Antiretroviral therapy response among HIV-2 infected patients: a systematic review

Ekouevi et al. BMC Infectious Diseases 2014, 14:461 http://www.biomedcentral.com/1471-2334/14/461 RESEARCH ARTICLE Open Access Antiretroviral therapy response among HIV-2 infected patients: a systematic review Didier K Ekouevi1,2,3,4*, Boris K Tchounga1,2,3, Patrick A Coffie1,5,6, Joseph Tegbe1, Alexandra M Anderson1, Geoffrey S Gottlieb7, Marco Vitoria8, François Dabis2,3 and Serge P Eholie1,5,6 Abstract Background: Few data are available on antiretroviral therapy (ART) response among HIV-2 infected patients. We conducted a systematic review on treatment outcomes among HIV-2 infected patients on ART, focusing on the immunological and virological responses in adults. Methods: Data were extracted from articles that were selected after screening of PubMed/MEDLINE up to November 2012 and abstracts of the 1996–2012 international conferences. Observational cohorts, clinical trials and program reports were eligible as long as they reported data on ART response (clinical, immunological or virological) among HIV-2 infected patients. The determinants investigated included patients’ demographic characteristics, CD4 cell count at baseline and ART received. Results: Seventeen reports (involving 976 HIV-2 only and 454 HIV1&2 dually reactive patients) were included in the final review, and the analysis presented in this report are related to HIV-2 infected patients only. There was no randomized controlled trial and only two cohorts had enrolled more than 100 HIV-2 only infected patients. The median CD4 count at ART initiation was 165 cells/mm3, [IQR; 137–201] and the median age at ART initiation was 44 years (IQR: 42–48 years). Ten studies included 103 patients treated with three nucleoside reverse transcriptase inhibitors (NRTI). Protease inhibitor (PI) based regimens were reported by 16 studies. Before 2009, the most frequent PIs used were Nelfinavir and Indinavir, whereas it was Lopinavir/ritonavir thereafter. The immunological response at month-12 was reported in six studies and the mean CD4 cell count increase was +118 cells/μL (min-max: 45–200 cells/μL). Conclusion: Overall, clinical and immuno-virologic outcomes in HIV-2 infected individuals treated with ART are suboptimal. There is a need of randomized controlled trials to improve the management and outcomes of people living with HIV-2 infection. Keywords: HIV-2, Clinical response, Immunological response, Virological response, Antiretroviral treatment Background Although human immunodeficiency virus type 1 (HIV-1) infection is responsible for most of the global AIDS pandemic, HIV type 2 (HIV-2) is not infrequent in West Africa and is an additional and important cause of burden of disease with a limited spread to other regions of the world [1-3]. Overall in West Africa, between 10 and 20% of HIV infections include HIV-2 with a significant proportion of dually infected or reactive HIV-1 + 2 individuals * Correspondence: 1 Programme PACCI, site ANRS, Abidjan, Côte d’Ivoire 2 ISPED, Centre INSERM U897-Epidémiologie-Biostatistique, Université Bordeaux, F-33000 Bordeaux, France Full list of author information is available at the end of the article [4,5]. Interestingly, the prevalence of HIV-2 infections seems to be declining in West Africa, although the reasons remain unclear [1,6-9]. Compared to HIV-1, HIV-2 infection is characterized by a longer clinical asymptomatic latency period [10], a slower T lymphocyte CD4 (CD4) depletion [11,12] and a lower plasma viral load (VL) [13,14]. Nevertheless, HIV-2 infection can lead to clinical AIDS [15,16] and death [17-19] and such patients may clearly benefit from antiretroviral therapy (ART). The 2013 World Health Organization (WHO) guidelines recommended the combined use of either three nucleoside reverse transcriptase inhibitors (NRTIs) or two NRTIs plus one protease inhibitor (PI) as the initial © 2014 Ekouevi et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ekouevi et al. BMC Infectious Diseases 2014, 14:461 http://www.biomedcentral.com/1471-2334/14/461 ART regimen for HIV-2 infection in a public health approach, [20]. These guidelines were based on observational studies with limited data. Their application could lead to the unavailability of effective second-line agents for HIV-2 infected patients in areas with limited access to ART, since phenotypic cross-resistance with PIs as well as NRTIs is a significant issue for HIV-2 [21-25]. No randomized clinical trial has assessed the efficacy of specific ART regimens in treatment-naïve HIV-2–infected patients [26,27]. However, observational cohort studies in developed countries [15,28,29] have reported different and generally poorer treatment responses in HIV-2 patients compared to HIV-1 patients. Similar results were reported in a larger cohort collaboration in West Africa [30]. Additionally, data from few cohort studies conducted in resource-limited settings, such as Senegal [23-25], Gambia [18,31-33], Cote-d’Ivoire [34] are focused generally on treatment outcomes or genotyping resistance mutation in HIV-2 infected patients. Data comparing different ARV regimens among HIV-2 patients are even scarcer. Only one European cohort study has reported better immunological and virological responses to ritonavir-boosted PI-containing ART in antiretroviral-naïve HIV-2–infected patients compared to three NRTIs [15]. Overall, there has been minimal evidence-based recommendation regarding the best use of ART for HIV-2 infection [20,33,35-37]. We initiated this systematic review on ART response among HIV-2 and HIV-1/HIV-2 dually infected patients, to describe the different ART options that have been used and the different outcomes of these treatments. Methods We conducted this systematic review according to the criteria set forth by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group [38]. Eligibility criteria All studies, without design, place or language restrictions, were considered if they met the following four selection criteria: 1) data on clinical response (death or worsening of WHO stage), 2) data on immunological or virological response or both, sorted by ART regimen, 3) at least five patients receiving each drug regimen, 4) an available abstract, an article or an oral poster presentation. We included retrospective and prospective studies that reported responses to ART among HIV-2 and HIV-1/HIV-2 dually infected patients whatever the first-line regimen received. We excluded the case series with less than five patients. We also excluded studies that only rep (...truncated)