Antiviral Therapy 2012; 17:1291–1300 (doi: 10.3851/IMP2407)
Original article The clinical benefits of antiretroviral therapy in severely immunocompromised HIV-1-infected patients with and without complete viral suppression Amanda Mocroft1*, Wendy P Bannister1, Ole Kirk2,3, Justyna D Kowalska2, Peter Reiss4, Antonella D’Arminio‑Monforte5, Jose Gatell 6, Martin Fisher 7, Hanna Trocha8, Aza Rakhmanova9, Jens D Lundgren2,3, the EuroSIDA Study in EuroCOORD† Research Department of Infection and Population Health, University College London, London, UK Copenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark 3 Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark 4 Academisch Medisch Centrum bij de Universiteit van Amsterdam, Amsterdam, the Netherlands 5 Istituto Di Clinica Malattie Infettive e Tropicale, Milan, Italy 6 Hospital Clinic i Provincial, Barcelona, Spain 7 Royal Sussex County Hospital, Brighton, UK 8 Medical University, Gdansk, Poland 9 Medical Academy Botkin Hospital, St Petersburg, Russia 1 2
*Corresponding author e-mail:
[email protected] A full list of the EuroSIDA study group can be found via Additional file 1
†
Background: The aim of this study was to determine whether there is a protective effect of combination antiretroviral therapy (cART) on the development of clinical events in patients with ongoing severe immunosuppression. Methods: A total of 3,780 patients from the EuroSIDA study under follow-up after 2001 with a current CD4+ T-cell count ≤200 cells/mm3 were stratified into five groups: group 1, viral load (VL)100,000 copies/ml (IRR 0.66; 95% CI 0.44–1.00). Similar relationships were seen for non-AIDS events and AIDS events when considered separately. Conclusions: In patients with ongoing severe immunosuppression, cART was associated with significant clinical benefits in patients with suboptimal virological control or virological failure.
Introduction HIV-related morbidity and mortality have significantly decreased since the introduction of combination antiretroviral therapy (cART) into clinical practice; cART suppresses HIV replication and hence allows immune reconstitution [1–4]. The CD4+ T-cell ©2012 International Medical Press 1359-6535 (print) 2040-2058 (online)
AVT-12-OA-2489_Mocroft.indd 1291
count and HIV viral load (VL) are both established predictors of clinical prognosis, although there is evidence to suggest a residual benefit of treatment independent of CD4+ T-cell count and VL [5–8]. There are concerns that continuation of treatment in the 1291
26/10/2012 13:54:17
A Mocroft et al.
presence of detectable viraemia increases the likelihood of evolving drug-resistant HIV, which limits future treatment options [5,9,10]. In the clinical setting, especially in settings where viral load monitoring or the availability of alternate drugs to switch to in case of viral failure are limited, patients might be maintained on cART for extended periods of time despite viral failure [5,11,12]. In the modern cART era, patients with ongoing severe immunosuppression (CD4+ T-cell count ≤200 cells/mm3) are in a minority [5,13,14]; severe immunosuppression might result from the late presentation of HIV or from failure to achieve a satisfactory response to cART due to non-adherence or development of antiretroviral resistance. Morbidity and mortality associated with both AIDS and non-AIDS events is highest in these patients [15,16]. Whether cART continues to be clinically effective in the absence of virological control remains an important clinical question that has significant implications for the design of treatment programmes, especially in the resource-constrained environment. Previous research in the early cART era among immunosuppressed patients demonstrated a consistent treatment effect (independent of latest CD4+ T-cell counts) for AIDS and death [6,17,18]. However, there have been significant treatment advances since 2001 [19,20], as well as changes in our understanding of the role of HIV viral load in disease progression and developments in viral load monitoring [21,22]. Moreover, we now have an increased appreciation of the role of non-AIDS- defining events such as cancer, cardiovascular, liver and renal diseases [23–25]. The aim of the present study was to evaluate the clinical benefit of cART, measured in terms of fatal and non-fatal AIDS and non-AIDS events, over and above that captured by CD4+ T-cell count and VL in patients with a current CD4+ T-cell count ≤200 cells/mm3 with and without viral suppression.
Methods Patients The EuroSIDA study is a prospective, observational cohort of 16,597 HIV-1-infected patients in 102 centres across 33 European countries, Israel and Argentina. The study has been described in detail previously [26]. In brief, patients were enrolled into eight cohorts from May 1994 onwards. Information is collected on a standardized data collection form every 6 months, including all CD4+ T-cell counts and VLs measured since the last follow-up and starting and stopping dates of all antiretroviral drugs. Dates of diagnosis of all clinical AIDS-defining illnesses are recorded using the 1993 clinical definition of AIDS from the Centers for Disease Control [27]. All deaths were also recorded, with cause of death determined by 1292
AVT-12-OA-2489_Mocroft.indd 1292
the Coding Causes of Death in HIV (CoDe) protocol and by applying a standardized algorithm [28,29]. To ensure correct patient selection and to verify that accurate data are supplied, members of the coordinating office visit all centres to check the information provided against case notes for all patients with clinical events and 10% of randomly selected patients per year.
Statistical methods Patients were included in the analysis if they had at least 1 month of prospective follow-up time in EuroSIDA with a CD4+ T-cell count ≤200 cells/mm3 after 1 January 2001, when information on non-AIDS events began to be routinely collected and quality assured. Follow-up time was divided into calendar months and patients contributed to the person-years of follow-up (PYFU) if the CD4+ T-cell count in that month (or the preceding 6 months) was ≤200 cells/ mm3 and the VL was monitored within 28 days of the CD4+ T-cell count. PYFU were allocated to one of five groups depending on viral suppression and use of cART: group 1, VL1/1/2001 n=13,276
Current CD4+ T-cell count ≤200 cells/mm3; VL stratified into five groups n=3,198
Group 1 VL
