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.

Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 Infection in KwaZulu-Natal, South Africa.

BACKGROUND: Multisystem inflammatory syndrome in children (MIS-C) following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been infrequently described in Africa. OBJECTIVE: To describe the clinical characteristics, outcomes and associations of severe disease in children hospitalized with MIS-C in KwaZulu-Natal. METHODS: Retrospective multicenter study of children (0-13 years) who met the Centers for Disease Control and Prevention criteria for MIS-C. Children with shock were compared with children without shock to determine the characteristics of severe MIS-C. RESULTS: Twenty-nine children with MIS-C were identified, the mean age was 55 (SD ±45) months, 25 (86%) were Black-African, and 8 (28%) had pre-existing comorbidities. The predominant presenting symptoms included fever 29 (100%), gastrointestinal symptoms 25 (83%), skin rash 19 (65%), and shock 17 (59%). Children with shock had significantly increased CRP (P = 0.01), ferritin (P < 0.001), troponin-T (P = 0.02), B-type natriuretic peptide (BNP) (P = 0.01), and lower platelets (P = 0.01). Acute kidney injury (P = 0.01), cardiac involvement (P = 0.02), and altered levels of consciousness (P = 0.03) were more common in children with shock. The median length of hospital stay was 11 (IQR 7-19) days, with a mortality of 20.6%. Children who did not survive had significantly higher ferritin levels 1593 (IQR 1069-1650) ng/mL versus 540 (IQR 181-1156) ng/mL; P = 0.03) and significantly more required mechanical ventilation (OR 18; confidence interval 1.7-191.5; P = 0.005). CONCLUSIONS: Hospitalized children with MIS-C in KwaZulu-Natal had more aggressive disease and higher mortality than children in better-resourced settings. Markedly elevated biomarkers and critical organ involvement were associated with severe disease. Risk factors for poor outcomes include higher ferritin levels and the need for mechanical ventilation.

Next-generation point-of-care testing in pediatric human immunodeficiency virus infection facilitates diagnosis and monitoring of treatment.

Point-of-care (PoC) testing facilitates early infant diagnosis (EID) and treatment initiation, which improves outcome. We present a field evaluation of a new PoC test (Cepheid Xpert® HIV-1 Qual XC RUO) to determine whether this test improves EID and assists the management of children living with human immunodeficiency virus (HIV) infection. We compared 2 PoC tests with the standard-of-care (SoC) test used to detect HIV infection from dry blood spots in newborn infants at high risk of in utero infection. We also evaluated the ability of the PoC tests to detect HIV total nucleic acid (TNA) in children living with HIV infection who had maintained undetectable plasma viremia following very early combination antiretroviral therapy (cART) initiation. Qualitative (Qual) detection of HIV using the Xpert® HIV-1 Qual XC RUO ("RUO") and Xpert® HIV-1 Qual ("Qual") PoC tests was compared in 224 infants with the SoC DBS Roche COBAS® HIV-1/HIV-2 qualitative test. The same 2 PoC tests were also evaluated in 35 older children who had initiated cART before 21 days of age and maintained undetectable plasma viremia for a mean of 25 months. No discrepancies were observed in detection of HIV infection via the 2 PoC tests or the SoC test in the 224 neonates studied, but only 95% of the SoC test results were generated compared with 100% of the PoC test results (P = .0009). The cycle threshold values for the research use only (RUO) assay were the lowest of the 3 assays (P < .0001 in each case). In 6 of the 35 early-treated aviremic children, HIV TNA was detected by RUO but not Qual. The RUO assay outperforms Qual in detecting HIV-1 infection. RUO would therefore potentially improve EID and assist in identifying cART-adherent early-treated children with the lowest HIV TNA levels and the highest HIV cure potential.

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

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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.