocystis species that affects humans is now referred to as Pneumocystis jiroveci, and “carinii” has now been taken out of the name, although the abbrevia- tion PCP remains (Stringer 2002). Today, the majority of patients diagnosed with PCP are not on antiretroviral drugs, because many of them either do not know their HIV infection status. In Europe between 1997–2004, among 760 cases of so-called “late presenters” who were diagnosed with HIV infection and AIDS at the same time, PCP (35%) was the most frequent OI (Mussini 2008). In many cases with known HIV infection, 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.

Malegra FXT
9 of 10 - Review by Q. Samuel
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