Human Milk Oligosaccharides,Microbiome,Antiretroviral Therapy and HIV Infected Mothers: Reasons to Still Promote Breastfeeding in HIV Context of Lactating Countries,a Mini-Narrative Review

Abstract

Breastfeeding is the preferred feeding for newborns during the first 6 months of life and until the age of 2 years or beyond. The benefits of breastfeeding remain significant, even in cases of HIV infection. The introduction of antiretroviral therapy(ART) has greatly reduced the risk of HIV transmission from mother to child through breastfeeding. As a result, breast milk is recommended for infants born to HIV-positive mothers, regardless of the mother’s HIV status. Nevertheless, breastfeeding still poses a risk of HIV transmission in the era of eliminating vertical transmission. This mini-narrative review will highlight the continued benefits of breast milk for both HIV-infected and uninfected infants, focussing on the changes in bioactive components of breast milk, such as human milk oligosaccharides, and their effects on the gut microbiota. Additionally, this review will recommend strategies to improve safe breastfeeding practices in the context of HIV when mothers are receiving ART.

Introduction – General Information on Breast Milk and Its Importance in Child Survival

Breast milk has clear and well-documented benefits for the survival and neurological development of the newborn and infant. These benefits on growth, brain development and cognition are increasingly supported. Moreover, these benefits persist in the long term, with reductions in metabolic syndrome and cardiovascular and metabolic diseases, including diabetes, which contribute to the genesis of adult diseases.^{1 -5} The advantages of breastmilk are linked on the one hand to the macro and micro nutritional properties of mother’s milk but much more to the presence in breast milk of bioactive substances among which are included: antioxidants, growth factors (epidermal, hepatic, neuronal and vascular), adipokins (anti-inflammatory cytokines); and other bioactive proteins such as immunoglobulins, lactoferrin, lysozyme, casein and lactalbumin and carbohydrate substances, notably the oligosaccharides of breast milk, the role of which are prebiotics is no longer questionable.^{6 -9} In addition, several neonatal conditions may be avoided thanks to the protective effect of breast milk, among which we will note: ulceronecrotizing enterocolitis, bronchopulmonary dysplasia, retinopathy of prematurity, in addition to the anti-infectious prevention and the anti-allergic effect.^{10 -12} All of these elements must affect and modulate the constitution of the intestinal microbiome, which is considered the second brain. ¹³ In terms of public health, breastfeeding therefore constitutes a key element of all childhood development strategies in terms of the fight against infant mortality, particularly in countries with limited resources, making it possible to avoid around 800 000 deaths per year. The WHO’s critical and imperative programmes aim to ensure that at least 50% of children are exclusively breastfed for up to 6 months by 2025.^{14 -18} Several countries are taking action to reach this rate of 6 months of exclusive breastfeeding completion, even if the implementation of these programmes encounters enormous difficulties on the ground. Certain campaigns to supplement infant feeding before 6 months may result in non-compliance with the marketing code for breast milk substitutes.^19,20 Recently, breastfeeding recommendations are the same for children born to HIV-uninfected mothers as for those of exposed children.^17,18

Review Objective and Methodology

This short narrative review aims to provide an update on the importance of breastfeeding in the context of maternal HIV infection, with a focus on recent data on the specific profile of oligosaccharides in breast milk of infected women, the effects on the microbiome and possible interactions with antiretroviral treatment. A comprehensive manual research was done. The keywords for this digital search on PubMed and Google Scholar were: breastfeeding, HIV, exposed uninfected child, breast milk oligosaccharides, microbiome and antiretroviral treatment. Search strategy included papers published in English or French. The narrative compilation summarised the most relevant articles.

Informed Consent/Patient Consent

Informed consent or patient consent was not required for this study.

Results and Synthesis of Key Points

Breast Milk in the HIV Context: The Challenge

Despite all the numerous advantages previously described, the issue of breastfeeding and breast milk is unique in the context of HIV. The problem of this challenge of exclusive breastfeeding during the first 6 months of life reached its peak in the context of feeding newborns of HIV-positive mothers. Indeed, despite its multiple anti-infectious properties, breastmilk in certain cases, particularly in cases of maternal HIV infection, is a road to vertical transmission depending on the duration of breastfeeding, the type of breastfeeding especially the practice of mixed feeding; depending on the state of maternal HIV infection (maternal viral load, level of immunosuppression) as well as local conditions for example, existence of subclinical or subclinical mastitis.^{21 -23}

However, starting ARVs makes it possible to reduce this risk of transmission significantly, provided viral load in breast milk becomes undetectable, that breastfeeding practices are correctly supervised and that the mother is fully adherent to her antiretroviral treatment. In certain cases, this antiretroviral treatment of the mother was supplemented by antiretroviral treatment of the newborns for a period which could extend up to a year to guarantee non-contamination of the children by their infected mother, likely non-compliant to ART.^{21,22,24 -26}

In recent years, new paediatric HIV infections result from contamination during pregnancy or breastfeeding and are a major target for intervention. ²⁴ In fact, breastfeeding is possible in the context of HIV, and is subject to correct intake and correct adherence to antiretroviral treatment and for good reason, many properties of breast milk are preserved even in HIV-positive women. In the remainder of this review, we will analyse variants in breast milk properties in infected mothers, the effects observed in exposed, uninfected children and the effects on the microbiome, and further justify, on the one hand, the continuation of breastfeeding to guarantee the survival of exposed, uninfected children.

HIV Transmission in Lactating HIV-infected Women

In any case, the transmission of HIV from mother to child and its risk has been estimated for the post-natal period at approximately 1% per month of breastfeeding, which can therefore increase the rate of transmission by 30% to 45% in the event of prolonged breastfeeding for more than 12 months in the absence of antiretroviral treatment.^22,27 It nevertheless remains that certain breastfeeding practices before the advent of generalised antiretroviral treatment saw a control of transmission through breast milk in the event of good breastfeeding, with transmission rates that did not exceed 4%; the current recommended transmission rate in breastfeeding populations according to recommendations for the elimination of mother-to-child transmission of HIV.^{28 -31}

The above explains that despite having HIV, a certain number of components of breast milk prevent the transmission of HIV from mother to child, making the great majority of women HIV non-transmitters; and their milk could have bioactive properties superior to transmitting mothers. It is therefore important to highlight the main bioactive components of breast milk with protective effects and then discuss questions related to antiretroviral treatment regarding these components.

Human Milk Oligosaccharides, Breastmilk and HIV

Breast milk sugars are composed of 85% lactose and between 10% and 15% breast milk oligosaccharides. The benefits of these oligosaccharides are increasingly documented through their role as prebiotic agents; they substantially modify the composition of the intestinal microbiome, preventing the occurrence of digestive infections and other infections, depending on their concentration. In addition, they are increasingly added to the composition of artificial infant formula.^32,33

Considering the differential factors between women who transmit HIV through breastfeeding and those who do not transmit it, after adjustment for factors such as maternal CD 4 rate, viral load and other elements of scalability of HIV infection, both quantity and quality of HMO can affect the risk of transmission. A higher concentration of oligosaccharides in breast milk was observed in non-transmitting women in a study that also reported a protective effect of non-3-sialyllactose. ³⁴ In addition to this protective effect, a direct action of HMO has been documented as Human milk oligosaccharides reduce HIV-1-gp120 binding to dendritic cell-specific on human dendritic cells, and this may limit HIV-1 entry across the infant’s mucosal. ³³ In fact, the oligosaccharides of breast milk, by their anti-adherent properties, can prevent the attachment of the virus to the target cells by limiting the junction with the protein glycans. These are perceived as potential antivirals not only for HIV infection but also for other antiviral infections, such as rotavirus infections, through the property of entry inhibitors.^35,36

In addition to the risk of anti-infectious transmission, the concentration of HMO creates a maternal bond in HIV infected women, leading to different mortality risks in children HIV exposed, uninfected during breastfeeding. This reduction in mortality seemed more obvious at the age of 2 years during the period of breastfeeding and not after, particularly in exposed non-infected children with higher maternal breast-milk concentrations of 2-linked fucosylated HMOs after adjustment for confounders. ³⁵ Furthermore, in a study in Kenya, the concentrations of HMO measured on a cohort during the first year of life were able to show effects on growth, particularly weight-for-age and height-for-age in HIV exposed uninfected children, with an improvement in growth in the event of a higher of concentrations of sialylated HMOs, 6-sialyllactose and sialyllactose-N-tetraose, confirming a relationship between some oligosaccharides of breast milk and post natal growth amongst this population. ³⁶ In fact, the benefits of HMOS on growth, morbidity of HIV exposed uninfected infants is a current area of research to better understand their overall effects on induced health and microbiome.^37,38

Gut Microbiota and Breast Milk in HIV Exposed Uninfected Infants

Certainly, bioactive factors and oligosaccharides in breast milk are known to influence the constitution and composition of the intestinal microbiome, an important element for preventing infection and structuring immunity.

Several studies appear to report deleterious effects of maternal HIV infection on the microbiome of exposed, uninfected children, which may contribute to a double excess mortality of these children compared to those unexposed to HIV. The question remains whether these facts are influenced by breastfeeding and maternal immunosuppression. In a study in Kenya, the characterisation of the bacterial microbiome and the DNA virome of breast milk at 1 month postpartum was done in women not receiving combined antiretroviral treatment with high or low CD4 levels. Among these women, the breastmilk virome was essentially composed of cytomegalovirus, and the diversity of both the bacterial microbiome and the virome did not appear to be affected by the level of immunosuppression, indicating the resilience of subpopulations in the context of immunosuppression and compartmentalisation of breast milk. ³⁸ Furthermore, in a similar study, the composition of the virome and bacterial microbiome of breastmilk in an HIV-endemic population revealed a greater bacterial diversity in exclusively breastfeeding women compared to those practising mixed feeding. Similarly, a higher frequency of lactobacilli was noted in cases of concomitant HIV/RNA detection. Overall, the composition of the breast milk microbiome appears to be affected by HIV status, type of lactation and may vary over time. ³⁹ The evolution of gut microbiome in a double population of HIV exposed uninfected children compared to those unexposed, shows some insignificant differences around 28 weeks, but these small differences were called to disappear within 3 years, cancelling any additional risk of vulnerability among HIV exposed uninfected children.^{39 -41}

Microbiome, HIV and Antiretroviral

The benefit of ART during breastfeeding to alleviate vertical transmission of HIV is no longer questionable. ARV acts by reducing both the quantity of virus in maternal plasma and in breastmilk, notably in cell-free-associated virus, with a reduction in HIV/RNA copies in breastmilk but a low effect on HIV/DNA. ⁴² These effects are correlated with the concentration of ARVs in breastmilk, accounting for the compartmentalisation of breastmilk. Antiretroviral therapy can affect the composition of the microbiome through different mechanisms, with different microbial colonisation resulting in lower bacterial diversity caused by altered microbial metabolism that may inactivate cytochrome P450.^{41 -43} Of note, the presence of high concentrations of antiretroviral ART metabolites (Lamivudine or Nevirapine(NVP)) in breastmilk was associated with a lower abundance of bifidobacteria in the infant’s gut microbiome, and this association correlated with NVP concentration in breastmilk. This could suggest the addition of bifidobacteria-based probiotics in breastfed children on maternal triple therapy or reinforcing the idea of prophylaxis in the infant. ⁴³ However, these data are controversial, as the dynamics of the microbiome composition did not appear to be affected by short antiretroviral regimens in the immediate postpartum period in Kenyan women, unlike antibiotics. ⁴⁴

Regarding Dolutegravir, its passage into breast milk has been shown at levels not worrisome for the safety of the newborn, which justifies its continued use in pregnant and breastfeeding women without any mentioned effect on the quality of the microbiome.^45,46

What is Next for Better Securing Breastmilk in the HIV Context?

The importance of breastfeeding even in populations born to HIV positive mothers is still relevant. The importance and effectiveness of antiretroviral therapy have significantly reduced the number of new HIV vertical transmissions, including through breastfeeding. The effects on the microbiome seem marginal or temporary. The generalisation of Dolutegravir use, which can be used effectively even in the last trimester of pregnancy, should be pursued, given its proven safety during breastfeeding. ⁴⁵ Overall, the passage of ARVs into breast milk, as objectified by the plasma concentration ratio/breast milk, is below the required safety thresholds, and the doses ingested by the child are infinitesimal. ⁴⁷ However, given the persistent risk of new paediatric HIV infections, particularly in the case of maternal contamination during breastfeeding, questions relating to preexposure prophylaxis (PreP) must be anticipated. ⁴⁸ At last, reducing new paediatric infections during breastfeeding overrides access to ARVs, and requires both sustained counselling and close monitoring of adherence to ensure viral load become undetectable. ⁴⁹

Conclusion

HIV transmission through breastfeeding still contributes to almost 50% of new HIV paediatric infections. The importance of breastfeeding is critical to achieving HIV-free survival in the context of the HIV epidemic and breastfeeding populations of resource-limited areas. This mini-narrative review relates the benefits of breastfeeding in children born to HIV-infected mothers, the importance of ARVs to limit their contamination, while recalling the benefits of oligosaccharides in breast milk in this population.

The issue of the concentration of antiretrovirals in the breast milk of mothers that can modify the intestinal microbiome of the child is counterbalanced by the limitation of the risk of acquiring an HIV infection; in addition, the prospects of using dolutegravir, which passes little into breast milk, should limit the deleterious effects on the intestinal microbiome of the child. Overall, the proven efficacy and safety of antiretrovirals urgently require the continuation of their use while reinforcing maternal adherence to this treatment to limit new paediatric HIV infections amongst HIV lactating mothers.