HIV epidemiology is changing, and prevention of mother-to-child transmission (PMTCT) strategies has been continuously optimized.1–3 The synergic effect of prenatal and neonatal antiretroviral therapy (ART), elective caesarean delivery, and the avoidance of breastfeeding have resulted in MTCT rates <1% in high-income countries.1
From a global perspective, the progression to the current standard of care has been achieved through several steps. Under the 2010 World Health Organization (WHO) Guidelines, countries had the option to choose between 2 prophylaxis regimens for pregnant women living with HIV and their infants, based on maternal CD4+ T lymphocyte (option A and option B).4 Starting from 2010, Malawi adopted the option B plus strategy, including ART administration to all HIV-positive pregnant mothers, regardless of their clinical and immunological stage, obtaining transmission rates less than 2%.5 The 2012 WHO-updated guidelines emphasized option B plus advantages.6 In 2014–2015, the START and TEMPRANO trails provided conclusive evidence of benefits from universal antiretroviral treatment in all persons living with HIV, initiated soon after diagnosis.7,8 As a result, international guidelines have been updated and universal treatment recommended, with pregnancy included as one of the conditions that increase the urgency to initiate therapy.9–12
Over the past years, there has been a rapid scale-up of services to prevent MTCT worldwide. An estimated 77% of pregnant or breastfeeding women living with HIV were receiving ART for PMTCT in 2015, with respect to 50% in 2010,13 and the worldwide annual number of new pediatric infections dropped by 50% in the 2010–2016 period (from 300,000 to 160,000), especially in the 22 high-priority countries selected by the Global Plan toward the elimination of new HIV infections among children and keeping their mothers alive (Global Plan).14 However, despite this global commitment, achieving HIV vertical transmission rates ≤5% in breastfeeding and ≤2% in non-breastfeeding populations remains challenging in many settings, including most sub-Saharan African countries.15
Even in high-income countries, cases of vertical transmission continue to occur. Possible reasons include failures to administer appropriate and timely prophylaxis, the late diagnosis in pregnancy, the emergence of antiretroviral-resistant viruses, and poor maternal adherence.16 In high-risk scenarios, combination neonatal prophylaxis (CNP) with 2 or 3 drugs has been demonstrated to reduce MTCT rates.16 Other new strategies have been developed to optimize the management of women with undetectable viral load (VL) at delivery, supporting the use of vaginal delivery.17 Accordingly, accumulating data confirm that scheduled caesarean delivery does not confer any additional benefit in reducing HIV-1 transmission in mothers with undetectable VL, whereas there is evidence that complication rates for caesarean deliveries are higher in HIV-1–infected women compared with HIV-1 uninfected women.18
In the light of changing guidelines' recommendations, it is fundamental to collect data “on the field,” investigating the strategies adopted by experts in different situations, and evaluating MTCT rates. We hereby analyze available data regarding a large cohort of Italian children born to HIV-1–infected mothers over a 20-year period and evaluated risk factors for HIV MTCT.
To evaluate PMTCT strategies adopted by Italian clinicians in different clinical scenarios and their modifications over years.
To investigate the MTCT rates and risk factors for HIV-1 transmission in a large population of infants born in Italy to HIV-1–infected mothers in the highly active ART era.
The Italian Register for HIV Infection in Children is a nationwide multicenter study of children perinatally exposed to HIV-1 that was instituted in 1985. The Register's data source is a network of pediatric clinical centers located throughout Italy.19 These centers, which participate voluntarily, aim to enroll all children born to HIV-1–infected mothers and forward data to 2 coordinating centers, located at the Departments of Pediatrics of the University of Florence and the University of Turin.
Data regarding mother–child pairs are collected using specific individual forms for registration and follow-up, and they are treated anonymously, as previously described.20–22 In particular, baseline information is collected on the infant's demographics, age at first observation, mode of delivery, gestational age, type of feeding, and neonatal prophylaxis. Maternal data included information regarding ART used before and during pregnancy, intrapartum ART and VL at delivery, and within 4 weeks (collected from 2001). Information on virus drug resistance, maternal concomitant infections, compliance to therapy, and reason and time of maternal diagnosis is not collected; maternal age, ethnicity, and maternal immunological condition at the time of delivery are known in a minority of cases.23–25 Both baseline and follow-up information on the infant's infection status, HIV-1 antibodies, and VL are collected.
HIV-1 infection was diagnosed by the persistence of HIV-1 antibodies after 18 months of life or before 18 months, by detection of viral markers (by DNA or RNA polymerase chain reaction) on at least 2 occasions (excluding cord blood). Uninfected children were defined as those with negative HIV-1 antibodies and/or negative polymerase chain reaction on at least 2 occasions. Neonatal prophylaxis was defined as any course of one or more antiretroviral drugs administered with a prophylactic purpose and initiated within the first 72 hours of life. CNP was defined as combination of 2 or more antiretroviral drugs administered for PMTCT. Maternal VL at delivery was defined as the closest measurement before delivery within 8 weeks.
Preterm and early preterm deliveries were defined as the delivery before 37 and 32 completed weeks of gestation, respectively. Caesarean section was considered elective if performed before the rupture of membranes and the onset of labor and nonelective if performed after the rupture of membranes, the onset of labor, or both.26
Data were reported as median and interquartile range (IQR) or absolute numbers and percentages. The nonparametric U Mann–Whitney test, the Fisher exact test, or the χ2 test was used to compare continuous or categorical variables, as appropriate. All significant tests were 2-sided. Univariate and multivariate logistic regression analyses were performed to investigate the association between several parameters and risk of MTCT, calculating odds ratios and 95% confidence intervals (CIs). Variables included in the univariate analysis were birth period (1996–2003, 2004–2010, and 2011–2016), sex, child's nationality (categorized as born in Italy to Italian mother or born in Italy to foreign mother), preterm delivery (categorized as ≤32, 33–36, and ≥37 weeks), type of delivery (categorized as elective caesarean section, nonelective caesarean section, vaginal delivery with detectable or missing VL at delivery, or vaginal delivery with undetectable VL), intrapartum intravenous zidovudine (ZDV) use, maternal VL (categorized as <400 or ≥400 copies/mL), antenatal ART, breastfeeding or formula feeding, neonatal prophylaxis type (categorized as none, 1 drug, 2 drugs, or 3 drugs), and followed up since birth or after birth. Factors significantly (P < 0.05) associated with MTCT risk at univariate analysis were included in the multivariate analysis. The Kaplan–Meier analysis with the log-rank test was performed to analyze differences in cumulative survival between infected and not infected children.
Statistical analyses were performed using the STATA/SE version 10.0 software package (Stata Corporation, College Station, TX). The χ2 Mantel–Haenszel test for trend was calculated using Epi Info software to test for trends over time.27 A P value <0.05 was considered significant.
Data from 6503 children born in Italy from 1996 to 2016 were included; 348 of them were perinatally infected. Characteristics of the study children, according to the birth period, are reported in Table 1. Median age at the last visit was 11.4 years (IQR: 6.0–15.4) for HIV-infected children vs. 1.3 years (IQR: 0.5–2.0) for not infected children (P < 0.0001); 6098/6503 (93.8%) children were followed up since birth. Median age at the first visit was 10.2 months for children not followed up since birth (IQR: 3.8–34.9 months).
Overall, MTCT rate decreased from 8.1% (95% CI: 7.2 to 9.2; 251/3080) in 1996–2003; 3.1% (95% CI: 2.5 to 3.9; 80/2570) in 2004–2010; down to 2.1% (95% CI: 1.2 to 3.2; 17/858) in the 2011–2016 period (P < 0.0001), whereas considering only children followed up since birth, MTCT rate was 3.5% (95% CI: 2.8 to 4.2; 96/2783) in 1996–2003; 1.4% (95% CI: 1.0 to 2.0; 36/2480) in 2004–2010; and 1.1% (95% CI: 0.4 to 1.8; 9/835) in 2011–2016 (P < 0.0001).
Among the 405 children not followed up from birth, 207 (51.1%) infants were infected. In this subgroup, MTCT rates were 66.0% (134/203) among breast-fed infants and 34.0% (56/165) among not-breast-fed infants, whereas MTCT was 45.9% (17/37) in the group of infants with missed information regarding the feeding.
Summarizing characteristics of the 17 HIV-infected children born in the most recent period (11 males, 2 extremely preterm infants, 4 preterm infants, and 9 born to immigrant mothers): maternal VL was known (and detectable) in 4/17 cases; ART before pregnancy was administered to one mother (with detectable VL at delivery); ART during pregnancy for more than 2 weeks was administered to 3 mothers (with detectable VL at delivery); 5 mothers received intrapartum ART; 8 delivered vaginally; and neonatal prophylaxis was administered to 9 infants (including 3 CNP).
In our cohort, the proportion of children born in Italy to foreign mothers increased from 18.3% in 1996%–2003% to 65.2% in 2011–2016 (P < 0.0001; Table 1). Most foreign mothers originated from sub-Saharan Africa (n = 1549) and the Eastern Europe (n = 266). The proportion of vaginal delivery from mothers with undetectable plasma VL increased over time and reached 9.9% in the 2011–2016 period (P < 0.0001; Table 1).
The proportion of women receiving ART before the pregnancy increased from 3.6% to 57.9% (P < 0.0001; Table 1), whereas ART during pregnancy was used in 77.9% of mothers in 1996–2003, reaching 93.2% in the 2011–2016 period (P < 0.0001) (Table 1).
Intrapartum ZDV was administered to 56.1% mothers in 1996–2003; 84.9% in the 2004–2010 period; and 90.1% in 2011–2016 (P < 0.0001; Table 1). No infection occurred in the subgroup of 181 infants whose mothers displayed undetectable VL at delivery and did not receive intrapartum zidovudine. The proportion of breast-fed infants was 4.4% in 1996–2003 and decreased over time to 1.3% in the 2011–2016 period (P < 0.0001; Table 1).
CNP use also significantly increased over time (Table 1). The most frequently used regimens for neonatal prophylaxis were ZDV + single-dose nevirapine (sdNVP; n = 90); ZDV + sdNVP + lamivudine (3 TC) (n = 57); ZDV + 3 TC (n = 43); and ZDV + 3 TC + lopinavir/ritonavir (rLPV) (n = 15), followed by ZDV + NVP (3 doses) (n = 3); ZDV + NVP (2 doses) +3 TC (n = 2); ZDV + 3 TC + nelfinavir (NVF) (n = 1); ZDV + didanosine (n = 1); and ZDV + rLPV (n = 2) (see Table 1, Supplemental Digital Content, http://links.lww.com/QAI/B183).
Use of neonatal prophylaxis by gestational age is reported in Table 2. Notably, 4.7% of extreme premature infants received CNP. Among 83 preterm infants receiving CNP, including 11 extremely preterm infants, 36 received AZT + sdNVP; 25 received AZT + sdNVP + 3 TC; 14 received AZT + 3 TC, 6 AZT + 3 TC + LPV/RTV; 1 AZT + 3 TC + NVF, and 1 AZT + DDI. Median duration was similar in infants receiving one-drug prophylaxis (42 days, median; IQR: 40–43) and those receiving CNP (41 days, median; IQR: 28–42). In particular, in preterm infants receiving CNP, median duration was 41 days (IQR: 39–43) in those ≤32 weeks; 42 days (IQR: 39–44) in those with GA of 33–37 weeks; and 42 days (IQR: 41–43) in infants born after 37 weeks of GA.
Considering maternal VL vs. prophylaxis type, MTCT rate was 0.11% (3/2659) in the subgroup of infants with undetectable maternal VL and receiving one-drug neonatal prophylaxis and 0.0% (0/47) in the subgroup of infants with undetectable maternal VL and receiving CNP. On the other hand, as expected, MTCT was 3.5% (21/605) in the subgroup of infants with detectable maternal VL and receiving one-drug, and 7.8% (5/64) in the subgroup of infants with detectable maternal VL and receiving CNP.
Univariate and Multivariate Analyses for MTCT Risk
At univariate analysis, factors significantly associated with increased risk of MTCT were early birth period, vaginal delivery or nonelective caesarean delivery (vs. elective caesarean delivery), prematurity (<32 weeks), breastfeeding, no maternal ART (none or <4 weeks), lack of intrapartum i.v. ZDV, maternal VL at delivery >400 copies per milliliter, CNP or lack of neonatal prophylaxis, and age at first visit (Table 3).
At multivariate analysis, factors remaining significantly associated with MTCT risk were vaginal delivery with detectable or missing VL or nonelective caesarean delivery (vs. elective caesarean delivery), prematurity (≤32 weeks), breastfeeding, no maternal ART (none or <4 weeks), detectable maternal VL at delivery (≥400 copies/mL), lack of neonatal prophylaxis, and age at first visit (Table 3).
Similar results were obtained in a subanalysis performed only in children followed up since birth (see Table 2, Supplemental Digital Content, http://links.lww.com/QAI/B183).
In this study, data from a large cohort of children exposed perinatally to HIV-1 were analyzed. Over the years, epidemiologic characteristics changed, in line with data recently reported in other high-income countries.28 The transmission rate progressively decreased over time, and at the same time, prophylaxis strategies have been implemented, including the use of CNP. Notably, in the last period, 46 women did not receive any treatment during pregnancy, 32 had vaginal delivery with detectable viremia, 11 breast-fed their infants, and 10 infants did not receive any type of neonatal prophylaxis (all of them were followed up after birth), suggesting that these mothers were not identified through the pregnancy screening. This is in line with other recent reports regarding the need to implement the current screening programs in high-income countries.29
On the other hand, the number of women with complete viral control has been increasing over the years. In this subgroup, vaginal delivery has become a safe option and is now recommended by international guidelines.30–32 In our study, no infant out of 117 born vaginally to mothers with undetectable VL at delivery was infected, confirming guidelines' recommendations.30
The use of CNP for infant at high risk of HIV-1 infection increased over the years. Interestingly, it was largely (4%) used in early preterm infants (<32 weeks' gestation), contrary to the current US guideline recommendations that discourage this practice because of lack of dosing and safety data.11 A large number of different regimens were used as CNP: the recommended regimen ZDV plus 3 NVP doses was used only in 5 infants, probably because it relies on the results of a randomized controlled trial published in 2012.33 Moreover, also considering that this regimen is recommended only in one restricted high-risk situation (untreated mother), some experts may have tailored the antiretroviral drugs on the specific infant's situation. The ZDV + NVP + 3 TC combination, which was also used in the only available trial,34 was highly used in our study (57 infants) with a 5.3% transmission rate, similarly to the randomized controlled trial findings (7.4%).35 As previously reported, CNP was not associated with lower MTCT transmission risk at multivariate analysis, probably due to residual confounding or to the fact that CNP may be effective only in a subgroup of high-risk infants.
Risk factors for MTCT observed in our study were expected and in line with previous reports,35–43 with the exception of maternal origin, which was previously described as risk factor for transmission, but not confirmed in a recent European study.44 We may speculate that in recent years, care of immigrant mothers has been improved. However, we may not exclude that unknown confounders may have influenced the analysis. A recent US study has also shown that immigrant mothers deserve special focus for prevention of perinatal HIV-1 infection.43
Intrapartum ZDV therapy was not associated with decreased MTCT risk at the multivariate analysis. Similar results have emerged from a French Study collecting data from 11,538 deliveries. Intrapartum ZDV was associated with reduced MTCT rate in women with virological failure despite ART, whereas in women with undetectable VL at delivery, in the absence of any obstetrical risk factor, no different MTCT rate was observed (0.0% without intrapartum i.v. ZDV vs. 0.6% with i.v. ZDV; P = 0.17).45 Indeed, intrapartum ZDV is no more recommended for mothers under ART with low VL. For instance, the US Department of Health and Human Services (DHHS) guidelines advise to use intrapartum ZDV only in women with VL >1000 copies per milliliter (or unknown HIV-1 RNA) near delivery.11 Accordingly, in our data set, no infection occurred in this subgroup of children.
Our observational study has several limitations: data regarding resistance profile, adherence, timing and duration of maternal infection, drug dosing, and toxicity were lacking. However, despite these limitations, our study provides an updated view on the “real clinical practice” at a nationwide level.
The PMTCT is one of the great achievements in pediatric research and one of the greatest public health successes in the past 40 years.46 Our findings confirm the previously well-reported risk factors for MTCT, but also underline the need for a better implementation of the current Italian screening program in pregnancy, considering that perinatal HIV infections still continue to occur. Moreover, our data suggest inadequate adherence to guidelines' recommendations suggesting that timing dissemination of updated key messages should be improved. Finally, we documented a large use of CNP in preterm infants: this practice may be dangerous, because of the lack of safety data, and its efficacy and effectiveness is unproven.
Appendix 1. Working group
Silvia Garazzino, Erika Silvestro (Torino), Claudia Tagliabue, Gabriele Ferraris, Iginio Contardi, Giuseppe Banderali, Rita Lipreri, Paola Marchisio, Samantha Bosis (Milano), Francesca Capra, Sara Pulcini, Valentina Zapponi (Brescia), Carlotta Montagnani, Elisabetta Venturini, Alessandra Lumaca, Barbara Bortone (Firenze), Maura Agnese, Eugenia Bruzzese, Luigi Tarallo, Grazia Isabella Continisio, Antonietta Giannattasio, Alfredo Guarino (Napoli), Rosanna Cordiali (Ancona), Giulia Zagni, Monica Ficara (Modena), Anna Maria Casadei, Guido Castelli Gattinara, Hyppolite Tchidjou, Paolo Palma, Salvatore Catania (Roma), Pietro Barilla (Parma), Andrea Pession, Francesco Baldi, Matilde Ciccia, MG Zaniboni (Bologna), Alessandro Mazza, Anita Cappellari (Trento), Maria Sole Acutis, Antonio Di Biagio, Lucia Taramasso, Elisabetta Bondi (Genova), Rita Consolini (Pisa), Amelia Romano, Ernesto Dalle Nogare (Palermo), Donatella Gariel, Maurizio Dedoni, Carlo Dessì (Cagliari), Paolina Olmeo (Sassari), Giancarlo Gargano (Reggio Emilia), Luisa Abbagnato (Como), Letizia Cristiano (Taranto), Federica Visintini (Udine), Domenico Larovere (Bari), Maurizio Bigi (Foggia), Antonio Pellagatta (Varese), Maria Rita Govoni (Ferrara), Antonia Aliffi (Catania), Elisa Anastasio (Catanzaro), Leonardo Felici (Pesaro), Santina Merlino (Cuneo), Vincenzo Portelli (Trapani), Giuseppe Sabatino (Chieti), Carlo Amoretti (Imperia), Angelo Antonellini (Ravenna), Mauro Stronati (Mantova), Per Giorgio Chiriacò (Brindisi), Luigina Boscardini (Viterbo), Graziano Memmini (Livorno), Caterina Ruggeri (Messina), and Eliana Audennio (Asti).
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