Tenofovir safe in pregnancy in macaque model

A paper authored by Koen Van Rompay and coworkers published in the September 2008 edition of Antimicrobial Agents and Chemotherapy showed findings from animal studies of tenofovir use from infancy to adulthood including pregnancy. [1]

Tenofovir is highly effective in the simian immunodeficiency virus (SIV) macaque model of HIV infection. This paper reports extended safety and efficacy data from a study of 32 animals that received prolonged (>1- to 13-year) daily subcutaneous tenofovir regimens.

The authors report that the likelihood of renal toxicity (proximal renal tubular dysfunction [PRTD]) correlated with plasma drug concentrations, which were dose and age-dependent. They found that below a threshold AUC for tenofovir in plasma of 10gh/ml, (an exposure several fold higher than that in humans receiving 300 mg oral formulation tenofovir disoproxil fumarate [TDF]), prolonged tenofovir administration was not associated with PRTD using urinalysis, serum chemistry analyses, bone mineral density, and clinical observations.

When they looked at low-dose maintenance regimens, they found plasma tenofovir concentrations and intracellular tenofovir diphosphate concentrations were similar to or slightly higher than those found in humans receiving TDF. The authors note that no new toxicities were identified in this study and the available evidence does not suggest teratogenic effects of prolonged low-dose tenofovir treatment.

Despite the presence of the reverse transcriptase mutation K65R in all SIV-infected animals, 6 animals suppressed and maintained undetectable viral load for up to 12 years of TFV monotherapy. With regards to tenofovir exposure in utero, the authors report that one female macaque had been started at birth on continuous low-dose tenofovir. Her plasma TFV AUCs were four- to six fold higher than those observed with the oral TDF regimen in humans. After 10 years, this animal has not demonstrated any signs of toxicity and has delivered three healthy offspring that showed normal pre- and post-natal development (including renal parameters and bone development) for up to 5 years of age.

They explain that although the number of animals studied is small and further investigation is warranted, these preliminary findings with tenofovir during pregnancy are consistent with the available human data from the Antiretroviral Pregnancy Registry, which show no indications of an increased risk of birth defects after in utero exposure to tenofovir. [2] The authors conclude that their findings show the safety and sustained benefits of prolonged tenofovir-containing regimens throughout development from infancy to adulthood, including pregnancy.

They write: “These observations support the long-term treatment of HIV-infected humans with TFV-containing regimens. Continued monitoring of these animals as they progress toward geriatric age will provide further valuable information on prolonged treatment with TFV-containing regimens, with the ultimate goal of giving HIV-infected persons a normal life span.”