Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission.

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3-10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = -0.51 versus r = -0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero-acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.

Author Correction: Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection.

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Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection.

Female children and adults typically generate more efficacious immune responses to vaccines and infections than age-matched males, but also suffer greater immunopathology and autoimmune disease. We here describe, in a cohort of > 170 in utero HIV-infected infants from KwaZulu-Natal, South Africa, fetal immune sex differences resulting in a 1.5-2-fold increased female susceptibility to intrauterine HIV infection. Viruses transmitted to females have lower replicative capacity (p = 0.0005) and are more type I interferon-resistant (p = 0.007) than those transmitted to males. Cord blood cells from females of HIV-uninfected sex-discordant twins are more activated (p = 0.01) and more susceptible to HIV infection in vitro (p = 0.03). Sex differences in outcome include superior maintenance of aviraemia among males (p = 0.007) that is not explained by differential antiretroviral therapy adherence. These data demonstrate sex-specific innate immune selection of HIV associated with increased female susceptibility to in utero infection and enhanced functional cure potential among infected males.

Delayed cord clamping in South African neonates with expected low birthweight: a randomised controlled trial.

OBJECTIVE: To evaluate safety and haematological effects of delayed cord clamping (DCC) in infants with expected low birthweight born in a resource-poor setting. METHODS: Randomised controlled trial involving pregnant women in early labour ≥18 years with intrapartum symphysal-fundal height ≤32 cm. Mothers were randomised for either early cord clamping (ECC, <30 s) or DCC (2-3 min after birth). RESULTS: We included 104 vigorous infants born by vaginal delivery, of whom 39% had a birthweight <2500 g. Infant haemoglobin (Hb) levels 24 h after birth were significantly higher in the DCC group (18.0 g/dl vs. 16.8 g/dl, P = 0.006). Despite successful placental transfusion, hyperbilirubinemia and hyperviscosity were not observed. Two months after birth, there were no differences in Hb between groups (9.9 g/dl vs. 9.8 g/dl, P = 0.60), but the infants in the DCC group had better weight gain from baseline than those with ECC (2.2 kg vs. 1.9 kg, P = 0.058). CONCLUSIONS: In this South African cohort of newborns with a subnormal distribution of birthweight delayed cord clamping was a safe procedure. Two months after birth the effect of DCC on Hb was not detectable anymore. DCC should be promoted in every singleton delivery in a resource-poor setting irrespective of the birthweight.