Quantifying the Dynamics of HIV Decline in Perinatally Infected Neonates on Antiretroviral Therapy

Abstract

Background: Mathematical modeling has provided important insights into HIV infection dynamics in adults undergoing antiretroviral treatment (ART). However, much less is known about the corresponding dynamics in perinatally infected neonates initiating early ART.

Setting: From 2014 to 2017, HIV viral load (VL) was monitored in 122 perinatally infected infants identified at birth and initiating ART within a median of 2 days. Pretreatment infant and maternal covariates, including CD4 T cell counts and percentages, were also measured.

Methods: From the initial cohort, 53 infants demonstrated consistent decline and suppressed VL below the detection threshold (20 copies mL) within 1 year. For 43 of these infants with sufficient VL data, we fit a mathematical model describing the loss of short-lived and long-lived infected cells during ART. We then estimated the lifespans of infected cells and the time to viral suppression, and tested for correlations with pretreatment covariates.

Results: Most parameters governing the kinetics of VL decline were consistent with those obtained previously from adults and other infants. However, our estimates of the lifespan of short-lived infected cells were longer than published values. This difference may reflect sparse sampling during the early stages of VL decline, when the loss of short-lived cells is most apparent. In addition, infants with higher pretreatment CD4 percentage or lower pretreatment VL trended toward more rapid viral suppression.

Conclusions: HIV dynamics in perinatally infected neonates initiating early ART are broadly similar to those observed in other age groups. Accelerated viral suppression is also associated with higher CD4 percentage and lower VL.

Figure 1:. Structure of data analysis.

Infants from the original study were partitioned into different analysis subsets according to specific criteria. Boxes with dark outlines represent the partitioning criteria and shaded boxes without outlines describe the resulting subsets. ‘Reliable confidence intervals’ are confidence intervals on parameter estimates not exceeding two orders of magnitude

Figure 2:. Eleven infants fit using the biphasic model.

Each panel represents one infant (ID inset top right; BP stands for ‘biphasic’). Points represent viral load data, black solid lines are the biphasic model fit, and the black dashed horizontal line indicates the detection threshold. The phase transition occurs when the first decline phase meets the second, and the time at which the drug regimen changed is depicted by the vertical green line.

Figure 3:. Distribution of infected cell lifespans.

(A) Estimates from the biphasic model (n = 11). The short-lived lifespan was calculated as 1/δ, and the long-lived lifespan as 1/γ The dashed vertical line represents the cutoff threshold separating the short and long-lived distributions. (B) Estimates from the single phase model (n = 32) were calculated as $1/\widehat{\gamma }$. The dashed vertical line represents the cutoff threshold defined in (A). (C) Combined distributions of the estimated lifespan of short-lived cells (left; n = 23) and long-lived cells (right; n = 31) after partitioning the single phase estimates in (B) according to the cutoff threshold.

Figure 4:. 32 infants fit using the single phase model.

Each panel represents a different infant (ID inset top right; SP stands for ‘single phase’). Points represent the viral load data, solid lines are the single phase model fit, and dashed horizontal lines indicate the detection threshold.

Figure 5:. Time to suppression (TTS) is associated with baseline CD4 percentage and viral load.

(A) Comparison of TTS estimation by parametric and non-parametric methods for 43 infants fit using the biphasic or single phase models (correlation = 0.96, p < 2 × 10⁻¹⁶). Estimates are reported in days since ART initiation, and each infant is represented by their corresponding ID. (B) Non-parametric TTS estimates (in days) for all 53 infants who reached viral suppression. (C) Association between non-parametric TTS and baseline CD4 percentage (correlation = −0.36, p = 0.057). Twelve of the 53 infants were not included due to missing CD4 percentage measurements. (D) Association between non-parametric TTS and log10 baseline viral load for all 53 infants (correlation = 0.40, p = 0.01).