Original article Pharmacokinetics, safety and efficacy of ritonavir boosted atazanavir (300/100 mg once daily) in HIV 1-infected pregnant women

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1 Antiviral Therapy 2015; 20: (doi: /IMP2936) Original article Pharmacokinetics, safety and efficacy of ritonavir boosted atazanavir (300/100 mg once daily) in HIV 1-infected pregnant women Minh P Lê 1 *, Laurent Mandelbrot 2,3, Diane Descamps 4,5, Cathia Soulié 6,7,8, Houria Ichou 9, Agnès Bourgeois Moine 10, Florence Damond 5, Sylvie Lariven 11, Marc-Antoine Valantin 12, Roland Landman 4,11, Philippe Faucher 10, Roland Tubiana 12, Dominique Duro 2,3, Françoise Meier 3, Sylvie Legac 11, Patricia Bourse 12, Emmanuel Mortier 13, Marc Dommergues 14, Vincent Calvez 6,7,8, Sophie Matheron 4,11, Gilles Peytavin 1,4 1 APHP, Bichat-Claude Bernard Hospital, Clinical Pharmaco-Toxicology Department, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France 2 Paris-Diderot University, Paris, France 3 APHP, Louis Mourier Hospital, Department of Obstetrics and Gynecology, Hôpitaux Universitaires Paris Nord Val de Seine, DHU Risks in Pregnancy, Colombes, France 4 IAME, UMR 1137, INSERM University of Paris Diderot, Sorbonne Paris Cité, Paris, France 5 APHP, Bichat-Claude Bernard Hospital, Virology Department, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France 6 APHP, Pitié-Salpêtrière Hospital, Virology Department, Paris, France 7 Sorbonne Universités, UPMC Univ Paris 06-UMR_S 1136 Pierre Louis Institute of Epidemiology and Public Health, Paris, France 8 INSERM-UMR_S 1136 Pierre Louis Institute of Epidemiology and Public Health, Paris, France 9 APHP, Louis Mourier Hospital, Virology Department, Hôpitaux Universitaires Paris Nord Val de Seine, Colombes, France 10 APHP, Bichat-Claude Bernard Hospital, Department of Obstetrics and Gynecology, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France 11 APHP, Bichat-Claude Bernard Hospital, Infectious Diseases Department, Hôpitaux Universitaires Paris Nord Val de Seine, Paris, France 12 APHP, Pitié-Salpêtrière Hospital, Infectious Diseases Department, Paris, France 13 APHP, Louis Mourier Hospital, Department of Internal Medicine, Hôpitaux Universitaires Paris Nord Val de Seine, Colombes, France 14 APHP, Pitié-Salpêtrière Hospital, Department of Obstetrics and Gynecology, Paris, France *Corresponding author minh.le@bch.aphp.fr Background: Atazanavir/ritonavir (ATV/r) is a boosted protease inhibitor recommended to minimize the risk of mother-to-child HIV-1 transmission (MTCT). We aimed to assess the pharmacokinetics, safety and efficacy of ATV/r in HIV-1-infected pregnant women and their neonates. Methods: A multicentre, cross-sectional, non-interventional cohort of HIV-1-infected pregnant women receiving ATV/r (300/100 mg once daily) who delivered in three Paris hospitals from 2006 to 2013 was designed. We determined antiretroviral trough plasma concentrations using liquid chromatography mass spectrometry at each of the three trimesters, delivery and post-partum. ATV concentrations at 24 h (C24h) were interpreted by the ng/ml efficacy tolerance thresholds. Safety data and newborn HIV status were recorded. A mother s virological failure was defined as two successive measurements of plasma HIV-1 RNA>50 copies/ml within the 2 months before delivery. Results: 103 pregnant women were included, mostly from sub-saharan Africa (88%). ATV C24h at each of the three trimesters and delivery remained similar to post-partum values. No dose adjustment was needed during pregnancy. The median plasma ratio of fetal/ maternal ATV level was 0.19 (n=28). Only three patients showed two successive detectable viral loads but <400 copies/ml. Among 82 available newborn data, 16 were born preterm. Three in utero deaths occurred. Tolerance was good with one case of maternal grade 3 hyperbilirubinaemia, no cases in neonates at delivery and no clinically relevant adverse event. No case of MTCT was reported. Conclusions: In this population, an ATV/r-containing antiretroviral regimen demonstrated good pharmacokinetics, virological efficacy and safety. No significant impact of pregnancy on ATV C24h was found. No dose adjustment was required International Medical Press (print) (online) 507

2 MP Lê et al. Introduction Atazanavir/ritonavir (ATV/r) is one of the main ritonavir-boosted protease inhibitors (PI/r) used in HAART regimens to treat HIV-1-infected patients and particularly to prevent mother-to-child HIV transmission (MTCT) in pregnant women. However, published data on ATV treatment in pregnant women are still scarce [1]. During pregnancy, dose adjustment of PI/r is sometimes considered, because physiological changes and their pharmacokinetic consequences can decrease plasma PI exposure, particularly in the third trimester [2,3]. However, increased doses of PI/r might be associated with increased risk of adverse effects such as gastrointestinal or metabolic disorders, elevated activity of liver enzymes or renal disorders (that is, lithiasis). According to national guidelines in France [4] and the ATV prescribing information [5], ATV/r is the only PI/r for which once daily dosing is recommended during the entire pregnancy. In addition, even if therapeutic drug monitoring (TDM) is not systematically prescribed for HIV-1-infected pregnant women receiving PI-based ART, French national guidelines recommend TDM to ensure the efficacy of ART and prevent MTCT, particularly when started during pregnancy or in case of adherence issues. The aim of this study was to assess the pharmacokinetics of a standard dose of ATV/r (300/100 mg once daily), the impact of co-administration of tenofovir (TFV), as well as the safety, and efficacy of ATV/r-containing ART regimen during pregnancy. Methods Study design, patients and treatment The present study was a cross-sectional, non-interventional cohort study conducted in Paris. We included pregnant women with confirmed HIV-1 infection, 18 years old, receiving an ART regimen including ATV/r until delivery, who had routine TDM and who delivered in one of the three participating hospitals from 2006 to Patients were included from our TDM database. Data were then completed from the DAT AIDS database and from the ANRS CO01 EP13 cohort study with informed consent, as previously described [6]. We excluded patients receiving unboosted ATV or an ATV/r daily dose other than 300/100 mg and patients who did not receive ATV/r until delivery. Nevertheless, we described patients who discontinued the ATV/r-containing regimen treatment but they were not taken into account in the pharmacokinetic analysis. All antiretrovirals (ARVs) authorized by the Food & Drug Administration (USA) and European Medicines Agency during pregnancy could be used during this study. Maternal data (that is, age, weight, origin ethnicity, parity, time since HIV diagnosis, time since ARV treatment, time since ATV/r treatment, plasma viral loads, CD4 + T-cell counts) and newborn data (that is, delivery mode, newborn weight, Apgar score) as well as tolerance data (bilirubinaemia, clinically relevant adverse events) were recorded. Baseline characteristics were defined as data collected within 2 months before pregnancy. Biological assessments Routine TDM was performed in a single centre. Steady-state concentrations were measured at 24 ±4 h post-dose (C24h). Sampling was performed at least 2 weeks after the initiation of ATV/r treatment, at the three trimesters, delivery and post-partum (within 2 months after delivery). The French national guidelines recommend routine TDM of HIV-infected women from the second trimester. In some mother newborn pairs, monitoring of both the maternal and umbilical cord blood collection was performed at delivery to assess the ratio of fetal to maternal ARV concentration. Simultaneous plasma ARV level determinations involved liquid chromatography tandem mass spectrometry (Acquity UPLC/TQD, Waters Corp., Milford, MA, USA) as described [7], with modification. The limits of quantification (LOQ) were defined as 20 ng/ml for ATV and 10 ng/ml for ritonavir (RTV), emtricitabine (FTC), TFV, abacavir (ABC), lamivudine (3TC) and zidovudine (ZDV). By convention, concentrations below the LOQ were defined as LOQ/2 for statistical analysis and the determination of the ratio of fetal to maternal levels. ATV C24h was interpreted with the thresholds of efficacy (150 ng/ml, corresponding to the 10-fold protein binding-adjusted 90% effective concentration for wild-type virus) and tolerance (850 ng/ml) [8,9]. With ATV C24h steady-state status over the pregnancy, the proportion of patients with ATV C24h<150 or >850 ng/ml were analysed for each trimester, delivery (however, ARV plasma concentrations were not at 24 h post-dose) and post-partum. The other biological tests were those performed according to French national guidelines at monthly clinics in on-site hospital laboratories. Immuno-virological data (CD4 + T-cell count, plasma HIV-1 RNA with thresholds of 50 copies/ml and 400 copies/ml) were assessed before pregnancy (within 6 months), for each trimester, the start of ATV/r treatment, delivery and post-partum. Virological failure was defined as two successive plasma HIV-1 RNA measurements >50 copies/ml within the 2 months before delivery. Mother s hyperbilirubinaemia was defined as a total bilirubin level with grade 1 (21 38 µmol/l), grade 2 (38 85 µmol/l), grade 3 ( µmol/l) and grade 4 (>170 µmol/l). Neonatal hyperbilirubinaemia was defined as a total bilirubin level >250 µmol/l in the International Medical Press

3 PK, safety and efficacy of ATV/r in pregnant women 5 days following birth [10]. Infants were followed according to national guidelines and their HIV infection status was determined as previously described [11]. Statistical analysis All data (demographic and baseline characteristics) and end point variables are summarized with descriptive statistics as median with IQR (25 75%) and/or coefficients of variation. ANOVA and Student s t-tests were performed with R software (the R Foundation for Statistical Computing, Vienna, Austria); P<0.05 was considered statistically significant. ATV C24h at the three trimesters was compared to post-partum. Then, ATV C24h were also compared between patients who received co-administration of TFV and patients who did not receive TFV. Results Patients We studied pharmacological samples from a total of 103 HIV-1-infected pregnant women (median [IQR] age 34 years [31 37 years], body mass index before pregnancy 25 kg/m 2 [21 28 kg/m 2 ], 27 among 88 patients with available information on parity [31%] were nulliparous); most (88%) were from sub-saharan Africa (Table 1); 11 patients were not included in the pharmacokinetic study: switch to a darunavir/rtv-containing regimen for hyperbilirubinaemia, n=6; switch back to a lopinavir/rtv-containing regimen (former ARV regimen) for digestive intolerance or hyperbilirubinaemia, n=4; and switch to raltegravir because of intolerance to RTV, n=1 (Table 2). Overall, 26% of patients were ARV-naive at the initiation of ATV/r-containing regimen, 24% were treated with ATV/r-containing regimen in the year of pregnancy and 13% started ARV treatment only for prevention of MTCT according to the recommendations in force as of the different periods of the study. 12% of patients were coinfected with HBV or HCV. The doses of the other ARV drugs were prescribed according to the respective product information. ATV/r treatment was mostly associated with FTC- TFV disoproxil fumarate (FTC-TDF) (42%), 3TC- ZDV (24%) or ABC-3TC (12%; Table 1). Pharmacokinetics We collected 366 blood samples from 103 mothers for pharmacokinetic analysis. During pregnancy, overall median ATV and RTV C24h were 687 ng/ml (431 1,113 ng/ml) and 20 ng/ml (5 42 ng/ml), respectively. At the three trimesters and at delivery, ATV C24h remained statistically similar (P>0.05) to post-partum values. A secondary analysis comparing third trimester paired to delivery and post-partum data (n=42) revealed no difference in ATV C24h (P=0.997). Data were similar for patients with and without co-administration of TDF (Figure 1). ATV C24h was 150 ng/ml in most patients (>85%) whatever the pregnancy trimester of sampling. At delivery, 6 patients had ATV C24h<150 ng/ml, whereas their ATV C24h values (that is, third trimester) was 150 ng/ml. However, plasma HIV-1 RNA level remained undetectable for all of them. Over the three trimesters, at delivery and post-partum, median (IQR) plasma FTC C24h was 113 ng/ml ( ng/ml, n=147); TFV C24h, 44 ng/ml (25 66 ng/ml, n=159); 3TC C24h 12 ng/ml (10 27 ng/ml, n=66) and 3TC C12h 79 ng/ml ( ng/ml, n=73). ABC C24h (n=58) and ZDV C12h (n=73) were mostly below the LOQ. At delivery, median (IQR) maternal ATV plasma level was 996 ng/ml (25 75%: 666 2,552 ng/ml, n=48) and time since last intake was 13 h (12 22 h), cord plasma ATV level was 146 ng/ml ( ng/ml, n=28) and Table 1. Baseline characteristics of HIV-1-infected women Characteristic Value Patients, n 103 Age, years 34 (31 37) Ethnicity African 91 (88) Caucasian 7 (7) South American 3 (3) Others 2 (2) Information available on parity 88 (85) Nulliparous 27 (31) Duration since HIV diagnosis, years 7 (3 9) Duration of ARV treatment, years 5 (2 8) Duration of treatment with ATV/r, months 15 (3 30) ARV-naive 27 (26) Start of ATV/r in the year of pregnancy 25 (24) Time of ATV/r initiation (weeks of gestation) 12 (9 17) Zenith of plasma HIV RNA for naive patients, 4.7 ( ) log 10 copies/ml Treatment started only for prevention of 13 (13) mother-to-child transmission HBV coinfection 6 (6) HCV coinfection 4 (4) HBV/HCV coinfection 2 (2) Body mass index before pregnancy, kg/m 2 25 (21 28) CD4 + T-cell nadir, cells/mm ( ) Associated ARV drugs FTC/TDF 44 (42) 3TC/ZDV 25 (24) 3TC/ABC 23 (22) Others 11 (12) Data are medians and IQR (25 75%) or n (%). ABC, abacavir; ARV, antiretroviral; ATV/r, atazanavir/ritonavir; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine; 3TC, lamivudine. Antiviral Therapy

4 MP Lê et al. Table 2. Patients who switched to another ARV treatment with ATV C24h, adverse event, the trimester of switch and the ARV switched to ARV switch Patient ATV C24h, ng/ml Adverse event Trimester ARV switched to Grade II hyperbilirubinaemia 2 DRV/r 2 <20 Grade I hyperbilirubinaemia and adherence issues 2 DRV/r 3 1,510 Grade I hyperbilirubinaemia 2 DRV/r Grade I hyperbilirubinaemia 3 DRV/r Grade I hyperbilirubinaemia 1 DRV/r 6 68 Grade II hyperbilirubinaemia and adherence issues 3 DRV/r Grade II hyperbilirubinaemia 1 LPV/r Grade I hyperbilirubinaemia 3 LPV/r 9 82 Digestive intolerance 2 LPV/r Digestive intolerance 1 LPV/r Intolerance to ritonavir 3 RAL ARV, antiretroviral; ATV C24h, atazanavir plasma level at 24-h post-dose; DRV/r, darunavir/ritonavir; LPV/r, lopinavir/ritonavir; RAL, raltegravir. Figure 1. Atazanavir plasma concentrations during pregnancy and post-partum, with and without tenofovir ATV C24h, ng/ml 5,000 With TDF Without TDF 95% IQR 75% Median IQR 25% 4,000 3,000 2,000 1,000 P=NS P=NS P=NS P=NS P=NS 5% Number of patients, n ATV C24h<150 ng/ml, n (%) ATV C24h>850 ng/ml, n (%) (10) 4 (40) T1 T2 T3 D PP (14) 2 (7) 7 (16) 1 (3) 5 (10) 0 (0) 2 (7) 6 (8) 5 (24) 12 (40) 15 (34) 12 (35) 19 (39) 8 (44) 12 (40) 22 (31) 26 2 (8) 12 (46) Atazanavir (ATV) plasma concentrations at 24-h post-dose (ATV C24h) at each trimester of pregnancy (T1, T2 and T3), at delivery (D) and post-partum (PP) with and without tenofovir (TDF). 44/103 patients (42%) received TDF. ANOVA test reported no significant difference (NS) in ATV concentration between the different groups. ratio of fetal to maternal ATV level was 0.19 ( ; n=28). The ratio of fetal to maternal level for FTC was 1.20 ( , n=9); TFV, 1.20 ( , n=9); 3TC, 2.43 ( , n=3) and ZDV, ( , n=3). Immuno-virological results Before pregnancy, 50% of patients had a nadir CD4 + T-cell count <200/mm 3 (Table 1). In ARV-naive patients, the median plasma HIV-1 RNA level was approximately 4.7 log 10 copies/ml. Among 324 tests performed from 93 women, CD4 + T-cell count was not modified from the start of ATV/r treatment to post-partum. At the start of ATV/r treatment, the median CD4 + T-cell count was 390/mm 3 ( /mm 3, n=17) for patients who started ATV during pregnancy, and 414/mm 3 ( /mm 3, n=50) for patients who started ATV before pregnancy. Median CD4 + T-cell count merged for the three trimesters and at delivery and post-partum was 477/mm 3 ( /mm 3, n=257 samples). At third trimester, median CD4 + T-cell count was 482/mm 3 ( /mm 3, n=75 patients) International Medical Press

5 PK, safety and efficacy of ATV/r in pregnant women Among the 345 viral load tests performed from 94 women, the percentage of detectable plasma HIV-1 RNA decreased during pregnancy. At start of ATV/r, plasma HIV-1 RNA level was <50 copies/ml for 58% of patients (n=67). Among the 28 patients with plasma HIV-1 RNA level >50 copies/ml, median value was 259 copies/ml ( copies/ml) and 8 patients had plasma HIV-1 RNA level >400 copies/ml. At delivery or at the last sampling before delivery (at third trimester), plasma HIV-1 RNA level was <50 copies/ml for 81 over 84 patients corresponding to 97% virological success. Only three deliveries occurred without confirmation of undetectable plasma HIV-1 RNA; plasma HIV-1 RNA levels were 86, 112 and 160 copies/ml, respectively. We found no plasma HIV-1 RNA level >400 copies/ml at third trimester or delivery. The three patients, who delivered with detectable plasma HIV-1 RNA, were receiving FTC/TDF (n=2) and 3TC/ZDV (n=1), and ATV C24h was >150 ng/ml. Amplification of viral genome for assessment of resistance mutations was not achieved for these three patients as plasma HIV-1 RNA values were <400 copies/ml. Perinatal outcomes Among the 103 patients, 3 cases of stillbirth occurred at 22, 31 and 37 weeks of gestation; all were receiving the study treatment and all were on ATV/r before conception (duration of ATV/r-containing regimen at time of adverse event: 2, 1 and 6 years of previous ATV/r exposure, respectively). All had effective ATV C24h before the adverse event. The delivery mode was assessed for 88 women. It was vaginal for 40 cases and by caesarean for 48. The median (IQR) gestational age at delivery was 38 weeks (37 39 weeks; n=82), birth weight 2,970 g (2,755 3,358 g) and Apgar score 10. Among the 82 newborns with complete data, 16 were premature (<37 weeks gestation). No case of MTCT was observed. Tolerance During pregnancy, the overall median (IQR) maternal bilirubin level was 22 µmol/l (15 35 µmol/l; n=194 samples), with only one case of grade 3 hyperbilirubinaemia. No other adverse event was observed. The median neonatal bilirubin level was 44 (29 56 µmol/l; n=48 newborns); five newborns had a bilirubin level >100 µmol/l and none >250 µmol/l. To these results, 11 patients (who were previously excluded for the pharmacokinetic analysis) were added. From them, eight patients switched to another PI/r because of hyperbilirubinaemia, however, only two patients reported ATV C24h>850 ng/ml. The three mothers who experienced in utero deaths had viral control with one patient presenting ATV C24h 150 ng/ml. Discussion This study is one of the largest cohorts of HIV-1-infected pregnant women, mostly from sub-saharan Africa receiving ATV/r (300/100 mg once daily). Pharmacokinetic results were consistent with previous data [12 14]. We did not find that a higher dose of ATV/r (400/100 mg once daily) was required during the second and third trimesters of pregnancy, despite what was indicated in the product information. Different ATV/r dosing regimen (that is, 200/100 or 400/100 mg once daily) were excluded from this study in order to keep a homogeneous sample of patients and to avoid bias from the pharmacological analysis. Moreover, ATV/r (300/100 mg once daily) represents the great majority of the dosing regimen prescribed in France. A review of six previous studies [1] suggests no difference in ATV C24h at third trimester versus second trimester and post-partum. An increase in ATV dose regimen to 400/100 mg once daily was considered relevant, particularly with TDF co-treatment. However, we found no significant impact of TDF coadministration on ATV C24h. Previous data suggested that TFV might decrease ATV plasma exposure because of a possible interaction with efflux transporters [14,15]. A decrease in the plasma exposure of ATV was reported in pregnant patients receiving ATV/r with versus without TDF (area under the curve [0 24] AUC=28.8 mg h/ml [n=20] versus 41.9 mg h/ml [n=18] at third trimester). In the same study, ATV C24h were lower with TDF (500 ng/ml [n=20] versus 700 ng/ml [n=20]). Concerning the placental transfer through the ratio of fetal to maternal ATV level, some data are available [16,17]. The high protein binding capacity of PIs might limit the placental transfer. We found a median fetal/maternal ratio of ATV of 0.19 (n=28), which is consistent with previous studies, showing a mean plasma fetal/maternal ATV ratio of 0.13 (95% CI 0.10, 0.16) [18] based on 14 mother infant pairs and 0.21 (range ) [19], based on 18 mother infant pairs. This relatively limited diffusion could be related to the placental barrier, including action of transporters, and protein-binding ratio [12]. However, we did not assess the protein-binding ratio, because previous results did not find a significant variation in the ratio during pregnancy [13]. Plasma concentrations of other ARVs were consistent with historical data. Nucleoside reverse transcriptase inhibitors with short plasma half-lives of elimination (ABC and ZDV) were at undetectable levels. The fetal/ maternal ratio, particularly for 3TC and ZDV and to a lesser extent FTC and TFV, might be explained by a non-reciprocal transport through the placental membrane or amniotic fluid [15,18]. Our results on other ARVs are consistent with previous results [10]. Antiviral Therapy

6 MP Lê et al. Adherence among patients receiving TDF could be assessed in light of the TFV reported concentrations. Indeed, TFV presents a long plasma half-life of elimination among the other NRTIs. Thus, in our study, all patients receiving TDF were considered to be adherent. In our study, 6 patients had ATV C24h<150 ng/ml at delivery. However, ATV C24h 150 ng/ml were reported on previous samples including third trimesters. These results suggest a transient non-adherence. In this population, a regimen of ATV/r of 300/100 mg once daily demonstrated good virological efficacy throughout pregnancy. Most patients were not ARVnaive and only 13 had started the regimen only to prevent MTCT. We found no change in CD4 + T-cell count in patients receiving an ATV/r-containing regimen throughout the pregnancy and post-partum. Indeed, 97% of patients achieved virological success with the regimen. We found a good tolerance profile of the ATV/rcontaining regimen, despite approximately 40% of patients presenting ATV C24h>850 ng/ml (Table 3), the tolerance threshold, ATV treatment was maintained. These results were consistent with previous data [1]. Only one woman presented a grade 3 hyperbilirubinaemia. Overall, less than 10% of the patients discontinued ATV treatment for intolerance. Moreover, among the 48 newborns with available data, only 10% (n=5) had a bilirubin level >100 µmol/l. The risk of hyperbilirubinaemia was previously reported, with some children requiring phototherapy [19], but no case of bilirubin level at risk for cerebral damage has been reported. In conclusion, in this sample of 103 HIV-1-infected pregnant mostly sub-saharan women receiving an ATV/r-containing regimen, ATV C24h did not differ throughout pregnancy and post-partum. The use of TDF with ATV/r did not affect ATV C24h. Moreover, no dose adjustment was required at third trimester, which suggests that ATV/r at 300/100 mg once daily should be adequate during pregnancy, with or without TDF. Virus was controlled in nearly all patients receiving ATV/r until delivery and no MTCT was reported to this day. Nevertheless, TDM might be recommended during third trimester to document efficacy, tolerance or adherence issues. Our data support the use of ATV/r in pregnancy. Acknowledgements Preliminary analysis results were published at the Conference on Retroviruses and Opportunistic Infections, 3 6 March 2014, Boston, MA, USA (poster number 889). This study was funded by a grant from Bristol Myers Squibb, USA. Disclosure statement MPL received travel grants from Bristol Myers Squibb. LM received lecturing fees from Bristol Myers Squibb and Gilead Sciences. DD received travel grants from ViiV Healthcare, Janssen-Cilag, MSD and Bristol Myers Squibb. M-AV received travel grants from Gilead Sciences, Janssen-Cilag, Bristol Myers Squibb and ViiV Healthcare. VC and GP received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol Myers Squibb, Gilead Sciences, Janssen, Merck, ViiV Healthcare and Splicos. The remaining authors declare no competing interests. References 1. Eley T, Bertz R, Hardy H, Burger D. Atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. Antivir Ther 2013; 18: Table 3. Plasma level of ATV and RTV at C24h (with 300/100 mg once daily) at each trimester, delivery and post-partum First trimester Second trimester Third trimester Delivery a Post-partum Median gestational age, weeks (IQR 25 75%) 12 (8 14) 22 (20 25) 33 (31 36) Number of patients ATV C24h Median plasma level, ng/ml (IQR 25 75%) 592 ( ) 631 (244 1,005) 665 (471 1,063) 996 (666 2,552) 914 (557 1,152) CV, % Median time since last intake, h (IQR 25 75%) 13 (12 22) <150 ng/ml, n (%) 3 (10) 9 (13) 6 (8) N/A 2 (4) >850 ng/ml, n (%) 8 (27) 26 (37) 29 (37) N/A 25 (56) RTV C24h b Median plasma level, ng/ml (IQR 25 75%) 29 (5 61) 18 (5 39) 21 (5 39) 18 (5 40) 21 (5 41) CV, % ANOVA test reported no significant difference in atazanavir (ATV) concentration between the different groups excluding the delivery column. a ATV and ritonavir (RTV) plasma levels were not at 24 h post-dose (C24h). b RTV C24h< limit of quantification (LOQ)=10 ng/ml defined as LOQ/2 = 5 ng/ml. CV, coefficient of variation; N/A, not applicable International Medical Press

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