8th Report from: 7th Conference on Retroviruses and Opportunistic Infections,
San Francisco, Wednesday Feb 2
Treatment Issues for Preventing Mother To Infant HIV Transmission
Of 8 HIV-infected women who completed study receiving NFV+AZT+3TC to prevent mother-to-child transmission of HIV, all were HIV uninfected at 38
weeks of age
Nevirapine can be effectively used to prevent mother-to-infant HIV-infection, however the dosing of nevirapine required may be uncertain and
is discussed below
In 1989, a registry was established to track women who receive antiretroviral therapy to prevent transmission of HIV to their newborns. Of
916 evaluable cases reported to date, registry data demonstrate no increase in the prevalence of birth defects among first trimester zidovudine
monotherapy exposures, although the power to detect such an increase is limited
Preliminary information on AZT use during pregnancy and in newborn after birth, and its potential effect on resistance and infant response to therapy
is discussed below
PACTG 353 A Phase I Study of Safety, Pharmacokinetics, and Antiviral Activity of Combination Nelfinavir (NFV), ZDV, and 3TC in HIV-Infected Pregnant Women
and Their Infants.
Y. BRYSON, A. STEK, M. MIRICHNICK, J. CONNOR, S. HUANG, M. HUGHES, L. MOFENSON, M. CULANE, J. SNIDOW, and M. GERSTEN. Univ. of California, Los
Angeles; Univ. of Southern California, Los Angeles; Boston Univ., MA; Univ. of California, San Diego; Harvard Univ., Boston MA; NIH, Bethesda, MD; Glaxo
Wellcome, Res. Triangle Park, NC; and Agouron Pharmaceuticals, La Jolla, CA.
In order to assess safety, pharmacokinetics (pk) and antiviral activity of nelfinavir (NFV) in combination with ZDV and 3TC in HIV infected pregnant
women and their infants 10 HIV infected pregnant women (14-34 weeks gestation) were enrolled and received oral (po) NFV (750mgtid), ZDV
(200mgtid), 3TC (150 mg bid), during ges and postpartum (pp) and po NFV, 3TC, and IV ZDV in labor. Infants received 6 wks of po NFV (10mg/kg tid), ZDV
(2.6mg/kg tid) and 3TC (2mg/kg bid). Viral load, CD4 count, NFV pk and clinical and lab toxicities were assessed. 8 of 10 women completed the
study; 1 had a therapeutic abortion, 1 had a fetal demise due to obstetrical complications. Women tolerated the Rx without significant toxicity. There
was a significant decrease in maternal plasma HIV RNA levels from baseline to del and pp (med -1.8, and -2.4 log, p=0.01) and 6/8 had plasma viremia of
<400 HIV RNA cp/ml at del. CD4 count and % increased from baseline to del and pp (med CD4 cells/ml 220/ 308/ 415) (mean CD4% 20,23,30) rsp. (p= 0.005).
8 infants had a med ges age of 38 wks (range 35-40wks) and all were HIV uninfected. One infant who did not receive study drugs died with clinical
sepsis and pulmonary hypertension (not study related). Transient grade 2/3 decreases in Hb and/or neutrophils occurred in 7 infants, which resolved with
discontinuation of ZDV. Maternal NFV Pk during pregnancy and 6 wks pp was similar. The med maternal NFV plasma levels at del was 2 mg/ml. Cord blood
levels were undetectable or low in all infants. At one week of life, the med NFV levels were low (pre-dose 0.74ug/ml, Cmax 1.23 ug/ml). Combination of NFV
ZDV and 3TC was well tolerated in HIV infected pregnant women and their infants and resulted in significant decreases in maternal plasma viremia and
increases in CD4 cells. Pregnancy had no effect on maternal NFV pk and placental transfer of NFV was poor. The initial dose of 10mg/kg NFV used in
the infant was inadequate and further study of a higher dose (40 mg/kg bid) is underway.
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Pharmacokinetics of Nevirapine (NVP) in Pregnant Women and in Their Infants Following In Utero Exposure.
M. MIROCHNICK*^{1}, S. SIMINSKI^{2}, T. FENTON^{2}, J. SULLIVAN^{3}, and the PACTG 250 Protocol Team. ^{1}Boston Univ. Sch. of Med., MA; ^{2}Frontier
Sci. and Technology Res. Fndn., Amherst, NY and Brookline, MA; and ^{3}Univ. of Massachusetts Med. Ctr., Worcester.
Background: Administration of a single maternal 200 mg oral NVP dose during
labor and a single oral 2 mg/kg NVP dose to the infant at 48-72 hours of life maintains serum NVP conc above 100 ng/ml (10x the in vitro IC50) throughout
the first week of life in infants born to mothers with no previous exposure to NVP.(JID 1998;178:368-74.) With chronic therapy NVP induces activity of
its own elimination pathway, accelerating clearance. No previous data are available describing NVP pk in mothers during pregnancy and in infants with
prolonged in utero NVP exposure before birth.
Methods: Pregnant women received daily 200 mg NVP doses starting at 38 wks
gest; pk sampling was performed after the 1st dose. NVP dosing continued through labor; infants received 2 mg/kg NVP at 48-72 hours of life. Infant
samples for NVP conc were obtained from cord blood, before the NVP dose, 24 hrs after the dose and on day 7. Serum NVP conc were determined by HPLC. The
data were compared to those from previous cohorts with initiation of maternal dosing during labor.
Results: 11 women were enrolled; 1 infant died in utero prior to the start
of maternal NVP dosing. Maternal pk profiles after initial doses at 38 wks gest were similar to those from non-pregnant women, but t1/2 was decreased
compared to women dosed during labor (45.6 +/- 12.4 hrs vs 72.5 +/- 36.2 hrs, p=0.037). Compared to infants whose mothers began NVP in labor, the infants
whose mothers began NVP during pregnancy had increased median cord blood NVP conc (2396 vs 1147ng/ml) and pre-dose conc (928 vs 475), but NVP conc fell
below 100 ng/ml before age 7 days in 4 of 10 infants.
Conclusion: NVP pk in pregnant women are similar to those in non-pregnant
women. However, when maternal NVP began during pregnancy, a single infant NVP dose at 48-72 hours after birth did not maintain NVP conc above 100
ng/ml through age 7 days in 4 of 10 infants, presumably due to in utero induction
of NVP elimination enzymes. Infants born to mothers receiving sustained NVP therapy prior to labor must be dosed more frequently to maintain therapeutic
NVP conc throughout the first week of life.
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Plasma Clearance of Nevirapine Is Increased in Neonates of Mothers Treated with Nevirapine during Pregnancy.
G. P. TAYLOR*^{1}, D. BACK^{2}, E. G. H. LYALL^{1}, C. STAINSBY^{1}, A. DE
RUITER^{3}, G. TUDOR-WILLIAMS^{1}, and J. N. WEBER^{1}. ^{1}Imperial Coll. Sch. of Med., London, UK; ^{2}Univ. of Liverpool, UK; and ^{3}St. Thomas's
Hosp., London, UK.
Background: Adequate concentrations of nevirapine (>100 ng/ml plasma) have
been demonstrated for up to 7 days following a single maternal 200mg dose given in labour followed by a single 2mg/kg dose to the neonate age 48-72
hours. In our centre, Combivir plus nevirapine is commonly prescribed during the second and third trimesters to pregnant women with high plasma HIV load.
As the pharmacokinetics of nevirapine in pregnancy have not been described we have monitored steady state concentrations in mothers and their neonates.
Subjects: 18 women taking nevirapine during pregnancy and their infants.
Methods: Plasma separated from heparinised whole blood, stored at -20 C.
Plasma nevirpaine concentration determined by High Performance Liquid Chromatography.
Discussion: The steady state plasma concentrations of nevirapine in the mothers are similar to those reported in non-pregnant adults and higher than
with a single nevirapine dose (1710ng/ml) Although the cord and neonate plasma concentrations at 24 hours are consequently higher (2580 ng/ml v 1390
ng/ml) they have declined by 36% within the first 24 hours. Samples from later timepoints have been collected but further studies are required to
determine the optimal regimen in these circumstances.
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Assessing the Teratogenic Potential of Antiretroviral Drugs: Data from the Antiretroviral Pregnancy Registry.
P. M. GARCIA*^{1}, D. H. WATTS^{2}, H. E. FOX^{3}, R. SAMELSON^{4}, E. RODRIGUEZ^{5}, C. SCHWAMLEIN^{6}, and J. ELDER^{7} for the APR.
^{1}Northwestern Med. Sch., Chicago, IL; ^{2}NIH/NICHD, Bethesda, MD; ^{3}Johns Hopkins Med. Ctr., Baltimore, MD; ^{4}Albany Med. Coll., Albany,
NY; ^{5}FDA, Bethesda, MD; ^{6}Abbott Labs., Chicago, IL; and ^{7}PharmaRes. Corp., Wilmington, NC.
Objective: To detect any increased rate or pattern of birth defects from exposure to antiretroviral drugs used in pregnancy.
Methods: A registry was established in 1989 of pregnancies exposed to antiretroviral agents prospectively reported by health care providers. Timing
of exposure and dosage is obtained. Immediate newborn outcome data are solicited at the time of delivery. Birth defect risks are compared with data
from the CDC's population-based birth defects surveillance system.
Results: As of July 1999, 916 evaluable, prospective cases have been reported. The prevalence of birth defects among first trimester exposures is
2.0/100 live births (7 defects / 343 LB, 95%Cl = 0.9%, 4.3%) for any antiretroviral drug. The greatest number of first trimester exposures has
been reported for zidovudine monotherapy, and there was one defect among these 111 live births (0.9%, 95% CI 0%, 5.6%). This prevalence does not
significantly differ from those diagnosed within the first day of life by the CDC surveillance program (2.17%, 95% CI 2.10%, 2.23%). No consistent or
unique pattern of defects was seen.
Conclusion: To date, registry data demonstrate no increase in the prevalence
of birth defects among first trimester zidovudine monotherapy exposures, although the power to detect such an increase is limited. Accumulated cases
of exposures to other antiretroviral agents are, as yet, insufficient to make reliable assessments of fetal risk. Prospective reports of antiretroviral
exposures are critically important to determine their teratogenic potential and can be made by calling (800) 258-4263.
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Association of Maternal ZDV Use during Pregnancy and Infant ZDV Genotypic Resistance with Rapid Disease Progression among Infants in the WITS.
J. PITT*^{1«2}, R. COLGROVE^{3}, B. THOMPSON^{2«4}, A. JAPOUR^{5}, and S.
WELLES^{6}. ^{1}Columbia Univ., New York, NY; ^{2}Women and Infants Transmission Study (WITS); ^{3}Harvard Med. Sch., Boston, MA; ^{4}C-TASC,
Baltimore, MD; ^{5}Abbott Labs., Chicago, IL; and ^{6}Univ. of Minnesota, Minneapolis.
Factors associated with ZDV genotypic drug resistance (RT mutations at codons 41, 67, 70, 210, 215, or 219) in infant isolates from birth through 6 mos.,
and the impact of resistance on rapid disease progression (CDC Category 3 CD4 cell decline or Clinical Category C disease within the first year) were
evaluated in 57 HIV+ infants enrolled in the WITS through March 1994. 17 women were treated with ZDV for HIV symptoms; 40 received no ZDV. Overall,
19/57 (33%) of infants were rapid progressors. While maternal ZDV use during pregnancy was significantly associated with resistance in infants [OR= 5.0
(95% CI: 1.5,17.5)], maternal plasma HIV RNA level had a trend towards association as well [OR = 11.4 (0.9,142.9) per each 500,000 copies]. Infant
ZDV use during the first 6 mos. was not associated with resistance (p=0.48). Univariate analysis identified maternal ZDV use during pregnancy [OR = 4.9
(1.5,16.6)] and infant 1-2 mo. peak plasma HIV RNA levels [OR = 1.2 (>1.0,1.43) per 500,000 copies] as significantly associated with progression.
Maternal plasma HIV RNA at delivery [OR = 5.4 (0.6,51.8) per 500,000 copies] and genotypic resistance in infants [OR = 2.6 (0.8,8.9)] were not
significant. Infant ZDV use during the first 6 mos. was not associated with progression (p=.66). In 2-parameter models, maternal ZDV use during pregnancy
remained significantly associated with progression [OR = 4.6 (1.1,19.3)] when adjusted for infant peak plasma HIV RNA [OR = 1.13(<1.0,1.4) per 500,000
copies]. Infant genotypic resistance after adjustment for infant peak plasma HIV RNA was not significant [adjusted OR= 3.5 (0.8,15.4]. While maternal
antenatal ZDV use reduces perinatal transmission, ZDV use during pregnancy and early infant peak RNA levels may impact progression in infants who
acquire HIV despite maternal ZDV use. Further studies with a larger sample size are needed to better define the role of infant genotypic resistance