Archive for November, 2009

When to Start Antiretroviral Therapy in Resource-Limited Settings

Annals of Internal Medicine  20 Jul 2009

Rochelle P. Walensky, MD, MPH; Lindsey L. Wolf, SB; Robin Wood, FCP, MMed, DTM&H; Mariam O. Fofana, AB; Kenneth A. Freedberg, MD, MSc; Neil A. Martinson, MBBCh, MPH; A. David Paltiel, PhD; Xavier Anglaret, MD, PhD; Milton C. Weinstein, PhD; and Elena Losina, PhD, for the CEPAC-International Investigators*

From the Massachusetts General Hospital, Brigham and Women’s Hospital, Harvard University Medical School, Harvard School of Public Health, and Boston University School of Public Health, Boston, Massachusetts; University of Cape Town, Cape Town, and Perinatal HIV Research Unit, Johannesburg, South Africa; Johns Hopkins University, Baltimore, Maryland; Yale School of Medicine, New Haven, Connecticut; and Université Victor Segalen Bordeaux 2, Bordeaux, France.

Background: The results of international clinical trials that are assessing when to initiate antiretroviral therapy (ART) will not be available for several years.

Objective: To inform HIV treatment decisions about the optimal CD4 threshold at which to initiate ART in South Africa while awaiting the results of these trials.

Design: Cost-effectiveness analysis by using a computer simulation model of HIV disease.

Data Sources: Published data from randomized trials and observational cohorts in South Africa.

Target Population: HIV-infected patients in South Africa.

Time Horizon: 5-year and lifetime.

Perspective: Modified societal.

Intervention: No treatment, ART initiated at a CD4 count less than 0.250 x 109 cells/L, and ART initiated at a CD4 count less than 0.350 x 109 cells/L.

Outcome Measures: Morbidity, mortality, life expectancy, medical costs, and cost-effectiveness.

Results of Base-Case Analysis: If 10% to 100% of HIV-infected patients are identified and linked to care, a CD4 count threshold for ART initiation of 0.350 x 109 cells/L would reduce severe opportunistic diseases by 22 000 to 221 000 and deaths by 25 000 to 253 000 during the next 5 years compared with ART initiation at 0.250 x 109 cells/L; cost increases would range from $142 million (10%) to $1.4 billion (100%). Either ART initiation strategy would increase long-term survival by at least 7.9 years, with a mean per-person life expectancy of 3.8 years with no ART and 12.5 years with an initiation threshold of 0.350 x 109 cells/L. Compared with an initiation threshold of 0.250 x 109 cells/L, a threshold of 0.350 x 109 cells/L has an incremental cost-effectiveness ratio of $1200 per year of life saved.

Results of Sensitivity Analysis: Initiating ART at a CD4 count less than 0.350 x 109 cells/L would remain cost-effective over the next 5 years even if the probability that the trial would demonstrate the superiority of earlier therapy is as low as 17%.

Limitation: This model does not consider the possible benefits of initiating ART at a CD4 count greater than 0.350 x 109 cells/L or of reduced HIV transmission.

Conclusion: Earlier initiation of ART in South Africa will probably reduce morbidity and mortality, improve long-term survival, and be cost-effective. While awaiting trial results, treatment guidelines should be liberalized to allow initiation at CD4 counts less than 0.350 x 109 cells/L, earlier than is currently recommended.

Primary Funding Source: National Institute of Allergy and Infectious Diseases and the Doris Duke Charitable Foundation.



November 30, 2009 at 11:43 pm Leave a comment

Clinical management of human infection with pandemic (H1N1) 2009

WHO World Health Organization

November 2009

Revised guidance OMS


A novel influenza A (H1N1) virus of swine origin emerged among people in Mexico during the spring of 2009 and spread with travellers worldwide, resulting in the first influenza pandemic since 1968. As of October 2009, 195 countries have reported confirmed human cases of pandemic (H1N1) 2009. While the majority of illnesses caused by pandemic (H1N1) 2009 virus infection have been self-limited mild-to-moderate uncomplicated disease, severe complications including fatal outcomes have been reported….


November 30, 2009 at 5:58 pm Leave a comment

The Emergency Use Authorization of Peramivir for Treatment of 2009 H1N1 Influenza

N Engl J of Medicine Nov. 2009

Debra Birnkrant, M.D., and Edward Cox, M.D., M.P.H.

On October 23, 2009, Food and Drug Administration (FDA) Commissioner Margaret Hamburg issued an Emergency Use Authorization (EUA) for peramivir for intravenous injection (BioCryst Pharmaceuticals). Peramivir is an unapproved investigational neuraminidase inhibitor that may be effective in treating certain hospitalized adult and pediatric patients with suspected or confirmed cases of 2009 H1N1 influenza. The EUA allows health care providers to use peramivir, subject to specified conditions. This is the first EUA that has been issued for an unapproved drug.

The legal standard for the authorization of an EUA during a declared public health emergency requires a finding that it is “reasonable to believe” that the product “may be effective,” as well as a finding that its known and potential benefits outweigh its known and potential risks.1 There must also be no other adequate, approved, and available treatment alternatives for the specific indication. This is a lower evidentiary standard than that used for marketing approval, which requires a finding of “substantial evidence” of efficacy for the proposed use based on adequate and well-controlled trials, as well as a robust safety evaluation…



November 30, 2009 at 5:49 pm Leave a comment

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents -November 3, 2008

Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents -November 3, 2008

Developed by the DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents – A Working Group of the Office of AIDS Research Advisory Council (OARAC)

November 30, 2009 at 12:41 pm Leave a comment

CD4+ Count–Guided Interruption of Antiretroviral Treatment

N Engl J of Medicine  No.30, 2006  V.355  N.22  p.2283-2296

The Strategies for Management of Antiretroviral Therapy (SMART) Study Group

Background Despite declines in morbidity and mortality with the use of combination antiretroviral therapy, its effectiveness is limited by adverse events, problems with adherence, and resistance of the human immunodeficiency virus (HIV).

Methods We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease.

Results A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1).

Conclusions Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy.




November 30, 2009 at 12:40 pm Leave a comment

When to Start Antiretroviral Therapy?

Clinical  Infect Diseases  15 Dec  2008  V.47  N.12  p. 1580-6

Timothy J. Wilkin and Roy M. Gulick

Division of International Medicine and Infectious Diseases, Weill‐Cornell Medical College, New York, New York

The optimal time to start antiretroviral therapy (ART) for human immunodeficiency virus (HIV)–infected individuals remains uncertain. Although current ART regimens are effective in suppressing viremia and enhancing immune function and are increasingly convenient and well tolerated, ongoing concerns remain about adherence, drug-related toxicities, drug resistance, and cost. Although few clinical trials results are currently available to inform the question of when to start ART, large clinical cohorts clearly have demonstrated the benefits of earlier initiation of ART for reducing both HIV-related and non-HIV–related clinical events. Additional data suggest that the strategy of earlier initiation of ART is cost-effective and efficient. Consequently, many antiretroviral guidelines from around the world now recommend routine initiation of ART when the CD4 cell count decreases to <350 cells/μL or at higher CD4 cell counts for certain subgroups of HIV-infected individuals, such as pregnant and/or breast-feeding women and persons with HIV-related nephropathy or hepatitis virus coinfection. Additional cohort and clinical trials data are needed.



November 30, 2009 at 12:39 pm Leave a comment

Serum procalcitonin and C-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis.

Clin Infect Dis. 15 July 2004  V.39  N.2  p.206-17


Liliana Simon,1 France Gauvin, 2 Devendra K. Amre,2 Patrick Saint‐Louis,3 and Jacques Lacroix2

1Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut; and Departments of 2Pediatrics and 3Clinical Biochemistry, University of Montreal, Quebec

A meta-analysis was performed to evaluate the accuracy of determination of procalcitonin (PCT) and C-reactive protein (CRP) levels for the diagnosis of bacterial infection. The analysis included published studies that evaluated these markers for the diagnosis of bacterial infections in hospitalized patients. PCT level was more sensitive (88% [95% confidence interval {CI}, 80%–93%] vs. 75% [95% CI, 62%–84%]) and more specific (81% [95% CI, 67%–90%] vs. 67% [95% CI, 56%–77%]) than CRP level for differentiating bacterial from noninfective causes of inflammation. The Q value for PCT markers was higher (0.82 vs. 0.73). The sensitivity for differentiating bacterial from viral infections was also higher for PCT markers (92% [95% CI, 86%–95%] vs. 86% [95% CI, 65%–95%]); the specificities were comparable (73% [95% CI, 42%–91%] vs. 70% [95% CI, 19%–96%]). The Q value was higher for PCT markers (0.89 vs. 0.83). PCT markers also had a higher positive likelihood ratio and lower negative likelihood ratio than did CRP markers in both groups. On the basis of this analysis, the diagnostic accuracy of PCT markers was higher than that of CRP markers among patients hospitalized for suspected bacterial infections.





November 28, 2009 at 5:38 pm Leave a comment

Preparing for 2009 H1N1 Influenza

N Engl J of Medicine  Nov 12, 2009  V.361  N.20  p.1991-1993


Richard P. Wenzel, M.D., and Michael B. Edmond, M.D., M.P.H.

In 1743, when disease was presumed to be astral in origin, European newspapers reported on a contagious influence (influenza in Italian) that was being visited on the citizens of Rome. Two hundred years later, Wilson Smith and colleagues would isolate an influenza A virus, one of the members of the orthomyxovirus family.1 The key reservoirs of all influenza A viruses are migrating waterfowl, and intermittently, other hosts, such as pigs and people, are infected. Further classification of influenza A viruses is based on the specific hemagglutinin viral attachment spike and neuraminidase disengagement spike; the latter is cleaved when newly minted viruses emerge from infected cells. Smith’s isolate was a variant of the H1N1 agent that caused the pandemic of 1918–1919, and H1N1 progeny persisted until the emergence of the Asian influenza pandemic strain (H2N2) in 1957. However, a new H1N1 strain of swine influenza emerged in 1976, and variants of this virus continue to circulate as one of the seasonal strains.



November 28, 2009 at 5:32 pm Leave a comment

Cross-Reactive Antibody Responses to the 2009 Pandemic H1N1 Influenza Virus

N Engl J of Medicine  Nov 12, 2009  V.361  N.20  p.1945-1952

Kathy Hancock, Ph.D., Vic Veguilla, M.P.H., Xiuhua Lu, M.D., Weimin Zhong, Ph.D., Eboneé N. Butler, M.P.H., Hong Sun, M.D., Feng Liu, M.D., Ph.D., Libo Dong, M.D., Ph.D., Joshua R. DeVos, M.P.H., Paul M. Gargiullo, Ph.D., T. Lynnette Brammer, M.P.H., Nancy J. Cox, Ph.D., Terrence M. Tumpey, Ph.D., and Jacqueline M. Katz, Ph.D.

Background A new pandemic influenza A (H1N1) virus has emerged, causing illness globally, primarily in younger age groups. To assess the level of preexisting immunity in humans and to evaluate seasonal vaccine strategies, we measured the antibody response to the pandemic virus resulting from previous influenza infection or vaccination in different age groups.

Methods Using a microneutralization assay, we measured cross-reactive antibodies to pandemic H1N1 virus (2009 H1N1) in stored serum samples from persons who either donated blood or were vaccinated with recent seasonal or 1976 swine influenza vaccines.

Results A total of 4 of 107 persons (4%) who were born after 1980 had preexisting cross-reactive antibody titers of 40 or more against 2009 H1N1, whereas 39 of 115 persons (34%) born before 1950 had titers of 80 or more. Vaccination with seasonal trivalent inactivated influenza vaccines resulted in an increase in the level of cross-reactive antibody to 2009 H1N1 by a factor of four or more in none of 55 children between the ages of 6 months and 9 years, in 12 to 22% of 231 adults between the ages of 18 and 64 years, and in 5% or less of 113 adults 60 years of age or older. Seasonal vaccines that were formulated with adjuvant did not further enhance cross-reactive antibody responses. Vaccination with the A/New Jersey/1976 swine influenza vaccine substantially boosted cross-reactive antibodies to 2009 H1N1 in adults.

Conclusions Vaccination with recent seasonal nonadjuvanted or adjuvanted influenza vaccines induced little or no cross-reactive antibody response to 2009 H1N1 in any age group. Persons under the age of 30 years had little evidence of cross-reactive antibodies to the pandemic virus. However, a proportion of older adults had preexisting cross-reactive antibodies.



November 28, 2009 at 5:30 pm Leave a comment

Acute HIV Infection — New York City, 2008

MMWR Weekly  November 27, 2009  V.58  N.46  p.1296-1299

Acute human immunodeficiency virus (HIV) infection (AHI) is a highly infectious phase of disease that lasts approximately 2 months and is characterized by nonspecific clinical symptoms (1). AHI contributes disproportionately to HIV transmission because it is associated with a high level of viremia, despite negative or indeterminate antibody (Ab) tests (2). Diagnosis of AHI with individual or pooled nucleic acid amplification tests (p-NAAT) can enable infected persons to adopt behaviors that reduce HIV transmission, facilitate partner referral for counseling and testing, and identify social networks of persons with elevated rates of HIV transmission (3). The national HIV surveillance case definition does not distinguish AHI from other stages of HIV infection (4), and the frequency of AHI among reported HIV cases is unknown. In 2008, to increase detection of AHI and demonstrate the feasibility of AHI surveillance, the New York City Department of Health and Mental Hygiene (NYC DOHMH) initiated p-NAAT screening at four sexually transmitted disease (STD) clinics and enhanced citywide HIV surveillance (using a standard case definition) to differentiate AHI among newly reported cases. Seventy cases of AHI (representing 1.9% of all 3,635 HIV diagnoses reported in New York City) were identified: 53 cases from enhanced surveillance and 17 cases from p-NAAT screening (representing 9% of 198 HIV diagnoses at the four clinics). Men who have sex with men (MSM) constituted 81% of AHI cases. Screening STD clinic patients, especially MSM, with p-NAAT can identify additional cases of HIV infection. Surveillance for AHI is feasible and can identify circumstances in which HIV prevention efforts should be intensified.

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November 26, 2009 at 11:47 am Leave a comment

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