By the end of 2023, an estimated 39.9 million individuals were living with HIV globally, of whom 30.7 million were receiving antiretroviral therapy (ART) (1). In China, 31 provinces reported 1,355,017 current people living with HIV(PLWH) by the end of 2024 (2). The ART coverage rate in China increased from 74.04% in 2016 to 92.9% in 2020, maintaining stability thereafter. ART effectively suppresses viral replication, reducing HIV viral load (VL) to undetectable levels and realizing the “U=U” principle (Undetectable = Uninfectious) (3). However, emerging evidence shows that persistent viral suppression is not achieved in all patients, leading to low level viraemia (LLV).

The US Department of Health and Human Services defines LLV as VL < 200 cp/mL (4); the Chinese AIDS Diagnosis and Treatment Guidelines (2024 Edition) specify VL of 50 ~ 200 cp/mL (5); while the World Health Organization and China’s National Free Antiviral Drug Treatment Manual (5th Edition) define it as VL between 50 and 1,000 cp/mL (6, 7). Evidence indicates that LLV among PLWH retains the potential for HIV transmission (8). LLV promotes drug resistance mutations, increasing the risk of virological failure (VF), and exacerbates immune activation and inflammatory responses, thereby elevating the risk of AIDS defining and non AIDS defining diseases (9–11). Compared to virologically suppressed PLWH, individuals with LLV exhibit a significantly elevated risk of all-cause mortality, warranting heightened attention to their disease management (12, 13).

China has made substantial progress in HIV/AIDS prevention and control, with both treatment coverage and viral suppression rates exceeding 90%, keeping the national epidemic at a low-prevalence level (14). However, the prevalence of LLV has risen gradually in recent years, surpassing 30% in certain provinces (15). This not only poses a significant threat to the survival of PLWH but also emerged as a critical gap hindering further improvements in the quality of China’s HIV/AIDS prevention and control efforts. Evidence serves as the cornerstone of clinical decision making, with high quality evidence providing invaluable references for researchers and clinicians (16). An integrated analysis of the prevalence and influencing factors of LLV among PLWH in China would facilitate the optimization of national HIV/AIDS prevention and control strategies and the standardized management of LLV. Accordingly, this study aims to synthesize existing clinical evidence via meta-analysis to characterize the current landscape of LLV among PLWH. The ultimate goal is to provide evidence-based support for the development of effective LLV intervention and prevention measures, as well as the formulation of personalized treatment regimens.

The “China AIDS Control and Prevention Plan (2024–2030)” aims to achieve the public health goal of ending AIDS by 2030 (37). While China has made substantial progress in AIDS prevention and control, persistent LLV poses risks of HIV transmission, VF, and drug resistance, challenging the realization of this goal. This systematic review synthesized data on LLV prevalence and associated factors among PLWH in China. Findings showed an overall LLV prevalence of 10.6%, with significant risk factors including baseline VL > 10⁵ cp/mL, baseline CD4 < 350 cells/μL, initiation of protease inhibitor (PI)-based regimens, treatment regimen changes, poor ART adherence, age ≥ 50 years, and ART initiation at ≥ 50 years. Homosexual transmission was identified as a protective factor.

Our study revealed an overall LLV prevalence of 10.6% among PLWH in China, which is lower than the global rate (13.81%) reported by Zhao et al., and consistent with the domestic prevalence (10.12%) documented in this article (38). However, this study was subject to some publication bias, potentially attributed to limited sample size of included studies, heterogeneity in patient demographics (e.g., baseline CD4 counts, ART regimens, follow up durations), variations in VL detection sensitivity, and diverse data sources. Following bias correction via the trim and fill method, the pooled LLV prevalence increased from 10.6 to 22.2%, suggesting the true prevalence among PLWH may be even higher. These findings indicate prior studies might have underestimated LLV risk, prompting clinicians to remain alert for virologic “pseudosuppression” while advocating for standardized LLV definitions and enhanced reporting of negative outcomes.

Subgroup analysis of LLV prevalence revealed that the incidence of Blip viraemia was significantly higher than pLLV among PLWH. Previous studies have confirmed that viral blips are closely associated with abnormal immune activation (39). For such patients, increasing the frequency of VL testing and closely monitoring intra-patient viral dynamics are recommended. Timely intervention should be implemented to prevent disease progression and exacerbation. Our analysis further revealed a higher prevalence of LLV in the 50 ~ 200 cp/mL VL range compared to 201 ~ 400 cp/mL and 401 ~ 1,000 cp/mL tiers. Zhang et al. demonstrated that LLV confers an increased risk of VF only when VL reaches ≥ 400 cp/mL (15). However, emerging evidence indicated that patients with 50 ~ 200 cp/mL VL still exhibited significantly higher risks of virological non-suppression and treatment failure compared to those with persistently undetectable VL (40, 41). The southern region exhibited a slightly higher prevalence than the northern region, indicating that the prevalence of LLV varies by region in China. Differences in regional economic levels, ART regimens, VL detection technologies, and detection frequencies all lead to variations in the prevalence rates (42). However, the impact of these factors on the prevalence rate varies among different studies, and it is necessary to analyze them specifically according to different circumstances. Kanapathipillai et al. found that high-income regions perform VL testing more frequently than middle and low-income regions (43). This allows earlier detection of LLV at lower thresholds, enabling timely treatment intervention or regimen adjustment, which may explain regional prevalence disparities. Future research priorities should include upgrading detection technologies, reducing sequencing costs, enhancing assay efficiency, adopting highly sensitive VL testing, and implementing routine VL monitoring to enable prompt LLV detection and early intervention.

Baseline CD4 level is strongly associated with LLV. CD4 + T cell counts correlate positively with immune function, such that patients with low baseline CD4 levels exhibit more severe immune damage. This enhances persistent viral replication and drug resistance development, promoting LLV emergence (44). Additionally, LLV is linked to decay of viral reservoirs established prior to ART. PLWH with extremely low baseline CD4 counts typically harbor larger HIV reservoirs with prolonged decay kinetics, thereby increasing LLV risk (45).

Our analysis showed that while LLV prevalence did not differ significantly among NNRTI, PI, and INSTI-based treatment regimens, PI-based regimens exhibited numerically higher LLV rates. Notably, PI-based regimen at initiation was identified as an independent risk factor for LLV among PLWH. This could be attributed to two plausible mechanisms: (1) patients on PI-based regimens often have poorer baseline health, or switch to second-line PI regimens due to first-line ART resistance or VF, which may predispose to LLV (46); (2) prior research suggests that PI-based ART is associated with larger peripheral blood HIV reservoir sizes compared to NNRTI regimens (47).

This study identified poor ART Adherence as the most significant predictor (OR = 3.019), consistent with findings by Zaçe et al. (48). Unfortunately, among the included studies, three primary articles refer to this influencing factor (21, 22, 28), but their definitions of “poor ART adherence” are inconsistent, precluding the extraction and integration of a unified definition. Consequently, this paper only conducts a preliminary analysis of the literature mentioning this factor, without more in-depth and precise exploration. PLWH poor compliance are strongly linked to LLV and subsequent VF, likely due to missed doses leading to subtherapeutic drug concentrations and incomplete viral suppression (49, 50). Adherence management represents a key intervention target for LLV, as it significantly improves virological suppression rates in this population (51). Strategies should include comprehensive analysis of adherence determinants, patient-centered communication to address barriers, and ART regimen optimization to enhance compliance and prevent LLV.

In contrast to findings from other studies, our research identified ART treatment regimen changes as a critical risk factor for LLV among PLWH. Wen et al. demonstrated that frequent regimen changes may reduce plasma concentrations of antiretroviral drugs to subtherapeutic levels, thereby compromising viral suppression and predisposing patients to LLV (28). It has been proposed that treatment regimen changes may be associated with poor medication adherence and suboptimal disease control—factors that confer a higher risk of LLV among PLWH (25). Inter-drug variability in ADME (absorption, distribution, metabolism, excretion) properties may lead to subtherapeutic drug levels following regimen shifts. Additionally, drug–drug interactions (DDI) between ART or with co-administered medications, drug-food interactions, and absorption issues may reduce drug concentrations, increasing the risk of LLV. Recommendations include considering pharmacological factors, with ART regimen optimization guided by resistance test results, patient adherence, regimen resistance barriers, HIV RNA levels, and other treatment history. This also should account for DDI, drug-food interactions, adverse events, pill burden, and dietary requirements (52, 53).

Notably, age ≥ 50 years and ART initiation age ≥ 50 years were identified as independent risk factors for LLV, which is consistent with previous findings. Older adults typically exhibit lower educational attainment and risk awareness, accompanied by insufficient medication adherence. Additionally, they tend to have a suboptimal immune response to treatment, ultimately contributing to adverse clinical outcomes (54). Further studies have demonstrated that in older population receiving ART, age-related impairments in protein homeostasis, dysregulated stress responses, cellular senescence, and chronic inflammation are more likely to interfere with in vivo drug activity, diminish therapeutic efficacy, and thereby increase susceptibility to LLV (55). Mechanistically, LLV primarily arises from HIV reservoirs harbored in immature T cells of infected individuals (56). A larger HIV reservoir size and delayed viral clearance are associated with a higher propensity for LLV induction. Consequently, patients who initiate ART at a later stage face an elevated risk of developing LLV (57). In conclusion, to reduce the incidence of LLV, early initiation of ART should be prioritized for PLWH. Moreover, increased frequency of VL monitoring is recommended for older population, enabling timely detection and management of LLV.

This study identified a baseline VL > 10⁵ cp/mL as a risk factor for LLV. VL is a key indicator for assessing the efficacy of ART, which functions by suppressing VL to undetectable levels through combination regimens—thereby delaying disease progression and extending survival. Baseline VL levels dictate the extent of immune reconstitution in AIDS patients post-ART; a high baseline VL (>10⁵ cp/mL) reflects severe immune dysfunction, rendering such patients more susceptible to LLV (58). Single-cell sequencing data reveal that 23.5% of CD4 + T cells in patients with high baseline VL harbor proviral DNA, with integration sites predominantly near oncogenes—potentiating reactivation of latent viruses, a critical mechanism underlying LLV (59, 60). Additionally, high baseline VL correlates with a larger HIV reservoir, which exhibits enhanced capacity for releasing detectable virus, thereby increasing treatment difficulty and LLV risk (61). Thus, for confirmed PLWH with high baseline VL, early initiation of ART is imperative to facilitate immune reconstitution, prevent the establishment of a large viral reservoir, and mitigate LLV risk.

Significantly, homosexual transmission was identified as a protective factor for LLV. This may be ascribed to the relatively active social organizations among MSM. These organizations facilitate earlier detection of HIV infection, timely access to ART, and consistent follow-up interventions (25). Furthermore, following ART initiation, the viral suppression rate in this population rises rapidly—an outcome that ultimately lowers their risk of developing LLV (62).

Our systematic review and meta-analysis demonstrate several strengths regarding representativeness. First, the included studies encompass 12 cities across both southern and northern China, covering both economically developed and underdeveloped regions, which largely captures the major cities with HIV-infected populations in China. Second, prior studies have demonstrated that in medical research, studies with a sample size < 200 tend to systematically overestimate effect sizes in meta-analyses (63). Given the typical sample sizes of observational and cross-sectional studies in HIV/AIDS research, studies with a sample size of less than 300 were excluded to minimize potential effect size bias and overall risk of bias. Notably, most of the included studies (n = 15) reported age and sex distribution data, which largely reflect the epidemiological characteristics of PLWH with LLV. Furthermore, among the 20 included studies, 18 adopted the LLV diagnostic criterion of 50 ~ 1,000 cp/mL, and two studies simultaneously employed both the 50 ~ 1,000 cp/mL and 50 ~ 200 cp/mL criteria, which enhanced the robustness of the conclusions.

However, there are also several limitations: (1) The limited number of included studies, potentially influenced by study design and inclusion/exclusion criteria, warrants future re-analysis with expanded inclusion of high quality research. (2) Most included studies did not report data on VL detection methods or testing frequencies. The absence of such information may introduce uncertainty into our results. Future studies should prioritize evaluating outcomes associated with different detection methods and frequencies, rather than relying solely on pooled analyses of heterogeneous data. (3) The included studies had different definitions for certain influencing factors (such as “poor ART adherence”), which made it impossible to conduct more precise and in-depth analyses. In the future, this issue should be given due attention, and efforts should be made to promote the standardization and unification of standards and definitions in the field of AIDS, so as to carry out clinical research of higher quality and higher standards. (4) Evidence of publication bias was detected, and despite subgroup analysis of LLV prevalence, significant heterogeneity persisted across study results. Thus, these findings should be interpreted with caution.

This study demonstrates that the prevalence of LLV among PLWH is moderate to low following active ART in China. However, the results exhibit substantial heterogeneity. After adjusting for publication bias, the estimated LLV prevalence increased, indicating that the LLV burden in China has been underestimated. Given the adverse clinical consequences of LLV, screening for LLV-related risk factors prior to ART initiation is warranted. Future research should prioritize prospective studies to standardize LLV management and monitoring protocols, as well as implement early interventions tailored to identified risk factors.