Current situation of the pharmacogenetics of immune recovery in treated HIV-infected patients
2014; Future Medicine; Volume: 15; Issue: 5 Linguagem: Inglês
10.2217/pgs.14.1
ISSN1744-8042
AutoresFrancesc Vidal, Manuel Leal, José Alcamı́, Peré Domingo,
Tópico(s)Pneumocystis jirovecii pneumonia detection and treatment
ResumoPharmacogenomicsVol. 15, No. 5 EditorialFree AccessCurrent situation of the pharmacogenetics of immune recovery in treated HIV-infected patientsFrancesc Vidal, Manuel Leal, José Alcamí & Pere DomingoFrancesc Vidal* Author for correspondence: E-mail Address: fvidalmarsal.hj23.ics@gencat.catInfectious Diseases & HIV/AIDS Unit, Department of Internal Medicine, Hospital Universitari de Tarragona Joan XXIII, IISPV, Universitat Rovira i Virgili, Tarragona, Spain, Manuel LealLaboratorio de Inmunovirologia del VIH, UGC de Enfermedades Infecciosas, Microbiologia y Medicina Preventiva, Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocio/CSIC/Universidad de Sevilla, Spain, José AlcamíUnidad de Inmunopatologia del Sida, Centro Nacional de Microbiologia, Instituto de Salud Carlos III, Madrid, Spain & Pere DomingoHospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, SpainPublished Online:5 May 2014https://doi.org/10.2217/pgs.14.1AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: antiretroviral therapyHIVpharmacogeneticspoor immune recoveryClinical relevance of poor immune recovery in treated HIV-infected patientsHIV infection usually causes a progressive reduction in the number of circulating CD4+ T cells over time. CD4+ T-cell lymphocyte destruction is often profound enough to put a given patient at risk of developing opportunistic infections with a significant rate of morbidity and mortality [1]. One of the objectives of highly active antiretroviral therapy (HAART) is to reverse the CD4+ T-cell count reduction, increasing their numbers to a level that puts patients out of risk of opportunistic infections. While this is achieved in a substantial number of patients, up to 20% of infected subjects who successfully suppress plasma viremia to below the limit of detectability do not sufficiently gain CD4+ T cells [1]. Currently, there is special interest in patients who maintain a very low CD4+ T-cell count close to the threshold for the risk of acquisition of opportunistic infections (200 cells/µl) despite a long-term suppressive treatment. These patients, known as 'poor recoverers' [1,2], represent a major clinical problem since they have worse outcomes than those that experience good immune recovery when on HAART.Pharmacogenetic assessment of immune recovery in treated HIV-infected patients: rationale & studiesPharmacogenetics in the HIV treatment setting has had some important successes, in particular determining HLAB*5701 as a predictive factor of the hypersensitivity reaction caused by the use of abacavir [3]. Another pharmacogenetic assessment that has a clinical application is the association between IL28B genetic variants and the success of HCV treatment in both HCV mono-infected patients and in those HCV–HIV coinfected [4]. These two pharmacogenetic outcomes have moved from the research laboratory to the clinical area where current standard HIV care includes determining HLAB*5701 before prescribing abacavir and, in the HCV coinfected, assessing IL28B before anti-HCV treatment [5,6]. These two examples can serve as a model for investigating the effect of host genetic variants in several other clinical scenarios in HIV-infected patients, such as the degree of immune recovery.Mechanistically, immune recovery due to HAART might be linked to the functional enhancement of several components of the immune system, particularly those involved in CD4+ T-cell homeostasis, but it might also be related to the different activity of drug-metabolizing systems. There is a growing body of literature regarding the pharmacogenetics of CD4+ T-cell gain due to HAART in HIV-infected patients (reviewed in [7]). Most of the studies have been designed to investigate the effect of a single or a few gene variants on a given immune recovery phenotype or have assessed the effect of multiple genes (multigene models) [8,9]. The genome-wide association study (GWAS) approach has not yet been used with this objective. Most of the genes assessed have been investigated because of the biological plausibility of their encoded proteins, which might be involved in the pathophysiology of CD4+ T-cell loss and gain. Among these 'candidate genes' particular attention has been paid to chemokines and chemokine receptors, cytokines and cytokine receptors, members of the HLA system, apoptosis-related genes and genes encoding for antiretroviral drugs transporters and metabolizing enzymes.Regarding chemokine/chemokine receptors, despite some inconsistent data, genetic variants of CCR5 and some of its natural ligands have been linked to the degree of immune recovery. This pathway merits further investigation to evaluate its role as a possible therapeutic target [8–11], and this is highlighted by the potential role of the CCR5 antagonist for improving immune recovery in severely immunosuppressed patients. Variation in the CX3CR1 and in CCR2/CCL2 genes has also been associated with quantitative immune recovery in some studies, although their minor relevance as HIV coreceptors in vivo makes a significant role unlikely for polymorphisms in these genes in the natural history of infection and immune recovery following HAART. As far as cytokines are concerned, genetic variation within the IL7/IL7R axis might modulate the magnitude of the gains in CD4+ T cells. In fact, the therapeutic use of IL7 in poor recoverers is currently being explored. Some significant associations with genetic variation in other cytokines (IL2, IL6, IL10, IL15) have been reported, but the data arises from single studies and results need further replication [7,12–14]. Regarding apoptosis parameters and molecular changes in mitochondrial DNA, the little data available at present is inconsistent, and this therefore requires more investigation [7,15–17]. There is also scarce data regarding the HLA system, but it seems that genetic variation in class I HLA molecules might modulate the extent of immune recovery, and so this merits further investigation at the mechanistic level [7,18]. Finally, it has been suggested that there are several variants in genes that encode for proteins related to antiretroviral drug metabolism involved in HAART-induced CD4+ T-cell gains in HIV-infected patients. Data is, however, very inconsistent and further confirmation is needed in accurately designed studies [7,19,20].Critical analysis of the current situation of the pharmacogenetics assessment of immune recovery in treated HIV-infected patientsAvailable data suggest that immune recovery during antiretroviral therapy is a complex phenotype influenced by multiple genetic variants. Despite several inconsistencies, data in some studies show strong associations between CCR5/CCL3L1, genetic variants and immune recovery. The reported associations between CX3CR1, CCR2/CCL2, some interleukin (IL7/IL7R) and class I HLA polymorphisms and the amount of immune recovery are weaker. The mechanistic pathways linking these polymorphisms with immune recovery are largely unknown and require further research.Most of the studies conducted in the field have important weaknesses limiting the value of the findings reported, such as the design of the studies, the type of patients and cohorts assessed, the definitions of the immune recovery outcome, and the extent of the genetic assessment carried out. Regarding study design, most of the studies in the field are retrospective analyses of a prospectively collected cohort, or are simply retrospective. Very few investigations have actually been designed and conducted prospectively. Regarding the type of patients assessed, studies are extremely heterogenous and seriously biased because they include both naive patients who are starting their first HAART and patients who have been treated previously with suboptimal antiretroviral drug regimens and subsequently changed to a HAART scheme. Furthermore, the number of patients evaluated varies greatly between studies, from a few dozen to several hundreds. Consequently, several investigations are flawed due to the small number of patients assessed and many findings have not been replicated subsequently. This is especially true in investigations conducted on cohorts of mixed populations, which are particularly difficult to interpret, since associations reported in a particular ethnicity might not be reproduced in others and cannot be extrapolated with any confidence. With respect to outcome definitions, the categorization of the main end point of such studies, which is the amount of CD4+ T-cell gain after a given set-point from the beginning of HAART (or the speed to reach a given threshold of CD4+ T cells) is very heterogenous across the studies. This is not unexpected because of the lack of a standardized definition about what is considered 'poor recovery'. This limitation is a major problem, since it is unlikely that combined analyses or meta-analyses of the currently published data would improve our current knowledge. Finally, most of the studies reviewed have suffered from limited genetic scope, since only one or a few polymorphisms were evaluated. The findings of such 'candidate gene' studies are often not replicated. Further studies are warranted to improve the current body of knowledge of the impact of host genetics in the immune response in treated HIV-infected patients.New studies are necessary to minimize these limitations. An ideal study in this field would be prospective with a prolonged longitudinal follow-up, adequately powered in terms of the number of patients assessed, a clear definition of 'poor recovery' would be demarcated and, more importantly, the outcome defined for the assessment of the CD4+ T-cell gain would be clinically relevant. Regarding genetic evaluation, studies making a more ambitious effort at covering genetic variation more widely are particularly important. Efforts in the field of pharmacogenetics are increasingly moving towards capturing genetic variations of more than only a few genes. Thus, a multigene approach or, better, still a GWAS approach, would render clinically relevant conclusions [9,21]. Meanwhile, pharmacogenetic studies of the magnitude of immune recovery in treated HIV-infected patients remain within the research laboratory.Financial & competing interests disclosureThis work was partially financed by grants from the Fondo de Investigación Sanitaria (FIS PI05/1591; PI07/0976, PI10/2635, PI11/02512, PI12/0506, PI13/0796 and PI13/1912), Instituto de Salud Carlos III; Fondo Europeo para el Desarrollo Regional (FEDER); Ministerio de Sanidad Política Social e Igualdad (EC11–293); Red Investigación en Sida (RIS), Instituto de Salud Carlos III (ISCIII-RETIC RIS-IP01, RD12/0017/0005, RD12/0017/0014, RD12/0017/0015 and RD12/0017/0029); Fundación Progreso y Salud (PI-0081–2011); Pfizer/ViiV Healthcare (Grant numbers WS2425049, WS843413); Gilead Sciences; Programa de Suport als Grups i Xarxes de Recerca, Agència de Gestió d'Ajuts Universitaris i de la Recerca (2009SGR1061). 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Retrovirology9,70 (2012).Crossref, Medline, Google ScholarFiguresReferencesRelatedDetailsCited ByAIDS Clinical Research in Spain—Large HIV Population, Geniality of Doctors, and Missing Opportunities30 May 2018 | Viruses, Vol. 10, No. 6Precision medicine for HIV: where are we?Jessica Cusato, Sarah Allegra, Amedeo De Nicolò, Andrea Calcagno & Antonio D'Avolio5 December 2017 | Pharmacogenomics, Vol. 19, No. 2 Vol. 15, No. 5 Follow us on social media for the latest updates Metrics History Published online 5 May 2014 Published in print April 2014 Information© Future Medicine LtdKeywordsantiretroviral therapyHIVpharmacogeneticspoor immune recoveryFinancial & competing interests disclosureThis work was partially financed by grants from the Fondo de Investigación Sanitaria (FIS PI05/1591; PI07/0976, PI10/2635, PI11/02512, PI12/0506, PI13/0796 and PI13/1912), Instituto de Salud Carlos III; Fondo Europeo para el Desarrollo Regional (FEDER); Ministerio de Sanidad Política Social e Igualdad (EC11–293); Red Investigación en Sida (RIS), Instituto de Salud Carlos III (ISCIII-RETIC RIS-IP01, RD12/0017/0005, RD12/0017/0014, RD12/0017/0015 and RD12/0017/0029); Fundación Progreso y Salud (PI-0081–2011); Pfizer/ViiV Healthcare (Grant numbers WS2425049, WS843413); Gilead Sciences; Programa de Suport als Grups i Xarxes de Recerca, Agència de Gestió d'Ajuts Universitaris i de la Recerca (2009SGR1061). F Vidal (INT11/240 and INT12/282) and P Domingo (INT12/383 and INT13/232) were supported by a grant from the Programa de Intensificación de la Actividad Investigadora, Instituto de Salud Carlos III, Madrid, Spain. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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