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Pregnancy outcomes and infant growth among babies with in-utero exposure to tenofovir-based preexposure prophylaxis for HIV prevention

Heffron, Reneea,b; Mugo, Nellya,e; Hong, Tinga; Celum, Conniea,b,c; Marzinke, Mark A.g,h; Ngure, Kennetha,i; Asiimwe, Stephenj; Katabira, Ellyk; Bukusi, Elizabeth A.a,d,f; Odoyo, Josephinef; Tindimwebwa, Ednaj; Bulya, Nuluk; Baeten, Jared M.a,b,c for the Partners Demonstration Project and the Partners PrEP Study Teams

Author Information
doi: 10.1097/QAD.0000000000001867
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Abstract

Background

Oral preexposure prophylaxis (PrEP) using tenofovir-based antiretrovirals, particularly the combination emtricitabine/tenofovir disoproxil fumarate (FTC/TDF), is a recommended HIV prevention strategy for individuals with substantial risk of HIV infection [1–3]. Risk of HIV infection is heightened during pregnancy, likely because of behavioral and biologic factors, and interventions to safely protect women against HIV acquisition during pregnancy are a priority [4–7]. Global guidelines recommend PrEP for HIV prevention during pregnancy [3,8]; however, only data from women living with HIV using tenofovir as part of combination HIV treatment regimens and women treating hepatitis B are available to contribute to safety considerations for PrEP when used during pregnancy [9]. These prior studies have established a lack of teratogenicity with tenofovir use during pregnancy [10] but some have suggested that in-utero tenofovir exposure could lead to stunting in infant bone growth [11–13].

In an open-label PrEP demonstration study in Kenya and Uganda, women who became pregnant while using PrEP were offered the choice to continue PrEP throughout their pregnancy. We assessed pregnancy outcomes and infant growth characteristics, and compared PrEP-exposed pregnancies to PrEP-unexposed pregnancies observed among women randomized to the placebo arm of a separate PrEP efficacy trial.

Methods

Data were from women enrolled in two longitudinal studies of tenofovir-based PrEP. PrEP-exposed women were participating in the Partners Demonstration Project, an open-label PrEP delivery study for high-risk HIV serodiscordant couples in four sites in Kenya and Uganda conducted from 2012 to 2016. Study procedures included quarterly study visits with the provision of PrEP until the point when the partner living with HIV had used antiretroviral therapy (ART) for at least 6 months. HIV-negative participants had normal kidney function at enrollment (hepatitis B surface antigen negative and creatinine clearance >60 ml/min) and had 6-monthly creatinine monitoring. At each visit, HIV-negative partners were tested for HIV, screened for acute HIV symptoms, dispensed FTC/TDF PrEP, and counseled about adherence to the daily PrEP regimen. Point-of-care urine β-human chorionic gonadotropin (hCG) tests were conducted to identify pregnancy at the study screening visit and as clinically indicated thereafter (e.g. when missed menses was reported).

A mid-study protocol modification allowed women becoming pregnant while on PrEP the opportunity to have monthly visits during pregnancy (for more frequent clinical monitoring), the choice to discontinue PrEP during pregnancy or continue following a monthly dispensing schedule, and to have their infants enrolled for quarterly measurement of length, weight, and head circumference during their first year. Additional counseling at the time of pregnancy discovery focused on the risks and benefits of PrEP use during pregnancy including the largely reassuring data on pregnancy outcomes and infant growth among women using TDF and FTC as part of combination HIV treatment, the risk of incident HIV infection during pregnancy, and consequences of acute maternal HIV infection to babies.

Participants using PrEP were issued electronic medication event monitoring (MEMS) bottle caps that recorded the date and time when every opening occurred. Additionally, archived plasma samples collected monthly from pregnant women dispensed PrEP were shipped on dry ice to the Clinical Pharmacology Analytical Laboratory at Johns Hopkins University for tenofovir quantification using liquid chromatographic-tandem mass spectrometry (LC-MS/MS), with a limit of quantification of 0.31 ng/ml [14].

For comparison, data from PrEP-unexposed pregnancies were contributed by women in the placebo arm of the Partners PrEP Study, a phase III, double-blind PrEP efficacy study conducted at nine clinical research sites in Kenya and Uganda from 2008 to 2012. At enrolment, HIV-negative participants had normal kidney function and were not infected with hepatitis B [15]. HIV-negative partners completed monthly study visits for HIV testing, study drug dispensing, adherence counseling, and urine hCG testing. Study drug was withheld from women at their first positive pregnancy test result; pregnant women remained in the study and their infants were enrolled for quarterly measurement of length, weight, and head circumference during their first year.

In both studies, obstetric history was collected through self-report and the outcome of the current pregnancy was verified through antenatal records with careful follow up by the study safety monitor to ensure data completeness and accuracy. Any woman who seroconverted to HIV while pregnant was immediately referred for prevention of mother-to-child services and study staff followed the case to ensure efficient antiretroviral initiation. Infants born to HIV-infected mothers were tested for HIV according to national guidelines, which included DNA polymerase chain reaction testing at 6 weeks after birth; results were recorded on study forms after study staff verified with the infant's clinic records.

Statistical methods

Multiple regression analyses compared pregnancy outcomes and infant growth among pregnancies exposed and unexposed to PrEP. For comparisons of pregnancy loss, multivariable generalized estimating equations were used to account for multiple pregnancies per woman. For comparisons of preterm delivery of a live birth and congenital anomalies, exact logistic regression was used as there were no preterm deliveries or congenital anomalies among babies exposed to PrEP. For comparisons of growth characteristics, the 2006 World Health Organization (WHO) growth standard by age in days was used to calculate age-adjusted and sex-adjusted z-scores for infants born at term (gestational age ≥37 weeks) [16]; for infants born less than 37 weeks, preterm growth standards were used and z-scores were adjusted for gestational age [17]. Two sample t-tests were used to test the difference between PrEP-exposed and PrEP-unexposed infant growth at each time point and linear mixed-effects models were used to compare the growth trajectories over time. SAS 9.4 (Cary, North Carolina, USA) was used for all analyses.

Protection of human subjects

The protocols for both studies were approved by the Institutional Review Board at the University of Washington and local ethics committees for each site. Written informed consent was obtained from all participants in English or their preferred local language.

Results

In the Partners Demonstration Project, 30 pregnancies from 30 women were exposed to PrEP (88% of women offered the choice to continue PrEP during pregnancy). In the Partners PrEP Study, 88 women from the placebo arm with no exposure to PrEP reported 96 pregnancies. PrEP-exposed women were slightly younger than PrEP-unexposed women (median age 25 versus 28), had no children more frequently (46.7 versus 13.6%), and greater likelihood for HIV acquisition from their HIV-infected male partners (risk scores = 7 versus 4 based on a validated tool) [18]. Maternal obstetric histories were similar including the frequency of prior pregnancy loss (23.3% PrEP-exposed and 39.6% PrEP-unexposed, P = 0.1), preterm live births (0% PrEP-exposed and 9.4% PrEP-unexposed, P = 0.1), and other complications (0 in both cohorts). No women from the PrEP-exposed cohort seroconverted to HIV during pregnancy whereas six women unexposed to PrEP seroconverted. No babies were HIV-infected at birth.

Among women offered PrEP during pregnancy, 22 (73.3%) were dispensed PrEP at least once and two elected to discontinue PrEP prior to the end of pregnancy. Women were dispensed PrEP a median of 6 months (IQR 4–8) during pregnancy. On the basis of MEMS data, 52% of women took at least 80% of expected doses. On the basis of plasma tenofovir quantification, 74% (115/154) of samples had tenofovir detected and 40.3% had concentrations at least 35 ng/ml, consistent with daily PrEP use [19].

Of the 30 pregnancies that were PrEP-exposed, 83% resulted in a live birth and 17% resulted in a pregnancy loss (7% at <20 weeks and 10% at 20–36 weeks, Table 1). The frequency of live birth was similar among PrEP-unexposed pregnancies (live birth = 68%, P = 0.10). There were no preterm deliveries among the 25 live births with PrEP exposure, which was not statistically different from those without PrEP exposure (7.7% of PrEP-unexposed births were preterm, P = 0.4). There were no congenital anomalies present in babies born to women using PrEP and five babies (7.7%) with congenital anomalies born to women with no PrEP exposure (P = 0.6 for the difference in frequency).

T1-17
Table 1:
Pregnancy outcomes among women exposed and unexposed to preexposure prophylaxis.

Quarterly infant growth measurements from birth to 1 year were conducted for 93% of all expected visits after accounting for four infant deaths in the PrEP-unexposed cohort. z-scores for infant weight were similar between PrEP-exposed and PrEP-unexposed infants at every quarterly visit (Fig. 1a). Adjusted z-scores for length were slightly lower for PrEP-exposed infants at month 1 (mean z-score −1.73 for the PrEP-exposed versus −0.79 for the PrEP-unexposed, P = 0.05) and month 3 (mean z-score −1.66 versus z-score −0.42, P = 0.02, Fig. 1b). However, by 12 months, length z-scores were higher for PrEP-exposed infants (z-score for the PrEP-exposed −0.03 versus −1.07, P = 0.03). Head circumference followed a similar pattern with a slightly lower head circumference for PrEP-exposed infants at birth (mean z-score 0.24 for the PrEP-exposed versus 1.07 for the PrEP-unexposed, P = 0.04) and similar head circumference at 12 months (mean z-score −0.01 versus 0.3, P = 0.4, Fig. 1c). In linear mixed-effect regression models, the slope for z-scores for weight and length were statistically greater among PrEP-exposed relative to PrEP-unexposed infants (P < 0.001 for both of the slope differences) whereas the slope difference for head circumference was not statistically different (P = 0.07). Results were similar in separate sensitivity analyses that: restricted to infants that had complete follow-up data for 1 year after birth (n = 17 PrEP-exposed and 49 PrEP-unexposed infants) and included only PrEP-exposed infants whose mothers had tenofovir detected in at least 75% of samples collected during pregnancy (n = 11).

F1-17
Fig. 1:
Age and sex-adjusted z-scores for infant (a) weight, (b) length, and (c) head circumference.Slopes for z-scores for weight (0.01 for PrEP-exposed and −0.06 for PrEP-unexposed, slope difference = 0.07) and length (0.19 for PrEP-exposed and −0.04 for PrEP-unexposed, slope difference = 0.23) are greater among PrEP-exposed relative to PrEP-unexposed infants (P < 0.001 for both). In sensitivity analysis restricted to infants with complete follow-up data for 1 year, trajectories were similar: for weight, slopes for z-scores are 0.01 for PrEP-exposed and −0.06 for PrEP-unexposed (slope difference = 0.07, P = 0.005); for length, slopes for z-scores are 0.16 for PrEP-exposed and −0.04 for PrEP-unexposed (slope difference = 0.2, P < 0.001). In sensitivity analysis restricted to infants whose mothers had tenofovir detected in at least 75% of samples collected during pregnancy, trajectories were also similar: for weight, slopes for z-score are 0.06 for PrEP-exposed and −0.06 for PrEP-unexposed (slope difference = 0.12, P < 0.001); for length, z-score are 0.24 for PrEP-exposed and −0.04 for PrEP-unexposed (slope difference = 0.27, P < 0.001). PrEP, preexposure prophylaxis.

Discussion

To our knowledge, these are the first data to assess pregnancy outcomes and infant growth among HIV-negative women who used tenofovir-based PrEP throughout pregnancy to prevent HIV acquisition. The frequency of pregnancy loss, preterm delivery, and congenital anomalies were not different when mothers used PrEP throughout pregnancy. Although some of the measures of infant size were smaller at birth for infants exposed to PrEP, PrEP-exposed and unexposed infants were of similar average size 1 year after birth. Our sample size is small and although these results are reassuring, they should be regarded as preliminary, potentially laying expectations that the findings be upheld in larger cohorts and registry data. In resource-constrained settings, the background prevalence of preterm birth and low birth weight is 12 and 16% [20,21] whereas 2.7% of babies born with antiretroviral exposure have congenital anomaly [22]. Our data are also reassuring relative to these rates.

Nearly 90% of women elected to continue PrEP during pregnancy. However, our MEMS data, corroborated by TFV quantification, suggest that not all women were fully adherent to the daily dosing regimen. More data are needed to establish therapeutic levels of TFV during pregnancy, as hemodilution may impact tenofovir availability. An immediate priority is to formulate messages for pregnant women using PrEP during pregnancy that describe elevated HIV risk and PrEP adherence information.

In many regions, and especially those where women bear a great burden of HIV infection, women spend a substantial proportion of their reproductive years pregnant and PrEP offers a well tolerated HIV prevention option. As PrEP delivery becomes widespread in these regions, children exposed to PrEP during organogenesis and fetal development and early in infancy can continue to be monitored and contribute more safety data. For women with substantial HIV risk, our data uphold current WHO recommendations about PrEP use during pregnancy.

Acknowledgements

We thank the couples who participated in this study for their motivation and dedication and the referral partners, community advisory groups, institutions, and communities that supported this work. The authors acknowledge the Director, KEMRI for support. The Partners Demonstration Project was funded by the Bill & Melinda Gates Foundation (OPP1056051), the National Institute of Mental Health of the US National Institutes of Health (R01MH095507), and the United States Agency for International Development (AID-OAA-A-12-00023). The Partners PrEP Study was funded by the Bill & Melinda Gates Foundation (OPP47674). This work was also supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00-HD076679). This work was made possible by the generous support of the American people through USAID; the contents are the responsibility of the authors and do not necessarily reflect the views of USAID, NIH, or the United States Government.

Author contributions: R.H. and J.M.B. conceived the study. R.H. wrote the first draft of the manuscript. T.H. performed statistical analyses. J.M.B., C.C., and R.H. were awarded grants to fund the study. M.M. oversaw laboratory technicians that performed analyses of tenofovir concentrations. N.M., K.N., S.A., E.K., E.B., J.O., E.T. and N.B. led the site teams that collected the data. All authors contributed critical revisions to the analysis and interpretation and reviewed the final manuscript draft.

Partners Demonstration Project Team: Coordinating Center (University of Washington) and collaborating investigators (Harvard Medical School, Johns Hopkins University, Massachusetts General Hospital): Jared Baeten (protocol chair), Connie Celum (protocol co-chair), Renee Heffron (project director), Deborah Donnell (statistician), Ruanne Barnabas, Jessica Haberer, Harald Haugen, Craig Hendrix, Lara Kidoguchi, Mark Marzinke, Susan Morrison, Jennifer Morton, Norma Ware, Monique Wyatt.

Project sites: Kabwohe, Uganda (Kabwohe Clinical Research Centre): Stephen Asiimwe, Edna Tindimwebwa; Kampala, Uganda (Makerere University): Elly Katabira, Nulu Bulya; Kisumu, Kenya (Kenya Medical Research Institute): Elizabeth Bukusi, Josephine Odoyo; Thika, Kenya (Kenya Medical Research Institute, University of Washington): Nelly Rwamba Mugo, Kenneth Ngure.

Data Management was provided by DF/Net Research, Inc (Seattle, Washington, USA). PrEP medication was donated by Gilead Sciences.

Partners PrEP Study Team:

University of Washington Coordinating Center and Central Laboratories: Connie Celum (principal investigator, protocol co-chair), Jared M. Baeten (medical director, protocol co-chair), Deborah Donnell (protocol statistician), Robert W. Coombs, Lisa Frenkel, Craig W. Hendrix, Jairam Lingappa, M. Juliana McElrath.

Study sites and site principal investigators: Eldoret, Kenya (Moi University, Indiana University): Kenneth Fife, Edwin Were; Kabwohe, Uganda (Kabwohe Clinical Research Center): Elioda Tumwesigye; Jinja, Uganda (Makerere University, University of Washington): Patrick Ndase, Elly Katabira; Kampala, Uganda (Makerere University): Elly Katabira, Allan Ronald; Kisumu, Kenya (Kenya Medical Research Institute, University of California San Francisco): Elizabeth Bukusi, Craig Cohen; Mbale, Uganda (The AIDS Support Organization, CDC-Uganda): Jonathan Wangisi, James Campbell, Jordan Tappero; Nairobi, Kenya (University of Nairobi, University of Washington): James Kiarie, Carey Farquhar, Grace John-Stewart; Kenya Medical Research Institute, Nairobi, Kenya: Nelly Rwamba Mugo; Tororo, Uganda (CDC-Uganda, The AIDS Support Organization): James Campbell, Jordan Tappero, Jonathan Wangisi.

Data management was provided by DF/Net Research, Inc. (Seattle, USA) and site laboratory oversight was provided by Contract Laboratory Services (University of the Witwatersrand, Johannesburg, South Africa).

Funding: The Partners Demonstration Project was funded by the Bill & Melinda Gates Foundation (OPP1056051), the National Institute of Mental Health of the US National Institutes of Health (R01 MH095507) and the United States Agency for International Development (AID-OAA-A-12-00023). The Partners PrEP Study was funded by the Bill & Melinda Gates Foundation (OPP47674). Additional support for this work was provided by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (R00HD076679) and the University of Washington Center for AIDS Research, an NIH funded program under award number AI027757, which is supported by the following NIH Institutes and Centers (NIAID, NCI, NIMH, NIDA, NICHD, NHLBI, NIA, NIGMS, NIDDK). This work is made possible by the generous support of the American people through USAID; the contents are the responsibility of the authors and do not necessarily reflect the views of USAID, NIH, or the United States Government.

The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Conflicts of interest

Gilead Sciences donated the PrEP medication but had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

There are no conflicts of interest.

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* Members of the study teams are listed in the Acknowledgement section.

Keywords:

HIV prevention; infant growth; pregnancy; pregnancy outcomes; preexposure prophylaxis

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