Second-generation mother-to-child HIV transmission in South Africa is characterized by poor outcomes.

OBJECTIVE: The worldwide incidence of pregnancy for women living with perinatal HIV infection is increasing. Subsequently, there is growing risk of second-generation mother-to-child HIV transmission. The infant clinical outcomes for such a phenomenon have yet to be described. DESIGN: As part of a wider observational study in KwaZulu-Natal, South Africa, six infants with in-utero HIV infection were identified as being born to mothers with perinatal HIV infection. METHODS: Blood results and clinical data were collected in the first 3 years of life. In two cases, sample availability allowed confirmation by phylogenetic analysis of grandmother-to-mother-to-child HIV transmission. RESULTS: Outcomes were poor in all six cases. All six mothers had difficulty administering twice daily combination antiretroviral therapy to their infants due to difficulties with acceptance, disclosure, poor health and being themselves long-term nonprogressors. Nonnucleoside reverse transcriptase inhibitor-resistant virus was detected in all mothers tested. None of the infants maintained suppression of viraemia on combination antiretroviral therapy. One infant died, and another was lost to follow-up. CONCLUSION: As the numbers of second-generation mother-to-child transmissions increase, it is important to highlight that this mother-infant dyad represents an extremely vulnerable group. In order for them to survive and thrive, these infants' mothers require their specific needs to be addressed and given intensive support.

Early Initiation of Antiretroviral Therapy Following In Utero HIV Infection Is Associated With Low Viral Reservoirs but Other Factors Determine Viral Rebound.

BACKGROUND: Early HIV diagnosis allows combination antiretroviral therapy (cART) initiation in the first days of life following in utero (IU) infection. The impact of early cART initiation on infant viral reservoir size in the setting of high-frequency cART nonadherence is unknown. METHODS: Peripheral blood total HIV DNA from 164 early treated (day 0-21 of life) IU HIV-infected South African infants was measured using droplet digital PCR at birth and following suppressive cART. We evaluated the impact of cART initiation timing on HIV reservoir size and decay, and on the risk of subsequent plasma viremia in cART-suppressed infants. RESULTS: Baseline HIV DNA (median 2.8 log10 copies/million peripheral blood mononuclear cells, range 0.7-4.8) did not correlate with age at cART initiation (0-21 days) but instead with maternal antenatal cART use. In 98 infants with plasma viral suppression on cART, HIV DNA half-life was 28 days. However, the probability of maintenance of plasma aviremia was low (0.46 at 12 months) and not influenced by HIV DNA load. Unexpectedly, longer time to viral suppression was associated with protection against subsequent viral rebound. CONCLUSIONS: With effective prophylaxis against mother-to-child transmission, cART initiation timing in the first 3 weeks of life is not critical to reservoir size.

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

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 18-38) and 75 infants diagnosed via standard-of-care (SoC) laboratory-based testing initiated cART at 10 days (IQR 8-13). 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 5.6-39.6; 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. FUNDING: Wellcome Trust, National Institutes of Health.

Increasing Diagnostic Uncertainties in Children With In Utero HIV Infection.

We present a case of an in utero HIV-infected child, who on day 1 of life had a positive whole blood total nucleic acid test but viral load <20 RNA copies/mL. Dried blood spot total nucleic acid testing was negative on day 1, 10 and at 3 months, while on ART prophylaxis then positive at 5 months after prophylaxis ended. Retrospective peripheral blood mononuclear cells HIV DNA testing from day 1 of life was positive, confirming in utero infection.