The effect of maternal viral load on the risk of perinatal transmission of HIV‐1
Thea, Donald M.1,9; Steketee, Richard W.3; Pliner, Vadim1; Bornschlegel, Katherine2; Brown, Teresa3; Orloff, Sherry3; Matheson, Pamela B.1; Abrams, Elaine J.4; Bamji, Mahrukh5; Lambert, Genevieve6; Schoenbaum, Ellie A.7; Thomas, Pauline A.2; Heagarty, Margaret4; Kalish, Marcia L.3; New York City Perinatal HIV Transmission Collaborative Study Group
1Medical and Health Research Association, New York, New York
2New York City Department of Health, New York, New York
3Centers for Disease Control and Prevention, Atlanta, Georgia
4Harlem Hospital, New York, USA
5Metropolitan Hospital, New York, USA
6Bronx-Lebanon Hospital, Bronx, New York, USA
7Albert Einstein College of Medicine, Bronx, New York, USA.
8See Appendix for other members.
9Requests for reprints to: Dr Donald M. Thea, New York City Perinatal Transmission Collaborative Study Group, Box 044, 125 Worth Street, New York NY 10013, USA.
Sponsorship: This work was funded by cooperative agreement no. U64 CCU 200937 with the Centers for Disease Control and Prevention through a grant to Medical and Health Research Association of New York City, Inc.
Note: The use of trade names is for identification only and does not imply endorsement by the Public Health Service or the US Department of Health and Human Services.
Date of receipt: 30 August 1996; revised: 11 December 1996; accepted: 20 December 1996.
Objective: To determine the effect of maternal viral load at delivery on the risk of perinatal transmission of HIV-1.
Design: A nested case–control study within a prospectively followed cohort of HIV- 1-infected pregnant women and their infants.
Setting: The multicenter New York City Perinatal HIV Transmission Collaborative Study.
Participants: Fifty-one women who gave birth to HIV-1-infected infants were frequency-matched within CD4+ cell count quintiles with 54 non-transmitting mothers.
Main outcome measures: Maternal quantity of HIV-1 viral RNA was assayed in plasma obtained near delivery using the nucleic acid sequence-based amplification assay system.
Results: Viral RNA was detected in 73 (70%) out of 105 women and the median viral load was 16 000 RNA copies/ml in transmitters and 6600 in non-transmitters (P < 0.01). When adjusted for maternal CD4+ count near delivery, women with measurable viral load were nearly sixfold more likely to transmit HIV-1 than women with viral load below detection [adjusted odds ratio (AOR), 5.8; 95% confidence interval (CI), 2.2–15.5]. The odds ratio for perinatal transmission of log10 viral load, adjusted for CD4 count was 2.7 (95% CI, 1.5–5.1). When stratified by the stage of HIV-1 disease, the only group with significant association between log10 viral load and transmission were AIDS-free women with CD4+ count > 500 x 106/l (AOR, 9.1; 95% CI, 2.6–31.5).
Conclusions: High maternal viral load increases the likelihood of perinatal transmission of HIV-1 in women without AIDS and advanced immunosuppression. HIV-1-infected pregnant women without advanced disease, shown by others to have the lowest risk of perinatal transmission, may benefit the most from efforts to identify and decrease viral load at delivery.
The World Health Organization estimates that by the year 2000, 10 million children will have been born infected by HIV-1 . Approximately 7000 children are born each year in the United States to women infected with HIV-1, and without intervention, between 15 and 30% of these children will be HIV-infected . In February 1994, the AIDS Clinical Trials Group (ACTG) protocol 076 Study Group reported that zidovudine given to selected HIV-1-infected women during pregnancy and delivery, and postnatally to their infants, reduces the rate of perinatal transmission by a factor of two-thirds . The mechanism of this reduction is not known but it is presumed that zidovudine reduces perinatal HIV-1 transmission by decreasing maternal viral load, altering viral infectivity, or preventing the establishment of fetal infection after exposure to HIV-1 during gestation, labor and delivery.
Quantitative measures of circulating HIV-1, such as limiting-dilution viral culture and circulating levels of p24 antigen, have been used to estimate viral load but are relatively insensitive [4–9], and studies of the correlation of p24 antigenemia with perinatal transmission have yielded conflicting results [10,11]. Newer and more sensitive methods of viral quantification based on amplification of nucleic acids or signal [5,12,13] are now available to accurately measure HIV-1 RNA in plasma. Using one of these newer techniques, nucleic acid sequence-based amplification (NASBA), we examined maternal viral load and its relationship to perinatal HIV-1 transmission in a subgroup of pregnant women who were enrolled in a prospective study of perinatal HIV-1 transmission between 1990 and 1994.
Materials and methods
We conducted a nested, case–control analysis of the relationship of plasma HIV-1 burden in HIV-1-infected women and perinatal transmission enrolled into the New York City (NYC) Perinatal HIV Transmission Collaborative Study, a longitudinal study of perinatal HIV-1 transmission and the natural history of pediatric HIV-1 disease progression at eight NYC health-care institutions (see Appendix). Enrollment criteria and protocol design for the larger study have been described elsewhere . All women in this analysis were enrolled before or within 2 weeks of delivery after giving informed consent, and were examined at regular intervals along with their infants. Three mothers in the sample had twins; both infants in each set had concordant HIV-1 infection status (one pair infected and two pairs not infected), and delivery variables (e.g., gestational age, internal fetal scalp monitoring, duration of membrane rupture) were obtained for twin A only. One additional mother gave birth twice during the study period and both infants were included in the analysis; one was infected and one not infected. During prenatal visits and at delivery, medical history, physical examination, and phlebotomy were performed. Maternal demographic information, HIV-1 risk factors and medical histories were collected by questionnaire at the initial visit and at each follow-up visit as appropriate. Information on zidovudine use during pregnancy was recorded, abstracted from the medical record or obtained by maternal self-report. Information on maternal illicit hard drug use, defined as any heroin, cocaine, or street methadone use during pregnancy, was obtained using maternal and baby toxicology results (for heroin and cocaine) as well as through self-report, whereas information on smoking was based on self-report only. Intrapartum information was collected at delivery, obtained by hospital chart review, or ascertained from birth certificates. Two women and their neonatal infants included in this analysis received zidovudine as part of the ACTG 076 protocol.
Routine laboratory testing of maternal and infant blood samples included a determination of lymphocyte subsets by flow cytometry, and of HIV-1 antibody by enzyme-linked immunosorbent assay and Western blot assay performed at the NYC Department of Health, Bureau of Laboratories. To establish infant infection status, the earliest available infant blood specimen was assayed for the presence of HIV-1 proviral DNA by polymerase chain reaction (PCR) . Blood for viral load studies was collected in standard heparinized vacuum tubes (Becton Dickinson, Rutherford, New Jersey, USA), delivered by overnight courier at ambient temperatures to the Centers for Disease Control and Prevention (CDC) where it was separated by Ficoll-Hypaque upon arrival. Plasma supernatant was aliquoted into one of two types of tubes: (1) non-autoclaved Oak Ridge tubes (Nalgene, Rochester, New York, USA) stored at −20°C, and (2) radiation-sterilized cryogenic virals (Sarstedt, Newton, North Carolina, USA), stored at −70°C. Total time from phlebotomy to freezing was between 24 and 30 h. CD4+ cell count determinations were obtained within 2 weeks of viral load samples.
Determination of perinatal transmission
A child was considered HIV-1-infected if any of the following occurred: (i) two separate blood samples were positive for HIV-1 proviral DNA by PCR; (ii) the former CDC criteria for P2  classification was met with either an AIDS-defining illness or death attributed to an HIV-1-related illness; (iii) the child was HIV-1 Western blot-positive at or beyond 15 months of age. A child was considered uninfected if no AIDS-defining illnesses were diagnosed and HIV-1 serology was negative on one or more occasions, or at least two samples were negative by PCR (with at least one drawn after 2 months of age), and no samples tested positive or inconclusive.
Nested sample inclusion criteria
Of the 90 transmitting mothers enrolled into the study from April 1990 to August 1994, we identified 54 available repository plasma samples that had been obtained between 8 weeks before and 2 weeks after delivery on mothers with complete CD4 count and delivery data. Due to the high correlation between CD4+ cell count and both viral load [4,8,17–21] and perinatal transmission of HIV-1 [14,22,23], we attempted to reduce potential bias by selecting a control group that was frequency-matched for CD4+ cell count from among the mothers of uninfected children who had available plasma and CD4+ data. To do this, we determined the CD4+ cell count quintile ranges for the 54 mothers in the transmitting group and randomly selected a corresponding number of non-transmitting control women within each of these CD4+ ranges. We controlled for any residual confounding that remained within quintiles by including CD4+ count in the logistic regression analyses.
Plasma HIV-1 RNA was measured at CDC using the NASBA HIV-1 RNA quantification (QT) kit (Organon-Teknika, Durham, North Carolina, USA), an isothermal nucleic acid amplification assay that has been adapted for use with HIV-1 . The assay was performed according to the manufacturer's specifications by personnel blinded to transmission status. The NASBA QT system estimates the amount of RNA in the original sample based on data generated from native RNA and three synthetic internal RNA calibrators. The assay threshold of sensitivity is 100 copies of viral RNA per input volume. For this analysis input volumes were 100 µl yielding a threshold of 1000 copies/ml. According to the manufacturer, duplicate assays are not necessary because of good precision (<0.3 logs) produced by the use of internal RNA calibrators.
Maternal and delivery factors known or possibly associated with transmission were entered separately into a logistic regression model containing log10 viral RNA copy number and CD4+ cell count to estimate the effect of each factor on the relationship between viral load and risk of transmission.
Univariate comparisons of maternal and delivery characteristics by transmission status were tested for significance with Fisher's exact test (dichotomous characteristics) and the Wilcoxon test (continuous characteristics). Mantel–Haenzel χ2 test for trend was used to compare the frequency of detectable viral RNA by sampling year, the distribution of transmitting women by year of enrollment and comparisons of the proportion of women with detectable viral RNA in each category of CD4+ count (<200, 200–499 and ≥ 500 × 106/l). The Kruskall–Wallis test was used for comparisons of viral load among CD4+ cell count groups and the Wilcoxon test was used to compare viral load between transmitting and non-transmitting women. The Pearson product–moment correlation was used to measure the relationship between CD4+ cell count and log10 viral load. The likelihood ratio test (for the logistic regression model with main and interaction terms compared with main effects only) was used to test the presence of interaction effects between viral load and the stage of HIV-1 disease on transmission.
For analyses in which viral load or log viral load was used as a continuous variable, subthreshold viral load values were assigned the arbitrary value 999. Means of duplicate runs, when present, were used in all analyses. The robustness of analyses to changes in this subthreshold value was assessed by substituting (i) 500, (ii) 1, and (iii) a random number between 1 and 1000 for 999, and comparing effects with those of the ‘999’ model. In all logistic regression models used in this analysis and with all the imputation schemes, log10 viral load remained the only significant predictor of perinatal transmission.
All probability values given are two-tailed, and the threshold of statistical significance was set at P = 0.05. All analyses were performed with SAS statistical software (SAS Institute, Cary, North Carolina, USA).
The final analysis set consisted of 105 maternal samples (51 women who transmitted HIV-1 to their infant and 54 who did not) because three specimens from transmitting women produced assay results which were invalid due to incomplete or inconsistent amplification of the internal RNA standards. A comparison of the demographic and delivery characteristics by transmission status is shown in Tables 1 and 2. No significant differences in maternal age, HIV-1 risk behavior, illicit hard drug or zidovudine use during pregnancy, stage of HIV-1 disease, lymphocyte subsets, delivery exposure to maternal secretions, delivery mode or duration of membrane rupture were detected between the transmitting and non-transmitting mothers. None of the women breastfed their infants.
Twenty (19%) of the 105 women reported taking zidovudine during pregnancy: seven (14%) of the 51 transmitters and 13 (24%) of the 54 non-transmitters (P = 0.22). Except for the two women enrolled in ACTG 076, zidovudine was given for maternal indications in each case, and used for a median duration of 18.4 weeks (range, 3–227 weeks) prior to viral load sampling. The median viral load did not differ between women taking zidovudine (14 000 RNA copies/ml) and women who did not (10 500 RNA copies/ml; P = 0.50).
Viral load testing
HIV-1 viral RNA was below the threshold of detection (1000 RNA copies/ml) in one or both specimens from 32 (30%) women. The median viral copy number for all women was 12 000 RNA copies/ml and among women with one or both values above the threshold was 20 000 RNA copies/ml.
Analysis of the storage tube type and storage temperature (−20°C versus −70°C) indicated no statistically significant or systematic differences in viral RNA recovery, or alteration in the effect of viral load on perinatal transmission (data not shown).
The mean time of blood sampling was 6.1 days before delivery (range, 53 days before to 14 days after), and did not differ by perinatal transmission status of the women. Neither the likelihood of finding measurable viral RNA among all 105 women (P = 0.93) nor the log10 RNA copy number among the 73 women with measurable virus (P = 0.12) was associated with the year of sampling, suggesting that no significant degradation of viral RNA occurred during the 6 months to 5 years that samples were frozen in the repository. The distribution of enrollment year was similar between transmitting and non-transmitting mothers (P = 0.3) indicating no secular trend in enrollment to a particular study group.
Among factors possibly associated with transmission, only AIDS at delivery and CD4 count below 200 were associated with the detection of viral load (P < 0.01 and P = 0.03, respectively).
Viral load and parameters of maternal HIV-1 disease
Higher viral load was associated with advanced maternal disease stage, as measured by clinical status or CD4+ cell count. The median viral load among the 26 (25%) women with AIDS (revised 1993 CDC case definition ) at delivery was significantly higher (24 500 RNA copies/ml) than among the 79 women who were AIDS-free at delivery (8050 RNA copies/ml; P < 0.001). This difference may have been minimized by the greater use of zidovudine among women with AIDS (46%) than among women without AIDS (10%). CD4+ cell count was inversely associated with the level of viral RNA among the 105 women (r = −0.25; P = 0.01). Moreover, viral RNA was measurable in all 11 women with CD4+ cell counts < 200 × 106/l, in 29 out of 39 (74%) women with CD4+ cell counts from 200 to 500 × 106/l, but in only 33 out of 55 (60%) of women with counts of 500 × 106/l or greater (P < 0.01).
Viral load and transmission
Perinatal transmission of HIV-1 was significantly associated with the presence of measurable HIV-1 RNA. In this sample, matched by CD4+ count quintile, 22% (seven out of 32) of the women with viral load measurements below the detection threshold transmitted HIV-1 to their infant compared with 60% (44 out of 73) of women with measurable plasma viral RNA [adjusted for CD4+ count, adjusted odds ratio (AOR), 5.8; 95% confidence interval (CI), 2.2–15.5].
Viral load was significantly higher in women who transmitted HIV-1 to their infants (Fig. 1). In each group of women stratified by CD4+ count, higher viral load occurred among those who transmitted virus to their infants (Table 3), but these differences were not statistically significant in women with CD4+ counts below 500 × 106/l. The most significant differences in viral load were seen in the least immunosuppressed group of 55 women with CD4+ counts over 500 × 106/l. In this group, both the median viral load (11 500 versus < 1000) and the proportion with measurable virus [22 out of 25 versus 11 out of 30; AOR (adjusted for CD4+ count), 12.0; 95% CI, 2.9–49.7] were significantly higher among those who transmitted HIV-1.
In a univariate analysis, none of the maternal or delivery factors we examined (AIDS, and CD4 count during pregnancy, maternal zidovudine use, smoking, gravidity/parity, Cesarean section, duration of membrane rupture, duration of labor, gestational age, maternal age, and prolonged exposure to maternal blood or secretions) was associated with perinatal transmission, nor was an association found when analysis was restricted to women with low (below median) or undetectable viral load. In the logistic regression analysis, log10 viral RNA copy number was significantly associated with perinatal transmission [AOR (adjusted for CD4+), 2.7; 95% CI, 1.5–5.1; P < 0.01]. Although the possible confounding effect of maternal immune suppression (as measured by CD4 count) on viral load and perinatal transmission was partly addressed by the design of this CD4 frequency-matched study, systematic viral load variation within CD4 quintiles might have occurred. An analysis of log10 viral copy number stratified by maternal CD4 count and the presence of AIDS indicated that the degree of viral load had a pronounced effect on the likelihood of perinatal transmission among women without AIDS and whose CD4 count was > 500 × 106/l (AOR, 9.1; 95% CI, 2.6–31.5), a questionable effect among women without AIDS whose CD4 count was between 200 and 500 × 106/l (AOR, 2.0; 95% CI, 0.7–6.1), and no effect among women with AIDS (AOR, 0.5; 95% CI, 0.1–2.3). The difference between these three odds ratios was statistically significant (P = 0.01).
Since a statistically significant effect of viral load on transmission was found only among women without AIDS and with CD4 count > 500 × 106/l, further analyses were conducted only on this subgroup of women. To determine whether this strong effect of viral load on perinatal transmission among women with less advanced disease was confounded by other maternal or obstetric characteristics, the following predictor variables were added individually to a logistic regression model containing log10 viral load and CD4+ count: zidovudine use, duration of labor, gravidity, smoking or illicit hard drug use, maternal age, gestational age at delivery, and mode of delivery. None of these items substantially reduced the estimated odds ratio of viral load (Table 4). Controlling for duration of membrane rupture increased the estimated AOR of viral load on perinatal transmission to 48.6 (95% CI, 4.2–564); however, there was no statistically significant interaction found between duration of membrane rupture and log10 viral load. No other evidence of interactions or confounding was detected.
This study of a prospectively enrolled cohort of HIV-1-infected pregnant women provides a quantitative estimate of the effect of maternal plasma viral burden near delivery on the likelihood of perinatal transmission. These findings, controlled for CD4 count, a strong predictor of both viral load and perinatal transmission, indicate that there is a nearly threefold increase in the likelihood of perinatal HIV-1 transmission for each additional log10 in viral load. In addition, it appears that this effect of high viral load on perinatal transmission is the most pronounced in women with less advanced HIV-1 disease. Viral load was the only predictor of transmission and remained strongly predictive despite the inclusion into the logistic regression model of other maternal and delivery factors known or suspected to affect the risk of transmission.
It is not clear why the association between viral load and perinatal transmission appears to be more pronounced among women with the least immunosuppression. The high level of viremia that occurs during primary HIV-1 infection  has been implicated in increased post-natal transmission in women who breastfeed . Similarly, high viral load among women seroconverting during pregnancy has been proposed as a mechanism for perinatal transmission. However, none of the women in this study with high CD4 counts and viral load had evidence of recent HIV-1 infection (data not shown). Alternatively, other factors associated with advanced immunosuppression, disease stage, and possible increased virulence such as syncytium-inducing or slow-growing viral phenotype [28,29], viral lymphocytotropism [28,29], or the presence of neutralizing antibodies to autologous virus [29,30], may have contributed to perinatal transmission and have obscured the relationship between high viral load and perinatal transmission in the women with AIDS.
These results confirm and extend the findings of previous studies of viral load and perinatal transmission that have used smaller samples and different assay techniques. Weiser et al.  found higher cell-associated viral titres by endpoint dilution of viral culture of peripheral blood mononuclear cells (PBMC) among five transmitting and 14 non-transmitting mothers. Likewise, Borkowsky et al. , using a branched chain DNA amplification assay, found that a significantly higher proportion of transmitting mothers (five out of 11, 45%) than non-transmitting mothers (eight out of 48, 17%) had detectable virus, and that transmitting mothers had fivefold more infected PBMC than nontransmitters. Possible confounding factors, including CD4+ cell count were not controlled in either study.
Our results also support the recent findings of Dickover et al.  who showed that plasma viral load was the strongest predictor of perinatal transmission among several measures of viral load (e.g., quantitative DNA PCR, quantitative plasma and PBMC coculture, and immune-complex dissociated p24 antigen). Similar to recent reports by others [34–36], we could not confirm the presence of a threshold effect of viral load on perinatal transmission. We did not identify a viral load level above or below which transmission consistently occurred, nor could we identify maternal or delivery factors that were significantly associated with perinatal HIV-1 transmission among women with low or undetectable viral load. Although study limitations may have limited our ability to detect a transmission threshold, we suspect that our findings simply confirm the multi-factorial nature of perinatal transmission whereby high HIV-1 viral load is an important but not sufficient risk for perinatal transmission.
The findings in this report have some limitations. Free plasma viral RNA is subject to degradation by circulating RNases and degranulated polymorphonuclear cells in whole blood . For this study whole blood was collected in heparinized tubes without centrifugation and kept at ambient temperature for approximately 24–30 h until separated. In addition, samples were stored frozen at −20°C or below for up to 5 years, during which time some additional degradation may have occurred. Therefore, the levels reported here are undoubtedly lower than the actual circulating levels of plasma viral RNA at the time of phlebotomy. However, two recent studies that examined the in vitro loss of plasma viral RNA in standard heparinized vacuum tubes found that 53–63% of viral RNA remains measurable after the first 24–30 h of storage of unspun tubes at ambient temperatures [38,39]. Moreover, we could not detect any correlation between low viral copy number and the number of years samples were frozen in storage. Nonetheless, the rate of degradation of viral RNA should not differ systematically between transmitting and non-transmitting mothers, and thus should not bias comparisons between these two groups.
The demonstration that zidovudine reduces the risk of perinatal transmission of HIV-1  is among the most important AIDS research findings to date. Among the presumed mechanisms for this reduction in transmission is a zidovudine-induced decrease in maternal viral load. The data presented here support the role of high plasma viral load in perinatal transmission of HIV-1, but also suggest that this role is greater among women with less advanced disease. It is these women, thought to be at relatively lower risk of perinatal transmission, who if demonstrated to have high viral load, may benefit the most from aggressive antiretroviral therapy to decrease the viral burden during pregnancy and delivery. Further research is needed to verify that decreasing viral load is a mechanism by which zidovudine reduces perinatal transmission and to determine the different roles of cell-associated and free virus in both in utero and intrapartum transmission of HIV-1.
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Other members of the New York City Perinatal HIV Transmission Collaborative Study include
New York City Department of Health: Sarah T. Beatrice, Mary Ann Chiasson, Erica DeBernado, Sylvia Hutchison, Katherine McVeigh, William Oleszko, Amado Punsalang.
Medical and Health Research Association of New York City, Inc.: Tina Alford, Abraham Betre, Mark Cappelli, Nilda Carrasquillio, Nancy Cruz, Julia Floyd, Virginia Foye-Sousou, Dorothy Jones Jessop, Luis Macias, Debbie Ng, Katherine Nelson, Jeanette Rios, Lucille Rosenbluth, Roxanne Hodge, Hany Tadros, Jeremy Weedon, Sadarryle Young, Zhong-Ren Zhang.
NYU Medical Center–Bellevue Hospital Center: Renee Courtland, Mitzi Daligadu, William Hoover, Dora Lopez, Henry Pollack, Keith Krasinski.
Harlem Hospital Center: Ameritha Belmore, Susan Champion, Julia Floyd, Cynthia Freedland, Susan Lovich, Pamela Prince, Adrienne Rogers, Maria Suarez.
Lincoln Hospital: Jean Chow, Aditya Kaul, Sharon Nachman, Kiran Shah.
Metropolitan Hospital Center: S. Ahmed, Elmer Agustin, Roger Henriquez, Lynn Jackson, Nancy Cruz, Eileen Sacharzky, Sylvia I. Losub.
Center for Comprehensive Health Practice: Richard Brotman, Stanley Blanch, Jesse Brutus, Carol Day, David Hutson, Wendy Rhinehart, Raymond Simon, Victor Turkell.
Mount Sinai Hospital: Katherine T. Grimm.
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