Impact of antiretroviral therapy during acute or early HIV infection on virologic and immunologic outcomes: results from a multinational clinical trial

Abstract

Objective: To assess how antiretroviral therapy (ART) initiation during acute or early HIV infection (AEHI) affects the viral reservoir and host immune responses.

Design: Single-arm trial of ART initiation during AEHI at 30 sites in the Americas, Africa, and Asia.

Methods: HIV DNA was measured at week 48 of ART in 5 million CD4 + T cells by sensitive qPCR assays targeting HIV gag and pol . Peripheral blood mononuclear cells were stimulated with potential HIV T cell epitope peptide pools consisting of env , gag , nef, and pol peptides and stained for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines.

Results: From 2017 to 2019, 188 participants initiated ART during Fiebig stages I ( n = 6), II ( n = 43), III ( n = 56), IV ( n = 23), and V ( n = 60). Median age was 27 years (interquartile range 23-38), 27 (14%) participants were female, and 180 (97%) cisgender. Among 154 virally suppressed participants at week 48, 100% had detectable HIV gag or pol DNA. Participants treated during Fiebig I had the lowest HIV DNA levels ( P < 0.001). Week 48 HIV DNA mostly did not correlate with concurrent CD4 + or CD8 + T cell HIV-specific immune responses (rho range -0.11 to +0.19, all P > 0.025). At week 48, the magnitude, but not polyfunctionality, of HIV-specific T cell responses was moderately reduced among participants who initiated ART earliest.

Conclusion: Earlier ART initiation during AEHI reduced but did not eliminate the persistence of HIV-infected cells in blood. These findings explain the rapid viral rebound observed after ART cessation in early-treated individuals with undetectable HIV DNA by less sensitive methods.

Figure 1.

CONSORT Diagram. This diagram displays the progression of participants through screening, enrollment, allocation, and follow-up in the A5354 single-arm, open-label study to evaluate the impact of ART initiation during AEHI on viral persistence and development of HIV-specific immune responses, using the standard recommended by the CONSORT Group. The study had a target enrollment of 50 participants in each of Study Group 1 (Fiebig I/II), Study Group 2 (Fiebig III/IV), and Study Group 3 (Fiebig V). Fiebig staging and group assignment were conducted retrospectively using centralized testing of blood specimens from the enrollment visit. Participants without confirmed HIV or in Fiebig stage VI were withdrawn from the study. The primary analysis population was restricted to participants with no ART interruption of ≥7 consecutive days, HIV-1 RNA <50 copies/mL at week 48, and available HIV DNA results at week 48. Abbreviations: LTFU, lost to follow-up

Figure 2.

Proportion of participants who achieved plasma HIV RNA suppression targets, by study groups and Fiebig stages. Panel A displays the proportion of participants with plasma HIV-1 RNA less than 50 copies/mL by study group. Panel B displays the proportion of participants with plasma HIV-1 RNA target not detected by study group. Panel C displays the proportion of participants with plasma HIV-1 RNA less than 50 copies/mL by Fiebig stage. Panel D displays the proportion of participants with plasma HIV-1 RNA target not detected by Fiebig stage. Vertical bars represent 95% confidence intervals calculated using the exact binomial distribution.

Figure 3.

HIV DNA (copies per million CD4⁺ T-cells) after 48 weeks of antiretroviral therapy, by Study Group and Fiebig Stage. Panel A displays the Week 48 HIV gag DNA by study group. Panel B displays the Week 48 HIV pol DNA by study group. Panel C displays the Week 48 HIV gag DNA by Fiebig stage. Panel D displays the Week 48 HIV pol DNA by Fiebig stage. Undetectable measurements are indicated with open symbols. Vertical bars represent the interquartile range and are bisected with a horizontal line at the median. *p<0.05, **p<0.01.

Figure 4.

Change in HIV DNA (copies per million CD4⁺ T-cells) from prior to ART initiation and after 48 weeks of antiretroviral therapy, by Study Group and Fiebig Stage. Panel A displays the HIV gag DNA by study group. Panel B displays the HIV pol DNA by study group. Panel C displays the HIV gag DNA by Fiebig stage. Panel D displays the HIV pol DNA by Fiebig stage. Vertical bars represent interquartile ranges.

Figure 5.

CD4⁺ and CD8⁺ T-cell-specific immune responses during suppressive antiretroviral therapy, by Study Group. HIV-specific immune responses were assessed by stimulation of peripheral blood mononuclear cells with T-cell epitope peptide pools (env, gag, nef, and pol peptides) and staining for expression of CD3, CD4, CD8, and intracellular cytokines/chemokines (CD40L, Mip1b, IFN-g, and TNF-a). Responses were calculated by subtracting the corresponding background control value (media control) from the value measured for a specific participant. A positive result was defined as any functional response above the background (unstimulated condition) to one or more intracellular cytokines/chemokines. Panel A displays week 48 total percent CD4⁺ T-cell-specific immune responses to env, gag, nef, and pol peptides by Study Group. Panel B displays week 48 total percent CD8⁺ T-cell-specific immune responses by Study Group. Vertical bars represent interquartile ranges. *p<0.05, **p<0.01.