Factors associated with immunological non-response in HIV patients receiving antiretroviral therapy in Southeast Asia: A systematic review

Abstract

Objective

This systematic review summarizes factors associated with immunological non-response (INR) among people with HIV on antiretroviral therapy (ART) in Southeast Asia.

Methods

We conducted a systematic search of PubMed, ScienceDirect, DOAJ, and Lens.org for studies published between 2010 and 2025. Observational studies examining immunological outcomes following ART initiation and related factors were included. Study quality was assessed using the Newcastle–Ottawa Scale, and results were synthesized using a harvest plot.

Result

Ten eligible studies were included in the synthesis, comprising a total of 6,988 participants with substantial heterogeneity observed across studies. Factors associated with INR included age, sex, baseline CD4 cell count, HIV RNA levels, and co-infections. Among these factors, baseline CD4 cell count at the initiation of ART emerged as the most consistently associated determinant; lower baseline CD4 levels were linked to a higher risk of INR even with virological suppression.

Conclusion

This review highlights baseline immunological status at ART initiation as a key predictor of immunological non-response in Southeast Asia. These findings underscore the critical importance of early HIV diagnosis and timely initiation of ART to prevent advanced immune damage and optimize immunological recovery.

Keywords

HIV immunological non-response immune reconstitution antiretroviral therapy southeast asia

Introduction

Antiretroviral therapy (ART) effectively suppresses HIV replication, increases CD4 cell count, improves immune function, and reduces HIV-related morbidity and mortality. However, not all patients achieve an optimal immunological recovery.^1,2 Approximately 10–45% of people living with HIV (PLWH) on effective ART fail to attain adequate immune reconstitution, even with successful viral suppression.^1,3–7 This condition is referred to as immunological non-response (INR).^2,3,6,8,9

In general, INR refers to a persistently low CD4 cell count after a certain duration of ART, although the specific time frame and thresholds vary across studies.² The World Health Organization (WHO) defines INR in adults as a CD4 cell count ≤250 cells/mm³ following prior clinical failure, or a persistently low CD4 cell count below 100 cells/mm³ after six months of ART.¹⁰ The reported prevalence of INR in Southeast Asia varies across studies, reflecting differences in study populations and definitions used.^11–13

The mechanisms underlying INR are multifactorial and involve impaired CD4 cell production, increased immune activation and cell destruction, and dysregulation of immune homeostasis. Additional factors, including residual viral replication and host-related characteristics, may further contribute to inadequate immune recovery despite effective ART.^3,8,14–19 Several demographic, clinical, and virological factors have been associated with INR, including age, sex, baseline CD4 cell count, co-infections, and treatment-related factors such as ART regimen and adherence.^{1,3,5–9,18,20–23}

INR reflects impaired immune function and is associated to higher morbidity and mortality compared with individuals who achieve adequate immune recovery. Its clinical consequences extend beyond AIDS-related conditions and include cardiovascular disease, osteoporosis, bone fractures, liver disease, and malignancies.^1,2,4

Although several factors associated with INR have been reported globally, evidence from Southeast Asia remains relatively limited and fragmented. The region is characterized by diverse healthcare systems, varying levels of access to antiretroviral therapy, and inconsistent availability of immunological and virological monitoring.^24–26 Furthermore, studies from Southeast Asia are often underrepresented in global syntheses, making it difficult to draw region-specific conclusions. Therefore, a focused synthesis of evidence from this region is warranted to better inform clinical practice and policy in similar settings.

Methods

Search strategy

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines,²⁷ and the Synthesis Without Meta-analysis (SWiM) reporting guideline.²⁸ The review was not prospectively registered; however, a preliminary protocol was developed prior to the literature search and is available upon request. To ensure originality, we searched the International Prospective Register of Systematic Reviews (PROSPERO) and confirmed that no similar review had been registered. A comprehensive literature search was performed across four electronic databases—PubMed, ScienceDirect, DOAJ, and Lens. org—to identify studies examining factors associated with INR among people living with HIV receiving antiretroviral therapy.

We developed the search strategy for PubMed using a combination of Medical Subject Headings (MeSH) terms and free-text keywords related to “HIV,” “antiretroviral therapy,” “immunological non-response,” and “Southeast Asia.” Searches in Lens.org were conducted using free-text keywords combined with Boolean operators. Databases with limited Boolean search functionality, such as ScienceDirect and DOAJ, were search using a concept-based approach. We used core relevant keywords and repeated searches to ensure comprehensive coverage. The search was restricted to articles published between 2010 and 2025. In addition, we manually screened the reference lists of eligible studies to identify publications that may not have been captured in database searches.

Selection criteria

This systematic review included all observational study designs, including cohort, case–control, and cross-sectional studies. Interventional studies, clinical trials, case reports, systematic reviews, and meta-analyses were excluded. The search was limited to articles published in English-language, peer-reviewed journals due to resource constraints, which may have resulted in the exclusion of relevant regional literature indexed in local databases.

INR was defined as the primary outcome of this review. No universally accepted consensus on the definition of INR among people living with HIV currently exists. Therefore, this review included all studies that classified immune outcomes as successful or failed according to their study-specific criteria. Studies that did not explicitly define immune response categories, but reported CD4 recovery trajectories and related influencing factors were included as indirect evidence of INR. Secondary outcomes comprised factors reported to be associated with INR.

Data extraction and quality appraisal

All studies meeting the initial eligibility criteria were independently screened by two reviewers through title and abstract assessment. Subsequently, full-text articles were reviewed to determine final inclusion in the systematic review. Extracted data included year of publication, first author, study location, study design, population characteristics, duration of follow-up, sample size, number of INR cases, and reported effect size estimates for each investigated factor.

The methodological quality of included studies was independently assessed by two reviewers using the Newcastle–Ottawa Scale (NOS). This scale evaluates three main domains: selection (0–4 points), comparability (0–2 points), and outcome (0–3 points), with a maximum of 9 points. Studies with higher NOS scores were considered to have better methodological quality.^29,30 Any discrepancies between reviewers were resolved through discussion until consensus was achieved. The certainty of the synthesis findings was considered qualitatively based on study quality, consistency of results, and methodological limitations.

Data synthesis

Given substantial heterogeneity across studies in operational definitions of INR, follow-up duration, analytical methods, and data availability, quantitative synthesis via meta-analysis was not performed. Therefore, factors reported to be associated with INR were synthesized narratively using a vote-counting approach based on the direction of effect.^28,31

When sufficient data were available, the direction of association between each factor and the outcome was classified as “increased risk,” “reduced risk,” or “no association.” These labels indicated whether a factor was associated with a higher or lower likelihood, or with no statistically meaningful relationship with INR.

Findings from individual studies were visually summarized using harvest plots and direction of effect plots (provided in the supporting information), which illustrate the direction and strength of evidence by study size and methodological quality.^32,33 The direction of effect was primarily determined based on results from multivariable analyses and by descriptive analyses demonstrating consistency in the direction of associations over the follow-up period.

Results

Flow diagram

The literature search across four electronic databases identified 1,258 records. After the removal of duplicates and screening for eligibility, ten studies met the inclusion criteria and were included in the final systematic review (Figure 1).

Figure 1.

Flow diagram.

Characteristics of included studies

Among the ten included studies, three were conducted in Thailand and two in Indonesia, while the remaining studies originated from Laos, Cambodia, Malaysia, Vietnam, and the Philippines. All studies used a retrospective cohort design and included a total of 6,988 participants. (Table 1).

Table 1.

Characteristics of included studies.

Author(s)	Pub. year	Country	Study design	Characteristics of study population	Sample size	INR defitinions	NOS
Tanuma et al.	2017	Vietnam	Retrospective cohort	≥18 years	1013	Increase CD4 cell count <100 cells/mm³ at 24 months	7
Han et al.	2020	Thailand	Retrospective cohort	ART naïve; ≥18 years	375	CD4 cell count <200 cells/mm³ for 3 years with HIV RNA levels 400 copies/mL	8
Limmade et al.	2019	Indonesia	Retrospective cohort	ART naïve; ≥18 years; not pregnant	105	CD4 cell count <200 cells/mm³ at 6/12/36 motnhs	7
Vaswani et al.	2022	Philippine	Retrospective cohort	≥18 years; not pregnant	302	CD4 cell count <200 cells/mm³ after 6 month	7
Chow et al.	2015	Malaysia	Retrospective cohort	Adult; ART naïve	103	CD4 cell count <350 cells/mm³ after ± 34 month	8
Khienprasit et al.	2011	Thailand	Retrospective cohort	≥15; ART naïve	535	CD4 cell count <350 cells/mm³ despite HIV-1 RNA <50 copies/mL after ≥ 2years	7
Rachman et al.	2025	Indonesia	Retrospective cohort	≥18 years; not pregnant	382	CD4 cell count < 350 cells/mm³ despite HIV-1 RNA <50 copies/mL after 2 years	8
Griensven et al.	2014	Cambodia	Retrospective cohort	Adult; ART naïve	3089	Longitudinal CD4 recovery	8
Bastard et al.	2013	Laos	Retrospective cohort	≥16 years; ART naïve; not pregnant	913	Longitudinal CD4 recovery	7
Than et al.	2012	Thailand	Retrospective cohort	HCV (+) & HCV (-) HIV patients	171	Longitudinal CD4 recovery	7

Prevalence of immunological non-response

The definitions of INR varied across the included studies, with CD4 cell count cut-offs ranging from <100 cells/mm³, <200 cells/mm³, and <350 cells/mm³. The timing of immunological assessment following ART initiation also differed considerably, spanning from 6 to 36 months. As a result, reported INR prevalence estimates showed substantial heterogeneity, ranging from 7.7% to 52.3%, as summarized in Table 2. A detailed summary of the definitions used across studies is provided in supporting information.

Table 2.

Prevalence of INR among included studies.

Author (s)	Cutoff CD4	Observation period (months)	INR (%)
Tanuma et al.	<100 cells/mm³	24	167 (16.5)
Han et al.	<200 cells/mm³	36	29 (7.7)
Limmade et al.	<200 cells/mm³	6/12/36	51 (48.6)
Vaswani et al.	<200 cells/mm³	6	104 (34.4)
Chow et al.	<350 cells/mm³	± 34	42 (40.8)
Khienprasit et al.	<350 cells/mm³	24	179 (33.5)
Rachman et al.	<350 cells/mm³	24	200 (52.3)

Factors associated with immunological non-response

The harvest plot revealed varying levels of consistency in the evidence regarding factors associated with INR among people living with HIV receiving ART in Southeast Asia (Figure 2). Among all evaluated factors, a low baseline CD4 cell count emerged as the most consistent determinant of increased INR risk (Table 3). All studies assessing this factor (n = 6) reported a positive association between lower CD4 cell count at ART initiation and the occurrence of INR, with no studies demonstrating a null or protective effect.

Figure 2.

Harvest plot factors associated with immunological non-response.

Table 3.

Main finding: Factors associated with immunological non-response.

Author (s)	Main findings
Tanuma et al.	Male and HCV antibody positivity were associated with a higher likelihood of impaired early immune recovery. In contrast, the use of d4T (compared with AZT) and EFV (compared with NVP) was associated with a reduced risk of impaired early immune recovery. Age, IDU, HBs antigen positive, AIDS before ART, and the use of TDF (vs AZT) were not significantly associated with the outcome.
Han et al.	Older age and a pre-ART CD4 cell count ≤100 cells/mm³ were associated with an increased likelihood of suboptimal immune recovery. Conversely, pre-ART HIV RNA levels were associated with a reduced risk of suboptimal immune recovery. In contrast, sex, baseline CDC stage, BMI, HBV coinfection, baseline Hb, and HCV coinfection showed no significant associations with the outcome.
Limmade et al.	Ethnicity (non-Papuan vs Papuan) and a baseline CD4 cell count >100 cells/mm³ were associated with a reduced likelihood of being a poor immune responder. In contrast, age and the decline in viral load at six months were not significantly associated with poor immune responder.
Vaswani et al.	Leukopenia, azithromycin use, and cotrimoxazole use were associated with a higher likelihood of having a CD4 cell count <200 cells/mm³ after at least six months of ART. In contrast, anemia, thrombocytopenia, age, sex, marital status, occupation, coinfection Hepatitis B, coinfection Hepatitis C, and antiretroviral regimen were not significantly associated with this outcome.
Chow et al.	Female, baseline CD4 cell count, baseline HIV RNA levels, and duration of follow-up were strongly associated with the rate of CD4 cell recovery. In contrast, ethnicity (non-Chinese vs Chinese), route of HIV transmission, age, time from presentation to cART initiation, and coinfection status (TB/HBV/HCV) were not significantly associated with immune recovery.
Khienprasit et al.	A baseline CD4 cell count <100 cells/mm³ and a CD4 cell increase of <50 cells/mm³ after six months of ART were associated with a higher likelihood of immunological failure. In contrast, sex, age, route of HIV transmission, area of residence (urban vs rural), health insurance status, OI prior to cART, HCV positive, HBV positive, and adherence rate were not significantly associated with immunological failure.
Rachman et al.	A baseline CD4 cell count <200 cells/mm³ and attainment of a bachelor’s degree or higher were associated with an increased likelihood of poor CD4 recovery. In contrast, anal sexual transmission were negatively associated with immunological non-response. Sex, other mode of HIV transmission, BMI, HIV clinical stage, and ART regimen were not significantly associated with INR.
Griensven et al.	CD4 recovery was significantly delayed in patients with HBV coinfection, whereas no significant delay was observed in those with HCV coinfection.
Bastard et al.	Patients with higher baseline CD4 cell count achieved a higher long-term CD4 reconstitution and women demonstrated superior immune recovery compared with men.
Than et al.	HIV patients without HCV co-infection experience better CD4 cell recovery over time

IDU (Injection Drug Use), CDC (Centers for Disease Control and Prevention), BMI (Body Mass Index), Hb (Hemoglobin), OI (Opportunistic Infection).

In contrast, older age showed inconsistent findings. While two studies reported an increased risk of INR among older individuals, the majority (n = 5) found no statistically significant association. A similar pattern was observed for male sex, with three studies reporting an increased risk and four studies reporting no significant association; none identified a protective effect.

For baseline HIV-RNA levels, the available evidence (n = 2) consistently suggested an association with a reduced risk of INR, although the small number of studies limits the strength of this conclusion. For hepatitis C virus (HCV) co-infection, most studies (n = 4) reported no significant association, while two studies suggested an increased risk. A comparable pattern was observed for hepatitis B virus (HBV) co-infection, where the majority of studies (n = 4) found no association and only one study reported an increased risk of INR.

Routes of HIV transmission and body mass index were consistently not associated with INR; however, this finding was based on a limited number of studies (n = 2). Several additional factors were reported by only a single study, including use of stavudine (d4T), efavirenz (EFV), ethnicity, educational level, leukopenia, use of azithromycin, use of cotrimoxazole, and a CD4 cell increase of <50 cells/mm³ after six months of ART. Although these factors were reported to be significantly associated with INR, the limited evidence precludes definitive conclusions. These findings should therefore be interpreted with caution and require validation in larger, multi-center studies.

Discussion

Given the substantial heterogeneity in definitions of INR and study designs, this review did not aim to generate pooled estimates. Instead, we sought to identify and summarize factors consistently associated with INR across studies in Southeast Asia. The included studies varied considerably in their operational definitions of INR, duration of follow-up, and analytical approaches. In addition, inconsistent reporting of quantitative data and non-uniform outcome measures precluded meta-analysis. Therefore, findings were synthesized narratively and supported by descriptive visualizations to illustrate patterns of association.

Our literature review identified several risk factors consistently associated with INR in at least two studies, including age, sex, baseline CD4 cell count, HIV-RNA levels, coinfections, HIV transmission route, and BMI. However, among all evaluated factors, only baseline CD4 cell count demonstrated a consistent association across all included studies. Most investigations treated baseline CD4 cell count as a primary variable and consistently showed that lower baseline CD4 levels were associated with an increased risk of INR. These findings are consistent with evidence from studies in other populations, which have shown that poor baseline immunological status is a key predictor of INR.^9,20 However, this association should be interpreted with caution, as several studies incorporated similar CD4 thresholds into the definition of INR, which may introduce circular reasoning and overestimate the observed effect.

Several studies reported that a low baseline CD4 cell count was strongly associated with suboptimal immune recovery, even among patients who achieved virological suppression, whereas higher baseline CD4 levels were associated with a greater likelihood of achieving optimal CD4 reconstitution.^12,34–36 In addition to influencing the rate of CD4 recovery, baseline CD4 levels also determined long-term absolute CD4 outcomes, with a significantly lower proportion of patients reaching clinically relevant CD4 thresholds (e.g., ≥350 cells/mm³) among those with low baseline CD4 cell count.^37,38

From a biological perspective, this phenomenon likely reflects more extensive immune system damage prior to ART initiation, including thymic dysfunction, reduced production of naïve T cells, increased T-cell destruction, and chronic immune activation and exhaustion. These mechanisms collectively limit immune regenerative capacity, even after viral replication has been effectively controlled.^2,8,20,38

Patients with low CD4 cell count at the time of HIV diagnosis commonly present with advanced clinical disease, and previous studies have shown that most individuals in WHO clinical stages III and IV fail to achieve CD4 levels ≥350 cells/mm³ following antiretroviral therapy.³⁹ Overall, these findings highlight baseline immunological status at ART initiation as the most consistent predictor of immunological reconstitution failure and emphasize the critical importance of early ART initiation to optimize long-term immune recovery.

These findings are in line with World Health Organization (WHO) recommendations advocating ART initiation for all individuals living with HIV, regardless of CD4 cell count, aiming to prevent further immune damage and improve long-term clinical outcomes.¹⁰ This issue is particularly relevant in Southeast Asia, where, despite approximately 85% of people living with HIV being diagnosed and 74% receiving antiretroviral therapy, coverage remains below the global targets of 95–90–86. This gap underscores the urgency of strengthening early HIV screening and expanding timely access to ART as key strategies to prevent immunological reconstitution failure and improve long-term immunological outcomes.⁴⁰

Age has frequently been reported as a factor associated with INR, although findings across studies were inconsistent. Two studies reported that older age was associated with a higher risk of INR, which may be biologically explained by immunosenescence. Ageing is associated with reduced production of naïve T cells, accumulation of senescent T cells, and diminished capacity to regenerate the CD4 cell compartment following immunological damage. Furthermore, progressive thymic involution with advancing age further constrains immune recovery following ART initiation.^2,12,36

However, not all studies included in this review identified a consistent association between age and INR. This inconsistency may be influenced by differences in age distribution, duration of HIV infection prior to treatment, and other confounding factors, suggesting that the effect of age on immune reconstitution may be indirect and mediated by baseline immunological status.

The association between sex and INR also showed inconsistent findings across studies. Three studies reported differences in immune recovery by sex, indicating that women tended to experience better immune recovery following ART initiation, whereas male sex was more frequently associated with suboptimal immune recovery.^11,35,37 Biologically, genetic, hormonal, and immunological differences between men and women may influence CD4 recovery. However, in Southeast Asia, social and structural factors—including delayed access to healthcare, differences in healthcare-seeking behavior, treatment adherence, family responsibilities, employment demands, stigma, and imbalanced sex distributions within study populations—may act as confounders and contribute to the observed variability.^37,41 Future studies should collect and adjust for these variables.

Higher baseline HIV-RNA levels were reported to be negatively associated with INR, although the available evidence was limited to two studies.^12,35 This finding is consistent with cohort studies from Europe demonstrating that higher viral load at ART initiation is strongly associated with greater CD4 cell recovery following treatment.⁴² This observation has been hypothesized to reflect a larger pool of infected CD4 cells sequestered within lymphoid tissues, which may be rapidly redistributed into the peripheral circulation following ART initiation.¹²

Several studies reported that the presence of coinfections contributed to an increased risk of immunological reconstitution failure, with more consistent effects observed for hepatitis C virus (HCV) coinfection.^11,43,44 Nevertheless, the overall impact of coinfections on INR varied substantially across studies. This variability is likely influenced by differences in coinfection prevalence, disease severity, the status and effectiveness of coinfection treatment, all of which may modify immune responses to ART. Additionally, not all studies distinguished between active coinfection and a history of prior infection, potentially contributing to heterogeneous effect estimates.

Limitations should be considered when interpreting the findings of this systematic review. First, the definition of INR varied substantially across studies, which limited the comparability of results. Second, not all studies incorporated virological parameters. We recommend that future studies explicitly require virological suppression (e.g., HIV RNA <50 copies/mL) in INR definitions to reduce misclassification. Third, limited access to certain scientific databases may have affected the completeness of study identification, particularly regional or local publications from Southeast Asia that are not indexed in major international databases. We did not conduct subgroup analyses by country or ART regimen due to inconsistent reporting; such analyses in future reviews could clarify contextual differences. Lastly, some included studies were conducted more than a decade ago and may not reflect modern ART regimens. Updated regional studies are needed. Nevertheless, this review provides a comprehensive overview of factors associated with immunological reconstitution failure in Southeast Asia and highlights gaps in the existing evidence that warrant further investigation in future studies.

Research and policy implication

Based on the findings of this review, several implications for clinical practice and future research in Southeast Asia can be identified. Routine assessment of baseline CD4 cell count should be prioritized at ART initiation, as it remains the most consistent predictor of immunological non-response. Individuals initiating ART with CD4 cell count below 200 cells/mm³ may benefit from closer immunological monitoring, including more frequent CD4 cell evaluation and enhanced clinical follow-up, particularly in resource-limited settings. Integration of co-infection screening, especially for hepatitis B and C, into routine HIV care is also important, given its potential impact on immune recovery. For future research, adoption of standardized definitions of INR, such as the WHO criteria, is essential to improve comparability across studies. A proposed standardized definition of INR for Southeast Asia is presented in supporting information. In addition, expanding search strategies to include regional databases and non-English literature, such as the ASEAN Citation Index and Herdin Plus may enhance the representativeness of evidence in Southeast Asia.

Supplemental material

Supplemental material - Factors associated with immunological non-response in HIV patients receiving antiretroviral therapy in Southeast Asia: A systematic review

Supplemental material for Factors associated with immunological non-response in HIV patients receiving antiretroviral therapy in Southeast Asia: A systematic review by Efrida and Aziizah Yuza in Antiviral Therapy.

Footnotes

Acknowledgements

Translation and paraphrasing were assisted by ChatGPT. All scientific content, data interpretation, and conclusions were independently developed and verified by the authors.

ORCID iDs

Efrida

Aziizah Yuza

Author contributions

All authors contribute equally to the conception, data extraction, analysis, and writing of this manuscript. All authors approved the final version.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

All data analyzed in this study are included in the published articles and their supplementary information.*

Supplementary information

The Supporting information includes the detailed Search Strategy, Newcastle-Ottawa Scale assessment, Definitions of Immunological Non-Response (INR) in Included Studies, Analytical Results from the Included Studies, Proposed Immunological Non-Response (INR) Definition for Southeast Asia, Effect Direction Plot, the PRISMA 2020 checklist, and the SWiM checklist.

Supplemental material

Supplemental material for this article is available online.

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