Epidemiology & Social
Breastmilk RNA viral load in HIV-infected South African women: effects of subclinical mastitis and infant feeding
Willumsen, Juana Fa; Filteau, Suzanne Ma; Coutsoudis, Annac; Newell, Marie-Louiseb; Rollins, Nigel Cc; Coovadia, Hoosen Mc; Tomkins, Andrew Ma
From the aCentre for International Child Health and the bCentre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, University College London, UK and the cDepartment of Paediatrics and Child Health, University of Natal Medical School, Durban.
Requests for reprints to: Dr J. Willumsen, Centre for International Child Health, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK.
Received: 21 February 2002; revised: 25 June 2002; accepted: 22 October 2002.
Objective: To investigate determinants of breastmilk RNA viral load among HIV-infected South African women, with particular attention to infant feeding mode and subclinical mastitis.
Design: Observational, longitudinal study.
Methods: Information on current infant feeding practice and a spot milk sample from each breast were obtained from 145 HIV-infected lactating women at 1, 6 and 14 weeks postpartum. The sodium/potassium (Na+/K+) ratio in milk was taken as an indicator of subclinical mastitis. The association between milk RNA viral load and maternal and infant characteristics was investigated using uni- and multivariate models.
Results: Milk viral load was below the limit of detection of the HIV RNA assay (< 200 copies/ml) in 63/185 (34.1%), 73/193 (37.8%) and 68/160 (42.5%) of samples at 1, 6 and 14 weeks, respectively. Multivariate models predicted between 13 and 26% of variability in milk viral load in the first 14 weeks. Low blood CD4 cell count (< 200 × 106 cells/l) during pregnancy and raised milk Na+/K+ ratio were significantly associated with raised milk RNA viral load at all times, but there were no consistent associations between infant feeding mode and RNA viral load in milk. There was a non-significant trend for the six infants known to be infected postnatally, compared with the 88 infants who remained uninfected, to have been exposed to breastmilk of higher viral load at each time point.
Conclusions: Breast milk HIV RNA viral load in the first 14 weeks of life varied; high levels were associated with subclinical mastitis and severe maternal immunosuppression. Multivariate models had limited predictive value for milk RNA viral load, illustrating the multiple contributors to viral load.
Breastfeeding increases the risk of postnatal mother-to-child HIV transmission . However, results from a recent study in Durban suggest that infants who are exclusively breastfed have a lower risk of HIV infection than infants mixed-fed with breastmilk plus other foods or liquids . It remains unclear how exclusive breastfeeding would reduce the risk of transmission but both maternal and infant health factors could be important. Previous work in the same setting investigated whether mixed feeding, relative to exclusive breastfeeding, increased infant intestinal permeability [3,4] or immune system activation, both of which could potentially increase postnatal HIV infection of breastfed infants . However, these infant-related mechanisms did not explain the protective effect of exclusive breastfeeding compared with mixed feeding .
The present study considers maternal factors, in particular subclinical mastitis, which is defined as a raised sodium/potassium (Na+/K+) ratio in breastmilk in the absence of symptoms of clinical mastitis [7–9]. Subclinical, like clinical, mastitis can result from several causes, such as a local mammary inflammation in response to either mechanical or infectious insult ; milk stasis and mammary gland involution as a result of reduced breastmilk production, as seen during weaning ; micronutrient deficiencies [8,12]; or systemic infection . During subclinical mastitis, disruption of mammary epithelial tight junctions may allow plasma constituents such as Na+ to leak into the alveolus [10,14], and inflammatory chemokine production [7,8,13] can increase influx of leukocytes. These conditions could result in an increase in breastmilk HIV viral load; consequently, subclinical mastitis has been tentatively implicated in the increased risk of postnatal HIV transmission . However, since both mastitis and detectable milk virus are often transient and unilateral [10,15], breastmilk from a single time point and a single breast will not provide a clear picture of the role of subclinical mastitis in postnatal HIV transmission. The associations between subclinical mastitis, breastmilk RNA viral load and infant feeding practices were investigated at three time points in a longitudinal study of breastfeeding HIV-infected women.
The field work for the study was conducted from November 1997 to December 1999. Initially women were recruited from an ongoing randomized placebo-controlled study of vitamin A supplementation during pregnancy based at McCord's Hospital, Durban , but after July 1998 women were recruited for this study only from the City Health Department Primary Health Care Clinic at Cato Manor, Durban. Women who, after counselling on HIV and infant feeding in accordance with UNAIDS guidelines , chose to breastfeed their infant were invited to participate in the study after giving written informed consent. They were supported throughout pregnancy and informed about the potential benefits of exclusive breastfeeding and how best to achieve this. Maternal blood CD4 and CD8 cell counts were measured by FACScan (Becton Dickinson, San Jose, California, USA), and socioeconomic data was collected at recruitment into the study during the third trimester of pregnancy. Gestational age at birth was determined from last menstrual period.
Women were asked to return with their infants to the study clinic at 1, 6 and 14 weeks postpartum. Women were asked about infant feeding practices and infant morbidity using standardized questionnaires. Infants were classified as exclusively breastfed if the mother reported giving only breastmilk and no other liquids or foods, apart from prescription medicines . All other breastfed infants were classified as mixed-fed. Infants were weighed to the nearest 10 g. Women were asked to provide a breastmilk sample of approximately 7 ml from each breast by hand expression into a sterile polypropylene screw-top jar. In some cases, sample size was decreased since women could not always provide sufficient sample from both breasts.
Breastmilk samples were stored in a cool place and processed within 2 h of collection. Samples of whole milk were stored at −80°C until analysed for Na+/K+ by flame photometry and for the inflammatory chemokine interleukin-8 by enzyme-linked immunosorbent assay . Severe subclinical mastitis was defined as an Na+/K+ ratio > 1.0 [7,8,19]. HIV RNA was measured in the cell-free supernatant produced by centrifuging 3 ml of whole milk at 1000 × g for 10 min and discarding the fat layer and cell pellet. The cell free supernatant was stored at −80°C until analysed for HIV RNA by the polymerase chain reaction (PCR) using Amplicor HIV-1 Monitor 1.5 (Roche Diagnostic Systems, Branchburg, New Jersey, USA), which has been shown to be sensitive for HIV clades present in KwaZulu-Natal (personal communication, Dr Dennis York, University of Natal Medical School, 1999). All samples were stored and analysed in batches during the period of fieldwork and within 2 months of completion of the study.
Information on infant HIV status was available from the initial vitamin A supplementation study within which this work was nested [2,16] for 131/145 infants and was determined by RNA PCR (Roche Molecular Systems, Branchburg, New Jersey, USA).
Data were entered and double-checked using EpiInfo version 6 and statistical analyses were carried out using SPSS 6.1.3 for Windows (SPSS Inc., Chicago, Illinois, USA). Variables that were not normally distributed were natural log (Na+/K+ ratio and interleukin-8) or log base 10 (milk viral load) transformed and geometric means and 95% confidence intervals (CI) reported. Gestational age (< 37 or ≥ 37 weeks) and CD4 cell count (< 200, 200–500, and >500 × 106 cells/l) were categorized. Univariate and multivariate analyses were carried out by linear regression for continuous dependent variables and logistic regression for categorical dependent variables to investigate factors associated with breastmilk RNA viral load levels. The interaction between breastmilk Na+/K+ ratio and feeding mode was also investigated since poor breastfeeding practices, which could result in milk stasis, are known to increase milk Na+/K+ ratio . Because of intraindividual differences in breastmilk Na+/K+ and viral load observed in many cases, data from both breasts of each woman at each time were included in all analyses except those for infant HIV status, for which the mother–infant pair was the unit of analysis.
A total of 145 lactating HIV-infected women and their infants were recruited into the study. Figure 1 shows the number of women sampled at each time point and explains the flow of women in and out of the study. Cessation of breastfeeding before 14 weeks was the main reason for leaving the study (29 mother–infant pairs) but 15 pairs were lost to follow-up and three infants died. Subject characteristics are shown in Table 1. The majority of women were unemployed, living in informal housing and had no electricity or running water.
Severe subclinical mastitis (Na+/K+ >1.0) was present in both breasts in 13/126 (10.3%) of women at 1 week, 4/116 (3.4%) of women at 6 weeks, and 2/83 (2.4%) of women at 14 weeks. In addition, severe subclinical mastitis in one breast only was present in 30/126 (23.8%) of women at 1 week, 22/116 (19.0%) of women at 6 weeks, and 19/83 (22.9%) of women at 14 weeks. The prevalence of bilateral subclinical mastitis decreased over time but unilateral did not.
Milk viral load was below the limit of detection of the HIV RNA PCR assay (< 200 copies/ml) in 63/185 (34.1%), 73/193 (37.8%) and 68/160 (42.5%) of samples at 1, 6 and 14 weeks, respectively . The mean RNA viral loads for only those samples with detectable virus were 2630 copies/ml (95% CI, 1895–3650; n = 122) at 1 week, 2831 copies/ml (95% CI, 2029–3948; n = 120) at 6 weeks and 2809 copies/ml (95% CI, 1995–3955; n = 92) at 14 weeks. In further analyses, breastmilk samples with undetectable RNA viral load were assigned the detection cutoff value of 200 copies/ml. Geometric mean HIV RNA viral load was 1094 copies/ml (95% CI, 829–1443; n = 185) at 1 week, 1039 copies/ml (95% CI, 790–1366; n = 193) at 6 weeks and 914 copies/ml (95% CI, 690–1210; n = 160) at 14 weeks.
Results of univariate analyses are shown in Table 2. At all times, there was a significant positive association between the natural log of milk Na+/K+ ratio and the log milk RNA viral load and between the interleukin-8 concentration and the log milk RNA viral load (P < 0.001). Breastmilk RNA viral load was higher at 1 week (P = 0.003) and 6 weeks (P = 0.004) in women who were more immunosuppressed, as indicated by CD4 cell count < 200 × 106 cells/l. Feeding mode was significantly (P = 0.017) associated with log milk RNA viral load only at 14 weeks, when women exclusively breastfeeding had higher log milk RNA viral load than those mixed-feeding. The log breastmilk RNA viral load was higher for girls than for boys at 1 week (P = 0.023) and 14 weeks (P = 0.031),. At 1 week, women who were delivered by caesarean section had a lower milk viral load than those who were delivered vaginally (P = 0.029). At 14 weeks, a larger percentage infant weight gain since the previous visit was associated with a lower log breastmilk RNA viral load (P = 0.022).
The results of multivariate analyses are shown in Table 3, with variables selected because they were of interest a priori or because they were significantly related to milk RNA viral load in univariate analyses. Interleukin-8 concentration was not included in multivariate analyses because of its high degree of colinearity with Na+/K+ ratio [correlation coefficients positive and statistically significant (P < 0.001) at all times]. The week 1 association of viral load with mode of delivery was considered to be a consequence of confounding with unmeasured factors and, therefore, was not included. Multivariate models predicted 25.9% of the variation in breastmilk log viral load at 1 week, 13.4% at 6 weeks, and 20.7% at 14 weeks. The natural log Na+/K+ ratio was significantly associated with log RNA viral load at all three times (1 week, P = 0.022; 6 weeks, P = 0.002; 14 weeks, P = 0.007). Feeding mode was not significantly associated with log milk RNA viral load at 1 week (P = 0.123) and 6 weeks (P = 0.978), but at 14 weeks exclusive breastfeeding was significantly associated with a 0.45 log copies/ml increase in HIV RNA load compared with mixed feeding (P = 0.014). A CD4 cell count of < 200 × 106 cells/l during pregnancy was associated with an increased log milk RNA viral load at all three times (1 week, P = 0.014; 6 weeks, P = 0.010; 14 weeks, P = 0.032) compared with women having a CD4 cell count >500 × 106 cells/l. Greater percentage weight gain since the previous visit was associated with a decreased log RNA viral load (B = −0.46, P = 0.047 at 6 weeks; B = −0.865, P = 0.009 at 14 weeks).
Mode of feeding may be related to the effect of Na+/K+ ratio, as a measure of subclinical mastitis, on log RNA viral load in milk. The interaction between mode of feeding and the natural log Na+/K+ ratio was investigated at each time and found to be statistically significant only at 1 week (P < 0.001), with a coefficient for the natural log Na+/K+ ratio of 2.05 (95% CI, 1.30–2.79) for mixed feeders and −1.09 (95% CI, −1.65 to −0.53) for exclusive breastfeeders.
This study was not designed to investigate the relationship between breastmilk Na+/K+ or RNA viral load and postnatal transmission of HIV to the infant. However, as HIV status was known for 131 infants, its association with breastmilk components and maternal CD4 cell count was explored. At the last sample available, 89 infants were HIV negative but for one of these no milk data were available; 25 infants were positive by the 6 week sample (i.e., first positive at birth, 1 or 6 weeks); six were known to be negative in the 6 week sample, and positive thereafter; and 11 infants were positive in the only sample available, usually that taken at 6 or 9 months. Therefore, 25 infants were assumed to have been infected in utero or perinatally; six infants were assumed to be infected postnatally through breastfeeding; and 11 were infected at an unknown time. Table 4 shows the mean for the higher value of viral load or Na+/K+ of each woman's breasts at each time; this analysis was chosen to investigate whether the maximum value an infant is exposed to at any time predicts risk of postnatal HIV transmission. At each time, maximum RNA viral load in milk for infants infected postnatally tended to be higher than in milk for infants who remained uninfected, but this never reached statistical significance. Infants infected in utero or perinatally were exposed to milk with the highest viral load at all times, especially week 1. The Na+/K+ ratio was significantly higher, compared with the uninfected group, at 14 weeks in the milk of women whose infants were infected postnatally (P = 0.021), and at 6 weeks in milk of women whose infants were infected before 6 weeks (P < 0.001) or at an unknown time (P = 0.009). Only at 6 weeks was there a significant difference (chi-square, P = 0.004) in proportion of women with severe subclinical mastitis (Na+/K+ >1.0): percentage unilateral and bilateral severe subclinical mastitis, respectively, was 13 and 1% in women with uninfected infants, 21 and 16% in women with infants infected before 6 weeks, 50 and 0% in women with infants infected after 6 weeks, and 44 and 0% in women with infants infected at an unknown time. There was a non-significant trend (ANOVA P = 0.062) for CD4 cell count during pregnancy to be lowest in the group infected in utero or perinatally.
High HIV DNA and RNA viral loads in plasma [20,21] and milk [9,22] are risk factors for mother-to-child transmission and may, in part, explain the increased risk of transmission from women with advanced stages of HIV infection, as indicated by low blood CD4 cell count [16,23], and with recent primary HIV infection . The present study investigated determinants of milk RNA viral load in an effort to understand the lower rate of vertical transmission with exclusive breastfeeding . The association between RNA viral load and subclinical mastitis was investigated since the latter could theoretically result in higher free and cell-associated virus in milk.
RNA was detectable in only about 60% of samples at each time and the multivariate models were not strong predictors of milk RNA viral load at any point in the first 14 weeks postpartum. In other work from this cohort, the ability to predict a woman's milk viral load was complicated by the great variability in viral load between breasts and across time , suggesting undefined local control mechanisms. Nevertheless, subclinical mastitis was consistently associated with higher viral load after allowing for maternal immunosuppression, feeding mode and weight gain. Advanced immunosuppression (CD4 cell count < 200 × 106 cells/l) was associated with about 0.5 log copies/ml higher breastmilk RNA viral load at each time compared with women with CD4 cell count > 500 × 106 cells/l. It is possible that the correlation between milk Na+ and RNA viral load among HIV-infected women in the present study and in Malawi  was secondary to systemic infections , which may have increased mammary permeability and plasma viral load. Both of these could, in turn, contribute to increased milk viral load. However, systemic infection tends to induce bilateral subclinical mastitis , whereas after 1 week, most subclinical mastitis was unilateral, possibly because of poor lactation practice, which induces milk stasis and leads to increased permeability.
We hypothesized that exclusive breastfeeding would be associated with lower RNA viral load and decreased subclinical mastitis. In our analysis, feeding mode was assessed dichotomously as exclusive breastfeeding or not, with no detailed information about breastfeeding practices; however, given the support for exclusive breastfeeding in this setting, very few women reported mixed feeding and it is likely that they were not actually adding much to the breastmilk. There was no interaction between feeding mode and the effect of Na+/K+ ratio on RNA viral load at 6 and 14 weeks, although it is important to note that there were few women giving mixed feeds. The significant interaction at 1 week is hard to interpret as it relates to a time when lactation is being established and biochemical changes are rapid . It is possible that exclusive breastfeeding at this time was able to protect against the increased viral load associated with subclinical mastitis, but, equally, some women may not have been able to breastfeed exclusively for other health reasons, which may have induced subclinical mastitis. This is another reason to suspect an interaction between maternal health and feeding practice, leading to increased risk of HIV transmssion.
The sample size of this study was not sufficiently large to determine the influence of subclinical mastitis and breastmilk RNA viral load on postpartum transmission of HIV since only six infants were known to have become HIV positive by the PCR assay later than 6 weeks. Nevertheless, there was a trend for higher viral load at all times in the mothers of the postnatally infected group compared with the uninfected group and a significantly higher Na+/K+ ratio in milk at 14 weeks. Women whose infants became HIV positive by 6 weeks tended to have the highest milk viral load. These infants may have acquired infection through breastmilk early in life, but available techniques cannot distinguish this from delivery-acquired infection. Furthermore, the high viral load likely indicates more advanced maternal disease, as suggested by the low CD4 cell count in this group, and thus overall high risk of transmission.
The finding in both uni- and multivariate analyses that mothers of infants who gained more weight by 6 or 14 weeks had lower breastmilk viral load at that time may be caused by the infant's efficient emptying of the breast, which would avoid milk stasis, subclinical mastitis and other conditions favouring the shedding of HIV into breastmilk. Such increased growth and demand for breastmilk may explain the lower viral load in milk of women feeding boys than girls in univariate analyses, although this effect was no longer significant in multivariate analyses.
Breastfeeding remains a cornerstone for child health in developing countries. For the vast majority of women infected with HIV, guaranteed access to nutritionally complete breastmilk substitutes and hygienic conditions in which to prepare feeds is unachievable. Therefore, low-cost methods are urgently needed to make breastfeeding as safe as possible for these women and infants. Given the great variability of milk viral load over time, such that its measurement at any given time is not reliably indicative of the extent of an infant's exposure to virus, any intervention to reduce postnatal transmission has to reduce viral load consistently. Such interventions could include, in addition to antiretroviral drugs, strategies to reduce subclinical mastitis, although it is not yet known to what extent the association between subclinical mastitis and milk viral load is causal. Furthermore, in the present study, only about 60% of women at each time had detectable RNA in milk and only 40% of these women had mild or severe subclinical mastitis; the attributable fraction of subclinical mastitis to detectable viral load is less than 5%. Nevertheless, strategies that might decrease subclinical mastitis – prevention or rapid treatment of infections, extra lactation counselling or micronutrient supplementation – merit investigation since they are relatively low cost and involve strengthening maternal care during pregnancy, at delivery and postpartum; they can, therefore, be directed towards improving overall health of all women without the need for HIV testing.
The authors gratefully acknowledge the assistance of the teams providing counselling, support and clinical care to the mothers involved during data collection; the superintendent and staff of McCord's Hospital and the Durban City Health Department and the staff of Cato Manor clinic for permission to work at these sites; laboratory staff, including Frances Taylor, Subitha Dwarika and Dennis York for assistance with analyses and Linsay Gray for help with statistical analyses.
Sponsorship: We are grateful for funding for the study from the UK Department for International Development, UNICEF South Africa, and Virgin Airways through the Great Ormond Street Hospital Trustees. This work was undertaken in collaboration with Great Ormond Street Hospital for Children NHS Trust which receives a proportion of its funding from the NHS Executive.
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