Symptomatic Illness and Low CD4 Cell Count at HIV Seroconversion as Markers of Severe Primary HIV Infection

et al. (2013) Symptomatic Illness and Low CD4 Cell Count at HIV Seroconversion as Markers of Severe Primary HIV Infection. PLoS ONE 8(11): e78642. doi:10.1371/journal.pone.0078642 Symptomatic Illness and Low CD4 Cell Count at HIV Seroconversion as Markers of Severe Primary HIV Infection Sara Lodi 0 Martin Fisher 0 Andrew Phillips 0 Andrea De Luca 0 Jade Ghosn 0 Ruslan Malyuta 0 Robert Zangerle 0 Santiago Moreno 0 Philippe Vanhems 0 Faroudy Boufassa 0 Marguerite Guiguet 0 Kholoud Porter 0 for CASCADE Collaboration in EuroCoord" 0 Roberto F. Speck, University Hospital Zurich, Switzerland 0 1 Instituto de Salud Carlos III , Madrid , Spain , 2 Brighton and Sussex University Hospitals National Health Service Trust , Brighton , United Kingdom , 3 University College of London , London , United Kingdom , 4 University Division of Infectious Diseases, University Hospital of Siena , Siena , Italy , 5 Universite Paris Descartes, EA 3620, Paris, France, 6 Perinatal Prevention of AIDS Initiative , Odessa , The Ukraine, 7 Innsbruck Medical University , Innsbruck , Austria , 8 Hospital Ramon y Cajal , Madrid , Spain , 9 Edouard Herriot Hospital , Lyon, and Universite' de Lyon 1, Lyon, France, 10 Inserm , CESP Centre for Research in Epidemiology and Population Health, U1018, Epidemiology of HIV and STI Team, Le Kremlin-Bicetre, France, 11 INSERM and UPMC Univ Paris 06, UMR S 943, Paris, France, 12 MRC Clinical Trials Unit at University College London , London , United Kingdom Background: The risk/benefit of initiating ART in primary HIV infection (PHI) is unclear. The benefits are more likely to outweigh the risks in patients with severe PHI. An accepted definition of severe PHI is, however, lacking. Methods: CASCADE patients with HIV test interval ,6 months were classified as severe and non-severe PHI based on whether the following traits were recorded in the first 6 months following seroconversion: severe specific pre-defined symptoms, central nervous system-implicated illness, and $1, $2 CD4,350 (and ,500) cells/mm3. For each definition, we used Kaplan-Meier curves and Cox survival models to compare time to AIDS/death, censoring at the earlier of last clinic visit or 1/1/1997, when combination antiretroviral therapy (cART) became available. Results: Among 1108 included patients mostly males (85%) infected through sex between men (71%), 366 were diagnosed with AIDS/died. The risk of AIDS/death was significantly higher for individuals with severe symptoms, those with $1 CD4,350 cells/mm3 or $2 CD4 ,500 cells/mm3 in the first 6 months [aHR (95% confidence interval) 2.1 (1.4,3.2), 2.0 (1.5,2.7), and 2.3, (1.5-3.5) respectively]. Median [interquantile range] survival for patients with $2, $1 and no CD4,350 cells/mm3 within 6 months of seroconversion was 3.9 [2.7,6.5], 5.4 [4.5,8.4] and 8.1 [4.3,10.3] years, respectively. The diagnosis of CNS-implicated symptoms was rare and did not appear to be prognostic. Conclusion: One CD4 count ,350 or two ,500 cells/mm3 within 6 months of seroconversion and/or severe illness in PHI may be useful early indicators of individuals at high risk of disease progression. - " Membership of the CASCADE Collaboration is provided in the Acknowledgments. Background Although the virological and clinical features of primary HIV infection (PHI) were described nearly 20 years ago [1,2], it has not been clearly established whether and what characteristics of that early phase are predictive of subsequent faster HIV disease progression. The risk/benefit trade-off of initiating ART in PHI is unclear but the benefits are more likely to outweigh the risks in patients with severe PHI. However, an accepted definition of severe PHI, based on clinical, virological and/or immunological characteristics during that initial period, is lacking. Several studies have suggested that presence of seroconversion illness with long-lasting symptoms is associated with poorer subsequent outcomes [3,4,5]. As some symptoms are more severe than others with symptoms ranging from a simple flu-like symptoms to aseptic meningitis [6], the illness itself and its intensity may be predictive of disease progression. In particular, symptoms which signify the involvement of the central nervous system (CNS), such as meningeocephalitis, are known to be lifethreatening, as demonstrated by a recent case of fatal brain necrosis in PHI [7]. Results from observational studies on the predictive value of immunological and virological markers in early HIV infection are inconsistent. Although it has been shown that low levels of CD4 cell count in early HIV infection are predictive of faster disease progression [8,9,10], to our knowledge no study has provided a practical definition of what CD4 cell level should be considered as low. US guidelines for antiretroviral treatment in HIV positive patients indicate cART as optional for patients with ongoing PHI and for those known to have seroconverted in the past 6 months, while European guidelines indicate optional treatment for patients with severe seroconversion illness, although a definition of severity is not provided [11,12]. The optimal management of patients diagnosed during PHI, however, remains unresolved. We have, therefore, used data from routine clinical practice of patients diagnosed with HIV during, or shortly after HIV seroconversion, to explore definitions of PHI severity based on clinical and immunological features in the first 6 months following HIV seroconversion before the initiation of cART. Patients We used data from CASCADE in EuroCoord (www. EuroCoord.net), a collaboration of cohorts of patients with wellestimated dates of HIV seroconversion in Europe, Australia, Canada, and sub-Saharan Africa [13]. The data for this study were pooled in 2006 and, unlike most recent updates, included information on reported seroconversion illness and specific symptoms. The date of HIV seroconversion, used to approximate the date of HIV infection, was estimated by various methods: most frequently as the midpoint between dates of the last negative and first positive HIV antibody test results, the date of laboratory evidence of seroconversion or the date of a seroconversion illness (and an earlier documented negative HIV test result). For this study we restricted to patients with laboratory evidence of seroconversion or an HIV test interval #6 months. Patients enrolled in cohorts not reporting information on seroconversion illness and/or with an estimated date of HIV seroconversion after 31/12/1996, when combination antiretroviral therapy (cART) became available, were excluded. Ethics statement All cohorts in CASCADE received approval from their individual ethics review boards. Approval was also given by all ethics review boards to pool anonymised data for analyses and dissemination (see Appendix S1). Signed informed consent was obtained from all patients. Definitions of severe primary HIV infection We explored the following definitions for PHI sever (...truncated)