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Meta-Analysis
. 2022 Mar 30:13:844023.
doi: 10.3389/fimmu.2022.844023. eCollection 2022.

Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis

Yuanhao Liang  1 , Hongqing Lin  1 , Emmanuel Enoch Dzakah  2 , Shixing Tang  1
Affiliations
Meta-Analysis

Influence of Combination Antiretroviral Therapy on HIV-1 Serological Responses and Their Implications: A Systematic Review and Meta-Analysis

Yuanhao Liang et al. Front Immunol. .

Abstract

We aimed to analyze HIV-1 seroreversion caused by combination antiretroviral therapy (cART) and to explore antibody levels of anti-HIV-1 as an alternative biomarker of HIV-1 reservoir. We searched PubMed, Embase, the Cochrane Library, and Web of Science up to August 2021 for publications about the performance of HIV-1 serological assays or the association between antibody responses against HIV-1 and HIV-1 reservoirs. Potential sources of heterogeneity were explored by meta-regression analysis, including the year of publication, country, pretreatment viral load, sample size, the timing of treatment, time on cART, and principle or type of serological assay. Twenty-eight eligible studies with a total population of 1,883 were included in the meta-analysis. The pooled frequency of HIV-1 seronegativity is 38.0% (95% CI: 28.0%-49.0%) among children with vertical HIV-1 infection and cART initiation at the age of less than 6 months, while the percentage of HIV-1 seronegativity declined to 1.0% (95% CI: 0%-3.0%) when cART was initiated at the age of >6 months. For adult patients, 16.0% (95% CI: 9.0%-24.0%) of them were serologically negative when cART was initiated at acute/early infection of HIV-1, but the seronegative reaction was rarely detected when cART was started at chronic HIV-1 infection. Substantial heterogeneity was observed among the studies to estimate the frequency of HIV-1 seronegativity in the early-cART population (I2 ≥ 70%, p < 0.05 and all), while mild heterogeneity existed for the deferred-cART subjects. Moreover, anti-HIV-1 antibody response positively correlates with HIV-1 reservoir size with a pooled rho of 0.43 (95% CI: 0.28-0.55), suggesting that anti-HIV antibody level may be a feasible biomarker of HIV-1 reservoir size.

Keywords: HIV-1 reservoir; HIV-1 serostatus; anti-HIV-1 antibody; antiretroviral therapy; meta-analysis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Flowchart depicting the systematic search conducted to identify eligible studies that reported frequency of HIV-1 seronegativity.
Figure 2
Figure 2
Forest plots of the pooled frequency of HIV-1 seronegativity in HIV-infected children according to the principles of HIV-1 serological assays. (A) The pooled frequency of HIV-1 seronegativity in vertically HIV-infected children of ≥16 months old and cART started at the age of <6 months. (B) The pooled frequency of HIV-1 seronegativity in vertically HIV-infected children of ≥16 months old and cART started at the age of >6 months. 2nd-G EIA, second-generation enzyme immunoassay; 3rd-G EIA, third-generation enzyme immunoassay; 4th-G EIA, fourth-generation enzyme immunoassay; 2nd-G rapid test, rapid test based on second-generation principles; 3rd-G rapid test, rapid test based on third-generation principles; cART, combination antiretroviral therapy.
Figure 3
Figure 3
Forest plots of the pooled frequency of HIV-1 seronegativity in HIV-infected adults according to the principles of HIV serological assays. (A) The pooled frequency of HIV-1 seronegativity in early-treated (<6 months post diagnosis) adult patients. (B) The pooled frequency of HIV-1 seronegativity in deferred-treated (>6 months post diagnosis) adult patients. 2nd-G EIA, second-generation enzyme immunoassay; 3rd-G EIA, third-generation enzyme immunoassay; 4th-G EIA, fourth-generation enzyme immunoassay; 2nd-G rapid test, rapid test based on second-generation principles; 3rd-G rapid test, rapid test based on third-generation principles.
Figure 4
Figure 4
The distribution of frequency of HIV-1 seronegativity in cART-treated vertically HIV-infected children (A) and adult patients (B) according to the time of cART initiation and the principles of HIV-1 serological assays. Bubble size is proportional to the duration of cART. 2nd-G test, HIV-1 serological test based on second-generation principle; 3rd-G test, HIV-1 serological test based on third-generation principle; 4th-G test, HIV-1 serological test based on fourth-generation principle; cART, combination antiretroviral therapy.
Figure 5
Figure 5
Funnel plot shows publication bias of the identified surveys for early-cART children (A), deferred-cART children (B), early-cART adults (C), and deferred-cART adults (D). cART, combination antiretroviral therapy.
Figure 6
Figure 6
Forest plots of the pooled Spearman’s correlation coefficient (rho) with the corresponding 95% CIs for the correlation between HIV-1-specific antibody titer and HIV-1 DNA burden in patients for all the eligible studies (A) or the studies without significant heterogeneity (B).
Figure 7
Figure 7
Forest plots of the pooled Spearman’s correlation coefficient (rho) with the corresponding 95% CIs for the correlation between HIV-1-specific antibody titer and HIV-1 DNA burden among HIV-infected population according to the serological test principles for all the eligible studies (A) or the studies without significant heterogeneity (B).
Figure 8
Figure 8
Funnel plot shows publication bias of the identified surveys to investigate the correlation between HIV-1-specific antibody titer and HIV-1 DNA burden.
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