Archive for July 18, 2013

Development of diagnostic criteria for serious non-AIDS events in HIV clinical trials.

HIV Clin Trials. 2010 Jul-Aug;11(4):205-19.

Lifson AR; INSIGHT Endpoint Review Committee Writing Group, Belloso WH, Davey RT, Duprez D, Gatell JM, Hoy JF, Krum EA, Nelson R, Pedersen C, Perez G, Price RW, Prineas RJ, Rhame FS, Sampson JH, Worley J, INSIGHT Study Group.

Collaborators (76)


Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota 55454-1015, USA.



Serious non-AIDS (SNA) diseases are important causes of morbidity and mortality in the HAART era. We describe development of standard criteria for 12 SNA events for Endpoint Review Committee (ERC) use in START, a multicenter international HIV clinical trial.


SNA definitions were developed based upon the following: (1) criteria from a previous trial (SMART), (2) review of published literature, (3) an iterative consultation and review process with the ERC and other content experts, and (4) evaluation of draft SNA criteria using retrospectively collected reports in another trial (ESPRIT).


Final criteria are presented for acute myocardial infarction, congestive heart failure, coronary artery disease requiring drug treatment, coronary revascularization, decompensated liver disease, deep vein thrombosis, diabetes mellitus, end-stage renal disease, non-AIDS cancer, peripheral arterial disease, pulmonary embolism, and stroke. Of 563 potential SNA events reported in ESPRIT and reviewed by an ERC, 72% met “confirmed” and 13% “probable” criteria. Twenty-eight percent of cases initially reviewed by the ERC required follow-up discussion (adjudication) before a final decision was reached.


HIV clinical trials that include SNA diseases as clinical outcomes should have standardized SNA definitions to optimize event reporting and validation and should have review by an experienced ERC with opportunities for adjudication.


July 18, 2013 at 1:44 pm

Inflammation, coagulation and cardiovascular disease in HIV-infected individuals.

PLoS One. 2012;7(9):e44454.

Duprez DA, Neuhaus J, Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, Ledergerber B, Lundgren J, Nixon D, Paton NI, Prineas RJ, Neaton JD; INSIGHT SMART Study Group.


University of Minnesota, Minneapolis, Minnesota, United States of America.



The SMART study was a trial of intermittent use of antiretroviral therapy (ART) (drug conservation [DC]) versus continuous use of ART (viral suppression [VS]) as a strategy to reduce toxicities, including cardiovascular disease (CVD) risk. We studied the predictive value of high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6) and D-dimer with CVD morbidity and mortality in HIV-infected patients who were enrolled in SMART beyond other measured CVD risk factors.


A blood sample was available in 5098 participants who were enrolled in the SMART study for the measurement of IL-6, hsCRP and D-dimer. Hazard ratios (HR) with 95% CI for CVD events were estimated for each quartile (Q) for each biomarker vs the 1(st) quartile and for 1 SD higher levels. For both treatment groups combined, unadjusted and adjusted HRs were determined using Cox regression models.


There were 252 participants who had a CVD event over a median follow-up of 29 months. Adjusted HRs (95% CI) for CVD for Q4 vs Q1 were 4.65 (2.61, 8.29), 2.10 (1.40, 3.16), and 2.14 (1.38, 3.33) for IL-6, hsCRP and D-dimer, respectively. Associations were similar for the DC and VS treatment groups (interaction p-values were >0.30). The addition of the three biomarkers to a model that included baseline covariates significantly improved model fit (p<0.001). Area under the curve (AUC) estimates improved with inclusion of the three biomarkers in a model that included baseline covariates corresponding to other CVD risk factors and HIV factors (0.741 to 0.771; p<0.001 for difference).


In HIV-infected individuals, IL-6, hsCRP and D-dimer are associated with an increased risk of CVD independent of other CVD risk factors. Further research is needed to determine whether these biomarkers can be used to improve CVD risk prediction among HIV positive individuals.


July 18, 2013 at 1:42 pm

Guidelines for Improving Entry Into and Retention in Care and Antiretroviral Adherence for Persons With HIV: Evidence-Based Recommendations From an International Association of Physicians in AIDS Care Panel

Annals of Internal Medicine 5 June 2012, Vol. 156. No. 11

Melanie A. Thompson, MD; Michael J. Mugavero, MD, MHSc; K. Rivet Amico, PhD; Victoria A. Cargill, MD, MSCE; Larry W. Chang, MD, MPH; Robert Gross, MD, MSCE; Catherine Orrell, MBChB, MSc, MMed; Frederick L. Altice, MD; David R. Bangsberg, MD, MPH; John G. Bartlett, MD; Curt G. Beckwith, MD; Nadia Dowshen, MD; Christopher M. Gordon, PhD; Tim Horn, MS; Princy Kumar, MD; James D. Scott, PharmD, MEd; Michael J. Stirratt, PhD; Robert H. Remien, PhD; Jane M. Simoni, PhD; and Jean B. Nachega, MD, PhD, MPH


After HIV diagnosis, timely entry into HIV medical care and retention in that care are essential to the provision of effective antiretroviral therapy (ART). Adherence to ART is among the key determinants of successful HIV treatment outcome and is essential to minimize the emergence of drug resistance. The International Association of Physicians in AIDS Care convened a panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence for people with HIV.


A systematic literature search was conducted to produce an evidence base restricted to randomized, controlled trials and observational studies with comparators that had at least 1 measured biological or behavioral end point. A total of 325 studies met the criteria. Two reviewers independently extracted and coded data from each study using a standardized data extraction form. Panel members drafted recommendations based on the body of evidence for each method or intervention and then graded the overall quality of the body of evidence and the strength for each recommendation.


Recommendations are provided for monitoring entry into and retention in care, interventions to improve entry and retention, and monitoring of and interventions to improve ART adherence. Recommendations cover ART strategies, adherence tools, education and counseling, and health system and service delivery interventions. In addition, they cover specific issues pertaining to pregnant women, incarcerated individuals, homeless and marginally housed individuals, and children and adolescents, as well as substance use and mental health disorders. Recommendations for future research in all areas are also provided.

The availability of potent antiretroviral therapy (ART) has resulted in remarkable decreases in HIV-related morbidity and mortality in the past 15 years (1–2). Entry into and retention in HIV medical care is critical to the provision of ART, and adherence to ART is among the key determinants of HIV treatment success (3–6). More than 2 decades of targeted research in these areas has produced a varied and complex evidence base that, to date, has not been fully evaluated or distilled into concrete recommendations for how to best monitor or support HIV care and ART adherence.

Recent data from the U.S. Centers for Disease Control and Prevention reveal that only 28% of persons with HIV in the United States have achieved viral suppression (7). Of those who knew they had HIV, only 69% were linked to care, and only 59% were retained in care (8). These figures and comparable global data (9–10) challenge us to explore best practices for improving entry into and retention in care on a global scale. Only with successful care linkage and retention can ART be accessed. Once patients are in care and are receiving treatment, high levels of adherence are required to prevent the selection of resistance mutations and subsequent virologic failure (11). In a global pooled sample of 33 199 adults taking ART in over 84 observational studies, only 62% of persons achieved adherence of at least 90% of doses (12). These data underscore the need for concise and clear evidence-based recommendations to help care providers monitor and support ART adherence.

In this context, the International Association of Physicians in AIDS Care (IAPAC) convened an expert panel to develop evidence-based recommendations to optimize entry into and retention in care and ART adherence and to monitor these processes. Members of the panel are listed in Appendix 1. These guidelines aim to define best practices that can be used by practitioners and health systems to improve adherence and, in turn, health outcomes. Our recommendations are based on the best published science; however, the evidence base remains insufficient in many areas. For that reason, we also highlight areas in which additional research is needed to inform future recommendations. We realize that implementation of these recommendations may, in some cases, require that new resources be identified to bring the benefit of best practices to our clinic populations. We believe that presenting recommendations based on rigorous science is the best avenue to achieve that end.


July 18, 2013 at 1:41 pm

The immune reconstitution inflammatory syndrome.

Indian J Dermatol. 2011 Sep-Oct;56(5):476-9.

Bosamiya SS.


Department of Dermatology, Surat Municipal Institute of Medical Education and Research, Umarwada, Surat, Gujarat, India.


A paradoxical clinical worsening of a known condition or the appearance of a new condition after initiating antiretroviral therapy in HIV-infected patients is defined as immune reconstitution inflammatory syndrome (IRIS). Because of wide variation in clinical presentation and the still increasing spectrum of symptoms and etiologies reported, diagnosis remains problematic. Furthermore, no test is currently available to establish an IRIS diagnosis. Until a greater understanding of the syndrome is achieved in different regions of the world, clinicians need to remain vigilant when initiating ART and individualize therapy according to known treatment options for the specific infectious agent.


July 18, 2013 at 1:38 pm

Poor immune reconstitution in HIV-infected patients associates with high percentage of regulatory CD4+ T cells.

PLoS One. 2013;8(2):e57336.

Horta A, Nobrega C, Amorim-Machado P, Coutinho-Teixeira V, Barreira-Silva P, Boavida S, Costa P, Sarmento-Castro R, Castro AG, Correia-Neves M.


Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.


CD4(+) regulatory T cells (Tregs) are essential for the maintenance of the immune system’s equilibrium, by dampening the activation of potential auto-reactive T cells and avoiding excessive immune activation. To correctly perform their function, Tregs must be maintained at the right proportion with respect to effector T cells. Since this equilibrium is frequently disrupted in individuals infected with the human immunodeficiency virus (HIV), we hypothesize that its deregulation could hamper immune reconstitution in patients with poor CD4(+) T cell recovery under highly active antiretroviral therapy (HAART). We analysed Tregs percentages amongst CD4(+) T cells in 53 HIV-infected patients under HAART, with suppression of viral replication and distinct levels of immune reconstitution. As controls, 51 healthy individuals were also analysed. We observed that amongst the patients with Nadir values (the lowest CD4(+) T cell counts achieved) <200 cells/µL, the individuals with high Tregs percentages (≥10% of total CD4(+) T cells) had the worse CD4(+) T cell reconstitution. In accordance, the well-described direct correlation between the Nadir value and CD4(+) T cell reconstitution is clearly more evident in individuals with high Tregs proportions. Furthermore, we observed a strong negative correlation between Tregs percentages and CD4(+) T cell recovery among immunological non-responder HIV(+) individuals. All together, this work shows that high Tregs frequency is an important factor associated with sub-optimal CD4(+) T cell recovery. This is particularly relevant for immunological non-responders with low Nadir values. Our results suggest that the Tregs proportion might be of clinical relevance to define cut-offs for HAART initiation.


July 18, 2013 at 1:37 pm

Cryptococcal meningitis in an HIV-1-infected person: relapses or IRIS? Case report and review of the literature.

Eur Rev Med Pharmacol Sci. 2013 Jun;17(11):1555-9.

Nunnari G, Gussio M, Pinzone MR, Martellotta F, Cosentino S, Cacopardo B, Celesia BM.


Department of Clinical and Molecular Biomedicine, Division of Infectious Diseases, University of Catania, Garibaldi Nesima Hospital, Catania, Italy.


After starting highly active antiretroviral therapy (HAART), HIV-infected patients may experience what is termed immune reconstitution inflammatory syndrome (IRIS). IRIS is characterized by a paradoxical inflammatory response to either previously or recently treated infections or unmasked subclinical infections, when the patient regains the ability to mount a suitable immune response against specific antigens or pathogens. Cryptococcal IRIS (C-IRIS) is thought to be mediated by recovery of Cryptococcus-specific immune responses, resulting in exaggerated host inflammatory responses. In HIV-positive subjects, two distinct modes of presentation of C-IRIS are recognized, “paradoxical” and “unmasking” C-IRIS. “Paradoxical” C-IRIS presents as worsening or recurrence of treated cryptococcal disease following HAART initiation, despite microbiological treatment success. In the “unmasking” form, patients with no prior diagnosis may develop acute symptoms of cryptococcosis, such as meningitis or necrotizing lymphadenopathy, after starting HAART. Here, we present the case of an HIV-positive man, who developed cryptococcal meningitis two months after having started HAART and experienced several meningeal relapses and a “paradoxical” C-IRIS during the following year.


July 18, 2013 at 1:36 pm


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