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Original Research |

Factors Associated With Lack of Viral Suppression at Delivery Among Highly Active Antiretroviral Therapy–Naive Women With HIV: A Cohort StudyFactors Associated With Lack of Viral Suppression

Ingrid T. Katz, MD, MHS; Erin Leister, MS; Deborah Kacanek, ScD; Michael D. Hughes, PhD; Arlene Bardeguez, MD; Elizabeth Livingston, MD; Alice Stek, MD; David E. Shapiro, PhD; and Ruth Tuomala, MD
[+] Article, Author, and Disclosure Information

From Brigham and Women's Hospital, Massachusetts General Hospital Center for Global Health, Harvard Medical School, and Harvard School of Public Health, Boston, Massachusetts; University of Medicine and Dentistry of New Jersey, Newark, New Jersey; Duke University School of Medicine, Durham, North Carolina; and University of Southern California Keck School of Medicine, Los Angeles, California.

Presented in part at the 19th Conference on Retroviruses and Opportunistic Infections Meeting, Seattle, Washington, 5 to 8 March 2012.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, Harvard Catalyst, or Harvard University and its affiliated acade mic health care centers.

Acknowledgment: The authors thank the women and infants who participated in IMPAACT Protocol 1025.

Grant Support: By the National Institute of Allergy and Infectious Diseases (U01 AI068632); the Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Mental Health (AI068632); and the Statistical and Data Analysis Center at Harvard School of Public Health (National Institute of Allergy and Infectious Diseases cooperative agreement 5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group and 1 U01 AI068616 with the IMPAACT Group). Support of the sites was provided by the National Institute of Allergy and Infectious Diseases and the Eunice Kennedy Shriver National Institute of Child Health and Human Development International and Domestic Pediatric and Maternal HIV Clinical Trials Network (contract N01-DK-9-001/HHSN267200800001C). Dr. Katz received funding through the National Institute of Mental Health (K23MH097667-01), the Harvard University Center for AIDS Research (National Institute of Allergy and Infectious Diseases fund 5P30AI060354-08), the KL2 MeRIT program of Harvard Catalyst | The Harvard Clinical and Translational Science Center (award UL1 RR 025758), and financial contributions from Harvard University and its affiliated academic health care centers.

Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2005.

Reproducible Research Statement:Study protocol: Available from Dr. Tuomala (e-mail, RTuomala@partners.org). Statistical code: Available from Ms. Leister (e-mail, ELeister@sdac.harvard.edu). Data set: Available from Dr. Shapiro (e-mail, Shapiro@sdac.harvard.edu).

Requests for Single Reprints: Ingrid T. Katz, MD, MHS, Division of Women's Health, Brigham and Women's Hospital, 1620 Tremont Street, 3rd Floor, Boston, MA 02120; e-mail, ikatz2@partners.org.

Current Author Addresses: Dr. Katz: Division of Women's Health, Brigham and Women's Hospital, 1620 Tremont Street, 3rd Floor, Boston, MA 02120.

Ms. Leister: Harvard School of Public Health, 651 Huntington Avenue, FXB 619, Boston, MA 02115.

Ms. Kacanek: Harvard School of Public Health, 651 Huntington Avenue, FXB 505, Boston, MA 02115.

Dr. Hughes: Harvard School of Public Health, 655 Huntington Avenue, Building II, Room 439A, Boston, MA 02115.

Dr. Bardeguez: Rutgers, New Jersey Medical School, MSB E-506,185 South Orange Avenue, Newark, NJ 07103.

Dr. Livingston: Duke University Medical Center, Box 3967, Durham, NC 27710.

Dr. Stek: University of Southern California, 1240 North Mission Road, Los Angeles, CA 90033.

Dr. Shapiro: Harvard School of Public Health, 651 Huntington Avenue, FXB 643B, Boston, MA 02115.

Dr. Tuomala: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.

Author Contributions: Conception and design: I.T. Katz, D. Kacanek, M.D. Hughes, A. Bardeguez, E. Livingston, A. Stek, D.E. Shapiro, R. Tuomala.

Analysis and interpretation of the data: I.T. Katz, E. Leister, D. Kacanek, M.D. Hughes, A. Bardeguez, E. Livingston, A. Stek, D.E. Shapiro, R. Tuomala.

Drafting of the article: I.T. Katz, E. Leister, D. Kacanek, E. Livingston, R. Tuomala.

Critical revision of the article for important intellectual content: D. Kacanek, M.D. Hughes, A. Bardeguez, E. Livingston, D.E. Shapiro, R. Tuomala.

Final approval of the article: I.T. Katz, E. Leister, D. Kacanek, M.D. Hughes, A. Bardeguez, E. Livingston, A. Stek, D.E. Shapiro, R. Tuomala.

Provision of study materials or patients: E. Livingston, A. Stek, R. Tuomala.

Statistical expertise: E. Leister, D. Kacanek, M.D. Hughes, D.E. Shapiro.

Obtaining of funding: D.E. Shapiro.

Collection and assembly of data: E. Livingston, A. Stek, R. Tuomala.


Ann Intern Med. 2015;162(2):90-99. doi:10.7326/M13-2005
Text Size: A A A

Background: A high delivery maternal plasma HIV-1 RNA level (viral load [VL]) is a risk factor for mother-to-child transmission and poor maternal health.

Objective: To identify factors associated with detectable VL at delivery despite initiation of highly active antiretroviral therapy (HAART) during pregnancy.

Design: Multicenter observational study. (ClinicalTrial.gov: NCT00028145)

Setting: 67 U.S. AIDS clinical research sites.

Patients: Pregnant women with HIV who initiated HAART during pregnancy.

Measurements: Descriptive summaries and associations among sociodemographic, HIV disease, and treatment characteristics; pregnancy-related risk factors; and detectable VL (>400 copies/mL) at delivery.

Results: Between 2002 and 2011, 671 women met inclusion criteria and 13.1% had detectable VL at delivery. Factors associated with detectable VL included multiparity (16.4% vs. 8.0% nulliparity; P = 0.002), black ethnicity (17.6% vs. 6.6% Hispanic and 6.6% white; P < 0.001), 11th grade education or less (17.6% vs. 12.1% had a high school diploma; P = 0.013), initiation of HAART in the third trimester (23.9% vs. 12.3% and 8.6% in the second and trimesters, respectively; P = 0.003), having an HIV diagnosis before the current pregnancy (16.1% vs. 11.0% during the current pregnancy; P = 0.051), and having the first prenatal visit in the third trimester (33.3% vs. 14.3% and 10.5% in the second and third trimesters, respectively; P = 0.002). Women who had treatment interruptions or reported poor medication adherence were more likely to have detectable VL at delivery.

Limitation: Data on many covariates were incomplete because women entered the study at varying times during pregnancy.

Conclusion: A total of 13.1% of women who initiated HAART during pregnancy had detectable VL at delivery. The timing of HAART initiation and prenatal care, along with medication adherence during pregnancy, were associated with detectable VL at delivery. Social factors, including ethnicity and education, may help identify women who could benefit from focused efforts to promote early HAART initiation and adherence.

Primary Funding Source: U.S. Department of Health and Human Services.

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Comments

Submit a Comment/Letter
Factors associated with lack of viral suppression at delivery
Posted on February 13, 2015
Anna Calzi, Francesca Bisio, Daniele Roberto Giacobbe
Clinica Malattie Infettive (DISSAL) - IRCCS San Martino-IST, Università di Genova
Conflict of Interest: None Declared
To the Editor,
We read with interest the recent study conducted by Katz and colleagues across several centers in the United States (1). The authors assessed the predictors of detectable HIV viral load (VL) at delivery among treatment-naïve women initiating highly active antiretroviral therapy (HAART) during pregnancy. One of the factors associated with lack of viral suppression at delivery was a high pretreatment VL, especially among those women who initiated HAART in the third trimester of pregnancy (1). We compared these results, obtained in the Western hemisphere, with our experience in a resource-limited country (2), where an even higher number of treatment-naive women initiate HAART late during pregnancy, thus possibly accounting for very high rates of detectable VL at delivery. From 2009 to 2012, we enrolled 802 HIV-positive pregnant women, of whom 471 initiated HAART for the first time during pregnancy (58.7%). Among them, 187/471 started HAART in the third trimester (39.7%). VL at the time of HAART initiation was measured in 251/471 (53.3%) of our treatment-naïve women, being ≥ 10 000 cp/mL in as many as 160 of them (63.7%). The rate of treatment-naïve women having a detectable VL at delivery was as high as 35.8% (82/229, missing = 242). In a univariate analysis, we found that a detectable VL at delivery was predicted both by a pretreatment VL > 10 000 cp/mL (odds ratio [OR] 4.3, 95% confidence intervals [CI] 2.1-8.7, p < 0.001) and by HAART initiation in the third trimester of pregnancy (OR 2.4, 95% CI 1.4-4.3, p = 0.002). Although our analysis was not adjusted for confounders such as type of HAART and adherence to treatment, these factors are unlikely to be able to considerably reduce the number of women with a detectable VL at delivery when high rates of both pretreatment VL and late HAART initiation are considered. In addition, these impressive rates might also account for a high proportion of infants in resource-limited countries that are exposed to high VL for at least the first six months of pregnancy, thus increasing both the risk of acquiring HIV during pregnancy and that of death among HIV-exposed, uninfected children (3). We have to intervene earlier.

References
1. Katz IT, Leister E, Kacanek D, Hughes MD, Bardeguez A, Livingston E, Stek A, et al. Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study. Ann Intern Med. 2015;162:90-99.
2. Bisio F, Masini G, Blasi Vacca E, Calzi A, Cardinale F, Bruzzone B, et al. Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo. J Antimicrob Chemother. 2013;68:1862–1871.
3. Kuhn L, Kasonde P, Sinkala M, Kankasa C, Semrau K, Scott N, et al. Does severity of HIV disease in HIV-infected mothers affect mortality and morbidity among their uninfected infants? Clin Infect Dis. 2005 Dec 1;41(11):1654-61.
Author's Response
Posted on March 27, 2015
Ingrid T. Katz, MD, MHS, David E. Shapiro, PhD, Ruth Tuomala, MD
Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Schoool of Public Health
Conflict of Interest: None Declared
We appreciate the comments provided by Calzi et al, in response to our recent manuscript focused on predictors of detectable HIV viral load (VL) at delivery among treatment-naïve women initiating highly active antiretroviral therapy (HAART) during pregnancy across several centers in the United States (1). We agree that early delivery of HAART to pregnant women in low and middle-income countries (LMICs) is an essential component in prevention of mother-to-child transmission (PMTCT) of HIV, which offers concurrent benefits for maternal health. Sub-Saharan Africa, in particular, needs to remain the focus of this effort, given 92% of pregnant women living with HIV reside in this region (2). The expansion of HAART in sub-Saharan Africa, as supported by programs such as the President’s Emergency Fund for AIDS Relief (PEPFAR) in conjunction with partner nations, has provided impressive gains in expanding treatment availability and PMTCT (3). Despite this, countries with a high prevalence of HIV, such as South Africa, had 40,000 new HIV pediatric infections in 2010 (3).
For HIV-infected women who do not present early during pregnancy, we support the incorporation of antiretrovirals, including any new agents which rapidly lower viral load, into HAART regimens during pregnancy. Research in LMICs is essential, and we are pleased to see the letter by Calzi et al. It is important to note that the high rates of detectable VL shown here need to be interpreted with caution, because about half of the women in this study did not have VL measurements (47% at the time of HAART initiation and 51% at delivery). If women perceived to be at higher risk were more likely to have VL measured, the estimated rates of detectable VL at HAART initiation and at delivery may be higher than the rates in the whole study population. No analyses were presented to assess the impact of missing VL data on the conclusions. In contrast, in our paper, 29% had missing pre-HAART VL and, by design, all of the women included had a VL at delivery. We performed multiple imputation analyses to assess the impact of missing pre-HAART VL data on our results. Ultimately, our hope is that ongoing research in this area can inform future clinical and programmatic efforts to eliminate transmission of HIV to newborns, and provide mothers with a healthy and safe pregnancy.


References
1. Katz IT, Leister E, Kacanek D, Hughes MD, Bardeguez A, Livingston E, Stek A, et al. Factors associated with lack of viral suppression at delivery among highly active antiretroviral therapy-naive women with HIV: a cohort study. Ann Intern Med. 2015;162:90-99.
2. Joint United Nations Programme on HIV/AIDS. UNAIDS Report on Sub-Saharan Africa. 2012. Geneva: http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/2012_FS_regional_ssa_en.pdf (Accessed 23 March, 2015)
3. Katz IT, Bassett IV, Wright AA. PEPFAR in transition--implications for HIV care in South Africa. N Engl J Med. 2013 Oct 10;369(15):1385-7
4. Black S, Zulliger R, Myer L, Marcus R, Jeneker S, Taliep R, Pienaar D, Wood R, Bekker LG. Safety, feasibility and efficacy of a rapid ART initiation in pregnancy pilot programme in Cape Town, South Africa. S Afr Med J. 2013 Jun 27;103(8):557-62.



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