In the regression analysis combining early and late discontinuers into a single group, continuers had a greater decrease in log D-dimer postpartum than discontinuers (estimated change: −1.51 versus −1.13, P = 0.002) (Fig. 3).
Of the 77 women with viral load results available at 6 weeks postpartum, 49% had viral loads >400 copies per milliliter [continuers: 30% (n = 13), discontinuers: 74% (n = 25), P < 0.001]. No significant differences were observed in biomarker trajectories for hsCRP and IL-6 by viral load. Women with viral loads ≤400 copies per milliliter had a greater decrease in log D-dimer postpartum compared with those with viral loads >400 copies per milliliter (estimated change: −1.61 versus −1.20, P = 0.005) (Fig. 3). There were differences in D-dimer by age and ethnicity. Women in the highest age quartile (32 years and older) had a higher log D-dimer at all 3 time points compared with younger women (difference = 0.25, P = 0.02). Hispanic women had a greater decrease in log D-dimer postpartum than non-Hispanic women (estimated change: −1.60 versus −1.19, P = 0.002).
Biomarkers and Pregnancy or Delivery Complications
Seventeen women (13% of the study population) had 20 pregnancy or delivery complications. One woman was excluded from this analysis because her first event occurred before her first biomarker measurement. The median time from biomarker collection to complication was 46 days (IQR: 30–75). Women who experienced at least 1 complication had higher levels of IL-6 at all 3 time points and a greater decrease in estimated log IL-6 postpartum (−1.53 versus −0.80, P = 0.007) compared with women who had no complications. Women who experienced at least 1 complication also had a higher log hsCRP at each time point compared with those with no complications and a higher log D-dimer at each time point, although these differences were not statistically significant (difference = 0.37, P = 0.09, and difference = 0.14, P = 0.36, respectively) (Fig. 4).
Biomarkers and Complications up to 6 Months Postpartum
Sixteen women had 24 incident postpartum clinical events, but no World Health Organization stage 4 events, significant non–AIDS-defining events, or deaths. No significant increase in the risk of events was observed for ART discontinuers compared with continuers. The most common clinical diagnoses were cervical dysplasia (10 events), bronchitis (4), and pneumonia (3). No significant association was observed between biomarker levels in the third trimester or at delivery and the incidence of postpartum clinical events.
Does ART Mediate Markers of Inflammation and Coagulation in Postpartum Women?
In this cohort of HIV-infected women from the United States and Puerto Rico with high CD4 counts, postpartum biomarkers markedly declined among all women, regardless of ART status. Unlike biomarker results from TI studies of nonpregnant women and men with HIV infection, the primary drivers of biomarker levels among our population were pregnancy and delivery. The contribution of inflammation from HIV infection versus pregnancy in our study is unclear because no HIV-uninfected subjects were included. Lack of virological suppression was associated with higher D-dimer levels, supporting the important role of virological suppression in the inflammatory milieu of HIV-infected individuals.
Studies of HIV-uninfected pregnant women show that uncomplicated pregnancy and delivery are characterized by a maternal inflammatory response.12,13 Elevations in D-dimer also have been described during normal pregnancy and uncomplicated delivery.14,15 Mikyas et al16 evaluated serum neopterin, beta-2-microglobulin, tumor necrosis factor alpha, and cell surface activation markers HLA-DR and CD38 on CD8 T cells in 99 HIV-infected women and 46 HIV-uninfected women during pregnancy and up to 6 months postpartum. Evidence of inflammation and cellular immune activation was found in all women at later stages of pregnancy, and the increases in HIV-infected women paralleled those seen in HIV-uninfected women, but at more marked levels. Truong et al17 also found increased levels of serum activation markers in HIV-infected and -uninfected pregnant women, with a rise postpartum despite various antiretrovirals, although postpartum ART blunted the effect. Taken together, these studies suggest that HIV-infected women experience an inflammatory response beyond that seen in healthy women with uncomplicated pregnancies. Our study lends support to the hypothesis that ART attenuates postpartum inflammation, with continuation of treatment associated with more rapid declines in postpartum D-dimer levels.
Association of Biomarkers With Subsequent Late Pregnancy and Delivery Complications Among HIV-Infected Women
CRP levels are elevated in healthy HIV-uninfected women with pre-eclampsia,18 rupture of membranes with chorioamnionitis,19 and preterm delivery,20 and elevated CRP at 9–13 weeks of gestation has been shown to be associated with the subsequent development of gestational diabetes.21 We found an association with IL-6 and pregnancy and delivery complications and a trend toward significance for hsCRP and D-dimer. If confirmed in larger studies, biomarker measurements could be useful for counseling when added to other known risks for adverse pregnancy outcomes (prior history of complications, smoking, hypertension, PI use) to encourage behavior change for modifiable risk factors and inform the need for closer follow-up for those at highest risk of complications.
Biomarkers in Pregnant and Postpartum Women With HIV: Lack of Association With Clinical Events up to 6 Months Postpartum
Controversy exists over whether pregnancy modifies HIV disease in regard to immunologic, virological, and/or clinical outcomes. CD4% seems to remain stable during pregnancy in HIV-infected women.22–25 Viral loads in women without primary acute infection have also been shown to remain stable during pregnancy in the absence of ART.23 Additionally, HIV-infected pregnant women do not seem to have an increased risk of virological failure on ART compared with nonpregnant women, regardless of whether they conceive on ART or initiate after pregnancy.26,27 Therefore, although existing data do not suggest that pregnancy itself accelerates HIV disease progression or that pregnancy increases the risk for virological failure, the potential contribution of a start–stop event or TI to HIV disease progression remains unclear. A recent study evaluated 206 ART-naïve pregnant women with CD4 counts >350 cells per cubic millimeter. No difference in CD4 counts and viral loads was observed over 1 year postpartum regardless of whether women continued or discontinued postpartum antiretrovirals, but more marked CD8+ T-cell immune activation (defined by CD38+ and DR+) was seen among the 59 women who discontinued antiretrovirals.28 In this study, the majority of women discontinued zidovudine monotherapy, and only 18 discontinued 3-drug ART postpartum, limiting the power to detect differences among ART continuers and discontinuers, and reducing the generalizability of the results.
Data on poor outcomes after TI have been obtained from men and nonpregnant women in studies across the globe, including 2 studies from Africa, Trivacan and Development of Antiretroviral Therapy in Africa, both stopped early due to an increased rate of morbidity and/or disease progression.3,5 SMART involved randomization of more than 5000 patients from 33 countries with baseline CD4 counts >350 cells per cubic millimeter (both ART-naïve and on ART), to take therapy continuously or interrupt therapy, with reinitiation for a CD4 decline to <250 cells per cubic millimeter. This trial was also stopped early for a higher risk of serious AIDS-related and non-AIDS events in the TI arm (relative risk: 5.80 and 1.63, respectively).4 We observed high peak median levels of all 3 biomarkers at delivery, over 4 times the latest median hsCRP level (24.0 versus 5.26 mg/L) observed before death among those who died in the SMART study, and over 3 times the latest D-dimer level (2.3 versus 0.70 µg/mL) observed before death in SMART. Caution must be used in generalizing data from these TI studies to pregnant and postpartum women who are younger and healthier with higher CD4 nadir and a shorter duration of ART exposure. IMPAACT’s Promoting Maternal and Infant Survival Everywhere (PROMISE 1077HS) study is an ongoing trial in which women who do not meet criteria for long-term ART (by country-specific guidelines) are randomized to continue or discontinue ART postpartum. Pending data from this trial, information is needed that can help to identify women with high CD4 counts who would most benefit from ART continuation postpartum.
Study Limitations and Weaknesses
Our study has several important limitations. Because the study population did not include HIV-uninfected women, we cannot comment on the contribution of HIV to absolute elevations in biomarkers. Approximately 70% of P1025 participants were excluded from our analysis due to missing samples, and although we did not detect differences other than ART regimen, we cannot exclude the possibility of other unmeasured differences between participants who did versus did not have plasma stored during the study. Additionally, of those women included, we do not have complete data on reasons for continuation versus discontinuation. Therefore, it is possible that women who continued ART in our sample may have been different, either clinically (ie, sicker) or in other ways (providers, insurance, social issues) than those who discontinued. Early in our analysis, we recognized that a subset of ART continuers were not virologically suppressed at 6 weeks postpartum and therefore evaluated groups using viral load data. This analysis was limited to the 77 women who had viral load data and may have been underpowered to detect differences in IL-6 and hsCRP and biased by the large amount of data missing from the analysis. Finally, preconception biomarker data and long-term data on biomarkers and clinical events are important to our understanding of inflammation in women during pregnancy and postpartum but were not collected in our study.
In contrast to results from TI studies in men and nonpregnant women, both ART continuers and ART discontinuers in this population of women with high nadir CD4 counts had significant decreases in the levels of D-dimer, hsCRP, and IL-6 postpartum. We did find a significantly more rapid decline in D-dimer levels in postpartum ART continuers compared with discontinuers and among those in whom viral loads were ≤400 copies per milliliter at 6 weeks postpartum. We found a significant association between IL-6 and subsequent pregnancy and delivery complications, but no significant associations between biomarker levels and AIDS and non–AIDS-defining clinical events up to 6 months postpartum. Future studies should evaluate preconception biomarker levels and incorporate longer postpartum follow-up to better characterize associations between biomarkers, ART status, and clinical events. Questions about use of ART in postpartum women must be answered through direct, carefully planned, randomized trials that inform clinical decision making for this unique subset of the HIV-infected population.
Members of the NWCS 101-P1025 Protocol Team include the following: R. M. Hoffman, E. Leister, D. Kacanek, D. E. Shapiro, J. S. Read, Y. Bryson, and J. S. Currier.
P1025 Team Acknowledgement: G. B. Scott, MD, University of Miami School of Medicine, Miami, FL; R. Tuomala, MD, Brigham and Women’s Hospital, Boston, MA; E. Smith, MD, National Institute of Allergy and Infectious Diseases Division of AIDS, Pediatric Medicine Branch, Bethesda, MD; H. Watts, MD, National Institute of Child Health and Human Development, Maternal and Pediatric Infectious Disease Branch, Bethesda, MD; K. M. Oden, MHS, International Maternal Pediatric Adolescent AIDS Clinical Trials Group, Silver Spring, MD; Y. Huo, MS, Harvard School of Public Health, Boston, MA; K. Patel, DSc, MPH, Harvard School of Public Health, Boston, MA; E. A. Barr, CPNP, CNM, MSN, University of Colorado Denver, The Children’s Hospital, Denver, CL; A. Bardeguez, MD, MPH, FACOG, University of Medicine & Dentistry of New Jersey, Newark, NJ; S. K. Burchett, MD, MSc, Harvard Medical School, Boston, MA; E. Livingston, MD, Duke University Medical Center, Durham, NC; A. M. Stek, MD, Keck School of Medicine, University of Southern California, Los Angeles, CA; M. T. Basar, BS, Frontier Science & Technology Research Foundation, Inc, Amherst, NY; A. Hernandez, MA, Frontier Science & Technology Research Foundation, Inc, Amherst, NY; A. Jennings, BS, Frontier Science & Technology Research Foundation, Inc, Amherst, NY; T. R. Cressey, PhD, BSc, Program for HIV Prevention & Treatment, Chang Mai, Thailand; and J. Bryant, MPA, Westat, Rockville, MD.
Participating sites and site personnel include the following: 5041 Children's Hospital of Michigan NICHD CRS (T. B. Jones, MD; E. Brown, RN; and N. Woods, RD); 5052 University of Colorado Denver NICHD CRS (A. Katai, MHA; T. Kennedy, FNP-BC; K. Kinzie, MSN, FNP-BC; J. Wallace, MSW; and CTSI Grant Number UL1 TR000154); 5031 San Juan City Hospital PR NICHD CRS (R. Diaz-Velasco, MD, FACOG, AAHIVS; M. Acevedo-Flores, MD, MT; E. Pérez-Hernández, BS, MEd, MA, MPH; and A. Rodriguez-Mimoso, MD, FACOG); 5048 USC LA NICHD CRS (A. Stek, MD; F. Kramer, MD; L. Spencer, MD; and J. Homans, MD); 4601 UCSD Maternal, Child, and Adolescent HIV CRS (A. Hull, MD; M. Caffery, RN, MSN; J. M.Manning RN, BSN; and S. A. Spector, MD); 4101 Columbia IMPAACT CRS; 4201 University of Miami Pediatric Perinatal HIV/AIDS CRS (G. B. Scott, MD; C. D. Mitchell, MD; S. Yasin, MD; and Safia Khan, MD); 5083 Rush University Cook County Hospital Chicago NICHD CRS (M. Aziz, MD; L. Logan, MD; J. Schmidt, MD; and H. Cejtin, MD); 5096 University of Alabama Birmingham NICHD CRS (M. Crain, MPH, MD; S. Robbins, BA; M. Parks, CRNP; and Y. Gamble Duke, MA); 6901 Bronx-Lebanon Hosp. IMPAACT CRS (M. Purswani, MD; S. Hagmann, MD, MSc, FAAP; J. Gutierrez, MD; and M. Vachon, LMSW, MPH); 5012 NYU School of Medicine NICHD CRS (W. Borkowsky, MD; M. Minter, RN; A. Kaul, MD; and N. Deygoo, MS); 3801 Texas Children's Hospital CRS (S. Buschur, RN, NMV; K. Pitts, CPNP; C. McMullen-Jackson, BSN, RN; and T. Aldape, LMSW; grant number AI069441); 4001 Chicago Children's CRS (Donna McGregor, RN); 5009 Children's Hospital of Boston NICHD CRS (S. K. Burchett, MD, MS; R. Tuomala, MD; A. Buck, RN; and C. Kneut, RN, CPNP); 5018 USF - Tampa NICHD CRS (P. Emmanuel, MD; K. Bruder, MD; and G. Lewis, RN); 6501 St Jude/UTHSC CRS (K. Knapp, MD; E. Thorpe, MD; N Sublette, FNP, PhD; and P. Finnie, MSN); 2802 NJ Medical School CRS (A. D. Bardeguez, MD, MPH; C. Calilap-Bernardo, RN; and L. Bettica, RN); 3601 UCLA-Los Angeles/Brazil AIDS Consortium CRS (J. G. Deville, MD; K. Nielsen-Saines, MD; N. Falgout, RN; and M. Carter, RN); 4005 Mt Sinai Hospital Med Center, Women's & Children's HIV Program (B. Wolfe, APN; and M. Hartrich, MPH); 5017 Seattle Children's Hospital CRS; 5023 Washington Hospital Center NICHD CRS (S. Zeichner, MD, PhD; S. R. Parker, MD; P. Tanjutco, MD; and V. Emmanuel, BA); 5028 University of Illinois College of Medicine at Chicago, Department of Pediatrics (K. Rich, MD; K. Hayani, MD; and J. Camacho, RN); 5051 University of Florida College of Medicine, Jacksonville (M. Rathore, MD; A. Mirza, MD; N. Maraqa, MD; and K Thoma, MA, CCRP); 5094 University of Maryland Baltimore NICHD CRS (D. Watson, MD; and C. Hilyard); 6601 University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (I. L. Febo, MD; V. Tamayo, MD; R. Santos, RN, MPH; and M. Cruz-Rodriguez); 5003 Metropolitan Hospital NICHD CRS; 5013 Jacobi Medical Center Bronx NICHD CRS (S. Gross, MD; M. Moore, MD; and C. Caines, RN); 5038 Yale University School of Medicine; 5045 Harbor UCLA Medical Center NICHD CRS (M. Keller, MD; S. Wettgen, RN, PNP; J. Hayes, RN; and Y. Gonzalez, RN); 5095 Tulane University New Orleans NICHD CRS (Y. Luster, RN; R. Maupin, MD; C. Dola, MD; and M. Silio, MD); 6701 The Children's Hosp. of Philadelphia IMPAACT CRS (S. D. Douglas, MD; R. M. Rutstein, MD; and C. A. Vincent, CRNP, MSN).
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Keywords:© 2013 by Lippincott Williams & Wilkins
HIV/AIDS; pregnancy and postpartum; inflammation; antiretroviral therapy