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Postuar nga Pashai_1987 dat 22 Dhjetor 2006 - 13:42:

Citim:
Po citoj ato q tha NS-6

beh,konsidero faktin qe ato qe do te te bejne analizen nuk eshte qe e bejne per here te pare ate gje keshtu qe atyre u duket e lehte per ta bere ...pastaj mendo nese do te ta benin gogol ate analize personave qe duhet ta bejne...do ta kishte bere kush deri me sot?thjesht merre si procedure te nevojshme qe mjeku e ka konsideru qe mund te te jape nje pergjigje per dhimbjen e kokes qe ke!gjithsesi,per cdo dyshim,mjeku qe po te kuron mund te te sqaroje shume me mire!
ishallah analiza te tregon se cfare ke,keshtu qe te fillosh nje kure sa me te sakte
te uroj nje sherim te shpejte nga ajo dhimbje koke!


faleminderit eshte shum e sjelshme nga ty qe mer mundimin dhe pergjigjesh sinqerisht un e vlersoj shum qe ne mund te diskutojm keshtu
un nuk eshte se ndjek ndonje kur sepse dhimbjet qe kam nuk jan per tu shqetesuar shum por ato ka mjeket shofin ne foto-scanner ne truruin tim -jan disa njolla te bardha por as nuk ikin as nuk shtohen- nuk eshte normale dhe qe kur ato me than kete un kam me shum dhimbje koke sepse ky fakt me shqeteson
faleminderit NS-6


Postuar nga NS-6 dat 06 Shkurt 2007 - 23:57:

Newly Diagnosed Myeloid Leukemia Responds to Imatinib

Cod. A07022007

In a 5-year follow-up of patients with newly diagnosed CML, imatinib was superior to interferon-{alpha} plus cytarabine.

The dramatic efficacy of imatinib (Gleevec) in chronic myeloid leukemia (CML) patients has made it a paradigm for targeted cancer therapies. Researchers now provide 5-year follow-up data on patients who were treated in the phase III, industry-sponsored, IRIS study. Eleven hundred six patients with newly diagnosed CML were randomized to daily oral imatinib or the combination of interferon-{alpha} plus cytarabine. The primary endpoint was event-free survival; secondary endpoints were complete hematologic, cytogenetic, and molecular responses. Crossover was allowed for inadequate response to or toxicity of originally assigned therapy; 65% of patients crossed over to imatinib, whereas only 3% crossed over to interferon-{alpha} plus cytarabine. As a result, very few patients received long-term interferon, and this report focused on the imatinib-treated patients.

By 12 months, 96% of imatinib patients achieved complete hematologic responses, and 69% achieved complete cytogenetic responses; these rates were 98% and 87%, respectively, at 5 years. At 5 years, 89% of patients were alive, and 83% had experienced no disease-related events. The estimated annual rates of progression to accelerated phase or blast crisis decreased over time: 1.5% in year 1, 1.8% in year 2, 1.6% in year 3, 0.9% in year 4, and 0.6% in year 5. All patients who achieved complete cytogenetic responses and molecular responses (defined as >3 log reduction in BCR-ABL transcripts) survived at 5 years, without progression to accelerated phase or blast crisis. No difference in survival was noted between patients who were assigned initially to imatinib and those who crossed over to imatinib. Side effects of imatinib therapy included edema, muscle cramps or joint pain, diarrhea, and rash. One patient developed heart failure.

Comment: Only 7% of imatinib-treated patients progressed to accelerated phase or blast crisis. Risk for progression decreased over time and was <1% in years 4 and 5 of imatinib therapy; overall survival of imatinib-treated patients was 89%. These impressive results confirm imatinib as standard therapy for initial treatment of CML patients. As noted by the authors, the current recommendation is to continue therapy indefinitely, because relapses occur in some patients when treatment is discontinued. Ongoing questions relate to administration of higher initial doses of imatinib and integration of next-generation kinase inhibitors (i.e., dasatinib and nilotinib) into treatment algorithms. Safety and toxicity of long-term therapy still require assessment, especially in view of recent reports of cardiomyopathy and congestive heart failure in a small subset of patients.

Michael E. Williams, MD

Published in Journal Watch Oncology and Hematology December 6, 2006


Postuar nga NS-6 dat 20 Shkurt 2007 - 22:20:

How Valuable Is the PPI Test for Diagnosing GERD?

Cod. A20022007

How Valuable Is the PPI Test for Diagnosing GERD?

Measuring symptom response to empirical PPI therapy is of little value in distinguishing primary care patients who have GERD.

Clinicians sometimes diagnose gastroesophageal reflux disease by evaluating symptom response to empirical therapy with a proton-pump inhibitor (PPI), but is this so-called "PPI test" reliable?

To evaluate the tests usefulness in primary care settings, Dutch investigators studied 74 adults with symptoms suggestive of GERD; all were recruited through primary care practices or advertisements. At baseline, each participant underwent a 24-hour pH study to determine the likelihood of a temporal association between symptoms and reflux. If the likelihood of an association was greater than 95%, the patient was considered to have GERD.

Each study participant then underwent a PPI test (receiving esomeprazole, 40 mg daily) for 13 days. If the subject reported overall symptom relief, the test was considered positive for GERD. Researchers then calculated the sensitivity and specificity of the PPI test on each of the 13 days, using the pH study results as the gold standard. The pH results were not revealed to the patient or treating physician until after completion of the PPI test. The study was supported by the maker of esomeprazole.

The results of the pH studies indicated that 70% of the study population had GERD. The mean sensitivity of the PPI test during the 13-day treatment period was 91% (95% CI, 78%96%), but the mean specificity was only 26% (95% CI, 10%49%). The positive likelihood ratio for the test was 1.2 (95% CI, 0.91.6) and varied little during the treatment period.

Comment: Sensitivity and specificity are relatively poor measures of the value of a diagnostic test, because they vary with disease prevalence in the population. Obviously, any test for GERD in a population of patients selected for symptoms would have high sensitivity and low specificity. A much more robust measure of the value of a test is the likelihood ratio, which measures whether a positive test influences the odds that a patient has the disease. In this study, the positive likelihood ratio was constant at 1.2 throughout 13 days, suggesting that the PPI test was of very little value in distinguishing patients who had GERD from those who did not in this selected population.

David J. Bjorkman, MD, MSPH (HSA), SM (Epid.)

Published in Journal Watch Gastroenterology February 9, 2007

Citation(s):

Aanen MC et al. Diagnostic value of the proton pump inhibitor test for gastro-oesophageal reflux disease in primary care. Aliment Pharmacol Ther 2006 Nov 1; 24:1377-84.


Postuar nga Fajtori dat 20 Shkurt 2007 - 22:32:

Kjo duhet spjeguar mire NS. Tashme kane dale rezultate skandaloze per besueshmerine e disa testeve.

Psh. nese ben testin per kancerin ne gjoks dhe del pozitiv mundesia qe te jete e vertete eshte 7.8 %. Ndersa kur ben testin e AIDS dhe del pozitiv ka vetem 50% mundesi qe ta kesh ne realitet.

Llogarite jane shume te thjeshta dhe do linin me goje hapur secilin. Po ju jap disa shifra se nuk kam kohe te bej gjithe llogarite tamam:

Nese 100 veta kane kancer testi do nxjerre 80% tamam dhe 20% gabim.
Nderkohe nese 100 veta nuk kane kancer testi do nxjerre 91% tamam (pa kancer) dhe 9% gabim (me kancer).

Ne pamje te pare duket sikur testi eshte goxha i sakte, por nese behen llogarite duke u bazuar tek epidemiologjia reale e semundjes, zbulon se testi nuk eshte aspak afidabel. Klecka qendron pikerisht tek ai 9% qe del me kancer kur nuk e ka. Duket gabim i vogel por popullsia qe s'ka kancer eshte shume e madhe dhe 9% jane jashtezakonisht shume. Si rrjedhoje perfundon qe shumica e atyre qe dalin pozitive jane efektivisht te shendetshem dhe vetem 7.8% e kane vertet.


Postuar nga NS-6 dat 20 Shkurt 2007 - 23:08:

kjo eshte mbi graden e specificitetit dhe sensibilitetit qe ka nje test dhe se keto 2 faktore jane te nderlidhur njeri me tjetrin.dmth sa me shume rrit aftesite e njerit aq me shume ul te tjetrit.ato ndjekin grafikun e Gaussit dhe jane ato pjese te deviancave qe perben problemin sepse nese ti tenton te shkosh ne drejtimin qe te shtosh sensibilitetin duke spostuar parametrat,ti ul specificitetin e asaj analize.nese ti thua qe ke nje sensibilitet 91% atehere ai test arrin ne 91% te rasteve te gjeje personat qe kane semundjen dhe mund te cilesohet sidoqofte i nje grade te mire si aftesi diagnostikuese.eshte normale qe per nje semundje me te perhapur,ajo grade gjithsesi eshte e ulet.por nga ana tjeter nje specificitet i ulet te ben qe ti te kesh edhe nje numer pacientesh qe gjithsesi ate semundje nuk e kane por diagnostikohen per te tille!

nje rast te mire per ceshtjen e sensilibitetit dhe specificitetit te ulet ke per markatoret tumorale qe edhe pse perdoren si markatore per tumore te ndryshme kane nje sensibilitet dhe specificitet te ulet,qe i ben te mos jene diagnostikues per kanceret.dhe prandaj,pervec PSA,sot per sot ato perdoren me shume si analiza per follow up te kancereve te ndryshem.

per testin e AIDS-it sot per sot ka analiza qe kapin graden e sensibilitetit te gati 100% sic eshte kerkimi i antigjenit viral p24


Postuar nga NS-6 dat 28 Shkurt 2007 - 16:25:

2 New Drugs Offer Options in H.I.V. Fight

Cod. A28022007

February 28, 2007

By LAWRENCE K. ALTMAN and ANDREW POLLACK

LOS ANGELES, Feb. 27 Two new AIDS drugs, each of which works in a novel way, have proved safe and highly successful in large studies, a development that doctors said here on Tuesday would significantly expand treatment options for patients.

The two drugs, which could be approved for marketing later this year, would add two new classes of drugs to the four that are available to battle H.I.V., the AIDS virus. That would be especially important to tens of thousands of patients in the United States whose treatment is failing because their virus has become resistant to drugs already in use.

This is really a remarkable development in the field, Dr. John W. Mellors of the University of Pittsburgh said at a news conference here at the 14th Annual Conference on Retroviruses and Opportunistic Infections.

Dr. Mellors, who was not involved in the studies but has been a consultant to the manufacturers of the drugs, said he wouldnt be going out on a limb to say the new results were as exciting as those from the mid-1990s, when researchers first discovered that cocktails of drugs could significantly prolong lives.

Dr. Scott Hammer, chief of infectious diseases at Columbia University Medical Center, who also was not involved in the studies but has been a consultant to the manufacturers, agreed that the new drugs will provide extended years of meaningful survival to patients.

One drug, maraviroc, was developed by Pfizer, which has already applied for approval to sell it. The Food and Drug Administration has scheduled an advisory committee meeting on April 24 to discuss the application.

The other drug, raltegravir, was developed by Merck, which has said it will apply in the second quarter for approval.

Experts said the new drugs would be used in combination with older drugs. Both drugs stem from scientific findings made a decade or more ago that have peeled back the intricate molecular process used by H.I.V. to infect human immune system cells and to replicate themselves.

While there are now more than 20 approved drugs to treat H.I.V. and AIDS, there are only four different mechanisms by which the drugs work. In many patients, the virus develops resistance to one or more drugs, usually because patients do not take their drugs on time as prescribed.

And if the virus develops resistance to one drug in a class, it often becomes resistant to others in that class and sometimes in other classes. So AIDS experts have said there is an urgent need for drugs that work by new mechanisms.

The two new drugs would represent the first new classes since 2003, when an injectable drug called Fuzeon was approved. They would be the first new classes of oral H.I.V. drugs in a decade.

Mercks drug works by inhibiting the action of integrase, an enzyme produced by the virus that incorporates the viruss genetic material into the DNA of a patients immune cell. Once incorporated, the viral DNA commandeers the cell to make more copies of the virus.

In two Merck studies involving a total of 700 patients, virus levels dropped to below 50 copies per milliliter of blood, an amount considered undetectable, in about 60 percent of patients who received raltegravir. That compared with about 35 percent of those who received a placebo.

The patients in the two Phase 3 trials, typically the last stage of testing before approval, were resistant to at least one drug in each of three classes of antiretroviral drugs. All the patients also received a combination of older drugs that their doctors deemed to be the most appropriate. The results reported here were after 16 weeks, in a study that is continuing so it is possible that longer-term side effects might yet arise.

Other integrase inhibitors, like one from Gilead Sciences, are also under development. Gileads drug is 18 months to 2 years behind Mercks.

Pfizers drug works by blocking a protein on human immune system cells that H.I.V. uses as a portal to enter and infect the cell. It would be the first drug that targets the human body rather than the virus.

The portal, known as CCR5, was discovered in 1996 by several groups of scientists, and there has been a race to develop drugs to block it.

In two Phase 3 studies sponsored by Pfizer involving 1,049 patients, more than 40 percent of patients who received maraviroc had undetectable levels of virus after 24 weeks of a 48-week study. That was about twice the rate of those who received placebo. As in the Merck trials, patients were resistant to three classes of drugs and were receiving an optimized combination of older drugs.

Some experts said they were a bit cautious about maraviroc, in part because it blocks a human protein instead of a viral one, with possible unknown long-term effects. One CCR5 inhibitor that was being developed by GlaxoSmithKline was dropped because it caused liver toxicity, and a second being developed by Schering-Plough appeared to possibly raise the risk of blood cancers.

But in Pfizers study there was no increased incidence of cancers. In one study there was a higher rate of death among those who took the drug, but Pfizer said the deaths were not associated with the drug.

Experts are also encouraged that about 1 percent of Caucasians have a particular mutation in both copies of their CCR5 gene that knocks out its function. These people are resistant to H.I.V. infection and apparently live otherwise normal lives.

Yet another issue is that some viruses use a different entry portal called CXCR4. Before getting maraviroc, patients will have to be tested to see which portal their virus uses, which would make the drug an early example of personalized medicine tailored to the patient.

The test, which will probably take two weeks for results, was developed by Monogram Biosciences of South San Francisco, Calif. It is expected to cost as much as $1,000, or more.

About 85 percent of newly infected patients have a virus that uses CCR5 while only about half of highly drug-resistant viruses use that portal. There has been some concern that blocking CCR5 would encourage the development of viruses that use the alternative portal and those viruses seem to be associated with worse outcomes.

But that has not proven so far to be a big problem, according to Edward A. Berger of the National Institute of Allergy and Infectious Diseases, who played a key role in the discovery of the two portals.

Government, academic and industry experts said there was no reliable estimate of the number of people who would need one of the new drugs. But the number is declining as more and better AIDS drugs become available.

The numbers are not what they used to be six years ago, said Norbert Bischofberger, executive vice president for research and development at Gilead, which makes some widely used AIDS drugs.

Both Merck and Pfizer say they are conducting studies testing their drugs for use as initial treatments. They would not say how much their drugs would cost.


Postuar nga cremaster dat 08 Mars 2007 - 06:48:

the most up to date, from uptodate.com

Cod. B08032007

Initial antiretroviral therapy for HIV infection

John G Bartlett, MD

UpToDate performs a continuous review of over 375 journals and other resources. Updates are added as important new information is published. The literature review for version 15.1 is current through December 2006; this topic was last changed on January 9, 2007. The next version of UpToDate (15.2) will be released in June 2007.

INTRODUCTION The battle against the human immunodeficiency virus (HIV) has been revolutionized by highly active antiretroviral therapy. Use of these regimens has resulted in substantial reductions in mortality, progression to AIDS, opportunistic infections (OIs), and hospitalizations in patients who respond to therapy, particularly those with an adequate lowering in HIV-1 RNA levels [1,2].

The newer regimens have also brought a host of new concerns including expense, side effects, drug interactions, difficulties in adhering to complicated regimens, emergence of drug resistance, and variations in response. There are now 22 FDA-approved antiretroviral drugs, with additional investigational agents in testing.

The management of antiretroviral therapy (ART) is complex and is best when delivered by providers with specific training. Multiple studies have shown that provider experience correlates with patient outcome [3-6]. US guidelines recommend that providers of HIV care have at least 25 active HIV-infected patients [7].

Indications for initiating antiretroviral therapy in treatment-naive patients, appropriate patient evaluation prior to initiation of therapy, and recommendations for ART regimens and monitoring are discussed here. Modification of ART regimens and their use in treatment-experienced patients, and the use of ART to treat acute HIV are discussed separately. (See "Modifying HIV antiretroviral therapy regimens" and see "Primary HIV-1 infection: Diagnosis and treatment"). Also discussed separately are an overview of the protease inhibitors and major clinical trials of various regimens. (See "HIV protease inhibitors" and see "Clinical trials of HIV antiretroviral therapy").

ABBREVIATIONS USED The following abbreviations are used in this topic for the various antiretroviral agents:

* ZDV: zidovudine; also known as AZT
* 3TC: lamivudine; also known as Epivir
* FTC: emtricitabine; also known as Emtriva
* Combivir: zidovudine (ZDV) plus lamivudine (3TC) in one pill
* d4T: stavudine; also known as Zerit
* ddI: didanosine
* ABC: abacavir; also known as Ziagen
* Trizivir: combines ZDV, 3TC, and ABC in one pill
* TDF: tenofovir; also known as Viread
* Truvada: combines TDF with FTC in one pill
* NVP: nevirapine; also known as Viramune
* EFV: efavirenz; also known as Sustiva
* DLV: delavirdine; also known as Rescriptor
* NLF: nelfinavir; also known as Viracept
* SAQ: saquinavir; also known as Invirase
* IND: indinavir; also known as Crixivan
* RTV: ritonavir; also known as Norvir
* LPV/RTV: lopinavir/ritonavir; also known as Kaletra
* FOS: fosamprenavir; also known as Lexiva
* ATZ: atazanavir; also known as Reyataz
* TPV: tipranavir; also known as Aptivus
* DRV: darunavir; also known as Prezista
* T-20; enfuvirtide; also known as Fuzeon

GOALS OF THERAPY The following are goals when administering ART:

* Suppress HIV viral load to less than 50 copies/mL for as long as possible

* Improve quality of life

* Preserve future therapeutic options

* Restore immune function (as indicated by CD4 cell count)

IMPACT OF THERAPY The introduction of highly active ART was accompanied by a dramatic decrease in the morbidity and mortality related to HIV infection. Death rates in the United States fell by 42 percent between 1996 and 1997, and an additional 15 percent from 1998 to 2000 [8]. National hospital discharge data show admissions for HIV-related complications decreased 30 percent in 1998 compared with 1995. A report from HIV clinics in eight cities in the United States conducted by the HIV Outpatient Study (HOPS) showed that the mortality of patients with a CD4 cell count below 100 cells/microL declined from 29.4 per 100 person-years in 1995 to 8.8 per 100 person-years in 1997 (show figure 1) [9]. Statistics from Europe are comparable [10,11]. The EuroSIDA cohort showed a dramatic decline in mortality from 23.3 per 100 patient-years in 1994 to 4.1 per 100 patient-years in 1998 [12]. A subsequent analysis has shown that treatment of HIV has added an average of 13 years of life to patients with HIV infection [13]. (See "Factors affecting HIV progression").

Rates of clinical progression were examined according to initial treatment regimen in a multicenter prospective study of ART-naive patients [14]. In an analysis of 17,666 patients with an HIV RNA level >1000 copies/mL who started therapy after January 1996, 1617 new AIDS events and 395 deaths were analyzed with the following observations:

* Compared with EFV, the adjusted hazard ratio (HR) for AIDS/death was 1.28 for NVP (95 percent CI, I.03-1.60), 1.31 for RTV (95 percent CI, 1.01-1.71), and 1.45 for RTV-boosted PIs (95 percent CI, 1.15-1.81).

* For death, the adjusted HR for NVP was 1.65 (95 percent CI, 1.16-2.36).

* The adjusted HR for death for the combination of d4T/3TC was 1.35 (95 percent CI, 1.14-1.59) compared with ZDV/3TC.

Since the outcomes were observational, the results may be affected by bias due to confounding [14]; however, this study raises questions regarding use of short-term surrogate endpoints in randomized trials, such as changes in CD4 cell counts and HIV RNA, as indicators of clinical outcomes, such as disease progression or death [15].

A major impact has been the decline in the three major opportunistic infections Pneumocystis pneumonia, Mycobacterium avium bacteremia, and disseminated cytomegalovirus infections; these declined during this period from 21.9 to 2.3 per 100 person-years [9].

Virologic outcomes The likelihood of achieving suppression of HIV as measured by HIV viral load depends on viral susceptibility and on patient adherence to an ART regimen. Overall, the probability of attaining an HIV viral load below 50 copies/mL one year after starting HAART in a patient who has not previously received ART ranges from 50 to 90 percent in various studies [16,17].

EVALUATION PRIOR TO INITIATION OF ANTIRETROVIRAL THERAPY

History and physical examination The history and physical examination in patients being considered for treatment with ART should focus on looking for evidence of symptomatic HIV disease (an indication for therapy), evidence of opportunistic infections that could initially flare with the immune reconstitution seen after starting ART, and any conditions likely to be exacerbated by specific ART medications.

Patients should be asked about prior opportunistic infections, weight loss, fevers, malaise, diarrhea, cognitive problems, neuropathy, visual problems, oral lesions, skin rashes or lesions, and any chronic complaints. Patients who have experienced a slow decline in function with HIV infection may not recognize their symptoms or may attribute them to normal aging, so careful questioning is important.

A careful physical examination should be performed with attention to oral and skin lesions, cognitive changes, and evidence of peripheral neuropathy. In patients with a very low CD4 cell count (below 50 cells/microL), a dilated fundoscopic exam performed by an ophthalmologist may be useful to detect asymptomatic cytomegalovirus retinitis.

Psychosocial evaluation A careful psychosocial history is a vital part of the evaluation of patients in whom ART is considered. Psychosocial factors can have a strong influence on patient adherence [18], and adherence is probably the most important factor in determining the success of an initial ART regimen.

Issues to consider include:

* Substance abuse: Substance abuse contributes to a disordered lifestyle and may lead to inadvertent missed medications doses.

* Psychiatric disorders: Depression, bipolar disorder, and other psychiatric disorders may interfere with a patient's ability or desire to adhere to a medication regimen.

* Housing: Patients with an unstable housing situation (such as the homeless) may have difficulties keeping medications available, remembering to take medications, and dealing with side effects such as diarrhea. However, many homeless patients can successfully take ART. As an example, in a prospective 12-month study of 148 homeless and marginally housed adults in San Francisco, 69 percent of patients continued to receive ART and average adherence in that group was 74 percent; 55 percent of those continuing ART had undetectable viral loads (below 400 copies/mL) [19].

* Support: Friends and family can be helpful in reminding patients to take ART medications. Patients who are trying to keep their HIV status from their close acquaintances may have difficulties, particularly with regimens that require frequent dosing.

* Work: Patients with irregular work schedules may have difficulty taking medications at prescribed times. Certain jobs also provide limited access to bathrooms and this can be an issue with medication side effects. The cognitive side effects seen with efavirenz in some patients can also interfere with job performance or safety.

* Ability to afford medications: Depending on where patients live, their economic resources, and their insurance, affordability of medications may be a major constraint in some cases.

Laboratory testing Screening laboratory testing in HIV infected patients is discussed in detail elsewhere. (See "Screening laboratory tests in HIV-infected patients").

All patients being considered for ART should have the following laboratory tests:

* Two measurements of the CD4 cell count, preferably at times when the patient is not acutely ill. (See "Techniques and interpretation of measurement of the CD4 cell count in HIV-infected patients").

* Measurement of the HIV viral load. (See "Techniques and interpretation of HIV-1 RNA quantitation").

* Complete blood count with differential.

* Electrolytes, BUN, creatinine, and glucose.

* Liver function tests and amylase.

* A lipid profile including triglycerides.

* Urinalysis

* Toxoplasmosis IgG

* VDRL

* Chest x-ray: this is considered optional but should be obtained in any patient with pulmonary symptoms or a positive PPD

* Serologic testing for hepatitis B and hepatitis C virus.

HIV resistance testing Resistance mutations to antiretroviral medications can be found in some treatment-naive patients. In a study of 1082 newly diagnosed adult patients seen in 10 US cities during 1997 to 2001, 8.3 percent had reverse transcriptase or major protease mutations associated with reduced antiretroviral susceptibility (mutations affecting NRTI susceptibility, 6.4 percent; NNRTI susceptibility 1.7 percent; PI susceptibility 1.9 percent) [20]. The prevalence of mutations was higher among men who had sex with men than among women or heterosexual men (11.6, 6.1, and 4.7 percent respectively), and was higher among whites than among African Americans or Hispanics (13.0, 5.4, and 7.9 percent respectively). Among patients whose partners reportedly took ART, the prevalence of mutations was 15.2 percent. Similar results have been found in other studies [21,22].

The percentage of patients with resistance mutations in these studies likely underestimated the actual number of patients with resistant virus as some mutations can be expected to revert to wild type over time. In addition, the data are relatively dated, reflecting the epidemiology of resistance from a number of years ago, and resistance patterns are continually changing. (See "Drug resistance testing in the clinical management of HIV infection", section on Interpretation of resistance testing).

We recommend routine HIV resistance testing prior to initiation of ART in all patients with a HIV RNA level >1000 copies/mL [7]. Most important will be detection of a K103N mutation which excludes utility of NNRTIs.

Recommendations for resistance testing in patients with primary HIV infection are discussed separately. (See "Primary HIV-1 infection: Diagnosis and treatment").

INDICATIONS FOR ANTIRETROVIRAL THERAPY The major factors used to indicate a need for initiation of antiretroviral therapy in patients who are felt to be willing and able to take ART are the presence of symptomatic HIV disease and the CD4 count [23]. In an analysis of 13 cohort studies including 12,574 HIV-infected patients followed for 24,310 patient-years, the CD4 count proved to be the most important indictor of progression to an AIDS-defining complication or death [24]. There is general agreement that patients with symptomatic HIV disease should receive ART [7,23].

For patients without symptoms, therapy should be initiated at some point after the CD4 cell count declines below 350/microL, but before it reaches 200/microL [23]. This decision should be influenced by the viral load, the CD4 slope or rate of decline, and patient readiness for treatment. Thus, a viral load >100,000 copies/mL, a CD4 decline of >100 cells/mm3 per year and a CD4 count of 220 cells (instead of 320/mm3, for example) would indicate more urgency [23].

There is less agreement about initiating therapy in other patient subgroups. Retrospective analyses of cohorts show that therapy in a patient with a CD4 cell count >200/microL has either no, or only a modest benefit [25-27], while others show substantial benefit [28]. No study has shown convincing evidence of benefit for treatment initiated when the CD4 count is >350/microL. In patients with a CD4 count between 200 and 350/microL, clinicians must consider the potential risks and benefits of treatment since current drugs have short- and long-term toxicity [29]. There is also the concern about increasing rates of drug resistance in HIV with consequences to both the patient and to society [30]. Other factors may also need to be considered, such as concurrent tuberculosis or chronic hepatitis C. (See "Treatment of tuberculosis in HIV-infected patients" and see "Epidemiology; natural history; and diagnosis of hepatitis C in the HIV-infected patient", section on "Effect of HIV on the natural history of HCV").

The viral load plays an uncertain role in the decision to treat HIV infection. The viral load correlates with the rate of CD4 decline, and in one study the CD4 decline was 4 percent per year for each log10 copies/mL [31]. Viral load is also an independent prognostic indicator [32]. Extremely high viral loads (>100,000 copies/mL) correlate with a poor prognosis [24,33,34] and viral load influences the probability of developing an opportunistic infection, which, for unclear reasons, appears to be unusual with viral loads 400 cells/microL or women with a CD4 count >250 cells/microL. (See "Side effects" below and see "Other considerations" below).

PI versus NNRTI-based HAART The major question confronting physicians and patients has been the relative merits of boosted PI-based HAART versus NNRTI-based HAART. ACTG 5142 compared the efficacy of EFV with two NRTIs versus LPV/r/ with two NRTIs versus EFV/LPV/r in 753 participants with a 96-week follow-up [52]. Viral suppression ( d4T > ddI > ZDV. ZDV use is associated with nausea, headache and bone marrow suppression. (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors").

* Among the NNRTIs, rash is common with NVP and is also seen with EFV. EFV commonly causes neurocognitive side effects including unusual dreams when it is taken at bedtime. These side effects often resolve over time [55]. NVP is associated with a high rate of hepatotoxicity, especially in women with a baseline CD4 cell count above 250/microL [56]. This may be a fulminant hepatitis with hepatic necrosis and hepatic failure. NVP should not generally be used as initial therapy in women with a CD4 cell count above 250/microL. Men with CD4 cell counts above 400/microL who are started on NVP may also be at increased risk for asymptomatic aminotransferase elevations [57], however most patients are not initiated on ART at CD4 cell counts this high. It is not known whether switching a patient from efavirenz to nevirapine after the CD4 cell count has risen constitutes the same risk.

Risk of resistance with poor adherence Multiple mutations are typically needed for HIV to develop resistance to the PIs and most of the NRTIs. Resistance to the entire class of NNRTIs can occur with a single mutation and this may be a consideration in patients who are felt to be unlikely to adhere to their ART regimen. Resistance to 3TC and FTC can also occur with a single mutation, however this mutation may decrease the reproductive fitness of HIV and it appears to enhance activity AZT, d4T and TDF. (See "Drug resistance testing in the clinical management of HIV infection").

Other considerations Efavirenz use requires adequate contraception in women of child-bearing potential given its teratogenic risk in the first trimester of pregnancy. (See "Antiretroviral treatment during pregnancy").

NVP is recommended as the NNRTI component for women who are pregnant or may become pregnant and have a CD4 count less than 250 cells/microL.

Drug interactions also need to be carefully considered before initiating any antiretroviral therapy regimen.

Summary Given the 20 antiviral drugs approved for use by the US FDA, a large number of potential regimens can be created. There is no one regimen that is considered most appropriate for all patients and experienced HIV care providers generally individualize regimens from the full menu of available options. Some of the specific considerations include:

* Of the NNRTIs, EFV is preferred due to its consistent efficacy and toxicity profile and low pill burden [39,40,43,47-51]. Disadvantages include a high rate of central nervous system toxicity during the first two to three weeks of therapy, and a single resistance mutation (K103N) confers high level resistance to this agents and other NNRTIs. It should not be used in women during the first trimester of pregnancy and should be avoided or used with great caution in women with child-bearing potential.

* NVP is recommended as the NNRTI component for women who are pregnant or may become pregnant or in men and women who have significant central nervous system side effects secondary to EFV. NVP should not be used in men or women with a CD4 count >400 cells and 250 cells, respectively.

* LPV/r-based regimens are popular because they have proven superior to others in clinical trials [41,42], durability has been shown with a five year follow-up, there is no evidence of PI resistance mutations with virologic failure when used as the initial PI, and the combination is available as a single coformulation. However, it has never been compared to EFV, although a trial is underway. Disadvantages of LPV/r include the need to take the medication with food, the need for twice daily dosing, gastrointestinal side effects with high rates of diarrhea, and lipid effects.

* ATV-based regimens may be the preferred choice in some patients. Advantages include potency comparable to EFV [43], low pill burden with once daily dosing, good boosting with RTV, negligible effects on lipids, and a unique resistance mutation (150L) that does not impact the activity of other PIs [58].

* The triple nucleoside regimen AZT/3TC/ABC is virologically inferior to EFV-based ART [59], and is not recommended for initial therapy. However, it may be the only good option for some patients. Other nucleoside regimens are significantly less potent, presumably due to the need to include a thymidine analogue [7,23].

* NVP should not be used for initial therapy in women with a baseline CD4 cell count above 250 cells/microL, given high rates of symptomatic hepatitis and cases of fatal hepatic necrosis even with careful monitoring of hepatic function and prompt discontinuation of NVP [56].

REGIMENS As discussed, a typical HAART regimen consists of a backbone of two NRTIs plus a base of a PI or NNRTI.

Expert guidelines Groups such as the International AIDS Society-USA Panel (IAS-USA) [23], and the US Department of Health and Human Services (DHHS) [7] (see "Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents; 2005") have published guidelines for initial ART.

The 2006 IAS-USA guidelines for initial ART recommend either of two basic three-drug regimens:

* EFV plus two NRTIs

OR

* A ritonavir-boosted protease inhibitor (LPV, ATZ, FOS or SAQ) plus two NRTIs

The IAS-USA guidelines recommend any of the following choices as the NRTI backbone:

* TDF and FTC
* ZDV and 3TC
* ABC and 3TC

The 2006 DHHS guidelines indicate preference for one of the following regimens for initial treatment selected on the basis of demonstrated potency in clinical trials, relatively low frequency of serious adverse reactions, substantial clinical experience, and a requirement for dosing no more than twice daily:

* LPV/r plus ZDV plus (either 3TC or FTC)
* EFV plus (either TDF or ZDV) plus (either 3TC or FTC)

Antiretroviral combinations to avoid Certain combinations of antiretroviral medications that might appear to fit into a standard pattern should be avoided either because of toxicity or lack of efficacy:

* AZT and d4T should not be used together as their actions are antagonistic.

* 3TC and FTC are similar drugs and should not be used together.

* The use of EFV and NVP together produces more side effects and is less efficacious than either drug alone [40]. (See "Clinical trials of HIV antiretroviral therapy"). While awaiting further studies, regimens should not combine NNRTIs outside of clinical trials.

* ddI should not be used in combination with d4T due to overlapping toxicities peripheral neuropathy, pancreatitis, and lipodystrophy [23,60-62].

* The three drug combination of abacavir, lamivudine, and tenofovir should not be used based on results from a randomized, multicenter study, which demonstrated high rates of virologic failure and resistance [63,64]. (See "Clinical trials of HIV antiretroviral therapy").

* Reports from several studies have suggested that the combination of TDF and ddI may have a high rate of early virologic failure [65-68]. Additionally, even in patients with viral suppression on such a regimen, CD4 cell counts may not show as much recovery as with other regimens or may actually decline [69-71].

* The NRTI ddC is generally not used, because of high rates of toxicity. The NNRTI delavirdine is also rarely used, and there are few data about its efficacy in ART regimens.

Recommendations in typical patients Appropriate initial ART regimens can be constructed using the above expert guidelines. Taking into consideration efficacy, ease of dosing, and toxicity, regimens constructed with an NNRTI base of EFV or a PI base of LPV/r or ATV/r are currently preferred by many experts. The following are examples of such regimens that may be appropriate in many patients:

* EFV 600 mg daily plus TDF/FTC (300 mg/200 mg) daily

When constructed with the combination medication Atripla, the above regimen requires only one pill taken once daily. EFV should not be used in women who are pregnant or are likely to become pregnant (see "Pregnancy" below).

* ATV 300 mg daily plus RTV 100 mg daily plus TDF/FTC (300 mg/200 mg) daily

* LPV/r (400 mg/100 mg) twice daily plus TDF/FTC (300 mg/200 mg) daily

The use of ZDV/3TC (300 mg/150 mg) twice daily in place of the TDF/FTC backbone is also appropriate in many patients, as is substituting 3TC 300 mg daily for FTC 200 mg daily in combination with TDF.

Considerations in selected clinical settings

Pregnancy The dual goals of antiretroviral therapy during pregnancy are to provide therapy for the mother and decrease perinatal transmission. Some recommend a delay in the initiation of therapy in the first trimester, but there is no consensus on this and no data to support it on the basis of cohort studies or the pregnancy registry [23]. All pregnant women should receive antiretroviral therapy in the third trimester, regardless of CD4 count, to decrease HIV transmission to the neonate. The selection of medication regimens is discussed elsewhere. (See "Antiretroviral treatment during pregnancy")

Women who are pregnant or potentially pregnant need to avoid EFV during the first trimester based on its teratogenic effects in primates and at least four cases of reported neural tube defects in exposed infants [7,72-74]. (See "Antiretroviral treatment during pregnancy"). NVP should not be started in women with a CD4 cell count above 250 cells/microL due to high rates of severe hepatotoxicity [56].

The recommended regimens based on clinical experience and pharmacokinetics during pregnancy are NFV (1250 mg BID) and SQV/r (1000 mg/BID); each of these should be combined with two nucleosides, preferably AZT/3TC. LPV/r is under investigation using standard dose but may require a higher dose in the third trimester. TDF should be avoided due to concerns about fetal bone formation.

Methadone recipients Drug interactions may be an important consideration in patients receiving methadone maintenance. The NNRTIs EFV and NVP can cause significant reductions in methadone levels which may result in opiate withdrawal symptoms [7]. The patient must be carefully monitored for withdrawal symptoms with appropriate dose adjustment of methadone. PIs also may reduce methadone levels, but the effect is less significant. Methadone decreases ddI concentrations a mean of 60 percent; thus, the ddI dose may need to be increased in methadone recipients who are also given ddI [75]. Drug interactions with buprenophine are less well studied.

Patients with TB Patients with active tuberculosis (TB) should always initiate treatment for TB immediately. HIV therapy is usually delayed at least two months to avoid simultaneous initiation of seven or eight medications, to avoid drug interactions with rifamycins, and to avoid the immune reconstitution inflammatory syndrome (see "Immune reconstitution inflammatory syndrome"). Patients with very low CD4 cell counts may be an exception, however due to an increased risk of mortality. This topic is discussed in detail elsewhere (See "Treatment of tuberculosis in HIV-infected patients").

Hepatitis Patients with chronic viral hepatis are at increased risk for drug-associated hepatotoxicity. In patients with chronic hepatitis B, there can also be flares of aminotransferases secondary to exacerbations of disease activity, immune reconstitution related to ART, the onset of resistance to antiretroviral drugs with dual HIV and HBV activity, or the discontinuation of drugs with anti-HBV activity (eg, 3TC, FTC, or TDF). This topic is discussed in detail elsewhere. (See "Treatment and prevention of hepatitis B in the HIV-infected patient").

Patients who require treatment with ribavirin for hepatitis C may need to consider drug interactions with ddI, and enhanced marrow toxicity with ZDV. (See "Management and treatment of hepatitis C in the HIV-infected patient").

Cardiovascular disease In patients with known CVD or at high risk for CVD, it makes sense to choose medications such as EFV, NVP, and ATV that are least likely to have a prominent effect on lipids.

Thymidine analogues (AZT, ddl and D4T) also effect blood lipids (as demonstrated in clinical trials ACTG 384, Gilead 903, and Gilead 934). The medication with the greatest impact, especially on tryglyceride levels, is d4T. Preferred NRTI pairings are TDF/FTC or 3TC/ABC.

Renal insufficiency TDF is generally well-tolerated, but should be used with caution, or avoided, in patients with preexisting renal insufficiency [23]. Dose modification is required in patients with a creatinine clearance 95 percent of prescribed pills in order to have an 80 percent probability of achieving a viral load of 48 oz per day) especially with pill ingestion. Must take on an empty stomach unless the drug is combined with RTV for boosting. Warn of sicca syndrome (dry eyes, skin, and mouth).

* Lamivudine (3TC) no serious side effects.

* Lopinavir (LPV) take with meals and warn of diarrhea that is usually managed with loperamide.

* Nelfinavir (NFV) take with high fat meal and warn of diarrhea that usually responds to loperamide or calcium.

* Nevirapine (NVP) warn of hepatotoxicity with need to monitor liver function tests, especially during the first 12 weeks. Major concern is hepatic necrosis with fever and rash. Also has a high rate of rashes including toxic epidermal necrolysis and Stevens-Johnson syndrome.

* Ritonavir (RTV) GI intolerance is a major problem and is dose-related. Patients may also note perioral tingling. Side effects are much less when RTV is used at "boosting" doses.

* Saquinavir (SQV) Invirase and Fortovase are formulations; both are often accompanied by GI intolerance, Fortovase more than Invirase.

* Stavudine (d4T) warn of peripheral neuropathy and pancreatitis. Long-term complications include relatively high rates of lipoatrophy and lactic acidosis, especially when combined with ddI. Must warn patient about the long-term cosmetic changes that result from loss of buccal fat.

* Tenofovir (TDF) take with meals; well tolerated but need to monitor for renal toxicity.

* Darunavir warn of GI intolerance and rash.

* Tipranavir (TPV) take with meals; can cause serious liver toxicity

* Zidovudine (ZDV) GI intolerance is common and may improve if given with meals or more frequent smaller doses. Also may cause headaches and asthenia. Main side effects are anemia and neutropenia. May cause lactic acidosis, increased triglycerides and facial fat atrophy, but the associated risk is less than with d4T.

MONITORING THERAPY

Visit frequency Patients who are started on ART should generally have follow-up within one to two weeks to ask patients about symptoms related to HIV infection, adverse effects of drugs, adherence to the regimen, and prevention of transmission.

Visits for this purpose should then be scheduled at least once every four to six weeks thereafter until stable. Once patients are stable on an ART regimen (typically after three to six months) visit frequency can decrease to every three months.

Laboratory monitoring Monitoring of the CD4 count and HIV viral load is discussed below. Specific ART medications may indicate a need for specific laboratory monitoring (show table 7), however the following battery of tests performed at the same time as the CD4 count and viral load may be simpler than trying to tailor the testing to the specific regimen:

* Complete blood count with differential
* BUN and creatinine
* Liver transaminases

Patients receiving IND should have periodic urine analyses, and patients receiving NVP should have liver transaminases monitored more frequently initially (at baseline, two weeks, four weeks, eight weeks, twelve weeks, and then every three months).

Lipid and glucose levels should be monitored at baseline, three months, six months, and then yearly.

Patients who have abnormalities on any of the monitoring tests that are not severe enough to warrant a change in therapy will generally require more frequent monitoring.

Virologic response The HIV viral load should be measured at four weeks after initiating HAART, again at eight to twelve weeks, and approximately every 12 weeks until the viral load is undetectable on standard assays (50 copies/mL (see "Virologic failure" below).

Blips This term refers to intermittent periods of "detectable viremia" meaning viral loads >50 copies/mL. These are common and usually indicate a lab error [23,82]. They do not require intervention with a new regimen unless the viral load is sustained at >50 copies/mL or perhaps >400 copies/mL [7]. (See "Modifying HIV antiretroviral therapy regimens", section on Blips).

Virologic failure Virologic failure is defined as the failure to achieve a viral load 50 copies/mL [23]. The expected response with sequential viral load determinations are shown in the table (show table 6). The ability to achieve specific viral load thresholds is dependent to a large extent on the baseline viral load. However, the expectation is that the initial antiretroviral regimen will achieve the goal of a viral load 1000 copies/mL and expertise in interpretation. (See "Drug resistance testing in the clinical management of HIV infection").

Evaluation of patients who are failing ART and modification of ART regimens is discussed in detail separately. (See "Modifying HIV antiretroviral therapy regimens").

Immune response The CD4 cell count should be measured approximately four weeks after starting therapy and then every three to four months, in tandem with HIV RNA levels.

Good viral suppression is usually accompanied by an increase in CD4 cell count of greater than or equal to50 cells/microL at four to eight weeks followed by a slower incremental increase of 50 to 100 cells/microL per year [90]. (See "Immune reconstitution inflammatory syndrome", section on Immunobiology and pathogenesis). The increase in CD4 cells may be slower in older patients [91].

Discordant results are seen in approximately 20 percent of patients and are usually unexplained [92]. However, in pooled data from cohorts, there is a consistent direct correlation between the CD4 slope and the decrease in viral load [90,92,93]. In patients who have discordant results, most authorities make therapeutic decisions based upon virologic results [7,94].

Immune reconstitution inflammatory syndrome Patients who initiate HAART in the setting of a low CD4 count (typically below 50 cells/microL) may develop an immune reconstitution inflammatory syndrome that has two forms:

* The most common form is a worsening of clinical manifestations related to a OI in the setting of immune reconstitution.

* The second form, which is less common, is de novo presentation of an OI that was presumably subclinical at the time HAART was initiated. This clinical presentation is seen most commonly with mycobacterial lymphadenitis (TB in resource-limited countries and M. avium in the US and Europe), cryptococcal meningitis, and CMV retinitis.

In some cases it may be difficult to distinguish immune reconstitution inflammatory syndrome from ART toxicity; the symptoms of abacavir hypersensitivity in particular may be similar to those with immune reconstitution. The diagnosis and management of immune reconstitution inflammatory syndrome is discussed in detail elsewhere. (See "Immune reconstitution inflammatory syndrome").

INDICATIONS FOR CHANGING THERAPY There are four common indications for changing the antiretroviral regimen:

* Virologic failure. (See "Virologic failure" above)
* Toxicity
* Difficulty adhering to the regimen
* Current antiretroviral regimen is suboptimal

Modification of ART regimens is discussed in detail separately. (See "Modifying HIV antiretroviral therapy regimens").

SUMMARY AND RECOMMENDATIONS

* Antiretroviral therapy (ART) has revolutionized the management of HIV infection with decreases in opportunistic infections and mortality rates.

* ART is complex, and, when possible, providers with training and expertise in HIV infection should initiate and manage ART.

* Prior to initiating ART, patients should undergo a careful history and physical examination with particular emphasis on evidence of symptomatic HIV disease as well as psychosocial factors that might interfere with adherence to an ART regimen.

* Laboratory testing prior to ART should include two measurements of the CD4 cell count, preferably at times when the patient is not acutely ill; measurement of the HIV viral load; a complete blood count with differential; electrolytes, BUN, creatinine, glucose; liver function tests; amylase; a lipid profile (including triglycerides); and serologic testing for syphilis, toxoplasmosis, hepatitis B and hepatitis C.

* Indications for therapy include symptomatic HIV disease (eg, an AIDS-defining diagnosis, wasting, or thrush). In asymptomatic patients, therapy should be initiated after the CD4 cell count declines below 350/microL, but before it reaches 200/microL. Providers should discuss the risks and benefits of ART with patients. The urgency to treat depends on the viral load and CD4 count decline.

* Many appropriate initial regimens can be constructed using published expert guidelines from the DHHS (show table 8) or the IAS-USA. Standard treatment consists of three active drugs against HIV including a dual nucleoside backbone and a third agent. For the third agent most experts currently would choose a regimen based on EFV 600 mg daily, ATV/r 300 mg/100 mg daily, LPV/r 400 mg/100 mg daily or FOS/r 1400 mg/200 mg daily. An NRTI backbone of TDF/FTC 300 mg/200 mg once daily, ZDV/3TC 600 mg/300 mg twice daily, or ABC/3TC 600 mg/300 mg once daily are commonly used.

* Adherence to a regimen (taking more than 95 percent of prescribed doses) is crucial to the success of ART and to preventing the development of HIV resistance. Patients should be advised of the importance of taking all or none of their ART medications.

* Patients should undergo frequent monitoring both with provider visits and laboratory testing after initiating ART. Patients who do not have the expected drop in HIV viral load after initiation of ART (show table 6) may be experiencing failure of the regimen and should be managed aggressively. (See "Virologic failure" above).

* Indications for changing therapy are virologic failure, toxicity, inability to comply with the regimen, or a suboptimal regimen. (See "Modifying HIV antiretroviral therapy regimens").


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Postuar nga NS-6 dat 08 Mars 2007 - 22:43:

HIV Transmission During Early Infection

Cod. A08032007

HIV Transmission During Early Infection

Nearly half of HIV transmission occurs less than 6 months after seroconversion.

The early stages of HIV infection are characterized by a high viral burden in blood and semen, which increases the risk for viral transmission. Knowing the proportion of HIV transmission that occurs during early infection is important for developing prevention strategies. Investigators in Quebec recently used comparative phylogenetic analysis to explore HIV transmission patterns among 593 patients with early HIV infection (<6 months after seroconversion) and 795 patients with chronic HIV infection.

Of 593 early infections, 293 (49.4%) segregated into one of 75 transmission clusters, with 2 to 17 infections per cluster. Half of these clusters included a mean of 2.7 infections; the other half, a mean of 8.8 infections. In contrast, only 21 of 660 treated chronic infections (3.2%) were clustered, with a mean cluster size of 3.1. HIV isolates from untreated and treated chronic infections co-clustered with early-infection HIV isolates in only 1% and 2.7% of cases, respectively. Analysis revealed that 49.4% of transmissions were attributable to early infections. Drug-resistance mutations were present in 14.7% of clustered transmissions at early stages of disease.

Comment: These findings confirm that a large proportion of HIV transmission occurs during early infection. Prompt detection of persons newly infected with HIV, followed by counseling to reduce high-risk behavior, is essential for reducing future transmission. Whether antiretroviral therapy during early infection benefits patients remains controversial, but as editorialists argue, reduction of transmission risk, through reduction of viral load, should also be considered a potential benefit of such treatment.

Daniel J. Diekema, MD, MS

Published in Journal Watch Infectious Diseases March 7, 2007


Postuar nga NS-6 dat 12 Mars 2007 - 22:56:

Do Corticosteroids Improve Outcome in Kawasaki Disease?

Cod. A12032007


Intravenous methylprednisolone is not indicated for the primary treatment of acute KD in children.

Kawasaki disease (KD) is a mucocutaneous vasculitis apparently triggered by an unknown infectious agent in infants and young children with a genetic predisposition. It is the leading cause of acquired heart disease in children. In Japan, KD affects 1 in every 185 children. In the multiethnic U.S., that figure is about 25 children per 100,000 (5000 new cases annually). Diagnosis rests on a constellation of clinical signs that often emerge over time, including rash, fever, conjunctivitis, erythema of the lips and oral mucosa, and cervical lymphadenopathy. There is no single diagnostic test. Untreated, KD leads to coronary artery aneurysms in up to 25% of children. Standard therapy is intravenous immunoglobulin (IVIG) and high-dose aspirin given within the first 10 days of illness. Even with early treatment, approximately 5% of children develop coronary artery aneurysms, 1% develop giant aneurysms, and some develop recurrent KD.

Until now, studies of the value of adding systemic corticosteroids to the standard treatment have been inconclusive. Investigators in the Pediatric Heart Network performed a multicenter, randomized, placebo-controlled, double-blind trial to see if IV methylprednisolone added to conventional IVIG and aspirin therapy would reduce coronary artery abnormalities in children with acute KD. Children seen between days 4 and 10 of fever who met other strict diagnostic criteria were enrolled. Those with previous IVIG therapy, recent systemic corticosteroid treatment, or previous KD were excluded. Over 2 years, 199 of the 589 children diagnosed with KD were enrolled. All patients received IVIG and high-dose aspirin; in addition, half received 30 mg/kg of IV methylprednisolone and half received placebo.

Compared with the placebo group, the corticosteroid group had shorter initial hospitalization and lower erythrocyte sedimentation rates at 1 week, but both groups had similar coronary dimensions at weeks 1 and 5. In addition, the total number of days of hospitalization, days of fever, incidences of IVIG retreatment, and number of adverse events did not differ between groups. The authors conclude that intravenous methylprednisolone therapy is not indicated in the primary treatment of acute KD in children.

Comment: The number of KD patients collected over a mere 2 years is staggering, especially given the broad exclusion criteria. As stated in the accompanying editorial, "the failure of corticosteroids to benefit these patients underscores the difference between KD and other chronic vasculitides." More prospective, randomized, controlled studies of other therapies are needed to improve outcomes in patients with KD, especially those who do not respond to IVIG therapy. Studies by a multicenter international genotyping consortium are currently examining the genetic component of KD.

Mary Wu Chang, MD

Published in Journal Watch Dermatology February 14, 2007


Postuar nga NS-6 dat 17 Mars 2007 - 00:23:

Cardiopulmonary resuscitation by bystanders with chest compression only

Cod. A17032007

hmmm,i found an article published by The Lancet talking about cardiopulmonary resuscitation...seems interesting...

here is the abstract because the full article was to be paid

Cardiopulmonary resuscitation by bystanders with chest compression only (SOS-KANTO): an observational study

Summary

Background
Mouth-to-mouth ventilation is a barrier to bystanders doing cardiopulmonary resuscitation (CPR), but few clinical studies have investigated the efficacy of bystander resuscitation by chest compressions without mouth-to-mouth ventilation (cardiac-only resuscitation).

Methods
We did a prospective, multicentre, observational study of patients who had out-of-hospital cardiac arrest. On arrival at the scene, paramedics assessed the technique of bystander resuscitation. The primary endpoint was favourable neurological outcome 30 days after cardiac arrest.

Findings
4068 adult patients who had out-of-hospital cardiac arrest witnessed by bystanders were included; 439 (11%) received cardiac-only resuscitation from bystanders, 712 (18%) conventional CPR, and 2917 (72%) received no bystander CPR. Any resuscitation attempt was associated with a higher proportion having favourable neurological outcomes than no resuscitation (50% vs 22%, p<00001). Cardiac-only resuscitation resulted in a higher proportion of patients with favourable neurological outcomes than conventional CPR in patients with apnoea (62% vs 31%; p=00195), with shockable rhythm (194% vs 112%, p=0041), and with resuscitation that started within 4 min of arrest (101% vs 51%, p=00221). However, there was no evidence for any benefit from the addition of mouth-to-mouth ventilation in any subgroup. The adjusted odds ratio for a favourable neurological outcome after cardiac-only resuscitation was 22 (95% CI 1242) in patients who received any resuscitation from bystanders.

Interpretation
Cardiac-only resuscitation by bystanders is the preferable approach to resuscitation for adult patients with witnessed out-of-hospital cardiac arrest, especially those with apnoea, shockable rhythm, or short periods of untreated arrest.

The Lancet 2007; 369:920-926


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