Oral zidovudine during labor to prevent perinatal HIV transmission, Bangkok: tolerance and zidovudine concentration in cord blood
Bhadrakom, Chaiporna; Simonds, R. J.bc; Mei, Joanne V.d; Asavapiriyanont, Suvannae; Sangtaweesin, Varapornf; Vanprapar, Niruna; Moore, Katy H. P.g; Young, Nancy L.bc; Hannon, W. Harryd; Mastro, Timothy D.bc; Shaffer, Nathanbc; for the Bangkok Collaborative Perinatal HIV Transmission Study Group
From the aSiriraj Hospital Faculty of Medicine, Siriraj Hospital, Bangkok, Thailand; bThe HIV/AIDS Collaboration, Nonthaburi, Thailand; cDivision of HIV/AIDS Prevention, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA; dDivision of Environmental Health Laboratory Sciences, CDC, Atlanta, GA, USA; eRajavithi Hospital, Department of Medical Services (DMS), Ministry of Public Health (MOPH), Bangkok, Thailand; fQueen Sirikit National Institute for Child Health, DMS, MOPH, Bangkok, Thailand; and gGlaxo-Wellcome, Inc., Research Triangle Park, NC, USA.
Sponsorship: This work was supported by the US Centers for Disease Control and Prevention, as part of a bilateral HIV/AIDS research collaboration with the Thai Ministry of Public Health. Glaxo-Wellcome provided the study drugs.
The use of trade names is for identification only and does not constitute endorsement by the Thai Ministry of Public Health, the US Department of Health and Human Services, the Public Health Service, or the Centers for Disease Control and Prevention.
Correspondence and requests for reprints to: R.J. Simonds, MD, The HIV/AIDS Collaboration, DMS 6 Building, Ministry of Public Health, Tivanon Road, Nonthaburi, 11000, Thailand. Tel: +66 2 591 8358; fax: +66 2 591 5443; e-mail: email@example.com
Received: 14 May 1999; accepted: 30 October 1999.
Objectives: To evaluate tolerance for the oral administration of zidovudine (ZDV) during labor and measure the resulting ZDV concentrations in umbilical cord blood.
Design: A cross-sectional study of women in a placebo-controlled trial of short-course ZDV (twice a day from 36 weeks' gestation until labor and every 3 h during labor) to prevent perinatal HIV transmission in Bangkok.
Methods: Umbilical cord blood was collected. Sixty control specimens and specimens from 372 women (182 in the ZDV group, 190 in the placebo group) were tested for ZDV by radioimmunoassay (lower detection limit < 1 ng/ml).
Results: All women in the ZDV group took one or more labor dose, 170 (93%) took their last dose within 3 h of delivery, and only five (3%) experienced nausea or vomiting, a proportion similar to the placebo group. The median concentration of ZDV in the cord blood in the ZDV group was 252 ng/ml (range, < 1–1133 ng/ml); 31 (17%) specimens were less than 130 ng/ml (0.5 μM), the concentration thought to be active against HIV in vitro. Median concentrations were 189 ng/ml in specimens from women taking one or two labor doses, 290 ng/ml in those taking three or four doses, and 293 ng/ml in those taking more than four doses (P < 0.01). The ZDV concentration was not associated with time since the last dose, body weight, or perinatal transmission.
Conclusion: Oral intrapartum ZDV was feasible and well tolerated. Most ZDV concentrations in the cord blood after oral dosing during labor were at therapeutic concentrations but were lower than those reported after continuous intravenous administration. Although concentrations were not associated with perinatal transmission, these data do not exclude the possibility that intrapartum and neonatal chemoprophylaxis is effective.
In 1994, the AIDS Clinical Trials Group 076 (ACTG 076) protocol demonstrated in the United States and France that the administration of zidovudine (ZDV) orally during pregnancy, intravenously during labor, and orally during the newborn period resulted in a reduction of transmission risk from 25 to 8%[1,2]. However, because of its cost and complexity, this regimen has not been implemented widely in developing countries, where most perinatal HIV transmission occurs . In Thailand, approximately 1.5% of women in antenatal care are infected with HIV, resulting in approximately 15 000 births to HIV-infected women each year [4,5]. To determine whether a shorter antiretroviral regimen feasible in Thailand and other developing countries might be safe and effective, we conducted a clinical trial of 300 mg ZDV administered orally twice a day starting at 36 weeks' gestation and every 3 h during labor; there was no newborn component. The trial demonstrated that this `Bangkok regimen' reduced the risk of transmission by 50%, and that 80% of the treatment effect could be explained by low viral load at delivery [6,7].
The goal of the intrapartum component of the ZDV regimen is to provide ZDV to the newborn to protect against infection after exposure to HIV during labor and delivery. Although the continuous infusion of ZDV used in the ACTG 076 regimen is the best way to ensure a consistent concentration in the newborn at delivery, intravenous administration is not practical in most developing countries. To simplify the intrapartum component, the Bangkok regimen used an oral dosing schedule (300 mg every 3 h during labor). This schedule was based on pharmacokinetic models and was designed to achieve a similar plasma concentration as the ACTG 076 intravenous regimen (2 mg/kg followed by 1 mg/kg per hour). However, little is known about how well women in labor can take, retain, and absorb ZDV administered orally during labor, or about the range of ZDV concentrations in newborns after oral administration. To evaluate the oral administration of ZDV during labor as part of a simplified ZDV regimen, useful in developing countries, we measured ZDV in cord blood specimens from infants in a randomized trial of short-course ZDV in Thailand.
Materials and methods
Umbilical cord blood was collected from 375 (95%) of 395 HIV-infected women enrolled in a randomized, placebo-controlled clinical trial evaluating the safety and efficacy of a short course of oral ZDV to prevent perinatal HIV transmission in two large hospitals in Bangkok [6,7]. All women provided informed consent and none breastfed their infants. Tablets containing 300 mg ZDV and identical tablets containing placebo provided by Glaxo-Wellcome, Inc. (Research Triangle Park, NC, USA) were packaged in identical `blister packs'. As each woman was enrolled, a coded packet of 10 tablets was stored in the hospital labor and delivery ward for her. The antenatal dose was one tablet twice a day from 36 weeks' gestation. Women were instructed to take an additional tablet and go to the hospital as soon as possible after the onset of labor (regular contractions or membrane rupture). In the labor and delivery ward, tablets were administered orally every 3 h by staff nurses, aided by a medication schedule and an alarm clock to mark the 3 h intervals at the bedside. Women scheduled for elective cesarean section were given tablets 12, 9, and 6 h before surgery.
Demographic information, obstetric history, and prepregnancy weight were collected at enrolment, and weight was measured at each antenatal visit. Gestational age was estimated from the date of the last menstrual period, physical examination, and if needed, fetal ultrasound. Laboratory evaluations were performed at enrolment and at delivery. The use of other medications was recorded during each antenatal visit and at delivery. The duration of treatment with the study drug was recorded from women's reports and pill counts at each weekly study visit and at delivery. The mode of delivery, other intrapartum medications, and the time of delivery were recorded after delivery. Times of all labor doses, side-effects, and any problems with administering the study drug were recorded by hospital staff nurses and verified by research staff. Infants who tested positive by HIV DNA polymerase chain reaction were considered to be infected, those with a negative polymerase chain reaction at 2 or more months of age were considered to be uninfected, and the remaining children were considered to have indeterminate infection status .
The study was approved by the Ethical Review Committee of the Ministry of Public Health of Thailand and the Institutional Review Board of the Centers for Disease Control and Prevention (CDC).
Cord blood testing
After the umbilical cord was clamped, blood was obtained either by needle aspiration of a cord vessel or by the collection of blood drained from the cord. Blood was collected into a serum separation tube, allowed to clot at room temperature, and transported to the local laboratory at 4°C, where it was centrifuged. The serum was stored in 1 ml aliquots at −70°C until testing (1–12 months after collection). Three of the 375 specimens had insufficient volume and were excluded from analysis. Three types of control serum were prepared at CDC in Atlanta: stock serum was used as the negative control, and ZDV was added to the stock serum to achieve ZDV concentrations of 50 ng/ml (low titer) or 1000 ng/ml (high titer). The three stocks of control serum were sent to Bangkok, where they were transferred into 20 1 ml aliquots that appeared to be identical to the cord blood aliquots. Ten control specimens of each type were intermixed with each of two batches of study samples, which were shipped frozen to Atlanta for testing.
Coded specimens were assayed for ZDV concentration according to the protocol of the ZDV–Trac 125I radioimmunoassay kit (DiaSorin Incorporated, Stillwater, MN, USA). From each sample, 100 μl of serum was diluted into 2 ml of kit diluent. The ZDV concentration in the test specimens was calculated against a standard calibration curve prepared from kit controls. The lower limit of detection of ZDV was less than 1 ng/ml.
Each specimen was assayed in duplicate in two separate runs, for a total of four replicates for each specimen. If the coefficient of variation for a given specimen was over 10%, the specimen was again tested in replicate, and the values from the discrepant run were disregarded. The reported results are the means of four values obtained for each specimen. In each run, two control pools provided in the kit and three control pools produced in the laboratory were assayed; all were within 95% of the control limits.
Epi Info software  was used to merge study variables with treatment assignment and ZDV concentration results and to analyse the data. Medians, means, and standard deviations were calculated for continuous variables. Distributions of cord blood concentrations between groups were compared by using the Kruskal–Wallis test. The proportion of specimens with concentrations of less than 130 ng/ml (0.5 μM), the concentration thought to be active against HIV in vitro, was calculated, and proportions were compared across groups by using the chi-square test, Fisher exact test, or chi-square test for linear trend.
Of the 432 specimens tested, 60 were laboratory control specimens, 190 were cord blood specimens from women in the placebo group, and 182 were cord blood specimens from women in the ZDV group. None of the 20 specimens from the negative control group or 190 specimens in the placebo group had measurable ZDV. The mean ZDV concentration was 63.2 ng/ml (SD, 9.1 ng/ml) in the low-titer (50 ng/ml) control group and 936.3 ng/ml (SD, 115.9 ng/ml) in the high-titer (1000 ng/ml) control group.
Characteristics of the 182 women in the ZDV group are shown in Table 1. All women took at least one labor dose (range, one to 20 doses; median three doses). The median time between last ZDV dose and delivery was 95 min; 93% of women took their last dose within 3 h of delivery. Only five (3%) women in the ZDV group and six (3%) women in the placebo group reported nausea or vomiting after taking the drug during labor, but these symptoms did not interfere with continuing to take the study drug.
The mean, median, minimum, and maximum ZDV concentrations in cord blood specimens from the 182 women in the ZDV group were 292, 252, less than 1, and 1133 ng/ml. Seventeen per cent of specimens had ZDV concentrations of less than 130 ng/ml (0.5 μM), and 52% had concentrations of less than 260 ng/ml (1 μM). ZDV was not detectable from the cord blood specimen from only one woman in this group. She had received two labor doses, the last one 55 min before giving birth vaginally.
The ZDV concentration correlated somewhat with the number of labor doses received (R2 = 0.08, Fig. 1); for women who took only one or two doses during labor, the median concentration was 189 ng/ml (Table 2). A significantly higher proportion of women who took only one or two labor doses (20 out of 77, 26%) had concentrations of less than 130 ng/ml compared with women who took more doses (11 out of 105, 10%, P = 0.006). The median ZDV concentration was higher among women who gave birth by cesarean section than among those who gave birth vaginally (331 versus 240 ng/ml, P = 0.03). However, the women who gave birth by cesarean section took more labor doses than did the women who gave birth vaginally (median four versus three, P = 0.02). Of the 27 women who gave birth by cesarean section, the six who received general anesthesia had much lower median ZDV concentrations than the 21 who received other types of anesthesia (115 versus 377 ng/ml, P = 0.02), despite a slightly higher median number of labor doses (six versus four, P = 0.17) and a similar median interval between the last dose and delivery (112 versus 92 min, P = 0.45).
The ZDV concentration was not significantly associated with the interval between the last labor dose and delivery (R2 = 0.0, Fig. 2), although the concentrations tended to be lower when the last dose was more than 3 h before delivery (Table 2). There also was no association with body weight at the last prenatal visit (approximately 1 week before delivery), the use of other medications during labor (Table 2), the CD4 lymphocyte count at delivery, liver enzyme or serum creatinine concentrations at delivery, or the duration of prenatal ZDV treatment (data not shown). There was no association between the concentration of ZDV in the cord blood and HIV transmission to the child, even when presumed in-utero infections were excluded (Table 2), and when adjusting for the mother's viral load at delivery (data not shown). The proportions of infected children were similar for those with concentrations of less than 130 ng/ml (10.0%) and those with concentrations of over 130 ng/ml (9.6%).
Oral dosing with 300 mg tablets of ZDV during labor was feasible and was well tolerated in this population of HIV-infected women in Thailand. All women took at least one labor dose, and 93% took a dose within 3 h of delivery. Only 3% of women experienced nausea or vomiting after a labor dose, and this proportion was the same for the ZDV and placebo groups.
The primary goal of using ZDV intrapartum is to achieve a concentration of ZDV in the fetus at the time of maximum exposure to HIV – during labor and delivery – that will inhibit the establishment of infection in the newborn, i.e. as chemoprophylaxis. In the ACTG 076 protocol, extended chemoprophylaxis was provided by a 6 week course of ZDV for newborns . With the ZDV regimen used in this study, the period of chemoprophylaxis lasts only until the intracellular ZDV-triphosphate concentration in the newborn at birth falls below that needed to inhibit viral replication.
Although ZDV chemoprophylaxis is thought to prevent transmission after occupational exposure to HIV, neither the concentration of ZDV nor the duration of treatment after exposure necessary for protection is known . In-vitro studies using a cytopathic protection assay have shown that ZDV concentrations of over 130 ng/ml inhibit the replication of HIV in human lymphocytes, although other assays have demonstrated inhibition at lower concentrations . In our study, 82% of children were born with ZDV concentrations of over 130 ng/ml, and 48% had at least twice this concentration. However, considering that the half-life of ZDV in the newborn is approximately 7–13 h [11–13], only approximately half the infants born to mothers receiving the Bangkok regimen would be expected to have in-vitro inhibitory plasma concentrations for more than half a day.
Another approach to interpreting these data on ZDV concentration in the cord blood after oral administration during labor is to compare them with concentrations after intravenous ZDV administration during labor. In the pharmacokinetic studies performed in preparation for ACTG 076, ZDV concentrations in the cord blood were measured in seven infants after intermittent intravenous administration of 140 mg of ZDV every 4 h (approximating a 200 mg oral dose five times a day) during labor . The mean concentration in these specimens was 280 ng/ml (SD, 140 ng/ml), similar to the mean concentration of 291 ng/ml observed in our study. However, with the regimen adopted in the ACTG 076 trial and now recommended in the United States (2 mg/kg loading dose followed by 1 mg/kg per hour infusion) , mean ZDV concentrations were 740 ng/ml in cord blood (n = 2) and 780 ng/ml in newborn plasma (n = 7)  in one study, and the median concentration was 450 ng/ml in cord blood in a second study (ACTG 296, n = 28) . The latter study also reported a median ZDV-triphosphate concentration of 70 fmol/106 cells, which the authors conclude was two to three times higher than those in HIV-infected persons taking oral ZDV therapy. One study of 21 women taking oral doses similar to the Bangkok regimen  reported a mean ZDV concentration in the cord blood of 232 ng/ml; another of nine women  reported a median concentration of 379 ng/ml. The cord blood ZDV concentrations achieved with oral dosing in the Bangkok regimen thus appear to be similar to those with intermittent intravenous dosing, but are approximately half those with continuous intravenous administration. Also, concentrations in fetal baboons were lower than those in their mothers after oral administration . Therefore, in settings where it is feasible, continuous intravenous infusion may be a better option for achieving high concentrations of ZDV at birth, although whether such high concentrations provide protection in the absence of continued dosing to the child is not known.
Women who received only one or two doses had significantly lower ZDV concentrations in the cord blood than those who received more doses. In addition, women whose last dose was over 3 h before delivery tended to have lower concentrations. Higher concentrations were found in women who gave birth by cesarean section, except in those who had general anesthesia, although the association with cesarean section may be confounded by the number of labor doses received. The most likely explanations for decreased ZDV concentrations in those who received general anesthesia are decreased absorption resulting from decreased intestinal perfusion and the muscle relaxant effect, which delays gastric emptying.
In this study, the concentration of ZDV in the cord blood was not associated with perinatal HIV transmission. In the light of the overall 50% protective effect of the Bangkok regimen in reducing the risk for transmission [6,7], the absence of an association between ZDV concentration in the newborn and transmission suggests that the intrapartum component of the Bangkok regimen may have played a small role, if any, in its overall efficacy. The finding that low maternal viral load at delivery explained approximately 80% of the treatment effect in this trial further supports this interpretation . Whether modifying this regimen to include a loading dose or more frequent dosing in labor would improve its efficacy is unknown, but is unlikely in the absence of infant dosing. Although such a change might increase the proportion of newborns with inhibitory concentrations of ZDV at birth, the short plasma half-life of ZDV prevents intrapartum dosing alone from providing sustained in-vitro inhibitory concentrations. In contrast, a drug with a longer half-life, such as nevirapine, can provide significant protection after dosing only during labor and once to the infant in the first 3 days of life .
Nonetheless, the lack of correlation between cord blood ZDV concentration after the use of the Bangkok regimen and transmission does not mean that ZDV chemoprophylaxis of the newborn may not be effective, either alone or as part of combined antenatal and newborn treatment. As our data suggest, chemoprophylaxis administered only during the intrapartum period can be expected to provide relatively low plasma concentrations of ZDV in the infant for only 1–2 days after delivery. These data are corroborated by another study showing that intrapartum dosing alone with ZDV and lamivudine had no effect on transmission . In contrast, the ACTG 076 regimen exposes the infant to higher concentrations of ZDV at delivery, and maintains high concentrations by providing ZDV to the infant for 6 weeks. It is possible that the infant component of the regimen may partly explain why the proportion of the treatment effect attributable to the reduction of maternal viral load estimated for the ACTG 076 regimen (11%)  was much smaller than for the Bangkok regimen (80%) . These data thus do not indicate whether chemoprophylaxis designed to provide a long period of viral inhibitory concentration in the newborn, such as a more potent antiretroviral medication, one with a longer half-life, or one continued in the infant, might be efficacious alone, as suggested recently [19–21], or might have made the Bangkok regimen more efficacious if added to it.
This study has several important limitations. First, ZDV concentrations were measured only at one timepoint, and more formal pharmacokinetic analyses were not done. Second, we did not measure the active intracellular triphosphate anabolite of ZDV, which has a longer in-vitro half-life (3–4 h) than the plasma half-life of ZDV (1 h) in adults [22,23], and may play an important role in viral inhibition. More detailed pharmacokinetic information from ACTG protocols 296 and 324 should help address these two issues. Third, the findings from our population of women in Thailand may not be generalizable to other developing countries, where the healthcare system may be less able to provide intrapartum medications.
Our finding that the use of an oral antiretroviral medication during labor is feasible and well tolerated supports further evaluation of oral doses of antiretroviral agents during labor. The recent finding that oral intrapartum nevirapine can substantially reduce transmission highlights the public health importance of the oral administration of antiretroviral agents in labor for preventing perinatal HIV transmission in developing countries .
Other members of the collaborative study group, not listed as co-authors: K. Limpakarnjanarat, W. Supapol, A. Bennetts, N. Chantharojwong, T. Naiwatanakul, J. Laosakkitiboran, P. Yuentrakul, C. Manopaiboon, R. Chuachoowong, P. Mock (HIV/AIDS Collaboration); S. Neungton, P. Chaisilwattana, A. Roongpisuthipong, A. Chalermchokcharoenkit, K. Sirimai, P. Phopong, P. Chaiyakul, P. Rattananikhom, R. Prechanont (Obstetrics/Gynecology), M. Tuchinda, S. Chearskul, K. Chokephaibulkit, S. Pichitchaichan, W. Boonyavit (Pediatrics) and C. Wasi (Microbiology, Faculty of Medicine Siriraj Hospital); P. Chinayon, W. Siriwasin, B. In-neam, S. Supatosa, C. Kannasot, S. Sangkasuwan, S. Leampojara, P. Pramukhakul (Obstetrics/Gynecology), S. Singhanati, G. Kaewchaiyo (Laboratory), J. Sawakwan, N. Montasewee (Nursing, Rajavithi Hospital); S. Horpaopan, T. Chotpitayasunondh, N. Waranawat, P. Na Chiengmai, R. Kulvisuthpravit, B. Phasukdee, P. Sojirat (Queen Sirikit National Institute for Child Health).
The authors also gratefully acknowledge the dedicated field work of the project study nurses and social workers: K. Neeyapun, B. Jetsawang (team leaders); S. Bhengsri, S. Henchaichon, S. Jalanchavanapate, K. Klumthanom, R. Krajangthong, C. Prasert, W. Sanyanusin, W. Suwannapha, S. Sorapipatana, S. Suwanmaitre, W. Triphanitchkul, and C. Yuvasevee.
The authors also thank N. Meredith for laboratory testing, Philip Mock for data analysis assistance, and Marie Morgan and Martha Rogers for critical review of the manuscript. Finally, they would like to thank the women who agreed to participate in this study.
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