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. Author manuscript; available in PMC: 2015 Jul 20.
Published in final edited form as: Ann Intern Med. 2015 Jan 20;162(2):90–99. doi: 10.7326/M13-2005

Factors Associated with Lack of Viral Suppression at Delivery among HAART-Naïve HIV-Positive Women in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) P1025 Study

Ingrid T Katz a,b,c,*, Erin Leister d, Deborah Kacanek d, Michael D Hughes d, Arlene Bardeguez e, Elizabeth Livingston f, Alice Stek g, David E Shapiro d, Ruth Tuomala a,c
PMCID: PMC4299931  NIHMSID: NIHMS630717  PMID: 25599347

Abstract

Background

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.

Setting

67 US AIDS clinical research sites.

Patients

HIV-1-positive pregnant women who initiated HAART during pregnancy.

Measurements

Descriptive summaries and associations between socio-demographic, HIV disease, treatment and pregnancy-related risk factors and detectable VL (>400copies/mL) at delivery.

Results

Between October 2002 and December 2011, 671 women met inclusion criteria and 13% had detectable VL at delivery. Factors associated with detectable VL included multiparity (16.4% vs 8% nulliparous, p=0.002), black non-Hispanic ethnicity (17.6% vs 6.6% Hispanic and 6.6% white/non-Hispanic, p<0.001), 11th grade or less education (17.6% vs.12.1% high school graduate and 6.7% some college or higher, p=0.013), and initiation of HAART in third trimester (23.9% vs 12.3% second and 8.6% first, p=0.002), timing of HIV diagnosis prior to current pregnancy (16.1% vs 11% during current pregnancy, p=0.051), and timing of first prenatal visit in 3rd trimester (33.3% vs 14.3% second and 10.5% first, p=0.002). Women who experienced treatment interruptions or reported poor medication adherence during pregnancy were more likely to have detectable VL at delivery than women with no interruptions or who reported better adherence.

Limitations

Women entered the study at varying times during pregnancy and for this and other reasons there was incomplete data on many covariates.

Conclusions

In this large U.S.-based cohort of HIV-1 positive women, 13% 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 appear to be modifiable factors associated with detectable VL at delivery. Social factors such as Black/non-Hispanic ethnicity and less than high school education may help to identify women at highest risk who may benefit from focused efforts to promote early treatment initiation and adherence to HAART.

Clinical Trial Registration Number

NCT00028145

Keywords: Antiretroviral therapy, pregnancy, maternal to child transmission, HIV, women

INTRODUCTION

The Centers for Disease Control and Prevention (CDC) estimates that 6,500 HIV-positive women give birth annually in the U.S. (1). High maternal plasma HIV-1 RNA level (viral load, VL) is a major risk factor for mother-to-child transmission (MTCT) (2–6). Use of Highly Active Antiretroviral Therapy (HAART) to suppress viral replication has become a mainstay in the management of HIV-positive pregnant women in developed nations, reducing MTCT rates at delivery to 1–2% (7–10).

Despite the widespread use of HAART in the U.S., some women still have detectable VL at delivery; every birth of an HIV-infected infant represents a missed prevention opportunity (11). Viral suppression reduces MTCT risk and confers important benefits to maternal health both during and after pregnancy (12, 13). Factors associated with detectable VL (VL >400 copies/mL) at delivery include advanced HIV disease, late initiation of HAART, and inability to adhere to treatment (14–16).

Results are mixed regarding the role of different antiretroviral (ARV) regimens. While one previous report showed virologic response to vary by regimen type (17), a large observational study found no difference in response by ARV regimen (18). A randomized trial of women with CD4+ ≥200 cells/μL in Botswana comparing the impact of a nucleoside reverse-transcriptase inhibitor [NRTI]-based regimen to a boosted protease-inhibitor [PI]-based regimen on VL at delivery observed high rates of virologic suppression at delivery and no difference between regimens (19).

The objective of this study was to identify risk factors associated with detectable VL at delivery among women who initiated HAART for the first time during pregnancy.

METHODS

Design

IMPAACT P1025 is a multicenter observational study in the U.S. (including Puerto Rico) designed to assess maternal and infant safety, and effectiveness of interventions prescribed for prevention of mother-to-child transmission (PMTCT) and women’s health. Enrollment began in October 2002. HIV-positive women 13 years of age and older could enroll between 8 weeks gestation and 14 days after delivery and again for subsequent pregnancies. Additional details of P1025 study procedures have been published (20). Institutional review boards approved the protocol at all 67 clinical sites, and written informed consent was obtained from those enrolled.

Eligibility

The study population eligible for this analysis included women who enrolled in P1025 for the first time prior to delivery, with an estimated date of confinement (EDC) on or before December 31, 2011, who had available VL data between 14 days before and 7 days after delivery, were ARV-naive prior to pregnancy, and initiated HAART during the index pregnancy. HAART was defined as a regimen of ≥3 antiretroviral drugs, including two NRTIs combined with either: 1) a non-nucleoside reverse transcriptase inhibitor (NNRTI); 2) an unboosted (without ritonavir) PI; 3) a boosted (with ritonavir) PI; or 4) a third NRTI.

Variable Selection

Analysis variable selection was driven by clinical hypotheses, using covariates known at baseline and others shown to be relevant in prior studies. The outcome of interest was detectable VL at delivery, defined as VL >400 copies/mL, the standard assay limit of quantification prior to 2008. Baseline characteristics were assessed at the time HAART was initiated in pregnancy and characteristics of antiretroviral management and adherence assessed through the remainder of the pregnancy.

Baseline characteristics included maternal age, race/ethnicity, and highest education level attained; obstetric information, including parity and timing of first prenatal visit; HIV and treatment characteristics, including trimester of HAART initiation, first HAART regimen used in pregnancy, timing of HIV diagnosis, CDC clinical classification (21), and pre-treatment CD4+ count and VL measures.

Using ARV regimen information collected via chart abstraction, we calculated the number of and reasons for regimen changes and medication interruptions that occurred during pregnancy. We did not consider a formulation change, or IV Zidovudine at time of delivery to be a regimen change. A medication interruption was defined as >1 day interval between a regimen stop date and subsequent regimen start date. Adherence to HAART was self-reported at each study visit using an interviewer-administered questionnaire, which included questions about the current regimen, the number of doses missed for each antiretroviral of the regimen over the 3 days prior to the study visit, and a multi-choice question regarding the last time a dose was missed (22). We selected the interviews completed closest to delivery for this analysis.

Statistical Analyses

We summarized and compared the distribution of the covariates of interest by trimester of HAART initiation, and compared the proportion with detectable VL at delivery across levels of each covariate, using Chi-square tests. We explored associations between covariates and VL at delivery using logistic regression models. Many covariates were closely related and we selected one covariate from each group of related covariates (maternal age and parity; regimen composition and calendar year; and timing of first prenatal visit, HIV diagnosis and HAART initiation) for inclusion in multivariable logistic regression models.

We used multiple imputation to account for the fact that pretreatment VL data were not available for 29% of women, due to P1025’s observational study design. Thirty imputations were used and the imputation model included all covariates from our final model, plus VL at delivery. Data were imputed using Proc MI under the assumption that missing pretreatment VL was missing at random (MAR), and final estimates were found using Proc MIANALYZE. Predicted probabilities, evaluated at the mean value of all other covariates in the model, were estimated from this model and reported as adjusted probabilities. To assess the sensitivity of our results to the multiple imputations, we also fit models on the subset of women with complete pretreatment VL data. We explored results by pre-treatment VL and timing of HAART initiation since we expected both factors would be strongly related to VL at delivery and to one another. Due to concerns that self-reported adherence data were missing non-randomly, we did not include adherence in our multivariable models and instead explored the association between adherence and VL at delivery more descriptively in women who had complete adherence data available. We considered a two-sided p-value <0.05 statistically significant and conducted all analyses with SAS version 9.2 software (SAS Institute Inc, Cary, North Carolina).

RESULTS

Of the 2294 women enrolled in P1025 with an EDC between 10/2002 and 12/2011, 1013 (44.2%) had not used ARVs prior to pregnancy. Of these, 15 women not on HAART during pregnancy, 186 who enrolled at or after delivery, and 141 with no delivery VL data were excluded, leaving 671 women eligible for this analysis. Women without delivery VL data were more likely to be black than women included in the analysis. The median number of participants per site was 6.5 (Q1–Q3: 4.0–14.0; range 1–63).

Table 1 describes baseline socio-demographic, HIV disease, and treatment characteristics of the cohort, by timing of HAART initiation. Of women with available data, most (88.1%) had VL >400 copies/mL prior to HAART initiation; 35.0% had VL between 10,000 – < 100,000 copies/mL, and 7.3% had VL ≥100,000 copies/mL. About half (52.6%) received a boosted PI-based regimen (79.3% received lopinavir/ritonavir and most of the remainder received atazanavir/ritonavir), 23.7% received an unboosted PI-based regimen (95.0% containing nelfinavir), 7.3% received an NNRTI-based regimen (85.7% containing nevirapine, and 14.3% efavirenz), and 16.4% received a triple NRTI-based regimen (majority with abacavir) as their initial regimen during pregnancy. Women who initiated HAART in the 3rd trimester were significantly more likely to be black, have started prenatal care and enrolled in P1025 later, been diagnosed with HIV more recently, and have a lower pre-treatment VL than those initiating HAART earlier in pregnancy. Multiparous women were older than nulliparous women (median age 28.8 vs 23.5, p<0.001) and those with more recent EDC (2008–2011) were more likely to have initiated use of boosted PI regimens (>70.9% vs <37.7% in years prior, p<0.001).

Table 1.

Baseline characteristics of HAART1-naïve women in P1025 from 2002–2011

By trimester of HAART initiation
Sociodemographic Characteristics Overall
N=671		 1st
N=128		 2nd
N=455		 3rd
N=88		 P-value2
Age (years)
 13–19 53 (7.9%) 10 (7.8%) 31 (6.8%) 12 (13.6%) 0.266
 20–34 540 (80.5%) 101 (78.9%) 373 (82.0%) 66 (75.0%)
 35+ 78 (11.6%) 17 (13.3%) 51 (11.2%) 10 (11.4%)
Race/Ethnicity
 Black Non-Hispanic 397 (59.2%) 66 (51.6%) 270 (59.3%) 61 (69.3%) 0.032
 Hispanic 198 (29.5%) 49 (38.3%) 127 (27.9%) 22 (25.0%)
 White Non-Hispanic/Other3 76 (11.3%) 13 (10.2%) 58 (12.7%) 5 (5.7%)
Highest level of education
 11th grade or less 239 (35.6%) 58 (45.3%) 148 (32.5%) 33 (37.5%) 0.041
 High school graduate/equivalent 313 (46.6%) 50 (39.1%) 218 (47.9%) 45 (51.1%)
 Some college 119 (17.7%) 20 (15.6%) 89 (19.6%) 10 (11.4%)
Parity
 Multiparous 409 (61.0%) 77 (60.2%) 284 (62.4%) 48 (54.5%) 0.38
 Nulliparous 262 (39.0%) 51 (39.8%) 171 (37.6%) 40 (45.5%)
Timing of first prenatal visit
 1st trimester 381 (56.8%) 117 (91.4%) 249 (54.7%) 15 (17.0%) <.001
 2nd trimester 244 (36.4%) 10 (7.8%) 190 (41.8%) 44 (50.0%)
 3rd trimester 27 (4.0%) 1 (0.8%) 1 (0.2%) 25 (28.4%)
Timing of P1025 enrollment
 1st/2nd trimester 244 (36.4%) 52 (40.6%) 189 (41.5%) 3 (3.4%) <.001
 3rd trimester 427 (63.6%) 76 (59.4%) 266 (58.5%) 85 (96.6%)
Calendar year
 2002–2005 195 (29.1%) 35 (27.3%) 131 (28.8%) 29 (33.0%) 0.195
 2006–2008 238 (35.5%) 37 (28.9%) 168 (36.9%) 33 (37.5%)
 2009–2011 238 (35.5%) 56 (43.8%) 156 (34.3%) 26 (29.5%)
HIV & Treatment Characteristics
HIV+ diagnosis timing
 During current pregnancy 392 (58.4%) 47 (36.7%) 277 (60.9%) 68 (77.3%) <.001
 Prior to pregnancy 279 (41.6%) 81 (63.3%) 178 (39.1%) 20 (22.7%)
Reason not on ARV prior to pregnancy
 Recent HIV diagnosis 358 (53.4%) 45 (35.2%) 255 (56.0%) 58 (65.9%) <.001
 Never prescribed/Not indicated for health 180 (26.8%) 50 (39.1%) 119 (26.2%) 11 (12.5%)
 Refused/did not tolerate/non-compliant 22 (3.3%) 5 (3.9%) 15 (3.3%) 2 (2.3%)
 No medical care 15 (2.2%) 0 (0.0%) 13 (2.9%) 2 (2.3%)
 Missing 96 (14.3%) 28 (21.9%) 53 (11.6%) 15 (17.0%)
Pre-treatment viral load (copies/mL) during pregnancy
 <10,000 275 (41.0%) 31 (24.2%) 200 (44.0%) 44 (50.0%) 0.021
 ≥10,000 202 (30.1%) 40 (31.3%) 139 (30.5%) 23 (26.1%)
 Missing 194 (28.9%) 57(44.5%) 116 (25.5%) 21 (23.9%)
Pre-treatment CD4+ count (cells/mm3) during pregnancy
 <200 57 (8.5%) 10 (7.8%) 37 (8.1%) 10 (11.4%) 0.314
 200–349 153 (22.8%) 20 (15.6%) 117 (25.7%) 16 (18.2%)
 350–499 106 (15.8%) 19 (14.8%) 76 (16.7%) 11 (12.5%)
 500+ 177 (26.4%) 31 (24.2%) 116 (25.5%) 30 (34.1%)
 Missing 178 (26.5%) 48 (37.5%) 109 (24.0%) 21 (23.9%)
CDC4 class
 A/B 640 (95.4%) 122 (95.3%) 433 (95.2%) 85 (96.6%) 0.843
 C 31 (4.6%) 6 (4.7%) 22 (4.8%) 3 (3.4%)
Initial HAART regimen5
 2 NRTIs/NNRTI 49 (7.3%) 7 (5.5%) 35 (7.7%) 7 (8.0%) 0.877
 2 NRTIs/PI 159 (23.7%) 30 (23.4%) 110 (24.2%) 19 (21.6%)
 2 NRTIs/PI/RTV 353 (52.6%) 73 (57.0%) 235 (51.6%) 45 (51.1%)
 3 NRTIs 110 (16.4%) 18 (14.1%) 75 (16.5%) 17 (19.3%)
Open in a new tab
1

HAART: Highly-active antiretroviral therapy.

2

Chi square test comparing characteristics by the three trimesters of HAART initiation (among non-missing data).

3

Included all other race responses (Asian, Pacific Islander, American Indian, Alaskan Native, unknown, and refused to report).

4

CDC: Centers for Disease Control

5

NRTI: nucleoside/nucleotide reverse-transcriptase inhibitor; NNRTI: non-nucleoside/nucleotide reverse-transcriptase inhibitor; PI: protease inhibitor; RTV: ritonavir.

Table 2 summarizes treatment management and adherence during pregnancy. Thirty-nine (5.8%) women had at least one treatment interruption during pregnancy. The median interruption duration was 12 days (Q1–Q3: 5, 39). The most common reasons reported for treatment interruptions were toxicity, teratogenicity, or obstetric complications (59.0%) and non-compliance (28.2%). Six discontinued completely (3 due to non-compliance, and 3 due to toxicity). In addition, 137 (20.4%) changed regimens at least once during pregnancy; 96 were exposed to 2 regimens, 33 were exposed to 3 regimens, and 8 were on 4 regimens. Women initiated on NNRTI regimens were most likely to change regimens and women initiated on triple NRTI regimens were least likely to change regimens relative to the other regimen types. The reasons reported for medication changes were toxicity, teratogenicity, or obstetric complication (40.9%); clinician request (30.7%); non-compliance (5.8%); patient request (3.6%); and virologic failure or drug resistance (3.6%). Of the 541 women (80.6%) with ARV adherence data available, 22.0% and 20.2% reported non-adherence within the preceding two weeks or three days, respectively, of the last adherence assessment prior to delivery. The percentage of women without adherence data appeared to differ according to race (higher among Hispanics and Blacks relative to white non-Hispanic women), site, calendar year, type of regimen, and overall duration of HAART during pregnancy.

Table 2.

Treatment management and adherence during pregnancy

By trimester of HAART1 initiation
Overall
N=671		 1st
N=128		 2nd
N=455		 3rd
N=88		 P-value2
Treatment management information from chart abstraction
Treatment interruptions
 At least one interruption 39 (5.8%) 11 (8.6%) 27 (5.9%) 1 (1.1%) 0.069
 No interruptions 632 (94.2%) 117 (91.4%) 428 (94.1%) 87 (98.9%)
Regimen changes
 At least one change 137 (20.4%) 35 (27.3%) 90 (19.8%) 12 (13.6%) 0.041
 No changes 534 (79.6%) 93 (72.7%) 365 (80.2%) 76 (86.4%)
Interviewer administered self-reported adherence at the visit closest prior to delivery
Last time missed HIV medication
 Never missed 292 (43.5%) 57 (44.5%) 189 (41.5%) 46 (52.3%) 0.103
 >2 weeks ago 130 (19.4%) 30 (23.4%) 87 (19.1%) 13 (14.8%)
 During previous 2 weeks 119 (17.7%) 19 (14.8%) 90 (19.8%) 10 (11.4%)
 Missing 130 (19.4%) 22 (17.2%) 89 (19.6%) 19 (21.6%)
Non-adherence in past 3 days
 Took all doses in last 3 days 424 (63.2%) 88 (68.8%) 279 (61.3%) 57 (64.8%) 0.083
 Missed at least 1 dose 107 (15.9%) 17 (13.3%) 82 (18.0%) 8 (9.1%)
 Missing 140 (20.9%) 23 (18.0%) 94 (20.7%) 23 (26.1%)
Open in a new tab
1

HAART: Highly-active antiretroviral therapy

2

Chi square test comparing characteristics by the three trimesters of HAART initiation (among non-missing data).

Table 3 summarizes pregnancy outcomes. Median gestational age at delivery was 38.3 weeks; 85.7% delivered at ≥37 weeks gestation. Of those with detectable VL at delivery, 64.8% delivered by Cesarean section and 35.2% delivered vaginally. In contrast, of those with VL <400 copies/mL at delivery, a significantly higher proportion (50.8%) delivered vaginally. We did not observe a statistically significant difference in gestational age at delivery by VL. There was 1 confirmed MTCT (0.2%); the mother was diagnosed with HIV during the pregnancy, and received HAART for 12 weeks before delivery. She had detectable VL (between 1,000 – <10,000 copies/mL) both pre-treatment and at time of delivery, and at her visit closest to delivery, she reported missing ARVs during the previous 2 weeks.

Table 3.

Pregnancy/Delivery/Infant Outcomes

Overall N=671
Delivery outcome
 Live birth 666 (99.3%)
 Stillbirth (IUFD1 ≥ 20 wks) 5 (0.7%)
Number of fetuses
 Singleton 663 (98.8%)
 Twins 8 (1.2%)
Gestational age at delivery
 <37 weeks 96 (14.3%)
 ≥37 weeks 575 (85.7%)
Live Births2 N=666
Delivery type
 Vaginal Delivery 327 (49.1%)
 Cesarean Section 338 (50.8%)
 Missing 1 (0.2%)
Infant birth weight class
 <2.5 kg 80 (12.0%)
 ≥2.5 kg 576 (86.5%)
 Missing 10 (1.5%)
Infant birth size class
 Large for gestational age 40 (6.0%)
 Appropriate for gestational age 579 (86.9%)
 Small for gestational age 44 (6.6%)
 Intrauterine growth restriction 2 (0.3%)
 Missing 1 (0.2%)
Infant HIV status3
 Infected 1 (0.2%)
 Uninfected 549 (82.4%)
 Indeterminate 39 (5.9%)
 Negative, based on best available data 77 (11.6%)
Open in a new tab
1

IUFD: intra-uterine fetal demise.

2

Certain information not evaluated or not available on still births.

3

Indeterminate: little to no test result information available; Negative, based on best available data: multiple negative tests, did not meet required timing of testing to meet the definition of uninfected.

Eighty-eight women (13.1%) had detectable VL at delivery. Of these, 59 (67.0%) had VL ≥1000 copies/mL; 13 (14.8%) had VL between 10,000 – < 100,000 copies/mL, and 3 (3.4%) had VL ≥100,000 copies/mL. In univariate comparisons, (Table 4), race/ethnicity, level of education, parity, timing of first prenatal visit, and timing of HAART initiation were associated with detectable VL at delivery. Data in women with pretreatment VL, suggested an association between higher proportions with detectable VL at delivery and higher (≥10,000 c/mL) pretreatment VL (15.8% vs. 10.2%, p=0.065). There was some evidence that the proportion with detectable VL at delivery was marginally higher with non-boosted PI-containing regimens compared with boosted PI-containing regimens (17.0% vs 11.6%, p=0.098). In the multivariable modelling following multiple imputation of missing pre-treatment VL (Table 4), the significant predictors in univariate analyses continued to be associated with VL at delivery. In addition, pretreatment viral load was significantly associated with VL at delivery. When the multivariable modeling was restricted to the subset of women with complete pre-treatment VL, results remained consistent.

Table 4.

Association of Pretreatment Factors with VL >400 copies/mL at Delivery

Viral load at delivery >400 copies/mL Multivariable Baseline Model (Pre-Treatment variables only)
Total N % P-value1 Adjusted Probability2 (95% CI) P-value3
671 88 13.1
Characteristics
Age (years)
 13–19 53 9 17.0% 0.25 13.6% (6.8, 25.3) 0.42
 20–34 540 73 13.5% 10.5% (8.0, 13.7)
 35+ 78 6 7.7% 5.1% (2.1, 11.7)
Parity4
 Nulliparous 262 21 8.0% 0.002
 Multiparous 409 67 16.4%
Race/Ethnicity
 Black Non-Hispanic 397 70 17.6% <0.001 15.1% (11.7, 19.3) <0.001
 Hispanic 198 13 6.6% 5.3% (3.0, 9.2)
 White Non-Hispanic/Other5 76 5 6.6% 4.9% (1.9, 11.8)
Highest level of education
 11th grade or less 239 42 17.6% 0.013 14.4% (10.3, 19.7) 0.002
 High school graduate/equivalent 313 38 12.1% 9.7% (6.8, 13.6)
 Some college or more 119 8 6.7% 4.7% (2.2, 9.7)
Pre-treatment viral load (copies/mL) during pregnancy
 <10,000 275 28 10.2% 0.065 8.1% (5.5, 11.8) 0.007
 ≥10,000 202 32 15.8% 12.9% (9.1, 18.0)
 Missing 194 28 14.4%
HAART6 initiation timing
 1st trimester 128 11 8.6% 0.003 6.6% (3.5, 12.0) 0.006
 2nd trimester 455 56 12.3% 9.5% (7.0, 12.8)
 3rd trimester 88 21 23.9% 20.8% (13.4, 30.9)
HIV diagnosis timing4
 Prior to current pregnancy 279 45 16.1% 0.051
 During current pregnancy 392 43 11.0%
First prenatal visit4
 1st trimester 381 40 10.5% 0.002
 2nd trimester 244 35 14.3%
 3rd trimester 27 9 33.3%
 Missing 19 4 21.1%
Initial HAART6 regimen7
 2 NRTIs/NNRTI 49 3 6.1% 0.14 4.2% (1.3, 12.9) 0.088
 2 NRTIs/PI 159 27 17.0% 13.4% (8.8, 19.9)
 2 NRTIs/PI/RTV 353 41 11.6% 9.0% (6.3, 12.6)
 3 NRTIs 110 17 15.5% 12.4% (7.5, 19.9)
Calendar year4
 2002–2004 116 18 15.5% 0.46
 2005–2007 241 34 14.1%
 2008–2011 314 36 11.5%
Open in a new tab
1

Chi square test comparing proportion of detectable VL across covariate levels (among non-missing data).

2

For a given covariate, predicted probabilities were estimated at mean of the other covariates in the model.

3

Overall Wald Chi-square test from logistic regression modeling, pooled over 30 imputations

4

Variables not selected for multivariable modeling due to association with other covariates.

5

Included all other race responses (Asian, Pacific Islander, American Indian, Alaskan Native, unknown, and refused to report)

6

HAART: highly-active antiretroviral therapy

7

NRTI: nucleoside/nucleotide reverse-transcriptase inhibitor; NNRTI: non-nucleoside/nucleotide reverse-transcriptase inhibitor; PI: protease inhibitor; RTV: ritonavir.

In univariate analyses of treatment management characteristics, women with at least one treatment interruption were more likely to have detectable VL at delivery than those with no interruption (28.2% vs. 12.2%, p=0.004), but regimen changes were not significantly associated with detectable VL at delivery. When treatment interruption was added to the multivariable model, it remained statistically significant (p=0.002, adjusted probability 24.3%; 95% CI (13.0, 40.8) with interruptions vs. 9.0%; 95% CI: (6.7, 11.9) with no interruptions) and the p-values and adjusted probabilities for the pretreatment variables did not change substantially. In the subset of women with complete adherence data (N=541), the proportion with detectable VL at delivery was highest among women who reported non-adherence in the previous 2 weeks (19.3%) vs. earlier (12.3%) or never (9.6%) (p=0.039).

There was some variation in the adjusted probabilities of detectable VL at delivery by pretreatment VL and trimester of HAART initiation, though estimates were imprecise. Among women with pre-treatment VL ≥10,000 c/mL, the adjusted probability of detectable VL at delivery increased if HAART was initiated later in pregnancy (1st trimester: adjusted probability 4.2%, 95% CI (1.0%, 15.8%); 2nd trimester: 12.8% (8.1%, 19.7%); 3rd trimester: 32.5% (16.1%, 54.6%)). However, among women with pretreatment VL <10,000 c/ml, there was much less of an increase in the adjusted probability of detectable VL at delivery with later HAART initiation (1st trimester: 7.8% (2.4%, 22.4%); 2nd trimester: 7.6% (4.6%, 12.2%); 3rd trimester: 9.5% (3.9%, 21.6%)).

DISCUSSION

In this large U.S.-based cohort of HAART-naive, HIV-1 positive women, 13% had detectable VL at delivery. While this percentage of women with persistent viremia at delivery is concerning, this estimate is lower than the 24% of HAART-naive women with detectable VL at delivery observed in an earlier U.S. cohort (18). The timing of HAART initiation, along with consistent usage during pregnancy, were associated with VL at delivery. Among women who initiated HAART in the 3rd trimester nearly one-quarter 23.9% had detectable VL at delivery.

A recent retrospective study from the United Kingdom recommended women with VL >10, 000 copies/mL should begin HAART by 20.4 weeks, while those with VL >100,000 copies/mL should start HAART without delay (23). In that study, women with VL <10,000 copies/mL could potentially begin HAART by 26.3 weeks to achieve an undetectable VL by delivery, but this should be balanced against the possible increased risk of in-utero transmission with a delayed start, or the risk of transmission should a premature delivery occur.

Our data suggest that the timing of HAART initiation may be more strongly associated with detectable viral load among women who have high pre-treatment VL (≥10,000 copies/mL) than among those who have lower pre-treatment VL (<10,000 copies/mL). The timing of HAART initiation during pregnancy deserves special attention, as vaginal delivery in HIV-positive pregnant women is recognized to be safer for women and equally safe as cesarean section for newborns if VL is non-detectable at delivery (24). For HAART-naive women, the updated USA DHHS perinatal guidelines from July 2012 recommend starting the regimen in the first trimester or delaying until 12 weeks’ gestation depending on CD4-cell count, HIV RNA levels, and maternal conditions such as nausea and vomiting. Earlier initiation of a combination regimen may be more effective in reducing transmission, but benefits must be weighed against potential fetal effects of first-trimester drug exposure (24).

One important consideration regarding when to start HAART extends beyond the benefits for maternal health and decreasing neonatal transmission rates. There is emerging literature focused on the effects of maternal viremia on long-term post-delivery outcomes in HIV-exposed, uninfected (HEU) children. Research from South Africa shows that both HIV-positive and HEU children under 1 year old were at increased risk of failing treatment for severe pneumonia (25). More recent findings corroborate the greater infectious morbidity among this population (26). Poor outcomes may relate to the fact that HEU infants have altered CD4 immunity during the first year of life (27). Infants born to immunosuppressed mothers have increased exposure to pathogens (28). Subsequent research has shown that HEU infants present a variety of immunological abnormalities, including impaired immune response to vaccines (29) as compared to non-exposed neonates, however it remains unclear if this is related to maternal HIV infection or to use of HAART (30).

Missing data precluded us from incorporating adherence data into a multivariable analysis, but it appears that women who reported suboptimal adherence had higher rates of detectable VL at delivery than women who reported optimal adherence. These findings are supported by other studies that show the importance of early HAART initiation (31), as well as medication adherence both within (32), and outside the context of pregnancy (33), and suggest that HAART can only achieve its optimal efficacy in prevention of mother-to-child transmission (MTCT), morbidity, and mortality if HIV-positive individuals initiate treatment in a timely manner, and adhere to their medications (34–36). Our findings provide further evidence of the importance of early HAART initiation (37) and support of medication adherence throughout pregnancy.

Women with higher pre-treatment VL and those on less potent regimens containing unboosted PIs had higher probability of having detectable VL at delivery. The AIDS 2012 IAS-USA treatment guidelines stressed that initial therapy for all adults, including pregnant women, should optimize potency of the regimen and be based on a combination of 2 NRTIs and a third agent, generally consisting of an NNRTI, a ritonavir-boosted PI, an integrase strand transfer inhibitor (InSTI), or, rarely, an agent that blocks the CC chemokine receptor 5 (CCR5) (38). Unboosted PIs are not considered first line therapy at this time, and our findings reflect the fact that a regimen containing a PI without ritonavir boosting is suboptimal, and this was generally not prescribed after 2007.

We also identified several sociodemographic factors associated the detectable viral load at delivery: Black non-Hispanic ethnicity and attainment of an educational level less than high school graduation. Prior studies have identified race-associated disparities in maternal HIV disease outcomes including high VL at delivery (16, 39–41). It is possible that experiences of race-based discrimination or lack of trust in the medical care system may pose barriers to engagement in care, which in turn could be associated with unsuppressed VL. For example, Bogart et al. found that African-American women frequently reported race-based discrimination when seeking family-planning and contraceptive services (42). In a different study of a random cross-sectional sample of African Americans, up to 60% endorsed HIV conspiracy beliefs (43), There may also be racial variations in drug pharmacokinetics during pregnancy and risk of virologic failure (44) or ethnic differences in the sites where patients receive care and resources devoted to promoting adherence. Education is an important social determinant of health. As a marker of socioeconomic status, lower education has been linked to suboptimal engagement in care, non-adherence to antiretroviral therapy, and lower rates of survival in individuals with HIV infection (45, 46). While the mechanisms linking lower educational attainment to detectable VL at delivery remain unclear, it may reflect lower levels of health literacy, or possibly be a marker of overall poverty. Lower health literacy and greater poverty-related stress have been linked to medication non-adherence and other negative health outcomes (47–49).

A limitation of this observational study is that women could enroll at any time during their pregnancy. Thus, there is incomplete data on some covariates and study entry did not correspond with entry into pre-natal care or initiation of treatment. Women who enrolled in the study during their 3rd trimester were more likely to have missing pre-treatment VL and CD4+ data. Also, correlations between maternal age and parity, calendar year and treatment regimen, and timing of HAART initiation, first prenatal visit, and HIV diagnosis prohibited drawing conclusions about the independent effects of these factors on detectable VL at delivery. Additionally, a large amount of missing adherence data and reliance on self-report for adherence precluded inclusion of adherence in multivariable analyses and results should be interpreted with caution. Despite this, our findings are consistent with prior studies related to medication adherence in a U.S.-based population of HIV-positive pregnant women (22).

Generalizability is uncertain because this study occurred at AIDS clinical trial sites and may not reflect patients in the community. These sites are geographically and demographically diverse, but small numbers of women at each site and lack of socio-demographic variation within sites inhibited our ability to account for site effects. Some sites enrolled mostly or all black Non-Hispanic women, while other sites enrolled mostly or all Hispanic women. This makes it possible that the association we found between ethnicity and VL was due to site factors rather than ethnicity. Finally, we did not have resistance data for most women. Despite these limitations, our study is one of the largest U.S.-based analyses evaluating the association between antiretroviral therapy and virologic suppression at delivery in the current era of HAART.

Our results suggest that women who initiate HAART in the 3rd trimester, have higher pre-treatment VL, or have suboptimal antiretroviral adherence are at increased risk for having detectable VL at delivery. Optimal care for HIV-positive, HAART-naive pregnant women should focus on initiation of HAART according to pre-treatment VL, and prior to the third trimester. Additional interventions should focus on early prenatal care, early HIV testing, and measures to support adherence to treatment throughout pregnancy in order to promote both maternal and infant health.

Acknowledgments

Financial Support Information: Dr. Hughes reports having been a paid member of data and safety monitoring boards for Boehringer Ingelheim, Pfizer, Tibotec and Medicines Development.

Primary Funding Source: The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group is funded by: US Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS.

Funding Statement:

Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632], the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) [AI068632]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) and the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C).

Dr. Katz received funding through 1K23MH097667-01, Harvard University Center for AIDS Research (HU CFAR NIH/NIAID 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.

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

APPENDIX

P1025 Team: Gwendolyn B. Scott, M.D., University of Miami School of Medicine, Miami, Florida, USA; Elizabeth Smith, M.D., National Institute of Allergy and Infectious Diseases Division of AIDS, Pediatric Medicine Branch, Bethesda, Maryland, USA; Heather Watts, M.D., National Institute of Child Health and Human Development, Pediatric, Adolescent, and Maternal AIDS (PAMA) Branch, Bethesda, Maryland, USA; KaSaundra M. Oden, M.H.S., International Maternal Pediatric Adolescent AIDS Clinical Trials Group, Silver Spring, Maryland, USA; Yanling Huo, M.S., Harvard School of Public Health, Boston, MA, USA; Kunjal Patel, D.Sc., M.P.H., Harvard School of Public Health, Boston, MA, USA; Emily A. Barr, C.P.N.P., C.N.M., M.S.N, University of Colorado Denver, The Children’s Hospital, Denver, Colorado, USA; Diane W. Wara, M.D., University of California at San Francisco, San Francisco, California, USA; Sandra K. Burchett, M.D., M.Sc., Harvard Medical School, Boston, MA, USA; Jenny Gutierrez, M.D., Bronx-Lebanon Hospital, Bronx, New York, USA; Kathleen Malee, Ph.D., Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA; Patricia Tanjutco, M.D., Washington Hospital Center, Washington, D.C., USA; Yvonne Bryson, MD, David Geffen School of Medicine, University of California, Los Angeles, California, USA; Michael T. Basar, B.S., Frontier Science & Technology Research Foundation, Inc., Amherst, New York, USA; Adriane Hernandez, M.A., Frontier Science & Technology Research Foundation, Inc., Amherst, New York, USA; Amy Jennings, B.S., Frontier Science & Technology Research Foundation, Inc., Amherst, New York, USA; Tim R. Cressey, Ph.D., B.Sc., Program for HIV Prevention & Treatment, Chang Mai, Thailand; Jennifer Bryant, M.P.A., Westat, Rockville, Maryland, USA.

Participating sites and site personnel include: 5041 Children’s Hospital of Michigan NICHD CRS (Theodore B. Jones, MD; Ernestine Brown, RN; Natalie Woods, RD); 5052 University of Colorado Denver NICHD CRS (Alisa Katai, MHA; Tara Kennedy, FNP-BC; Kay Kinzie, MSN, FNP-BC; Jenna Wallace, MSW; CTSI Grant Number UL1 TR000154); 5031 San Juan City Hospital PR NICHD CRS (Rodrigo Diaz-Velasco, MD, FACOG, AAHIVS; Midnela Acevedo-Flores, MD, MT; Elvia Pérez-Hernández, BS, MEd., MA, MPH; Antonio Rodriguez-Mimoso, MD; FACOG); 5048 USC LA NICHD CRS (Françoise Kramer, MD; LaShonda Spencer, MD; James Homans, MD; Andrea Kovacs, MD); 4601 UCSD Maternal, Child, and Adolescent HIV CRS (Andrew Hull, MD; Mary Caffery, RN, MSN; Jean M. Manning RN, BSN; Stephen A. Spector, MD); 4101 Columbia IMPAACT CRS; 4201 University of Miami Pediatric Perinatal HIV/AIDS CRS (Charles D. Mitchell, MD; Salih Yasin, MD; Safia Khan, MD); 5083 Rush University Cook County Hospital Chicago NICHD CRS (Mariam Aziz, MD; Latania Logan, MD; Julie Schmidt, MD; Helen Cejtin, MD); 5096 University of Alabama Birmingham NICHD CRS (Marilyn Crain, MPH, MD; Sharan Robbins, BA; Mickey Parks, CRNP; Yvonne Gamble Duke, MA); 6901 Bronx-Lebanon Hosp. IMPAACT CRS (Murli Purswani, MD; Stefan Hagmann, MD, MSc, FAAP; Mary Vachon, LMSW, MPH); 5012 NYU School of Medicine NICHD CRS (William Borkowsky, MD; Maryam Minter, RN; Aditya Kaul, MD; Nagamah Deygoo, MS); 3801 Texas Children’s Hospital CRS (Shelley Buschur, RN, NMV; Kathleen Pitts, CPNP; Chivon McMullen-Jackson, BSN, RN; Theresa Aldape, LMSW; Grant Number AI069441); 4001 Chicago Children’s CRS (Donna McGregor, RN); 5009 Children’s Hosp. of Boston NICHD CRS (Arlene Buck, RN; Catherine Kneut, RN, CPNP); 5018 USF - Tampa NICHD CRS (Patricia Emmanuel, MD; Karen Bruder, MD; Gail Lewis, RN); 6501 St. Jude/UTHSC CRS (Katherine Knapp, MD; Edwin Thorpe, MD; Nina Sublette, FNP, PhD; Pam Finnie, MSN); 2802 NJ Medical School CRS (Charmane Calilap-Bernardo, RN; Linda Bettica, RN); 3601 UCLA-Los Angeles/Brazil AIDS Consortium (LABAC) CRS (Jaime G. Deville, MD; Karin Nielsen-Saines, MD; Nicole Falgout, RN; Michele Carter, RN); 4005 Mt Sinai Hospital Med Center, Women’s & Children’s HIV Program (Brenda Wolfe, APN; Molly Hartrich, MPH); 5017 Seattle Children’s Hospital CRS; 5023 Washington Hospital Center NICHD CRS (Steven Zeichner, MD, PhD; Sara R. Parker, MD; Vanessa Emmanuel, BA); 5028 University of Illinois College of Medicine at Chicago, Department of Pediatrics (Kenneth Rich, MD; Karen Hayani, MD; Julia Camacho, RN); 5051 University of Florida College of Medicine, Jacksonville (Mobeen Rathore, MD; Ayesha Mirza, MD; Nizar Maraqa, MD; Kathleen Thoma, MA, CCRP); 5094 University of Maryland Baltimore NICHD CRS (Douglas Watson, MD; Corinda Hilyard); 6601 University of Puerto Rico Pediatric HIV/AIDS Research Program CRS (Irma L. Febo, MD; Vivian Tamayo, MD; Ruth Santos, RN, MPH; Maritza Cruz-Rodriguez); 5003 Metropolitan Hospital NICHD CRS; 5013 Jacobi Medical Center Bronx NICHD CRS (Susan Gross, MD; Michael Moore, MD; Carmen Caines, RN); 5038 Yale University School of Medicine; 5045 Harbor UCLA Medical Center NICHD CRS (Margaret Keller, MD; Spring Wettgen, RN, PNP; Judy Hayes, RN; Yolanda Gonzalez, RN); 5095 Tulane University New Orleans NICHD CRS (Yvette Luster, RN; Robert Maupin, MD; Chi Dola, MD; Margarita Silio, MD); 6701 The Children’s Hosp. of Philadelphia IMPAACT CRS(Steven D. Douglas, MD; Richard M. Rutstein, MD; Carol A. Vincent, CRNP, MSN).

Footnotes

These data were presented at The 19th Conference on Retroviruses and Opportunistic Infections Meeting, March 5–March 8 2012, Seattle.

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 academic health care centers.

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