One 211 meta-analysis compared fluvoxamine order glimepiride 2mg without prescription, paroxetine buy glimepiride online now, and sertraline to placebo buy glimepiride 2mg online, an additional meta-analysis summarized the comparative evidence and conducted indirect comparisons of 212 second-generation antidepressants using network-analysis order glimepiride once a day, and one systematic review 213 compared SSRIs to placebo. In addition, 6 placebo-controlled studies evaluated second- generation antidepressants currently not approved by the FDA for social anxiety disorder: two 214, 215 216, 217 218 escitalopram studies, two fluoxetine studies, one mirtazapine study, and one 219 nefazodone study. In general, inclusion was based on a criteria-based diagnosis (DSM-IV) of social anxiety 208, disorder. Several studies required a minimal duration of current illness of 6 months or greater. Second-generation antidepressants 65 of 190 Final Update 5 Report Drug Effectiveness Review Project The main outcome measures examined were mean change in anxiety as measured by one of several scales, including the Liebowitz Social Anxiety Scale (LSAS), the Brief Social Phobia Scale (BSPS), the HAM-A, and the social phobia subscale of the Marks Fear Questionnaire (MF). Social anxiety global assessment scales such as the Clinical Global Impression-Social Phobia Scale (CGI-SP) also were used. Several studies included patient-rated measures of anxiety using the Social Phobia Scale (SPS) or the Social Phobia Inventory (SPI). Disability, health status, quality of life, and comorbid depression were frequently assessed as secondary outcome measures. Among the included studies, loss to follow-up was between 20 percent and 36 percent. One study had a loss-to-follow-up differential between treatment groups greater than 10 percentage points (13. All included trials are characterized as efficacy studies. One study assessed relapse prevention randomizing escitalopram responders (CGI-I score of 1 or 2) to 24 weeks of 214 escitalopram or placebo. This study evaluated the rate of relapse between active treatment and placebo. SSRIs compared to SSRIs in adult outpatients with social anxiety disorder One fair-rated double-blinded RCT compared the efficacy and tolerability of one SSRI to another. In addition, a meta-analysis conducted indirect comparisons of second-generation antidepressants for the treatment of social anxiety disorder. Escitalopram compared with paroxetine One multinational study randomized 839 patients with social anxiety disorder to fixed doses of 209 escitalopram (5, 10, or 20 mg/d), paroxetine 20 mg/d, or placebo. Eligible patients had a baseline LSAS score of 70 or higher with a score of 5 or higher on one or more of the SDS subscales. Overall loss to follow-up in this 24-week trial was 29 percent. The primary outcome measure was mean change from baseline to week 12 in the LSAS total score; secondary outcome measures included the subscales, Clinical Global Impression of Improvement scale (CGI-I), Clinical Global Impression of Severity scale CGI-S, and the Sheehan Disability Scale (SDS). No significant differences in LSAS total score were observed between any escitalopram treatment group and the paroxetine group in the intention-to-treat analysis. The authors did not report any intention-to-treat results for secondary outcome measures. In the observed-cases-analysis at 24 weeks, escitalopram 20 mg/d was superior to paroxetine 20 mg/d on the CGI-S. Significant differences (favoring escitalopram 20 mg/d) were noted on the SDS at weeks 16 and 20, but differences between escitalopram and paroxetine were not significantly different at week 24. Indirect comparisons of escitalopram, fluvoxamine, paroxetine, and sertraline A good meta-analysis of second-generation antidepressants for social anxiety disorder utilized data of more than 6500 patients from three head-to-head trials and 15 placebo-controlled trials. To determine the comparative efficacy among drugs, authors employed network meta- 212 analyses. With the exception of one study, which included children and adolescents, trial populations consisted of adults with mean ages from 35 to 41 years and a relatively equal distribution of males and females. Baseline disease severity varied among participants (range of LSAS scores 74-97). Trials included in the analysis had to have a minimum duration of 12 weeks (range of study duration 12-28 weeks). Individual drugs were included in the network meta- Second-generation antidepressants 66 of 190 Final Update 5 Report Drug Effectiveness Review Project analysis when at least two similarly designed trials provided CGI-I data. Authors conducted a network-meta-analysis and found no significant differences in response among included SSRIs. Because of the limited number of component studies, however, estimates of relative effects were imprecise with wide confidence intervals which encompassed potentially important differences. SNRIs compared to SSRIs in adult outpatients with social anxiety disorder A good meta-analysis conducted indirect comparisons of second-generation antidepressants for the treatment of social anxiety disorder. Two fair double-blinded RCTs compared the efficacy and tolerability of one second-generation antidepressant to an SSRI. An additional Indirect comparisons of venlafaxine with SSRIs The above mentioned good meta-analysis of second-generation antidepressants for social anxiety disorder conducted indirect comparisons of venlafaxine with various SSRIs (escitalopram, fluvoxamine, paroxetine, and sertraline) using network-meta-analysis of data on more than 6500 212 patients three head-to-head trials and 15 placebo-controlled trials. The authors found no significant differences in any of the possible comparisons between venlafaxine and escitalopram, fluvoxamine, paroxetine, or sertraline. However, estimates had wide confidence intervals and encompassed potentially important differences. Venlafaxine compared with paroxetine 208, 210 Two 12-week multicenter trials compared venlafaxine ER to paroxetine and placebo. A 208 European trial randomized 436 patients with social anxiety disorder and an American trial 210 randomized 440 patients with social anxiety disorder to venlafaxine ER (75-225 mg/d), paroxetine (20-50 mg/d), or placebo. Eligible patients were 18 years or older who met DSM-IV criteria for social anxiety disorder at least 6 months before enrollment. In the European trial, significantly more females were randomized to placebo than to venlafaxine or paroxetine. The primary outcome measure was the LSAS; secondary outcome measures included the CGI-I, CGI-S, SPI, and SDI. The European trial also included a measure of work productivity WPAI. At 12 weeks, no significant differences in any outcome measure were observed between venlafaxine ER and paroxetine in either trial. Both venlafaxine ER and paroxetine were significantly better than placebo for all primary and secondary outcome measures (P<0. SSRIs compared to placebo in adult outpatients with social anxiety disorder One meta-analysis, one systematic review, and five placebo-controlled trials provide additional evidence. SSRIs compared with placebo One systematic review evaluated the efficacy of SSRIs compared with placebo in the treatment 213 of social anxiety disorder in adults. This review included placebo-controlled trials of SSRIs ranging in duration from 10-24 weeks and converted treatment effects to standardized effect sizes. Authors concluded that, in general, SSRIs are more effective than placebo in treating social anxiety disorder. Second-generation antidepressants 67 of 190 Final Update 5 Report Drug Effectiveness Review Project Escitalopram compared with placebo 215 One fair 12-week study compared flexible doses of escitalopram to placebo. This trial randomized 358 participants meeting DSM-IV criteria for social anxiety disorder with a score of at least 70 on the LSAS to escitalopram (10-20 mg/d) or placebo. Overall loss to follow-up was 19 percent (18% for placebo and 20% for escitalopram). The primary efficacy measure was the LSAS total score; secondary outcome measures included the LSAS subscales, CGI-S, CGI-I, SDS, and MADRS. At endpoint, escitalopram was significantly better than placebo as assessed by the LSAS total score (P<0. Results were similar to the placebo 209 comparison reported by Lader et al. The most common adverse event reported for escitalopram or placebo was headache (25% in both groups); compared to placebo, more patients randomized to escitalopram reported nausea (12% compared with 22%; P=NR). One fair relapse prevention study openly treated 517 patients with generalized social 214 anxiety disorder with escitalopram (10-20 mg/d) for 12 weeks. Responders (CGI-I score of 1 or 2) were randomized to 24 weeks of double-blind treatment with escitalopram or placebo. The primary efficacy parameter was time to relapse, defined as ≥ 10 point increase in LSAS total score from randomization. Of 372 randomized patients, 198 escitalopram-treated patients (65%) and 75 placebo-treated patients (41%) completed the 24-week study.
In February 2013 discount generic glimepiride uk, the development of Lersivirine was stopped by ViiV Healthcare when it became evident that there was no advantage over the available NNRTIs buy cheap glimepiride 4mg on-line. More recently order glimepiride 2 mg with visa, the delayed onset of seizures after fosdevirine exposure and persistence after discontinuation (which was without precedent in antiretroviral drug development) led to discontinuation of another promising NNRTI (Margolis 2014) purchase 4 mg glimepiride visa. AIC 292 is a new NNRTI from the German company AiCuris, which gained much attention at its first presentation at ICAAC in 2013 (Wildum 2013). As a diarylpyra- zole-carboxamide, it differs chemically from all other NNRTIs. AIC 292 is effective against NNRTI resistance mutations such as K103N, Y181C and G190A and even against L100I. In Phase I the compound was well tolerated at doses up to 1400 mg (n=16). There seems to be a low potential for interactions; half-life is 20 hours. It remains to be seen, if one of the big pharmaceutical players in HIV medicine will be interested. It is effective against wild type virus and against several NNRTI mutations such as Y181C (Côté 2014). The resistance profile is very similar to that of rilpivirine and etravirine. As all available NNRTIs is not effective against Y188L (Lai 2014). Safety and PK data were evaluated in healthy volunteers (Anderson 2013). In a first study on 18 ART-naive HIV+ patients, viral load felt by 1. In a Phase II study, in which different dosages from 25 to 200 mg doravirine were tested against efavirenz, 76% achieved an undetectable viral load, compared to 64% on efavirenz. There was no clear dose- effect relation (Morales-Ramirez 2014). For further development, MSD chose the 100 mg dosages. The resistance barrier is very high and the potential for interactions low (Hamatake 2007). Monotherapy trials with HIV+ patients showed a reduction of over 1. The data seem promising enough to start Phase IIb trials. However, the company’s website is strangely blank on the topic. Out of sight, out of mind: the following NNRTIs are no longer being developed: • Atevirdine – Upjohn focused their research on delavirdine (a good idea? ART 2017/2018: The horizon and beyond 125 • Calanolide A from Sarawak, poor efficacy • Capravirine (AG1549) from Pfizer, limited activity • DPC 083 (BMS-561390), poor PK/secure data • DPC 961 due to suicidal thoughts in healthy volunteers; DPC 963 • Emivirine (EMV, MKC-442, coactinone) from Triangle, due to limited activity • Fosdevirine (GSK 761, IDX-899) from ViiV Healthcare, seizures • GW420867X from ViiV, too much of a me-too drug • GW8248 and GW5624 from GSK, due to poor bioavailability • HBY-097 from Hoechst-Bayer, due to unfavorable side effects • Lersivirine from ViiV, nausea, no advantages (me-too drug) • Loviride, Janssen pharmaceuticals, due to limited activity in the CAESAR study • MIV-150 from Medivir, poor bioavailability, now b. Safety, Tolerability, and Pharmacokinetics of Single and Multiple Doses of MK-1439, a Novel HIV NNRTI, in Healthy Subjects. Discovery of MK-1439, an orally bioavailable non-nucleoside reverse transcriptase inhibitor potent against a wide range of resistant mutant HIV viruses. RDEA806, a potent NNRTI with a high genetic barrier to resistance. In vitro characterization of MK-1439, a novel HIV-1 nonnucleoside reverse transcriptase inhibitor. Margolis DA, Eron JJ, DeJesus E, White S, Wannamaker P, Stancil B, Johnson M. Unexpected finding of delayed- onset seizures in HIV-positive, treatment-experienced subjects in the Phase IIb evaluation of fosdevirine (GSK2248761). Antivir Ther 2014, 19: 69-78 Morales-Ramirez JO, Gatell JM, Hagins DP, et al. Safety and Antiviral Effect of MK-1439, A Novel NNRTI (+FTC/TDF) in ART-Naive HIV-Infected Patients. Phase 2a randomized controlled trial of short-term activity, safety, and phar- macokinetics of a novel nonnucleoside reverse transcriptase inhibitor, RDEA806, in HIV-1-positive, antiretrovi- ral-naive subjects. Antiviral activity of AIC292, a novel next-generation HIV- 1 non- nucleoside reverse transcriptase inhibitor. New protease inhibitors (PIs) Even among PIs, many agents have been lost along the way. Following the licens- ing of darunavir, not much can be expected from PIs in the near- to mid-term. This may also be due to the high bar for any new PI (Review: Pokorná 2009). DG17 is a prodrug of DG35 and has been under clinical testing for some time. One study showed a clear boosting effect with ritonavir and significant pharmacoen- hancement warranting further clinical development (Cherry 2008). SM-309515 is a PI from Sumitomo Pharmaceuticals and has apparently entered Phase I studies. Earlier versions failed due to the short half-life, and attempts have been made to improve this (Mimoto 2008). The drug showed activity in the presence of some PI mutations. Ritonavir boosting is purportedly being tested in humans. TMC-310911 is a new PI from Tibotec, currently being examined with the booster- drug TMC-558445 in a Phase I study. The drug was well tolerated by healthy volunteers, showing a good dose-PK-relation (Hoetelmans 2014). In HIV+ patients, monotherapy (boostered by ritonavir) led to a decline in viral load by 1. It remains to be seen if this sufficient for further development. Out of sight, out of mind, the following PIs are no longer being developed: • AG-001859 from Pfizer • Brecanavir from GSK, stopped in 2006 due to poor PK data • DPC 684/681, narrow therapeutic range due to cardiotoxicity • GS 9005, previously GS 4338, from Gilead • JE-2147, AKA AG1776, KNI-764 from Pfizer, no news since 1999 • KNI-272, Kynostatin – due to poor PK data • Mozenavir, DMP-450 from Gilead, a me-too drug, nothing new to offer • PL-110 (MK8122) from Merck, allowed the out-license to expire • RO033-4649 from Roche, probably too similar to saquinavir • SC-52151 and SC-55389A, poor bioavailability • TMC-126 from Tibotec, they concentrated on darunavir References Cherry CL, Hoy JF, Rowe JS, Krum H, Mills J, Lewin SR. Phase 1 single dose studies to optimize the pharmacoki- netics of DG17, a novel HIV-protease inhibitor pro-drug, using sodium bicarbonate and ritonavir. TMC310911, a novel hiv type 1 protease inhibitor, shows in vitro an improved resistance profile and higher genetic barrier to resistance compared with current protease inhibitors. Gulnik S, Afonina E, Eissenstat M, Parkin N, Japour A, Erickson J. SPI-256, a highly potent HIV protease inhibitor with broad activity against MDR strains. Antiviral activity and resistance profile of AG-001859, a novel HIV-1 pro- tease inhibitor with potent activity against protease inhibitor-resistant strains of HIV. Antiviral Therapy 2004; 9:S17 Hoetelmans RM, Dierynck I, Smyej I, et al. Safety and pharmacokinetics of the HIV-1 protease inhibitor TMC310911 coadministered with ritonavir in healthy participants: results from 2 phase 1 studies. Structure-activity relationships of novel HIV-1 protease inhibitors containing the 3-amino-2-chlorobenzoyl-allophenylnorstatine structure. Antiviral activity, pharmacokinetics, and safety of the HIV-1 pro- tease inhibitor TMC310911, coadministered with ritonavir, in treatment-naive HIV-1-infected patients. PL-100, a next generation protease inhibitor against drug-resistant HIV. New integrase inhibitors The integration of viral DNA, enabled by the HIV enzyme integrase into the host DNA, is a major step in the replication cycle of HIV. In 2007, raltegravir, the first integrase strand transfer inhibitor (INSTI) for treatment of HIV infection, was licensed, followed by the two INSTIs elvitegravir and dolutegravir (see Chapter 2). LEDGINs (or ALLINIs) are a new class of integrase inhibitors.
After inclusion and exclusion criteria were applied buy glimepiride 1 mg lowest price, 104 studies were included in this review (Figure 1) glimepiride 4 mg discount. Included studies for each between-drug comparison are shown in Table 2 buy 1mg glimepiride overnight delivery. We identified 1 or more studies for all comparisons of interest except for levalbuterol discount glimepiride 1 mg without prescription. Available studies compared it to albuterol but not to any other drugs. Of the 104 included studies, 9 studies were poor quality for measures of 13-22 effectiveness and are not discussed. For Update 1 we identified 510 new citations, of which 10 were included in the update, 9, 12 plus the 2 systematic reviews used as the basis for the review of ipratropium bromide. Quick-relief medications for asthma Page 14 of 113 Final Report Update 1 Drug Effectiveness Review Project Figure 1. Literature search results 7043 titles and abstracts were identified through searches of the Cochra ne Libra ry,M edline,electronicda ta ba ses, reference lists,a nd dossiers submitted by pha rma ceutica lcompa nies 6331 citations excluded at the title/abstract-level 712 full-text articles retrieved for moredetailedevaluation 610 a r t i c l e s e x c l u d e d : 28foreign language 3 outcome not included 35 drug not included 14 population not included a 96 wrong publication type 434 wrong study design 102 publications included: 95Asthma 83Effica cy/effectiveness 12S a fety 7Exercise-inducedbronchospasm 5Efficacy/effectiveness 2Safety a Wrong publication types included letters with insufficient information, editorials, non-systematic reviews, case reports, and case series with fewer than 10 patients. Quick-relief medications for asthma Page 15 of 113 Final Report Update 1 Drug Effectiveness Review Project Table 2. Quick-relief medications for asthma: included citations: efficacy, effectiveness, and safety Metaproterenol (original report Ipratropium a a Fenoterol Levalbuterol only) Pirbuterol Terbutaline bromide 83 Wraight 2004 21, 23-45 18, 46-60, 61 62-67 14, 15, 67, 68 13, 16, 19, 22, (IB vs. Albuterol 24 (24) 14 (15) 5 (6) 3 (4) 23 (22) ,102 34, 37, 44, 67, 69-82 IB+albuterol) 84 Salo 06, Charakaborti 85 06, Sharma 86 04, Watanasmsiri 87 06, Ranston 88 2005 (albuterol vs. IB+albuterol) a 89 34, 37, 44, 90- Fenoterol 1 (1) 12 (11) 97 88 Levalbuterol Ralston 2005 (levalbuterol vs. Systematic reviews The original report identified no systematic reviews of head-to-head comparisons of interest. In the Cochrane Database of Systematic Reviews there are a number of reviews related to inhaled beta -agonists. None of these reviews fulfilled our inclusion criteria; the most common reason2 was a focus on placebo-controlled trials (and not head-to-head trials). Since these reviews provide additional background and useful information, we have briefly summarized their scope and conclusions in Appendix C. We used 2 recent systematic reviews as the basis for our review of ipratropium bromide 9, 12 for Update 1. Both of these reviews focused on chronic asthma; 1 review was of children 9 more than 2 years of age with anticholinergic agent use for more than 1 week, the other review 12 was of adults with anticholinergic use for more than 24 hours. The results of these reviews are summarized below in the relevant section for each drug comparison. What are the comparative efficacy and effectiveness of quick-relief medications used to treat outpatients with bronchospasm due to asthma or to prevent or treat exercise-induced bronchospasm? Quick-relief medications for asthma Page 16 of 113 Final Report Update 1 Drug Effectiveness Review Project Albuterol compared with levalbuterol Demographic and study characteristics are summarized in Tables 4 and 5 and effectiveness outcomes in Table 6. Adult asthma 54 56 Nelson and colleagues and Pleskow and others examined 362 patients 12 years of age and older with moderate to severe asthma. Each participant was given a nebulizer 3 times daily of either levalbuterol (0. The mean number of puffs of rescue medication used per day decreased in all active treatment groups. The within-group change was significant for levalbuterol 1. Rescue medication use increased in the placebo group (P=0. The percentage of patients reporting asthma or asthma increase (these were not defined) appeared similar among all groups (statistics not provided). Other effectiveness measures were not reported in this study. The primary outcomes of this study were pulmonary function measures and the study was not powered to examine healthcare utilization. In the discussion section of the paper, however, the authors indicate that patients treated with levalbuterol required less additional therapy, and a greater percentage were discharged after 3 doses than after treatment with albuterol. However, hospitalization rates were similar between the 2 drugs for matched dosages. No statistical comparisons were presented for these outcomes. Two randomized controlled trials compared racemic albuterol to levalbuterol. Nowak and 102 colleagues enrolled 627 adults with acute asthma exacerbations presenting to the emergency department or to acute care clinics. Approximately two-thirds of these patients were African American. At the time of emergency department/clinic discharge, patients were given a 5-day course of oral corticosteroids and a blinded, nebulized study drug to be given 3 times a day for 3 days, then as needed for up to 3 times a day for 7 days. The time to meet emergency department or clinic discharge criteria (the primary outcome) did not differ between the 2 treatments: 76. Hospitalization rates were similar between groups (levalbuterol 7. Relapse rates at 7 and 30 days were also similar between groups (P>0. In the subgroup of subjects not on steroids at the time of the emergency department visit, fewer levalbuterol- than albuterol-treated patients required hospitalization (3. However, there was no significant difference in admission rates for the subgroup taking steroids at baseline. The focus of the study was the safety of long-term, regular use of levalbuterol metered dose inhaler. Pirbuterol metered dose inhaler was used as rescue medication. The study was originally designed for 12 Quick-relief medications for asthma Page 17 of 113 Final Report Update 1 Drug Effectiveness Review Project months of follow-up, but was modified to 6 months, with no rationale for this change provided. Attrition rates were high overall (44%) at 6-month follow-up; rates were even higher at 12 months (65% with levalbuterol and 57% with albuterol). Because of the high attrition and the change in follow-up period without provision of a rationale, this study was rated poor quality. Rates of asthma adverse events and asthma attacks (the latter defined as requiring hospitalization, a visit to the emergency department or clinic, or a burst of corticosteroids) were similar between groups. Rates of rescue medication use and daytime asthma control days were similar between groups (no statistics reported). Quality of life (as measured with the Adult Asthma Quality of Life Questionnaire) improved to a similar extent in both groups. Pediatric patients did, however, demonstrate a greater improvement in quality of life (as measured with the pediatric Asthma Quality of Life Questionnaire) with levalbuterol than with albuterol. No statistics were provided for the pediatric measures and the sample size was small (N=31). Pediatric asthma Symptoms and use of rescue medication did not differ between drugs in the 5 pediatric studies 51, 53, 57, 59, 61 that compared albuterol and levalbuterol. Two of these studies took place in the 57 emergency department. Qureshi and colleagues examined children aged 2 to 14 years (N=129) upon presentation to a pediatric emergency department with a moderate to severe acute asthma exacerbation (asthma score >8 out of a possible score of 15 or FEV1). These children were given 3 nebulized treatments of either albuterol 2. There were no significant differences between groups after the first, third, and fifth nebulizer treatments for the primary outcome of improvement in asthma score (validated score based on respiratory rate, auscultation, retractions, dyspnea, and oxygen requirement) or percentage of predicted FEV. Three treatments were given as needed at 20-minute intervals, along with oral steroids after the second treatment. There were no differences among groups for oxygen saturation, respiratory rate, peak flow rates, or the need for extra treatments. Three studies examined regular daily use of levalbuterol and albuterol. Milgrom and 53 colleagues examined 338 children aged 4 to 11 years with at least mild asthma for 60 days before screening and randomized them to receive 21 days of three-times-a-day levalbuterol 0. No significant differences were noted among the treatment groups for overall asthma symptom score, number of symptom-free days, quality of life, or use of rescue medication. Asthma control days were not different among groups for the first 14 days of treatment; however, from day 14 to 21, levalbuterol 0.
The numbers needed to treat to achieve one additional responder on American College of 76 Rheumatology 20/50/70 were 5 cheap 4 mg glimepiride fast delivery, 5 cheap glimepiride on line, and 7 generic 1 mg glimepiride with visa, respectively order generic glimepiride online. A placebo-controlled trial (n=47) 74 conducted in Asian patients reported similar findings. Anakinra 88 We identified one recent high-quality meta-analyses on the general efficacy of anakinra. Pooled results presented statistically significantly greater improvements of anakinra- than placebo-treated patients on all outcome measures (American College of Rheumatology 20/50/70, Health Assessment Questionnaire, and Patient Global Assessment). The numbers needed to treat to achieve one additional responder on American College of Rheumatology 20/50/70 were 8, 9, and 22, respectively. A placebo 143 controlled trial (n=54) conducted in Asian patients reported similar findings. Certolizumab pegol A good systematic review and meta-analysis of five randomized controlled trials including almost 2400 patients treated with certolizumab pegol or placebo reported statistically significantly higher American College of Rheumatology 50 response rates for patients on certolizumab pegol (relative risk, 2. The number needed to treat to achieve American College of Rheumatology 50 response was 4 (95% CI, 3 to 5). Patients treated with certolizumab pegol were also statistically significantly more likely to achieve remission (odds ratio, 3. Two studies, included in the systematic review above, also reported on work productivity 94,95 and work days missed because of rheumatoid arthritis. In the RAPID (Rheumatoid Arthritis Prevention of Structural Damage) 1 and RAPID 2 trials, patients on certolizumab pegol had statistically significantly greater work productivity and statistically significantly fewer work days 144 missed due to rheumatoid arthritis than those on placebo. Etanercept Two good meta-analyses examined the efficacy of etanercept in patients with rheumatoid 75,145 arthritis. Findings showed statistically significantly greater American College of Rheumatology 50 response rates after 6 months for patients treated with etanercept than placebo Targeted immune modulators 40 of 195 Final Update 3 Report Drug Effectiveness Review Project (relative risk, 5. The numbers needed to treat to achieve 1 additional 76 responder on American College of Rheumatology 20/50 were 6 and 6, respectively. One trial compared etanercept to methotrexate over 52 weeks in patients with early active 102 disease. Although the study failed to show statistically significant differences between etanercept (25 mg twice weekly) and methotrexate (20 mg/week) in health outcome measures (Short Form 36 Health Survey, Health Assessment Questionnaire, arthritis-specific health index), and American College of Rheumatology response rates at study endpoints (52 weeks), radiographic outcomes were statistically significantly better in patients on etanercept than on methotrexate. Improved radiographic outcomes were maintained during an extension of the Early 103 Rheumatoid Arthritis trial to 24 months. Golimumab A good systematic review and meta-analysis of four randomized controlled trials including more than 1700 patients treated with golimumab or placebo reported statistically significantly higher American College of Rheumatology 50 response rates for patients on golimumab (relative risk, 110 2. The number needed to treat to achieve American College of Rheumatology 50 response was 5 (95% CI, 2 to 20). Patients treated with golimumab were also statistically significantly more likely to achieve remission (relative risk, 5. Infliximab Four well-conducted meta-analyses determined the general efficacy of infliximab in rheumatoid 76,127,146,147 arthritis. Pooled results of these studies reported statistically significantly greater improvements of patients on infliximab than on placebo for all outcome measures. For 10 mg infliximab every 8 weeks, the American College of Rheumatology 50 response rate was 30% compared with 5% for placebo. The number needed to treat to achieve one additional response was 4. Rituximab Four fair-quality studies assessed the general efficacy of rituximab for the treatment of patients 128,130,132-135 with disease-modifying antirheumatic drug resistant rheumatoid arthritis. All five trials reported statistically significantly better efficacy outcomes for rituximab- than for placebo treated patients. For example, rituximab regimens (2 x 1000 mg) led to statistically significantly greater response rates on American College of Rheumatology 20 than placebo (51% compared 132-134 with 18%; P<0. Likewise, patients on rituximab achieved statistically significantly greater responses on American College of Rheumatology 50 (27% compared with 5%; P<0. Tocilizumab 148 149 Two systematic reviews, one good and one fair quality, confirmed the general efficacy of tocilizumab for the treatment of patients with rheumatoid arthritis. The good systematic review included eight randomized controlled trials which were conducted in clinically heterogeneous 148 populations. Some of the included studies enrolled patients with active rheumatoid arthritis despite methotrexate treatment, others included patients who had also failed antitumor necrosis factor drug treatment. Patients received 8 mg/kg or 4 mg/kg of intravenous tocilizumab every 4 Targeted immune modulators 41 of 195 Final Update 3 Report Drug Effectiveness Review Project weeks, or placebo. Pooled estimates showed statistically significantly greater response (American College of Rheumatology 50 response: relative risk, 3. The number needed to treat to achieve one additional responder on American College of 148 Rheumatology 50 was 5. Similarly, quality of life (Health Assessment Questionnaire) was also statistically significantly better in patients on tocilizumab). Targeted immune modulators 42 of 195 Final Update 3 Report Drug Effectiveness Review Project Table 8. Studies included for general efficacy in rheumatoid arthritis Author Study Primary Secondary Quality Year design Number Duration Comparisons outcome outcomes Population Results rating ABATACEPT Statistically significantly Abatacept + greater 64 methotrexate vs. ACR failed at least 76 MA 2869 Varying Withdrawals significantly Good 2008 placebo + 20/50/70 1 DMARD greater with methotrexate treatment adalimumab than with placebo Statistically Adalimumab + Active RA; had Number of ACR significantly fewer 74 methotrexate vs. ACR 20, DAS20, failed at least significantly 93 MA 2394 ACR 50 Good 2011 weeks placebo + HAQ 1 DMARD greater with methotrexate treatment certolizumab pegol than with placebo ETANERCEPT ACR 20/50/70 response rates Etanercept + Active RA; had statistically Alonso-Ruiz et al. ACR failed at least 76 MA 1637 Varying Withdrawals significantly Good 2008 placebo + 20/50/70 1 DMARD greater with methotrexate treatment etanercept than with placebo Up to 6 months statistically significantly higher ACR 50/70 response rates for etanercept than for methotrexate; early, active 102-104 no differences Bathon et al. At 12 RCT 632 52 weeks ACR-N, modified disease Fair methotrexate 70 months no Sharp duration: 1 differences in year. ACR 20 but less joint erosion for etanercept; no statistically significant differences in SF- 36, HAQ, and ASHI scores ACR 20/50 Active RA; had response rates Etanercept + failed at least statistically 75,145 Up to 52 methotrexate vs. ACR failed at least 76 MA 2581 Varying Withdrawals significantly Good 2008 placebo + 20/50/70 1 DMARD greater with methotrexate treatment infliximab than with placebo ACR 20/50/70 Active RA; had response rates Infliximab + failed at least statistically 75,127 Up to 52 methotrexate vs. ACR 50/70, DAS necrosis factor 132-134 RCT 520 24 weeks ACR 20 significantly Fair 2006 (REFLEX) placebo + 28, HAQ SF-36 therapy; mean greater with methotrexate disease rituximab + duration: 11. ACR 20/70, significantly 128,129 RCT 161 24 weeks rituximab + ACR 50 treatment; Fair 2004 DAS28 greater with cyclophosphamide vs. DAS28 greater with positive; mean methotrexate + rituximab + disease placebo methotrexate duration: 10. DAS28, HAQ-DI mean disease greater with methotrexate + duration: 7. Targeted immune modulators 47 of 195 Final Update 3 Report Drug Effectiveness Review Project Juvenile Idiopathic Arthritis Currently abatacept, adalimumab, etanercept, and tocilizumab are approved by the US Food and Drug Administration for the treatment of juvenile idiopathic arthritis. Summary of findings No evidence on the comparative effectiveness of targeted immune modulators for the treatment of juvenile idiopathic arthritis exists (Table 9). Five randomized controlled trials provided fair 150,151 152 153 154 155 evidence that abatacept, adalimumab, etanercept, infliximab, and tocilizumab are more efficacious than placebo for the treatment of juvenile idiopathic arthritis. Except for the infliximab trial, however, the highly selected study populations were likely to compromise the external validity of these studies. Some of these studies did not meet our formal eligibility criteria. Because these studies are the only available randomized controlled evidence on some drugs, we are still presenting main findings. Study populations and outcome measures Patients suffered from active polyarticular juvenile idiopathic arthritis and were between 2 and 19 years of age. They had active disease despite treatment with corticosteroids and methotrexate. Patients with concurrent medical conditions were excluded from trials. One trial on the efficacy and safety of tocilizumab included only patients suffering from systemic-onset juvenile 155 idiopathic arthritis. Except for the infliximab trial, all studies used withdrawal designs. After a run-in period with the active drug, only patients who responded, adhered to treatment, and had no intolerable adverse events were randomized to continue active treatment or placebo.
It is essential to implement a wide-reaching policy in the areas of sports cheap glimepiride 4 mg with amex, education best glimepiride 2mg, and health regarding the care that the whole population should take when practicing sports glimepiride 4 mg mastercard, irrespective of the presence of SCT order glimepiride 4 mg with visa. American College of Sports Medicine (ACSM) Team physicians and athletic trainers should familiarize themselves with the medical literature concerning SCT. Unwarranted restrictions or limitations on activity should not be placed on persons with SCT. If screening for SCT is conducted, it should be done on a voluntary basis with the informed consent of the person and should be offered to all persons. If a test is positive, the person should be offered genetic counseling for concerns such as family planning, and an explanation of a possibly remote and unclear risk involved with physical exercise and altitude. All exercising persons, including those with known SCT, should be counseled to avoid dehydration; should acclimatize gradually to heat and humidity; should condition carefully and gradually for several weeks before engaging in exhaustive exercise regimens; should acclimate to altitude over an appropriate amount of time; and should refrain from extreme exercise during acute illness, especially one involving fever. American Academy of Pediatrics (AAP) The AAP does not support routine carrier testing in minors when such testing does not provide health beneﬁts in childhood. The AAP advises against school-based testing or screening programs because the school environment is unlikely to be conducive to voluntary participation, thoughtful consent, privacy, conﬁdentiality, or appropriate counseling about test results. These recommendations were formally en- educate and improve the capacity of athletic coaches and trainers to dorsed by DHHS Secretary Kathleen Sebelius in June 2011. The American College of Sports Medicine (ACSM), which includes many subspecialists who serve as collegiate team physicians, does SACHDNC not have a formal position on SCT screening as a prerequisite for The US Department of Health and Human Services (DHHS) athletic participation; however, they believe that if screening occurs, Secretary’s Advisory Committee on Heritable Disorders in New- it should be voluntary and persons should be offered counseling to borns and Children (SACHDNC) developed a report in 2010 on include family planning. Unwarranted limitations of activities screening of US college athletes for their SCD carrier status. Student-athletes are Although persons should understand the medical and genetic encouraged to avoid dehydration, gradually acclimate to heat and consequences of SCT, the committee recommended that genetic new exercise routines, and to refrain from exercise during acute testing should not be a prerequisite for participation in sports unless febrile illnesses. The committee also recommended that all athletes be given The sickle gene frequency in Brazil is similar to that in the United education on safe practices for the prevention of exercise- and States, prompting representatives of the Brazilian Armed Forces, Hematology 2013 635 sports organizations, and sickle cell experts and other stakeholders References to consider implementation of a wide-reaching policy in 2007. Public health implica- consensus white paper was generated in which they concluded that tions of sickle cell trait: a report of the CDC meeting. Am J Prev there is no need to perform screening for hemoglobinopathies of Med. They emphasized the need to raise awareness independently associated with susceptibility to end-stage renal among the general population that, as long as basic hydration and disease in African Americans. Derebail VK, Nachman PH, Key NS, Ansede H, Falk RJ, Kshirsagar AV. High prevalence of sickle cell trait in African AAP Americans with ESRD. Sickle cell trait and the released a policy statement on ethical issues of genetic testing that risk of venous thromboembolism among blacks. Sickle cell trait and ics (ACMG), AAP does not support screening solely to determine development of microvascular complications in diabetes melli- carrier status unless the results have clear health beneﬁts. Sickle-cell trait: novel clinical signiﬁ- advise against school-based screening because the school environ- cance. Incidence of sudden cardiac death in national collegiate athletic association athletes. Goldsmith JC, Bonham VL, Joiner CH, Kato GJ, Noonan AS, The National Heart, Lung, and Blood Institute of the National Steinberg MH. Framing the research agenda for sickle cell trait: Institutes of Health and the Centers for Disease Control and building on the current understanding of clinical events and Prevention have convened consensus conferences recently to frame 1,8 their potential implications. Performance also organized a roundtable with representatives from 9. ACSM and the US Department of Defense, ACSM, NCAA, and content experts CHAMP summit on sickle cell trait: mitigating risks for from the ASH to examine strategies to mitigate risk associated with 9 warﬁghters and athletes. The best available evidence suggests that under extreme 2045-2056. Sickle-cell tion, SCT increases the relative risk of heat-related illness and trait as a risk factor for sudden death in physical training. Connes P, Reid H, Hardy-Dessources MD, Morrison E, Hue O. Plausible mechanisms have Physiological responses of sickle cell trait carriers during been proposed, but they are as yet untested6,11,28 and focused exercise. Data from new sources, including additional information regular physical activity on skeletal muscle structural, ener- from efforts by the military to mitigate heat-related risk; consistent getic, and microvascular properties in carriers of sickle cell comprehensive testing of athletes who experience severe myalgias trait. Exercise training blunts mandate on student-athletes are likely to make important contribu- oxidative stress in sickle cell trait carriers. Moderate endurance injuries and deaths and have no potential to harm may be the more exercise is not a risk for rhabdomyolysis or renal failure in prudent path. Effects of hydration and water Disclosures deprivation on blood viscosity during a soccer game in sickle Conﬂict-of-interest disclosure: The author has received research fund- cell trait carriers. Published online ahead of ing from Novartis, Glaxo Smith Kline, Eli Lilly, Amgen, and bluebird print June 9, 2012. Thompson, MD, MPH, Lurie Children’s Hospital Chi- 325-330. Exertional 312-227-4834; Fax: 312-227-9756; e-mail: a-thompson@ rhabdomyolysis: a clinical review with a focus on genetic northwestern. Natural history of exertional rhabdomy- to duty/return to play: conference proceedings. Jordan LB, Smith-Whitley K, Treadwell MJ, Telfair J, Grant 20. Update: exertional rhabdomyolysis, active AM, Ohene-Frempong K. Deuster PA, Contreras-Sesvold CL, O’Connor FG, et al. Committee on Bioethics, Committee on Genetics, The Genetic polymorphisms associated with exertional rhabdomyol- American College of Medical Genetics and Genomics So- ysis. Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, emy of Pediatrics. Policy statement: ethical and policy issues Bina S, Muldoon S. The ryanodine receptor type 1 gene in genetic testing and screening of children. Loosemore M, Walsh SB, Morris E, Stewart G, Porter JB, with sickle cell trait (SCT) without hemoglobin screening or Hb Montgomery H. Holcomb1 and Shibani Pati2 1Center for Translational Injury Research, Department of Surgery, and Texas Trauma Institute, University of Texas Medical School, Houston, TX; and 2Blood Systems Research Institute and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA Over the past century, blood banking and transfusion practices have moved from whole blood therapy to components. In trauma patients, the shift to component therapy was achieved without clinically validating which patients needed which blood products. Over the past 4 decades, this lack of clinical validation has led to uncertainty on how to optimally use blood products and has likely resulted in both overuse and underuse in injured patients. However, recent data from both US military operations and civilian trauma centers have shown a survival advantage with a balanced transfusion ratio of RBCs, plasma, and platelets. This has been extended to include the prehospital arena, where thawed plasma, RBCs, and antiﬁbrinolytics are becoming more widely used. The Texas Trauma Institute in Houston has followed this progression by putting RBCs and thawed plasma in the emergency department and liquid plasma and RBCs on helicopters, transfusing platelets earlier, and using thromboelastogram-guided approaches. These changes have not only resulted in improved outcomes, but have also decreased inﬂammatory complications, operations, and overall use of blood products. In addition, studies have shown that resuscitating with plasma (instead of crystalloid) repairs the “endotheliopathy of trauma,” or the systemic endothelial injury and dysfunction that lead to coagulation disturbances and inﬂammation. Data from the Trauma Outcomes Group, the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, and the ongoing Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial represent a decade-long effort to programmati- cally determine optimal resuscitation practices, balancing risk versus beneﬁts. With injury as the leading cause of death in patients age 1 to 44 years and hemorrhage the leading cause of potentially preventable death in this group, high-quality data must be obtained to provide superior care to the civilian and combat injured. Large-scale blood banking and transfusion originated during World transfusion practice mimicked the standard civilian approach, in War I, when blood transfusion was found to decrease mortality in which crystalloid was administered ﬁrst, followed by RBCs, then bleeding and severely injured soldiers. By 2005, a change blood was the sole transfusion product. In the 1960s and 1970s, had already occurred, revealed in the publication by Borgman et al component therapy became predominant in the Western world, describing the survival advantage of the 1:1 plasma and RBC ratio, a albeit with little if any quality data documenting clinical superiority balanced transfusion concept described as “Damage Control Resus- or even equivalence.
Deep infections with tissue destruction and abscess formation are rare in Europe and North America but common in tropical regions cheap glimepiride 2mg free shipping. According to Torssander (1988) onychomycosis due to dermatophytes is frequent in ART-naïve patients and diffi- cult to treat purchase glimepiride 2mg with mastercard. Nails are discolored (white buy glimepiride 4 mg low price, yellow purchase glimepiride amex, green, black), thickened and show growth disturbances (onychodystrophy). Subungual hyperkeratosis and onycholysis are common. Psoriasis, yeast infections and trauma can imitate onychomycosis so it is necessary to identify the causative organisms on KOH and fungal culture. Direct microscopic examination with the addition of 10-15% KOH solution shows translucent, septated hyphae (mycelium) and arthrospores. Calcofluor or Blankphor microscope slides can be used for diagnostic immunofluorescence microscopy. Culture on Sabouraud’s or Kimmig’s medium identifies different fungi by their growth characteristics. Treatment of superficial fungal infections of the skin is best achieved with topical broad spectrum antifungals such as ciclopirox or -azoles applied twice daily. In severe inflammatory disease it is helpful to start with combination therapy including topical corticosteroids for 3 or 4 days to achieve quick relief. Deep infections and infections involving terminal hairs (tinea capitis, tinea barbae) require systemic treatment with griseofulvin 500–1000 mg/day, terbinafine 250 mg/day, fluconazole 50 mg/day, or itraconazole 100–400 mg/day (Elewski 2001, Millikan 2001). There are different regimens to treat onychomycosis. Itraconazole and terbinafine are typically used for two months for fingernails and three months for toenails. Griseofulvin may be used for up to 9 months or longer, until the infection clears (Aly 1996, Myskowski 1997, Torssander 1988). If only the distal part of the nail plate is infected topical treatment 622 Interdisciplinary Medicine with nail varnish containing antifungals, which are able to penetrate the nail plate, are advised to avoid drug interactions between systemic antifungals and antiretro- viral medications (see chapter on Drug Profiles). If systemic therapy is necessary, flu- conazole has fewer drug interactions than other antifungals. Xerosis/Dry skin: Dry skin is a very frequent complication of any kind of immun- odeficiency. In the pre-ART era, we diagnosed dry skin in one in three HIV+ patients (Table 1). The patients complain of dry, itchy skin, which is exacerbated by any stim- ulus. Overall, these skin problems are very much like atopic dermatitis (Rudikoff 2002) and can culminate in acquired ichthyosis. The prevalence of dry skin decreases after the introduction of ART but can sometimes be seen in patients on indinavir (Garcia-Silva 2000). Some years ago, we found that the lipid film of the skin surface has a different composition in HIV+ patients although not diminished in quantity (Semrau, unpublished data). Dry itchy skin is treated with the application of emollients that contain 5 to 10% urea, or 3 to 4% lactic acid, and dexpanthenol. Patients should be advised to take maximum one shower every (other) day. In cases with severe inflammation and fissures (eczema craquele) topical Class 3 or 4 corticosteroids are very helpful in reducing symptoms. They should not be used for longer than 3 to 5 days. Molecular epidemiology of molluscum contagiosum virus and analysis of the host-serum antibody response in Spanish HIV-negative patients. Ivermectin alone or in combination with benzyl benzoate in the treatment of human immunodeficiency virus-associated scabies. Common superficial fungal infections in patients with AIDS. Bachmeyer C, Landgraf N, Cordier F, Lemaitre P, Blum L. Acinetobacter baumanii folliculitis in a patient with AIDS. Injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. Description of three cases and review of the literature. Emerg Med Clin North Am 2010, 28:393-407, Bharat A, Xie F, Baddley JW, Beukelman T, et al. Incidence and risk factors for progressive multifocal leukoen- cephalopathy among patients with selected rheumatic diseases. Biggar RJ, Engels EA, Frisch M, Goedert JJ; Risk of T-cell lymphomas in persons with AIDS. DRESS (drug rash with eosinophilia and systemic symptoms) syndrome asso- ciated with nevirapine therapy. Immune reconstitution inflammatory syndrome associated with Kaposi’s sarcoma. Papular follicular eruptions in human immunodeficiency virus-positive patients in South Africa. Incidence and risk factors for the occurrence of non-AIDS-defining cancers among HIV-infected individuals. Burkey MD, Wilson LE, Moore RD, Lucas GM, Francis J, Gebo KA. The incidence of and the risk factors for MRSA bacteraemia in an HIV-infected cohort in the HAART era. Changing morbidity of cutaneous diseases in patients with HIV after the introduction of highly active antiretroviral therapy including a protease inhibitor. A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associ- ated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. HIV-associated Skin and Mucocutaneous Diseases 623 Carr A, Samaras K, Burton S, et al. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resist- ance in patients receiving HIV protease inhibitors. Fosamprenavir: a review of its use in the management of antiretroviral therapy-naive patients with HIV infection. Chatzikokkinou P, Sotiropoulos K, Katoulis A, Luzzati R, Trevisan G. Seborrheic dermatitis – an early and common skin manifestation in HIV patients. The changing spectrum of the cutaneous manifestations of HIV disease. Cowan FM, Humphrey JH, Ntozini R, Mutasa K, Morrow R, Iliff P. Maternal Herpes simplex virus type 2 infec- tion, syphilis and risk of intra-partum transmission of HIV-1: results of a case control study. Anal Dysplasia and Anal Cancer in HIV-positive Individuals: Prevention, Diagnosis, Treatment. Eosinophilic pustular folliculitis: a comprehensive review of treatment options. Esser S, Reimann G, Brockmeyer NH, HIV-assoziierte Tumoren. Fontes V, Machet L, Huttenberger B, Lorette G, Vaillant L. Recurrent aphthous stomatitis: treatment with colchicine. High rate of Bartonella henselae infection in HIV-positive outpatients in Johannesburg, South Africa.
While our knowledge is still defi- cient buy cheap glimepiride 4mg line, some mediators of immune activation are known 4 mg glimepiride with visa. This is important for new therapeutic strategies targeting immune activation (Miedema 2013) order glimepiride 2mg without a prescription. Comprehensive epitope analysis of human immunodeficiency virus type 1 (HIV-1)-specific T-cell responses directed against the entire expressed HIV-1 genome demonstrate broadly directed responses discount glimepiride line, but no correlation to viral load. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Selective escape from CD8+ T-cell responses represents a major driving force of human immunodeficiency virus type 1 (HIV-1) sequence diversity and reveals constraints on HIV-1 evolution. Pathogenesis of HIV-1 Infection 41 Allers K, Hütter G et al. Single-stranded RNA derived from HIV-1 serves as a potent activator of NK cells. HIV-1 adaptation to NK-cell-mediated immune pressure. Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers. Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue. A direct estimate of the human alphabeta T cell receptor diversity. Neutralizing antibodies do not mediate suppression of human immunode- ficiency virus type 1 in elite suppressors or selection of plasma virus variants in patients on highly active anti- retroviral therapy. Cross-linking CD4 by HIV gp120 primes T cells for activation induced apoptosis. Isolation of a T-lymphotropic retrovirus from a patient at risk for AIDS. Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll- like receptor- viral RNA interactions. J Clin Invest 2005; Berzofsky JA, Bensussan A, Cease KB, et al. Antigenic peptides recognized by T lymphocytes from AIDS viral enve- lope-immune humans. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. CD4+ T cell depletion during all stages of HIV disease occurs pre- dominantly in the gastrointestinal tract. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Differential Th17 CD4 T-cell depletion in pathogenic and nonpatho- genic lentiviral infections. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Core structure of gp41 from the HIV envelope glycoprotein. Chen B, Vogan EM, Gong H, Skehel JJ, Wiley DC, Harrison SC. Structure of an unliganded simian immunodefi- ciency virus gp120 core. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. HIV-infected individuals receiving effective antiviral therapy for extended periods of time continually replenish their viral reservoir. Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. Clavel F, Guetard D, Brun-Vezinet F, Chamaret S, Rey MA, Santos-Ferreira O. Isolation of a new human retrovirus from West African patients with AIDS. Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus. HIV-1 nef protein protects infected primary cells against killing by cytotoxic T lymphocytes. Magnitude and complexity of rectal mucosa HIV-1-specific CD8+ T-cell responses during chronic infection reflect clinical status. HIV-1 auxiliary proteins: making connections in a dying cell. The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Genetic restrictions of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. Neutralizing antibody responses against autologous and heterologous viruses in acute versus chronic human immunodeficiency virus (HIV) infection: evidence for a constraint on the ability of HIV to completely evade neutralizing antibody responses. HIV infection, inflammation, immunosenescence, and aging. Identification of a major co-receptor for primary isolates of HIV-1. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. A dual-tropic primary HIV-1 isolate that uses fusin and the ß-chemo-kine recep- tors CKR-5, CKR-3, and CKR-2b as fusion cofactors. Breadth of human immunodeficiency virus-specific neutralizing activity in sera: clustering analysis and association with clinical variables. Persistent recognition of autologous virus by high-avidity CD8 T cells in chronic, progressive human immunodeficiency virus type 1 infection. Constraints on HIV-1 evolution and immunodominance revealed in monozy- gotic adult twins infected with the same virus. HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC- CKR-5. Programmed death 1 expression on HIV-specific CD4+ T cells is driven by viral replication and associated with T cell dysfunction. Relationships between CD4 independence, neutralization sensitivity and exposure of a CD4-induced epitope in an HIV-1 envelope protein. Cross-reactive neutralizing humoral immunity does not protect from HIV type 1 disease progression. Dendritic cell function during chronic hepatitis C virus and human immunodeficiency virus type 1 infection. HIV-1 entry cofactor: functional cDNA cloning of a seven-trans- membrane, G protein-coupled receptor. HIV controllers with HLA-DRB1*13 and HLA-DQB1*06 alleles have strong, polyfunc- tional mucosal CD4+ T-cell responses. Mucosal immune responses to HIV-1 in elite controllers: a potential correlate of immune control. Control of HIV-1 viremia and protection from AIDS are associated with HLA- Bw4 homozygosity. Human immunodeficiency virus type 1 activates plasmacytoid dendritic cells and concomitantly induces the bystander maturation of myeloid dendritic cells. Isolation of human T cell leukemia virus in acquired immune deficiency syndrome (AIDS). The gene product murr1 restricts HIV-1 replication in resting CD4+ lymphocytes. Gelderblom HR, Gentile M, Scheidler A, Özel M, Pauli G.