text:
Author Affiliations: AIDS Research Consortium of Atlanta, Atlanta, Georgia (Dr Thompson); University of California San Diego, La Jolla (Dr Schooley); New York University School of Medicine, New York (Dr Aberg); Hospital Juan Fernandez/University of Buenos Aires Medical School and Fundacion Huesped, Argentina (Dr Cahn); Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain (Dr Gatell); University Hospital Zurich, Division of Infectious Diseases and Hospital Epidemiology, University of Zurich, Zurich, Switzerland (Dr Günthard); Columbia University College of Physicians and Surgeons, New York, New York (Dr Hammer); Harvard Medical School, Boston, Massachusetts (Dr Hirsch); International AIDS Society–USA, San Francisco, California (Ms Jacobsen); BC-Centre for Excellence in HIV/AIDS, Providence Health Care and University of British Columbia, Vancouver, Canada (Dr Montaner); Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands (Dr Reiss); University of California San Diego and Veterans Affairs San Diego Healthcare System (Dr Richman); Luigi Sacco Hospital, Milan, Italy (Dr Rizzardini); University Hospital of Lausanne, Lausanne, Switzerland (Dr Telenti); University of California San Francisco and San Francisco Veterans Affairs Medical Center (Dr Volberding); and Hôpital Bichat-Claude Bernard and Xavier Bichat Medical School, Paris, France (Dr Yeni).
Context Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society–USA guidelines for the use of antiretroviral therapy in adults with HIV infection.
Objectives To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing.
Data Sources and Study Selection A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data.
Data Extraction and Synthesis New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus.
Conclusions Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count ≤500/μL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count >500/μL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.
Successful antiretroviral therapy (ART) is associated with dramatic decreases in AIDS-defining conditions and their associated mortality. Expansion of treatment options and evolving knowledge require revision of guidelines for the initiation and long-term management of ART in adults with HIV infection.
Since the 2008 International AIDS Society–USA ART guidelines,1 new data have emerged regarding timing of therapy, optimal regimen choices, and monitoring. There are also issues of special relevance to circumstances such as pregnancy, hepatitis virus coinfections, kidney disease, cardiovascular disease, and primary HIV infection. Analyses of clinical trials and epidemiologic cohorts have shed light on the role of ART in mitigating serious non-AIDS events associated with uncontrolled HIV replication. Newer drugs are better understood in terms of efficacy, toxicity, and potential uses. New data also suggest a role for ART in the prevention of HIV transmission.
The panel was convened in 1995 to develop evidence-based recommendations for ART for HIV-infected adults in developed-world settings.2 Members are appointed by International AIDS Society–USA according to clinical and research expertise. Current panel members do not participate in pharmaceutical marketing or promotional activities (eg, speakers' bureaus, industry satellites) during tenure on the panel. The current panel convened in January 2010 and met weekly in person or by teleconference. Data published or presented in specific scientific meetings since the last report1 were considered (eFigure). Data on file and personal communications were not considered except for data and safety monitoring board reports and US Food and Drug Administration alerts.
For identification of evidence, one member (P.A.V.) conducted a PubMed search of reports published since the last update. Search terms were HIV and antiretroviral, limited to humans, clinical trials, meta-analyses, randomized controlled trials, reviews, English, and adult, and yielded 582 citations. Of those, 194 citations were selected for review, eliminating those not relevant to adult care in resource-rich settings. Section teams identified abstracts from scientific conferences. Drug manufacturers were asked to provide published or presented data on updated clinical trials and adverse events for their products.
Section team leaders (J.A.A., P.C., J.S.G.M., G.R., and A.T.) summarized section consensus for group review and discussion. The quality and strength of the evidence were rated for each recommendation (eBox). Final recommendations were by full panel consensus.
Quiz Ref IDDeciding to start ART requires weighing the benefits of treatment on morbidity and mortality against its risks, including toxicity, resistance, drug interactions, and the costs and inconvenience of lifelong treatment. Sustained viral suppression restores and preserves immunologic function, decreasing opportunistic diseases and mortality. The patient must be ready and willing to adhere to lifelong therapy. Advances in ART continue to shift the therapeutic risk-benefit balance to earlier treatment. Improvements in potency, toxicity and tolerability, and pill burden allow for durable viral suppression for most patients.
The risks associated with ART have decreased, whereas concerns regarding the risks of long-standing untreated viremia have increased. Uncontrolled HIV replication and immune activation lead to a chronic inflammatory state, resulting in end-organ damage and comorbid conditions not previously thought to be associated with HIV infection. Several studies have shown that the life span of those with HIV infection still falls short of that of the general population, even at higher CD4 cell counts.3- 6 This life span decrease is related to serious, non-AIDS events attributed to chronic immune activation and the potentially permanent immune damage associated with prolonged immune depletion. In several data sets,3- 8 non-AIDS events were associated with elevated levels of viral replication and markers of immune activation and coagulation (including D-dimer, interleukin 6, or high-sensitivity C-reactive protein). Mortality from non-AIDS events now exceeds that of AIDS-defining opportunistic diseases in individuals receiving effective ART.9- 11
The strength of evidence supporting initiation of therapy increases as CD4 cell count decreases. In a cohort of 17 517 asymptomatic HIV-infected persons, initiating ART at a CD4 cell count greater than 500/μL decreased mortality by 94%, and initiating it at a CD4 cell count between 351 and 500/μL decreased mortality by 69%, although the numbers of deaths were low in both groups. The majority of deaths were from non-AIDS conditions.10 In an analysis of 62 760 persons in 12 cohorts, reduction in death was 23% and 45% for those beginning therapy with a CD4 cell count greater than 500/μL and 350 to 500/μL, respectively.12
Data from prospective observational cohorts and clinical trials demonstrate worse outcomes among patients who begin receiving ART at CD4 cell counts less than 350/μL or who have symptomatic HIV disease.1 Among 24 444 patients from 18 cohorts, there was no additional benefit from initiating therapy at CD4 cell counts of 451 to 550/μL compared with 351 to 450/μL. However, this analysis included only persons who began receiving ART at less than 550/μL.13 A randomized trial addressing the timing of initiation of therapy is under way. Indicators of rapid progression of disease, such as high HIV-1 RNA and rapid CD4 cell count decline, are recognized as reasons to initiate ART regardless of CD4 cell count.1 Older age is also associated with higher risk of AIDS and non-AIDS-related deaths. Quiz Ref IDPregnant women should be treated at least by the second trimester and therapy continued after birth.5,10,14- 18
HIV increases the risk of liver-related mortality in those with hepatitis B virus (HBV).19 Hepatitis B infection should not be treated with lamivudine or emtricitabine alone. If tenofovir is contraindicated, entecavir should be added.20 The durability of entecavir is compromised by previous HBV treatment failure with regimens including emtricitabine or lamivudine.21 Flares of hepatocellular inflammation may occur when therapy with agents active against HBV is discontinued or when HBV resistance to lamivudine or emtricitabine emerges in patients receiving these agents without tenofovir or entecavir.22,23 If ART must be interrupted, patients should be closely monitored for HBV reactivation.24
Patients with HIV–hepatitis C virus (HCV) coinfection progress to end-stage liver disease more rapidly than do HCV monoinfected patients.25 Clearance of HCV is associated with regression of liver fibrosis and a reduced risk of ART-related hepatotoxicity.26 In one study, abacavir with ribavirin was associated with a reduced rate of sustained HCV virologic response.27 Zidovudine, didanosine, and stavudine have overlapping hematologic and hepatic toxicities with current HCV therapy.25 Patients with HCV coinfection are at increased risk of hepatotoxicity, and certain ART regimens may require dose adjustment (see "Monitoring" section). Current HCV therapy has a higher probability of sustained HCV virologic response with HCV genotype 2 or 3; therefore, for patients with a high CD4 cell count and no imperative to begin ART, HCV treatment before ART may avoid cumulative drug toxicity and drug interactions.28
Renal disease ranges from HIV-associated nephropathy, to HIV-associated immune complex kidney disease, to thrombotic microangiopathy. In 5 cross-sectional cohort studies, 5.5% of patients had stages 3 to 5 chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 mL/min for more than 3 months). Older patients, blacks, persons with lower CD4 nadirs, and those with diabetes or hypertension have a higher risk of developing chronic kidney disease.29,30 Albuminuria and eGFR less than 60 mL /min per 1.73 m2 are independently associated with an increased risk of cardiovascular events.31 Tenofovir is associated with a decrease in GFR and tubular dysfunction; both indinavir (about 4% of patients)32 and atazanavir33 (uncommonly) are associated with nephrolithiasis. All nRTIs except abacavir may require dose adjustments according to the GFR.
Uncontrolled HIV infection is associated with increased cardiovascular risk.34 In a multivariate analysis involving 70 357 (487 HIV-infected and 69 870 HIV-uninfected) subjects, elevated high-sensitivity C-reactive protein and HIV were independently associated with acute myocardial infarction. With both risk factors, acute myocardial infarction risk increased greater than 4-fold.35 There were strong associations between overall mortality or cardiovascular disease and specific biomarkers. Although ART reduces the level of these biomarkers, they remain elevated compared with those of HIV-uninfected individuals. The clinical utility of these biomarkers for initiation or monitoring therapy is unknown. Modifiable cardiovascular risk factors should be aggressively addressed in all persons with HIV infection.
In a randomized controlled trial of when to initiate ART for patients with active opportunistic infections (excluding tuberculosis [TB]), early initiation (median, 12 days after presentation) reduced death or AIDS progression by 50% compared with beginning ART after the completion of opportunistic infection treatment.36 A South African randomized controlled trial including patients with TB and HIV demonstrated that initiating ART within 2 months of beginning tuberculosis treatment decreased mortality by 56% compared with initiating ART after completion of TB treatment.37 Immune reconstitution inflammatory syndromes occurred more often with early therapy, but no changes in ART were needed and no deaths were related to immune reconstitution inflammatory syndromes. Consideration must be given to the potential for drug interactions among therapies for opportunistic infections and ART.38,39
Patients who present with symptomatic primary HIV infection may progress more rapidly than those who present without symptoms.40,41 Antiretroviral therapy reduces the extremely high viral loads in primary infection and may reduce transmission.42,43 For patients presenting with asymptomatic primary infection, there are insufficient data for a recommendation on whether to treat immediately or defer; however, an analysis of 3019 seroconverters showed a 78% reduction in mortality when ART was initiated rather than delayed.12
Antiretroviral therapy reduces HIV transmission.44 Widespread use of ART during pregnancy has nearly eliminated mother-to-child transmission in the developed world.45,46 A meta-analysis concluded that ART also decreases the risk of HIV transmission to uninfected partners in HIV-serodiscordant heterosexual couples,43 and a cohort study of 3381 heterosexual serodiscordant couples showed a 92% reduction in transmission when ART was used by the infected partner.47 Another cohort study showed a strong association between increased ART coverage, decreased community plasma viral load, and decreased HIV incidence among injection drug users.48 Some mathematic models suggest that more aggressive ART coverage could reduce the incidence of new HIV infections49- 51; some field data also support this.42,52
Patient readiness for treatment is a key consideration when deciding when to initiate ART. There is no CD4 cell count threshold at which initiating therapy is contraindicated (BIIa). Initiation of therapy is recommended (Table 1) for symptomatic patients with established disease, regardless of CD4 cell count (AIa), and for asymptomatic individuals with CD4 cell counts less than or equal to 500/μL (AIa for < 350/μL, AIIa for ≤500/μL). Treatment should be considered for asymptomatic individuals with CD4 cell counts greater than 500/μL (CIII). Therapy is recommended regardless of CD4 cell count in the following settings: increased risk of disease progression associated with a rapid decline in CD4 cell count (ie, >100/μL per year) or a plasma HIV-1 RNA level greater than 100 000 copies/mL1 (AIIa); older than 60 years (BIIa); pregnancy (at least by the second trimester) (AIa); or chronic HBV or HCV coinfection (BIIa), although for patients with HCV genotype 2 or 3 and high CD4 cell counts, an attempt to eradicate HCV may be undertaken before ART is initiated (BIII); HIV-associated kidney disease (BIIa), avoiding drugs with potential adverse effects on the kidney (tenofovir, indinavir, atazanavir), if possible (AIIa)53; high cardiovascular risk (BIIa), modifiable risk factors for cardiovascular disease should be aggressively managed (AIa); opportunistic infections, including tuberculosis, with attention to drug interactions and the potential for immune reconstitution inflammatory syndromes (AIa); and symptomatic primary HIV infection to prevent rapid progression, to preserve immune function, and to limit ongoing transmission from this high-risk population (BIIa).42Quiz Ref IDOnce initiated, ART should be continued, except in the context of a clinical trial (AIa). Therapy should be considered where there is a heightened risk of HIV transmission (ie, HIV-serodiscordant couples) (BIIa), without supplanting traditional prevention approaches. Risk reduction counseling should be a routine part of care at each patient-clinician interaction.54
Selecting an initial regimen has long-standing consequences for future therapy. The initial regimen should be individualized according to resistance testing results and predicted virologic efficacy, toxicity and tolerability, pill burden, dosing frequency, drug-drug interactions, comorbidities, and patient and practitioner preference. In the absence of overriding considerations, cost and affordability should also be considered. Current evidence supports the combination of 2 nRTIs and a potent third agent from another class (Box). Fixed-dose formulations and once-daily regimens are generally preferred for initial therapy. The eTable presents a summary of selected clinical trial results in treatment-naive patients.
Dual nRTI Component
Available as fixed-dose combination alone and with efavirenz
Once daily
Low genetic barrier to resistance (emtricitabine)
Renal dysfunction, decreased bone mineral density associated with tenofovir influence choice
Available as fixed-dose combination
Weaker antiviral efficacy in treatment-naive patients withbaseline HIV-1 RNA >100 000 copies/mL
than tenofovir/emtricitabine
Low genetic barrier (lamivudine)
Need to screen for HLA-B*5701b to reduce risk of abacavir hypersensitivity
Abacavir may be associated with increased cardiovascularrisk
Key Third Agent
NNRTI class
Available in fixed-dose combination with tenofovir/emtricitabine, which has become standard-of-care
comparator regimen in most clinical trials
Low genetic barrier
Major psychiatric illness, first trimester of pregnancy, orintention to become pregnant influences choice
PI/r class
Widely prescribed when PI/r is chosen for initial therapy
Leaves options for future regimens
Less lipidogenic potential than lopinavir/r
Hyperbilirubinemia, need for acid-reducing agents, and risk of nephrolithiasis influence choice
Once daily in treatment-naive patients
Limited experience in treatment-naive patients, presence of other options in most naive patients, and
efficacy in patients with treatment experience, and multidrug-resistant virus influence choice
INSTI class (only 1 FDA approved at present time)
Twice daily
Low drug interaction potential
Rapid decline in HIV-1 RNA slope after initiation
Limited experience in naive patients, presence of other options in most naive patients, and efficacy
intreatment-experienced patients with multidrug-resistant virus influence choice
Extensive clinical experience
Comparator PI/r in many trials
Only PI coformulated with ritonavir (heat stable)
Can be given once daily in naive patients
Potential for hyperlipidemia and gastrointestinal adverse effects influences choice
Profile similar to lopinavir/r
May be useful when other initial PI/r not tolerated
CCR5 antagonist class
Targets host protein (viral coreceptor)
Need to perform viral tropism assay before use
Limited clinical experience in treatment-naive patients
Strategically, may be more useful in treatment-experienced patients or when primary (transmitted) drug
resistance is present but viral population should be exclusively receptor 5
Abbreviations: CCR5, CC chemokine receptor 5; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; INSTI, integrase strand transfer inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; nRTI, nucleoside or nucleotide analogue reverse transcriptase inhibitor; PI, protease inhibitor; /r, ritonavir boosted.aDetails, cautions, considerations, and supporting data1,17,55- 105 are described in the text.bBased on extensive clinical experience.cBased on antiviral efficacy and tolerability comparable to that of key third agents but more limited experience in treatment-naive patients.
Tenofovir has activity against both HIV-1 and HBV and a long intracellular half-life. Potent viral suppression and CD4 cell count increases occur when tenofovir and emtricitabine are used with a third agent. Alternative nRTIs are preferred over dose-adjusted tenofovir for patients with renal dysfunction.55 Tenofovir concentrations can be increased by some protease inhibitors (PIs), and studies have suggested a greater risk of renal dysfunction when tenofovir is used in PI-based regimens.56- 58 Tenofovir is available in fixed-dose, once-daily formulations with emtricitabine and with emtricitabine plus efavirenz.
HLA-B*5701 testing identifies persons at high risk for abacavir hypersensitivity.59,60 In the AIDS Clinical Trials Group study A5202, inferior virologic responses were observed with abacavir plus lamivudine compared with tenofovir plus emtricitabine in subjects with baseline HIV-RNA levels greater than 100 000 copies/mL. Abacavir plus lamivudine also was associated with more lipid abnormalities.61,62 The Data Collection on Adverse Events of Anti-HIV Drugs study, a large multinational observational cohort, found that recent, current, or cumulative use of abacavir predicted an increased risk of myocardial infarction, an association not observed with tenofovir.63,64 This risk was accentuated in participants who had preexisting cardiovascular risk factors. In contrast, in a pooled analysis of 52 clinical trials involving more than 9500 participants who received abacavir, no increased risk of myocardial infarction was found.65 Thus, no consensus has yet been reached on either the association or a possible mechanism.66
Lamivudine and emtricitabine are each well tolerated and select for the M184V mutation, which confers high-level resistance to both drugs but enhances the activity of tenofovir. Both are active against HBV but should only be used in combination with a second HBV-active drug when treating HIV-HBV coinfected patients. The role of zidovudine in initial regimens is limited by tolerability issues, as well as increased risk for lipodystrophy and hyperlipidemia compared with tenofovir.1 Stavudine and didanosine are not recommended for initial therapy because of increased toxicity of each.1 Combination regimens including 3 or 4 nRTIs alone are not recommended because of suboptimal virologic activity and increased toxicity.1,67
Several studies have shown consistently high and sustained rates of viral suppression with efavirenz in the initial regimen.1,68 Efavirenz was virologically superior to ritonavir-boosted lopinavir (lopinavir/r)69,70 and comparable to atazanavir/r61,62 and raltegravir.71 In AIDS Clinical Trials Group A5142 and 2 other studies, lopinavir/r showed better CD4 cell count responses and less drug resistance after virologic failure than efavirenz.69,72,73 Efavirenz is associated with rash and central nervous system adverse effects and should not be used during the first trimester of pregnancy or in women of childbearing age trying to conceive or not using effective and consistent contraception.17 Efavirenz is an inducer of cytochrome P450, and potential drug interactions are an important consideration. Baseline genotypic testing is important when considering nonnucleoside reverse transcriptase inhibitor (NNRTI) use. Primary NNRTI resistance rates vary from approximately 8.1% in the United States to 2.3% in Europe.74- 76
Nevirapine was noninferior to atazanavir/r (each combined with tenofovir plus emtricitabine) in a randomized controlled trial restricted to women and men with CD4 cell counts less than 250/μL and 400/μL, respectively.77 Nevirapine was similar virologically to lopinavir/r (again, each with tenofovir/emtricitabine) in a randomized trial of 500 African women with CD4 cell counts less than 200/μL.78 However, drug discontinuation because of adverse events was higher among nevirapine recipients.79,80 Serious hepatic events have been described within the first several weeks of initiation of nevirapine-based therapy but are less frequent if nevirapine is restricted to pretreatment CD4 cell counts less than 250/μL (women) or less than 400/μL (men).81 Patients who experienced CD4 cell count increases to levels above these thresholds with undetectable viremia as a result of previous ART safely switched to nevirapine therapy.82 The efficacy in initial therapy of etravirine, a newer NNRTI, has not yet been reported.
Atazanavir/r has greater virologic activity than unboosted atazanavir when combined with 2 nRTIs.83 Once-daily atazanavir/r and twice-daily lopinavir/r, both combined with tenofovir plus emtricitabine, showed similar virologic and CD4 cell count responses at 48 and 96 weeks.84,85 The hyperbilirubinemia, scleral icterus, or frank jaundice associated with atazanavir exposure is not accompanied by hepatic transaminase elevations but is more frequent with ritonavir boosting. Nephrolithiasis has occurred uncommonly with atazanavir, with or without ritonavir,33 and the eGFR may decrease when atazanavir is combined with tenofovir.86 Unboosted atazanavir should not be used with tenofovir.87 Atazanavir requires acidic gastric pH for dissolution. Thus, concomitant use of drugs that increase gastric pH, such as antacids, H2 antagonists, and particularly proton-pump inhibitors, may impair absorption of atazanavir and compromise its activity.88
Darunavir/r once daily was compared with standard doses of lopinavir/r (once or twice daily), each in combination with tenofovir plus emtricitabine. At 48 weeks, darunavir/r was noninferior to lopinavir/r, but virologic response rates were lower in the lopinavir/r arm among subjects with baseline HIV-1-RNA levels greater than 100 000 copies/mL. At 96 weeks, darunavir/r was virologically superior to lopinavir/r.89 Grade 2 to 4 adverse events, primarily diarrhea, were more frequent in the lopinavir/r arm.90 Darunavir/r is considered by many as less attractive in initial therapy because it is particularly useful for patients with PI-resistant virus.
Lopinavir/r demonstrates lower virologic efficacy but better CD4 response and fewer emergent resistance mutations than efavirenz.69,72,73 For initial therapy, once-daily and twice-daily lopinavir/r in combination with tenofovir plus emtricitabine achieved comparable rates of plasma HIV-1-RNA levels less than 50 copies/mL at 48 weeks,91 with similar rates of moderate to severe drug-related diarrhea. Other major adverse effects of lopinavir/r include insulin resistance and hyperlipidemia.
Twice-daily fosamprenavir/r and lopinavir/r, both administered with abacavir plus lamivudine, had comparable rates of virologic suppression and adverse events at 48 and 144 weeks.92 Once-daily vs twice-daily fosamprenavir/r did not differ in rates of virologic suppression.93
Saquinavir/r was compared with lopinavir/r, both with tenofovir plus emtricitabine, resulting in rates of viral suppression at 48 weeks of about 65% for each regimen; however, the statistical power of this study was limited by small sample size and short length of follow-up.94 Triglyceride levels were higher in the lopinavir/r arm. Although this was possibly a class effect, the Food and Drug Administration has issued a warning of a potential risk for QT-interval prolongation with saquinavir/r.95
Hepatic transaminase elevations can occur with any of the above regimens,96 especially in patients with underlying liver disease. Cumulative exposure to indinavir/r, lopinavir/r, and fosamprenavir/r (but not saquinavir/r) has also been associated with an increased risk of cardiovascular events.63,64,97 If possible, these drugs are best avoided in patients with elevated cardiovascular risk. Data concerning cardiovascular risk associated with atazanavir/r or darunavir/r are pending.
Raltegravir and efavirenz, each combined with tenofovir and emtricitabine, showed similar high virologic efficacy during 192 weeks.71,98,99 Raltegravir is well tolerated and has a favorable lipid and drug interaction profile; however, it is dosed twice daily and has a relatively low genetic barrier for selection of resistance mutations.100 Raltegravir is considered by some as less attractive for initial therapy because it is particularly useful for patients with drug-resistant virus.
The CC chemokine receptor 5 (CCR5) inhibitor maraviroc was compared with efavirenz, both in combination with zidovudine plus lamivudine, in 633 subjects with CCR5-tropic virus and no evidence of resistance to the study drugs.101 At 48 weeks, HIV-1 RNA less than 50 copies/mL was achieved in 65% and 69% of maraviroc and efavirenz recipients, respectively. The results did not meet prespecified criteria for noninferiority for maraviroc. Through 48 weeks, more participants discontinued maraviroc because of lack of efficacy (11.9% and 4.2%, respectively), whereas fewer participants discontinued maraviroc because of toxicity (4.2% and 13.6%, respectively). Follow-up results at 96 weeks demonstrated durable responses in both groups.102 Reanalysis of the results with a more sensitive tropism assay or with a genotype-based approach suggested that the differences between treatment arms could be attributed to misclassification of tropism in some patients by the older assay.101,103- 105 If only subjects with R5 virus at entry were considered, maraviroc appeared similar to efavirenz in antiretroviral activity. Maraviroc has not been evaluated extensively with other nRTI backbones in initial therapy.
Fixed-dose combinations are recommended when possible for convenience. Tenofovir plus emtricitabine is the recommended nRTI combination in initial therapy (A1a). If tenofovir plus emtricitabine cannot be used, abacavir plus lamivudine may be used as an alternative when HLA B*5701 testing results are negative, keeping in mind abacavir's lower efficacy at high viral loads (AIa) and its possible association with increased cardiovascular risk (AIIa). Zidovudine plus lamivudine should be reserved for instances in which neither tenofovir nor abacavir can be used. Three or 4 nRTIs alone are not recommended for initial therapy (AIa). Efavirenz (AIa), atazanavir/r (AIa), darunavir/r (AIa), or raltegravir (AIa) is recommended as the third component of an initial regimen. More evidence is available for efavirenz and atazanavir/r than for darunavir/r or raltegravir. Lopinavir/r, fosamprenavir/r, and maraviroc are alternative third-component choices (AIa). Neither saquinavir/r nor unboosted PIs, including atazanavir, are recommended for initial therapy (BIa). Nevirapine should be used as an alternative initial therapy only with pretreatment CD4 cell counts less than 250/μL (women) or less than 400/μL (men) (BI). Considerations for initial therapy in patients with specific conditions are summarized in Table 2.
Effective therapy should result in suppression to less than 50 copies/mL (polymerase chain reaction) or 75 copies/μL (branched DNA) by 24 weeks, regardless of previous treatment experience. Frequent HIV-1 RNA monitoring is recommended during the first year of ART to detect failure.106 Testing of HIV-1 RNA should be repeated 2 to 8 weeks after initiation, every 4 to 8 weeks until suppressed, and then every 3 to 4 months for at least the first year. CD4 cell counts should be monitored at least every 3 to 4 months after initiation of therapy, especially among patients with counts less than 200/μL, to determine the need for continuing opportunistic infection prophylaxis.107,108 In a EuroSIDA study, patients who maintained stable and fully suppressive ART for 1 year had a low chance of experiencing treatment failure in the ensuing months.109 Therefore, once viral replication is suppressed, monitoring intervals may be extended up to every 6 months among patients who remain virologically suppressed and have CD4 cell counts greater than 350/μL. More frequent monitoring is required for patients who have changed therapy because of virologic failure.110
Changes in assay methodology may result in detectable viral load in individuals with previously undetectable viremia.111,112 Detection artifacts have also been attributed to specific plasma processing practices.113 New assays may soon be available with a lower limit of 20 copies/mL; however, the clinical implications of viremia between 20 and 50 copies/mL are not yet clear. Confirmed viral load rebound on 2 separate tests at least 2 to 4 weeks apart should prompt a careful evaluation of regimen tolerability, drug-drug interactions, and patient adherence.
The prevalence of transmitted drug resistance varies in resource-rich societies from 8% to 16%.75,76,114 Baseline genotypic testing is recommended for all treatment-naive patients.81 For confirmed virologic failure, resistance testing is essential and should be performed while the patient is receiving the failing regimen, when possible. If the trajectory of HIV-1 RNA reduction is not optimal after a new regimen, archived mutations or minority variants may emerge. Minority variants not detected by current resistance testing have been associated with an increased risk of virologic failure; however, the assay thresholds that identify patients at greatest risk of experiencing poor outcomes have not been defined.40,115- 119 Tropism testing before use of a CCR5 antagonist is essential because this class has no activity against CX chemokine receptor 4 or dual-tropic viruses.101 Improvement in tropism assay methodology may further facilitate the clinical use of CCR5 antagonists.101,120
The frequency of monitoring for ART toxicity depends on the known toxicities of specific drugs and underlying comorbidities. Monitoring may occur every 2 to 8 weeks after initiation of therapy, decreasing to every 6 to 12 months after stabilization of HIV disease.108,121
Assessment of renal function should occur before initiation and during ART, in particular when tenofovir is used, allowing avoidance, dose modification, or timely substitution of another drug when appropriate.
The recommendations and algorithms of the National Osteoporosis Foundation122 and the World Health Organization fracture risk assessment tool123,124 are useful for the assessment of risk and prevention of osteoporotic fractures; however, these tools have not been specifically validated in the HIV-infected population. Vitamin D deficiency is common in the setting of HIV infection and may be associated with ART use.125 Monitoring of vitamin D levels may be of benefit.125- 127
Hepatic, cardiovascular, and renal complications may be associated with uncontrolled HIV replication. Clinical and laboratory assessment of relevant comorbid conditions should be performed before initiation of treatment and during follow-up.108,121 Cardiovascular disease risk should be assessed by available tools. The Framingham risk algorithm may be the most appropriate but may underestimate cardiovascular disease risk in the setting of HIV infection.128 Guidelines for the prevention and management of metabolic complications and noninfectious comorbidities in HIV infection are available.108,121
Therapeutic drug monitoring remains controversial.129 When assays are performed by a quality-assured laboratory, monitoring of PI and NNRTI levels may be useful in pregnant women, children, and patients with renal or liver impairment to minimize overexposure and adverse effects, manage potential drug-drug interactions, or evaluate virologic failure in the absence of resistance. As stated, HLA-B*5701 screening can identify patients at risk for abacavir-associated hypersensitivity.59
Plasma HIV-1 RNA levels should be monitored frequently when treatment is initiated or changed for virologic failure (AIIa) until they decrease below detection limits and regularly thereafter (BIII). Once the viral load is suppressed for a year and CD4 cell counts are stable at 350/μL or greater, viral load and CD4 cell counts can be monitored at intervals of up to 6 months in patients with dependable adherence (CIII). Baseline genotypic testing for resistance should be performed in all treatment-naive patients (AIIa) and in cases of confirmed virologic failure (AIa). HLA-B*5701 haplotype screening should be performed in any patient for whom abacavir is considered (AIa). Assessment of viral tropism is recommended before using maraviroc (AIa). Therapeutic drug monitoring is not recommended in routine care; however, selected patients might benefit from this intervention (CIII).
The virologic goal of treatment for first- and multiple-regimen failure is to achieve a plasma HIV-1 RNA level below the limit of detection of the most sensitive assays available. With the availability of new drugs and regimens, this goal now is achievable, even in most patients with multiregimen failure.130- 132 Reasons for viral rebound after complete suppression, such as poor adherence, drug-drug interactions, concurrent infections, and recent vaccinations, should be considered before the regimen is changed. Testing for an isolated detectable viral load should be repeated to exclude measurement error or self-resolving low-level viremia.1 Stage of HIV disease, nadir and current CD4 cell count, comorbidities, treatment history, current and previous drug resistance tests, and concomitant medications with potential for interactions should be considered when the new regimen is designed. Ideally 3, but at least 2, fully active drugs should be included and drugs from new classes should be considered. The toxicities of stavudine, didanosine, and to a lesser extent zidovudine make their use problematic, and they should be used only when options are limited.
Initial Failure of NNRTI-Based Regimens. Once failure has been confirmed, an NNRTI-containing regimen should be discontinued as soon as possible to minimize the selection of additional mutations. Initial NNRTI failures traditionally have been treated with 2 active nRTIs plus a PI/r, but raltegravir, maraviroc, and etravirine now provide additional options. According to potency and high genetic barrier, the inclusion of a PI/r should be considered whenever possible, but when not possible, an agent from a new class should be considered. Treatment-experienced patients receiving etravirine and darunavir/r plus an optimized background regimen had better virologic responses than those receiving placebo plus background regimen, with comparable tolerability at 48 weeks.133
Initial Failure of PI/r Regimens. Resistance to the PI/r component does not always emerge when regimen failure is detected, allowing the same drug or another in the PI class to be used in the next regimen. For early failures, strategic sequencing of PIs should be considered. If some degree of PI resistance exists, darunavir/r is likely to be preferred over lopinavir/r or tipranavir/r because of its superior tolerability and toxicity profile, as well as problematic drug interactions associated with tipranavir/r.1 If not previously used, an NNRTI may be included, provided that potential drug interactions are considered. Whenever possible, a new antiretroviral regimen should contain at least 2 fully active drugs.
Multidrug (Including PI and NNRTI) Resistance. In this setting, 3 active drugs, including new classes of agents (integrase strand transfer inhibitors or entry inhibitors), should be used. Individuals with multidrug-resistant virus usually benefit from a PI/r with activity against resistant strains, such as darunavir/r or tipranavir/r. Etravirine can be paired with darunavir/r (but not tipranavir/r) and may be of value, depending on the number of NNRTI mutations present. Enfuvirtide may be an option if no other new class can be used, despite the inconvenience of subcutaneous injection and injection site reactions. Dual-boosted PIs are not recommended.134 Lamivudine or emtricitabine is sometimes included to maintain the M184V mutation and decrease viral fitness, but there is no new evidence to support this approach. Another theoretically beneficial strategy is to use zidovudine to prevent the emergence of the K65R mutation in the presence of thymidine analogue mutations when using tenofovir in patients in whom nRTI-containing regimens are failing. However, no clinical benefit has been shown for this approach.135
Single-agent switches to decrease toxicity, avoid drug interactions, or improve convenience and adherence are possible, provided the potency of the regimen is maintained and drug interactions are managed. Although some studies have shown maintenance of virologic suppression with PI/r monotherapy as a simplification strategy,136 other studies have shown higher rates of failure, especially in the central nervous system,137 than with a combination including 2 nRTI plus a PI/r.138,139 Therefore, PI/r monotherapy is not recommended, except in exceptional circumstances when other drugs cannot be considered for reasons of toxicity/tolerability. Delaying switches when adverse effects persist may affect adherence and facilitate the emergence of resistance.
It may be desirable to switch to an equally effective regimen with fewer drugs or lower pill burden. Not all switches, even with a drug from a new class, are successful because the activity of the accompanying drugs in the regimen is a key determinant of outcome. Continuing lopinavir/r was virologically better than switching to raltegravir in patients with extensive previous 3-class ART experience and pre-existing nRTI resistance.140 With raltegravir, it is important to maintain a strong ART backbone, usually including a PI/r. Two smaller studies found that raltegravir was safe, well tolerated, and virologically similar when substituted for enfuvirtide in patients with multidrug-resistant HIV-1.141,142
Once-daily darunavir 800 mg/ritonavir 100 mg was noninferior to twice-daily darunavir 600 mg/ritonavir 100 mg in an open-label study in treatment-experienced patients.143 Dual therapy strategies intended to take advantage of drug interactions such as the combination of unboosted atazanavir and raltegravir are still experimental and are not recommended for clinical practice. For patients with virologic suppression who were receiving a boosted or unboosted PI-based regimen, switching to a once-daily regimen containing atazanavir provided better maintenance of virologic suppression, comparable safety, and improved lipids through 48 weeks compared with continued unmodified therapy.144
Treatment interruptions should be avoided.1 Interruptions, such as those for planned surgeries or severe toxicities in patients without options for switching, should consider the different half-lives of the regimen components; drugs should be discontinued in a staggered manner (or a PI/r temporarily substituted) when an NNRTI is a component.145
Quiz Ref IDMaintenance of regimen potency is the objective when switching ART regimens. Virologic failure of an initial regimen (confirmed measurable viremia) should be identified and treated as early as possible with at least 2 fully active drugs (AIa) to avoid the accumulation of resistance mutations. For NNRTI failures, the new combination usually should include a PI/r or an agent from a new class (AIa) if a PI/r is not possible. Etravirine may be a useful component of a new regimen for NNRTI failure but must be supported by a potent combination including a PI/r (AIa). Depending on the resistance profile and options available, inclusion of agents from new drug classes (raltegravir or maraviroc) should be considered (BIIb). Monotherapy with a PI/r should be avoided unless other drugs cannot be considered for reasons of toxicity/tolerability (AIa).
Quiz Ref IDDesign of a new regimen should consider previous drug exposure, previous resistance profile, drug interactions, and history of intolerance/toxicity (CIII). Treatment interruptions should be avoided, except in the context of controlled clinical trials (AIa). Elective treatment interruptions should consider the different half-lives of the regimen components, with stopping the drugs in a staggered manner when an NNRTI is a component (CIII).
Increasing evidence that insidious damage occurs during "asymptomatic" HIV infection underscores the potential benefit of ART, even when the risk of traditional AIDS-defining diseases is relatively low. The prominence of non-AIDS events as a major cause of morbidity and mortality in those with ongoing HIV replication suggests that early ART initiation may further improve the quality and length of life for persons living with HIV. The strategic use of newer drugs can improve tolerability, as well as provide durable and potent viral suppression in initial and subsequent therapy.
However, far too many HIV-infected persons present for medical care with advanced disease, both in wealthy and resource-limited settings. Universal voluntary HIV testing, comprehensive prevention services, and early linkage to care and treatment are necessary to ensure that advances in ART are made available during earlier disease stages. Advances in ART have shown that AIDS, as traditionally defined, can be prevented. One of the greatest challenges is that full implementation of these guidelines will require addressing social and structural barriers to diagnosis and care, as well as the pervasive stigma and discrimination associated with an HIV diagnosis.
Corresponding Author: Melanie A. Thompson, MD, 131 Ponce de Leon Ave NE, Ste 130, Atlanta, GA 30308 (firstname.lastname@example.com).
Author Contributions:Study concept and design: Thompson, Aberg, Cahn, Rizzardini, Telenti, Gatell, Günthard, Hammer, Hirsch, Jacobsen, Reiss, Richman, Volberding, Yeni, Schooley.
Acquisition of data: Thompson, Aberg, Cahn, Rizzardini, Telenti, Hammer, Volberding, Schooley.
Analysis and interpretation of data: Thompson, Aberg, Cahn, Montaner, Rizzardini, Telenti, Gatell, Günthard, Hammer, Hirsch, Reiss, Richman, Volberding, Yeni, Schooley.
Drafting of the manuscript: Thompson, Aberg, Cahn, Rizzardini, Telenti, Günthard, Hirsch, Jacobsen, Reiss, Richman, Volberding, Schooley.
Critical revision of the manuscript for important intellectual content: Thompson, Aberg, Cahn, Montaner, Rizzardini, Telenti, Gatell, Günthard, Hammer, Hirsch, Reiss, Richman, Volberding, Yeni, Schooley.
Obtained funding: Jacobsen, Volberding.
Administrative, technical, or material support: Montaner, Günthard, Hammer, Jacobsen, Volberding.
Study supervision: Thompson, Cahn, Telenti, Hammer, Hirsch, Jacobsen, Schooley.
Financial Disclosures: Dr Thompson reported receiving research grants awarded to AIDS Research Consortium of Atlanta from Abbott Laboratories, Avexa, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, GeoVax, Katketsuken, Koronis Pharmaceuticals, Merck Research Laboratories, Myriad, Ora-Sure, Panacos Pharmaceuticals (now Myriad), Pfizer, Progenics Pharmaceuticals, Roche Laboratories, Roche Molecular Systems, Serono, Theratechnologies Tibotec Therapeutics, Tobira Therapeutics, Trimeris, and VaxGen; has served on the scientific advisory boards or as a clinical trial design consultant for Chimerix, GeoVax, GlaxoSmithKline, Panacos Pharmaceuticals, Progenics Pharmaceuticals, and Tibotec Therapeutics; has received honoraria for scientific lectures from GlaxoSmithKline and Serono; and has served on data and safety monitoring boards for Tibotec Therapeutics. Dr Aberg reported serving as a scientific advisor to Abbott Laboratories, Boehringer Ingelheim Pharmaceutical, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Theratechnologies, Tibotec Therapeutics, and ViiV Healthcare; has received grants and research support from Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Schering-Plough, Theratechnologies, Tibotec Therapeutics, Virco Lab, and Wyeth; and has received honoraria from Abbott Laboratories, Bristol-Myers Squibb, and Gilead Sciences. Dr Cahn reported serving on the advisory boards for Avexa, Gilead Sciences, GlaxoSmithKline, Myriad Genetics, Merck, Pfizer, Pharmasset, Schering-Plough, and Tibotec Therapeutics; has served as an investigator for Avexa, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Pharmasset, Roche Laboratories, Schering-Plough, and Tibotec Therapeutics; and has received honoraria for speaking engagements from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck, Pfizer, and Tibotec Therapeutics. Dr Montaner reported receiving research grants from, and served as an ad hoc advisor or consultant to, Abbott Laboratories, Argos Therapeutics, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Cato Research Canada, ConjuChem Biotech, Gilead Sciences, GlaxoSmithKline, Hoffmann-La Roche, Johnson & Johnson, Merck Canada, Merck Frosst Laboratories, Pfizer Canada, Serono, Theratechnologies, and Tibotec Pharmaceuticals and has served on an endpoint adjudication committee for Schering-Plough. Dr Rizzardini reported receiving research grants from Gilead Sciences and Merck Sharp & Dohme. Dr Telenti reported receiving research grants or honoraria for lectures from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, and GlaxoSmithKline. Dr Gatell reported receiving research grants or honoraria for serving on advisory boards or for lectures from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharpe & Dohme, Pfizer, GlaxoSmithKline, Roche Laboratories, Theratechnologies, Tibotec Therapeutics, Tobira Therapeutics, and Virco Lab. Dr Günthard reported serving as a consultant and medical advisor for Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Gilead Sciences, GlaxoSmithKline, Pfizer, Tibotec Therapeutics, and ViiV Healthcare and has received unrestricted research and educational grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Pfizer. Dr Hammer reported serving on a scientific or clinical advisory boards for Merck, Progenics Pharmaceuticals, TaiMed Biologics, Tibotec Therapeutics, and Wyeth; has received clinical research contracts from Merck; and has served on data and safety monitoring boards and committees for Bristol-Myers Squibb and on the board of directors of SIGA Pharmaceuticals. Dr Hirsch reported serving on data and safety monitoring boards for Merck and TaiMed Biologics. Dr Reiss reported serving as a scientific advisor to Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Theratechnologies, Tibotec Therapeutics, and Tobira Therapeutics; has served on data and safety monitoring boards and endpoint adjudication committees for Tibotec Therapeutics; has received honoraria for speaking engagements at scientific conferences from Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, and Theratechnologies; and has received research support from Gilead Sciences, ViiV Healthcare, and Boehringer Ingelheim Pharmaceuticals. Dr Richman reported being a consultant to Anadys Pharmaceuticals, Biota, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Chimerix, Gen-Probe, Gilead Sciences, Idenix Pharmaceuticals, Koronis Pharmaceuticals, Merck, Monogram Biosciences, Myriad Genetics, Pfizer, Roche, Theraclone Sciences, and Tobira Therapeutics; has served on an endpoint adjudication committee for Schering-Plough; has been the recipient of a research grant from Merck; and has been a stock options holder of Chimerix and Idenix Pharmaceuticals. Dr Volberding reported serving on data and safety monitoring boards for Merck and TaiMed Biologics and on an endpoint adjudication committee for Schering-Plough; has provided paid expert testimony for commercial firms; has served on scientific or clinical advisory boards for Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, and Tobira Therapeutics; and has been the recipient of service grants for, or held contracts from, GlaxoSmithKline Italy. Dr Yeni reported receiving scientific grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Pfizer, Merck, and Roche Laboratories. Dr Schooley reported serving as a consultant to Achillion Pharmaceuticals, Anadys Pharmaceuticals, Ardea Biosciences, Gilead Sciences, GlaxoSmithKline, Inhibitex, iTherX, Johnson & Johnson, LabCorp, Merck, Myriad Biosciences, Pfizer, TaiMed Biologics, Tanox, Tobira Therapeutics, Vertex Pharmaceuticals, and Vical; has received grants from Gilead Sciences and Pfizer; and has stock options for Achillion Pharmaceuticals.
Funding/Support: This work was funded by the International AIDS Society–USA. Panel members serve in volunteer capacities (ie, are not compensated). No private sector or government funding was used to support the effort. The International AIDS Society–USA has received grants for selected CME activities (unrelated to guidelines development) from Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, Pfizer, Roche Laboratories, Tibotec Therapeutics, and ViiV Healthcare. Grants are pooled such that no single company supports any single effort.
Role of the Sponsor: The International AIDS Society–USA determined the need for updated recommendations, selected the panel members, and provided administrative oversight and financial support.
Additional Contributions: We thank Michelle Tayag Valderama, BS, who was compensated as an employee of the International AIDS Society–USA, for administrative support.
Some tools below are only available to our subscribers or users with an online account.
Download citation file:
Customize your page view by dragging & repositioning the boxes below.
More Listings atJAMACareerCenter.com >
Care at the Close of Life: Evidence and Experience
Overcoming the False Dichotomy of Curative vs Palliative Care for Late-Stage HIV/AIDS: "Let Me Live the Way I Want to Live, Until I Can't"
The Rational Clinical Examination: Evidence-Based Clinical Diagnosis
Evidence to Support the Update
All results at
JAMAevidence.com >


text:
Follow me on Twitter - www.twitter.com/ryinthehottub
Look at the Oklahoma City Thunder.. Rebranded and new colors when they moved.. And yes it was due to the fact that the city of seattle kept the sonic name and colors, but what do you think would happen if they stayed the sonics. People would still refer to them as Seattle..
New Orleans Fleur de Bees! And then just have that logo as the main one.
I'm sick of going to a lids store and all I can find I Charlotte Hornets hats. I prefer the Brass and would like a new set of colors not incorporating any form of teal. Krewe kinda grows on me too.
Ugh, the rebrand discussion again.
I'd like it to remain the Hornets (I support the Hornets brand as well as the New Orleans brand). But I understand where people come from in New Orleans when they say they want a new name. I just can't think of anything that would be cool when it comes to a name.
I like Gators the best out of all of them or maybe even Buccaneers (the old name). But again, I'm in love with the Hornets brand.
I like basketball
Twitter: @jsgrayson
To my knowledge the owner of OKC either left the naming rights to the city of Seattle or still retains them. Either way I will applaud his move being that in this day and age, moving a franchise can be a bit finicky for fans on both sides. I'm more than sure that had he chosen to keep the name and colors of the Sonics, he would have undoubtly pissed off Sonics fans even more so, but those of OKC I fail to believe wouldn't be all that mad because they stood on the side of gaining a franchise.
Had Shinn's ultimate plan come to fruition in keeping the team in OKC, would there still have been home grown fans there clamoring for a re-brand? Yes, there always are! It still wouldn't have happened since the Hornets were his baby and thus why we weren't given that option when the team moved here. It's understandable. If it were me I probably wouldn't have want to change it either, but then again we're talking about a guy who left because of more pressing issues outside the want of a new stadium. Rebranding the Hornets into something else was the furthest thing from his mind.
This is one of the reasons IMO that Shinn's baggage still casts a pall over this franchise til' this day despite a few changes here and there. Keep in mind that we were his fall back option once his inital plan to move to Memphis got booted in favor of the Grizzlies relocation there. Also a factor is that Memphis chose to keep it's name but at least a few years in the decided to change colors, graphics, etc. to leave behind those of their Vancouver days. I can say that yes it worked because their fans buy into their brand.
I'm not saying that we don't. We however were given a re-hashed product from an owner on his way out but desperatly trying to kindle a feel of his days in Charlotte. Would a new color scheme, no pinstripes, etc. have worked? Yes! People always buy into the new no matter how ugly it is which would bring me back to OKC. They have quite possibly the dumbest logo and color scheme in the NBA yet there fans buy into it because it is THEIRS!!!
OKC made the Thunder theirs. Memphis made the Grizzlies theirs. We haven't after all these years, shaken the ghosts of Charlotte's past. This being one of the many reasons that analysts across the world do not respect our franchise! Do you think we would have had the same problem had we gotten the T-Wolves and rebranded them into the Brass? No, because they would be N.O.'s franchise, new uniforms, new name, new look and that is what it takes these days to get peoples attention.
The Kings move from Sacramento to Anaheim and re-brand as the Royals. Nobody is going to call them the Kings! The Oakland A's are possibly moving to San Jose, people are still going to call them the Oakland A's! It's just the ways sports teams are preceived now and it sucks for us because we have a unique culture and city to go with that with all it's beaming creativity, we still have to rely upon a name that until it's gone, very few will associate with this city!
^^^^^^. Like the Brass,Krewe, and how about New Orleans JAM...short for Jambalaya!
I like the creativity, but Jam just feels too... 1990's to me
The New Orleans Name that Irritates Fans Who Only Support a Team Because of Its Name and Awful Teal Uniforms. It just slides of the tongue, no?
New Orleans My Lil Ponies
Cue UKP
You can assume the NBA would pressure Clay to sell the name and imagery back to Seattle if and when they get a team, but he doesn't hate too ... that was part of the exit deal and it was posted online for all to see.
There are currently 1 users browsing this thread. (0 members and 1 guests)

subset: commoncrawl


text:
|All Children's Patient, Connor Bruseski Receives the Tampa Bay Lightning's Community Hero Award
As a recipient of the 13th annual Tampa Bay Lightning's Community Hero Award, he'll get to do just that.
Connor, 8, received a $50,000 grant from the NHL club Friday afternoon in a sun-splashed ceremony in Zoe's Garden outside the hospital. And in a remarkable show of generosity and gratitude, the Tampa Bay area youngster will be donating $40,000 of that gift to All Children and, specifically, to the Vincent Lecavalier Pediatric Cancer and Blood Disorders Center - named after the current Lightning captain. He's donating the remaining $10,000 to the Children's Dream Fund.
Former Bolts captain Dave Andreychuk, now vice president of fans and business development for the club, was on hand to present the checks on behalf of the program created by Lightning owner Jeff Vinik. The initiative awards grants to individuals in the Tampa Bay community who are "catalysts for causes that enhance the lives of others, exhibit dedication and selflessness, make an impact on others and go above and beyond to inspire others."
Connor was spurred to action when he was flooded with gifts from family, friends and well-wishers during his treatment at All Children's. He wondered why he should receive so many presents and decided he wanted to help other kids fighting cancer get gifts as well. So, with the help of parents Mark and Wendy Bruseski, he created "Friends of Connor" to raise money to buy presents for other children dealing with oncology issues.
He designed 2,000 "Friends of Connor" wristbands and sold them for a $5 donation. Within 90 days, more than $14,000 had been raised. That number is now close to $20,000.
"Connor, you are a hero, and your actions inspire many people," Jenine Rabin, Executive Vice President of the ACH Foundation, told Connor as smiled broadly, standing beside twin sister Rylee and his parents.
Elizabeth Frazier, an executive with the Lightning Foundation, pointed out that Connor was now the youngest hero honored in the two-year-old program, which presents a $50,000 grant to a deserving individual for every home game on the schedule.
"Community heroes come in all different shapes, sizes, colors and causes and there is no one definition of what makes a community hero, and that's why it's so wonderful because it takes all different types of heroes to make a vibrant community," she said. "So thank you. You have your own life's journey you're going on. You're thinking of others. And I'm just so inspired by you.
"This program is more than just about giving $50,000 today to two organizations that are near and deal to your family's heart. It's really about telling your story to thousands of and thousands of Lightning fans out there so they can say, 'Connor, he's using his life to help other people."
Then it was time for Andreychuk to tell Connor and his family what was in store for them. Normally, the presentation would have been made in front of the fans on the ice at before a Lightning home game. But due to the ongoing lockout, Andreychuk has been making personal check presentations around the Tampa Bay. Once games resume, however, Connor and the Bruseski's will still be honored at a game.
"When we do get playing again, you guys are going to come down and watch our game," he said. "What happens normally is that I'm going to take you on a tour of the locker room while the players are on the ice just before the game. We're going to go sit on the bench and watch them warm up."
But there's something perhaps even more special in store. Connor's photo will displayed on the wall inside the locker room, along with a synopsis of his hero story, so all the players can read it before they play.
"That kind of impacts our players," he said. "When our players walk into the room for that game, your picture is up in that room. And they look at that picture and they see your story. And it inspires them to play, which I think is great (because) it happens every day. So not only are you impacting people here with all the great things you do, but you're making hockey players play."
With that, Andreychuk presented Connor with two checks, one for All Children's and the other for the Children's Dream Fund. The ACH gift will be divided three ways:
Some ¬will go toward providing financial assistance for families who can't afford to pay for hospitalization. The significance of this gesture can't be underestimated, especially given the fact that some 70 percent of All Children's families are on Medicaid. Connor's giving spirit will help alleviate the financial worries so many parents face as their child fights cancer.
Some will go to helping kids in the Lecavalier center enjoy a diversion from the enormous daily challenges they face. He's making it possible to purchase three Starlight Fun Centers: specially built entertainment units. Each center houses a Wii console and all the necessary accessories (such as two controllers and two nunchucks), a Sharp AQUOS flat screen television and DVD player, a library of 22 pre-loaded Wii games and dozens more DVDs that can be popped in.
The Starlight Fun Center is customized for hospital use, with wheels that allow it to roll easily and be played by kids without having to leave their beds. The game centers serve as a welcome pursuit for sick and injured children, helping offset the isolation and fear that they invariably experience while in the hospital.
"It's hard to have a game center without losing items," said ACH's Child Life director Kristin Maier. "This way, it's all enclosed. It's safe. It meets all standards of the hospital. It's easily cleaned. And we can take it to area's where kids spend long periods of time. And they can have an activity, because the Wii involves more than just sitting and playing a video game. It's actually a physical activity - and the whole family can get involved. It's a great way to engage the kids."
Finally, Connor has designated another portion of his grant to go toward funding an oncology research project at All Children's, which sees 125 new oncology patients annually. Given the hospital's expanded research mission as a partner of Johns Hopkins Medicine, his gift comes at an opportune time.
Connor's dad, Mark, spoke expressed his gratitude to the Lightning, All Children's and the Dream Fund for their work and talked of the long journey his family has been on.
"Cancer hit my life when I was a little boy about (Connor's age) when my father got diagnosed," he said. "I lost my father when I was 11. Fast forward to what's going on and it's been a crazy year. Being in this community and seeing what the Lightning has done before Connor was diagnosed, I opened (the paper) and saw what Mr. Vinik has done for the community and many recipients. To think (Connor) might be here today and what we ultimately turned this into is phenomenal. So I'm very thankful."
Mark, who works in software sales in the cancer prevention field, also singled out All Children's for the treatment and care afforded Connor.
"I've been around cancer care since I was a boy - that's my livelihood and on top of that now there's my child," he said. "And I've seen what this institution has done for the community. And the care that is given here is exceptional. I'm in hospitals and cancer centers just about every day of my life. And the care throughout - from the receptionists to the nurses on the floor, to the transporters ... it's been phenomenal. And Dr. (Nanette) Grana and the whole team - it's amazing what they can do for children."
"He's still in treatment, but I think he's about halfway through and he's doing great," she said.
Connor's generosity will also be felt in a big way with the Children's Dream Fund, emphasized executive director Cynthia Lake.
"It makes a huge difference," she said. "We have about 80 people waiting for a dream to come true. We'll take this money and put it toward our share of the Dream Program. And we'll make dreams come true with this money in honor of Connor."


text:
On the home page, the Scriture Project is introduced, including the following statement:
"With the input of the right scholars, we are confident that the Reason Project website will quickly become the preeminent place for scriptural criticism on the internet."
Q: What determines if a scholar is "right"?
Q: Is it assumed that eternal truth, such as scripture is alleged to convey, cannot be conveyed in a work that also exhibits the foibles listed in the introduction? (e.g. historical inaccuracy, internal contradictions, scientific errors, absurdity, injustice, cruelty, sexism, intolerance, etc.) If yes, what is the basis for such an assumption?


text:
National Rural Health Students' Network
The National Rural Health Students' Network (NRHSN) provides a voice for students who are passionate about improving health outcomes for rural and remote Australians.
It has more than 9,000 members who belong to 28 Rural Health Clubs at universities throughout the nation. They include students from medical, nursing and allied health courses.
The NRHSN offers multi-disciplinary networking, professional development and opportunities to raise community awareness of health issues.
Funded by the Australian Government, the NRHSN is supported by Rural Health Workforce Australia.
The NRHSN's new website, featuring its new branding, is coming soon!
NRHSN publications
To order any of the NRHSN publications please email us.
Ideas box
Have you got an idea for the NRHSN? Please email it through, we'd love to hear your suggestions.


text: ArticleRelated DiseasesImages & Quizzes smallermediumlarger 1 2 3 4 5 Next Bowel Incontinence(Fecal Incontinence) Take the Tummy Trouble Quiz Digestive Disease Myths Slideshow Pictures Ulcerative Colitis Slideshow Medical Author: Benjamin Wedro, MD, FACEP, FAAEM Benjamin Wedro, MD, FACEP, FAAEM Dr. Ben Wedro practices emergency medicine at Gundersen Clinic, a regional trauma center in La Crosse, Wisconsin. His background includes undergraduate and medical studies at the University of Alberta, a Family Practice internship at Queen's University in Kingston, Ontario and residency training in Emergency Medicine at the University of Oklahoma Health Sciences Center. View Full Profile Medical Editor: Bhupinder Anand, MD Bowel incontinence (fecal incontinence) definition What causes bowel incontinence? What are the symptoms of bowel incontinence? How is bowel incontinence diagnosed? What is the treatment for bowel incontinence? What about bowel incontinence in children? Can bowel incontinence be prevented? What is the prognosis for bowel incontinence? Patient Comments: Bowel Incontinence - CauseFind a local Gastroenterologist in your town Bowel incontinence (fecal incontinence) definition Fecal incontinence can be defined as the unintentional loss of stool (feces) or gas (flatus). It is often due to a failure of one or more of the components that allow the body to control the evacuation of feces, when it is socially appropriate. A normal bowel movement requires a complex interaction and feedback system between the nerves and muscles of the rectum and anus. The anatomy of this area is complicated. The rectum is a reservoir for holding stool. Two sphincters or circular muscles separate the rectum from the anus and control when the anus should allow a bowel movement. The internal anal sphincter (IAS) is under involuntary control of the body's nervous system, while the external anal sphincter (EAS) can be actively controlled by the indivdiual. In addition, the puborectalis muscle tugs at the junction of the rectum and anus, creating a 90 degree angle, which makes it harder for stool to move involuntarily into the anus. When the rectum is full and for a normal bowel movement to occur, the IAS relaxes just a little. Cells in the anus can detect feces or flatus and if the brain says that it is an opportune social time to pass gas or have a bowel movement, the puborectalis muscle relaxes, straightening the path from the rectum to the anus. Squatting or sitting helps increase the pressure within the abdomen, and muscles that surround the rectum squeeze its contents, the EAS relaxes and a bowel movement occurs. If it is not an appropriate time to open the bowel, the puborectalis muscle contracts, the EAS contracts, the rectum relaxes and stool is forced back into the upper part of the rectum, causing the urge to have a bowel movement to be temporarily quieted.What causes bowel incontinence? Reader Stories Read 2 Stories Share Your Story Fecal incontinence occurs because of an underlying disease or illness (it is not considered a "disease"). There are numerous potential causes and many patients have more than one reason to cause loss of bowel control. Damage to muscles and nerves may occur directly at the time of vaginal childbirth or after anal or rectal surgery. Neurologic diseases such as stroke, multiple sclerosis, spinal cord injury, and spina bifida can be potential causes of fecal incontinence. Complications of diabetes can also cause peripheral nerve damage leading to incontinence. Patients with inflammatory bowel disease (Crohn's disease, ulcerative colitis) and irritable bowel disease may develop fecal incontinence. Stool seepage is different than fecal incontinence. Minor staining can occur in people who have hemorrhoids, rectal fistula, rectal prolapse and poor hygiene. Other causes include chronic diarrhea, parasite infections, and laxative abuse. Paradoxical diarrhea or overflow incontinence may occur is a a person who has chronic constipation. In paradoxical diarrhea, stool fills the rectum, hardens and becomes impacted. Liquid stool leaks around the fecal mass, imitating incontinence. Medically Reviewed by a Doctor on 4/7/2015Next: What are the symptoms of bowel incontinence?1 2 3 4 5 Next Fecal Incontinence Index Find a Local Doctor Patient Comments Viewers share their comments Bowel Incontinence - Cause Question: What was the cause of your bowel incontinence? View 2 Comments • Submit » Bowel Incontinence - Symptoms Question: What symptoms did you experience with bowel incontinence? • Submit » Bowel Incontinence - Treatment Question: What was the treatment for your bowel incontinence? • Submit » Bowel Incontinence - Children Question: If your child had bowel incontinence, how was it treated? • Submit » Share this Article: Facebook Twitter Email Print Article Suggested Reading on Bowel Incontinence by Our Doctors Related Diseases & Conditions 22 articles Pinched Nerve A pinched nerve causes pain, numbness, or tingling in the affected area due to pressure on a nerve. Caral tunnel and sciatica are two examples of conditions Diarrhea Diarrhea is a change is the frequency and looseness of bowel movements. Cramping, abdominal pain, and the sensation of rectal urgency are all symptoms Constipation Constipation is defined medically as fewer than three stools per week and severe constipation as less than one stool per week. Constipation usually is Diabetes (Type 1 and Type 2) Diabetes is a chronic condition characterized by high levels of sugar (glucose) in the blood. The two types of diabetes are referred to as type 1 (insulin Crohn's Disease Crohn's disease is a chronic inflammatory disease, primarily involving the small and large intestine, but which can affect other parts of the digestive Multiple Sclerosis (MS) Multiple sclerosis or MS is an autoimmune disorder in which brain and spinal cord nerve cells become demyelinated. This damage results in symptoms that Irritable Bowel Syndrome (IBS) Irritable bowel syndrome (IBS) is a GI (gastrointestinal disorder) with symptoms of abdominal pain, bloating, increased flatus, cramping, diarrhea, constipation, Dementia Dementia is a significant loss of intellectual abilities such as memory capacity, severe enough to interfere with social or occupational functioning. There Ulcerative Colitis Ulcerative colitis is a chronic inflammation of the colon. Symptoms include abdominal pain, diarrhea, and rectal bleeding. Ulcerative colitis is closely Lumbar Spinal Stenosis Lumbar stenosis can be caused by degenerative arthritis (the most common cause), tumor, infection, or metabolic disorders (Paget's disease of the bone). Inflammatory Bowel Disease (Intestinal Problems of IBD) The inflammatory bowel diseases (IBD) are Crohn's disease (CD) and ulcerative colitis (UC). The intestinal complications of Crohn's disease and ulcerative Diabetes Treatment The major goal in treating diabetes is controlling elevated blood sugar without causing abnormally low levels of blood sugar. Treatment for type 1 diabetes Alzheimer's Disease Alzheimer's disease is a common cause of dementia. Symptoms and warning signs of Alzheimer's disease include memory loss, difficulty performing familiar Irritable Bowel Syndrome Triggers and Prevention Irritable bowel syndrome (IBS) is a functional disease that can affect the quality of those who suffer from this condition. Individuals with IBS can make Cauda Equina Syndrome Cauda equina syndrome is a medical emergency condition that is caused by the uncommon compression of the nerves at the end of the spinal cord. Symptoms Spinal Cord Injury: Treatments and Rehabilitation When vertebrae are broken or dislocated, the result can cause traumatic injury to the spinal cord. A spinal cord injury can have significant physiological Multiple Sclerosis Symptoms (MS Treatment Options) Multiple sclerosis (MS) symptoms vary from person to person, and can last for days to months without periods of remission. Symptoms of MS include problems Irritable Bowel Syndrome in Children Irritable bowel syndrome (IBS) in children is a functional gastrointestinal disorder with symptoms of abdominal pain, bloating, diarrhea or constipation. Alzheimer's Disease Patient Caregiver Guide Caring for a loved one or patient with Alzheimer's can become a difficult and overwhelming task at times. This guide helps caregivers of individual's with The Digestion Process (Organs and Functions) Digestion is the complex process of turning food you eat into the energy you need to survive. The digestive process also involves creating waste to be Neuromyelitis Optica Neuromyelitis optica (Devic's syndrome) is a disease of the CNS that affects the optic nerves and spinal cord. People with neuromyelitis optica develop Alzheimer's Disease Symptoms (and Stages) Alzheimer's disease symptoms often depend on the stage of the disease. Some of the early symptoms of Alzheimer's disease include problems thinking, mild Medications 3 articles Procedures & Tests 10 articles Pictures, Images & Quizzes 1 articles Doctor's & Expert's Views 1 articles Health News 5 articles Health Features 0 articles Privacy Policy GI Disorders Get the latest treatment options. By clicking submit I agree to WebMD's Privacy Policy


text:
Cary Fowler:
One seed at a time, protecting the future of food
The varieties of wheat, corn and rice we grow today may not thrive in a future threatened by climate change. Cary Fowler takes us inside a vast global seed bank, buried within a frozen mountain in Norway, that stores a diverse group of food-crop for whatever tomorrow may bring.
Similar topics
- Agriculture
- Biodiversity
- Biosphere
- Climate change
- Disaster relief
- Environment
This talk was presented at an official TED conference, and was featured by our editors on the home page.
Related talks
95 comments
Enthusiastically agree? Respectfully beg to differ? Have your say here.
Sort comments by
There are currently no comments for this talk.


text: GALLERIES Amy Lee 0 43 Back to Top ▲ Amy Lee Amy Lee Amy Lee Pictures AskMen Editors Share on Facebook Share on Twitter 0 Shares As the founder, frontwoman and driving creative force of Evanescence, Amy Lee has already made a mark: with her band, she's won two Grammy Awards, sold over 10 million copies of the album Fallen, and been featured in the soundtracks for such movies as Daredevil and The Punisher (the latter with Seether, not Evanescence). Continue reading Amy Lee's profile. Next Page gallery Comments Show Comments More Like This Promoted Around the Web Special Features Special Feature 100 Ways To Look Better Than You Do Now. Smooth Up, Man. Read More Special Feature From Dating To Fitness, Over 75 Ways Men Are Winning 2015 Read More ad