Association between nutritional status and the immune response in HIV + patients under HAART: protocol for a systematic review

Malnutrition is a persisting public health issue affecting over 850 million people worldwide and 200 million adults in Sub-Saharan Africa (SSA) [1, 2]. The term 'malnutrition’ is often used indifferently to refer both to undernutrition and overnutrition. In undernutrition, macro- and/or micronutrient supply are continuously below minimum dietary requirements, which leads to changes in body composition and diminished function [3, 4]. For the purpose of this systematic review, we will focus on undernutrition as a state of malnutrition.

Before the HIV epidemics, malnutrition was the first cause of immunosuppression worldwide [5]. Micro- and macronutrient deficiencies weaken the immune system through atrophy of the thymus and lymphoid tissue, alteration of T cell subsets, decrease of T cell counts and cytokine response [6, 7]. In protein energy malnutrition (PEM), cell-mediated and innate immunity [6, 8] are particularly lessened, thereby increasing the risk of viral infection (including HIV) and disease progression [9‐11]. Furthermore, persistent malnutrition leads to an inflammatory state through decreased leptin levels [12] and altered intestinal mucosa permeability which further augments the organism’s vulnerability to infection [5].

Countries where food insecurity and malnutrition are common are also stricken by high HIV incidence and prevalence rates [13, 14]. The effect of overlap between HIV infection and undernutrition in low- and middle-income countries (LMICs) on immunological function remains unclear [2, 14, 15]. HIV is a cause of nutritional deficiencies through its effect on nutrient absorption - for example, HIV-mediated inflammation and induced mucosal immune cell damage in the gastrointestinal tract leads to diarrhea and malabsorption, decreased intake - for example, odynophagia induced by esophageal candidiasis (an opportunistic infection (OI)) - limits the capacity to feed oneself. Finally, HIV itself or associated OI can result in increased energy expenditure [16‐18]. As such, malnutrition and HIV coexist in a vicious perpetuating cycle.

Increased availability of highly active antiretroviral therapy (HAART) in LMICs has led to some improvement of the nutritional status of patients [19‐22]. However, for certain individuals, undernutrition and weight loss persist despite therapy [17, 23, 24]. Just like with HIV, HAART and malnutrition contribute to a deadly cycle. Highly active antiretroviral therapy (HAART) leads to increased requirements for macro- and micronutrients, high metabolic demands [25] and low appetite [26] which perpetuate undernutrition [27]. Simultaneously, malnutrition exacerbates side effects [28‐31], alters drug pharmacokinetics [32], and impinges on adherence [33] thereby limiting the beneficial effects of the therapy. Like in ART-naive patients, suboptimal nutritional status amongst those treated is associated with disease progression and early death [34‐41]. As such, excess early mortality in patients initiating treatment in LMICs compared to high-income countries has been reported [42].

Despite theoretical and experimental evidence linking malnutrition and altered immune function, there exists no consensus concerning the impact of malnutrition on the immune response in HIV patients receiving tri-therapy. Numerous nutritional interventions have been attempted in seropositive populations under antiretroviral treatment (ART) without convincing clinical results. As such, a recent systematic review investigating nutritional interventions and clinical outcomes in high-, middle- and low-income countries failed to show any advantages in terms of CD4 or weight gain in those receiving food supplements [13]. In populations from LMICs, research has failed to demonstrate an association between lower CD4 counts and markers of undernutrition amongst newly diagnosed seropositive individuals compared to seronegative controls [43, 44]. In populations under combined antiretroviral treatment (cART), evidence so far appears contradictory. As underlined by Soeters (2008), a possible explanation for this absence of consensus could be the lack of homogeneity in the definition and conceptualization of malnutrition [4]. Various undernutrition syndromes have been grouped under the umbrella of malnutrition - protein-energy malnutrition (PEM), cachexia, sarcopenia, marasmus, kwashiorkor - each being the result of different pathophysiological processes and each leading to distinct morphological and biochemical modifications [4, 45]. Furthermore, there exists no unique indicator to capture malnutrition. As such, prevalence of malnutrition amongst HIV patients varies according to the instrument used [46]. In field studies, body composition is often evaluated using either body mass index (BMI), mid-upper arm circumference (MUAC), skinfolds (SK), or bioelectrical impedance (BIA); each method capturing a different aspect of body composition. The simplicity and cheapness of anthropometric techniques has made them popular in nutritional studies, independently of their appropriateness [47]. Some authors indicate that nutritional assessment should also include analysis of biochemical nutritional parameters such as albumin and C-reactive protein (CRP) to account for inflammation in the establishment and maintenance of malnutrition [4, 48].

Further evidence is required to clarify the association between nutritional status and immunological outcomes. For the purpose of this systematic review, we will use the operationalized definition of malnutrition proposed by Soeters (2008). In his model, Soeters attempts to regroup different pathophysiological explanations and consequences of malnutrition into one conceptual framework. This model feeds onto the different definitions that have been proposed to describe malnutrition. We will focus on the clinical assessment of body composition and inflammatory activity [4]. For the former, indicators investigated will include BMI, MUAC, SK, and BIA (as a measure of body cell mass (BCM)). As for the latter, markers investigated will include albumin, hemoglobin and C-reactive protein (CRP). These measures will be contrasted with one measure of function, namely the immune function. With this systematic review we hope to provide clarification concerning the cross-sectional and longitudinal associations between undernutrition and immune response in seropositive patients receiving ART in LMICs.

The guidelines proposed in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement will be used as a template for the development and execution of this review (Figure 1) [49]. The methodological choices described in this protocol have been inspired by previously published work from members of our group [50]. This systematic review protocol was registered with the PROSPERO database (registration number: CRD42014005961).

Although increased availability of first line HAART in LMICs has significantly reduced mortality and morbidity amongst people living with HIV/AIDS (PLA), undernutrition and weight loss persist [17, 23, 24]. Both act as strong predictors of excessive early mortality [35, 37, 40, 41]; possibly through poor immune reconstitution secondary to deficient nutritional status in PLA. With the rapid scale-up of ART programs, concerns have also been growing about the sustainability and effectiveness of such programs [14]. Currently, funds injected into HIV programs are diminishing and access to second line regimens in LMICs continues to be restricted. There is thus a growing need to optimize therapeutic success of first line ART, delay the need for therapeutic switch, and limit rates of resistance, which are on the rise, in those regions [66].

With this systematic review we hope to clarify the association between malnutrition and immunological response to HAART in HIV + population. More specifically, we wish to establish whether ART drug treatment is suboptimal in the undernourished. Our clinical goals are to: 1) facilitate the identification of patients at greater risk of inadequate immune response; and 2) help in differentiating between malnutrition in PLA and more advanced disease (that is greater inflammatory process). We believe our results will contribute to informing physicians and policy makers in settings where care strategies have to be optimized to limit therapeutic failure by shedding some light on the processes that contribute to suboptimal therapeutic response. We are aware that the studies we will uncover will present different limitations due to the complexity of the association of interest and the challenges associated with nutritional research in vulnerable groups. These limitations, as well as bias and precision of estimates, will be discussed in length in our review giving special attention to the possible publication bias of studies conducted in settings with limited resources and in non-English speaking populations by non-English speaking researchers. As suggested by the PRISMA statement, we wish this protocol to be part of an iterative process that respects accepted and transparent reporting methods [49].

MS is a MD/PhD candidate currently completing her dissertation on the subject of nutrition in HIV research at Montreal University.