Cancer and Long-term Toxicities in Children Exposed to Antiretroviral Drugs before Birth

By Liz Highleyman

Use of prophylactic antiretroviral therapy during pregnancy has dramatically reduced the risk of mother-to-child HIV transmission. On the whole, research has shown that the benefits of prophylaxis outweigh the risks, but concerns remain about the long-term effects of prenatal exposure.

Cancer in children exposed to NRTIs

In the October 18, 2008 issue of AIDS, French researchers described a study looking at the incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors (NRTIs).

Cancer cases were identified in a nationwide prospective cohort of HIV-uninfected children born to HIV-infected mothers using a standardized questionnaire during a prospective follow-up period of 2 years. Thereafter, cancers were detected via spontaneous "pharmacovigilance" declarations and cross-checking data with national childhood cancer registries. Standardized incidence ratios were calculated for incidence comparisons with the general French population.

Results

• A total of 10 cases of cancer were detected among 9127 NRTI-exposed HIV-uninfected children (total 53,052 person-years of follow-up).

• The median age at cancer diagnosis was 5.4 years.

• The overall cancer incidence in the exposed children did not differ significantly from that expected for the general population:

• 10 cases observed in the exposed children;
• 8.9 expected according to 1990-1999 national rates;
• 9.6 expected according to 2000-2004 national rates.

• Standardized incidence ratios were 1.1 and 1.0, respectively.

• 5 cases of central nervous system cancer were observed (standardized incidence ratios of 3.1 and 2.4).

• The relative risk of cancer for children exposed to a combination of didanosine (ddI; Videx) plus lamivudine (3TC; Epivir) was higher than for those exposed to zidovudine (AZT; Retrovir) monotherapy (hazard ratio 13.6)

"This study did not evidence an overall increase in cancer risk in [NRTI] exposed children until 5 years of age," the study authors concluded.

"Results suggesting associations with specific [NRTI] combinations need further investigations," they added. "A longer surveillance, including differential analysis of the different cancer sites and various [NRTIs] administered is warranted."

Blood and liver toxicities

W.H. Bae from Harvard University and colleagues assessed hematological (blood) and hepatic (liver) toxicities associated with in utero and breastfeeding exposure to maternal HAART among infants in Botswana (a nested cohort within the Mashi Study). Results were reported in the August 20, 2008 issue of AIDS.

Laboratory toxicities among infants born to women who initiated HAART before delivery were compared with toxicities among babies born to women who received zidovudine and a single dose of nevirapine (Viramune) or placebo during labor. Infants were randomly assigned to be breastfed with extended zidovudine or formula-fed.

The investigators measured the infants' hemoglobin concentrations, absolute neutrophil (a type of immune system white blood cell) and platelet counts, and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels from birth through 7 months of age. Grade 3 and 4 toxicities were compared according to antiretroviral exposure status.

Results

• In utero exposure to combination HAART was associated with increased risk for neutropenia (low neutrophils count) in infants up to 1 month of age.

• 21.7% of HAART-exposed infants developed neutropenia, compared with 5.5% of infants exposed to zidovudine alone (P < 0.01).

• However, neutropenia was no longer associated with prenatal exposure to HAART after 1 month of age.

• Postnatal exposure to HAART was not associated with hematological or hepatic toxicities.

• Laboratory toxicities were clinically asymptomatic in all but 1 infant.

"Exposure to maternal HAART in utero may increase the risk for infant neutropenia, particularly among breastfed infants, but the clinical significance of this finding is uncertain," the investigators concluded. "The lack of association between exposure to HAART through breastfeeding and long-term toxicities in infants is reassuring but deserves study in larger cohorts."

Mitochondrial function

In another recent study, Helene Cote from the University of British Columbia and colleagues looked at the effects of perinatal antiretroviral therapy on infant mitochondrial function. Mitochondrial toxicity is a known side effect of certain NRTIs and can lead to manifestations such as lipoatrophy and liver damage. Findings were published in the September 15, 2008 Journal of Infectious Diseases.

The researchers compared blood mitochondrial DNA (mtDNA) levels and mtDNA gene expression (mtRNA) in HIV-uninfected, antiretroviral-exposed infants born to HIV positive mothers, comparing them with mtDNA levels and mtDNA gene expression in control infants born to HIV negative women. Blood samples were obtained at various time points from birth through 8 months.

Results

• Log10 mtDNA levels at birth were higher in antiretroviral-exposed infants than in control infants, although the difference did not reach statistical significance (P = 0.07 for samples obtained 0-3 days after birth).

• mtDNA levels in the antiretroviral-exposed infants increased further during the postnatal zidovudine prophylaxis period, from age 4 days through 6 weeks (P = 0.001).

• mtDNA Levels remained significantly higher than levels observed in control infants through the end of the study.

• In contrast, log10 mtRNA levels at birth were lower in antiretroviral-exposed infants compared with control infants (P = 0.03).

• However, mtRNA levels were not statistically different later on.

Based on these findings, the study authors wrote, "When control infants and antiretroviral-exposed infants were compared, the mtDNA level was increased but mitochondrial gene expression was decreased in antiretroviral-exposed infants."

"These differences persisted after zidovudine was discontinued, suggesting that changes in mitochondrial proliferation and/or expression take place during and after antiretroviral exposure," they added. "These changes are likely the effects of the antiretroviral drugs on mitochondria. The clinical relevance and long-term impact of these alterations must be studied."

10/21/08

References

V Benhammou, J Warszawski, S Bellec, and others. Incidence of cancer in children perinatally exposed to nucleoside reverse transcriptase inhibitors. AIDS 22(16): 2165-2177. October 18, 2008. (Abstract).

WH Bae, C Wester, LM Smeaton, and others. Hematologic and hepatic toxicities associated with antenatal and postnatal exposure to maternal highly active antiretroviral therapy among infants. AIDS 22(13): 1633-1640. August 20, 2008. (Abstract).

HCF Cote, J Raboud, A Bitnun, and others. Perinatal exposure to antiretroviral therapy is associated with increased blood mitochondrial DNA levels and decreased mitochondrial gene expression in infants. Journal of Infectious Diseases 198(6): 851-859. September 15, 2008. (Abstract).