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      Early Antiretroviral Therapy Reduces AIDS Progression/Death in Individuals with Acute Opportunistic Infections: A Multicenter Randomized Strategy Trial

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          Abstract

          Background

          Optimal timing of ART initiation for individuals presenting with AIDS-related OIs has not been defined.

          Methods and Findings

          A5164 was a randomized strategy trial of “early ART” - given within 14 days of starting acute OI treatment versus “deferred ART” - given after acute OI treatment is completed. Randomization was stratified by presenting OI and entry CD4 count. The primary week 48 endpoint was 3-level ordered categorical variable: 1. Death/AIDS progression; 2. No progression with incomplete viral suppression (ie HIV viral load (VL) ≥50 copies/ml); 3. No progression with optimal viral suppression (ie HIV VL <50 copies/ml). Secondary endpoints included: AIDS progression/death; plasma HIV RNA and CD4 responses and safety parameters including IRIS.

          282 subjects were evaluable; 141 per arm. Entry OIs included Pneumocytis jirovecii pneumonia 63%, cryptococcal meningitis 12%, and bacterial infections 12%. The early and deferred arms started ART a median of 12 and 45 days after start of OI treatment, respectively.

          The difference in the primary endpoint did not reach statistical significance: AIDS progression/death was seen in 20 (14%) vs. 34 (24%); whereas no progression but with incomplete viral suppression was seen in 54 (38%) vs. 44 (31%); and no progression with optimal viral suppression in 67 (48%) vs 63 (45%) in the early vs. deferred arm, respectively (p = 0.22). However, the early ART arm had fewer AIDS progression/deaths (OR = 0.51; 95% CI = 0.27–0.94) and a longer time to AIDS progression/death (stratified HR = 0.53; 95% CI = 0.30–0.92). The early ART had shorter time to achieving a CD4 count above 50 cells/mL (p<0.001) and no increase in adverse events.

          Conclusions

          Early ART resulted in less AIDS progression/death with no increase in adverse events or loss of virologic response compared to deferred ART. These results support the early initiation of ART in patients presenting with acute AIDS-related OIs, absent major contraindications.

          Trial Registration

          ClinicalTrials.gov NCT00055120

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          Most cited references16

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          Late diagnosis of HIV infection: epidemiological features, consequences and strategies to encourage earlier testing.

          Caroline Sabin, Antonella Monforte, Enrico Girardi (2007)
          A substantial proportion of HIV-infected individuals do not present for HIV testing until late in infection; these individuals are often ill, have a high mortality risk, and are less likely to respond to treatment when initiated. Furthermore, late presentation means that opportunities to reduce onward transmission, either by reducing high-risk behaviours or by reducing an individual's infectivity, are missed. The proportion of HIV-infected individuals who present late has remained relatively stable over the past decade, despite several attempts to encourage earlier diagnosis. Late presenters tend to be those at lower perceived risk of infection, those who are not routinely offered HIV testing, and are often from marginalized groups. Strategies that encourage earlier testing, including routine HIV testing in healthcare settings where high-risk individuals attend frequently, the availability of HIV testing services in non-medical settings, and partner notification schemes or peer-led projects to encourage high-risk individuals to attend for testing, may all increase the proportion of HIV-infected individuals who are aware of their HIV status, thus helping to control the spread of the epidemic. This review summarizes recent evidence on the epidemiology of late presentation and its impact on clinical progression, and describes several key strategies that may encourage earlier diagnosis.
          Article 0 comments Cited 96 times – based on 0 reviews     Review now
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            HIV-infected adults with a CD4 cell count greater than 500 cells/mm3 on long-term combination antiretroviral therapy reach same mortality rates as the general population.

            Charlotte Lewden, Geneviève Chêne, Philippe Morlat … (2007)
            To compare mortality rates in combination antiretroviral therapy (cART)-treated HIV-infected adults with mortality in the general population according to the level of CD4 cell count reached and the duration of exposure to cART. HIV-infected adults initiating a protease inhibitor-containing treatment between 1997 and 1999 were selected in the Agence Nationale de Recherches sur le Sida et les hepatites virales (ANRS) APROCO and AQUITAINE cohorts. CD4 cell counts were estimated during follow-up using a 2-phase mixed linear model. Standardized mortality ratios (SMRs) were computed in reference to the 2002 French population rates, overall and for the time period spent with a CD4 count >or=500 cells/mm3. To identify if and when mortality rates reached values of the general population, SMRs were computed successively with truncation at each year of follow-up. The 2,435 adults (77% men, baseline median age = 36 years, and baseline median CD4 count = 270 cells/mm3) had a median follow-up of 6.8 years. The SMR was 7.0 (95% confidence interval [CI]: 6.2 to 7.8). During the 5,402 person-years spent with a CD4 count >or=500 cells/mm3, the mortality reached the level of the general population after the sixth year after cART initiation (SMR = 0.5, 95% CI: 0.1 to 1.6). Although overall mortality was higher in cART-treated HIV-infected adults, a subgroup with especially good prognosis can be identified, and these characteristics should be targeted for long-term treatment.
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              Incidence and risk factors for the immune reconstitution inflammatory syndrome in HIV patients in South Africa: a prospective study.

              W. D. F. Venter, Robert Murdoch, Annelies van Rie … (2008)
              To determine the incidence, clinical manifestations, risk factors and outcome of immune reconstitution inflammatory syndrome (IRIS) in South Africa. Prospective surveillance cohort and nested case-control study in a large, University hospital-based antiretroviral therapy (ART) clinic. A total of 423 ART-naive HIV-infected South African patients were followed for signs and symptoms IRIS during the first 6 months of ART. We also performed a nested case-control study with controls matched to IRIS cases on ART duration. During the first 6 months of ART, 44 (10.4%) patients experienced IRIS for an overall incidence rate of 25.1 cases per 100 patient-years. Diagnoses included tuberculosis (18/44, 41%), abscess formation and suppurative folliculitis (8/44, 18.2%), varicella zoster (6/44, 13.6%), herpes simplex (4/44, 9.1%), cryptococcal meningitis (3/44, 6.8%), molluscum contagiosum (3/44, 6.8%), and Kaposi's sarcoma (2/44, 4.5%). Median IRIS onset was 48 days (interquartile range, 29-99) from ART initiation. In comparison with controls, IRIS cases had significantly lower CD4 cell counts at baseline (79 versus 142 cells/microl; P = 0.02) and at IRIS diagnosis (183 versus 263 cells/microl; P = 0.05), but similar virological and immunological response to ART. In multivariable analyses, higher baseline CD4 cell count was protective of developing IRIS (HR 0.72 per 50 cells/microl increase). Most IRIS cases were mild, with ART discontinued in three (6.8%) patients, corticosteroids administered to four (9.1%) patients, and hospitalization required in 12 (27.3%) patients. Two deaths were attributable to IRIS. IRIS may affect 10% of patients initiating ART in Africa, particularly those with advanced immunosuppression, but severe, life-threatening IRIS is uncommon.
              Article 0 comments Cited 79 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                : Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2009
                Publication date (Electronic): 18 May 2009
                Volume: 4
                Issue: 5
                Electronic Location Identifier: e5575
                Affiliations
                [1 ]Stanford University AIDS Clinical Trials Unit, Stanford University, Stanford, California, United States of America
                [2 ]Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, United States of America
                [3 ]University College Dublin, Belfield, Ireland
                [4 ]University of Southern California, Los Angeles, California, United States of America
                [5 ]Wits Health Consortium, Helen Joseph Hospital, Johannesburg, South Africa
                [6 ]Frontier Science & Technology Research Foundation, Amherst, New York, United States of America
                [7 ]Social & Scientific Systems, Inc., Silver Spring, Maryland, United States of America
                [8 ]Statistical and Data Analysis Center, Harvard School of Public Health, Boston, Massachusetts, United States of America
                St. Vincent's Hospital, Australia
                Author notes

                Conceived and designed the experiments: ARZ JA IS EH CS WP. Performed the experiments: ARZ IS AS WP. Analyzed the data: ARZ JA LK IS AS CS WP. Contributed reagents/materials/analysis tools: LK CS. Wrote the paper: ARZ JA LK IS AS EH CS WP. Chair of protocol: ARZ. Senior statistician: JA.

                Article
                Publisher ID: 09-PONE-RA-08190R1
                DOI: 10.1371/journal.pone.0005575
                PMC ID: 2680972
                PubMed ID: 19440326
                SO-VID: 1e7f612d-602b-442f-964c-61ce2927f711
                Copyright © Zolopa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                Date received : 15 January 2009
                Date accepted : 13 March 2009
                Page count
                Pages: 10
                Categories
                Subject: Research Article
                Subject: Evidence-Based Healthcare
                Subject: Immunology/Immune Response
                Subject: Infectious Diseases/HIV Infection and AIDS
                Subject: Public Health and Epidemiology/Global Health
                Subject: Public Health and Epidemiology/Infectious Diseases

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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