Zambian newborns exposed to HIV and antiretroviral drugs: Evolution of neutrophil cell count in the first 6 months. Sub-­study of the ANRS 12174 trial in Zambia

Background: The efficacy of antiretroviral drugs (ARVs) for the prevention of HIV transmission from mother to child is one of the greatest successes of antiretroviral therapy. However, concern has been expressed in several studies about potential side effects of antenatal and neonatal exposure to antiretroviral drugs such as the occurrence of low neutrophil cell in infants during the early months of life. A number of children were potentially eligible for the ANRS 12174 trial but were finally not included because their absolute neutrophil counts was low. These children are provided with nevirapine according to WHO recommendations and the national programme. Objectives: To investigate evolution of the neutrophil cell count during the first 6 months of life in HIV-­‐exposed, uninfected children subjected to antiretroviral drugs perinatally and with low neutrophil count. Design: A prospective longitudinal cohort study related to the ANRS 12174 trial. Subjects and methods: We enrolled 56 uninfected infants born to HIV-­‐positive mothers on antiretroviral drugs (zidovudine, lamivudine, nevirapine) during pregnancy and child birth, 18 with neutrophil count too low to be included in the trial (“study group”, receiving nevirapine during breastfeeding as ‘standard of care’) and 38 with neutrophil count just above the cut-­‐off for inclusion in the trial (“comparative group”, receiving one of the two study drugs, lamivudine/ Kaletra®). Maternal CD4+ cell counts were assessed before delivery and neonatal characteristics include gender, gestational age, weight and length. Clinical condition, growth and absolute neutrophil count were followed up to 26 weeks of age. Non-­‐improvers were compared to improvers. Results: The mean gestational age at birth was 38.0 (SD ± 1.7) weeks and the mean birth weight was 3.0 (±0.4) kg. There was gender balance in the group of 56 enrolled infants, 27 girls and 29 boys. The mean absolute neutrophil counts at day 7 and at week 26 were: 1) in the study group, 1.0 (±0.2) and 1.6 (± 0.7), respectively; and 2) in the comparative group 1.4 (±0.2) and 2.1 (±1.2), respectively. The non-­‐improvers in terms of absolute neutrophil count (= deteriorating, remaining low or very slight improvement) in the study and the comparative group were 5/18 and 6/38 infants, 6 respectively). No statistical association was found between non-­‐improvement and selected potential predictors. All infants were apparently thriving with no apparent concurrent conditions and did not receive any other medications except for septrim and the follow-­‐up drugs. There was no statistically significant difference in growth between the non-­‐improvers and the improvers. Conclusion: With the limitations of this study, such as small sample size, lack of appropriate control group, low follow-­‐up intensity, short duration of follow-­‐up and the question mark around the usefulness of the DAIDS tables, we conclude that 1) infants exposed to HIV-­‐1/ART antenatelly and who received nevirapine or lamivudine/Kaletra® from birth up to age week 26 may be at risk for transient low absolute neutrophil count; 2) such neutropenia can be moderate to severe and still not generate any apparent morbidity in the form of hospitalisations or other severe illnesses; 3) over the first 6 months, there is a good chance that the child recovers spontaneously and 4) these infants as a group present a growth as expected which is an indication that they are doing OK