Publications by authors named "George R Seage"

154 Publications

Longitudinal changes in epigenetic age in youth with perinatally acquired HIV and youth who are perinatally HIV-exposed uninfected.

AIDS 2021 04;35(5):811-819

Gangarosa Department of Environ mental Health, Emory University Rollins School of Public Health, Atlanta, Georgia.

Objectives: To quantify the rate of change in epigenetic age compared with chronological age over time in youth with perinatally acquired HIV (YPHIV) and youth who are perinatally HIV-exposed uninfected (YPHEU).

Design: Longitudinal study of 32 YPHIV and 8 YPHEU with blood samples collected at two time points at least 3 years apart.

Methods: DNA methylation was measured using the Illumina MethylationEPIC array and epigenetic age was calculated using the Horvath method. Linear mixed effects models were fit to estimate the average change in epigenetic age for a 1-year change in chronological age separately for YPHIV and YPHEU.

Results: Median age was 10.9 and 16.8 years at time 1 and 2, respectively. Groups were balanced by sex (51% male) and race (67% black). Epigenetic age increased by 1.23 years (95% CI 1.03--1.43) for YPHIV and 0.95 years (95% CI 0.74--1.17) for YPHEU per year increase in chronological age. Among YPHIV, in a model with chronological age, a higher area under the curve (AUC) viral load was associated with an increase in epigenetic age over time [2.19 years per log10 copies/ml, (95% CI 0.65--3.74)], whereas a higher time-averaged AUC CD4+ T-cell count was associated with a decrease in epigenetic age over time [-0.34 years per 100 cells/μl, (95% CI -0.63 to -0.06)] in YPHIV.

Conclusion: We observed an increase in the rate of epigenetic aging over time in YPHIV, but not in YPHEU. In YPHIV, higher viral load and lower CD4+ T-cell count were associated with accelerated epigenetic aging, emphasizing the importance of early and sustained suppressive treatment for YPHIV, who will receive lifelong ART.
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http://dx.doi.org/10.1097/QAD.0000000000002805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969428PMC
April 2021

How to best conduct universal HIV screening in emergency departments is far from settled.

J Am Coll Emerg Physicians Open 2021 Feb 14;2(1):e12352. Epub 2021 Jan 14.

Department of Emergency Medicine Brigham and Women's Hospital Harvard Medical School Boston Massachusetts USA.

HIV screening in the emergency department (ED), including universal screening irrespective of risk assessments, has shown strong promise in past studies, identifying many new cases of HIV infection among those who lack access to traditional HIV testing services. Yet, over the years a consistent set of challenges and limitations have presented themselves in settings throughout the United States. We review considerations for evaluating and improving the success of ED-based HIV screening programs in the United States.
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http://dx.doi.org/10.1002/emp2.12352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812459PMC
February 2021

Genomics Links Inflammation With Neurocognitive Impairment in Children Living With Human Immunodeficiency Virus Type-1.

J Infect Dis 2021 Sep;224(5):870-880

Department of Pediatrics, University of California San Diego, La Jolla, California, USA.

Background: We identified host single-nucleotide variants (SNVs) associated with neurocognitive impairment (NCI) in perinatally HIV-infected (PHIV) children.

Methods: Whole-exome sequencing (WES) was performed on 217 PHIV with cognitive score for age (CSA) < 70 and 247 CSA ≥ 70 (discovery cohort [DC]). SNVs identified in DC were evaluated in 2 validation cohorts (VC). Logistic regression was used to estimate adjusted odds ratios (ORs) for NCI. A human microglia NLRP3 inflammasome assay characterized the role of identified genes.

Results: Twenty-nine SNVs in 24 genes reaching P ≤ .002 and OR ≥ 1.5 comparing CSA < 70 to CSA ≥ 70 were identified in the DC, of which 3 SNVs were identified in VCs for further study. Combining the 3 cohorts, SNV in CCRL2 (rs3204849) was associated with decreased odds of NCI (P < .0001); RETREG1/FAM134B (rs61733811) and YWHAH (rs73884247) were associated with increased risk of NCI (P < .0001 and P < .001, respectively). Knockdown of CCRL2 led to decreased microglial release of IL-1β following exposure to ssRNA40 while knockdown of RETREG1 and YWHAH resulted in increased IL-1β release.

Conclusions: Using WES and 2 VCs, and gene silencing of microglia we identified 3 genetic variants associated with NCI and inflammation in HIV-infected children.
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http://dx.doi.org/10.1093/infdis/jiaa792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408770PMC
September 2021

Adverse Birth Outcomes in Botswana Among Women With Vertically or Horizontally Acquired Human Immunodeficiency Virus.

J Pediatric Infect Dis Soc 2021 Apr;10(3):252-258

Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

Background: Women with vertically acquired HIV (VHIV) may have a greater risk of adverse birth outcomes than women with horizontally acquired HIV (HHIV).

Methods: The Tsepamo study performed birth outcomes surveillance at 8 government delivery sites in Botswana from July 2014 through March 2019. Pregnant women diagnosed with HIV before their 11th birthday received VHIV status, and other women had HHIV. Small for gestational age (SGA), preterm delivery (PTD), stillbirth, and neonatal death were compared using χ2 and Fisher's exact tests. Log-binomial regression models determined risk ratios (RRs).

Results: VHIV women (n = 402) aged 15-27 years were identified over 4 years of surveillance and compared with HHIV women (n = 8465) of the same age. VHIV women were more likely to use nevirapine (NVP)-based antiretroviral treatment (ART) in pregnancy and to have SGA and very SGA infants, but less likely to have very PTD infants. In unadjusted analyses, VHIV women had a higher risk of any adverse birth outcome combined (RR = 1.21, 95% confidence interval [CI], 1.08-1.36). After adjusting for potential confounders, particularly use of NVP-based regimens, the risk of adverse birth outcomes among VHIV and HHIV women was similar.

Conclusions: NVP-based ART is a primary and modifiable risk factor for adverse birth outcomes. Updating ART regimens could improve birth outcomes for women with HIV.
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http://dx.doi.org/10.1093/jpids/piaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023308PMC
April 2021

Safety of in-utero antiretroviral exposure: neurologic outcomes in children who are HIV-exposed but uninfected.

AIDS 2020 07;34(9):1377-1387

Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.

Objective: To evaluate whether there is an increased risk of neurologic diagnoses in children who are HIV-exposed but uninfected (CHEU) exposed in utero to specific antiretroviral medications.

Design: Prospective cohort study of CHEU enrolled from 2007 to 2017.

Methods: We evaluated children for neurologic case status, including microcephaly, febrile seizures, seizure disorders, ophthalmologic disorders, and other neurologic disorders. Adjusted relative risks (aRRs) were estimated for the association between in-utero antiretroviral exposure and neurologic case using log-binomial regression, accounting for potential confounders. Sensitivity analyses were conducted to evaluate robustness of findings.

Results: Among 3747 eligible CHEU, 231 (6.2%) met neurologic case criteria (95% CI 5.4--7%). Most eligible children (86%) were exposed in utero to combination antiretroviral regimens. In adjusted models, children exposed to efavirenz at any time during pregnancy had higher risk of neurologic case status (aRR = 1.53, 95% CI 0.94--2.51). This association was stronger when comparing efavirenz exposure at conception to no exposure during pregnancy (aRR = 1.92, 95% CI 1.09--3.36) and considering follow-up and case diagnosis only through age 2 (aRR = 2.14, 95% CI 1.11--4.12). Children exposed to didanosine at conception and during the first trimester had increased risk of neurologic case status (aRR = 2.28, 95% CI 1.07--4.87 and aRR = 2.02, 95% CI 1.01--4.04, respectively), compared with didanosine-unexposed children. Children with dolutegravir exposure had some suggestion of increased risk of neurologic case (aRR = 2.43, 95% CI 0.75--7.84), which was observed consistently across several sensitivity analyses.

Conclusion: Efavirenz and didanosine exposure during pregnancy were associated with higher risk of neurologic abnormalities in CHEU, and dolutegravir exposure showed some suggestive associations, which warrant further monitoring.
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http://dx.doi.org/10.1097/QAD.0000000000002550DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136420PMC
July 2020

The Challenges of Parameterizing Direct Effects in Individual-Level Simulation Models.

Med Decis Making 2020 01;40(1):106-111

Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1177/0272989X19894940DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989037PMC
January 2020

Trends in post-partum viral load among women living with perinatal HIV infection in the USA: a prospective cohort study.

Lancet HIV 2020 03 20;7(3):e184-e192. Epub 2019 Dec 20.

Department of Epidemiology, Harvard T H Chan School of Public Health, Boston, MA, USA.

Background: Small studies reported poor post-partum outcomes among young women living with perinatal HIV infection who are now ageing into adulthood and becoming pregnant. For targeted clinical intervention, we sought to identify women in this population at risk of poor post-partum virological control.

Methods: We abstracted data on pregnancy history for women living with perinatal HIV infection in the Pediatric HIV/AIDS Cohort Study-AMP Up protocol, a prospective study of young adults living with perinatal HIV from 14 sites in the USA. Linear models with generalised estimating equations described trends in HIV viral load through 1 year post-pregnancy by pregnancy outcome. We used group-based trajectory modelling to identify viral load trajectory groups in the first post-partum year after livebirths. We then compared sociodemographic and clinical factors across identified groups. We defined viraemia as 400 copies per mL or more.

Findings: Between April 15, 2014, and Oct 1, 2017, we enrolled 323 women, of whom 234 had perinatal HIV infection, and reported age at sexual debut and history of heterosexual vaginal intercourse. Of the 172 pregnancies recorded in these women, 147 (85%, 104 livebirths and 43 spontaneous or elective abortions) were eligible for post-pregnancy viral load trajectory analyses (ie, had at least two viral loads in the year after end of pregnancy). Viral load increased by 0·7 log copies per mL (95% CI 0·5 to 1·0) in the first 12 weeks post partum after 104 livebirths, and subsequently stabilised from 13 weeks to 1 year post partum (slope -0·01 log copies per mL, 95% CI -0·3 to 0·3). By comparison, the average viral load trajectory after 43 spontaneous or elective abortions remained at less than 400 copies per mL. We identified three distinct groups of viral load trajectories after 104 livebirths, classified as reflecting sustained suppression (31 [30%]), rebound viraemia (55 [53%]), and persistent viraemia (18 [17%]). Women with sustained post-partum suppression were older at conception (22·9 years, IQR 19·4-25·9) than those with rebound viraemia (20·4 years, 18·8-22·2), or persistent post-partum viraemia (19·0 years, 17·7-20·5). Pre-conception viraemia and immune suppression were also strong risk factors for post-partum viraemia.

Interpretation: Despite success achieving viral load suppression during pregnancy, women living with perinatal HIV infection have a high risk of post-partum viraemia. Younger age at conception, pre-conception viraemia, and pre-conception immune suppression could identify women in this population most likely to benefit from post-partum adherence interventions.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3018(19)30339-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6956402PMC
March 2020

Antiretroviral Prescribing Practices Among Pregnant Women Living With HIV in the United States, 2008-2017.

JAMA Netw Open 2019 12 2;2(12):e1917669. Epub 2019 Dec 2.

Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.

Importance: Since 1994, the US Department of Health and Human Services has published treatment guidelines for pregnant women living with HIV. Understanding how well prescribing patterns correspond with treatment guidelines could inform health policy and influence future clinical practice.

Objectives: To compare antiretroviral prescribing practices over time among pregnant women living with HIV with Department of Health and Human Services treatment guidelines and identify factors associated with receiving recommended regimens.

Design, Setting, And Participants: A prospective cohort study of 1582 pregnant women living with HIV were enrolled in the Pediatric HIV/AIDS Cohort Study Surveillance Monitoring of ART (antiretroviral therapy) Toxicities study between January 1, 2008, and June 30, 2017. The study was conducted at 18 academic research hospitals in the United States.

Exposures: Antiretroviral medications (ARVs) prescribed during pregnancy.

Main Outcomes And Measures: Proportion of regimens prescribed to pregnant women living with HIV qualifying as preferred or alternative according to Department of Health and Human Services guidelines, stratified by timing of initiation.

Results: Of 1867 pregnancies (among 1582 pregnant women living with HIV with a mean [SD] age of 28.6 [6.1] years at conception), 1264 (67.7%) occurred among women self-identified as black, 480 (25.7%) self-identified as white, and 123 (6.6%) self-identified as other or unreported race/ethnicity. Antiretroviral medications were initiated prior to conception for 790 women (42.3%), resumed during pregnancy for 625 women (33.5%), and initiated during pregnancy for 452 women (24.2%). Only 925 pregnancies (49.5%) were associated with prescribed ARVs designated as preferred or alternative, while 492 (26.4%) involved ARVs with insufficient evidence for use during pregnancy and 136 (7.3%) involved ARVs that were not recommended during pregnancy. A higher proportion of treatment-naive pregnant women initiating ARVs were prescribed preferred or alternative ARVs compared with those resuming ARVs or those treated with ARVs before conception (316 of 452 [69.9%] vs 325 of 625 [52.0%] vs 284 of 790 [35.9%]; P < .001). A total of 91 of 452 women (20.1%) initiating ARVs during pregnancy were prescribed ARVs with insufficient evidence for use during pregnancy or not recommended during pregnancy. Among women resuming ARVs, those with a viral load greater than 1000 copies/mL early in pregnancy had higher odds of being prescribed guideline-recommended ARVs (adjusted odds ratio, 2.03 [95% CI, 1.33-3.10]) compared with those with a viral load of 400 copies/mL or less.

Conclusions And Relevance: This study suggests that US ARV prescribing practices for pregnant women living with HIV do not align well with national guidelines. This finding is particularly concerning when treatment is initiated during pregnancy. Further research is needed to understand disparities between prescribing practices and evidence-based guideline recommendations.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.17669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991210PMC
December 2019

Maternal Zika Virus Infection: Association With Small-for-Gestational-Age Neonates and Preterm Birth.

Obstet Gynecol 2019 12;134(6):1197-1204

Bureau of Communicable Disease, New York City Department of Health and Mental Hygiene, Queens, and the Bureau of Vital Statistics, New York City Department of Health and Mental Hygiene, New York, New York; and the Harvard T. H. Chan School of Public Health and the Medical Practice Evaluation Center, Division of Infectious Disease, Massachusetts General Hospital, Boston, Massachusetts.

Objective: To evaluate whether antenatal Zika virus infection is associated with risk of having a small-for-gestational-age (SGA) neonate, risk of preterm birth, and lower mean birth weight of term neonates.

Methods: For this retrospective observational study, we linked birth record data for women who delivered liveborn singleton neonates in New York City in 2016 to data for pregnant women with Zika virus infection reported to the New York City Health Department. We restricted the analysis to nonsmoking, nonwhite women and adjusted for maternal characteristics. Among women with antenatal Zika virus infection, we used modified Poisson regression to assess risks of having an SGA neonate and of delivering preterm, and linear regression to assess the association of infection with mean birth weight of term neonates.

Results: Of 116,034 deliveries of singleton neonates in New York City in 2016, 251 (0.2%) were to women with antenatal Zika virus infection. A higher percentage of women with Zika virus infection delivered an SGA neonate compared with those without (11.2% vs 5.8%; adjusted relative risk [RR] 1.8; 95% CI 1.3-2.6). There was no difference in preterm birth prevalence for women with and without Zika virus infection (adjusted RR 1.0; 95% CI 0.69-1.6). Mean birth weight of term neonates born to women with Zika virus infection was 47 g less (95% CI -105 to 11 g); this difference was not statistically significant in crude or adjusted analyses.

Conclusion: For a cohort of New York City women, antenatal Zika virus infection was associated with an increased risk of having an SGA neonate, but not preterm birth or lower mean birth weight of term neonates. This supports a putative association between Zika virus infection during pregnancy and SGA.
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http://dx.doi.org/10.1097/AOG.0000000000003577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147828PMC
December 2019

Association of maternal antiretroviral use with microcephaly in children who are HIV-exposed but uninfected (SMARTT): a prospective cohort study.

Lancet HIV 2020 01 15;7(1):e49-e58. Epub 2019 Nov 15.

Seattle Children's Hospital and University of Washington, Seattle, WA, USA.

Background: Perinatal HIV transmission has substantially decreased with combination antiretroviral regimens, but complications in children who are HIV-exposed but uninfected, such as microcephaly, warrant ongoing surveillance. We aimed to evaluate whether individual in utero antiretroviral exposures were associated with increased risk of microcephaly based on long-term follow-up of infants and children who are HIV-exposed but uninfected.

Methods: We evaluated children aged younger than 18 years who were HIV-exposed but uninfected with at least one head circumference measurement while enrolled in the Surveillance Monitoring for ART Toxicities (SMARTT) study at 22 clinical sites in the USA, including Puerto Rico. This prospective cohort study was done by the Pediatric HIV/AIDS Cohort Study network. Microcephaly was defined as having a head circumference Z score <-2 according to the 2000 US Centers for Disease Control and Prevention growth charts for children 6-36 months old and according to Nellhaus standards (head circumference <2nd percentile) after 36 months (SMARTT criteria); an alternate definition for microcephaly was based on applying Nellhaus standards across all ages (Nellhaus criteria). Modified Poisson regression models were fit to obtain relative risks (RRs) for associations between in utero antiretroviral exposure and microcephaly status, adjusted for potential confounders. Neurodevelopmental functioning was compared in children who are HIV-exposed but uninfected with or without microcephaly.

Findings: Between March 21, 2007, and Aug 1, 2017, 3055 participants enrolled in SMARTT had at least one head circumference measurement. The cumulative incidence of microcephaly over a median of 5·1 years of follow-up (IQR 3·0-7·2) was 159 (5·2%, 95% CI 4·4-6·1) by Nellhaus criteria and 70 (2·3%, 1·8-2·9) by SMARTT criteria. In adjusted models, in utero exposure to efavirenz (4·7% exposed) was associated with increased risk of microcephaly by both Nellhaus standards (adjusted RR 2·02, 95% CI 1·16-3·51) and SMARTT criteria (2·56, 1·22-5·37). These associations were more pronounced in children exposed to combination regimens of efavirenz that included zidovudine plus lamivudine than those including tenofovir plus emtricitabine. Protective associations were observed for darunavir exposure (adjusted RR 0·50, 95% CI 0·24-1·00). Children who are HIV-exposed but uninfected with microcephaly had lower mean scores on neurodevelopmental assessments at age 1 and 5 years and a higher prevalence of neurodevelopmental impairment than those without microcephaly.

Interpretation: These findings support consideration of alternatives to efavirenz as part of first-line antiretroviral therapy for pregnant women.

Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development.
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http://dx.doi.org/10.1016/S2352-3018(19)30340-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6952580PMC
January 2020

International prospective observational cohort study of Zika in infants and pregnancy (ZIP study): study protocol.

BMC Pregnancy Childbirth 2019 Aug 7;19(1):282. Epub 2019 Aug 7.

Maternal-Infant Studies Center (CEMI), San Juan, Puerto Rico.

Background: Until recently, Zika virus (ZIKV) infections were considered mild and self-limiting. Since 2015, they have been associated with an increase in microcephaly and other birth defects in newborns. While this association has been observed in case reports and epidemiological studies, the nature and extent of the relationship between ZIKV and adverse pregnancy and pediatric health outcomes is not well understood. With the unique opportunity to prospectively explore the full spectrum of issues related to ZIKV exposure during pregnancy, we undertook a multi-country, prospective cohort study to evaluate the association between ZIKV and pregnancy, neonatal, and infant outcomes.

Methods: At research sites in ZIKV endemic regions of Brazil (4 sites), Colombia, Guatemala, Nicaragua, Puerto Rico (2 sites), and Peru, up to 10,000 pregnant women will be recruited and consented in the first and early second trimesters of pregnancy and then followed through delivery up to 6 weeks post-partum; their infants will be followed until at least 1 year of age. Pregnant women with symptomatic ZIKV infection confirmed by presence of ZIKV RNA and/or IgM for ZIKV will also be enrolled, regardless of gestational age. Participants will be tested monthly for ZIKV infection; additional demographic, physical, laboratory and environmental data will be collected to assess the potential interaction of these variables with ZIKV infection. Delivery outcomes and detailed infant assessments, including physical and neurological outcomes, will be obtained.

Discussion: With the emergence of ZIKV in the Americas and its association with adverse pregnancy outcomes in this region, a much better understanding of the spectrum of clinical outcomes associated with exposure to ZIKV during pregnancy is needed. This cohort study will provide information about maternal, fetal, and infant outcomes related to ZIKV infection, including congenital ZIKV syndrome, and manifestations that are not detectable at birth but may appear during the first year of life. In addition, the flexibility of the study design has provided an opportunity to modify study parameters in real time to provide rigorous research data to answer the most critical questions about the impact of congenital ZIKV exposure.

Trial Registration: NCT02856984 . Registered August 5, 2016. Retrospectively registered.
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http://dx.doi.org/10.1186/s12884-019-2430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686399PMC
August 2019

Fc Characteristics Mediate Selective Placental Transfer of IgG in HIV-Infected Women.

Cell 2019 06 13;178(1):190-201.e11. Epub 2019 Jun 13.

Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA; Duke Human Vaccine Institute, Duke University Medical Center, Durham, NC 27710, USA; Department of Pediatrics, Duke University Medical Center, Durham, NC 27710, USA. Electronic address:

The placental transfer of maternal IgG is critical for infant protection against infectious pathogens. However, factors that modulate the placental transfer of IgG remain largely undefined. HIV-infected women have impaired placental IgG transfer, presenting a unique "disruption model" to define factors that modulate placental IgG transfer. We measured the placental transfer efficiency of maternal HIV and pathogen-specific IgG in US and Malawian HIV-infected mothers and their HIV-exposed uninfected and infected infants. We examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, IgG subclass, and glycan signatures and their association with placental IgG transfer efficiency. Maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcγRIIa and FcγRIIIa, and Fc region glycan profiles were associated with placental IgG transfer efficiency. Our findings suggest that Fc region characteristics modulate the selective placental transfer of IgG, with implications for maternal vaccine design and infant health.
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http://dx.doi.org/10.1016/j.cell.2019.05.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727200PMC
June 2019

Botswana should consider expansion of free antiretroviral therapy to immigrants.

J Int AIDS Soc 2019 06;22(6):e25328

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1002/jia2.25328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562114PMC
June 2019

Disparities in HIV Viral Suppression Among Adolescents and Young Adults by Perinatal Infection.

Am J Public Health 2019 07;109(7):e9

Kunjal Patel and George R. Seage III are with the Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA. Sandra K. Burchett is with the Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston. Rohan Hazra is with the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD. Russell B. Van Dyke is with the Department of Pediatrics, Tulane School of Medicine, New Orleans, LA.

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http://dx.doi.org/10.2105/AJPH.2019.305108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6603449PMC
July 2019

Human Papillomavirus Antibody Levels and Quadrivalent Vaccine Clinical Effectiveness in Perinatally Human Immunodeficiency Virus-infected and Exposed, Uninfected Youth.

Clin Infect Dis 2019 09;69(7):1183-1191

Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Background: Persons who are infected with human immunodeficiency virus (HIV) are at high risk of human papillomavirus (HPV)-associated cancers. The objectives are to compare antibody titers to HPV 6, 11, 16, and 18 and rate of abnormal cytology between perinatally HIV-infected (PHIV) and perinatally HIV-exposed, uninfected (PHEU) youth.

Methods: This is a prospective observational cohort study of HPV4 vaccinated youth performed as part of the multicenter Pediatric HIV/AIDS Cohort Study Adolescent Master Protocol. Seroconversion and geometric mean titer (GMT) against HPV types 6, 11, 16, and 18 were calculated. Vaccine effectiveness included rates of abnormal cervical cytology and genital warts.

Results: Seroconversion to HPV 6, 11, 16, and 18 occurred in 83%, 84%, 90%, and 62% of 310 vaccinated PHIV youth compared to 94%, 96%, 99%, and 87% of 148 vaccinated PHEU youth, respectively (P < .05 for all comparisons). GMTs were lower in the PHIV vs PHEU within each category of HPV4 doses received. Higher GMTs were associated with younger age, lower HIV type 1 RNA viral load, and higher CD4% at first HPV4 vaccination, as well as shorter duration between last vaccine dose and antibody specimen. Abnormal cytology occurred in 33 of 56 PHIV and 1 of 7 PHEU sexually active vaccinated females, yielding incidence rates per 100 person-years of 15.0 (10.9 to 20.6) and 2.9 (0.4 to 22.3), respectively.

Conclusion: Antibody titers to HPV4 were lower for all serotypes in PHIV compared to PHEU youth. Protection against abnormal cytology was also diminished in sexually active PHIV females.
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http://dx.doi.org/10.1093/cid/ciy1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938204PMC
September 2019

The association between oral disease and type of antiretroviral therapy among perinatally HIV-infected youth.

AIDS 2018 11;32(17):2497-2505

Department of Pediatrics, Division of Adolescent and Young Adult Medicine, University of California, Los Angeles, Los Angeles, California, USA.

Objectives: This study explores the association between combination antiretroviral therapy (cART) and oral health outcomes (dental and periodontal) among perinatally HIV-infected (PHIV) youth.

Methods: We conducted a cross-sectional study of oral health among PHIV youth participating in the Oral Health substudy of the Pediatric HIV/AIDS Cohort Study (PHACS). Dentists at research sites were trained/calibrated on how to perform a standardized oral mucosal, dental and periodontal examination. They assessed the decayed-missing-filled-surfaces and teeth index (DMFS/T). The number of decayed surfaces and teeth and the number of teeth with gingival bleeding on probing for each participant were derived from the examination. Data for analysis included lifetime measurements of CD4 cell count and viral load, sociodemographic information and current/past history of ART.

Results: Among 209 PHIV youth, 95% were on ART at the time of enrolment. Among 143 PHIV youth on the same cART for at least 1 year, we found that the mean decayed teeth score of those receiving cART containing an integrase inhibitor was 86% higher than that of those on cART without an integrase inhibitor after adjusting for age, lifetime proportion of unsuppressed viral load and CD4 cell count nadir. Initiating protease inhibitors before age 6 years was associated with a significantly lower DMFT score than participants who initiated at age 6 years and older.

Conclusion: Our study revealed that PHIV youth who received cART containing an integrase inhibitor had a significantly higher number of untreated active caries than those on cART without an integrase inhibitor. This may warrant closer dental surveillance of those receiving an integrase inhibitor.
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http://dx.doi.org/10.1097/QAD.0000000000001965DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494108PMC
November 2018

Surviving and Thriving-Shifting the Public Health Response to HIV-Exposed Uninfected Children: Report of the 3rd HIV-Exposed Uninfected Child Workshop.

Front Pediatr 2018 30;6:157. Epub 2018 May 30.

Departments of Internal Medicine and Pediatrics, Masschusetts General Hospital, Boston, MA, United States.

Great gains were achieved with the introduction of the United Nations' Millennium Development Goals, including improved child survival. Transition to the Sustainable Development Goals (SDGs) focused on surviving, thriving, and transforming, representing an important shift to a broader public health goal, the achievement of which holds the promise of longer-term individual and societal benefits. A similar shift is needed with respect to outcomes for infants born to women living with HIV (WLHIV). Programming to prevent vertical HIV transmission has been successful in increasingly achieving a goal of HIV-free survival for infants born to WLHIV. Unfortunately, HIV-exposed uninfected (HEU) children are not achieving comparable health and developmental outcomes compared with children born to HIV-uninfected women under similar socioeconomic circumstances. The 3rd HEU Child Workshop, held as a satellite session of the International AIDS Society's 9th IAS Conference in Paris in July 2017, provided a venue to discuss HEU child health and development disparities. A summary of the Workshop proceedings follows, providing current scientific findings, emphasizing the gap in systems for long-term monitoring, and highlighting the public health need to establish a strategic plan to better quantify the short and longer-term health and developmental outcomes of HEU children.
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http://dx.doi.org/10.3389/fped.2018.00157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989128PMC
May 2018

Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine.

N Engl J Med 2018 04;378(17):1593-1603

From the Departments of Epidemiology (K.R., G.R.S., P.L.W., S.H.-D., K.P.) and Biostatistics (P.L.W., D.E.S.) and the Center for Biostatistics and AIDS Research (Y.H., D.E.S., K.P.), Harvard T.H. Chan School of Public Health, and the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (K.R.), Boston; the Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago (E.G.C.); the Department of Medicine and Division of Infectious Diseases, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J.S.C., R.M.H.); and the Department of Pediatrics, University of Colorado School of Medicine, Aurora (E.B.).

Background: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r).

Methods: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding.

Results: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV-3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight.

Conclusions: The risk of adverse birth outcomes was not higher with TDF-FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1701666DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5984044PMC
April 2018

Antiretroviral Therapy and Mortality in Rural South Africa: A Comparison of Causal Modeling Approaches.

Am J Epidemiol 2018 08;187(8):1772-1779

Africa Health Research Institute, Durban and Somkhele, South Africa.

Estimation of causal effects from observational data is a primary goal of epidemiology. The use of multiple methods with different assumptions relating to exchangeability improves causal inference by demonstrating robustness across assumptions. We estimated the effect of antiretroviral therapy (ART) on mortality in rural KwaZulu-Natal, South Africa, from 2007 to 2011, using 2 methods with substantially different assumptions: the regression discontinuity design (RDD) and inverse-probability-weighted (IPW) marginal structural models (MSMs). The RDD analysis took advantage of a CD4-cell-count-based threshold for ART initiation (200 cells/μL). The 2 methods yielded consistent but nonidentical results for the effect of immediate initiation of ART (RDD intention-to-treat hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.35, 1.26; RDD complier average causal effect HR = 0.56, 95% CI: 0.41, 0.77; IPW MSM HR = 0.49, 95% CI: 0.42, 0.58). Although RDD and IPW MSM estimates have distinct identifying assumptions, strengths, and limitations in terms of internal and external validity, results in this application were similar. The differences in modeling approaches and the external validity of each method may explain the minor differences in effect estimates. The overall consistency of the results lends support for causal inference about the effect of ART on mortality from these data.
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http://dx.doi.org/10.1093/aje/kwy065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070080PMC
August 2018

In-utero exposure to antiretrovirals and neurodevelopment among HIV-exposed-uninfected children in Botswana.

AIDS 2018 06;32(9):1173-1183

Department of Psychiatry, Children's Hospital Boston.

Objective: Conflicting data exist regarding the impact of in-utero exposure to maternal combination antiretrovirals. We compared neurodevelopmental outcomes between HIV-exposed-uninfected (HEU) children exposed in utero to three-drug combination antiretroviral therapy (ART) vs. zidovudine (ZDV) monotherapy.

Design: Prospective study of child neurodevelopment, nested within two cohorts of HIV-infected mothers and their children in Botswana (one observational, one interventional).

Methods: The Tshipidi and Mma Bana studies enrolled HIV-infected women during pregnancy and followed their HEU children for 24 months. Mothers took three-drug ART or ZDV during pregnancy. ART-exposed babies were mostly breastfed, and ZDV-exposed were formula-fed. Neurodevelopmental outcomes, measured at 24 months using Bayley Scales of Infant and Toddler Development Third Edition (Bayley-III) and Development Milestones Checklist (DMC), were compared in adjusted linear regression according to antiretroviral exposure.

Results: Of 598 HEU children with valid neurodevelopment assessments, 382 were ART-exposed and 210 were ZDV-exposed. Adjusted mean Bayley-III scores were similar among ART-exposed vs. ZDV-exposed, with adjusted mean differences (95% confidence interval): Bayley-III Cognitive: -0.3 (-1.4, 0.9); Gross Motor: 0.8 (-0.1, 1.7); Fine Motor: 0.5 (-0.2, 1.3); Expressive Language: 0.7 (-0.3, 1.7); Receptive Language: 0.1 (-0.7, 0.8); and DMC Locomotor: 0.0 (-0.5, 0.6); Fine Motor: 0.3 (-0.3, 0.8); Language: -0.1 (-0.5, 0.4); Personal-Social: 0.2 (-0.7, 1.1). Similarly, when restricted to formula-fed children in one cohort (Tshipidi), there were no differences in adjusted mean scores.

Conclusion: Neurodevelopmental outcomes at 24 months of age were similar in ART-exposed vs. ZDV-exposed HEU children. Maternal ART with breastfeeding does not appear to have an adverse effect on neurodevelopment.
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http://dx.doi.org/10.1097/QAD.0000000000001790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5945299PMC
June 2018

Impact of early antiretroviral therapy eligibility on HIV acquisition: household-level evidence from rural South Africa.

AIDS 2018 03;32(5):635-643

Africa Health Research Institute, KwaZulu-Natal, South Africa.

Objectives: We investigate the effect of immediate antiretroviral therapy (ART) eligibility on HIV incidence among HIV-uninfected household members.

Design: Regression discontinuity study arising from a population-based cohort.

Methods: Household members of patients seeking care at the Hlabisa HIV Treatment and Care Programme in rural KwaZulu-Natal South Africa between January 2007 and August 2011 with CD4 cell counts up to 350 cells/μl were eligible for inclusion if they had at least two HIV tests and were HIV-uninfected at the time the index patient linked to care (N = 4115). Regression discontinuity was used to assess the intention-to-treat effect of immediate versus delayed ART eligibility on HIV incidence among household members. Exploiting the CD4 cell count-based threshold rule for ART initiation (CD4 < 200 cells/μl until August 2011), we used Cox proportional hazards models to compare outcomes for household members of patients who presented for care with CD4 cell counts just above versus just below the ART initiation threshold.

Results: Characteristics of household members of index patients initiating HIV care were balanced between those with an index patient immediately eligible for ART (N = 2489) versus delayed for ART (N = 1626). There were 337 incident HIV infections among household members, corresponding to an HIV incidence of 2.4 infections per 100 person-years (95% confidence interval 2.5-3.1). Immediate eligibility for treatment reduced HIV incidence in households by 47% in our optimal estimate (hazard ratio = 0.53, 95% confidence interval 0.30-0.96), and by 32-60% in alternate specifications of the model.

Conclusion: Immediate eligibility of ART led to substantial reductions in household-level HIV incidence.
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http://dx.doi.org/10.1097/QAD.0000000000001737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832606PMC
March 2018

Simulations for designing and interpreting intervention trials in infectious diseases.

BMC Med 2017 12 29;15(1):223. Epub 2017 Dec 29.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Interventions in infectious diseases can have both direct effects on individuals who receive the intervention as well as indirect effects in the population. In addition, intervention combinations can have complex interactions at the population level, which are often difficult to adequately assess with standard study designs and analytical methods.

Discussion: Herein, we urge the adoption of a new paradigm for the design and interpretation of intervention trials in infectious diseases, particularly with regard to emerging infectious diseases, one that more accurately reflects the dynamics of the transmission process. In an increasingly complex world, simulations can explicitly represent transmission dynamics, which are critical for proper trial design and interpretation. Certain ethical aspects of a trial can also be quantified using simulations. Further, after a trial has been conducted, simulations can be used to explore the possible explanations for the observed effects.

Conclusion: Much is to be gained through a multidisciplinary approach that builds collaborations among experts in infectious disease dynamics, epidemiology, statistical science, economics, simulation methods, and the conduct of clinical trials.
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http://dx.doi.org/10.1186/s12916-017-0985-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747936PMC
December 2017

Using Observational Data to Calibrate Simulation Models.

Med Decis Making 2018 02 15;38(2):212-224. Epub 2017 Nov 15.

Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA (EJM, JMR, GRS, SL, MAH).

Background: Individual-level simulation models are valuable tools for comparing the impact of clinical or public health interventions on population health and cost outcomes over time. However, a key challenge is ensuring that outcome estimates correctly reflect real-world impacts. Calibration to targets obtained from randomized trials may be insufficient if trials do not exist for populations, time periods, or interventions of interest. Observational data can provide a wider range of calibration targets but requires methods to adjust for treatment-confounder feedback. We propose the use of the parametric g-formula to estimate calibration targets and present a case-study to demonstrate its application.

Methods: We used the parametric g-formula applied to data from the HIV-CAUSAL Collaboration to estimate calibration targets for 7-y risks of AIDS and/or death (AIDS/death), as defined by the Center for Disease Control and Prevention under 3 treatment initiation strategies. We compared these targets to projections from the Cost-effectiveness of Preventing AIDS Complications (CEPAC) model for treatment-naïve individuals presenting to care in the following year ranges: 1996 to 1999, 2000 to 2002, or 2003 onwards.

Results: The parametric g-formula estimated a decreased risk of AIDS/death over time and with earlier treatment. The uncalibrated CEPAC model successfully reproduced targets obtained via the g-formula for baseline 1996 to 1999, but over-estimated calibration targets in contemporary populations and failed to reproduce time trends in AIDS/death risk. Calibration to g-formula targets improved CEPAC model fit for contemporary populations.

Conclusion: Individual-level simulation models are developed based on best available information about disease processes in one or more populations of interest, but these processes can change over time or between populations. The parametric g-formula provides a method for using observational data to obtain valid calibration targets and enables updating of simulation model inputs when randomized trials are not available.
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http://dx.doi.org/10.1177/0272989X17738753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771959PMC
February 2018

Neurodevelopment of HIV-Exposed and HIV-Unexposed Uninfected Children at 24 Months.

Pediatrics 2017 Oct 14;140(4). Epub 2017 Sep 14.

Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana;

Background: We sought to determine if HIV-exposed uninfected (HEU) children had worse neurodevelopmental outcomes at 24 months compared with HIV-unexposed uninfected (HUU) children in Botswana.

Methods: HIV-infected and uninfected mothers enrolled in a prospective observational study ("Tshipidi") in Botswana from May 2010 to July 2012. Child neurodevelopment was assessed at 24 months with the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III: cognitive, gross motor, fine motor, expressive language, and receptive language domains) and the Development Milestones Checklist (DMC), a caregiver-completed questionnaire (locomotor, fine motor, language and personal-social domains). We used linear regression models to estimate the association of in-utero HIV exposure with neurodevelopment, adjusting for socioeconomic and maternal health characteristics.

Results: We evaluated 670 children (313 HEU, 357 HUU) with ≥1 valid Bayley-III domain assessed and 723 children (337 HEU, 386 HUU) with a DMC. Among the 337 HEU children with either assessment, 122 (36%) were exposed in utero to maternal 3-drug antiretroviral treatment and 214 (64%) to zidovudine. Almost all HUU children (99.5%) breastfed, compared with only 9% of HEU children. No domain score was significantly lower among HEU children in adjusted analyses. Bayley-III cognitive and DMC personal-social domain scores were significantly higher in HEU children than in HUU children, but differences were small.

Conclusions: HEU children performed equally well on neurodevelopmental assessments at 24 months of age compared with HUU children. Given the global expansion of the HEU population, results suggesting no adverse impact of in-utero HIV and antiretroviral exposure on early neurodevelopment are reassuring.
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http://dx.doi.org/10.1542/peds.2017-0988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5613819PMC
October 2017

A Comparison of Agent-Based Models and the Parametric G-Formula for Causal Inference.

Am J Epidemiol 2017 Jul;186(2):131-142

Decision-making requires choosing from treatments on the basis of correctly estimated outcome distributions under each treatment. In the absence of randomized trials, 2 possible approaches are the parametric g-formula and agent-based models (ABMs). The g-formula has been used exclusively to estimate effects in the population from which data were collected, whereas ABMs are commonly used to estimate effects in multiple populations, necessitating stronger assumptions. Here, we describe potential biases that arise when ABM assumptions do not hold. To do so, we estimated 12-month mortality risk in simulated populations differing in prevalence of an unknown common cause of mortality and a time-varying confounder. The ABM and g-formula correctly estimated mortality and causal effects when all inputs were from the target population. However, whenever any inputs came from another population, the ABM gave biased estimates of mortality-and often of causal effects even when the true effect was null. In the absence of unmeasured confounding and model misspecification, both methods produce valid causal inferences for a given population when all inputs are from that population. However, ABMs may result in bias when extrapolated to populations that differ on the distribution of unmeasured outcome determinants, even when the causal network linking variables is identical.
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http://dx.doi.org/10.1093/aje/kwx091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5860229PMC
July 2017

Zidovudine use in pregnancy and congenital malformations.

AIDS 2017 07;31(12):1733-1743

aDivision of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School bDepartment of Epidemiology cDepartment of Biostatistics, Harvard T.H. Chan School of Public Health dDepartment of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Objective: There is inconsistent evidence that zidovudine use during pregnancy increases overall, cardiac, and male genital malformations.

Design: We conducted a systematic review and meta-analysis of zidovudine use and malformations and, using Bayesian methods, combined it with data from a cohort study of mother-infant pairs in the nationwide Medicaid Analytic eXtract (MAX).

Methods: Using MAX data (2000-2010), we identified pregnant women with HIV treated with antiretroviral therapy (ART). Women with at least one zidovudine dispensing during the first trimester were compared to women receiving ART without zidovudine in the first trimester. Malformation outcomes were defined using diagnosis/procedure codes. To adjust for confounding, we performed 1 : 1 propensity score matching. Bayesian methods require specification of a prior, which we developed in the meta-analysis. Logistic regression models combined MAX data with the prior, estimating odds ratios (ORs) and 95% credible intervals.

Results: Fourteen articles contributed information on overall malformations, seven on cardiac malformations, and five on male genital malformations. In MAX, matching led to a sample of 735 women each in the zidovudine and comparator groups. When comparing first trimester zidovudine use to other ART, the Bayesian procedure yielded OR estimates slightly above the null for overall [OR = 1.11, 95% credible interval (0.80-1.55)] and cardiac [OR = 1.30 (0.63-2.71)] malformations. There were no zidovudine-exposed cases of male genital malformations in MAX, but the meta-analysis yielded elevated OR estimates [OR = 2.57 (1.26-5.24)].

Conclusion: For most malformations, first-trimester zidovudine was not associated with increased risk. The potential increase in male genital malformations was small in absolute terms, and should be evaluated further.
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http://dx.doi.org/10.1097/QAD.0000000000001549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5534355PMC
July 2017

Displacement of sexual partnerships in trials of sexual behavior interventions: A model-based assessment of consequences.

Epidemics 2017 09 2;20:94-101. Epub 2017 Apr 2.

Department of Epidemiology, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA; Center for Communicable Disease Dynamics and Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA.

We investigated the impact of the displacement of sexual activity from adherent recipients of an intervention to others within or outside a trial population on the results from hypothetical trials of different sexual behavior interventions. A short-term model of HIV-prevention interventions that lead to female rejection of male partnership requests showed the impact of displacement expected at the start of a trial. An agent-based model, with sexual mixing and other South African specific demographics, evaluated consequences of displacement for sexual behavior interventions targeting young females in South Africa. This model measured the cumulative incidence among adherent, non-adherent, control and non-enrolled females in a hypothetical trial of HIV prevention. When males made more than one attempt to seek a partnership, interventions reduced short-term HIV infection risk among adherent females, but increased it among non-adherent females as well as controls, non-enrolled (females eligible for the trial but not chosen to participate) and ineligible females (females that did not qualify for the trial due to age). The impact of displacement depends on the intervention and the adherence. In both models, the risk to individuals who are not members of the adherent intervention group will increase with displacement leading to a biased calculation for the effect estimates for the trial. Likewise, intent-to-treat effect estimates become nonlinear functions of the proportion adherent.
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http://dx.doi.org/10.1016/j.epidem.2017.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610917PMC
September 2017

Comparison of dynamic monitoring strategies based on CD4 cell counts in virally suppressed, HIV-positive individuals on combination antiretroviral therapy in high-income countries: a prospective, observational study.

Lancet HIV 2017 06 11;4(6):e251-e259. Epub 2017 Apr 11.

Yale School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare System, West Haven, CT, USA.

Background: Clinical guidelines vary with respect to the optimal monitoring frequency of HIV-positive individuals. We compared dynamic monitoring strategies based on time-varying CD4 cell counts in virologically suppressed HIV-positive individuals.

Methods: In this observational study, we used data from prospective studies of HIV-positive individuals in Europe (France, Greece, the Netherlands, Spain, Switzerland, and the UK) and North and South America (Brazil, Canada, and the USA) in The HIV-CAUSAL Collaboration and The Centers for AIDS Research Network of Integrated Clinical Systems. We compared three monitoring strategies that differ in the threshold used to measure CD4 cell count and HIV RNA viral load every 3-6 months (when below the threshold) or every 9-12 months (when above the threshold). The strategies were defined by the threshold CD4 counts of 200 cells per μL, 350 cells per μL, and 500 cells per μL. Using inverse probability weighting to adjust for baseline and time-varying confounders, we estimated hazard ratios (HRs) of death and of AIDS-defining illness or death, risk ratios of virological failure, and mean differences in CD4 cell count.

Findings: 47 635 individuals initiated an antiretroviral therapy regimen between Jan 1, 2000, and Jan 9, 2015, and met the eligibility criteria for inclusion in our study. During follow-up, CD4 cell count was measured on average every 4·0 months and viral load every 3·8 months. 464 individuals died (107 in threshold 200 strategy, 157 in threshold 350, and 200 in threshold 500) and 1091 had AIDS-defining illnesses or died (267 in threshold 200 strategy, 365 in threshold 350, and 459 in threshold 500). Compared with threshold 500, the mortality HR was 1·05 (95% CI 0·86-1·29) for threshold 200 and 1·02 (0·91·1·14) for threshold 350. Corresponding estimates for death or AIDS-defining illness were 1·08 (0·95-1·22) for threshold 200 and 1·03 (0·96-1·12) for threshold 350. Compared with threshold 500, the 24 month risk ratios of virological failure (viral load more than 200 copies per mL) were 2·01 (1·17-3·43) for threshold 200 and 1·24 (0·89-1·73) for threshold 350, and 24 month mean CD4 cell count differences were 0·4 (-25·5 to 26·3) cells per μL for threshold 200 and -3·5 (-16·0 to 8·9) cells per μL for threshold 350.

Interpretation: Decreasing monitoring to annually when CD4 count is higher than 200 cells per μL compared with higher than 500 cells per μL does not worsen the short-term clinical and immunological outcomes of virally suppressed HIV-positive individuals. However, more frequent virological monitoring might be necessary to reduce the risk of virological failure. Further follow-up studies are needed to establish the long-term safety of these strategies.

Funding: National Institutes of Health.
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http://dx.doi.org/10.1016/S2352-3018(17)30043-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5492888PMC
June 2017
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