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Cytomegalovirus (CMV) DNA load in breast milk of human immunodeficiency virus-positive women and infant CMV infection acquisition are not reduced with long-term antiretroviral therapy

2017; Elsevier BV; Volume: 23; Issue: 7 Linguagem: Inglês

10.1016/j.cmi.2017.02.004

1469-0691

Marina Giuliano, Maria Franca Pirillo, Giuseppe Liotta, Mauro Andreotti, Marco Floridia, Fausto Ciccacci, Haswel Jere, Jean Baptiste Sagno, Roberta Amici, S Mancinelli, Maria Cristina Marazzi, Stefano Vella, Leonardo Palombi,

HIV Research and Treatment

in low-income countries, where breastfeeding is the norm, infant cytomegalovirus (CMV) infection is very common [[1]Chang T.S. Wiener J. Dollard S.C. Amin M.M. Ellington S. Chasela C. et al.Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers.AIDS. 2015; 29: 831-836Crossref PubMed Scopus (16) Google Scholar], due to almost universal CMV seropositivity in mothers and virus shedding in breast milk at high copy number, with higher levels in human immunodeficiency virus (HIV) -positive women [2Jim W.T. Shu C.H. Chiu N.C. Chang J.H. Hung H.Y. Peng C.C. et al.High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants.Pediatric Infect Dis J. 2009; 28: 891-894Crossref PubMed Scopus (46) Google Scholar, 3Musonda K.G. Nyonda M. Filteau S. Kasnga L. Monze M. Gompels U.A. Increased cytomegalovirus secretion and risks of infant infection by breastfeeding duration from maternal human immunodeficiency virus positive compared to negative mothers in sub-Saharan Africa.J Pediatr Infect Dis Soc. 2016; 5: 138-146Crossref PubMed Scopus (7) Google Scholar]. In such settings, breastfeeding is considered a major route of CMV acquisition. Different reports have shown lower rates of infant CMV acquisition in the era of antiretroviral treatment (ART), compared with the era in which HIV-positive mothers were not treated. This has been shown both for congenital infection [[4]Guibert G. Warszawski L. Le Chenedac J. Blanche S. Benmebarek Y. Mandelbrot L. et al.Decreased risk of congenital cytomegalovirus infection in children born to HIV-1-infected mothers in the era of highly active antiretroviral therapy.Clin Infect Dis. 2009; 48: 1516-1525Crossref PubMed Scopus (65) Google Scholar] and for perinatal/early postpartum transmission in a non-breastfeeding population [[5]Frederick T. Homans J. Spencer L. Kramer F. Stek A. Operskalski E. et al.The effect of prenatal highly active antiretroviral therapy on the transmission of congenital and perinatal/early postnatal cytomegalovirus among HIV-infected and HIV-exposed infants.Clin Infect Dis. 2012; 55: 877-884Crossref PubMed Scopus (38) Google Scholar]. However, studies in breastfeeding populations assessing infant CMV infection at 12–24 months of age, have shown high rates of CMV positivity (>80%) also in the presence of maternal ART [[1]Chang T.S. Wiener J. Dollard S.C. Amin M.M. Ellington S. Chasela C. et al.Effect of cytomegalovirus infection on breastfeeding transmission of HIV and on the health of infants born to HIV-infected mothers.AIDS. 2015; 29: 831-836Crossref PubMed Scopus (16) Google Scholar]. In these studies, however, women had received a relatively short-term ART during pregnancy and postpartum (up to 6 months), which had limited effects in reducing breast-milk CMV viral load. There have been suggestions that a longer duration of ART, inducing a better immunological control, could have a greater impact on breast-milk viral load, and it is therefore relevant to evaluate this hypothesis in the context of an Option B-plus approach. For this reason we conducted this study to evaluate if ART administered during pregnancy for more than 4 months and for 1 year after delivery could influence CMV viral load in breast milk in HIV-positive women and CMV acquisition in infants. We studied mothers and infants enrolled in an observational study aimed to assess infant growth under the Option B-plus approach (life-long antiretroviral administration for all HIV-infected pregnant women). The study was approved by the National Health Research Committee in Malawi. In the study, HIV-positive pregnant women received as soon as possible during pregnancy a combination regimen including tenofovir, lamivudine and efavirenz and continued it indefinitely after delivery. Breastfeeding was recommended up to 2 years of age with the first 6 months of exclusive breastfeeding. Breast milk samples were collected from mothers 1 and 12 months after delivery. Blood samples were collected from infants at 12 months of age. Cytomegalovirus DNA was assessed in breast milk using the kPCR CMV DNA Assay (Siemens Healthcare, Erlangen, Germany) with a limit of detection of 215 IU/mL (2.33 log10 IU/mL). Infant CMV serology was performed using the Enzygnost CMV IgG assay (Siemens Healthcare). HIV RNA was quantified in plasma and breast milk using the Versant kPCR 1.0 assay (Siemens Healthcare) with a detection limit of 37 copies/mL (1.6 log10 copies/ml). Characteristics of the 30 women included in the study are reported in Table 1. Women had received a median of 17 weeks of therapy during pregnancy. Breast milk CMV DNA was 4.4 log10 IU/mL at Month 1 and 4.4 log10 IU/mL at Month 12. In two samples at Month 12 CMV DNA was not detectable. There was no correlation between CMV DNA at either Month 1 or Month 12 and duration of antiretroviral treatment during pregnancy, CD4+ cell count, HIV RNA levels in plasma or breast milk. Out of 14 infant samples tested at 12 months of age, 13 (92.8%) were IgG positive.Table 1Patient characteristicsCharacteristicValueMothers, n.30Age, years27.5 (23.0–31.3)ART duration in pregnancy, days121.5 (61.5–138.0)Baseline CD4+ cell count, cells/mm3469 (268–548)Plasma HIV RNA load at Month 1, log10 copies/mL1.6 (1.6–2.8)Breast-milk HIV RNA load at Month 1, log10 copies/mL1.6 (1.6–1.6)Breast-milk CMV DNA load at Month 1, log10 IU/mL4.4 (4.0–5.1)CD4+ cell count at Month 12, cells/mm3637 (560–801)Plasma HIV RNA load at Month 12, log10 copies/mL1.6 (1.6–1.8)Breast-milk HIV RNA load at Month 12, log10 copies/mL1.6 (1.6–1.6)Breast-milk CMV DNA load at Month 12, log10 IU/mL4.4 (3.7–4.9)Results are reported as medians (interquartile range).Abbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; HIV, human immunodeficiency virus. Open table in a new tab Results are reported as medians (interquartile range). Abbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; HIV, human immunodeficiency virus. Postnatal acquisition of CMV infection is generally considered not associated with major health problems (with the possible exception of transmission of infection in premature and low-birthweight infants [[6]Hamprecht K. Maschmann J. Jahn G. Poets C.F. Goelz R. Cytomegalovirus transmssion to preterm infants during lactation.J Clin Virol. 2008; 41: 198-205Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar]), in comparison with the case for congenital infections. However, an association between CMV infection acquired through breastfeeding and impairment of growth parameters has been reported in Zambia [[7]Gompels U.A. Larke N. Sanz-Ramos M. Bates M. Musonda K. Manno D. et al.Human cytomegalovirus infant infection adversely affects growth and development in maternally HIV-exposed and unexposed infants in Zambia.Clin Infect Dis. 2012; 54: 434-442Crossref PubMed Scopus (71) Google Scholar]. Different studies have shown that CMV DNA load in breast milk is higher in mothers who transmit CMV infection to their infants compared with those who do not transmit [[2]Jim W.T. Shu C.H. Chiu N.C. Chang J.H. Hung H.Y. Peng C.C. et al.High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants.Pediatric Infect Dis J. 2009; 28: 891-894Crossref PubMed Scopus (46) Google Scholar]. The hypothesized mechanism by which ART may play a role in infant CMV infection acquisition is that with restored immunological control the quantity of circulating virus is reduced and mucosal shedding is decreased. Our findings showed that the immune reconstitution secondary to long-term ART (>15 months with an increase in median CD4+ cell count from 469/mm3 at baseline to 637/mm3 1 year after delivery) did not result in a significant decline in CMV DNA viraemia in breast milk, which remained high and stable between 1 and 12 months after delivery. Also, CMV rate of infection in 1-year-old children was high, suggesting no protection from the acquisition of CMV infection with the Option-B plus approach. Other strategies are needed to reduce the burden of infant CMV disease in low-income settings. S.V. has received honoraria from ViiV, Gilead and Merck for scientific board membership. The remaining authors have no conflicts of interest to declare. This work was supported by a grant from the Ministry of Health, Rome, Italy (grant no. 3C04/1) and by Esther-Italy, Ministry of Health (grant no. 9M34).