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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e31802c5441
Clinical Science

Triple Antiretroviral Prophylaxis Administered During Pregnancy and After Delivery Significantly Reduces Breast Milk Viral Load: A Study Within the Drug Resource Enhancement Against AIDS and Malnutrition Program

Giuliano, Marina MD*; Guidotti, Giovanni MD*; Andreotti, Mauro BSc*; Pirillo, Maria F BSc*; Villani, Paola BSc†; Liotta, Giuseppe MD‡; Marazzi, Maria Cristina MD§; Mancini, Maria Grazia BSc*; Cusato, Maria PharmD†; Germano, Paola MSc∥; Loureiro, Sandra MD¶; Ceffa, Susanna BSc∥#; Regazzi, Mario PharmD†; Vella, Stefano MD*; Palombi, Leonardo MD‡

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From the *Istituto Superiore di Sanità, Rome, Italy; †IRCCS Policlinico S. Matteo, Pavia, Italy; ‡University of Tor Vergata, Rome, Italy-Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) Program; §Libera Università Maria SS. Assunta (LUMSA), Rome, Italy-DREAM Program; ∥DREAM Program, Community of S. Egidio, Italy; ¶Direçao Provincial de Saude, Maputo, Mozambique; and #University of Pisa, Pisa, Italy.

Received for publication April 11, 2006; accepted October 19, 2006.

Reprints: Marina Giuliano, MD, Department of Drug Research and Evaluation, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy (e-mail: giuliano@iss.it).

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Abstract

Background: The administration of antiretroviral therapy to lactating women could represent a possible strategy to reduce postnatal HIV transmission. In this study, we assessed the effect of antiretroviral treatment on breast milk viral load and determined plasma and breast milk drug concentrations in pregnant women receiving highly active antiretroviral therapy (HAART).

Methods: We studied 40 women receiving zidovudine, lamivudine, and nevirapine from 28 weeks of gestation to 1 month postpartum (group A) and 40 untreated pregnant women (group B). Blood and breast milk samples were collected at delivery and 7 days postpartum.

Results: Women in group A had received a median of 85 days of therapy before delivery. Median breast milk concentrations of nevirapine, lamivudine, and zidovudine were 0.6, 1.8, and 1.1 times, respectively, those in maternal plasma. HIV RNA levels in breast milk were significantly lower in group A than in group B (median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at day 7; P < 0.001 for both comparisons).

Conclusions: Antiretroviral drugs administered during the last trimester of pregnancy and after delivery reach levels similar to or higher than plasma concentrations in breast milk and can significantly reduce HIV RNA levels. Our data support the potential role of maternal HAART prophylaxis in reducing the risk of breast-feeding-associated transmission.

Antiretroviral regimens administered during pregnancy and around delivery are effective in reducing mother-to-child HIV transmission. Their benefits in resource-limited countries can be severely compromised by the subsequent transmission associated with breast-feeding, however.1-3 The use of replacement feeding in these settings is strongly influenced by reasons of safety, cost, feasibility, and social acceptance and represents a valid option only for a limited number of women. Strategies under evaluation that could allow “safe” breast-feeding include modification of the type (exclusive vs. mixed) and duration of breast-feeding, daily administration of antiretroviral prophylaxis to breast-feeding infants, and maternal highly active antiretroviral therapy (HAART) prophylaxis.4

We conducted a pilot study to collect information for the design of a clinical study to assess the safety and efficacy of maternal HAART prophylaxis for the prevention of breast-feeding-associated transmission. The aim of the pilot study was 2-fold: first, to compare the breast milk viral load of women receiving antiretroviral therapy with that of untreated women and, second, to determine the concentrations of antiretroviral drugs in plasma and breast milk of treated women.

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METHODS

Participants

The study was conducted in Mozambique. Two groups of HIV-positive pregnant women were enrolled. Group A included women attending the antenatal clinic in Matola, Maputo, which is part of the Drug Resource Enhancement Against AIDS and Malnutrition (DREAM) program designed and managed by the Community of S. Egidio (faith-based Italian nongovernmental organization). The DREAM program includes comprehensive prevention and care for HIV-positive women, their children, and their husbands.5 Group B included women attending the antenatal clinic in Machava, Maputo, where routine HIV testing is not performed and antiretroviral prophylaxis is not administered to pregnant women. There were no specific inclusion criteria, and mothers recruited for groups A and B were those who consecutively, after the start of the study, accepted participation. Group A women were enrolled during pregnancy (when on treatment), whereas group B women were tested for HIV at delivery and, if positive, asked to participate. The study was approved by the National Ethics Committee of Mozambique, and all women provided written informed consent for participation in the study.

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Antiretroviral Regimens

Group A women received antiretroviral combination regimens (generic formulations of zidovudine [or stavudine if hemoglobin was <8 g/dL] plus lamivudine and nevirapine) starting at 28 weeks of gestational age (or as soon as possible after the first trimester for the women meeting the 2003 World Health Organization [WHO] criteria for treatment6) until 1 month postpartum. All infants of both groups of women received a single dose of nevirapine within 72 hours of birth. After delivery, women in group B were enrolled in the DREAM program and received antiretroviral therapy if meeting the criteria for treatment.

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Collection and Processing of Samples

All women were instructed not to breast-feed their infants, and free formula feeding was provided soon after delivery to all women. From delivery until 1 week postpartum, breast milk was expressed manually 5 times a day. Within 3 days after delivery (time 0) and 1 week after delivery (time 7) 10 mL of blood and 10 mL of colostrum/breast milk were collected from all women. Samples were processed within 12 hours at the local laboratory in Maputo. Plasma was stored at −80°C. One milliliter of breast milk was separated and frozen (whole milk). The remaining 9 mL was centrifuged at 1000g × 10 minutes. The lipid layer and the supernatant (skim milk) were separated and frozen. Breast milk cells were washed once in phosphate-buffered saline (PBS) and stored at −80°C as dry pellets.

All stored samples were shipped in dry ice and processed at the Istituto Superiore di Sanità (National Institute of Health in Italy).

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Quantification of Plasma and Breast Milk HIV RNA

Plasma HIV-1 RNA levels were measured using the Amplicor UltraSensitive HIV-1 Monitor (version 1.5; Roche Molecular Diagnostics, Mannheim, Germany) with a lower detection limit of 50 copies/mL. The Amplicor assay was modified to quantify HIV-1 RNA copies in whole breast milk and breast milk fractions to reduce inhibition of reverse transcriptase polymerase chain reaction (RT-PCR) amplification.7 All breast milk samples were centrifuged at 23,500g for 1 hour at 4°C, lipids were removed using filter paper, and the supernatants were discarded. Pellets were resuspended in 500 μL of PBS and centrifuged at 23,500g for 1 hour at 4°C. After discarding the supernatants, the samples were processed according to the manufacturer's protocol.

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Quantification of Breast Milk HIV DNA

DNA was extracted from breast milk pellets using the QIAamp DNA Blood Mini kit (Qiagen, Hilden, Germany).

The HIV DNA load was measured by real-time PCR technology. The ABI Prism 7500 Real Time PCR System (Applied Biosystems, Foster City, CA) was used for PCR amplification, acquisition, and data analysis. The amount of HIV proviral DNA was determined by amplifying a region of gag that is highly conserved in known sequences (Los Alamos HIV sequence database) of clade C (predominant in Mozambique) and B viruses. The sequence of the internal probe was 5′-GCATTATCAGAAGGAGCCACCCCACAA-3′ (VIC-TAMRA), and the forward and reverse primer sequences were 5′-AGCCCAGAAGTAATACCCATGTTT-3′ and 5′-TGCTTGATGTCCCCCCACT-3′, respectively. The 8E5 cell line, a T-lymphoblastoid cell line that contains a single defective genome copy of HIV (clade B) per cell, was used to generate standard curves for HIV-1 DNA and RNase P quantification. The TaqMan RNase P Control Reagents Assay (VIC-Tamra; Applied Biosystems) was used to determine the genomic DNA quantity.

All samples and controls were run in triplicate, and the normalized value of the HIV-1 DNA load was expressed as the number of HIV copies/106 cells. HIV-1 and RNase P standard curves had slopes between −3.28 and −3.52, and the coefficients of correlation were >0.98. The limit of detection was 10 copies/106 cells.

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Analysis of Drug Concentrations

Plasma and whole breast milk concentrations of the 3 antiretroviral drugs (nevirapine, lamivudine, and zidovudine) were determined in a single central laboratory using specific and validated reverse-phase high-performance liquid chromatography (HPLC) methods with ultraviolet detection.8-10 The limits of quantification (LOQ) of these assays were 50 ng/mL, 20 ng/mL, and 20 ng/mL for nevirapine, lamivudine, and zidovudine, respectively. Interday precision based on quality control samples was <10% for nevirapine and <15% for lamivudine and zidovudine. Calibration standards demonstrated fair linearity, resulting in correlation coefficients of >0.995 over the standard concentration ranges of 50 to 12,000 ng/mL (nevirapine) and 20 to 4,000 ng/mL (lamivudine and zidovudine). Concentrations less than the LOQ were reported as equal to 0.

Simultaneous maternal blood and breast milk sampling allowed calculation of the milk/plasma concentration ratio (M/P ratio) at each sampling time so as to express the quantity of drugs in milk as a function of the maternal plasma concentration. M/P ratios were determined only for women who had both plasma and breast milk detectable levels.

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Statistical Analysis

Descriptive results are presented as means, medians, and percentages. To compare means, medians, and proportions between groups, the Student t test, Mann-Whitney U test, χ2 test, and Fisher exact test were used as appropriate. The correlations between plasma and breast milk HIV RNA levels and between drug levels and plasma/breast milk HIV RNA were determined using the Pearson correlation coefficient. Logistic regression was used to determine the probability of achieving levels of HIV RNA <400 or <50 copies/mL in breast milk. Calculations were performed using SPSS version 13.0 (SPSS, Chicago, IL).

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RESULTS

Between August and December 2004, a total of 80 women were enrolled in the study: 40 in group A and 40 in group B. Patients' characteristics are reported in Table 1. Women in group A had received a median of 85 days of antiretroviral therapy. The CD4+ cell count at delivery was higher in group A (median = 551 cells/mm3) than in group B (median = 347 cells/mm3) (P < 0.001).

Table 1
Table 1
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HIV RNA levels in plasma and in all breast milk fractions were significantly lower in group A in comparison to group B at both study time points (in plasma: median of 2.2 vs. 4.8 log at delivery and 2.3 vs. 4.9 log at time 7; in whole milk: median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at time 7; P < 0.001 for all comparisons; Table 2). In untreated women, HIV RNA in breast milk fractions was approximately 1 log lower than in plasma, whereas in group A, HIV RNA levels in plasma and in breast milk were similar. In the untreated group, the plasma HIV RNA load was positively correlated with the HIV RNA load in whole breast milk (r = 0.71 at time 0 and r = 0.72 at time 7, P < 0.001). To assess the sensitivity for the detection of HIV RNA of the different breast milk fractions, we evaluated the samples in which HIV RNA was measured in all 3 components (n = 120, including both groups and both time points). The rate of detection of HIV RNA (>50 copies/mL) in whole milk (91 of 120 samples [75.8%]) was higher (P = 0.025) than in the lipid layer (74 of 120 samples [61.6%]) but not significantly different in skim milk (80 of 120 samples [66.7%]).

Table 2
Table 2
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The proportion of women with HIV RNA <400 copies/mL in plasma and in breast milk fractions was significantly higher in group A than in group B (Table 3). Mothers receiving treatment were almost 5 times more likely at time 0 and 12 times more likely at time 7, respectively, to have HIV RNA <400 copies/mL in whole breast milk in comparison to untreated women (odds ratio [OR] = 4.8, 95% confidence interval [CI]: 1.7 to 13.6 for time 0; OR = 11.7, 95% CI: 3.9 to 34.1 at time 7). In a multivariate model including treatment and CD4+ cell count at delivery (as a continuous variable or categorized with values greater than or less than the median level), the only independent factor associated at both time points with a level of HIV RNA <400 copies/mL in breast milk was the administration of HAART (including categoric CD4+ cell count, OR = 3.9, 95% CI: 1.3 to 11.6 at time 0; OR = 9.9, 95% CI: 3.3 to 29.7 at time 7). At time 0, the proportion of women with levels of HIV RNA <50 copies/mL in whole breast milk was similar in group A (21.1%) and group B (11.7%), whereas at time 7, the proportions were significantly different (43.5% in group A and 12.8% in group B; see Table 3) and treated women were 5 times more likely to have HIV RNA <50 copies/mL in breast milk (OR = 5.2, 95% CI: 1.7 to 16.3). In a multivariate model including CD4+ cell count, HAART administration and CD4+ cell count (as a continuous or as a categoric variable) were independently associated with levels <50 copies/mL in breast milk at time 7 (OR = 4.0, 95% CI: 1.2 to 13.0 for HAART; OR = 3.9, 95% CI: 1.2 to 12.4 for categoric CD4+ cell count).

Table 3
Table 3
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There was a trend toward a significant difference in the detection of HIV DNA in breast milk cells between the 2 groups: 13 (32.5%) of 40 of group A women and 22 (55%) of 40 of group B women had >10 DNA copies/106 cells (P = 0.07). Mean values among patients with detectable DNA were 185.7 copies/106 cells in group A and 232 copies/106 cells in group B (see Table 2). Among the 13 women in group A who had detectable HIV DNA, only 1 had undetectable HIV RNA in breast milk; of the 22 untreated women with detectable HIV DNA, 3 had HIV RNA <50 copies in breast milk.

The median time between ingestion of the last dose of antiretroviral drugs and collection of maternal blood samples and breast milk was 5.3 hours (range: 0-99 hours) for the samples collected after delivery and 6 hours (range: 4.3-20 hours) for the samples collected 7 days postpartum. Table 4 reports the concentrations of the 3 antiretroviral drugs in plasma and breast milk at the 2 study time points in women in group A. Drugs levels in plasma and breast milk were similar at delivery and 7 days postpartum. At time 0, 6 (15%) of 40 women had undetectable nevirapine plasma levels, but 2 of them had measurable concentrations in breast milk; at time 7, nevirapine was undetectable in plasma in 4 (11.1%) of 36 patients, although in 2 cases, it was measurable in breast milk samples. At time 0, 20 (50%) of 40 patients had undetectable lamivudine levels, and among these patients, 9 had measurable concentrations in breast milk; at time 7, 4 (11.8%) of 34 patients had undetectable lamivudine levels in plasma and breast milk. Zidovudine was not found in the plasma of 22 (66.7%) of 33 patients at time 0, but it was measurable in the breast milk of 7 of these 22 women; at time 7, 16 (55%) of 29 women had no drug in plasma, but 4 of them had measurable levels in breast milk. In 9 cases, zidovudine was not detectable in plasma at either time point, and in 2 cases, zidovudine and lamivudine were undetectable at time 0 or time 7.

Table 4
Table 4
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Overall, among women with detectable plasma drug levels, median breast milk concentrations of nevirapine, lamivudine, and zidovudine were 0.6, 1.8, and 1.1 times higher than those in maternal plasma, respectively.

The relation between drug levels and plasma and breast milk HIV RNA levels was evaluated, and only plasma nevirapine levels at time 7 were inversely correlated with plasma HIV RNA load (r = −0.559, P = 0.01). The HIV RNA load in whole breast milk among compliant women (defined as those with plasma levels of the 3 drugs measured and detectable at each time point) versus noncompliant women was also compared. No significant difference was found at time 0 (breast milk HIV RNA median of 2.3 log in 9 fully compliant women vs. 2.2 log in 22 partially compliant women) or time 7 (breast milk HIV RNA median of 2.5 log in 10 fully compliant women vs. 1.7 log in 19 partially compliant women; P = not significant).

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DISCUSSION

Breast-feeding-associated transmission accounts for a significant proportion of HIV pediatric infections in the developing countries. Because replacement feeding is a feasible option only for a few women in those countries, there is an urgent need to develop strategies that could allow breast-feeding without its being associated with a risk of transmission. One possible strategy might be represented by the administration of antiretroviral combination prophylaxis to lactating women.

In our pilot study, we have shown that the level of breast milk HIV RNA in all the breast milk fractions of the women receiving triple-combination prophylaxis for approximately 3 months during pregnancy and after delivery was significantly lower than the corresponding level in the untreated women and that the proportion of women with an undetectable breast milk viral load was significantly higher in the treated women. Because the risk of postnatal transmission has been found to be related to the presence of detectable HIV in breast milk,11-13 our data support the role of maternal HAART prophylaxis in preventing breast-feeding-associated transmission.

Virologic analysis of breast milk in HIV-positive untreated women has been reported in previous articles.11,14-17 In our study, we found that a high proportion (up to 90%) of untreated women had detectable HIV RNA in breast milk and that the concentrations of HIV RNA were higher (range: 0.4-1.7 log) than previously reported. We hypothesized that the modifications we included in the processing of specimens may have played a role in obtaining greater sensitivity, although we cannot exclude the possibility that differences in CD4 cell values in the different populations could have influenced the results. The higher prevalence of cell-free HIV RNA in colostrum compared with mature milk11 could represent another possible explanation. Among the different breast milk fractions, whole breast milk and skim milk had similar sensitivities in detecting HIV RNA, although, differently from what was previously reported,15 the lipid fraction was less sensitive. We therefore suggest that for the determination of HIV RNA in the breast milk compartment, whole milk (not requiring any processing) should be used in future evaluations.

Other studies have investigated the effect of antiretroviral drugs on breast milk viral load; zidovudine prophylaxis administered from 36 weeks of gestation until 1 week postpartum17 was associated with decreased levels of HIV RNA in the breast milk compartment at day 8 after delivery compared with placebo, and in a second study,13 nevirapine received by mothers during labor resulted in levels of HIV RNA approximately 1 log lower (for up to 3 weeks) compared with zidovudine administered from 34 weeks until delivery. The RNA decrease obtained in these studies is lower than that observed in our group of women (1.7-log decrease at time 7 in comparison to no treatment). In a recent article,18 HAART administration in women with CD4+ counts <200 cells/mm3 was shown to be associated with suppression of HIV RNA in breast milk. Although our data are not directly comparable (our women had a broader range of CD4+ cell counts because most of them received HAART only for mother-to-child transmission prevention), a greater percentage of women in that study reached undetectable levels of viral load in breast milk compared with our results. We hypothesize that 2 possible factors could account for the difference: the greater sensitivity in our study in detecting HIV RNA in breast milk (reported previously) and the high serum concentrations of nevirapine (approximately 60% higher than those expected) in the study by Shapiro et al.18 We have excluded the possibility that a possible lack of drug compliance influenced our results, because breast milk HIV RNA levels between fully compliant and partially compliant women were not significantly different in a secondary analysis.

In our study, HIV DNA in breast milk cells, also shown to be associated with transmission through breast-feeding,19,20 was detected in 32.5% and 55% of women in groups A and B, respectively, with a trend toward statistical significance of this difference. Although these results might further support the role of maternal HAART prophylaxis, it has to be underlined that the magnitude of the HAART effect was lower for DNA in comparison to HIV RNA, as previously suggested.18

Our data on drug concentrations showed results similar to those reported elsewhere,21-23 with nevirapine having higher plasma concentrations with respect to breast milk and lamivudine and zidovudine with similar or higher concentrations in breast milk. The M/P ratios were obtained at different time points after drug administration, and the mean values obtained may represent a relatively accurate estimation of M/P ratios for these drugs. In some cases (approximately 20% for zidovudine or lamivudine and 10% for nevirapine), drug concentrations were detectable in breast milk in the absence of plasma levels, thus suggesting a possible lag in elimination of drugs in breast milk.

Plasma levels of nevirapine during the dosing interval were in the expected range in the compliant patients, except for 3 patients who had levels greater than 6.0 μg/mL (range: 8.9-10.3 μg/mL); therefore, our study did not confirm previous findings of higher nevirapine concentrations in African women.24 The percentage of women with undetectable plasma drug levels was higher at time 0 (within 3 days of delivery) than at time 7; in particular, the rate of undetectable levels decreased from 50% to 11.8% for lamivudine and from 66.7% to 55% for zidovudine, probably because of increased drug adherence in the postpartum period as compared with the labor and delivery periods. The high rate of women with undetectable concentrations of zidovudine in both cases is accounted for by the marked short plasma half-life of the drug (t1/2 = 1.1 hour), however, as referred to in the sampling times. We did not find significant correlations between drug concentrations and plasma/breast milk viral loads (with the exception of nevirapine plasma levels and the plasma HIV RNA load at time 7), although this might be attributable to the limited statistical power to detect these correlations because of the small number of women.

A limitation of the present study is that it would be difficult to extrapolate our results directly to other drug regimens, because other antiretrovirals can have different penetration in breast milk and different efficacy in lowering viral load.

In conclusion, we showed that a combination of zidovudine, lamivudine, and nevirapine administered during and after pregnancy reached levels similar to or higher than plasma concentrations in breast milk and was able to significantly reduce the virus load in this compartment in a group of women living with HIV/AIDS in sub-Saharan Africa.

Further data are needed on the pharmacokinetics of antiretrovirals in breast milk over a longer postpartum period and on the infant safety of maternal HAART administration so as to assess the possible efficacy of this strategy. The information about maternal prophylaxis then needs to be evaluated together with the data of other preventive strategies so as to select the best option in terms of safety, efficacy, and cost.

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ACKNOWLEDGMENTS

The authors thank Aventis Isis (Italy) for providing free breast pumps to obtain breast milk samples and all the women who volunteered for the study.

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Keywords:

antiretroviral therapy; breast-feeding; mother-to-child transmission; Mozambique

© 2007 Lippincott Williams & Wilkins, Inc.

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