Stunting (linear growth failure) is of considerable global health importance because it contributes to ±15% of under-5 mortality, impairs neurodevelopment, and reduces economic productivity in adulthood. HIV-exposed uninfected (HEU) infants have more stunting than HIV-unexposed infants, but the causes are uncertain. The growth hormone axis is an important regulator of infant growth through hepatic synthesis of insulin-like growth factor 1 (IGF-1), and may be disrupted by chronic inflammation and acute infections. We hypothesized that inflammation and viral infections disrupt the growth hormone axis in HEU infants, and contribute to linear growth impairment.
This study used data and stored plasma samples from 243 HEU infants and 100 HIV-unexposed infants recruited to the ZVITAMBO trial in Zimbabwe prior to ART availability. Length was measured at birth, 6 weeks, 3 months and 6 months of age and converted into length-for-age Z-scores (LAZ). Plasma IGF-1, C-reactive protein (CRP) and cytomegalovirus (CMV) viremia were measured at 6 weeks of age by ELISA (IGF-1, CRP) and real-time quantitative DNA PCR (CMV). Unpaired t-tests were used to compare continuous variables and linear regression models were used to determine associations between variables.
Mean IGF-1 concentrations at 6 weeks were significantly lower in HEU compared to HIV-unexposed infants (29.5 vs. 32.6ng/mL; P=0.01). IGF-1 concentrations at 6 weeks were positively correlated with LAZ at 6 weeks, 3 months and 6 months of age, and negatively correlated with CRP (β= -0.84; P=0.03). HEU and HIV-unexposed infants had a similarly high prevalence of CMV viremia at 6 weeks of age (81.4% vs. 74%; P=0.14), but HEU infants had higher mean CMV viral loads (P=0.005). Among infants with CMV viremia, CMV viral loads were inversely associated with IGF-1 concentrations in HEU infants (β= -1.16; P=0.008) but not in HIV-unexposed infants (β = 0.21; P=0.83).
IGF-1 at 6 weeks was associated with subsequent linear growth through 6 months of age. Increased inflammation was associated with lower IGF-1 concentrations, meaning the pro-inflammatory state of HEU infants may be one driver of growth impairment. An inverse relationship between CMV viral load and IGF-1 in HEU infants, but not in HIV-unexposed infants, is consistent with previous findings that suggest poorer handling of viral infections in HEU infants. Targeted interventions for HEU infants may be necessary to reduce stunting and its associated negative effects.