Atazanavir levels reduced during pregnancy, especially when used with tenofovir

Blood levels of the protease inhibitor atazanavir (Reyataz) are reduced during pregnancy, research published in the online edition of the Journal of Acquired Immune Deficiency Syndromes shows.

Atazanavir levels were even lower when pregnant women took the drug in combination with tenofovir (Viread, also in the combination pills Truvada and Atripla).

All the women were taking the standard once-daily dose of atazanavir/ritonavir 300/100 mg.

Results also showed that trough concentrations were below the target level in 6% of women treated with atazanavir without tenofovir and in 15% of those taking a combination that included both drugs.

“Until more is known about the relationship between atazanavir plasma concentrations and virologic response, a reasonable goal for atazanavir dosing during pregnancy is to achieve plasma exposure in pregnant women equivalent to that seen in nonpregnant adults treated with standard dose,” comment the investigators. They therefore recommend that pregnant women should receive a once daily dose of 400 mg of atazanavir, boosted by 100 mg of ritonavir (Norvir).

HIV therapy during pregnancy substantially reduces the risk of mother-to-child HIV transmission and protects the health of the mother. Treatment options for pregnant women include a boosted protease inhibitor in combination with two nuceoloside/nucleotide reverse transcriptase inhibitors (NRTIs). A regimen that includes atazanavir/ritonavir is an option for pregnant women, especially those who have previous experience of HIV therapy.

It is already known that blood levels of some other protease inhibitors are reduced during pregnancy. However, there is uncertainty about the pharmacokinetics of atazanavir in pregnant women.

Atazanavir is often combined with tenofovir, but this combination has been associated with a reduction of approximately 25% in atazanavir levels. There is currently no information on the atazanavir levels in pregnant women who are also being treated with tenofovir.

The International Medical Pediatric Adolescent AIDS Clinical Trial (Impact) 1026s study is examining the pharmacokinetics of antiretrovirals in HIV-positive pregnant women.

A total of 38 women enrolled in the study were taking atazanavir (21 in combination with tenofovir), and these women had their blood levels of atazanavir intensively monitored over a 24 hour period both during pregnancy and then again six to twelve weeks after delivery.

At the time of delivery, viral load was undetectable in eleven of 16 women not taking tenofovir and in 17 of the 19 patients receiving tenofovir (viral load results were unavailable for three patients). The women had 38 infants, and 37 were HIV-negative. The remaining child had a negative HIV PCR test at birth and again five weeks later, but was then lost to follow-up.

Concentrations of atazanavir during the third trimester were significantly lower than those seen in non-pregnant individuals (without tenofovir, area under the curve [AUC], 41.9 vs. 57.9 mcg*hr/ml,  p = 0.02; with tenofovir, AUC, 28.8 vs. 39.6 mcg*hr/ml, p = 0.04).

The target atazanavir concentration during pregnancy was at least 29.4 mcg*hr/ml. During the third trimester, this target was not met by 33% of those not taking tenofovir and 55% of individuals who were also treated with this drug.

Trough concentrations of atazanavir fell below the target 0.15 mcg/ml in 6% of those not taking tenofovir and 15% taking tenofovir.

Median concentrations of atazanavir were significantly lower during pregnancy than after delivery for both groups of women (p = 0.002; p = 0.0008), confirming that pregnancy affected the pharmacokinetics of the drug.

Blood cord and maternal delivery samples were collected from 35 mother-infants pairs. Maternal levels of atazanavir were above the limit of detection in 29 individuals. The median concentration of atazanavir in the cord was 0.16 mcg/ml and 0.83 mcg/ml in the mother.

“We have shown that median atazanavir [levels] are reduced by 30 – 34% during pregnancy compared to postpartum and are reduced both during pregnancy and postpartum by an additional 25% when coadministered with tenofovir,” write the investigators.

Although no cases of mother-to-child transmission were confirmed, the investigators were concerned that up to 15% of women had levels of atazanavir that were below the recommended trough level.

They therefore suggest that a higher dose of atazanavir should be used during pregnancy.

After considering a number of alternatives, the researchers concluded that a once-daily dose of 400/100 mg atazanavir/ritonavir would be the safest and most convenient option.