Tenofovir adversely affects development in foetal monkeys

Studies have shown that the newest antiretroviral to be approved by the US Food and Drug Administration (FDA), tenofovir (Viread), crosses the placenta in sufficient quantities to result in sustained reductions in viral load in simian immunodeficiency virus (SIV)-infected foetal monkeys. In some studies, however, chronic exposure to tenofovir has been shown to cause significant bone-related toxicity in 25% of the monkey infants studied.

In order to better clarify the potential risk of toxicity in foetal monkeys exposed to tenofovir, investigations were conducted using four gravid rhesus monkeys that were given 30mg/kg subcutaneously of tenofovir once daily from days 20 to 150 of gestation. The study results were recently published in the Journal of Acquired Immune Deficiency Syndromes.

The investigators found that although the infants did not develop any gross structural abnormalities and had relatively normal foetal development, they had lower overall body weights and crown-rump lengths than those for age-matched controls, a significant reduction in circulating IGF-I (insulin-like growth factor), a small reduction in foetal bone porosity, and transient alterations in maternal body weights and bone-related biomarkers during the treatment period.

The authors conclude: “Although tenofovir is highly efficacious, when considering the treatment of gravid individuals, several factors should be considered. First, we have shown that exposure to tenofovir at 30mg/kg can have an impact on select foetal parameters, including body weight, circulating IGFs (insulin-like growth factors), and bone porosity… Nevertheless, the benefits of tenofovir, including efficacy when administered once daily to HIV- and SIV-infected individuals and efficiency in crossing the placenta in quantities sufficient to suppress viral load, must also be considered.

“Although the efficient placental transport and significant reduction of viral loads in SIV-infected foetuses were shown to result in healthy newborns in our prior studies, the potential long-term ramifications of exposure may warrant more restricted use in pregnancy and at significantly lower doses than the one investigated in these studies.”

Comment

It should be noted that the daily dose of tenofovir administered to the monkeys in this study (30mg/kg) corresponds to a daily dose in humans of about 2100mg per day. The approved dosage of tenofovir as a component of HIV treatment is 300 mg per day.

The tenofovir in this study was also administered subcutaneously to these monkeys which should provide close to 100% bioavailability. In humans, however, tenofovir is dosed orally with an oral bioavailability of 25-40% depending on fasting state.

A rough calculation would suggest, therefore that the doses of tenofovir used in this study were 17 to 28 times higher than the therapeutic levels achieved during HIV treatment.

Caution would seem to be warranted in the interpretation of these findings and further studies are needed to determine the correct role (if any) of tenofovir in pregnant women. Given the delayed development of resistance and the long half-life of this agent it may represent a useful candidate for inclusion in MTCT regimens.