Protease inhibitors in pregnancy

Polly Clayden, HIV i-Base

Since the report of hepatoxicity risk in women with CD4 counts above 250 cells/mm3 receiving nevirapine, the need has increased for more information on use of protease inhibitors in pregnancy.

Two posters from the Perinatal Pregnancy Group London and The University of Nijmegan, Netherlands showed data on use of atazanavir and saquinavir (500mg formulation) respectively.

Atazanavir

Macky Natha and co-workers presented findings from a report of 33 pregnancies among women receiving atazanavir (ATV) [1]. ATV is labelled pregnancy category B but there have been concerns about infant hyperbilirubinaemia with use of this drug in pregnancy. Nevertheless, ATV is increasingly used by pregnant women, both already on treatment and those for whom it is initiated in pregnancy.

This was a case note review of all women attending 9 HIV units in London to February 2007, who were receiving ATV in pregnancy. Data were collected on maternal CD4 count, viral load, toxicity, and plasma ATV concentrations. Infant data included serum bilirubin, use of phototherapy, and, where available, HIV status at 3 months. Adverse events were also recorded in both mothers and infants.

The investigators identified 31 women with a total of 33 pregnancies. All but two women received the 300mg/100mg ATV/RTV dose.

There were 2 miscarriages at 12 and 16 weeks and 1 woman was still pregnant at the time of review.

20 women had conceived when on ATV. Their median viral load at their first antenatal visit was 98 copies/mL (range <50-101454 copies/mL) and median CD4 count 262 cells/mm3 (range 61-660 cels/mm3). 10 women initiated treatment at 22 weeks gestation. All had viral load <50 copies/mL and a median CD4 count of 270 cells/mm3 (range 151-930 cells/mm3) at baseline.

At delivery median viral load and CD4 counts were <50 copies/mL (range 50-28189 copies/mL) and 269 cells/mm3 (range 67-910 cells/mm3) respectively. 23/30 women had an undetectable viral load. Median maternal bilirubin level was 30 (range 4 to 76) umol/l [1.8 (range 0.2-4.4) mg/dL] and 23/26 mothers had a raised bilirubin (>17umo/L [>1 mg/dL]).

ATV concentration measurements were available for 19 mothers (performed at a median of 30 weeks gestation). 16 were taken in the third trimester and the mean trough ATV concentration was 373 mg/L and all but two were above the recommended therapeutic concentration of 100 mg/L.

29 infants were born at a median of 38 weeks gestation (19 planned cesarian sections, 9 emergency cesarian sections, 2 planned spontaneous vaginal delivery). Mean birth weight was 2894g (range 1080-4050g) and median infant bilirubin levels were 71 umo/L (range 10 to 191) (4.2 mg/dL, range 0.6 to 11.2).

No infants required phototherapy and no birth defects were detected. The investigators reported the median time since delivery was 12 months (range 1-26 months) and all infants were uninfected at time of review.

The investigators wrote: To our knowledge, this is the largest reported case series of the use of ATV in pregnancy. Atazanavir was well tolerated in our cohort and most women had good immunological and virological responses. Maternal plasma levels, where measured, were adequate. No early infant morbidity as a result of in utero exposure to ATV was demonstrated.

Saquinavir

David Burger and co-workers presented findings from a pharmacokinetic (PK) study of saquinavir new formulation (500mg tablet) and ritonavir dosed at 1000/100mg BID in pregnancy. [2] SQV is also labelled pregnancy category B.

This was a prospective multicentre study of 14 HIV-positive women initiating SQV-containing treatment in pregnancy. At week 33 (+/-2 weeks), a 12-hour pharmacokinetic curve was recorded. Blood was sampled prior to dosing with a standardised breakfast and at t = 1, 2, 3, 4, 6, 8, 10, and 12 hours post-dosing.

The investigators reported that mean (+/- standard deviation [SD]) values for SQV AUC0-12h, Cmax and Cmin were 19.3 (7.4) mg/L.h, 3.8 (1.5) mg/L, and 1.4 (0.78) mg/L, respectively. For RTV mean values for AUC0-12h, Cmax and Cmin were 5.8 (2.5) mg/L.h, 1.1 (0.51) mg/L, and 0.44 (0.22) mg/L, respectively.

They noted that SQV PK parameters were comparable to those reported in a previous study using the same formulation in non-pregnant healthy volunteers at the licensed dose of 1000/100 mg BID. None of the 14 women showed a subtherapeutic Cmin of SQV (defined as <0.10 mg/L. For 2 women a 12-hour PK curve was also recorded during the second trimester (week 20) or 4 to 6 weeks post-partum. SQV PK parameters in these women were not different from those reported during third trimester.

The investigators concluded: Saquinavir pharmacokinetics when taken as the new 500-mg tablet formulation and boosted with RTV at a dose of 1000/100 mg twice daily were adequate in all 14 women investigated. No difference was observed in pharmacokinetics of saquinavir between 2nd and 3rd trimester. In contrast to observations with other PI (ie, NFV, lopinavir/RTV), saquinavir pharmacokinetics appear not to be influenced by pregnancy.

References:

Natha M, Hay P, Taylor G et al. Atazanavir use in pregnancy: A report of 33 cases. Abstract 750.
Burger D, A Eggink A, van der Ende ME et al. The pharmacokinetics of saquinavir in new tablet formulation + ritonavir (1000/100 mg twice daily) in HIV-1-infected Pregnant Women. 14 CROI, Los Angeles 2007. Poster abstract 741.