Addition of one week of postpartum treatment with tenofovir and emtricitabine to single dose nevirapine given at childbirth was safe and prevented the emergence of nevirapine resistance in mothers, according to the findings of a small pilot study presented this week at the Fifteenth Conference on Retroviruses and Opportunistic Infections in Boston.
Although tenofovir and emtricitabine are widely used in adult treatment, their safety and effectiveness in the prevention of mother to child transmission have not been tested.
Tenofovir and emtricitabine are associated with a low rate of toxicity in adults, are dosed once daily in a single tablet and have a long half-life, meaning that high drug levels can be maintained for long periods. These qualities make the drugs an attractive potential back-up for single-dose nevirapine, which frequently induces resistance when given as a single dose, potentially compromising future treatment options for both mother and infant.
The ANRS (National Agency for AIDS Research) decided to investigate the safety and efficacy of tenofovir (TDF) and emtricitabine (FTC) given together for PMTCT.
TEmAA ANRS 12109 (Tenofovir-Emtricitabine for PMTCT in Africa and Asia), a phase II open-label clinical trial, enrolled 38 HIV-infected women from sites in the Ivory Coast, Cambodia, and South Africa. The median age of participants was 27, median CD4 count was 450 cells/mm3, and median HIV-1 RNA was 4.1 log10 copies/mL.
All women received zidovudine (ZDV) from the time of enrolment (~28 to 38 weeks gestation) until the onset of labour. At that time, sd-NVP was given as well as two tablets of TDF/FTC (Truvada). Following delivery, TDF/FTC was given as one tablet once daily, for a week. Infants were given sd-NVP syrup on day 1 and ZDV syrup for 7 days.
Study outcomes were TDF/FTC safety, PK, frequency of viral resistance, maternal viral load, and estimation of transmission rate in the mother-infant pairs.
Grades 3/4 adverse events occurred in 24% of the women (9/38) and these included anaemia and leucopenia. There were 39 live births (1 set of twins). Nine infants (23%) suffered clinically adverse events; four of whom died (meningitis, gastroenteritis, intestinal obstruction, and severe idiopathic encephalopathy).
Maternal viral load dropped nearly one log at 2 days postpartum, but returned to baseline at 4 weeks. Plasma HIV-1 RNA was detected in two of the 39 infants at 3 days and was confirmed at 4 weeks postpartum. Both infections occurred in utero
There were no findings of genotypic viral resistance to ZDV, NVP, FTC, or TDF in mothers or infants. The investigators concluded that this combination is well-tolerated in women and newborns and that 7 days of postpartum therapy appeared to avoid NVP-resistance mutations and effectively suppress viral replication. No intrapartum HIV transmission was reported.
In a tenofovir PK substudy, investigators found that 2 tablets of TDF/FTC given at the initiation of labour and thereafter at the normal once-daily dose for 7 days produced TDF concentrations similar to those of non-pregnant, HIV-infected individuals taking the normal dose of TDF 300mg and FTC 200 mg daily.
Absorption of TDF was faster and greater in those women who had a caesarean section. TDF had good placental transfer and neonatal plasma half-life was just over 8 hours, suggesting low concentration soon after delivery.
Administering TDF 13mg/kg to the infant as soon as possible after birth results in neonatal concentrations comparable to those seen in adults.
Arrive E et al. The TEmAA ANRS 12109 phase II Trial, step 1: tolerance and viral resistance after single-dose nevirapine and short-course of tenofovir disoproxil fumarate and emtricitabine to prevent mother-to-child transmission of HIV-1. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 45b, 2008.
Hirt D et al. Population pharmacokinetics of tenofovir in HIV-1-infected pregnant women and their neonates: TEmAA ANRS 12109. Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, abstract 47LB, 2008.