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Efficacy of darunavir despite low plasma trough levels during late pregnancy in an HIV-hepatitis C virus-infected patient

Pacanowski, Jérômea; Bollens, Dianea; Poirier, Jean-Marieb,e; Morand-Joubert, Laurencec,e; Castaigne, Vaninad; Girard, Pierre-Mariea,e; Meyohas, Marie-Carolinea,e

doi: 10.1097/QAD.0b013e32832e534b
Correspondence
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aService des maladies infectieuses et tropicales, France

bLaboratoire de Pharmacologie, France

cLaboratoire de Virologie, France

dService de Gynécologie – Obstétrique, Hôpital Saint-Antoine, Assistance Publique – Hôpitaux de Paris, France

eUniversité Paris 6 – Pierre et Marie Curie (UPMC), Paris, France.

Received 7 May, 2009

Accepted 18 May, 2009

Correspondence to Dr Jérôme Pacanowski, MD, Service des maladies infectieuses et tropicales, Hôpital Saint-Antoine, Paris, France. Tel: +33 1 49 28 24 38; fax: +33 1 49 28 21 49; e-mail: Jerome.pacanowski@sat.aphp.fr

Highly active antiretroviral therapy is mandatory for HIV-infected pregnant women, not only for maternal health, but also in order to prevent mother to child transmission. Protease inhibitors pharmacokinetics is altered during late pregnancy [1], and some antiretroviral-experienced patients may have viral resistance to lopinavir, a widely prescribed protease inhibitor in this setting. We report a case of an HIV-hepatitis C virus (HCV) infected pregnant woman, who received darunavir at the end of pregnancy, and who experienced low plasma darunavir trough levels. (Fig. 1)

Fig. 1

Fig. 1

In March 2007, a 50-year-old woman diagnosed with HIV and HCV infections in 1995 became pregnant after intrauterine insemination. She was receiving a combination of tenofovir, abacavir, atazanavir and ritonavir-boosted fosamprenavir. At diagnosis of pregnancy, CD4-T cell count, plasma HIV-RNA and plasma HCV-RNA were 192/mm3 (15%), 162 copies/ml and 2.532.820 UI/ml, respectively. Liver stiffness was measured by transient elastography and its value was 9 kPa (F2-F3). Plasma HIV-RNA was 358 copies/ml and 99 copies/ml at weeks 15 and 27 of amenorrhea, respectively. Trough (Cmin) of atazanavir and amprenavir plasma concentrations was 396 and 538 ng/ml, respectively. As compared with pharmacokinetic parameters observed in this protease inhibitor combination in healthy individuals (Cmin values of 2290 and 723 ng/ml for atazanavir and amprenavir, respectively [2]), Cmin observed in this pregnant patient were low. Amprenavir Cmin was significantly lower than its Cmin cut-off reported in experienced patients (1600 ng/ml [3]) whereas atazanavir Cmin was in therapeutic range (150–850 ng/ml [4]). The reverse transcriptase gene bore the M41L, D67N, V118I, L210W and T215Y and K219R mutations, conferring resistance to zidovudine, didanosine, stavudine, with possible resistance to abacavir and tenofovir. No mutations conferring resistance to nonnucleoside reverse transcriptase inhibitors were found. The protease gene bore the L10I, L24I, L33F, E35D, M36V, K43T, G48V, I54V, I62V, L63P, V82A, I84V mutations, conferring resistance to indinavir, nelfinavir, saquinavir, fosamprenavir, atazanavir and possible resistance to lopinavir and tipranavir, according to the ANRS algorithm for interpretation of resistance genotyping [5]. Atazanavir and fosamprenavir were discontinued. A new regimen combining 300/600 mg lamivudine/abacavir daily (q.d.), 300 mg tenofovir q.d. and 600/100 mg twice daily (b.i.d.) of ritonavir boosted darunavir (DRV) was initiated at week 30 of amenorrhea. Therapeutic drug monitoring showed low darunavir Cmin (1168 ng/ml and 1302 ng/ml 2 weeks and 3 weeks after its initiation, respectively) as compared with those observed in Power 1 and Power 2 trials (3529 ng/ml) and 1.7–1.9-fold lower to its Cmin cut-off in pretreated patients with a 4–40 baseline DRV fold change (2262 ng/ml) [6]. Darunavir dose was subsequently increased (900 mg b.i.d.), without reaching adequate trough concentrations (1560 ng/ml and 1400 ng/ml, 2 weeks and 3 weeks after adjustment, respectively). The newborn infant was plasma HIV-RNA and HCV-RNA negative at 6 months. Darunavir Cmin levels rose during the first weeks postpartum (3896 ng/ml and 6036 ng/ml, 10 days and 2 months postpartum, respectively). The daily dose of darunavir and ritonavir was then decreased to 600/100 mg b.i.d. and a darunavir Cmin of 2660 ng/ml was measured.

There is very little experience of darunavir prescription during pregnancy [7,8]. Amprenavir and darunavir infratherapeutic levels were observed in our pregnant patient despite the absence of gastrointestinal side effects or poor adherence, and darunavir levels rose to usual values after delivery. Previous studies have reported decreased levels of other protease inhibitors during the third trimester of pregnancy in comparison with postpartum or nonpregnant women [1,9]. Further pharmacokinetic studies of darunavir during pregnancy are needed. No general recommendation can be drawn from a single case-report, but our observation suggests that darunavir could be a valuable option in pregnancy despite altered pharmacokinetics.

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