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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Keywords:© 2000 Lippincott Williams & Wilkins, Inc.
labor; obstetrics; pharmacokinetics; umbilical cord blood; vertical HIV transmission; zidovudine