Atazanavir and darunavir in pregnant women with HIV: evaluation of laboratory and clinical outcomes from an observational national study

Atazanavir and darunavir in pregnant women with HIV: evaluation of laboratory and clinical... Abstract Background Atazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparative data in pregnant women are limited. We assessed the safety and activity profile of these two drugs in pregnancy using data from a national observational study. Methods Women with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measures and main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatal gestational age-adjusted birthweight Z-score). Results Final analysis included 500 pregnancies with either atazanavir (n = 409) or darunavir (n = 91) exposure. No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA, haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the two groups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides (median 235.5 versus 179 mg/dL; P = 0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03 versus 3.27; P = 0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54 versus 0.32 mg/dL; P < 0.001). Conclusions In this observational study, the two main HIV PIs currently recommended by perinatal guidelines showed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in terms of main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug in some particular situations where the different impacts of treatment on lipid profile and bilirubin may have clinical relevance. Introduction Current guidelines for HIV treatment usually recommend atazanavir and darunavir (with low-dose ritonavir) as preferred HIV PIs in pregnant women.1,2 There is, however, limited comparative information for these two drugs with respect to metabolic profile in pregnancy, effective viral suppression before delivery and, in general, pregnancy and infant outcomes. In order to further explore this issue, we analysed a national cohort of pregnant women with HIV, comparing in women with gestational exposure to atazanavir or darunavir some laboratory parameters, such as plasma lipid profile, HIV viral load, liver function tests and haemoglobin, and some maternal and infant outcomes, such as preterm delivery, low birthweight, non-elective caesarean section and birthweight Z-score. Patients and methods Data from the Italian National Programme on Surveillance of Antiretroviral Treatment in Pregnancy were used. This is a national observational study of pregnant women with HIV established in Italy in 2001. The women and infants are followed during routine clinical care and treatments are decided by the treating physician, usually according to existing guidelines. Laboratory and clinical data are collected from hospital records of obstetrics, infectious diseases and paediatrics departments, following the women’s consent, using a patient information sheet that has received approval by the competent Ethics Committee (National Institute for Infectious Diseases L. Spallanzani, Rome). Gestational age is determined on the basis of the last menstrual period, ultrasound biometry or both. Preterm and very preterm delivery are defined as delivery before 37 and 32 completed weeks of gestation, respectively, and low and very low birthweight by values below 2500 and 1500 g, respectively. Caesarean section is considered elective if performed before the rupture of membranes and the onset of labour and non-elective if performed after the rupture of membranes or onset of labour or both. All the results reported here are based on data extracted from the general database on 20 June 2017 and refer to pregnancies that occurred since May 2004 (date of first reported exposure to atazanavir). The main outcomes evaluated were non-elective caesarean section, preterm and very preterm delivery, low and very low birthweight and gender- and gestational age-adjusted percentiles for birthweight (calculated according to national reference standards).3 Other outcomes included HIV transmission, infant mortality and birth defects, defined according to the Antiretroviral Pregnancy Registry definition.4 In women exposed to atazanavir or darunavir in pregnancy without discontinuation the following laboratory parameters were also compared: ALT, bilirubin, haemoglobin, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol and total cholesterol/HDL cholesterol ratio. Recommended drug dosages followed existing guidelines. Laboratory indexes were summarized as medians with IQRs and compared using the Mann–Whitney U-test. Qualitative variables were compared using the χ2 or Fisher’s test. P values <0.05 were considered statistically significant. All analyses were performed using SPSS software, version 22 (IBM Corp, 2013, Armonk, NY, USA). Ethics approval Ethics approval was obtained from the Ethics Committee of the I.N.M.I. Lazzaro Spallanzani in Rome (ref. deliberation 578/2001, 28 September 2001). Results First exposure to atazanavir in pregnancy was reported in 2004 and first exposure to darunavir in 2007. Between May 2004 and June 2017, 3045 pregnancies were reported. Following exclusion of 140 recent pregnancies (4.6%) with possible reporting delay (outcome not reported within 18 months from expected date of delivery) and of 790 cases (25.9%) with missing outcome information >18 months from expected date of delivery, 2115 pregnancies (69.5%) with available information on pregnancy outcome were considered. Among the cases excluded, 580 had no information at all except for date of last menstrual period and age (the basic clinical information required for the initial report of the pregnancy). The remaining 350 excluded cases had some information available and were compared with the 2115 cases considered for subsequent analyses (Table 1, left side). For some laboratory variables, only a limited proportion of the 350 excluded cases had available information, because missing outcome was also associated with missing laboratory data at the start of pregnancy. No differences were found between the two groups for age, CD4 count, plasma HIV viral load, months since HIV diagnosis, total bilirubin, plasma triglycerides, total cholesterol, total cholesterol/HDL cholesterol ratio and ALT. The two groups were also similar for nationality, history of drug use, HCV seropositivity, diagnosis of HIV in pregnancy, history of hypertension, nephropathy and diabetes, and parity. Excluded women were more commonly on ART at conception and HBV positive (Table 1, left side). Among the 350 cases excluded, 66 had exposure to atazanavir, 22 to darunavir and 2 to both drugs. Table 1. Baseline characteristics of the population studied according to outcome status (left side) and to exposure in pregnancy to the two drugs studied (right side)   350 with outcome unknown  2115 with outcome known  Pa  409 with outcome known, atazanavir  91 with outcome known, darunavir  Pa    n  median (IQR)  n  median (IQR)    n  median (IQR)  n  median (IQR)    Age (years)  343  32 (27–37)  2096  33 (29–36)  0.233  409  34 (30–38)  91  32 (27–37)  0.012  CD4 count (cells/mm3)  208  547 (404–696)  931  512 (360–710)  0.509  195  560 (389–752)  51  560 (361–725)  0.543  HIV-RNA (log copies/mL)  177  1.70 (1.60–3.35)  869  1.70 (1.60–3.04)  0.872  278  1.70 (1.57–3.48)  60  1.60 (1.57–2.15)  0.025  Months since HIV diagnosis  331  42 (8–101)  2044  53 (9–114)  0.084  401  68 (25–127.5)  89  89 (29.5–223)  0.022  Total bilirubin (mg/dL)  36  0.40 (0.33–0.52)  1007  0.50 (0.34–0.79)  0.101  270  1.03 (0.47–2.14)  58  0.35 (0.28–0.53)  <0.001  Plasma triglycerides (mg/dL)  27  91 (67–119)  952  90 (68–126)  0.746  239  86 (66–121)  47  93 (73–129)  0.274  Total cholesterol (mg/dL)  31  183 (155–195)  958  169 (147–194)  0.282  245  163 (143–183)  46  166 (150–190.25)  0.619  Total cholesterol/HDL cholesterol ratio  24  3.01 (2.48–3.47)  611  3.00 (2.57–3.56)  0.497  181  3.13 (2.65–3.56)  31  3.15 (2.50–3.83)  0.760  ALT (U/L)  15  15 (8–20)  345  16 (12–22)  0.171  127  16 (12–22)  48  14.5 (11–19.75)  0.230    n  %  n  %    n  %  n  %    Foreign nationality  337  59.1  1998  53.6  0.063  402  51.2  89  44.9  0.282  History of drug use  333  6.3  2064  6.2  0.914  407  5.9  89  4.5  0.801  HCV positive  318  13.5  1946  12.9  0.759  381  11.8  85  15.3  0.379  Diagnosis of HIV in pregnancy  331  21.5  2044  22.5  0.683  401  14.5  89  11.2  0.720  History of hypertension  328  3.0  2065  1.8  0.147  408  2.2  91  1.1  0.698  History of nephropathy  328  0.3  2060  0.9  0.254  407  1.2  91  1.1  1.000  History of diabetes  327  1.2  2057  2.1  0.273  404  3.2  91  2.2  1.000  At least one previous pregnancy  333  76.6  2064  75.6  0.694  407  78.1  91  73.6  0.353  On treatment at conception  345  62.3  2067  55.7  0.021  409  62.3  91  65.9  0.522  HBV positive  306  15.0  1954  10.5  0.019  393  11.7  87  14.9  0.405    350 with outcome unknown  2115 with outcome known  Pa  409 with outcome known, atazanavir  91 with outcome known, darunavir  Pa    n  median (IQR)  n  median (IQR)    n  median (IQR)  n  median (IQR)    Age (years)  343  32 (27–37)  2096  33 (29–36)  0.233  409  34 (30–38)  91  32 (27–37)  0.012  CD4 count (cells/mm3)  208  547 (404–696)  931  512 (360–710)  0.509  195  560 (389–752)  51  560 (361–725)  0.543  HIV-RNA (log copies/mL)  177  1.70 (1.60–3.35)  869  1.70 (1.60–3.04)  0.872  278  1.70 (1.57–3.48)  60  1.60 (1.57–2.15)  0.025  Months since HIV diagnosis  331  42 (8–101)  2044  53 (9–114)  0.084  401  68 (25–127.5)  89  89 (29.5–223)  0.022  Total bilirubin (mg/dL)  36  0.40 (0.33–0.52)  1007  0.50 (0.34–0.79)  0.101  270  1.03 (0.47–2.14)  58  0.35 (0.28–0.53)  <0.001  Plasma triglycerides (mg/dL)  27  91 (67–119)  952  90 (68–126)  0.746  239  86 (66–121)  47  93 (73–129)  0.274  Total cholesterol (mg/dL)  31  183 (155–195)  958  169 (147–194)  0.282  245  163 (143–183)  46  166 (150–190.25)  0.619  Total cholesterol/HDL cholesterol ratio  24  3.01 (2.48–3.47)  611  3.00 (2.57–3.56)  0.497  181  3.13 (2.65–3.56)  31  3.15 (2.50–3.83)  0.760  ALT (U/L)  15  15 (8–20)  345  16 (12–22)  0.171  127  16 (12–22)  48  14.5 (11–19.75)  0.230    n  %  n  %    n  %  n  %    Foreign nationality  337  59.1  1998  53.6  0.063  402  51.2  89  44.9  0.282  History of drug use  333  6.3  2064  6.2  0.914  407  5.9  89  4.5  0.801  HCV positive  318  13.5  1946  12.9  0.759  381  11.8  85  15.3  0.379  Diagnosis of HIV in pregnancy  331  21.5  2044  22.5  0.683  401  14.5  89  11.2  0.720  History of hypertension  328  3.0  2065  1.8  0.147  408  2.2  91  1.1  0.698  History of nephropathy  328  0.3  2060  0.9  0.254  407  1.2  91  1.1  1.000  History of diabetes  327  1.2  2057  2.1  0.273  404  3.2  91  2.2  1.000  At least one previous pregnancy  333  76.6  2064  75.6  0.694  407  78.1  91  73.6  0.353  On treatment at conception  345  62.3  2067  55.7  0.021  409  62.3  91  65.9  0.522  HBV positive  306  15.0  1954  10.5  0.019  393  11.7  87  14.9  0.405  a Mann-Whitney U-test for quantitative variables; χ2 or Fisher’s test for categorical variables. Among the 2115 cases with known outcome, 409 (19.3%) had exposure to atazanavir during pregnancy, 91 (4.3%) to darunavir and 8 (0.4%) to both (sequentially). Cases sequentially exposed to both drugs were excluded from all comparisons, leaving 500 evaluable cases. Following the first exposure reported, the proportion of exposed pregnancies increased significantly over time for both drugs (P < 0.001, χ2 for trend), with a peak in 2013 for atazanavir (62/173, 35.8% of all pregnancies) and in 2014 for darunavir (27/143, 18.9%). Among cases exposed in pregnancy to either drug, 315 (63.0%) were on treatment at the start of pregnancy, with no differences between groups (atazanavir: 255/409, 62.3%; darunavir: 60/91, 65.9%; P = 0.522, χ2 test). Only a small fraction of such cases had a subsequent discontinuation (39/315, 12.4%), with no significant differences between groups (atazanavir: 34/255, 13.3%; darunavir: 5/60, 8.3%; P = 0.290, χ2 test). In most of these discontinuations, atazanavir or darunavir was replaced by other drugs for treatment optimization, in the absence of toxicity or treatment inefficacy (data not shown). The comparison of baseline characteristics (epidemiology, HIV infection and laboratory data) for the two treatment groups is shown in Table 1 (right side). At the start of pregnancy, women on atazanavir were older, had a shorter interval since HIV diagnosis, slightly higher median plasma HIV-RNA levels and significantly higher plasma total bilirubin levels. No other significant differences were found in laboratory measures or in demographic and clinical characteristics (Table 1, right side). The comparison of the main laboratory indexes, performed in women with continued exposure in pregnancy to either drug without discontinuation, showed some significant differences between the two groups (Table 2). Treatment with darunavir was associated with higher levels of plasma triglycerides (significant at third trimester) and higher values of the total cholesterol/HDL cholesterol ratio (significant at both first and third trimesters), while treatment with atazanavir was associated with higher levels of plasma bilirubin (significant at both trimesters). No differences were observed at either trimester in levels of haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol, and in changes observed between first and third trimesters for all the above parameters (all P values ≥0.15; Table 2). Table 2. Laboratory measures at first and third trimesters of pregnancy and changes over time in women receiving either atazanavir or darunavir during entire pregnancy   First trimester, median (IQR)   Third trimester, median (IQR)   Median change (IQR), first to third trimester   atazanavir  darunavir  P  atazanavir  darunavir  P  atazanavir  darunavir  P  Plasma total bilirubin (mg/dL) (n: atazanavir 129, darunavir 29)  1.70 (0.96–2.50)  0.31 (0.25–0.64)  <0.001  1.54 (1.03–2.30)  0.32 (0.25–0.47)  <0.001  −0.15 (−0.74 to + 0.45)  −0.02 (−0.15 to + 0.01)  0.331  ALT (U/L) (n: atazanavir 73, darunavir 30)  16 (12.0–21.5)  18 (12.0–22.2)  0.428  18 (12–27)  16 (13–26.5)  0.780  2 (−2.5 to + 9.5)  −1 (−4.2 to + 8.0)  0.497  Haemoglobin (g/dL) (n: atazanavir 75, darunavir 28)  12.5 (11.9–13.2)  12.5 (12.1–13.1)  0.809  11.8 (10.8–12.3)  11.5 (10.5–12.2)  0.276  −0.7 (−1.8 to − 0.1)  −1.0 (−2.35 to − 0.42)  0.240  Plasma triglycerides (mg/dL) (n: atazanavir 95, darunavir 20)  87 (68–128)  111.5 (80.5–158.7)  0.072  179 (148–224)  235.5 (177.7–352.5)  0.032  90 (61–126)  119 (59.5–159.2)  0.150  Plasma total cholesterol (mg/dL) (n: atazanavir 96, darunavir 20)  163.5 (140.2–184.7)  161.5 (146.0–189.2)  0.778  211 (189.5–251.5)  201 (179.7–293.2)  0.962  54 (32.2–75.0)  58.5 (1.25–103.0)  0.792  Plasma HDL cholesterol (mg/dL) (n: atazanavir 71, darunavir 13)  55 (46–67)  50 (45–56)  0.115  68 (55–82)  59 (56–72.5)  0.350  11 (2–23)  14 (10.5–18.5)  0.380  Plasma LDL cholesterol (mg/dL) (n: atazanavir 46, darunavir 9)  86.5 (70.7–108.0)  116 (79–132)  0.111  111 (83–129.7)  132 (90.5–187)  0.092  19 (4.0–50.2)  40 (4.5–66.5)  0.158  Total cholesterol/HDL cholesterol ratio (n: atazanavir 71, darunavir 13)  2.97 (2.45–3.48)  3.62 (2.80–4.11)  0.018  3.27 (2.58–3.90)  4.03 (3.28–4.90)  0.028  0.282 (−0.117 to + 0.734)  0.475 (−0.582 to + 1.362)  0.591    First trimester, median (IQR)   Third trimester, median (IQR)   Median change (IQR), first to third trimester   atazanavir  darunavir  P  atazanavir  darunavir  P  atazanavir  darunavir  P  Plasma total bilirubin (mg/dL) (n: atazanavir 129, darunavir 29)  1.70 (0.96–2.50)  0.31 (0.25–0.64)  <0.001  1.54 (1.03–2.30)  0.32 (0.25–0.47)  <0.001  −0.15 (−0.74 to + 0.45)  −0.02 (−0.15 to + 0.01)  0.331  ALT (U/L) (n: atazanavir 73, darunavir 30)  16 (12.0–21.5)  18 (12.0–22.2)  0.428  18 (12–27)  16 (13–26.5)  0.780  2 (−2.5 to + 9.5)  −1 (−4.2 to + 8.0)  0.497  Haemoglobin (g/dL) (n: atazanavir 75, darunavir 28)  12.5 (11.9–13.2)  12.5 (12.1–13.1)  0.809  11.8 (10.8–12.3)  11.5 (10.5–12.2)  0.276  −0.7 (−1.8 to − 0.1)  −1.0 (−2.35 to − 0.42)  0.240  Plasma triglycerides (mg/dL) (n: atazanavir 95, darunavir 20)  87 (68–128)  111.5 (80.5–158.7)  0.072  179 (148–224)  235.5 (177.7–352.5)  0.032  90 (61–126)  119 (59.5–159.2)  0.150  Plasma total cholesterol (mg/dL) (n: atazanavir 96, darunavir 20)  163.5 (140.2–184.7)  161.5 (146.0–189.2)  0.778  211 (189.5–251.5)  201 (179.7–293.2)  0.962  54 (32.2–75.0)  58.5 (1.25–103.0)  0.792  Plasma HDL cholesterol (mg/dL) (n: atazanavir 71, darunavir 13)  55 (46–67)  50 (45–56)  0.115  68 (55–82)  59 (56–72.5)  0.350  11 (2–23)  14 (10.5–18.5)  0.380  Plasma LDL cholesterol (mg/dL) (n: atazanavir 46, darunavir 9)  86.5 (70.7–108.0)  116 (79–132)  0.111  111 (83–129.7)  132 (90.5–187)  0.092  19 (4.0–50.2)  40 (4.5–66.5)  0.158  Total cholesterol/HDL cholesterol ratio (n: atazanavir 71, darunavir 13)  2.97 (2.45–3.48)  3.62 (2.80–4.11)  0.018  3.27 (2.58–3.90)  4.03 (3.28–4.90)  0.028  0.282 (−0.117 to + 0.734)  0.475 (−0.582 to + 1.362)  0.591  All P values: Mann–Whitney U-test. The main pregnancy outcomes for the two groups are summarized in Table 3. No significant differences were observed between the two groups, with similar rates of preterm and very preterm delivery, low and very low birthweight, pregnancies not ending in a live birth, emergency caesarean delivery, complications of delivery, neonatal death and birth defects. The two groups were also similar for increase in body weight in pregnancy (median 11 kg in both groups; IQR 8–14 for atazanavir, 7.5–13 for darunavir; P = 0.669) and for rates of urinary infections, vaginal infections, hypertension, glucose metabolism abnormalities and anaemia (data not shown). Among 353 infants with HIV status available, only one case of HIV transmission (0.3%) was observed (in the atazanavir group). Among the five neonatal deaths reported, three were in severely preterm infants (<30 weeks), likely caused by complications related to prematurity, one was due to respiratory failure in an infant with congenital defects and the other occurred in a term infant with neonatal streptococcal sepsis. Table 3. Pregnancy outcomes   Entire study populationa  Atazanavir  Darunavir  Pb  HIV viral load <50 copies/mL at third trimester, %  73.8 (1013/1372)  81.6 (239/293)  83.6 (56/67)  0.669  Pregnancy not ending in a live birth, %c  9.8 (114/1168)  8.3 (21/253)  15.3 (9/59)  0.103  Non-elective caesarean section, %  18.7 (326/1746)  18.6 (67/361)  18.3 (13/71)  0.961  Preterm delivery (<37 weeks), %d  19.0 (338/1780)  17.4 (63/362)  18.9 (14/74)  0.755  Very preterm delivery (<32 weeks), %  2.1 (37/1780)  1.9 (7/362)  2.7 (2/74)  0.653  Low birthweight (<2500 g), %d  20.7 (345/1666)  20.4 (70/343)  16.9 (12/71)  0.500  Very low birthweight (<1500 g), %d  2.7 (45/1666)  2.6 (9/343)  4.2 (3/71)  0.440  Small by gestational age, %e  12.7 (197/1553)  12.0 (39/326)  11.3 (8/71)  0.869  Large by gestational age, %e  6.9 (107/1553)  5.8 (19/326)  5.6 (4/71)  0.605  Complications of delivery, %f  6.4 (110/1722)  9.3 (33/353)  5.6 (4/71)  0.488  Neonatal/infant death, %  0.7 (13/1847)  1.3 (5/374)  0  0.404  Birth defects, %g  4.8 (44/921)  5.8 (12/207)  7.7 (3/39)  0.713    Entire study populationa  Atazanavir  Darunavir  Pb  HIV viral load <50 copies/mL at third trimester, %  73.8 (1013/1372)  81.6 (239/293)  83.6 (56/67)  0.669  Pregnancy not ending in a live birth, %c  9.8 (114/1168)  8.3 (21/253)  15.3 (9/59)  0.103  Non-elective caesarean section, %  18.7 (326/1746)  18.6 (67/361)  18.3 (13/71)  0.961  Preterm delivery (<37 weeks), %d  19.0 (338/1780)  17.4 (63/362)  18.9 (14/74)  0.755  Very preterm delivery (<32 weeks), %  2.1 (37/1780)  1.9 (7/362)  2.7 (2/74)  0.653  Low birthweight (<2500 g), %d  20.7 (345/1666)  20.4 (70/343)  16.9 (12/71)  0.500  Very low birthweight (<1500 g), %d  2.7 (45/1666)  2.6 (9/343)  4.2 (3/71)  0.440  Small by gestational age, %e  12.7 (197/1553)  12.0 (39/326)  11.3 (8/71)  0.869  Large by gestational age, %e  6.9 (107/1553)  5.8 (19/326)  5.6 (4/71)  0.605  Complications of delivery, %f  6.4 (110/1722)  9.3 (33/353)  5.6 (4/71)  0.488  Neonatal/infant death, %  0.7 (13/1847)  1.3 (5/374)  0  0.404  Birth defects, %g  4.8 (44/921)  5.8 (12/207)  7.7 (3/39)  0.713  a All cases followed since May 2004. b Comparison between atazanavir- and darunavir-exposed women, χ2 or Fisher’s test. c Calculated on cases exposed (on treatment) at the start of pregnancy. d Livebirths only. e Birthweight <10th (small) or > 90th (large) percentile by age and gender, singletons only. f Mostly represented by anaemia, fever or wound infections. g Livebirths from mothers on treatment at the start of pregnancy. Discussion Current guidelines for pregnant women with HIV usually recommend atazanavir or darunavir (both with low-dose ritonavir) as the preferred PIs for use in pregnancy.1,2 The present analysis, based on 500 pregnancies exposed, provides new comparative information. The proportion of evaluable cases reflects the earlier introduction and more common use of atazanavir compared with darunavir. Reassuringly, all the main pregnancy and infant outcomes were equally frequent in the two groups and the rate of HIV transmission was minimal, with only one case reported. Although this case series is to our knowledge the largest comparing these two drugs in pregnant women, caution is necessary in the interpretation of outcome data for several reasons. The number of events, particularly for some infrequent outcomes (such as very preterm delivery and very low birthweight), was small and the absence of significant differences should be considered within the context of the statistical power of the study, which can be adequate to detect only large differences between groups. Overall, the rates of all main events were similar to those of the entire study population of pregnant women with HIV, as shown in Table 3, but for some outcomes the numbers show some variability between groups that should be explored in larger studies, possibly pooling data from multiple cohorts. In terms of laboratory outcomes, the two drugs were equally effective in producing an undetectable viral load at the end of pregnancy, indicating comparable virological efficacy in pregnancy, with even higher rates of viral suppression compared with the entire study population (Table 3). Some differences were observed in some laboratory indexes: atazanavir was clearly associated with higher levels of bilirubin, but with no higher rates of drug discontinuation or adverse outcomes, in line with other observations that indicate that the clinical impact of this drug effect in both mothers and infants is generally limited.5–7 Apart from bilirubinaemia, the only other significant differences observed between the two drugs in laboratory parameters involved a slightly better metabolic profile with atazanavir. This drug has shown a favourable lipid profile in clinical trials8,9 and in pregnancy10 compared with lopinavir, but there are less consistent findings regarding the comparison with darunavir in terms of lipid profile.11–15 The present study indicates in pregnant women a better lipid profile with atazanavir compared with darunavir, with lower triglyceride levels (contrary to some studies in the general population that showed an opposite effect)12,13 and a lower total cholesterol/HDL cholesterol ratio (consistent with Martinez et al.,11 2014). Although pregnancy may induce significant effects on lipid levels,16 most of the observed differences were already present at the start of pregnancy and are therefore likely to reflect general differences in the metabolic profile of the two drugs and not a specific differential effect of pregnancy, as also suggested by the similar changes observed with the two drugs in all laboratory parameters between first and third trimesters. Finally, the differences in laboratory measures were not accompanied by substantial differences in clinical outcomes, including those potentially related to metabolic status, such as maternal weight gain and prevalence of large infants by gestational age. Overall, given the increased cardiovascular risk associated with higher values of the total cholesterol/HDL cholesterol ratio17and the potential association of early hypertriglyceridaemia with subsequent occurrence of gestational diabetes, pre-eclampsia18,19 and fetal macrosomia,20 clinicians could consider atazanavir as a preferable choice in particular situations where additional risk factors for the above clinical conditions are present. On the other hand, darunavir may be preferred when hyperbilirubinaemia may pose some concern. The main limitation of this study, together with the sample size considerations discussed above, is represented by the non-randomized attribution of treatment, which does not allow us to exclude some selection bias in prescribing. Randomized studies are, however, difficult to perform in pregnancy and almost all available information is based on studies with an observational design. Overall, this study provided new comparative information on use of atazanavir and darunavir in pregnancy, with a relatively large sample size that included 500 cases. Overall, the main study findings, showing no evidence of a difference in risk of adverse pregnancy outcomes, support current recommendations. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug only in particular situations where the expected impact of treatment on lipid profile and bilirubin may be clinically relevant. Acknowledgements We thank Cosimo Polizzi and Alessandra Mattei of the Istituto Superiore di Sanità in Rome, Italy, for providing technical secretarial support for this study. No compensation was received for this contribution. Members of The Italian Group on Surveillance of Antiretroviral Treatment in Pregnancy Project coordinators: M. Floridia, M. Ravizza, E. Tamburrini. Participants: M. Ravizza, E. Tamburrini, F. Di Lorenzo, G. Sterrantino, M. Meli, I. Campolmi, F. Vichi, B. Del Pin, R. Marocco, C. Mastroianni, V. S. Mercurio, A. Maccabruni, D. Zanaboni, G. Guaraldi, G. Nardini, C. Stentarelli, B. Beghetto, A. M. Degli Antoni, A. Molinari, M. P. Crisalli, A. Donisi, M. Piepoli, V. Cerri, G. Zuccotti, V. Giacomet, S. Coletto, F. Di Nello, C. Madia, G. Placido, P. Milini, F. Savalli, V. Portelli, F. Sabbatini, D. Francisci, C. Papalini, L. Bernini, P. Grossi, L. Rizzi, M. Bernardon, G. Maso, E. Rizzante, C. Belcaro, A. Meloni, M. Dedoni, F. Ortu, P. Piano, A. Citernesi, I. Bordoni Vicini, K. Luzi, A. Spinillo, M. Roccio, A. Vimercati, F. M. Crupano, D. Calabretti, G. Simonazzi, F. Cervi, E. Margarito, M. G. Capretti, C. Marsico, G. Faldella, M. Sansone, P. Martinelli, A. Agangi, A. Capone, G. M. Maruotti, C. Tibaldi, L. Trentini, T. Todros, G. Masuelli, V. Frisina, I. Cetin, T. Brambilla, V. Savasi, C. Personeni, C. Giaquinto, M. Fiscon, E. Rubino, L. Franceschetti, R. Badolato, B. Tassis, G. C. Tiso, O. Genovese, C. Cafforio, C. Pinnetti, G. Liuzzi, A. M. Casadei, A. F. Cavaliere, M. Cellini, A. M. Marconi, S. Dalzero, V. Sacchi, M. Ierardi, C. Polizzi, A. Mattei, M. F. Pirillo, R. Amici, C. M. Galluzzo, S. Donnini, S. Baroncelli, M. Floridia. Pharmacokinetics: P. Villani, M. Cusato. Advisory Board: A. Cerioli, M. De Martino, F. Parazzini, E. Tamburrini, S. Vella. SIGO-HIV Group National Coordinators: P. Martinelli, M. Ravizza. Funding This work (currently not funded) was supported in the past by a public research grant (ref.: H85E08000200005) from the Italian Medicines Agency (AIFA). Transparency declarations None to declare. References 1 Panel on Treatment of Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. 2 Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1. 22 Novembre 2016. http://www.salastampa.salute.gov.it/portale/news/p3_2_1_1_1.jsp?lingua=italiano&menu=notizie&p=dalministero&id=2760. 3 Bertino E, Spada E, Occhi L et al.   Neonatal anthropometric charts: the Italian Neonatal Study compared with other European studies. J Pediatr Gastroenterol Nutr  2010; 51: 353– 61. Google Scholar PubMed  4 Scheuerle A, Tilson H. Birth defect classification by organ system: a novel approach to heighten teratogenic signalling in a pregnancy registry. Pharmacoepidem Drug Saf  2002; 11: 465– 75. Google Scholar CrossRef Search ADS   5 McDonald C, Uy J, Hu W et al.   Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS Patient Care STDS  2012; 26: 259– 64. Google Scholar CrossRef Search ADS PubMed  6 Croom KF, Dhillon S, Keam SJ. Atazanavir: a review of its use in the management of HIV-1 infection. Drugs  2009; 69: 1107– 40. Google Scholar CrossRef Search ADS PubMed  7 Eley T, Huang SP, Conradie F et al.   Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. AIDS Res Hum Retroviruses  2013; 10: 1287– 92. Google Scholar CrossRef Search ADS   8 Molina JM, Andrade-Villanueva J, Echevarria J et al.   Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr  2010; 53: 323– 32. Google Scholar CrossRef Search ADS PubMed  9 Johnson M, Grinsztejn B, Rodriguez C et al.   96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS  2006; 20: 711– 8. Google Scholar CrossRef Search ADS PubMed  10 Floridia M, Ravizza M, Masuelli G et al.   Atazanavir and lopinavir profile in pregnancy: data from an observational national study. J Antimicrob Chemother  2014; 69: 1377– 84. Google Scholar CrossRef Search ADS PubMed  11 Martinez E, Gonzalez-Cordon A, Ferrer E et al.   Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir. HIV Med  2014; 15: 330– 8. Google Scholar CrossRef Search ADS PubMed  12 Saumoy M, Ordóñez-Llanos J, Martínez E et al.   Atherogenic properties of lipoproteins in HIV patients starting atazanavir/ritonavir or darunavir/ritonavir: a substudy of the ATADAR randomized study. J Antimicrob Chemother  2015; 70: 1130– 8. Google Scholar PubMed  13 Martinez E, Gonzalez-Cordon A, Ferrer E et al.   Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial. Clin Infect Dis  2015; 60: 811– 20. Google Scholar CrossRef Search ADS PubMed  14 Ofotokun I, Na LH, Landovitz RJ et al.   Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis  2015; 60: 1842– 51. Google Scholar CrossRef Search ADS PubMed  15 Kelesidis T, Tran TTT, Brown TT et al.   Changes in plasma levels of oxidized lipoproteins and lipoprotein subfractions with atazanavir-, raltegravir-, darunavir-based initial antiviral therapy and associations with common carotid artery intima-media thickness: ACTG 5260s. Antivir Ther  2017; 22: 113– 26. Google Scholar CrossRef Search ADS PubMed  16 Floridia M, Tamburrini E, Ravizza M et al.   Lipid profile during pregnancy in HIV-infected women. HIV Clin Trials  7: 184– 93. CrossRef Search ADS PubMed  17 Prospective Studies Collaboration, Lewington S, Whitlock G et al.   Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet  2007; 370: 1829– 39. Google Scholar CrossRef Search ADS PubMed  18 Enquobahrie DA, Williams MA, Qiu C et al.   Early pregnancy lipid concentrations and the risk of gestational diabetes mellitus. Diabetes Res Clin Pract  2005; 70: 134– 42. Google Scholar CrossRef Search ADS PubMed  19 Clausen T, Djurovic S, Heriksen T et al.   Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. BJOG  2001; 108: 1081– 7. Google Scholar PubMed  20 Di Cianni G, Miccoli R, Volpe L et al.   Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. Diabet Med  2005; 22: 21– 5. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Atazanavir and darunavir in pregnant women with HIV: evaluation of laboratory and clinical outcomes from an observational national study

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Oxford University Press
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0305-7453
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1460-2091
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10.1093/jac/dkx478
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Abstract

Abstract Background Atazanavir and darunavir represent the main HIV PIs recommended in pregnancy, but comparative data in pregnant women are limited. We assessed the safety and activity profile of these two drugs in pregnancy using data from a national observational study. Methods Women with atazanavir or darunavir exposure in pregnancy were evaluated for laboratory measures and main pregnancy outcomes (e.g. preterm delivery, low birthweight, non-elective caesarean section and neonatal gestational age-adjusted birthweight Z-score). Results Final analysis included 500 pregnancies with either atazanavir (n = 409) or darunavir (n = 91) exposure. No differences in pregnancy outcomes, weight gain in pregnancy, drug discontinuations, undetectable HIV-RNA, haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol were observed between the two groups. At third trimester, exposure to darunavir was associated with higher levels of plasma triglycerides (median 235.5 versus 179 mg/dL; P = 0.032) and a higher total cholesterol/HDL cholesterol ratio (median 4.03 versus 3.27; P = 0.028) and exposure to atazanavir was associated with higher levels of plasma bilirubin (1.54 versus 0.32 mg/dL; P < 0.001). Conclusions In this observational study, the two main HIV PIs currently recommended by perinatal guidelines showed similar safety and activity in pregnancy, with no evidence of differences between the two drugs in terms of main pregnancy outcomes. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug in some particular situations where the different impacts of treatment on lipid profile and bilirubin may have clinical relevance. Introduction Current guidelines for HIV treatment usually recommend atazanavir and darunavir (with low-dose ritonavir) as preferred HIV PIs in pregnant women.1,2 There is, however, limited comparative information for these two drugs with respect to metabolic profile in pregnancy, effective viral suppression before delivery and, in general, pregnancy and infant outcomes. In order to further explore this issue, we analysed a national cohort of pregnant women with HIV, comparing in women with gestational exposure to atazanavir or darunavir some laboratory parameters, such as plasma lipid profile, HIV viral load, liver function tests and haemoglobin, and some maternal and infant outcomes, such as preterm delivery, low birthweight, non-elective caesarean section and birthweight Z-score. Patients and methods Data from the Italian National Programme on Surveillance of Antiretroviral Treatment in Pregnancy were used. This is a national observational study of pregnant women with HIV established in Italy in 2001. The women and infants are followed during routine clinical care and treatments are decided by the treating physician, usually according to existing guidelines. Laboratory and clinical data are collected from hospital records of obstetrics, infectious diseases and paediatrics departments, following the women’s consent, using a patient information sheet that has received approval by the competent Ethics Committee (National Institute for Infectious Diseases L. Spallanzani, Rome). Gestational age is determined on the basis of the last menstrual period, ultrasound biometry or both. Preterm and very preterm delivery are defined as delivery before 37 and 32 completed weeks of gestation, respectively, and low and very low birthweight by values below 2500 and 1500 g, respectively. Caesarean section is considered elective if performed before the rupture of membranes and the onset of labour and non-elective if performed after the rupture of membranes or onset of labour or both. All the results reported here are based on data extracted from the general database on 20 June 2017 and refer to pregnancies that occurred since May 2004 (date of first reported exposure to atazanavir). The main outcomes evaluated were non-elective caesarean section, preterm and very preterm delivery, low and very low birthweight and gender- and gestational age-adjusted percentiles for birthweight (calculated according to national reference standards).3 Other outcomes included HIV transmission, infant mortality and birth defects, defined according to the Antiretroviral Pregnancy Registry definition.4 In women exposed to atazanavir or darunavir in pregnancy without discontinuation the following laboratory parameters were also compared: ALT, bilirubin, haemoglobin, triglycerides, total cholesterol, HDL cholesterol, LDL cholesterol and total cholesterol/HDL cholesterol ratio. Recommended drug dosages followed existing guidelines. Laboratory indexes were summarized as medians with IQRs and compared using the Mann–Whitney U-test. Qualitative variables were compared using the χ2 or Fisher’s test. P values <0.05 were considered statistically significant. All analyses were performed using SPSS software, version 22 (IBM Corp, 2013, Armonk, NY, USA). Ethics approval Ethics approval was obtained from the Ethics Committee of the I.N.M.I. Lazzaro Spallanzani in Rome (ref. deliberation 578/2001, 28 September 2001). Results First exposure to atazanavir in pregnancy was reported in 2004 and first exposure to darunavir in 2007. Between May 2004 and June 2017, 3045 pregnancies were reported. Following exclusion of 140 recent pregnancies (4.6%) with possible reporting delay (outcome not reported within 18 months from expected date of delivery) and of 790 cases (25.9%) with missing outcome information >18 months from expected date of delivery, 2115 pregnancies (69.5%) with available information on pregnancy outcome were considered. Among the cases excluded, 580 had no information at all except for date of last menstrual period and age (the basic clinical information required for the initial report of the pregnancy). The remaining 350 excluded cases had some information available and were compared with the 2115 cases considered for subsequent analyses (Table 1, left side). For some laboratory variables, only a limited proportion of the 350 excluded cases had available information, because missing outcome was also associated with missing laboratory data at the start of pregnancy. No differences were found between the two groups for age, CD4 count, plasma HIV viral load, months since HIV diagnosis, total bilirubin, plasma triglycerides, total cholesterol, total cholesterol/HDL cholesterol ratio and ALT. The two groups were also similar for nationality, history of drug use, HCV seropositivity, diagnosis of HIV in pregnancy, history of hypertension, nephropathy and diabetes, and parity. Excluded women were more commonly on ART at conception and HBV positive (Table 1, left side). Among the 350 cases excluded, 66 had exposure to atazanavir, 22 to darunavir and 2 to both drugs. Table 1. Baseline characteristics of the population studied according to outcome status (left side) and to exposure in pregnancy to the two drugs studied (right side)   350 with outcome unknown  2115 with outcome known  Pa  409 with outcome known, atazanavir  91 with outcome known, darunavir  Pa    n  median (IQR)  n  median (IQR)    n  median (IQR)  n  median (IQR)    Age (years)  343  32 (27–37)  2096  33 (29–36)  0.233  409  34 (30–38)  91  32 (27–37)  0.012  CD4 count (cells/mm3)  208  547 (404–696)  931  512 (360–710)  0.509  195  560 (389–752)  51  560 (361–725)  0.543  HIV-RNA (log copies/mL)  177  1.70 (1.60–3.35)  869  1.70 (1.60–3.04)  0.872  278  1.70 (1.57–3.48)  60  1.60 (1.57–2.15)  0.025  Months since HIV diagnosis  331  42 (8–101)  2044  53 (9–114)  0.084  401  68 (25–127.5)  89  89 (29.5–223)  0.022  Total bilirubin (mg/dL)  36  0.40 (0.33–0.52)  1007  0.50 (0.34–0.79)  0.101  270  1.03 (0.47–2.14)  58  0.35 (0.28–0.53)  <0.001  Plasma triglycerides (mg/dL)  27  91 (67–119)  952  90 (68–126)  0.746  239  86 (66–121)  47  93 (73–129)  0.274  Total cholesterol (mg/dL)  31  183 (155–195)  958  169 (147–194)  0.282  245  163 (143–183)  46  166 (150–190.25)  0.619  Total cholesterol/HDL cholesterol ratio  24  3.01 (2.48–3.47)  611  3.00 (2.57–3.56)  0.497  181  3.13 (2.65–3.56)  31  3.15 (2.50–3.83)  0.760  ALT (U/L)  15  15 (8–20)  345  16 (12–22)  0.171  127  16 (12–22)  48  14.5 (11–19.75)  0.230    n  %  n  %    n  %  n  %    Foreign nationality  337  59.1  1998  53.6  0.063  402  51.2  89  44.9  0.282  History of drug use  333  6.3  2064  6.2  0.914  407  5.9  89  4.5  0.801  HCV positive  318  13.5  1946  12.9  0.759  381  11.8  85  15.3  0.379  Diagnosis of HIV in pregnancy  331  21.5  2044  22.5  0.683  401  14.5  89  11.2  0.720  History of hypertension  328  3.0  2065  1.8  0.147  408  2.2  91  1.1  0.698  History of nephropathy  328  0.3  2060  0.9  0.254  407  1.2  91  1.1  1.000  History of diabetes  327  1.2  2057  2.1  0.273  404  3.2  91  2.2  1.000  At least one previous pregnancy  333  76.6  2064  75.6  0.694  407  78.1  91  73.6  0.353  On treatment at conception  345  62.3  2067  55.7  0.021  409  62.3  91  65.9  0.522  HBV positive  306  15.0  1954  10.5  0.019  393  11.7  87  14.9  0.405    350 with outcome unknown  2115 with outcome known  Pa  409 with outcome known, atazanavir  91 with outcome known, darunavir  Pa    n  median (IQR)  n  median (IQR)    n  median (IQR)  n  median (IQR)    Age (years)  343  32 (27–37)  2096  33 (29–36)  0.233  409  34 (30–38)  91  32 (27–37)  0.012  CD4 count (cells/mm3)  208  547 (404–696)  931  512 (360–710)  0.509  195  560 (389–752)  51  560 (361–725)  0.543  HIV-RNA (log copies/mL)  177  1.70 (1.60–3.35)  869  1.70 (1.60–3.04)  0.872  278  1.70 (1.57–3.48)  60  1.60 (1.57–2.15)  0.025  Months since HIV diagnosis  331  42 (8–101)  2044  53 (9–114)  0.084  401  68 (25–127.5)  89  89 (29.5–223)  0.022  Total bilirubin (mg/dL)  36  0.40 (0.33–0.52)  1007  0.50 (0.34–0.79)  0.101  270  1.03 (0.47–2.14)  58  0.35 (0.28–0.53)  <0.001  Plasma triglycerides (mg/dL)  27  91 (67–119)  952  90 (68–126)  0.746  239  86 (66–121)  47  93 (73–129)  0.274  Total cholesterol (mg/dL)  31  183 (155–195)  958  169 (147–194)  0.282  245  163 (143–183)  46  166 (150–190.25)  0.619  Total cholesterol/HDL cholesterol ratio  24  3.01 (2.48–3.47)  611  3.00 (2.57–3.56)  0.497  181  3.13 (2.65–3.56)  31  3.15 (2.50–3.83)  0.760  ALT (U/L)  15  15 (8–20)  345  16 (12–22)  0.171  127  16 (12–22)  48  14.5 (11–19.75)  0.230    n  %  n  %    n  %  n  %    Foreign nationality  337  59.1  1998  53.6  0.063  402  51.2  89  44.9  0.282  History of drug use  333  6.3  2064  6.2  0.914  407  5.9  89  4.5  0.801  HCV positive  318  13.5  1946  12.9  0.759  381  11.8  85  15.3  0.379  Diagnosis of HIV in pregnancy  331  21.5  2044  22.5  0.683  401  14.5  89  11.2  0.720  History of hypertension  328  3.0  2065  1.8  0.147  408  2.2  91  1.1  0.698  History of nephropathy  328  0.3  2060  0.9  0.254  407  1.2  91  1.1  1.000  History of diabetes  327  1.2  2057  2.1  0.273  404  3.2  91  2.2  1.000  At least one previous pregnancy  333  76.6  2064  75.6  0.694  407  78.1  91  73.6  0.353  On treatment at conception  345  62.3  2067  55.7  0.021  409  62.3  91  65.9  0.522  HBV positive  306  15.0  1954  10.5  0.019  393  11.7  87  14.9  0.405  a Mann-Whitney U-test for quantitative variables; χ2 or Fisher’s test for categorical variables. Among the 2115 cases with known outcome, 409 (19.3%) had exposure to atazanavir during pregnancy, 91 (4.3%) to darunavir and 8 (0.4%) to both (sequentially). Cases sequentially exposed to both drugs were excluded from all comparisons, leaving 500 evaluable cases. Following the first exposure reported, the proportion of exposed pregnancies increased significantly over time for both drugs (P < 0.001, χ2 for trend), with a peak in 2013 for atazanavir (62/173, 35.8% of all pregnancies) and in 2014 for darunavir (27/143, 18.9%). Among cases exposed in pregnancy to either drug, 315 (63.0%) were on treatment at the start of pregnancy, with no differences between groups (atazanavir: 255/409, 62.3%; darunavir: 60/91, 65.9%; P = 0.522, χ2 test). Only a small fraction of such cases had a subsequent discontinuation (39/315, 12.4%), with no significant differences between groups (atazanavir: 34/255, 13.3%; darunavir: 5/60, 8.3%; P = 0.290, χ2 test). In most of these discontinuations, atazanavir or darunavir was replaced by other drugs for treatment optimization, in the absence of toxicity or treatment inefficacy (data not shown). The comparison of baseline characteristics (epidemiology, HIV infection and laboratory data) for the two treatment groups is shown in Table 1 (right side). At the start of pregnancy, women on atazanavir were older, had a shorter interval since HIV diagnosis, slightly higher median plasma HIV-RNA levels and significantly higher plasma total bilirubin levels. No other significant differences were found in laboratory measures or in demographic and clinical characteristics (Table 1, right side). The comparison of the main laboratory indexes, performed in women with continued exposure in pregnancy to either drug without discontinuation, showed some significant differences between the two groups (Table 2). Treatment with darunavir was associated with higher levels of plasma triglycerides (significant at third trimester) and higher values of the total cholesterol/HDL cholesterol ratio (significant at both first and third trimesters), while treatment with atazanavir was associated with higher levels of plasma bilirubin (significant at both trimesters). No differences were observed at either trimester in levels of haemoglobin, ALT, total cholesterol, HDL cholesterol and LDL cholesterol, and in changes observed between first and third trimesters for all the above parameters (all P values ≥0.15; Table 2). Table 2. Laboratory measures at first and third trimesters of pregnancy and changes over time in women receiving either atazanavir or darunavir during entire pregnancy   First trimester, median (IQR)   Third trimester, median (IQR)   Median change (IQR), first to third trimester   atazanavir  darunavir  P  atazanavir  darunavir  P  atazanavir  darunavir  P  Plasma total bilirubin (mg/dL) (n: atazanavir 129, darunavir 29)  1.70 (0.96–2.50)  0.31 (0.25–0.64)  <0.001  1.54 (1.03–2.30)  0.32 (0.25–0.47)  <0.001  −0.15 (−0.74 to + 0.45)  −0.02 (−0.15 to + 0.01)  0.331  ALT (U/L) (n: atazanavir 73, darunavir 30)  16 (12.0–21.5)  18 (12.0–22.2)  0.428  18 (12–27)  16 (13–26.5)  0.780  2 (−2.5 to + 9.5)  −1 (−4.2 to + 8.0)  0.497  Haemoglobin (g/dL) (n: atazanavir 75, darunavir 28)  12.5 (11.9–13.2)  12.5 (12.1–13.1)  0.809  11.8 (10.8–12.3)  11.5 (10.5–12.2)  0.276  −0.7 (−1.8 to − 0.1)  −1.0 (−2.35 to − 0.42)  0.240  Plasma triglycerides (mg/dL) (n: atazanavir 95, darunavir 20)  87 (68–128)  111.5 (80.5–158.7)  0.072  179 (148–224)  235.5 (177.7–352.5)  0.032  90 (61–126)  119 (59.5–159.2)  0.150  Plasma total cholesterol (mg/dL) (n: atazanavir 96, darunavir 20)  163.5 (140.2–184.7)  161.5 (146.0–189.2)  0.778  211 (189.5–251.5)  201 (179.7–293.2)  0.962  54 (32.2–75.0)  58.5 (1.25–103.0)  0.792  Plasma HDL cholesterol (mg/dL) (n: atazanavir 71, darunavir 13)  55 (46–67)  50 (45–56)  0.115  68 (55–82)  59 (56–72.5)  0.350  11 (2–23)  14 (10.5–18.5)  0.380  Plasma LDL cholesterol (mg/dL) (n: atazanavir 46, darunavir 9)  86.5 (70.7–108.0)  116 (79–132)  0.111  111 (83–129.7)  132 (90.5–187)  0.092  19 (4.0–50.2)  40 (4.5–66.5)  0.158  Total cholesterol/HDL cholesterol ratio (n: atazanavir 71, darunavir 13)  2.97 (2.45–3.48)  3.62 (2.80–4.11)  0.018  3.27 (2.58–3.90)  4.03 (3.28–4.90)  0.028  0.282 (−0.117 to + 0.734)  0.475 (−0.582 to + 1.362)  0.591    First trimester, median (IQR)   Third trimester, median (IQR)   Median change (IQR), first to third trimester   atazanavir  darunavir  P  atazanavir  darunavir  P  atazanavir  darunavir  P  Plasma total bilirubin (mg/dL) (n: atazanavir 129, darunavir 29)  1.70 (0.96–2.50)  0.31 (0.25–0.64)  <0.001  1.54 (1.03–2.30)  0.32 (0.25–0.47)  <0.001  −0.15 (−0.74 to + 0.45)  −0.02 (−0.15 to + 0.01)  0.331  ALT (U/L) (n: atazanavir 73, darunavir 30)  16 (12.0–21.5)  18 (12.0–22.2)  0.428  18 (12–27)  16 (13–26.5)  0.780  2 (−2.5 to + 9.5)  −1 (−4.2 to + 8.0)  0.497  Haemoglobin (g/dL) (n: atazanavir 75, darunavir 28)  12.5 (11.9–13.2)  12.5 (12.1–13.1)  0.809  11.8 (10.8–12.3)  11.5 (10.5–12.2)  0.276  −0.7 (−1.8 to − 0.1)  −1.0 (−2.35 to − 0.42)  0.240  Plasma triglycerides (mg/dL) (n: atazanavir 95, darunavir 20)  87 (68–128)  111.5 (80.5–158.7)  0.072  179 (148–224)  235.5 (177.7–352.5)  0.032  90 (61–126)  119 (59.5–159.2)  0.150  Plasma total cholesterol (mg/dL) (n: atazanavir 96, darunavir 20)  163.5 (140.2–184.7)  161.5 (146.0–189.2)  0.778  211 (189.5–251.5)  201 (179.7–293.2)  0.962  54 (32.2–75.0)  58.5 (1.25–103.0)  0.792  Plasma HDL cholesterol (mg/dL) (n: atazanavir 71, darunavir 13)  55 (46–67)  50 (45–56)  0.115  68 (55–82)  59 (56–72.5)  0.350  11 (2–23)  14 (10.5–18.5)  0.380  Plasma LDL cholesterol (mg/dL) (n: atazanavir 46, darunavir 9)  86.5 (70.7–108.0)  116 (79–132)  0.111  111 (83–129.7)  132 (90.5–187)  0.092  19 (4.0–50.2)  40 (4.5–66.5)  0.158  Total cholesterol/HDL cholesterol ratio (n: atazanavir 71, darunavir 13)  2.97 (2.45–3.48)  3.62 (2.80–4.11)  0.018  3.27 (2.58–3.90)  4.03 (3.28–4.90)  0.028  0.282 (−0.117 to + 0.734)  0.475 (−0.582 to + 1.362)  0.591  All P values: Mann–Whitney U-test. The main pregnancy outcomes for the two groups are summarized in Table 3. No significant differences were observed between the two groups, with similar rates of preterm and very preterm delivery, low and very low birthweight, pregnancies not ending in a live birth, emergency caesarean delivery, complications of delivery, neonatal death and birth defects. The two groups were also similar for increase in body weight in pregnancy (median 11 kg in both groups; IQR 8–14 for atazanavir, 7.5–13 for darunavir; P = 0.669) and for rates of urinary infections, vaginal infections, hypertension, glucose metabolism abnormalities and anaemia (data not shown). Among 353 infants with HIV status available, only one case of HIV transmission (0.3%) was observed (in the atazanavir group). Among the five neonatal deaths reported, three were in severely preterm infants (<30 weeks), likely caused by complications related to prematurity, one was due to respiratory failure in an infant with congenital defects and the other occurred in a term infant with neonatal streptococcal sepsis. Table 3. Pregnancy outcomes   Entire study populationa  Atazanavir  Darunavir  Pb  HIV viral load <50 copies/mL at third trimester, %  73.8 (1013/1372)  81.6 (239/293)  83.6 (56/67)  0.669  Pregnancy not ending in a live birth, %c  9.8 (114/1168)  8.3 (21/253)  15.3 (9/59)  0.103  Non-elective caesarean section, %  18.7 (326/1746)  18.6 (67/361)  18.3 (13/71)  0.961  Preterm delivery (<37 weeks), %d  19.0 (338/1780)  17.4 (63/362)  18.9 (14/74)  0.755  Very preterm delivery (<32 weeks), %  2.1 (37/1780)  1.9 (7/362)  2.7 (2/74)  0.653  Low birthweight (<2500 g), %d  20.7 (345/1666)  20.4 (70/343)  16.9 (12/71)  0.500  Very low birthweight (<1500 g), %d  2.7 (45/1666)  2.6 (9/343)  4.2 (3/71)  0.440  Small by gestational age, %e  12.7 (197/1553)  12.0 (39/326)  11.3 (8/71)  0.869  Large by gestational age, %e  6.9 (107/1553)  5.8 (19/326)  5.6 (4/71)  0.605  Complications of delivery, %f  6.4 (110/1722)  9.3 (33/353)  5.6 (4/71)  0.488  Neonatal/infant death, %  0.7 (13/1847)  1.3 (5/374)  0  0.404  Birth defects, %g  4.8 (44/921)  5.8 (12/207)  7.7 (3/39)  0.713    Entire study populationa  Atazanavir  Darunavir  Pb  HIV viral load <50 copies/mL at third trimester, %  73.8 (1013/1372)  81.6 (239/293)  83.6 (56/67)  0.669  Pregnancy not ending in a live birth, %c  9.8 (114/1168)  8.3 (21/253)  15.3 (9/59)  0.103  Non-elective caesarean section, %  18.7 (326/1746)  18.6 (67/361)  18.3 (13/71)  0.961  Preterm delivery (<37 weeks), %d  19.0 (338/1780)  17.4 (63/362)  18.9 (14/74)  0.755  Very preterm delivery (<32 weeks), %  2.1 (37/1780)  1.9 (7/362)  2.7 (2/74)  0.653  Low birthweight (<2500 g), %d  20.7 (345/1666)  20.4 (70/343)  16.9 (12/71)  0.500  Very low birthweight (<1500 g), %d  2.7 (45/1666)  2.6 (9/343)  4.2 (3/71)  0.440  Small by gestational age, %e  12.7 (197/1553)  12.0 (39/326)  11.3 (8/71)  0.869  Large by gestational age, %e  6.9 (107/1553)  5.8 (19/326)  5.6 (4/71)  0.605  Complications of delivery, %f  6.4 (110/1722)  9.3 (33/353)  5.6 (4/71)  0.488  Neonatal/infant death, %  0.7 (13/1847)  1.3 (5/374)  0  0.404  Birth defects, %g  4.8 (44/921)  5.8 (12/207)  7.7 (3/39)  0.713  a All cases followed since May 2004. b Comparison between atazanavir- and darunavir-exposed women, χ2 or Fisher’s test. c Calculated on cases exposed (on treatment) at the start of pregnancy. d Livebirths only. e Birthweight <10th (small) or > 90th (large) percentile by age and gender, singletons only. f Mostly represented by anaemia, fever or wound infections. g Livebirths from mothers on treatment at the start of pregnancy. Discussion Current guidelines for pregnant women with HIV usually recommend atazanavir or darunavir (both with low-dose ritonavir) as the preferred PIs for use in pregnancy.1,2 The present analysis, based on 500 pregnancies exposed, provides new comparative information. The proportion of evaluable cases reflects the earlier introduction and more common use of atazanavir compared with darunavir. Reassuringly, all the main pregnancy and infant outcomes were equally frequent in the two groups and the rate of HIV transmission was minimal, with only one case reported. Although this case series is to our knowledge the largest comparing these two drugs in pregnant women, caution is necessary in the interpretation of outcome data for several reasons. The number of events, particularly for some infrequent outcomes (such as very preterm delivery and very low birthweight), was small and the absence of significant differences should be considered within the context of the statistical power of the study, which can be adequate to detect only large differences between groups. Overall, the rates of all main events were similar to those of the entire study population of pregnant women with HIV, as shown in Table 3, but for some outcomes the numbers show some variability between groups that should be explored in larger studies, possibly pooling data from multiple cohorts. In terms of laboratory outcomes, the two drugs were equally effective in producing an undetectable viral load at the end of pregnancy, indicating comparable virological efficacy in pregnancy, with even higher rates of viral suppression compared with the entire study population (Table 3). Some differences were observed in some laboratory indexes: atazanavir was clearly associated with higher levels of bilirubin, but with no higher rates of drug discontinuation or adverse outcomes, in line with other observations that indicate that the clinical impact of this drug effect in both mothers and infants is generally limited.5–7 Apart from bilirubinaemia, the only other significant differences observed between the two drugs in laboratory parameters involved a slightly better metabolic profile with atazanavir. This drug has shown a favourable lipid profile in clinical trials8,9 and in pregnancy10 compared with lopinavir, but there are less consistent findings regarding the comparison with darunavir in terms of lipid profile.11–15 The present study indicates in pregnant women a better lipid profile with atazanavir compared with darunavir, with lower triglyceride levels (contrary to some studies in the general population that showed an opposite effect)12,13 and a lower total cholesterol/HDL cholesterol ratio (consistent with Martinez et al.,11 2014). Although pregnancy may induce significant effects on lipid levels,16 most of the observed differences were already present at the start of pregnancy and are therefore likely to reflect general differences in the metabolic profile of the two drugs and not a specific differential effect of pregnancy, as also suggested by the similar changes observed with the two drugs in all laboratory parameters between first and third trimesters. Finally, the differences in laboratory measures were not accompanied by substantial differences in clinical outcomes, including those potentially related to metabolic status, such as maternal weight gain and prevalence of large infants by gestational age. Overall, given the increased cardiovascular risk associated with higher values of the total cholesterol/HDL cholesterol ratio17and the potential association of early hypertriglyceridaemia with subsequent occurrence of gestational diabetes, pre-eclampsia18,19 and fetal macrosomia,20 clinicians could consider atazanavir as a preferable choice in particular situations where additional risk factors for the above clinical conditions are present. On the other hand, darunavir may be preferred when hyperbilirubinaemia may pose some concern. The main limitation of this study, together with the sample size considerations discussed above, is represented by the non-randomized attribution of treatment, which does not allow us to exclude some selection bias in prescribing. Randomized studies are, however, difficult to perform in pregnancy and almost all available information is based on studies with an observational design. Overall, this study provided new comparative information on use of atazanavir and darunavir in pregnancy, with a relatively large sample size that included 500 cases. Overall, the main study findings, showing no evidence of a difference in risk of adverse pregnancy outcomes, support current recommendations. Based on the minor differences observed in laboratory measures, prescribing physicians might prefer either drug only in particular situations where the expected impact of treatment on lipid profile and bilirubin may be clinically relevant. Acknowledgements We thank Cosimo Polizzi and Alessandra Mattei of the Istituto Superiore di Sanità in Rome, Italy, for providing technical secretarial support for this study. No compensation was received for this contribution. Members of The Italian Group on Surveillance of Antiretroviral Treatment in Pregnancy Project coordinators: M. Floridia, M. Ravizza, E. Tamburrini. Participants: M. Ravizza, E. Tamburrini, F. Di Lorenzo, G. Sterrantino, M. Meli, I. Campolmi, F. Vichi, B. Del Pin, R. Marocco, C. Mastroianni, V. S. Mercurio, A. Maccabruni, D. Zanaboni, G. Guaraldi, G. Nardini, C. Stentarelli, B. Beghetto, A. M. Degli Antoni, A. Molinari, M. P. Crisalli, A. Donisi, M. Piepoli, V. Cerri, G. Zuccotti, V. Giacomet, S. Coletto, F. Di Nello, C. Madia, G. Placido, P. Milini, F. Savalli, V. Portelli, F. Sabbatini, D. Francisci, C. Papalini, L. Bernini, P. Grossi, L. Rizzi, M. Bernardon, G. Maso, E. Rizzante, C. Belcaro, A. Meloni, M. Dedoni, F. Ortu, P. Piano, A. Citernesi, I. Bordoni Vicini, K. Luzi, A. Spinillo, M. Roccio, A. Vimercati, F. M. Crupano, D. Calabretti, G. Simonazzi, F. Cervi, E. Margarito, M. G. Capretti, C. Marsico, G. Faldella, M. Sansone, P. Martinelli, A. Agangi, A. Capone, G. M. Maruotti, C. Tibaldi, L. Trentini, T. Todros, G. Masuelli, V. Frisina, I. Cetin, T. Brambilla, V. Savasi, C. Personeni, C. Giaquinto, M. Fiscon, E. Rubino, L. Franceschetti, R. Badolato, B. Tassis, G. C. Tiso, O. Genovese, C. Cafforio, C. Pinnetti, G. Liuzzi, A. M. Casadei, A. F. Cavaliere, M. Cellini, A. M. Marconi, S. Dalzero, V. Sacchi, M. Ierardi, C. Polizzi, A. Mattei, M. F. Pirillo, R. Amici, C. M. Galluzzo, S. Donnini, S. Baroncelli, M. Floridia. Pharmacokinetics: P. Villani, M. Cusato. Advisory Board: A. Cerioli, M. De Martino, F. Parazzini, E. Tamburrini, S. Vella. SIGO-HIV Group National Coordinators: P. Martinelli, M. Ravizza. Funding This work (currently not funded) was supported in the past by a public research grant (ref.: H85E08000200005) from the Italian Medicines Agency (AIFA). Transparency declarations None to declare. References 1 Panel on Treatment of Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. http://aidsinfo.nih.gov/contentfiles/lvguidelines/perinatalgl.pdf. 2 Linee Guida Italiane sull’utilizzo dei farmaci antiretrovirali e sulla gestione diagnostico-clinica delle persone con infezione da HIV-1. 22 Novembre 2016. http://www.salastampa.salute.gov.it/portale/news/p3_2_1_1_1.jsp?lingua=italiano&menu=notizie&p=dalministero&id=2760. 3 Bertino E, Spada E, Occhi L et al.   Neonatal anthropometric charts: the Italian Neonatal Study compared with other European studies. J Pediatr Gastroenterol Nutr  2010; 51: 353– 61. Google Scholar PubMed  4 Scheuerle A, Tilson H. Birth defect classification by organ system: a novel approach to heighten teratogenic signalling in a pregnancy registry. Pharmacoepidem Drug Saf  2002; 11: 465– 75. Google Scholar CrossRef Search ADS   5 McDonald C, Uy J, Hu W et al.   Clinical significance of hyperbilirubinemia among HIV-1-infected patients treated with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS Patient Care STDS  2012; 26: 259– 64. Google Scholar CrossRef Search ADS PubMed  6 Croom KF, Dhillon S, Keam SJ. Atazanavir: a review of its use in the management of HIV-1 infection. Drugs  2009; 69: 1107– 40. Google Scholar CrossRef Search ADS PubMed  7 Eley T, Huang SP, Conradie F et al.   Clinical and pharmacogenetic factors affecting neonatal bilirubinemia following atazanavir treatment of mothers during pregnancy. AIDS Res Hum Retroviruses  2013; 10: 1287– 92. Google Scholar CrossRef Search ADS   8 Molina JM, Andrade-Villanueva J, Echevarria J et al.   Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr  2010; 53: 323– 32. Google Scholar CrossRef Search ADS PubMed  9 Johnson M, Grinsztejn B, Rodriguez C et al.   96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. AIDS  2006; 20: 711– 8. Google Scholar CrossRef Search ADS PubMed  10 Floridia M, Ravizza M, Masuelli G et al.   Atazanavir and lopinavir profile in pregnancy: data from an observational national study. J Antimicrob Chemother  2014; 69: 1377– 84. Google Scholar CrossRef Search ADS PubMed  11 Martinez E, Gonzalez-Cordon A, Ferrer E et al.   Early lipid changes with atazanavir/ritonavir or darunavir/ritonavir. HIV Med  2014; 15: 330– 8. Google Scholar CrossRef Search ADS PubMed  12 Saumoy M, Ordóñez-Llanos J, Martínez E et al.   Atherogenic properties of lipoproteins in HIV patients starting atazanavir/ritonavir or darunavir/ritonavir: a substudy of the ATADAR randomized study. J Antimicrob Chemother  2015; 70: 1130– 8. Google Scholar PubMed  13 Martinez E, Gonzalez-Cordon A, Ferrer E et al.   Differential body composition effects of protease inhibitors recommended for initial treatment of HIV infection: a randomized clinical trial. Clin Infect Dis  2015; 60: 811– 20. Google Scholar CrossRef Search ADS PubMed  14 Ofotokun I, Na LH, Landovitz RJ et al.   Comparison of the metabolic effects of ritonavir-boosted darunavir or atazanavir versus raltegravir, and the impact of ritonavir plasma exposure: ACTG 5257. Clin Infect Dis  2015; 60: 1842– 51. Google Scholar CrossRef Search ADS PubMed  15 Kelesidis T, Tran TTT, Brown TT et al.   Changes in plasma levels of oxidized lipoproteins and lipoprotein subfractions with atazanavir-, raltegravir-, darunavir-based initial antiviral therapy and associations with common carotid artery intima-media thickness: ACTG 5260s. Antivir Ther  2017; 22: 113– 26. Google Scholar CrossRef Search ADS PubMed  16 Floridia M, Tamburrini E, Ravizza M et al.   Lipid profile during pregnancy in HIV-infected women. HIV Clin Trials  7: 184– 93. CrossRef Search ADS PubMed  17 Prospective Studies Collaboration, Lewington S, Whitlock G et al.   Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet  2007; 370: 1829– 39. Google Scholar CrossRef Search ADS PubMed  18 Enquobahrie DA, Williams MA, Qiu C et al.   Early pregnancy lipid concentrations and the risk of gestational diabetes mellitus. Diabetes Res Clin Pract  2005; 70: 134– 42. Google Scholar CrossRef Search ADS PubMed  19 Clausen T, Djurovic S, Heriksen T et al.   Dyslipidemia in early second trimester is mainly a feature of women with early onset pre-eclampsia. BJOG  2001; 108: 1081– 7. Google Scholar PubMed  20 Di Cianni G, Miccoli R, Volpe L et al.   Maternal triglyceride levels and newborn weight in pregnant women with normal glucose tolerance. Diabet Med  2005; 22: 21– 5. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 1, 2018

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