Antiretroviral therapy (ART) transformed the course of HIV infection, improving patient prognosis, quality of life and life expectancy.1,2 After ART initiation, plasma viral load drops to undetectable levels in individuals with good adherence and without resistance-associated mutations,3 and CD4+ T-cell count increases rapidly initially, followed by a longer period of slower rise.4 Some authors describe a CD4+ T-cell count plateau, whereas others report increases even after several years of therapy, depending on different factors such as age, pre-ART CD4+ T-cell count, and viral load.5–8 However, some individuals are unable to restore satisfactory CD4+ T-cell counts despite full virologic suppression (usually defined as <50 copies/mL),9,10 and have higher mortality and morbidity.4,11 The proportion of individuals with unsatisfactory immunological recovery despite viral suppression has been reported to be between 9% and 45% depending on the cohorts and criteria used. However, the diversity of the criteria renders estimates on prevalence problematic.
In the absence of consensual criteria, it is difficult to compare and combine coherent and solid results from different research groups. In clinical trials aiming to improve CD4+ T-cell recovery,12–21 variability in selection criteria precludes definitive conclusions.22 Although difficult to achieve, a consensual definition is mandatory to compare and combine data from distinct studies/cohorts.
We here analyze the diversity in terminologies and criteria applied to people living with HIV (PLWH) with full virologic response to ART but impaired immune recovery, and establish the relative frequency of terms and criteria used. We discuss the terms and criteria used and suggest possibilities for a consensual definition, aiming to establish grounds for further discussions to reach consensus. For convenience, we use the term “immunological nonresponse” (INR), as it was the most frequently used term on the included studies.
This systematic review was conducted according to PRISMA practice standards. The manuscript follows PRISMA and MOOSE checklists,23,24 adapted as needed. The review protocol was not registered in PROSPERO, because a review of definitions, rather than outcomes, does not fit the database format.
Records were retrieved from PubMed, using a search strategy that combined MeSH terms and common expressions used to describe PLWH with impaired immune recovery despite virologic suppression during ART (available in the Supplementary Material). After abstract and title screening, all studies or reports that used the concept of INR, published in English between January 2009 and September 2018, were included, unless they addressed pediatric or pregnant women populations.
A single representative term for INR was selected from each publication. Terms used in the different publications were then compared and summarized in a table. We also summarized the criteria to define INR used in the different studies. These included at least one immune recovery surrogate and at least one threshold value for that surrogate. Criteria were considered combined when including more than one surrogate or more than one threshold value, simultaneously or alternatively. Time points to assess INR status were expressed in time after ART initiation or in time of virologic suppression, in weeks, months, or years. To simplify comparison, we converted all timepoints to months. Records were then grouped by similar criteria, and 2 tables listing single and combined criteria were produced. In these tables, 2 types of frequencies were included for each criterion: n = absolute frequency, and ni = frequency considering only independent publications (ie, with no authors in common).
Procedures used for record search, screening, and data analysis are described in detail in the Supplementary Material.
On October 26, 2018, the PubMed search yielded 1360 documents sourced from 345 journals. Fifteen additional documents were included based on expert recommendations. Two independent reviewers screened titles and abstracts of the 1375 documents and excluded 1251 that were beyond the scope of this review. Twenty-one additional documents were excluded after full-text assessment because of: absence of virologic suppression (n = 6); severe lack of information (n = 2); and definition criteria not explicit (n = 12). Final analyses of INR definition included 103 publications (Fig. 1 and see Table S1, Supplemental Digital Content, http://links.lww.com/QAI/B373).
The 103 included studies were published in 41 peer reviewed journals, mainly in the scope of Immunology, Infectious Diseases, and/or Virology (Scopus sub-subject areas) (see Table S2, Supplemental Digital Content, http://links.lww.com/QAI/B373). Most studies (78%) were in journals ranked Q1 by CiteScore in at least one of their attributed sub-subjects in 2017.
Studies were evenly distributed across the years (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/B373). Nine studies focused exclusively on men (n = 8; 8%) or women (n = 1; 1%). All other studies (n = 94; 91%) included participants of both sexes, with a male percentage between 24% and 97% (median 79%, interquartile range 19%).
Seven studies (7%) corresponded to international projects, including large collaborations/consortia (see Table S3, Supplemental Digital Content, http://links.lww.com/QAI/B373). The other 96 studies (93%) enrolled participants from 30 different countries. These were mostly (n = 25; 83%) upper -middle- and high-income countries according to the 2017 World Bank classification (see Tables S4 and S5, Supplemental Digital Content, http://links.lww.com/QAI/B373). Studies from upper-middle- and high-income countries had higher percentage of males than studies from low and lower-middle income countries (see Figure S2, Supplemental Digital Content, http://links.lww.com/QAI/B373).
All terms applied to INR in the 103 publications presented 2 elements: (1) an adjective (eg, “discordant,” “inadequate,” “immunological,” “impaired,” “poor,” or “suboptimal”) and (2) a noun to describe the alterations in immunologic state of PLWH during ART (eg, “reconstitution,” “recovery,” “response,” or “restoration”). Terms that included “CD4” (eg, “CD4 T cell-recovery,” and “CD4 T cell repopulation”) were separated from the terms that used a less specific expression (eg, “immune reconstitution,” and “immunological response”). Terms with common adjectives or nouns were then grouped, resulting in 22 different categories (Table 1). When all orthographic variations and synonyms were considered, more than 50 different expressions were obtained. Considering only the set of 22 categorical terms (T.), the 3 more frequent were: “immunological non-responders” (n = 24, T.6 in Table 1); “discordant immunological response” (n = 18, T.3 in Table 1), and “suboptimal CD4+ T-cell recovery” (n = 9, T.20 in Table 1).
To understand whether the same authors contributed with multiple instances of the same term, the frequency of each term in publications with no authors in common was also analyzed (ni in Table 1). In this case, the most frequent expressions were still “immunological non-responders” (ni = 15, T.6 in Table 1) and “discordant immunological response” (ni = 9, T.3 in Table 1), followed by “suboptimal CD4+ T-cell recovery” and “poor CD4+ T cell recovery” (both with ni = 7, T.18 and T.20 in Table 1, respectively). As expected, publications with authors in common tended to share similar terms. In a few cases, publications with authors in common used different terms (eg, “immunological non-responders,” “low CD4 T-cell reconstitution,” and “poor CD4+ cell recovery” in Refs. 13,25,26).
The 103 studies included 73 different criteria to classify INR individuals. Of these, 48 (66%) were single criteria, defined as not reaching a single threshold of a single surrogate, and 25 (34%) were combined criteria, defined as multiple conditions considered simultaneously (AND) or alternatively (OR). All criteria used CD4+ T-cell counts to evaluate immune recovery during ART, either as absolute number, in 59 of the 73 criteria (81%; C.1-C.35 in Table 2, and C.49-C.68 and C.70-C.73 in Table 3), or as the change in CD4+ T-cell count compared with a baseline value, in the remaining 14 criteria (19%; C.36-C.48 in Table 2 and C.69 in Table 3). Of the 59 criteria that used absolute CD4+ T-cell counts as surrogate of the immune recovery, 38 (64%) were single criteria. In the other 21 (36%), the absolute CD4+ T-cell count was combined with CD4+ T-cell count change, and/or CD4/CD8 ratio.
Fifty-eight criteria were unique, and only 15 were used in more than one study. Of these, only 9 were used by groups with no authors in common (C.9, C.10, C.20-C.23, C.33, C.45, and C.61 in Tables 2 and 3). The 3 most used criteria considered CD4+ T-cell counts <350 cells/µL after ≥24 months of virologic suppression (n = 8, C.22 in Table 2); <250 cells/µL after ≥24 months of virologic suppression (n = 5, C.12 in Table 2); and <350 cells/µL after ≥24 months of ART (n = 4, C.21 in Table 2).
The most frequently used thresholds were “<350 cells/µL” (n = 35) and “<200 cells/µL” (n = 22), evaluated “at or after at least 12 months” (n = 36) of ART or virologic suppression and “at or after at least 24 months” (n = 35) of ART or virologic suppression.
Terms standardization is as old as human language, and assumes particular relevance in the context of scientific communication.27 In 1986, to avoid the multiplicity of names used for the “AIDS virus” (Human T-lymphotropic virus III (HTLV-III); lymphadenopathy-associated virus; immunodeficiency-associated virus; and AIDS associated retrovirus), the International Committee for the Taxonomy of Viruses recommended the use of the term “human immunodeficiency virus” and of the abbreviation “HIV.”28 This consensus was essential to expand scientific knowledge on HIV.
PLWH on ART who experience unsatisfactory immune recovery despite full virologic suppression have higher morbidity and mortality,9 but the data on these individuals are difficult to combine because of the lack of a standardized case definition.11,22 Although previous reviews mentioned or discussed this problem,22,29,30 or addressed clinical outcomes,11 this is the first to systematically analyze INR terminology and defining criteria.
Our results show striking diversity in terms and definitions used in the literature. This diversity may be even higher because some publications included several different expressions used interchangeably throughout the text, from which we analyzed only the most representative. The meaning of each term found in this review may generate different interpretations. Furthermore, some abbreviations are commonly used with a different meaning in the clinical context (e.g., “INR” for “international normalized ratio”). These problems are discussed in detail in the supplementary material (see Table S6, Supplemental Digital Content, http://links.lww.com/QAI/B373).
Seventy-three different criteria to define INR were found. Most studies (81%) used CD4+ T-cell counts and only 19% used the change compared with baseline. In a review article, Cenderello and De Maria22 have explained the limitations of each situation, which are related to grouping together different recovery patterns. The use of CD4+ T-cell count threshold to define INR pools together individuals who started with different values (eg, <100 and 200–350 cells/µL), but achieved the same CD4+ T-cell counts at a determined time point, although they present different CD4+ T-cell count trajectories. But the use of CD4+ T-cell count change groups individuals who started with different CD4+ T-cell counts, although they present different immune recovery dynamics.
Regarding the 3 most frequent criteria, 2 used a threshold of 350 cells/µL, and 2 used the time point ≥24 months of virologic suppression. Theoretically, lower thresholds and distant time points are more restrictive, and tend to narrow the concept of INR. For example, fewer PLWH are expected to have “CD4+ T-cell count <250 cells/µL after ≥12 months of ART” than those with “CD4+ T-cell count <350 cells/µL after ≥12 months of ART” or “CD4+ T-cell count <250 cells/µL after ≥6 months of ART.” However, all these criteria identify groups with a presumable higher risk of morbidity and mortality when compared with groups with higher CD4+ T cell-counts at the same time point.11 Earlier time points are less restrictive and may lead to include PLWH with slower immune response, who may reach normal CD4+ T-cell counts after a longer period. This may lead to spend resources in PLWH with better prognosis (compared with those with more restrictive INR criteria), and to biased conclusions in clinical trials (eg, underestimating INR impact in the clinical outcome; no benefit of closer follow-up, treatment intensification, or new therapeutic strategies in INR compared with controls). Nonetheless, earlier time points allow earlier and more impactful interventions.
To define a standard criterion, one needs to first discuss how restrictive it must be to represent the true clinical outcome of these individuals. A standard definition should also clearly state whether the time point is considered from the beginning of ART or of virologic suppression, and in the latter, how virologic suppression should be assessed. “Persistent virologic suppression” is a subjective expression because of the occurrence of blips. A good example of a clear virologic suppression definition, from Pacheco et al,31 is “all viral load measurements during this period (first 2 years of ART) <500 copies/mL, allowing for exceptions during the first 24 weeks,” although the threshold should be <50 instead of <500 copies/mL and viral blips should also be contemplated.
Pre-ART CD4+ T-cell counts influence the immune recovery pattern, and the lower the values at baseline, the more difficult it is to reach the threshold. Moreover, isolated CD4+ T-cell count measurements may not reflect the immune recovery pattern, because many factors, such as co-existing infections, influence the absolute CD4+ T-cell count at a given time point. Thus, a standard definition should also include the conditions under which PLWH meet or fail the criteria.
Other parameters may also be useful to classify ART response based on the immune recovery. Cenderello and De Maria22 suggested including age, nadir CD4+ T-cell count, CD4/CD8 ratio, and presence of AIDS-defining and non-AIDS-defining events in the classification of ART response based on the immune recovery. ART status (naive vs. experienced), baseline viral load, and other immunologic parameters could also have prognostic value.32–35 INR individuals could benefit from a prognostic index including these and/or other parameters, similar to the International Prognostic Index for patients with aggressive non-Hodgkin lymphoma.36
Although CD4+ T-cell count change over the first few months is important for PLWH initiating ART, absolute counts are more relevant for PLWH on ART for many years, because the increase in CD4+ T-cell counts is expected to be higher in the first months than after 24 months of ART.4 Individuals with low CD4+ T-cell counts at diagnosis, with or without opportunistic infections, are more likely to develop INR over time. Although some of these individuals may be able to normalize their immune system during ART, lower initial increases in CD4+ T cell-counts presumably preclude recovery to normal levels. Taking this into consideration, we propose 2 criteria to be applied to PLWH with CD4+ T-cell counts below a specific cut-off (eg, <200 cells/µL) at ART initiation, identifying different INR stages: (1) a CD4+ T-cell count change <50 cells/µL assessed at a relatively early time point (eg, 6 months of ART) identifies individuals at high risk of developing INR over time; and (2) an absolute CD4+ T-cell count <350 cells/µL after an extended period on ART (eg, ≥24 months of ART) identifies INR individuals whose CD4+ T-cell counts should have already reached their maximum potential and remain below the expected values. These definitions should be validated in large studies.
One strength of this review is the transparent and comprehensive search strategy, encompassing a large set of terms. As limitations, the publication search was restricted to one search engine, and a set of search terms had to be defined a priori, so the existence of other terminologies cannot be excluded. However, the latter limitation was partially overcome by the broadness of the search strategy. Records published before 2009 were not considered because they may include terms and criteria that have fallen into disuse. Although a structured quality analysis of the included studies is not described, the fact that most studies were published in journals ranked Q1 by CiteScore assures, at least in part, the study quality. Future research should also include analysis of nadir CD4+ T-cell counts, ART schemes, and clinical outcomes. In addition, 2 important gaps identified in this review should also be addressed: most studies report data from upper-middle- and high-income countries, as also observed by Kelly et al11; and samples from upper-middle- and high-income countries include more males than samples from low and lower-middle income countries, thus introducing gender differences when comparing these 2 settings.
A standard term and consensual defining criteria for INR that are supported by the HIV clinical and research community are urgently needed.11,22,27,32 To achieve those, we suggest a similar process as the one undertaken by the Sedentary Behavior Research Network for standardization of the terminology and definitions related to sedentary behaviors.37 The process consisted of a literature review by an expert committee to identify and modify key terms; then, Sedentary Behavior Research Network members provided feedback on the proposed terms and draft definitions through an online survey, ultimately leading to consensual definitions, including caveats and examples. To follow this example, the main HIV international associations could join efforts to nominate a committee of experts or working group to propose a consensual INR term and definition criteria. The participation and feedback of professionals and researchers in the field would favor the wide support and adoption of the proposed term and definition. After adoption of a consensual term and criteria, clinical outcomes of INR individuals could be assessed by determining the risk of mortality, AIDS or serious non-AIDS events. Sex differences, age, and other confounding variables should be analyzed by subgroup analysis in large prospective studies.
This review raises awareness on the diversity of terminologies and criteria for INR found in the literature, and may serve as a basis for decision-makers, researchers, and clinicians to discuss this problem. Standardization of INR terminology and criteria could lead to new interventions, policies, and practices to improve prognosis of PLWH.
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