An argument for routine therapeutic drug monitoring of HIV-1 protease inhibitors during pregnancy

Inadequate HIV protease inhibitor (PI) exposure is associated with acquired drug resistance and virological failure of therapy [1]. Certain disease states, such as chronic liver disease [2], have been shown to alter the pharmacokinetics of PIs. As pregnancy is associated with increases in plasma volume, fat stores, total body mass, cardiac output, glomerular filtration and altered protein binding [3,4], it is a condition in which altered PI pharmacokinetics may occur. If circulating levels of PIs are significantly lower during pregnancy, the potential for virological breakthrough and the development of drug resistance exists, with important implications for the health of the mother and her child. We describe a woman with HIV infection who developed virological breakthrough while receiving PI-based antiretroviral therapy, and in whom pregnancy appeared to contribute to suboptimal circulating PI levels. The patient was a 35-year-old woman originally from Zaire diagnosed with HIV infection in 1992. She initially received zidovudine in 1993, to which zalcitabine was added in 1996. In July 1997 her plasma HIV-RNA level (pVL) was 8564 copies/ml, her CD4 cell count was 243 cells/μl (10%), and her regimen was modified to indinavir 800 mg every 8 h, zidovudine 600 mg twice a day, and lamivudine 150 mg twice a day. In February 1999 her pVL was less than 500 copies/ml. Because she developed nephrolithiasis, indinavir was changed to nelfinavir 1250 mg twice a day in May 1999. At that time her pVL was less than 50 copies/ml and her CD4 cell count was 384 cells/μl (24%). On 27 July 1999 at 20 weeks’ gestation, her pVL was 131 copies/ml. Subsequent values were 62, 228 and 2720 copies/ml on 9 August, 12 October and 19 October, respectively. Because of the concern for altered nelfinavir pharmacokinetics during pregnancy resulting in virological breakthrough, a full pharmacokinetic profile was obtained on 18 October, when the patient was at 32 weeks of gestation. The pharmacokinetic parameters are summarized in Table 1. The plasma nelfinavir level 12 h after dosing (0.47 μg/ml) was below the estimated minimum in-vitro concentration to inhibit replication in 50% of wild-type isolates in 50% of human serum (IC50 = 0.52 μg/ml [5]). The dose of nelfinavir was changed to 1000 mg three times a day and 2 weeks later her pre-dose and 4 h post-dose nelfinavir levels were 1.02 and 2.23 μg/ml, respectively. Despite increased nelfinavir concentrations, her pVL did not become suppressed, although it did decrease to 478 copies/ml on 11 November 1999. On 23 November 1999 a scheduled caesarian section was performed, during which time she received intravenous zidovudine and a single oral dose of nevirapine 200 mg. On pharmacokinetic analysis 4 months after delivery, the pre-dose and 4 h post-dose nelfinavir concentrations were 3.79 and 7.03 μg/ml, respectively. Given such high levels and the unknown potential for toxicity, her dose was adjusted back to 1250 mg twice a day. A full pharmacokinetic profile was obtained 2 weeks later (6 months post-partum). Genotyping of the protease and reverse transcriptase sequences from the virus isolated on 11 November 1999 demonstrated mutations associated with decreased susceptibility to nelfinavir (M36I), zidovudine (K70R, D67N) and lamivudine (M184V).Table 1: Plasma pharmacokinetic parametersa. The oral clearance of nelfinavir increased by 2.5-fold and the volume of distribution decreased (18%) during pregnancy. The resulting 67% decrease in half-life and the larger decrease in total (area under the curve) compared with peak (Cmax) plasma exposures suggest that pregnancy affected the systemic clearance more than bioavailability. The probable significance of the corresponding decrease in drug exposure is illustrated by virological breakthrough and the development of genotypic drug resistance. Because viral replication was not suppressed at the time of delivery, an elective caesarian section and a single dose of nevirapine were recommended for both the patient and her child. The presence of pre-existing genotypic mutations when nelfinavir was started is possible, such that eventual virological breakthrough would have been likely. Regardless of this, initially adequate nelfinavir plasma levels would have resulted in a greater likelihood of sustained viral suppression. Biological and systematic variation may have contributed to changes in drug exposure, but the changes are probably too large for this to be the sole explanation. The apparent impact of pregnancy on nelfinavir pharmacokinetics that we observed probably also applies to the pharmacokinetics of other PI, although this remains to be established. For this reason, all pregnant women at our site who are taking a PI are requested to have therapeutic drug monitoring performed in the context of a clinical trial. Given the potential morbidity associated with inadequate circulating PI, an evaluation of the routine therapeutic drug monitoring of PI should be considered in all pregnant patients. Jonathan B. Angela Yasmin Khaliqa Michael L. Monpetitb D. William Camerona Keith Gallicanoa

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