Hematologic Effects of Maternal Antiretroviral Therapy and Transmission Prophylaxis in HIV-1-Exposed Uninfected Newborn Infants

Feiterna‐Sperling, Cornelia; Weizsaecker, Katharina; Bührer, Christoph; Casteleyn, S.; Loui, Andrea; Schmitz, Thomas; Wahn, V.; Obladen, Michael

doi:10.1097/qai.0b013e318042d5e3

Cited by 70 publications

(49 citation statements)

References 31 publications

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“…These observations are consistent with short-term hematological disturbances seen in clinics (12,25). However, in this pilot study, no correlation was found between intracellular NRTI-MP/TP concentrations and short-term toxicity data at birth and at 1 month, 3 months, and 6 months of age.…”

Section: Discussionsupporting

confidence: 79%

High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

Durand-Gasselin

Pruvost

Dehée

et al. 2008

Antimicrob Agents Chemother

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Section: Discussionsupporting

confidence: 79%

High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

Durand-Gasselin

Pruvost

Dehée

et al. 2008

Antimicrob Agents Chemother

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“…A previous study showed that newborns are likely to be overexposed to AZT/AZT-MP/AZT-TP and 3TC-TP during the first 2 weeks of life (10). These observations are consistent with short-term hematological disturbances seen in clinics (7,11). However, no correlation was found between intracellular nucleoside reverse transcriptase inhibitor monophosphate (NRTI-MP)/TP concentrations and short-term toxicity data at birth and at 1, 3, and 6 months of age.…”

Section: Discussionsupporting

confidence: 77%

“…Newborns are likely to be overexposed to intracellular phosphorylated nucleoside reverse transcriptase inhibitors (NRTIs), as was shown for lamivudine triphosphate (3TC-TP) and zidovudine triphosphate (AZT-TP) during the first 2 weeks of life (10). Indeed, high levels of AZT/AZT monophosphate (AZ-MP)/AZT-TP, and 3TC-TP were consistent with short-term hematological disturbance observed in clinics (7,11). If, as suggested by the literature (10), this overexposure was related to a more efficient phosphorylation due to a higher activation in the peripheral blood mononuclear cells (PBMCs) of the neonates than in adults, it could be the same for TFV-DP and could cause…”

mentioning

confidence: 89%

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Hirt

Ekouévi

Pruvost

et al. 2011

Antimicrob Agents Chemother

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The objective of this study was to investigate for the first time tenofovir (TFV) pharmacokinetics in plasma and peripheral blood mononuclear cells (PBMCs) of the neonate. HIV-1-infected pregnant women received two tablets of tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) at onset of labor and then one tablet daily for 7 days postpartum. A single dose of 13 mg/kg of body weight of TDF was administered to 36 neonates within 12 h of life after the HIV-1-infected mothers had been administered two tablets of TDF-emtricitabine at delivery. A total of 626 samples collected within the 2 days after the drug administration were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and analyzed by a population approach. In the neonate, the median TFV plasma area under the curve and minimal and maximal concentrations, respectively, were 3.73 mg/liter ⅐ h and 0.076 and 0.29 mg/liter. In PBMCs, TFV concentrations were detectable in all fetuses, whereas tenofovir diphosphate (TFV-DP) was quantifiable in only two fetuses, suggesting a lag in appearance of TFV-DP. The median TFV-DP neonatal concentration was 146 fmol/10 6 cells (interquartile range [IQR], 53 to 430 fmol/10 6 cells); two neonates had very high TFV-DP concentrations (1,530 and 2963 fmol/10 6 cells). The 13-mg/kg TDF dose given to neonates produced plasma TFV and intracellular active TFV-DP concentrations similar to those in adults. This dose should be given immediately after birth to reduce the delay before the active compound TFV-DP appears in cells.The combination tenofovir (TFV) disoproxil fumarate (TDF)-emtricitabine (FTC) has been considered during the perinatal period to prevent mother-to-child transmission (PMTCT) and/or to reduce viral resistance to nevirapine (NVP) (3, 8); its administration to pregnant women at the onset of labor followed by a single dose to the neonate was thus proposed. The TEmAA (Tenofovir/Emtricitabine in Africa and Asia) ANRS 12109 Trial study was an open, phase I/II trial built in two steps. In the first step, the TDF-FTC combination was administered to HIV-infected pregnant women, and the pharmacokinetics, safety, and toxicity were evaluated for mothers and their newborns (2). After estimation of the maternal and fetal FTC-tenofovir (TFV) pharmacokinetic profiles, the mother was proposed to renew the dose after 12 h if she had not delivered yet in order to maintain effective TFV fetal concentrations. Then, a 13-mg/kg of body weight TDF dose (at birth) was proposed for neonates to obtain similar exposure to that in adults (16). In the second step of the TEmAA study, the TDF-FTC combination was administered to HIV-infected pregnant women and to their newborns, allowing evaluation of these dose propositions based on the results obtained in the first step of the study. Tolerance and virological results have been reported elsewhere (24).TFV, like other nucleoside analogues, undergoes intracellular phosphorylation by various cellular kinases to an active diphosphate (TFV-DP), which competiti...

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“…Also, the antiretroviral (ARV) prophylaxis of vertical transmission can act on the placental environment, causing changes in cytokine expression (9). The newborns present abnormalities in mitochondrial function (2), in hematological features (5,10,17), and in the maturation of T and B lymphocytes (3,4,8,11,12,20,24,25).…”

mentioning

confidence: 99%

Impaired Humoral Response to Vaccines among HIV-Exposed Uninfected Infants

Abramczuk

Mazzola

Moreno

et al. 2011

Clin. Vaccine Immunol.

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Little is known about the vaccine protective response for infants born from HIV-infected mothers. We evaluated the antibody response to hepatitis B, tetanus, and diphtheria vaccine in vertically HIV-exposed uninfected infants and compared them to those of control infants not exposed to the virus. The quantitative determination of specific neutralizing antibodies against hepatitis B, diphtheria, and tetanus were performed blindly on serum samples. The results showed that 6.7% of the HIV-exposed uninfected individuals were nonresponders to hepatitis B vaccine (anti-HBs titer, <10 mIU/ml), and 64.4% were very good responders (anti-HBs titer, >1,000 mIU/ml), whereas only 3.6% of the nonexposed infants were nonresponders ( 2 ‫؍‬ 10.93; 1 df). The HIV-exposed uninfected infants showed protective titers for diphtheria and tetanus but lower geometric mean anti-tetanus titers compared to those of the HIV-unexposed infants. Our data point to the necessity of evaluating vaccine immune responses in these children and reinforced that alterations in lymphocyte numbers and functions reported for newborns from HIV-infected mothers interfere with the vaccine response.

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Hematologic Effects of Maternal Antiretroviral Therapy and Transmission Prophylaxis in HIV-1-Exposed Uninfected Newborn Infants

Abstract: Antiretroviral transmission prophylaxis is associated with significant anemia and neutropenia in HIV-uninfected infants during the first 3 months of life. Anemia was more profound in HAART-exposed infants.

Cited by 70 publications

References 31 publications

High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

High Levels of Zidovudine (AZT) and Its Intracellular Phosphate Metabolites in AZT- and AZT-Lamivudine-Treated Newborns of Human Immunodeficiency Virus-Infected Mothers

Plasma and Intracellular Tenofovir Pharmacokinetics in the Neonate (ANRS 12109 Trial, Step 2)

Impaired Humoral Response to Vaccines among HIV-Exposed Uninfected Infants

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