Galli L, Puliti D, Chiappini E, et al. Is the interruption of antiretroviral treatment during pregnancy an additional major risk factor for mother-to-child transmission of HIV type 1? Clin Infect Dis 2009;48:1310-7.
To evaluate the effects of discontinuing antiretroviral therapy (ART) during the first and third trimesters of pregnancy on the rate of mother-to-child transmission (MTCT) of HIV.
Prospective cohort study. Data came from the Italian Register for HIV Infection in Children, a nationwide multicenter study of children perinatally exposed to HIV-1 that was instituted in 1985. The network includes 106 participating pediatric centers throughout Italy and is representative of the overall population of exposed infants in Italy. Maternal interruption of ART was defined as the discontinuation of any ART for >15 days.
Infants of HIV-infected women receiving ART for their own health and not for prophylaxis. Only children born during 2002 through 2004 were evaluated. Of 1,016 mother-child pairs receiving ART during this time, 937 entered the study. Seventy-nine (7.8%) HIV-exposed infants were excluded because they were lost to follow-up before infection status was determined. Intrapartum and neonatal prophylaxis consisted of zidovudine in all but eight cases in which nevirapine was given. Discontinuation and subsequent continuation of ART was reported in 81 (8.6%) of the 937 mothers who were in the first trimester of pregnancy (median time at suspension, 6 weeks [interquartile range (IQR) 5-6 weeks]; median time without treatment, 8 weeks [IQR 7-11 weeks]) and in 11 (1.2%) of the mothers in the third trimester (median time at suspension, 32 weeks [IQR 23-36 weeks]; median time without treatment, 6 weeks [IQR 2-9 weeks]). Only one mother, who gave birth to an uninfected child, had treatment interrupted during both the first and third trimesters. Among women whose viral load at delivery was known, the mean plasma viral load was similar in those who had treatment interrupted in the first trimester (2.04 log10 copies/mL; 95% confidence interval [CI]: 1.81-2.26 log10 copies/mL) and in those who did not have treatment interrupted (2.04 log10 copies/mL; 95% CI: 1.95-2.14 log10 copies/mL; Student t test, -0.04; P=0.967).
HIV infection status of children, which was defined as reported in the database
HIV infection was detected in 12 children, giving an overall MTCT rate of 1.3% (95% CI: 0.7%-2.3%). Rate of MTCT was 4.9% (95% CI: 1.9%-13.2%) when ART was interrupted in the first trimester and 18.2% (95% CI: 4.5%-72.7%) when ART was interrupted in the third trimester. In a multiple logistic regression model, only interruption of ART during either the first (adjusted odds ratio [OR] 10.33, 95% CI: 2.02-52.91) or the third trimester (adjusted OR 46.86, 95% CI: 4.28-512.64); maternal mono- or dual therapy compared to highly active ART (HAART) (adjusted OR 0.17, 95% CI: 0.04-0.80); delivery by a mode other than elective cesarean delivery (adjusted OR 5.9, 95% CI: 0.93-37.28); and a viral load at delivery of >4.01 log10 copies/mL (adjusted OR 29.19, 95% CI: 1.80-473.81, compared to reference of <2.6 log10 copies/mL) were independently associated with an increased rate of MTCT. Other factors (maternal CD4+ cell count at delivery, trimester at the start of ART, child's sex, and intrapartum and neonatal antiretroviral prophylaxis) were not significantly associated with the rate of MTCT. When the 79 exposed infants lost to follow-up were included in the model, with the assumption that all these children were uninfected, results were unchanged.
The authors conclude that discontinuing ART during pregnancy increases the rate of MTCT of HIV-1, either when ART is stopped in the first trimester and subsequently restarted or when it is interrupted in the third trimester.
Using the Newcastle-Ottawa Quality Assessment Scale for cohort studies, this study was of good quality. The cohort was representative of infants exposed to HIV-1 in Italy. The use of multiple logistic regression models allowed for control of possible confounders. Because the data are from a large pediatric cohort, however, some detailed information on the mothers, such as maternal viral load at delivery and during gestation, reasons for ART discontinuation, compliance with ART, and genotype resistance in the mothers, was lacking. When mother-child pairs were compared according to whether maternal viral load was known or unknown, exactly the same MTCT rate was found. As an additional check, three logistic regression models were performed, but the main role of ART interruption in pregnancy was consistently found. Moreover, the study could not assess whether infected children born to mothers who had ART interrupted acquired the infection in utero or perinatally because the investigators did not systematically measure HIV-1 RNA or DNA load during the first 24- 48 hours of life. Because 79 infants were lost to follow-up, they were not included in the analysis, which may have introduced bias. Finally, the very low number of infected children in the whole cohort and, consequently, the wide confidence intervals, are additional caveats.
There is currently an experts' agreement discouraging interruption of ART during the first trimester of pregnancy in women infected with HIV-1. Before this study, however, this recommendation was poorly supported by data. This is the first study to reveal that discontinuing ART during pregnancy increases the rate of MTCT of HIV-1, either when ART is stopped in the first trimester and subsequently restarted or when it is interrupted in the third trimester. The last finding was partly expected, because discontinuation of treatment could lead to a viremic rebound(1, 2) and because a higher viral load near the time of delivery increases the risk of MTCT.(3,4)
The finding in this study supports recommendations to continue ART in pregnant women who are already receiving treatment for their health.
- Bucceri AM, Somigliana E, Matrone R, et al. Discontinuing combination antiretroviral therapy during the first trimester of pregnancy: insights from plasma human immunodeficiency virus-1 RNA viral load and CD4 cell count. Am J Obstet Gynecol 2003;89:545-51.
- The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med 2006;355:2283-96.
- Garcia PM, Kalish LA, Pitt J, et al, and the Women and Infants Transmission Study Group. Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission. New Engl J Med 1999;341:394-402.
- European Collaborative Study. Maternal viral load and vertical transmission of HIV-1: an important factor but not the only one. AIDS 1999;13:1377-85.