Meconium Tenofovir Concentrations and Growth and Bone Outcomes in Prenatally Tenofovir Exposed HIV-Uninfected Children

Sarah K Himes, Julia W Wu, Denise L Jacobson, Katherine Tassiopoulos, Rohan Hazra, Deborah Kacanek, Russell B Van Dyke, Kenneth C Rich, George K Siberry, Marilyn A Huestis, Pediatric HIVAIDS Cohort Study (PHACS), William Shearer, Mary Paul, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Delmyra Turpin, Renee Smith, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio, Sarah K Himes, Julia W Wu, Denise L Jacobson, Katherine Tassiopoulos, Rohan Hazra, Deborah Kacanek, Russell B Van Dyke, Kenneth C Rich, George K Siberry, Marilyn A Huestis, Pediatric HIVAIDS Cohort Study (PHACS), William Shearer, Mary Paul, Norma Cooper, Lynette Harris, Murli Purswani, Emma Stuard, Anna Cintron, Ana Puga, Dia Cooley, Doyle Patton, Deyana Leon, Ram Yogev, Margaret Ann Sanders, Kathleen Malee, Scott Hunter, William Borkowsky, Sandra Deygoo, Helen Rozelman, Katherine Knapp, Kim Allison, Megan Wilkins, Midnela Acevedo-Flores, Lourdes Angeli-Nieves, Vivian Olivera, Hermann Mendez, Ava Dennie, Susan Bewley, Russell Van Dyke, Karen Craig, Patricia Sirois, Marilyn Crain, Newana Beatty, Dan Marullo, Stephen Spector, Jean Manning, Sharon Nichols, Elizabeth McFarland, Emily Barr, Robin McEvoy, Mobeen Rathore, Kristi Stowers, Ann Usitalo, Kenneth Rich, Lourdes Richardson, Delmyra Turpin, Renee Smith, Arry Dieudonne, Linda Bettica, Susan Adubato, Gwendolyn Scott, Claudia Florez, Elizabeth Willen, Toinette Frederick, Mariam Davtyan, Maribel Mejia, Zoe Rodriguez, Ibet Heyer, Nydia Scalley Trifilio

Abstract

Background: Maternal tenofovir disoproxil fumarate (TDF) treatment among HIV-infected pregnant women results in fetal tenofovir (TFV) exposure. Fetal TFV toxicity was demonstrated in animals, but most clinical investigations have not observed toxicity in humans.

Methods: We evaluated HIV-exposed, uninfected infants in the Surveillance Monitoring for Antiretroviral Therapy Toxicities cohort of the Pediatric HIV/AIDS Cohort Study whose mothers were prescribed TDF for ≥ 8 third trimester weeks. Infant dual-energy X-ray absorptiometry scans were obtained at 0-4 weeks to measure whole body bone mineral content. Meconium TFV concentrations were quantified by liquid chromatography-tandem mass spectrometry.

Results: Fifty-eight TFV-exposed infants had meconium TFV quantified. Detectable concentrations were 11-48,100 ng/g; 3 infants had undetectable concentrations. Maternal TDF prescription duration ranged from 8 to 41 gestational weeks; infant gestational ages were 36-41 weeks. Meconium TFV concentrations were not correlated with TFV exposure duration or timing and did not vary by concomitant prescription of protease inhibitors. Increased meconium TFV concentrations were associated with greater gestational ages (ρ = 0.29, P = 0.03) and lower maternal plasma HIV RNA before delivery (ρ = -0.29, P = 0.04). Meconium TFV concentrations were not associated with infant weight, length (n = 58) or bone mineral content (n = 49).

Conclusions: For the first time, we explored associations between meconium TFV concentrations and infant growth and bone measurements; we did not observe a meconium concentration-dependent relationship for these infant outcomes. These findings support other clinical research failing to show dose-response relationships for growth and bone outcomes among intrauterine TFV-exposed infants. High meconium TFV concentrations correlated with low maternal viral load, suggesting maternal TDF adherence significantly contributes to meconium TFV concentrations.

Conflict of interest statement

Conflicts of Interest: Authors have no other funding or conflicts of interest to disclose.

Figures

Figure 1
Figure 1
Boxplots comparing median meconium TFV concentrations (square-root transformed) between infants born at

Figure 2

Maternal log HIV RNA plasma…

Figure 2

Maternal log HIV RNA plasma concentrations during the 3 rd trimester were associated…

Figure 2
Maternal log HIV RNA plasma concentrations during the 3rd trimester were associated with meconium tenofovir (TFV) concentrations from TFV-exposed infants (ρ=−0.29, P=0.04, n=51). HIV RNA concentrations <50 copies/mL were truncated to 50 copies/mL prior to log transformation as our quantitative polymerase chain reaction test was reliable only at values ≥50 copies/mL.
Figure 2
Figure 2
Maternal log HIV RNA plasma concentrations during the 3rd trimester were associated with meconium tenofovir (TFV) concentrations from TFV-exposed infants (ρ=−0.29, P=0.04, n=51). HIV RNA concentrations <50 copies/mL were truncated to 50 copies/mL prior to log transformation as our quantitative polymerase chain reaction test was reliable only at values ≥50 copies/mL.

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