Accurate assessment of the potential for CIR following ART is crucial for improving prognosis and guiding treatment decisions for PWH. This study aimed to develop and validate a prediction model to determine the likelihood of PWH achieving CIR at years 4, 5, and 6 after initiating ART. Participant data for model development were derived from initial routine laboratory tests performed post-HIV diagnosis, selected for their affordability, ease of collection, and broad applicability.
Direct comparison of our model with others is challenging due to differences in CIR definitions. In contrast to the findings of Zhang et al. [12], our CIR criteria were more stringent, defining the CIR as a CD4+ T cell count ≥ 500 cells/µL and a CD4/CD8 ratio ≥ 0.8, which has been proven to more accurately evaluate the extent of immune restoration in the "treat all" era [15]. Longitudinal research has suggested a gradual CIR process following ART, often exhibiting a prolonged plateau phase. Studies have indicated that total CD4+ T and CD8+ T cell turnover rates tend to stabilize after 12–36 months of ART and reach a plateau after 3–4 years of suppressive treatment [19, 20]. The Multicenter AIDS Cohort Study, which involved 314 PWH, revealed no increase in CD4+ T cell counts after 2–3 years of ART [21]. Similarly, the AIDS Clinical Trials Group (ACTG) study revealed that most changes in CD4+ T cell counts occur within the first year of ART, with no significant increases in the second or third year of therapy [22]. Based on these findings, our model was constructed using data from PWH who had undergone ART for a minimum of 3 years, aiming to forecast CIR at 4, 5, and 6 years post-ART initiation.
In this study, we identified several factors influencing the CIR, including age, diagnosis-treatment interval, marital status, infection route, baseline CD4+ T cell count, CD4/CD8 ratio, treatment regimen, and various hematological and biochemical parameters. The significance of baseline CD4+ T cell counts and the CD4/CD8 ratio in immune recovery has been extensively studied [15, 23–27]. For instance, among PWH with baseline CD4+ T cell counts of less than 50, 50–199, 200–349, and 350–499 cells/µL, the probabilities of achieving CD4+ T cell counts of 500 cells/µL or higher after ART vary considerably, ranging from 1.97%, 7.84%, 62.85%, and 71.07%, respectively [15]. Similarly, among PWH who started cART with less than 200 cells/µL, 57% did not reach 600 cells/µL after 7 years, while those with baseline counts of 200–349 CD4+ T cells/µL achieved this count in less than 2 years [23]. Previous studies have also demonstrated that the time required to achieve a 90% probability of CIR after two years of ART is significantly longer for PWH with a CD4/CD8 ratio less than 0.5 compared to those with a ratio greater than 0.5 [28]. These studies consistently demonstrated that higher baseline CD4+ T cell counts and CD4/CD8 ratioplay a crucial role in determining the rate and extent of immune recovery after ART, underscoring the importance of initiating ART at higher CD4+ T cell counts. Additionally, homosexual transmission and initial treatment regimens containing INSTIs were significantly associated with a lower rate of CIR. The impact of different infection routes on immune reconstitution is complex, with factors such as viral tropism, intestinal flora, and coreceptor switching linked to CIR in men who have sex with men (MSM) [29–31]. Research has indicated that only 60.5% of Chinese MSM have undergone HIV testing [32], which is attributed to limited awareness, social discrimination, and concealment of sexual orientation. Consequently, approximately 50% of Chinese MSM living with HIV are unaware of their serostatus, impacting timely diagnosis and access to treatment, which are crucial for effective immune reconstitution [32, 33].
In deciding on medication use, physicians consider various factors, including CD4+ T cell counts, virological efficacy, and drug tolerability. Preference is often given to more potent ART regimens when CD4+ T cell counts are low. In our cohort, participants who were initially prescribed INSTI-based regimens had average baseline CD4+ T cell counts of only 230 cells/µL. In contrast, those on NNRTI-based regimens had average baseline CD4+ T cell counts of 265 cells/µL, while those on PI-based regimens had average baseline CD4+ T cell counts of 320 cells/µL.
Regarding other influential factors, both a longer interval between HIV diagnosis and ART initiation and older age were associated with lower baseline CD4+ T cell counts. An extended interval between diagnosis and treatment can lead to increased HIV replication, more severe immune system damage, and an increased incidence of opportunistic infections. Previous studies have shown positive correlations between the length of the diagnosis-to-treatment interval and the progression of AIDS and mortality [34]. Additionally, older age may be associated with thymic atrophy, abnormal immune activation, and immunosenescence, all of which can accelerate HIV/AIDS progression and are closely associated with IIR [35–37]. Moreover, older PWH tend to receive a diagnosis at a later stage than younger individuals, further hindering immune recovery [38].
This study also revealed associations between immune reconstitution and various hematological and blood biochemical parameters, including HGB, Crea, PLT, Glu, ALT, and AST. Previous research has demonstrated that PWH with suboptimal CD4+ T cell recovery often have elevated platelet counts [39]. This could be attributed to the ability of platelets to directly interact with HIV, facilitating viral binding and entry into cells, with platelets further acting as a reservoir for the virus during chronic infection. In addition, platelet-CD4+ T cell aggregates display increased levels of activation, depletion, and apoptotic markers, suggesting a potential role for platelets in CD4+ T cell depletion [40]. However, further research is needed to clarify the relationships between the CIR and other blood biochemical parameters.
Given the complexity and importance of immune reconstitution, various studies have examined adjuvant therapeutic strategies to enhance CIR, including interleukin 2 (IL-2), methotrexate, statins, metformin, and other immunomodulators [41–43]. Furthermore, various immunotherapeutic approaches, such as broadly neutralizing antibodies, stem cell transplants, and therapeutic vaccines, are currently under investigation [44–46]. Recent clinical trials have shown the potential of (5R)-5-hydroxytriptolide to promote CD4+ T cell recovery and reduce inflammation in PWH, suggesting that this is a new approach for the treatment of IIR [47]. Despite these developments, many current clinical trials and research initiatives have yet to achieve success, spurring ongoing efforts to develop more efficient immunomodulators and therapeutic strategies.
Our study is distinguished by a relatively large sample size (N = 5 408) and extended follow-up period, with 85.11% of participants monitored for more than 5 years. However, several limitations should be considered. First, the retrospective nature of the study inherently limited the scope of the analysis and may have introduced biases. Furthermore, as the study was conducted at a single center without external validation, the generalizability of the findings may be limited. Therefore, caution should be exercised when extrapolating the results to other populations or regions. Second, the study primarily focused on PWH examination results at baseline and at the most recent follow-up. The predictors were derived from the initial test results following diagnosis, while the outcome indicators were based on the most recent test results. It is important to note that all immunological, virological, blood biochemical, and relevant indicators of routine laboratory tests in PWH change over time. Our study did not consider these dynamic changes during ART, which are crucial for a comprehensive understanding of the CIR, potentially leading to inaccurate estimations of the true risk of IIR in PWH. Finally, the absence of data on baseline viral load, viral load rebound, comorbidities, coinfections, treatment adherence, drug resistance, adverse effects, and changes in ART regimens for most participants is a significant limitation, as these factors could differentially impact the CIR but were not considered in our analysis.
Recent advances in medical research have deepened our understanding of HIV and the human immune system. Novel indicators, such as the percentage of naïve CD4+ T cells prior to ART in PWH, the ratio of naïve/effective memory CD4+ T cells [48], and the activity of the immunomodulatory kynurenine pathway in tryptophan catabolism, have emerged. These metrics show promise in predicting the normalization of CD4+ T cell counts. Although the current evidence remains inconclusive, these findings offer new possibilities for diagnosis and prediction. Additionally, advancements in artificial intelligence and machine learning are expected to yield new models and algorithms that can adapt to the dynamic shifts in PWH metrics, aiding healthcare professionals in making more informed decisions and improving longevity and quality of life for PWH.