Influence of episodes of intermittent viremia ("blips") on immune responses and viral load rebound in successfully treated HIV-infected patients

Abstract

Presenting episodes of intermittent viremia (EIV) under combination antiretroviral therapy (cART) is frequent, but there exists some controversy about their consequences. They have been described as inducing changes in immune responses potentially associated with a better control of HIV infection. Conversely, it has been suggested that EIV increases the risk of virological failure. A retrospective analysis of a prospective, randomized double-blinded placebo-controlled study was performed. Twenty-six successfully treated HIV-infected adults were randomized to receive an immunization schedule or placebo, and after 1 year of follow-up cART was discontinued. The influence of EIV on T cell subsets, HIV-1-specific T cell immune responses, and viral load rebound, and the risk of developing genotypic mutations were evaluated, taking into account the immunization received. Patients with EIV above 200 copies/ml under cART had a lower proportion of CD4(+) and CD4(+)CD45RA(+)RO(-) T cells, a higher proportion of CD8(+) and CD4(+)CD38(+)HLADR(+) T cells, and higher HIV-specific CD8(+) T cell responses compared to persistently undetectable patients. After cART interruption, patients with EIV presented a significantly higher viral rebound (p=0.007), associated with greater increases in HIV-specific lymphoproliferative responses and T cell populations with activation markers. When patients with EIV between 20 and 200 copies/ml were included, most of the differences disappeared. Patients who present EIV above 200 copies/ml showed a lower CD4(+) T cell count and higher activation markers under cART. After treatment interruption, they showed greater specific immune responses against HIV, which did not prevent a higher virological rebound. EIV between 20 and 200 copies/ml did not have this deleterious effect.

Trial registration: ClinicalTrials.gov NCT00329251.

Figures

FIG. 1.

(A) Samples of plasma viral load during treatment (months 0 to 12) with an assay with a limit of detection of 200 copies/ml. There were 22 detectable determinations. (B) Evolution of viral load (VL) in the detectable and undetectable group. After combined antiretroviral therapy (cART) interruption (month 12), detectable patients presented a higher peak VL (5.33 vs. 4.68 log10, p=0.022), a higher VL in month 14 (4.85 vs. 4.08 log10, p=0.005), and a higher AUC of VL after the interruption (13.51 vs. 9.57, p=0.007) (■ and black line, detectable group; Δ and gray line, undetectable group). Median and interquartile range are shown.

FIG. 2.

Evolution of immunological parameters during the study period. Months 0 to 12, patients were on cART. At month 12 cART was discontinued (shady area) [■ and black line, detectable (≥200 copies/ml) group; Δ and gray line, undetectable group]. (A–D) T cell subsets (CD4+, CD4+CD38+HLADR+, CD8+, and CD8+CD38+). (E–F) Lymphoproliferative responses against phytohemagluttinin (PHA) 1% and HIV p24. (G–H) HIV-specific CD8+ T cell responses against gag peptides p1, p2, p6, and p7 (small pool) and quotient between whole CD8+ T cell responses (SFC/106 PBMCs) and number of positive peptides detected. Median and interquartile range are shown.