Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges.

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Expert Opin Drug Saf. Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Expert Opin Drug Saf. 2016 November ; 15(11): 1501–1513. doi:10.1080/14740338.2016.1226281.

Surveillance monitoring for safety of in utero antiretroviral therapy exposures: current strategies and challenges Rebecca M. Zash1,2,3, Paige L. Williams2, Jeanne Sibiude4, Hermione Lyall5, and Fatima Kakkar6 1Beth

Israel Deaconess Medical Center, Boston, MA

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2Harvard

T. H. Chan School of Public Health, Boston, MA

3Botswana 4Groupe

Harvard AIDS Institute Partnership, Gaborone

hospitalier Cochin Port Royal, Paris, France; INSERM CESP 1018, Le Kremlin Bicêtre

France 5Imperial 6Centre

College Healthcare NHS Trust, London, United Kingdom

Hospitalier Universitaire, Sainte-Justine, Canada

Abstract

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Introduction—The use of antiretroviral therapy (ART) in pregnancy to prevent vertical HIV transmission has been one of the most successful public health programs in the last decade. As a result, an unprecedented number of women are taking ART at conception and during pregnancy. Given few randomized studies evaluating safety of different ART regimens in pregnancy, ongoing drug safety surveillance is critical. Areas Covered—This review aims to provide a rationale for ART drug safety surveillance, describe changing patterns of ART use and summarize current surveillance efforts in both lowresource and high-resource settings. Additionally, biostatistical approaches to and challenges in analysis of observational surveillance data are discussed. Expert Opinion—The global landscape of ART use in pregnancy is rapidly increasing and evolving. Any increase in adverse effects of in-utero exposure to ART has the potential to reduce

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Corresponding author: Paige Williams, PhD, Senior Lecturer and Director of Graduate Studies, Department of Biostatistics, Harvard T.H Chan School of Public Health, 665 Huntington Avenue, Boston, MA 02115, USA, [email protected], Phone: 617-432-3872. Rebecca Zash, MD, Instructor in Medicine, Division of Infectious Diseases, and Assistant Director of the Global Health Program, Internal Medicine Residency, Beth Israel Deaconess Medical Center, 110 Lowry St, Suite GB, Boston, MA 02114, USA, [email protected], Phone: 617-632-7706 Jeanne Sibiude, MD, MPH, Assistant Professor in Gynecology and Obstetrics, Groupe hospitalier Cochin Port Royal, 123 Bd de Port Royal, 75014, Paris, France, [email protected] Hermione Lyall, Bsc Hons, MbChB Hons, MD, FRCPCH, Consultant Paediatrician, Infectious Diseases, Imperial College Healthcare NHS Trust, St Mary Hospital, South Wharf Rd, London, W2 1NY, [email protected] Fatima Kakkar, MD, MPH, Assistant Professor of Pediatrics, Division of Infectious Diseases, Centre Hospitalier Universtaire SainteJustine, University of Montreal, 3175 Chemin de la Côte-Sainte-Catherine, Montréal, QC H3T 1C4, Canada, [email protected] Declaration of Interest: The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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the impact of improvements in infant morbidity and mortality gained from decreased vertical HIV transmission. ART drug safety surveillance should therefore be a critical piece of programs to prevent mother to child transmission in both high- and low-resource settings. Current surveillance efforts could be strengthened with long-term follow-up of exposed children, pooling of data across cohorts and standardized approaches to analysis. Keywords HIV; pregnancy; antiretroviral therapy; infant safety; surveillance programs

1. Introduction

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More than 1 million women per year receive 3-drug antiretroviral therapy (ART) during pregnancy [1] and expanding access to ART has been the critical step in reducing pediatric HIV infections worldwide [2]. ART in pregnancy also improves long-term maternal health, [3] and reduces HIV transmission to partners [4]. However, pregnant women have been excluded from most randomized-controlled drug trials of ART so safety data in pregnancy has historically been lacking [5,6].

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Recent evidence raises concerns about the safety of certain antiretroviral drugs used in pregnancy, including increased risk for adverse birth outcomes [3,7–16], problems with pediatric growth and neurodevelopment [17] and future risk of cancer [6, 18–20]. Also, HIVexposed, uninfected (HEU) children have increased morbidity and mortality when compared with HIV unexposed, uninfected (HUU) children.[21,22] While the cause of this increased mortality is multi-factorial, in utero exposure to ART may be a contributing factor. As programs to prevent mother to child transmission of HIV (PMTCT) rapidly move toward universal ART for pregnant women (World Health Organization (WHO) Option B) and continuation of this ART for life (WHO Option B+), an increase in adverse effects has the potential to reduce the impact of improvements in infant morbidity and mortality from decreased vertical HIV transmission.

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The vast majority (over 90%) of HIV-infected women live in low- and middle-income countries (LMIC), with the greatest number in sub-Saharan Africa [23]. In addition to taking ART during pregnancy, most women in LMIC breastfeed, further increasing pediatric exposure to ARVs through breast milk [24]. Systematic surveillance for adverse drug effects in resource-limited settings has been almost non-existent. Challenges arise because of poor documentation of medication exposure in pregnancy, the large proportion of women who deliver outside the health care setting, and resources required to prospectively follow women and their children in areas with poor research infrastructure. High-income countries face different challenges in ART safety surveillance due, in part, to difficulty in untangling the impact of substance use and socioeconomic factors from the impact of the ART [16, 25]. However, with over 1.5 million HIV-infected women becoming pregnant every year [26] and the rapid global scale-up of PMTCT, it is crucial to identify effective strategies to implement widespread, feasible and accurate surveillance in both high- and low-resource settings. In this paper we highlight reasons why continued monitoring remains critical, describe current and past surveillance programs in both higher resources settings and in low and Expert Opin Drug Saf. Author manuscript; available in PMC 2017 November 01.

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middle-income (LMIC) settings, and discuss the complexities involved in safely monitoring for in utero ART exposures.

2. In-utero Antiretroviral Therapy Exposure 2.1 The global burden of in-utero exposure to ART

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Women of reproductive age tend to be young and healthy with few chronic medical conditions requiring ongoing prescription medication use. Unlike most chronic diseases, which increase in frequency with age, HIV is most common in young, sexually active women with high rates of pregnancy. Therefore, the magnitude of ART exposure in pregnancy due to HIV in countries with generalized epidemics far outweighs that seen for any other drug in history. The most common medical conditions in women of reproductive age include epilepsy and depression. In the US, approximately 0.4% of pregnant women take an anti-epileptic medication [27], and almost 7% take an anti-depressant around the time of conception (though many stop after the pregnancy is discovered) [28]. In Europe, 3% of pregnant women report anti-depressant use [29] while in India, 8% of women take medication for any indication during pregnancy [30]. In contrast, in many countries in Southern Africa, more than 25% of all pregnant women have HIV and the proportion of those women on ART is rapidly rising [26].

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Over the last decade, there has been a global push for improvement in PMTCT program coverage. WHO has also updated guidelines to include universal ART for pregnant women regardless of CD4 count [31]. As a result, the number of HIV-infected pregnant women exposed to ART is increasing. UNAIDS estimates that only 14% of HIV-infected pregnant women in LMIC accessed ART in 2005. This rose to 73% in 2014 [24] and is expected to reach 90% by 2020 [32]. 2.2. Increasing proportion of women on ART prior to conception In addition to the increasing number of women accessing ART during pregnancy, women are increasingly on longer duration of ART in pregnancy (see Figure 1). This shift is occurring because the majority of the 22 countries where 90% of HIV-infected pregnant women live have adopted or are moving towards WHO Option B+ [33]. Additionally, the CD4 cutoff for adult ART eligibility in non-pregnant patients is rising, and WHO now recommends that both women and men identified with HIV infection start ART regardless of CD4 count [31]. Therefore, HIV-infected women are initiating antiretrovirals earlier in their reproductive years and more pregnancy conception is occurring while already on ART.

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One reason that the timing of ART is important is because the first trimester is the most vulnerable time for development of birth defects and therefore the time when teratogenic medications have the greatest impact. Emerging evidence suggests the risk of adverse birth outcomes, including preterm delivery (PTD), stillbirth (SB), low birth weight (LBW) and small for gestational age infants (SGA) is elevated particularly among women who start ART prior to conception [7,13,15,34]. Any increase in preterm and growth restricted babies places a particularly high burden on LMIC settings where there are fewer healthcare resources for neonatal care.

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Many early studies of HIV in pregnancy did not evaluate the time of initiation of ART as a risk factor for adverse outcomes. However, a 2007 meta-analysis of US and European data found almost 2-fold higher risk of preterm delivery among women started on ART prior to conception or in the first trimester (OR 1.71, 95% CI 1.09–2.67) [34]. A subsequent study from France also found increased risk for preterm delivery among women on ART prior to conception compared with those who started ART in pregnancy (aOR 1.31, 95% CI, 1.11– 1.55) [13]. A later US-based analysis also observed a higher risk of preterm birth for women who initiated PI-based regimens early in pregnancy (at conception or during the first trimester) as compared to those who initiated PI-based regimens later during pregnancy [35]. In Botswana, women on ART prior to conception were found to be at increased risk of preterm delivery (aOR 1.2, 95% CI 1.1, 1.4), SGA (aOR 1.3, 95% CI 1.0,1.5) and stillbirth (aOR1.5, 95% CI 1.2,1.8) compared with all other HIV-infected women [7]. The magnitude of stillbirths in Botswana was surprisingly high: 6.3% of women on ART from conception compared with 4.7% of those started on ART in pregnancy and 1.7% of those who started Zidovudine (ZDV) monotherapy in pregnancy.

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In the pre-ART era, adverse birth outcomes among HIV-infected women were the result of advanced maternal immunosuppression, high viral load and opportunistic infections (OIs) [36]. Women on ART prior to conception typically have high median CD4 counts, suppressed viral loads and are thus generally not at high risk for OIs. This suggests that adverse birth outcomes among women on ART at conception may be mediated by different mechanisms than untreated women. Though these mechanisms are not clear, epidemiologic differences between women on ART at conception and women starting ART in pregnancy may be important. Until recently, women in high-income countries who were on ART at conception typically had a longer history of HIV, exposure to more drug regimens and lower nadir CD4 counts than HIV-infected women starting ART. This raises the possibility that chronic inflammation, immune dysfunction or drug-resistant resistant virus could explain adverse birth outcomes.

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Other studies have linked adverse birth outcomes among women on ART with increased risk of maternal morbidity. Two studies, one from Italy and one from Latin America/Caribbean, found that taking ART at conception was a risk factor for pre-eclampsia among HIV-infected women [37,38]. Another study found an increase in gestational diabetes with the increased use of ART in American women [39]. However, other studies have found no association between ART and maternal hypertension, preeclampsia and gestational diabetes [40–42]. A study from the French Perinatal Cohort reported increased risk of elevated liver enzymes among women with PI-based therapy, and those with unexplained liver enzyme elevation were more likely to have preterm delivery [43]. Finally, there is concern that in-utero exposure to NRTIs, which are known to induce mitochondrial dysfunction could lead to long-term toxicity in the brain, heart and muscle tissue of the offspring [44]. With the global expansion of WHO Option B+ and resultant increase in the number of HIV-infected women on ART prior to conception, understanding the mechanisms underlying these adverse birth outcomes should be a research priority.


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2.3 Changing pattern of ART exposure over time

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There is a paucity of clinical trial data on the safety of different ARVs in pregnancy [45] and no single ART regimen has consistently been considered first-line for pregnant women. Recommended pregnancy regimens have changed over time based primarily on expert opinion, and differ in resource-rich and resource-poor settings (see figure 2a and 2b) [31, 46, 47]. Additionally, indications for some ARVs in pregnancy have changed over time. For example, initially raltegravir (RAL) was recommended specifically among women starting ART late during pregnancy to rapidly decrease viral load. Over time, raltegravir use has increased and it is now commonly used throughout all trimesters of pregnancy. Therefore, pregnant women have been exposed to many different ART regimens, sometimes for different indications, making individual drug effects difficult to tease apart. Some studies used historic controls to compare safety of drugs in pregnancy, however this can be biased by a change in obstetrical practices and or a change in HIV demographics over time [48].


Since 2012, tenofovir/emtricitabine or lamivudine/efavirenz (TDF/FTC or 3TC/EFV) has been the most commonly used ART in pregnancy in resource-limited settings and is recommended first line treatment for all adults, including pregnant women, by the WHO [31]. However, the US HIV treatment guidelines in 2016 downgraded TDF/FTC/EFV from first-line to an alternate regimen due to concerns about psychiatric and adverse renal/bone effects [46], and in several European countries, it has remained as an alternate regimen due to ongoing concern about the potential teratogenic effect of EFV [49]. Additionally, with the increasing popularity of integrase strand inhibitors (INSTIs) and recent FDA approval of tenofovir alafenamide (TAF), which is expected to have fewer side effects than TDF, the landscape of ART in pregnancy is likely to change again. Finally, there will be growing antiretroviral exposure among HIV-uninfected women with the use of pre-exposure prophylaxis (PrEP) [50]. In addition to surveillance of new ART, long-term follow up of older drugs remains important. ZDV and didanosine (ddI), drugs that were introduced in the 1990s have only recently shown associations with congenital cardiac defects and cancer, [51,52] respectively, which would not have been apparent without many years of data. Given the changing drugs and changing populations without safety data from clinical trials, ongoing ARV safety surveillance in pregnancy is clearly needed.

3. ART Safety Surveillance Programs 3.1 Ongoing surveillance in high-income countries

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Surveillance to detect adverse outcomes related to antiretroviral use in pregnancy currently exists in the United States, Canada, France and the United Kingdom. The Antiretroviral Pregnancy registry (APR), based in the US, is an international database collecting ARV exposure during pregnancy and birth defects voluntarily from medical providers [53]. The woman’s information is enrolled in the registry as early as possible during her pregnancy and then the pregnancy outcome is added after delivery. The primary goal is early detection of teratogenicity of ARV drugs or regimens. As of July 2015, the registry had prospectively determined the presence or absence of birth defects among 7738 live births [53].


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There are also several ongoing or recently completed US-based observational cohort studies that follow HIV-infected women and their children. The Surveillance Monitoring of ART Toxicities (SMARTT) Study conducted by the Pediatric HIV/AIDS Cohort study (PHACS) network is an NIH/NICHD-funded longitudinal cohort that examines short- and long-term outcomes among children exposed to HIV and ART in utero [54]. SMARTT employs an innovative trigger-based design to identify and evaluate adverse events. Participants who met a predefined clinical or laboratory threshold (trigger) undergo additional evaluations to define their case status. HIV-exposed uninfected youth (1–12 years at entry) enrolled into a “Static” Cohort, which completed enrollment in 2009 with 1240 youth and their caregivers, but continues follow-up until age 18. A second “Dynamic” cohort enrolls mothers and their infants during gestation or within 72 hours after birth, and also continues follow up to age 18; this cohort had enrolled 2411 mother-infant pairs as of May 2016, and continues to enroll 200–250 additional annually. Adverse birth outcomes such as preterm birth, congenital anomalies, abnormal neonatal fatty acid metabolism, and newborn bone mineral content have been evaluated. Due to its long-term follow-up, this cohort study is able to address adverse outcomes beyond the early infant period including language and hearing impairment, pre-school and school-aged neurocognitive functioning, metabolic and cardiovascular outcomes, and growth and pubertal maturation. Additional details of study design and key findings have been recently summarized [55].


Several other prospective US-based cohorts also followed children born to women with HIV infection, but are now closed. The P1025 perinatal study conducted by the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group enrolled mothers with HIV infection and their infants between 2002 and 2013, with a total of 2748 women and 3030 live-born infants enrolled. The study collected detailed information during pregnancy, allowing careful control for potential confounders. However, the study followed infants only for 1 year and reduced infant follow-up to 6 months in 2007; as a result, this study has primarily focused on adverse birth and early neonatal outcomes [56]. The Pediatric AIDS Clinical Trials Group (PACTG) 219/219C study followed 3552 infected children (90% perinatally-acquired) and 2342 HEU youth for long-term outcomes, including neurodevelopment and neurological functioning, congenital anomalies, growth, cancer and mitochondrial dysfunction [57–60]. The average age at study entry was for HEU children was 7 months and median follow-up was 3.6 years. Finally, the Women and Infant Transmission Study (WITS) was a prospective cohort study of perinatal HIV transmission conducted between 1990 and 2006 at 6 clinical centers in the US and Puerto Rico; the study enrolled 2841 children, the majority HEU (2470, 87%) [61]. Public use datasets are available through the U.S. National Technical Information Service (www.ntis.gov, accession # PB2009500037). In 1990, funded by the Public Health Agency of Canada, the Canadian Perinatal Surveillance Program (CPHSP) was initiated across 22 sites, and includes both a retrospective and a prospective component, with data on 3100 mother infant pairs as of 2014. This surveillance system provides information on perinatal transmission rates, missed opportunities for prevention, adverse birth outcomes, and trends in maternal ART use [62]. As a surveillance program, individual consent is not obtained, and the utility of the program is limited by availability of information on both infant outcomes and potential confounders. Expert Opin Drug Saf. Author manuscript; available in PMC 2017 November 01.

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A separate longitudinal cohort was established in 1988 to follow all pregnant women with HIV infection at Centre Hospitalier Universitaire (CHU) Sainte-Justine, the largest maternal child health center in Quebec, Canada (Centre Maternel et Infantile sur le SIDA). HIVpositive pregnant women who consented to the cohort were prospectively followed during pregnancy, and their infants until age 18. This cohort has yielded important information regarding the safety of ART exposures both prenatally and in the postnatal period, including extensive laboratory and lymphocyte measures in HEU children through 24 months of age [51].

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In Europe, surveillance studies of HEU youth focusing on ART safety are conducted in France, the United Kingdom, and among a collaboration of European countries. Since 1986, the Enquête Périnatale Française (EPF, ANRS C01/C011, French Perinatal Cohort) has enrolled over 20,000 HIV-infected women during pregnancy at 90 perinatal centers throughout France [63]. This study has broad representation, with about 95% of all HIVinfected pregnant women at the participating clinics providing informed consent and included (70% of all HIV-infected women delivering in France). HEU infants are examined at birth and periodically according to national guidelines through 18–24 months. The study has provided critical insight on the link between preterm birth and in utero ART exposure, and birth weight, which was not found to be associated with ART in this cohort [64]. Due to its large size, this study has also allowed evaluation of rarer adverse endpoints, such as congenital heart defects and cancer [13,52,65,66]. Although infant follow-up is limited to two years, precluding evaluation of most long-term outcomes, examination of cancer risk was possible through linkage with a national pediatric cancer registry.

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In the United Kingdom (UK) and Ireland, the National Study of HIV in Pregnancy and Childhood (NSHPC, www.ucl.ac.uk/nshpc) was established in the late 1980’s and continues to conduct active surveillance through linked obstetric and pediatric reporting; because records are obtained through national health information, no informed consent is obtained [8]. As of 2014, over 15,000 HEU children were estimated to be exposed in utero to combination ARVs and 25% were ART-exposed since conception. A consented cohort was also established between 2002 and 2005 called the “CHildren exposed to AntiRetroviral Therapy” (CHART) study, which was designed to expand and link to existing NSHPC surveillance data. Of 2104 eligible uninfected children born in the UK between 1996 and 2004, only 34% were enrolled in CHART; most of those not enrolled were either due to lack of clinic resources, inability to contact, or unwillingness of health professionals to approach the families [67]. The CHART team noted that comprehensive clinic-based follow-up of ART-exposed uninfected children is not a feasible strategy in the UK, and recommended exploration of other linkage-based approaches to utilize existing national surveillance data.

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The European Collaborative Study (ECS) is an observational cohort study of over 5000 HIVinfected pregnant women and their infants enrolling in 8 countries: Italy, Spain, UK, Netherlands, Denmark, Sweden, Belgium, and Germany [68]. A Ukraine site has also been established and provides data from a lower resource setting within Europe [69].


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3.2 Ongoing surveillance in low and middle-income countries

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There is a clear need for ongoing surveillance for ART safety in pregnancy in low and middle-income countries, where the majority of HIV-infected women live. In Botswana, there is a population-based birth outcomes surveillance study at 8 public hospitals representing almost 50% of the total births in the country [70]. Medical records are abstracted at the time of delivery from all births (HIV-infected and HIV-uninfected women) to determine ART exposure and timing. Due to the variety of regimens taken by women on reproductive age in Botswana (Figure 2b) this study will be able to directly compare stillbirth, preterm delivery, birthweight and congenital abnormalities by ART regimen (taken at conception).

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In South Africa, a government-initiated program is being piloted at 4 large hospitals in Kwa Zulu Natal [71]. This program combines birth outcomes surveillance at the time of delivery (for all births) with a smaller prospective cohort, enrolled at their first antenatal appointment and followed through delivery. In addition to ARVs, this program will be able to evaluate other medications taken during pregnancy that may be associated with HIV such as antituberculosis therapy and trimethoprim/sulfamethoxazole prophylaxis. A consortium of researchers from Burkina Faso, Mozambique and Kenya have set up surveillance to determine the impact of the first-trimester use of anti-malarial treatment on birth outcomes [72] and hope to use this same methodology to evaluate the safety of ART in pregnancy. Each country has a prospective cohort within a district covered by an operating health demographic surveillance system (HDSS). The HDSS provides baseline information for the population, identifies pregnant women for enrollment and allows linkages to outpatient and inpatient pharmacy records for drug exposures (and timing).

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In Malawi, plans are underway for a government-run program using a case-control design to determine whether ARVs are associated with birth defects [73]. Additionally, the World Health Organization is creating a centralized database for drug exposures in pregnancy [74]. The aim is to be able to pool data from LMICs in order to have power to study rare outcomes and rare exposures across different settings. 3.3 Research gaps in current surveillance programs

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There are several important research gaps that exist with the current surveillance studies and programs. First, surveillance in LMIC is not designed to follow up ART-exposed infants. The costs associated with following a cohort over many years may be prohibitive and retrospective design is not usually feasible because most HIV/ART-exposed children who test HIV-negative never know that they had an exposure in utero [75,76]. However, without long-term follow up it is impossible to evaluate for a link between in-utero ART exposure and birth defects found after the neonatal exam (such as cardiac defects), neurodevelopment, risks of co-morbidities including malignancy or problems with reproductive health in adulthood. Additionally, without infant follow up, the safety of infant ARV exposure via breastfeeding cannot be assessed, though breastfeeding is a common practice among HIVinfected women in resource limited settings [31].


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There is also little data available on the impact of ART on early spontaneous abortion (SAB), as most studies do not include adverse pregnancy outcomes that occur prior to 20– 24weeks GA. In order to study all SAB, pregnancies would need to be identified immediately after conception with close follow up to determine the timing of fetal demise as well as identify pregnancies that were terminated for fetal abnormalities or maternal reasons. While this may not be feasible, it might be possible to determine the risk of second-trimester SAB in settings where women usually initiate antenatal care in the first trimester.

4. Biostatistical Approaches to evaluation of surveillance data 4.1 The problem of identifying effects of individual ART drugs

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One complicating feature of safety monitoring for in utero ART exposures is that women do not just receive a single ARV drug during pregnancy; the majority receive a regimen of three (or more) different ARVs. While some ART regimens are more common than others (particularly in LMIC, where standard regimens may be more widely utilized according to government-provided therapy), there are currently about 25 different ARV drugs used during pregnancy within six different drug classes (nucleoside reverse transcriptase inhibitors, NRTIs; non-nucleoside reverse transcriptase inhibitors, NNRTIs; protease inhibitors, PIs; integrase inhibitors, fusion inhibitors, and co-receptor CCR5 blockers) creating hundreds of possible combinations. Toxicity of an individual ARV drug is thus very difficult to disentangle from the other concurrent ARV exposures. Pharmacokinetic interactions between pairs of ARV drugs may play a role in increasing risk for a specific ARV drug only when used together, and physiological changes during pregnancy may affect both metabolism and elimination of these drugs.

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Evaluating safety of in utero ARVs thus typically involves conducting a separate evaluation for each individual ARV drug, which leads to a large number of statistical estimates and tests (eg., p-values) and thus is often viewed as a multiple comparison problem. There are other factors that increase the “multiplicity” problem. For outcomes in which little prior biological or clinical information exists regarding the critical exposure window, and also the relative importance of duration versus timing of exposure, assessments are often conducted separately for each trimester of exposure, effectively tripling the number of models or assessments conducted.

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Compounding the “multiplicity” problem is the fact that a wide range of safety outcomes are typically considered important. These include birth outcomes, early and long-term growth, cardiovascular and metabolic health, laboratory abnormalities, behavioral outcomes (including cognitive, language, social, and behavioral functioning), hearing loss, cancer, academic achievement and employment, and ultimately reproductive health. The multiple ARV drugs, multiple time points (trimesters of pregnancy), and multiple outcomes yields a huge number of statistical comparisons; while our primary goal is to ensure true associations are detected, the inflation of Type I error and corresponding “false positive” associations claimed is a real concern.


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4.2 Possible biostatistical approaches


The optimal approach for evaluating safety of ARV exposures is to conduct a randomized clinical trial; this design is widely regarded as providing the best possible evidence for understanding both safety and efficacy of different ARV drugs or regimens. However, randomized trials are not always possible due to their expense and other logistical issues. In addition, most randomized trials have been designed to evaluate efficacy, and are underpowered for the evaluation of safety. Observational cohort studies can be extremely useful in evaluating multiple ARV regimens used in practice. However, their analysis typically requires more sophisticated epidemiological approaches in order to control for confounding by indication (eg., when clinicians prescribe certain ART regimens depending on health or other characteristics of their patients) and possible time trends in prescribing patterns. Confounding by indication is particularly important when certain regimens are prescribed specifically among women with low CD4 count (such as NVP) or among women initiating ART late in pregnancy (such as INSTIs) as both low CD4 count and initiation of ART late in the third trimester are associated with poorer perinatal outcomes and MTCT [77].

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Shifting trends in use of specific regimens, as highlighted in Figure 2a and 2b, is especially problematic when there are also shifts over time in prevalence or average severity of outcomes. For example, there was an increase in the prevalence of preterm birth from 1990 to 2010 in the general population, at the same time that new ARVs were utilized during pregnancy; failure to control for or stratify by delivery year could lead to false identification of associations with increased risk for preterm birth for newer ARV drugs. Another challenge is that over time ART has been offered at increasingly higher CD4 counts, resulting in an improvement in overall nadir CD4 counts and decrease in opportunistic infections. In ART safety analyses, these shifting trends in regimens can also make it difficult to determine whether the effect is directly due to medication or rather to unmeasured HIV-related factors such as immune dysfunction due to low nadir CD4 count. However, in the current era of universal antiretroviral therapy, it is neither relevant nor appropriate to make comparisons to children born to HIV-infected women who did not receive any ART in pregnancy.

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As noted previously, one standard approach for assessing ART safety is to examine the association of each individual ARV drug, in separate models, controlling for time period and other potential confounders as appropriate. Many of the observational cohort studies noted in Section 3 collect a rich set of demographic, socioeconomic, maternal and home environment measures that allow improved control for confounding. However, investigators rarely control for the other ARV drugs used in the same regimen due to the large number of models that would be needed to accomplish this. In addition, evaluation of each individual ARV drug essentially overlooks the fact that the comparison group is not “unexposed”; they instead reflect different combination regimens not including the specific drug of interest. Correia et al [78] have shown that such an approach can lead to biased estimates for individual ARV drugs, particularly in settings where an ARV drug that does impart increased risk for an adverse outcome is commonly used together with certain other ARV drugs. In


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this setting, the other ARV drugs commonly included in the same regimen will tend to have biased estimates of risk and lead to inflated false positive findings.

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In response, one of two approaches can be considered. The first is a comparative effectiveness (or comparative safety) approach, in which two currently used combination regimens are compared head to head, after controlling for any potential confounding factors which are associated with both use of each regimen and the outcome of interest. As an example, Jacobson et al evaluated infant growth among 2-year old infants in the PHACS SMARTT study whose mothers initiated ART during pregnancy with a regimen including both tenofovir disopropil fumarate (TDF) and emtricitabine (FTC) as compared to those whose mothers initiated a regimen containing zidovudine (ZDV) and lamivudine (3TC); they observed slightly higher weight-for-length Z-scores but no difference in length or head circumference [79]. Caniglia also utilized a comparative safety approach in evaluating neurodevelopmental scores in 1-year old SMARTT infants whose mothers initiated an atazanavir-containing ARV regimen in the first trimester of pregnancy as compared to those initiating regimens without atazanavir in the same trimester [80]. Such subgroup analyses often raise a conflict between a desire to include as many participants as possible with available outcome information as compared to limiting analysis to a relatively small subset deemed most appropriate for addressing the scientific question at hand.

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An extension of the comparative effectiveness approach which may be desirable when ART exposures affect later health measures, which in turn may result in changes to ART regimens, is to use marginal structural models as described by Hernan at al [81]. Marginal structural models are a class of causal models in which parameters are estimated through inverse-probability-of-treatment weighting; these models allow for appropriate adjustment for confounding in order to closely mimic the comparison that would be made in a randomized clinical trial [82,83]. A limitation of both comparative safety evaluations and marginal structural models is that they typically focus on one or two ARV drugs or regimens of interest, and are thus relevant to comparisons such as regimen containing drug A vs. not drug A, or regimen A vs. regimen B. As a result, they may not be useful for evaluating newer ART or those used more rarely, and still may neglect other ARV drugs used within the same regimen. These approaches may also require data that are not available within observational studies, such as detailed health history information (CD4 counts and HIV viral load measures) both prior to conception and/or ARV initiation, and subsequent to ARV treatment in pregnancy.

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The second type of approach is to use a safety screening approach which considers the larger number of individual ARV drugs utilized in practice and attempts to identify possible safety “signals”. One approach is to control the false discovery rate (FDR) as proposed by Benjamini and Hochberg to restrict the percentage of identified (eg., “significant”) findings that are false positives to a certain threshold, typically 5 to 10% [84]. This may have a benefit in reducing the Type I error rate, but it should be recognized that this is done at the expense of the false non-discovery rate [85]. Since screening studies for ART safety are generally recognized as exploratory and any findings as requiring subsequent confirmation in other studies, most investigators designing analyses of ART safety appropriately err on


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the side of allowing a higher Type I error rate to balance the primary aim of not missing a true association when one does exist [86].

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Another possible option is to utilize a hierarchical model to jointly evaluate a relatively large number of ARV drugs simultaneously under the assumption that drugs from the same drug class will have similar toxic effects. This approach utilizes a strategy similar to that proposed by Witte and Greenland for nutritional epidemiology studies, for which a random effect is specified for each “class” of nutrients, and has been previously utilized in the context of HIV-related research by Young et al [87–90]. Correia et al proposed extension of the hierarchical model to screen multiple ARV drugs for safety, with first-stage effects for drug class (NRTIs, NNRTIs, and PIs) and second-stage effects for individual drugs. This model assumes that the effect of each drug is the summation of the drug class and a residual effect specific to the individual drug. The effect for drugs less commonly used are pulled toward the “mean” effect averaged over more common drugs from the same drug class. Based on simulation studies under various “true effect” scenarios, Corriea found that the hierarchical modeling approach consistently outperformed the standard approach of separate models for each ARV drug in terms of reductions in the false discovery rate, and generally had high power to detect true associations when drugs within the same class had similar adverse effects. However, in scenarios in which drugs from the same class had effects in opposite directions, or only one drug in a class had a strong effect, larger sample sizes were required for the hierarchical model to perform well [78].

5.0 Conclusions

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Limitations of surveillance cohorts for addressing certain scientific questions are recognized. While surveillance in LMIC often has the necessary statistical power to evaluate birth outcomes among women on ART, the number of ART regimens in use is limited and there is a lack of long-term follow up of HEU youth in these settings. Cohorts in high-income countries, where both HIV and adverse birth outcomes are less common, still have an important role to play in providing safety data for newer ART and in identifying toxicities that may occur after the neonatal period. However, long-term follow up remains a challenge as many of the cohorts described in Section 3 are conducted in a setting in which maternal HIV status and perinatal exposure may be unknown to their children and the child’s physician, greatly reducing the feasibility of recruiting HEU youth for prospective cohort studies. Funding restrictions often limit the amount of support clinical practitioners can devote towards recruiting and following HEU youth and few of the cohorts include a comparison group of HIV-unexposed youth with similar socioeconomic backgrounds, which is necessary for providing context and interpretation of results.

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Appropriate biostatistical and epidemiologic approaches must be employed in any evaluation of observational data to control for potential confounders related to both exposures and outcomes. It should be recognized that full control for confounding may sometimes require data which are not available within observational studies, such as detailed health history information (CD4 counts and HIV viral load measures) both prior to conception and/or ARV initiation, and subsequent to ARV treatment in pregnancy. As safety studies, identification of


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possible toxicity of ARV exposures should be emphasized as a higher priority than protection against inflated Type I errors from multiple comparisons. Given the large number of HEU children to be born in the years to come, it is critical to document pregnancy outcomes in order to refine the optimal regimens to be used during pregnancy. ART during pregnancy is essential and life saving, however identifying those regimens that will minimize adverse health outcomes should be a global public health priority.

6.0 Expert Opinion 6.1 The need for surveillance in both resource-rich and resource-limited settings

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There are several reasons why the impact of in-utero ART exposure may differ in resourcelimited compared with resource-rich settings. First, the antiretroviral drugs and combinations used in each setting are different (Figure 2). Second, women living in lowincome countries often have lower BMI [91] and could expect higher drug levels, potentiating toxic effects. Third, in areas with limited clinical and laboratory monitoring of pregnant women, adverse effects of medications could persist longer or become more severe. Fourth, there is higher incidence of acute co-infections such as tuberculosis and malaria in many LMIC, introducing the possibility of drug-drug interactions with ART.

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Additionally, in sub-Saharan Africa (SSA), there are high rates of HIV-infection [26], high fertility rates [92], high rates of adverse birth outcomes and child mortality [93]. It is possible that this will lead to increased statistical power to detect differences in rare outcomes like stillbirth and pre-eclampsia. Finally, the HIV epidemic in SSA is more generalized so there is less of a concern that differences in birth outcomes could be due to confounding socioeconomic factors or lifestyle/drug use. For all of these reasons, it is very important that ART safety surveillance occur in many different settings in both high-income and low- and middle-income settings. 6.2 Understanding the mechanisms of adverse birth outcomes among women on ART

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Given the critical need for continued access to maternal ART and the concerning data about the risks of adverse birth outcomes, it is crucial to identify effective strategies to improve birth outcomes among women on ART. The first step is to identify the underlying pathways that threaten neonatal outcomes in these women, and determine if these pathways are amenable to interventions. ART is hypothesized to improve some adverse birth outcomes by reversing immunosuppression and possibly by preventing in-utero HIV infection [94]. Recent studies identify maternal hypertension as the most important risk factor for adverse birth outcomes among HIV-infected women on ART both epidemiologically and at placental examination [7,15,38, 95]. Women with chronic HIV infection on ART have underlying endothelial dysfunction [96] that may be exacerbated by the stress of pregnancy and lead to systemic hypertension, poor placentation and placental insufficiency. An important modulator of endothelial function in pregnancy is progesterone [97] and recent data suggest an association between ART and low progesterone resulting in adverse birth outcomes [98,99] (potentially connected by decreased prolactin regulation of progesterone


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metabolism, and mediated by a shift away from progesterone-induced Th-2 immunologic responses in normal pregnancy). Other possible mechanisms include direct toxicity of ART at the level of the placenta, mitochondrial dysfunction, DNA methylation, influence of the vaginal or placental microbiome on inflammatory response in pregnancy, CMV co-infection, or chronic immune dysfunction due to low nadir CD4 counts. Mechanistic studies in humans are urgently needed as an adjunct to widespread ARV safety surveillance. 6.3 Opportunities for pooling observational cohorts and linking registries to further research

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Despite the differences across surveillance cohorts in study design, populations enrolled, and prevalence of other concurrent risk factors, opportunities for collaboration across cohorts, networks and between different types of registries in specific focused areas should be promoted. First, pooled analyses may be advantageous from a power perspective when the outcomes of interest are rare, such as mortality, cancer occurrence, or specific types of birth defects, which often cannot be investigated adequately within a single study. For these types of outcomes, an alternative design such as a nested case-control study may be considered, by selecting appropriate controls within each cohort matched or otherwise comparable to cases. In addition, pooled collaborations may be useful for some newer ARV drugs for which there are limited numbers exposed in any one country or HIV network. It may not be feasible to continuously follow participants to evaluate longer-term outcomes such as cancer and cardiovascular events. However, this problem can be overcome by creating linkages between birth registries and other health registries, though this requires advanced planning, cooperation between agencies, and the availability of other registries which may not currently exist in LMICs.

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Secondly, a specific subgroup of growing interest with respect to in utero ARV exposures is that of perinatally HIV-infected (PHIV) women who are now themselves having children; evidence from some small studies has suggested the possibility of increased vulnerability among women who themselves have experienced lifelong chronic inflammation and immune suppression [100]. One study by Jao et al demonstrated that infants born to 25 women with perinatally-acquired HIV had significantly lower mean weight and height Z-scores through age 1 year than those of 99 women with HIV not acquired perinatally; larger studies are warranted to confirm such early growth differences and to evaluate longer-term outcomes often related to poor postnatal growth, such as cognitive functioning. Due to the currently limited numbers of PHIV women of reproductive age, such studies may be best achieved through international pooled collaborations. The implications of possible alterations in reproductive health may have wider repercussions in LMIC settings.

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Any attempt to pool data or conduct meta-analyses of existing studies must evaluate whether pediatric monitoring and measurement of the outcome were similar in all individual studies. This is of particular importance for outcomes that are not apparent or easy to evaluate at the time of birth, such as cardiac defects, or require more advanced laboratory, pathology or radiographic techniques to diagnose, such as mitochondrial dysfunction, cardiac disease and cancer. Differences in measurement or definitions of outcomes can lead both to under- and over-diagnosis and have to be considered during primary study design as it not possible to


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control for differences in meta-analysis or data pooling. It is encouraging that steps have been taken by the research community and by the WHO towards building future sustainable collaborations between key cohorts across the globe [74,78].

Acknowledgments The authors gratefully acknowledge the Department of Biostatistics at Harvard T. H. Chan School of Public Health for sponsoring the workshop on Issues in Evaluating Safety of Antiretroviral Exposures in HIV-exposed Uninfected Children in Boston, MA in February 2016. Funding:

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R Zash received funding from NIH/NIAID T32 5T32AI007433-21. PL Williams received funding from the Pediatric HIV/AIDS Cohort Study (PHACS), which is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development with co-funding from other NIH institutes through cooperative agreements with the Harvard T. H. Chan School of Public Health [grant number HD052102] and the Tulane University School of Medicine (HD052104).

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88. Witte JS, Greenland S, Haile RW, et al. Hierarchical regression analysis applied to a study of multiple dietary exposures and breast cancer. Stat Med. 1994; 5(6):612–621. 89. Young J, Glass TR, Bernasconi E, et al. Hierarchical modeling gave plausible estimates of associations between metabolic syndrome and components of antiretroviral therapy. J Clin Epidemiol. 2009; 62(6):632–41. [PubMed: 19108985] 90. Witte JS, Greenland S, Kim LL, et al. Multilevel modeling in epidemiology with GLIMMIX. Epidemiology. 2000; 11(6):684–688. [PubMed: 11055630] 91. WHO. [Last Accessed April 15 2016] Global Database on Body Mass Index. Available at http:// apps.who.int/bmi/ 92. Committee on Population, Division of Behavioral and Social Sciences and Education, National Academies of Sciences, Engineering, and Medicine. Recent fertility trends in sub-Saharan Africa: workshop summary. Washington DC: National Academies Press (US); Feb 18. 2016 93. Lawn JE, Blencowe H, Oza S, et al. Every newborn: progress, priorities, and potential beyond survival. Lancet. 2014; 384(9938):189–205. [PubMed: 24853593] 94. Thorne C, Patel D, Newell ML. Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe. AIDS. 2004; 18:2337–2339. [PubMed: 15577551] 95. Shapiro RL, Souda S, Parekh N, et al. High prevalence of hypertension and placental insufficiency, but no in utero HIV transmission, among women on HAART with stillbirths in Botswana. PLoS One. 2012; 7:e31580. [PubMed: 22384039] 96. Wang D, Melancon JK, Verbesey J, et al. Microvascular endothelial dysfunction and enhanced thromboxane and endothelial contractility in patients with HIV. J AIDS Clin Res. 2013; 4(12):267. [PubMed: 24967147] 97. Solages A, Vita JA, Thornton DJ, et al. Endothelial function in HIV-infected persons. Clin Infect Dis. 2006; 42:1325–1332. [PubMed: 16586393] 98. Meis PJ, Klebanoff M, Thom E, et al. Prevention of recurrent preterm delivery by 17 alphahydroxyprogesterone caproate. N Engl J Med. 2003; 348:2379–85. [PubMed: 12802023] 99. Papp E, Balogun K, Banko N, et al. Low prolactin and high 20-α-hydroxysteroid dehydrogenase levels contribute to lower progesterone levels in HIV-infected pregnant women exposed to protease inhibitor-based combination antiretroviral therapy. J Infect Dis. 2016; 213(10):1532–40. [PubMed: 26740274] 100. Jao J, Agwu A, Mhango G, et al. Growth patterns in the first year of life differ in infants born to perinatally vs. nonperinatally HIV-infected women. AIDS. 2015; 9(1):111–6.

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Article Highlights

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Describes the magnitude of antiretroviral use in pregnancy and the patterns of change over time in antiretroviral medication use in pregnancy around the globe

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Details current ART safety surveillance programs for pregnant women in both high-income and low- and middle-income countries

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Outlines current research gaps in surveillance and argues that continued and expanded surveillance in different settings is critical.

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Presents major methodologic difficulties and potential biostatistical approaches to the analysis of ART safety data from observational studies

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Highlights ways to pool data and link registries to improve the ability to identify the safest ART regimens for pregnancy

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Figure 1.

Increasing Percentage of HIV-infected women on Antiretroviral Treatment at Conception in the US and Botswana

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Figure 2.

Figure 2a. In utero Antiretroviral Exposure by Year of Birth in the US Surveillance Monitoring of ART Toxicities (SMARTT) Study


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Figure 2b. Antiretroviral (ART) Regimen Over Time in Botswana among Women on ART at Conception

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Author Manuscript Method of surveillance Pregnancy Registry Observational cohort of HIV-exposed infants followed to age 18; trigger-based design for adverse event identifiction

Observational cohort of women in pregnancy (HIV-exposed infants followed up to1 year) Observational cohort of children with perinatal exposure to HIV or HIV infection Prospective cohort of mother-infant pairs

Birth surveillance at 22 sites

Observational cohort at a single center, follow pregnant women and their children up to age 18 Birth surveillance capturing 70% of HIV-infected pregnant women in France and prospective follow up with infant at 18–24months

Active surveillance with linked obstetric and pediatric records through the National Health System

Adult HIV prevalence Varies 0.5%-0.9%*

0.5%-0.9%*

0.5%-0.9%*

0.5%-0.9%*

0.2%-0.4%*

0.2%-0.4%*

0.4%*

0.2%^

Program/Study (site)

Antiretroviral Pregnancy Registry (multi-national)

Surveillance Monitoring of ART Toxicities (United States)

IMPAACT P1025 (United States)

PACTG 219/219C (United States

Women and Infant Transmission Study (United States and Puerto Rico)

Canadian Perinatal Surveillance Program (Canada)

Centre Maternel et Infantile sur le SIDA (Quebec, Canada)

French perinatal cohort /EPF, ANRS C01/C011 (France)


National Study of HIV in Pregnancy and Childhood (United Kingdom and Ireland)

Adverse pregnancy, birth and neonatal outcomes (preterm delivery, birth weight, congenital abnormalities)

Adverse pregnancy, birth and neonatal outcomes (preterm delivery, birth weight, congenital abnormality) Cardiac defects Pediatric cancer Mitochondrial dysfunction HIV transmission

Adverse birth outcomes (preterm delivery, birth weight, congenital abnormality) Hematologic and immune function in infants HIV transmission

Adverse birth outcomes (preterm delivery, birth weight, congenital abnormality) Perinatal morbidity and mortality Maternal mortality HIV transmission

Preterm Delivery Low Birthweight Small for gestational age Postpartum maternal morbidity HIV Transmission

Long-term pediatric outcomes including: Neurodevelopment Growth and metabolic Cancer; clinical diagnoses Mitochondrial dysfunction

Adverse birth and neonatal outcomes, HIV transmission

Adverse birth and neonatal outcomes (preterm delivery, congenital abnormality) Infant and child growth Pediatric neurodevelopment (language, hearing, behavior, and cognitive functioning) Neurologic conditions Long-term metabolic and cardiovascular complications

Congenital abnormality

Outcomes captured

Surveillance Programs for HIV-exposed Infants and Children in High-Income Countries

1200 mother/infant pairs per year

1000 mother/infant pairs per year (total enrollment ~20,000)

Total enrollment: 1050 HIV-infected motherinfant pairs (2015)

Total enrollment: 3100 (2014)

Total enrollment: 2841 HIV-exposed infants

Total enrollment: 3552 HIV-infected and 2342 HEU infants

Total enrollment: 2,740 women and 3,000 infants

200–250

1300 American and 200 non-American women

Expected births under surveillance/yr

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Table 1

1988-current

1986-current

1988-current

1990-current

1990–2007

1993–2007

2002–2013

2005-current

1989-current

Years

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Adverse pregnancy, birth and neonatal outcomes (preterm delivery, birth weight, congenital abnormalities) HIV transmission

Anonymously linked to national cancer and death registries HIV transmission

Outcomes captured

Source: AVERT 2014: (https://www.avert.org/professionals/hiv-around-world/western-central-europe-north-america/uk)

^

Source: UNAIDS 2014 (http://www.unaids.org/en/regionscountries/countries)

*

Observational Cohort

0.2%^ (Western Europe) 0.8%* (Ukraine)

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European Collaborative Study (8 western European countries and Ukraine)

Author Manuscript Method of surveillance

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Adult HIV prevalence

1000 – 2000 mother/ infant pairs per year

Expected births under surveillance/yr

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Program/Study (site)

2000-current

Years

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Author Manuscript TDF/FTC/EFV ZDV/3TC/NVP TDF/FTC/NVP ZDV/3TC/LPv/r TDF/FTC/LPv/r TDF/FTC/EFV

TDF/FTC/EFV

TDF/FTC/EFV

25%

19%

11% (MZ) 1% (SG) 5% (KY) 10%

Botswana

South Africa

Mozambique, Senegal and Kenya

Malawi

Prospective cohort enrolled in pregnancy

2

Programmatic: Case-Control at the time of delivery

Research Population-based surveillance using HDDS data

Surveillance at the time of delivery

1

Programmatic

Research surveillance at the time of delivery

Method of surveillance

Accounting for >=80% of ART regimens used in pregnancy during years of surveillance

#

Source: UNAIDS 2014 (http://www.unaids.org/en/regionscountries/countries)

*

TDF=tenofovir FTC=emtricitabine EFV=efavirenz

Common Antiretrovirals in pregnancy#

HIV-prevalence in pregnancy*

Sites

Surveillance Programs for HIV-exposed Infants and Children in Low- and Middle-Income Countries

Congenital Abnormality

Stillbirth Preterm Delivery Birthweight Congenital Abnormality



Outcomes captured

3,600

10,000

40,000

24,000

Expected births under surveillance/ yr

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Table 2

Not yet begun

2011-current

2013-current

2014–2019

Years

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