HIGH-FREQUENCY failure of combination antiretroviral therapy in paediatric HIV infection is associated with unmet maternal needs causing maternal NON-ADHERENCE

Abstract

Background: Early combination antiretroviral therapy (cART) reduces the size of the viral reservoir in paediatric and adult HIV infection. Very early-treated children may have higher cure/remission potential. Methods: In an observational study of 151 in utero (IU)-infected infants in KwaZulu-Natal, South Africa, whose treatment adhered strictly to national guidelines, 76 infants diagnosed via point-of-care (PoC) testing initiated cART at a median of 26 h (IQR 18À38) and 75 infants diagnosed via standard-of-care (SoC) laboratory-based testing initiated cART at 10 days (IQR 8À13). We analysed mortality, time to suppression of viraemia, and maintenance of aviraemia over the first 2 years of life. Findings: Baseline plasma viral loads were low (median 8000 copies per mL), with 12% of infants having undetectable viraemia pre-cART initiation. However, barely one-third (37%) of children achieved suppression of viraemia by 6 months that was maintained to >12 months. 24% had died or were lost to follow up by 6 months. Infant mortality was 9.3%. The high-frequency virological failure in IU-infected infants was associated not with transmitted or acquired drug-resistant mutations but with cART non-adherence (plasma cART undetectable/subtherapeutic, p<0.0001) and with concurrent maternal cART failure (OR 15.0, 95%CI 5.6À39.6; p<0.0001). High-frequency virological failure was observed in PoC-and SoC-tested groups of children. Interpretation: The success of early infant testing and cART initiation strategies is severely limited by subsequent cART non-adherence in HIV-infected children. Although there are practical challenges to administering paediatric cART formulations, these are overcome by mothers who themselves are cART-adherent. These findings point to the ongoing obligation to address the unmet needs of the mothers. Eliminating the particular barriers preventing adequate treatment for these vulnerable women and infants need to be prioritised in order to achieve durable suppression of viraemia on cART, let alone HIV cure/remission, in HIV-infected children.

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

“…As stated above, suppression of viraemia on ART is strongly correlated within mother-child pairs (Fig. 3I, j), because of shared ART non-adherence rather than shared ART resistance 25 . Comparing male infants and mothers of males with female infants and mothers of females, viral suppression is correlated within pairs (Supplementary Fig.…”

Virologic Response to Very Early HIV Treatment in Neonates

“…It is also possible that infants born to mothers who did not receive ART may have had other host factors (HIV-specific immunity or genetic factors) that led to better viral control [ 29 , 30 ]. A similar finding was reported in a study of intrauterine-infected infants in KwaZulu-Natal, South Africa, where a longer duration of maternal ART during pregnancy was found to predict infant viral rebound [ 23 ]. Further data, particularly on maternal and infant drug resistance, are needed to disentangle and better understand these pathways.…”

“…Furthermore, similar to the Botswana study, we did not observe any association between gestational age and viral response. In contrast, a study of intrauterine-infected infants in KwaZulu-Natal, South Africa found that infants born at a younger gestational age had lower rates of viral rebound [ 23 ]. For breastfeeding, we found a signal that breastfeeding may be associated with better viral response to early ART.…”

Harnessing early life immunity to develop a pediatric HIV vaccine that can protect through adolescence

“…Yet, in 2018, worldwide, approximately 160,000 infants were infected with HIV [ 2 ]. The currently available ART-based measures to prevent MTCT in WLWH are limited by implementation challenges, such as suboptimal ART coverage of pregnant and breastfeeding women [ 3 ], poor adherence to ART [ 4 , 5 ] resulting in incomplete viral suppression and increased risk of drug resistance, and late presentation for prenatal care [ 6 ]. In addition, ART-based prophylactic strategies do not address the scenario of acute maternal infections that occur late during pregnancy or during the breastfeeding period [ 7 ].…”