Pharmacokinetics of tenofovir during pregnancy and postpartum.

OBJECTIVES: Tenofovir disoproxil fumarate (TDF) is increasingly used in the highly active antiretroviral therapy (HAART) regimens of pregnant women, but limited data exist on the pregnancy pharmacokinetics of chronically dosed TDF. This study described tenofovir pharmacokinetics during pregnancy and postpartum. METHODS: International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT) P1026s is a prospective, nonblinded pharmacokinetic study of HIV-infected pregnant women that included a cohort receiving 300 mg TDF once daily. Steady-state 24-hour pharmacokinetic profiles were measured at the second and third trimesters, postpartum, and in maternal and umbilical cord samples collected at delivery. Tenofovir was measured by liquid chromatography-mass spectrometry (LC-MS). The target area under the concentration versus time curve from time 0 to 24 h post dose (AUC) was ≥ 1.99 µg h/mL (nonpregnant historical control 10th percentile). RESULTS: The median tenofovir AUC was decreased during the second (1.9 µg h/mL) and third (2.4 µg h/mL; P = 0.005) trimesters versus postpartum (3.0 µg h/mL). Tenofovir AUC exceeded the target for two of four women (50%) in the second trimester, 27 of 37 women [73%; 95% confidence interval (CI) 56%, 86%] in the third trimester, and 27 of 32 women (84%; 95% CI 67%, 95%) postpartum (P > 0.05). Median second/third-trimester troughs were lower (39/54 ng/mL) than postpartum (61 ng/mL). Median third-trimester weight was greater for subjects below the target AUC versus those above the target (97.9 versus 74.2 kg, respectively; P = 0.006). The median ratio of cord blood to maternal concentrations was 0.88. No infants were HIV infected. CONCLUSIONS: This study found lower tenofovir AUC and troughs during pregnancy. Transplacental passage with chronic TDF use during pregnancy was high. Standard TDF doses appear to be appropriate for most HIV-infected pregnant women but therapeutic drug monitoring with dose adjustment should be considered in pregnant women with high weight (> 90 kg) or inadequate HIV RNA response.

Alteration in cytochrome P450 3A4 activity as measured by a urine cortisol assay in HIV-1-infected pregnant women and relationship to antiretroviral pharmacokinetics.

OBJECTIVES: Pregnancy results in physiological changes altering the pharmacokinetics of drugs metabolized by cytochrome P450 3A4 (CYP3A4). The urinary ratio of 6-ß hydroxycortisol to cortisol (6ßHF : F) is a marker of CYP3A4 induction. We sought to evaluate its change in antiretroviral (ARV)-treated HIV-1-infected women and to relate this change to ARV pharmacokinetics. METHODS: Women receiving various ARVs had pharmacokinetic evaluations during the third trimester of pregnancy (>30 weeks) and postpartum with determination of 6ßHF : F carried out on the same days. The Wilcoxon signed rank test was used to compare the ratio antepartum to postpartum. The relationship between the change in ratio and the change in pharmacokinetics was analysed using Kendall's tau. RESULTS: 6ßHF : F ratios were available for 107 women antepartum, with 54 having postpartum values. The ratio was higher antepartum (P=0.033) (median comparison 1.35; 95% confidence interval 1.01, 1.81). For 71 women taking a protease inhibitor (PI), the antepartum vs. postpartum 6ßHF : F comparison was marginally significant (P=0.058). When the change in the 6ßHF : F ratio was related to the change in the dose-adjusted ARV area under the plasma concentration vs. time curve (AUC) between antepartum and postpartum, the 35 subjects in the lopinavir/ritonavir (LPV/r) arms demonstrated an inverse relationship (P=0.125), albeit this correlation did not reach statistical significance. CONCLUSIONS: A 35% increase in the urinary 6ßHF : F ratio was measured during late pregnancy compared with postpartum, indicating that CYP3A induction occurs during pregnancy. The trend towards an inverse relationship between the change in the 6ßHF : F ratio and the change in the LPV AUC antepartum vs. postpartum suggests that CYP3A induction may be one mechanism behind altered LPV exposure during pregnancy.

Effect of pregnancy on emtricitabine pharmacokinetics.

OBJECTIVES: The aim of the study was to describe emtricitabine pharmacokinetics during pregnancy and postpartum. METHODS: The International Maternal Pediatric and Adolescent AIDS Clinical Trials (IMPAACT), formerly Pediatric AIDS Clinical Trials Group (PACTG), study P1026s is a prospective pharmacokinetic study of HIV-infected pregnant women taking antiretrovirals for clinical indications, including a cohort taking emtricitabine 200 mg once daily. Intensive steady-state 24-hour emtricitabine pharmacokinetic profiles were performed during the third trimester and 6-12 weeks postpartum, and on maternal and umbilical cord blood samples collected at delivery. Emtricitabine was measured by liquid chromatography-mass spectrometry with a quantification limit of 0.0118 mg/L. The target emtricitabine area under the concentration versus time curve, from time 0 to 24 hours post dose (AUC(0-24) ), was ≥7 mg h/L (≤30% reduction from the typical AUC of 10 mg h/L in nonpregnant historical controls). Third-trimester and postpartum pharmacokinetics were compared within subjects. RESULTS: Twenty-six women had pharmacokinetics assessed during the third trimester (median 35 weeks of gestation) and 22 postpartum (median 8 weeks postpartum). Mean [90% confidence interval (CI)] emtricitabine pharmacokinetic parameters during the third trimester vs. postpartum were, respectively: AUC: 8.0 (7.1-8.9) vs. 9.7 (8.6-10.9) mg h/L (P = 0.072); apparent clearance (CL/F): 25.0 (22.6-28.3) vs. 20.6 (18.4-23.2) L/h (P = 0.025); 24 hour post dose concentration (C(24) ): 0.058 (0.037-0.063) vs. 0.085 (0.070-0.010) mg/L (P = 0.006). The mean cord:maternal ratio was 1.2 (90% CI 1.0-1.5). The viral load was <400 HIV-1 RNA copies/mL in 24 of 26 women in the third trimester, in 24 of 26 at delivery, and in 15 of 19 postpartum. Within-subject comparisons demonstrated significantly higher CL/F and significantly lower C(24) during pregnancy; however, the C(24) was well above the inhibitory concentration 50%, or drug concentration that suppresses viral replication by half (IC(50) ) in all subjects. CONCLUSIONS: While we found higher emtricitabine CL/F and lower C(24) and AUC during pregnancy compared with postpartum, these changes were not sufficiently large to warrant dose adjustment during pregnancy. Umbilical cord blood concentrations were similar to maternal concentrations.

Lopinavir protein binding in HIV-1-infected pregnant women.

BACKGROUND: Pregnancy may alter protein binding (PB) of highly bound protease inhibitors due to changes in plasma concentrations of albumin and alpha-1 acid glycoprotein (AAG). Small changes in PB can greatly impact the fraction of drug unbound (FU) exerting pharmacological effect. We report lopinavir (LPV) PB during third trimester (antepartum, AP) compared to > or =1.7 weeks postpartum (PP) to determine if FU changes compensate for reduced total concentrations reported previously. METHODS: P1026s enrolled women receiving LPV/ritonavir, soft gel capsules 400/100 mg or 533/133 mg twice daily. LPV FU, albumin and AAG were determined AP and PP. RESULTS: AP/PP samples were available from 29/25 women respectively with all but one woman receiving the same dose AP/PP. LPV FU was increased 18% AP vs. PP (mean 0.96+/-0.16% AP vs. 0.82+/-0.21% PP, P=0.001). Mean protein concentrations were reduced AP (AAG=477 mg/L; albumin=3.28 mg/dL) vs. PP (AAG=1007 mg/L; albumin=3.85 mg/dL) (P<0.0001 for each comparison). AAG concentration correlated with LPV binding. Total LPV concentration did not correlate with LPV FU AP or PP. However, higher LPV concentration PP was associated with reduced PB and higher FU after adjustment for AAG. CONCLUSIONS: LPV FU was higher and AAG lower AP vs. PP. The 18% increase in LPV FU AP is smaller than the reduction in total LPV concentration reported previously and is not of sufficient magnitude to eliminate the need for an increased dose during pregnancy.

Pharmacokinetics of new 625 mg nelfinavir formulation during pregnancy and postpartum.

OBJECTIVES: Our objective was to evaluate the pharmacokinetics of nelfinavir (NFV) (625 mg tablets) 1250 mg twice daily during pregnancy and postpartum. METHODS: The participants were HIV-1-infected pregnant women enrolled in P1026s and receiving NFV (625 mg tablets) 1250 mg twice daily as part of routine clinical care. Intensive steady-state 12-h NFV pharmacokinetic profiles were performed during pregnancy and postpartum. The target NFV area under the plasma concentration-time curve (AUC(0-12)) was >or=10th percentile NFV AUC(0-12) in non-pregnant historical controls (18.5 microg h/mL). RESULTS: Of 27 patients receiving NFV, pharmacokinetic data were available for four (second trimester), 27 (third trimester) and 22 (postpartum) patients. The NFV maximum concentration (C(max)), 12-h post-dose concentration (C(12)) and AUC(0-12) were significantly lower during the third trimester compared to postpartum (P

Pharmacokinetics and safety of nelfinavir when used in combination with zidovudine and lamivudine in HIV-infected pregnant women: Pediatric AIDS Clinical Trials Group (PACTG) Protocol 353.

BACKGROUND: Combination antiretroviral regimens including nelfinavir (NFV) are commonly used in pregnancy. We studied the safety, antiviral effect, and pharmacokinetics of NFV and its M8 metabolite with two dosing regimens in combination with zidovudine (ZDV) and lamivudine (3TC) in HIV-infected pregnant women. METHOD: HIV-infected pregnant women between 14 and 34 weeks gestation received NFV (Cohort 1: 750 mg tid, n = 10; Cohort 2: 1250 mg bid, n = 23) with ZDV and 3TC. Serial blood sampling for NFV concentrations was performed antepartum (AP) and 6 weeks postpartum (PP). Maternal and cord blood samples were also obtained at delivery. NFV and M8 levels were determined by high-performance liquid chromatography. The pharmacokinetic (PK) target was an extrapolated NFV AUC0-24 > 30 mug . h/mL. Mothers were followed frequently for potential clinical and laboratory toxicity. RESULTS: Overall, NFV in combination with ZDV and 3TC was well tolerated. The PK target was met in 3/8 AP and 5/7 PP in Cohort 1 and 17/21 AP and 16/17 PP in Cohort 2. When Cohort 2 NFV PK parameters AP and PP were compared, median Cmax (3.90 microg/mL vs. 5.01 microg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 microg . h/mL, p < .05) were increased PP and oral clearance (Cl/F; 44.2 vs. 28.8 L/h, p < .05) was decreased PP. The average M8/NFV ratio was increased PP compared to AP (0.085 vs. 0.29, p < .001). Placental transfer of NFV was low with a median cord blood:maternal plasma ratio at delivery of 0.05. Maternal mean CD4+ T cell counts increased significantly and plasma HIV-1 RNA levels decreased from entry to delivery and 6 to 12 weeks postpartum. CONCLUSION: NFV used in combination with ZDV and 3TC was well tolerated in pregnant HIV-infected women and produced a significant improvement in HIV disease parameters. NFV drug exposure is inadequate in most pregnant women receiving 750 mg tid but is much improved with 1250 mg bid. NFV crosses the placenta poorly. The AP increase in NFV oral clearance and decrease in M8/NFV ratio suggest that CYP3A activity increases relative to CYP2C19 activity during pregnancy.

Depo-medroxyprogesterone in women on antiretroviral therapy: effective contraception and lack of clinically significant interactions.

We conducted an open-label, steady-state pharmacokinetic (PK) study of drug interactions among HIV-infected women treated with depo-medroxyprogesterone acetate (DMPA) while on nucleoside analogues plus nelfinavir (N=21), efavirenz (N=17), or nevirapine (N=16); or nucleosides only or no antiretroviral therapy as a control group (N=16). PK parameters were estimated using non-compartmental analysis, with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of ARV PKs before and 4 weeks after DMPA dosing. Plasma progesterone levels were measured at baseline and at 2, 4, 6, 8, 10, and 12 weeks after DMPA dosing. There were no significant changes in MPA area under the concentration curve, peak or trough concentrations, or apparent clearance in the nelfinavir, efavirenz, or nevirapine groups compared to the control group. Minor changes in nelfinavir and nevirapine drug exposure were seen after DMPA, but were not considered clinically significant. Suppression of ovulation was maintained.

Incorporation of zidovudine into leukocyte DNA from HIV-1-positive adults and pregnant women, and cord blood from infants exposed in utero.

OBJECTIVE: The nucleoside analog 3'-azido-3'-deoxythymidine (ZDV) has widespread clinical use but also is carcinogenic in newborn mice exposed to the drug in utero and becomes incorporated into newborn mouse DNA. This pilot study was designed to determine ZDV incorporation into human blood cell DNA from adults and newborn infants. DESIGN: In this prospective cohort study, peripheral blood mononuclear cells (PBMC) were obtained from 28 non-pregnant adults and 12 pregnant women given ZDV therapy, six non-pregnant adults with no exposure to ZDV, and six non-pregnant adults who last received ZDV > or = 6 months previously. In addition, cord blood leukocytes were obtained from 22 infants of HIV-1-positive, ZDV-exposed women and from 12 infants unexposed to ZDV. There were 11 mother-infant pairs involving HIV-1 -positive women. METHODS: DNA was extracted from PBMC obtained from non-pregnant HIV-1-positive adults taking ZDV, pregnant HIV-1-positive women given ZDV during pregnancy, and from adults not taking ZDV. Cord blood leukocytes were examined from infants exposed to ZDV in utero and from unexposed controls. DNA samples were assayed for ZDV incorporation by anti-ZDV radioimmunoassay (RIA). RESULTS: The majority (76%) of samples from ZDV-exposed individuals, pregnant women (8 of 12), non-pregnant adults (24 of 28), or infants at delivery (15 of 22), had detectable ZDV-DNA levels. The range of positive values for ZDV-treated adults and infants was 25-544 and 22-452 molecules ZDV/10(6) nucleotides, respectively. Analysis of 11 mother-infant pairs showed variable ZDV-DNA incorporation in both, with no correlation by pair or by duration of drug treatment during pregnancy. Two of the 24 samples from individuals designated as controls were positive by anti-ZDV RIA. The 20-fold range for ZDV-DNA values in both adults and infants suggested large interindividual differences in ZDV phosphorylation. CONCLUSIONS: Incorporation of ZDV into DNA was detected in most of the samples from ZDV-exposed adults and infants. Therefore, the biologic significance of ZDV-DNA damage and potential subsequent events, such as mutagenicity, should be

Risk factors for preterm birth, low birth weight, and intrauterine growth retardation in infants born to HIV-infected pregnant women receiving zidovudine. Pediatric AIDS Clinical Trials Group 185 Team.

OBJECTIVE: To evaluate independent contributions of maternal factors to adverse pregnancy outcomes (APO) in HIV-infected women receiving antiretroviral therapy (ART). DESIGN: Risk factors for preterm birth (< 37 weeks gestation), low birth weight (LBW) (< 2500 g), and intrauterine growth retardation (IUGR) (birth weight < 10th percentile for gestational age) examined in 497 HIV-infected pregnant women enrolled in PACTG 185, a perinatal clinical trial. METHODS: HIV RNA copy number, culture titer, and CD4 lymphocyte counts were measured during pregnancy. Information collected included antenatal use of cigarettes, alcohol, illicit drugs; ART; obstetric history and complications. RESULTS: Eighty-six percent were minority race/ethnicity; 86% received antenatal monotherapy, predominantly zidovudine (ZDV), and 14% received combination antiretrovirals. Preterm birth occurred in 17%, LBW in 13%, IUGR in 6%. Risk of preterm birth was independently associated with prior preterm birth [odds ratio (OR) 3.34; P < 0.001], multiple gestation (OR, 6.02; P = 0.011), antenatal alcohol use (OR, 1.91; P = 0.038), and antenatal diagnosis of genital herpes (OR, 0.24; P = 0.022) or pre-eclampsia (OR, 6.36; P = 0.025). LBW was associated with antenatal diagnosis of genital herpes (OR, 0.08; P = 0.014) and pre-eclampsia (OR, 5.25; P = 0.049), and baseline HIV culture titer (OR, 1.41; P = 0.037). IUGR was associated with multiple gestation (OR, 8.20; P = 0.010), antenatal cigarette use (OR, 3.60; P = 0.008), and pre-eclampsia (OR, 12.90; P = 0.007). Maternal immune status and HIV RNA copy number were not associated with APO. CONCLUSIONS: Risk factors for APO in antiretroviral treated HIV-infected women are similar to those reported for uninfected women. These data suggest that provision of prenatal care and ART may reduce APO.

Incorporation of zidovudine into cord blood DNA of infants and peripheral blood DNA of their HIV-1-positive mothers.

The nucleoside analogue 3'-azido-3'-deoxythymidine (AZT) is a weak carcinogen in adult female mice and a moderately strong carcinogen in the offspring of female mice given the drug during gestation. In addition, incorporation of AZT into DNA was observed in multiple organs of transplacentally exposed newborn mice. Here we investigate the incorporation of AZT into peripheral leukocyte DNA of HIV-1-positive adult pregnant women given AZT for variable times during gestation and cord blood of infants exposed to AZT in utero. The length of treatment varied between 10 days and 9 months. High molecular weight DNA was extracted from maternal peripheral blood mononuclear cells (PBMC) and infant cord blood. A specific AZT-DNA radioimmunoassay was used to determine the amount of AZT incorporated into leukocyte DNA. Incorporation of AZT into DNA ranged up to 183.3 and 344.5 molecules of AZT/10(6) nucleotides in the mothers and infants, respectively, and was detected in about 70% of samples. Therefore, AZT-induced mutagenic events are possible in the majority of adults and infants. No correlation was found between level of incorporation and length of AZT treatment, suggesting that the differences observed among the individuals arise from variability in AZT metabolism. These data support previous observations that a high degree of inter-individual variability in AZT phosphorylation occurs in primates.

Risk factors for trichomoniasis among women with human immunodeficiency virus (HIV) infection at a public clinic in Los Angeles County, California: implications for HIV prevention.

Persons with human immunodeficiency virus (HIV) infection who subsequently develop an acute sexually transmitted disease have an increased probability of transmitting HIV. Therefore, characterizing such persons can help direct prevention efforts to a group who are likely to be continuing sources of HIV transmission. We assessed the incidence and factors associated with trichomoniasis in a cohort of HIV-infected women receiving care at a public clinic in Los Angeles County, California from 1992 through 1995. Demographic, clinical, and behavioral data were available from medical records and from patient interviews. Trichomonas infection was the most frequently identified sexually transmitted disease and was found in 37 (17.4%) of 212 women representing a crude incidence rate of 14.1 per 100 person-years experience. The crude rate of trichomoniasis was highest in black women (69.0 per 100 person-years), women with a history of trading sex for drugs or money (51.0 per 100 person-years), those using crack or cocaine (35.5 per 100 person-years), women with four or more sex partners (43.0 per 100 person years), and those born in the United States (23.3 per 100 person-years). Among women with severe immunosuppression (CD4+ count < 200), 18.4% (18 of 98) were diagnosed with trichomoniasis. After multivariate analysis using a Cox proportional hazards approach, black race (adjusted rate ratio [RR] = 5.6, 95% confidence interval [CI] = 2.3, 13.3) continued to be strongly associated with Trichomonas infection. Trading sex for money or drugs (adjusted RR = 25.2, 95% CI = 4.3, 148.6) and single marital status (adjusted RR = 3.7, 95% CI = 1.1, 13.0) were independent risk factors for trichomoniasis in nonblack women but not among black women. Data from this study indicate that Trichomonas may be a frequently acquired infection in HIV-positive women. Our findings suggest that HIV-infected women who are black, and nonblack women who trade sex for money or drugs or are unmarried, are at increased risk of trichomoniasis and therefore may be more likely to transmit HIV infection. Local HIV prevention strategies should target such women for intervention efforts.

Chronic administration of nevirapine during pregnancy: impact of pregnancy on pharmacokinetics.

OBJECTIVES: To determine the impact of pregnancy on the pharmacokinetics (PK) of nevirapine (NVP) during chronic dosing in HIV-infected women and appropriate NVP dosing in this population. METHODS: Twenty-six pregnant women participating in two open-label Pediatric AIDS Clinical Trials Group studies (P1022 and P1026S) were evaluated. Each patient received 200 mg NVP every 12 h and had PK evaluations during the second or third trimester; these evaluations were repeated postpartum. Paired maternal and cord blood NVP concentrations were collected at delivery in nine patients. Ante- and postpartum comparisons were made using paired t-tests and using a 'bioequivalence' approach to determine confidence interval (CI). RESULTS: The average NVP Area Under the Curve (AUC) was 56 +/- 13 mcg(*)h/mL antepartum and 61 +/- 15 mcg(*)h/mL postpartum. The typical parameters +/- standard error were apparent clearance (CL/F)=3.51 +/- 0.18 L/h and apparent volume of distribution (Vd/F)=121 +/- 19.8 L. There were no significant differences between antepartum and postpartum AUC or pre-dose concentrations. The AUC ratio was 0.90 with a 90% CI of the mean equal to 0.80-1.02. The median (+/- standard deviation) cord blood to maternal NVP concentration ratio was 0.91 +/- 0.90. CONCLUSIONS: Pregnancy does not alter NVP PK and the standard dose (200 mg every 12 h) is appropriate during pregnancy.

Evaluation of a rapid optical immunoassay-based test for group B streptococcus colonization in intrapartum patients.

OBJECTIVE: To compare an optical immunoassay (OIA) rapid diagnostic kit to standard culture for the diagnosis of vaginal colonization with group B streptococcus (GBS) and to assess the accuracy and reproducibility of the OIA results. METHOD: A total of 301 patients in labor were prospectively evaluated for GBS colonization with a test approved by the Food and Drug Administration (STREP B OIA kit, Biostar, Boulder, CO, USA) and by culture. The vagina was simultaneously sampled with two swabs. Rectal culture was obtained separately. RESULTS: By the criterion of a positive culture, the vagina was colonized by GBS in 33 of 301 (11%) patients; and the rectum in 42 of 301 (13.9%). The vagina or rectum or both were colonized by CBS in 54 of 301 (17.9%) of patients. The OIA had sensitivity, specificity, positive predictive value and negative predictive value of 63.6%, 86.3%, 37.5% and 94.8%, respectively. The OIA had a kappa statistic score of 0.59. CONCLUSION: The OIA is not an adequately sensitive rapid kit for reliable detection of GBS colonization of the vagina. The results of the OIA were only moderately accurate and reproducible.

Fetal responses to maternal and fetal methamphetamine administration in sheep.

OBJECTIVES: The current study was designed to test the hypothesis that maternally administered methamphetamine decreases fetal PaO2 by reducing uterine blood flow and to determine the cardiovascular and blood gas responses to varying doses of methamphetamine given both to the fetus and the mother. STUDY DESIGN: Nine near-term pregnant sheep were surgically instrumented to measure maternal and fetal blood pressure and heart rate and uterine and umbilical blood flow. Fetal blood gases and pH were determined before and after each dose of methamphetamine. Methamphetamine was administered as intravenous bolus injections (30 to 35 minutes separating administration of each dose) into the maternal femoral vein in increasing doses of 0.03, 0.1, 0.3, and 1.0 mg/kg and on a separate days to the fetus into the hind limb vein as doses of 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg estimated fetal weight. RESULTS: Maternal methamphetamine administration produced a dose-related increase in maternal and fetal blood pressure and uterine vascular resistance, whereas uterine blood flow decreased in a dose-related fashion. Umbilical blood flow tended to increase slightly, but this did not reach significance. Fetal PaO2 decreased significantly, whereas fetal pH decreased only modestly. Direct fetal administration of methamphetamine produced dose-related increases in fetal blood pressure and umbilical blood flow and a significant decrease in fetal pH but no change in fetal PaO2. CONCLUSIONS: The fetal PaO2 decrease observed after maternal administration of methamphetamine appears to be a result of decreased uteroplacental perfusion, whereas the observed changes in fetal blood pressure and fetal pH appear to be a result of the direct action of methamphetamine on the fetus.

Maternal and fetal cardiovascular responses to methamphetamine in the pregnant sheep.

OBJECTIVES: Our purpose was to evaluate the maternal and fetal cardiovascular effects of maternally administered methamphetamine and to determine the extent of placental transfer. STUDY DESIGN: Seven near-term pregnant sheep were surgically instrumented to measure maternal and fetal blood pressure and heart rate, cardiac output, uterine flow, and umbilical flow. A single dose of methamphetamine 1 mg/kg was administered as a bolus to study maternal and fetal cardiovascular responses and placental transfer. RESULTS: Maternal administration of methamphetamine caused increases in maternal blood pressure, heart rate, cardiac output, and systemic vascular resistance and decreased uterine blood flow. Peak maternal changes occurred within 10 minutes after methamphetamine administration and were near baseline by 180 minutes. Fetal blood pressure increased and returned slowly to baseline by 2 hours. After an initial decrease fetal heart rate increased above baseline values over the next 2 hours. Umbilical blood flow also decreased initially and then increased slightly. Fetal pH and PO2 tended to decrease. Maternal and fetal methamphetamine levels reached a maximum of 2.9 and 1.9 micrograms/ml, respectively. Rapid and significant placental transfer, delayed excretion into the amniotic fluid, and slow elimination from the maternal and fetal circulation were demonstrated. CONCLUSION: Methamphetamine readily crosses the ovine placenta, producing significant and long-lasting maternal and fetal cardiovascular effects, which may have long-term consequences, especially if administered repetitively.

The relationship of pregnancy to the use of highly active antiretroviral therapy.

OBJECTIVE: Public health agencies have recommended that the criteria for the use of highly active antiretroviral therapy should not be modified because of pregnancy. However, little information has been published with regard to the degree to which these recommendations are being followed. We report here the frequency of highly active antiretroviral therapy use among pregnant women in the Women's Interagency HIV Study and compare the frequencies of its use by pregnant women meeting published criteria for implementing highly active antiretroviral therapy and its use by nonpregnant women meeting the same criteria. STUDY DESIGN: From October 1994 through November 1995, a total of 2059 human immunodeficiency virus type 1-seropositive women were enrolled in a cohort study. Participants were evaluated at baseline and at 6-month intervals with standardized interview instruments. In addition to a general physical examination at each visit, patients had a urine pregnancy test performed and were asked about current pregnancies, pregnancies since the last visit, and which antiretroviral medications they had used since the last visit. Highly active antiretroviral therapy was defined according to 1997 National Institutes of Health guidelines. RESULT: At each calendar interval after October 1996, a greater proportion of nonpregnant women than pregnant women reported the use of highly active antiretroviral therapy. The use of monotherapy declined for both groups during the course of multiple calendar periods (P <.01), although the use of monotherapy remained higher among the pregnant women. In any given calendar period, pregnant women meeting published criteria for highly active antiretroviral therapy use were slightly less likely than similar nonpregnant women to receive highly active antiretroviral therapy (odds ratio, 0.28-0.98). Because of the sample size these differences reached significance in only one calendar period (P =.02). With time pregnant women did demonstrate an increase in the percentage receiving highly active antiretroviral therapy. In nearly all calendar periods a larger percentage of pregnant than nonpregnant women were receiving a regimen that included zidovudine. CONCLUSIONS: Highly active antiretroviral therapy is being received by an increasing percentage of women who meet published criteria for its use, and pregnancy is a relatively small impediment to its use. Further efforts are needed to bolster the use of highly active antiretroviral therapy by all appropriate candidates and to ensure equal access to this therapy for pregnant women. Because of the increasingly frequent use of highly active antiretroviral therapy during pregnancy, ongoing efforts are needed to monitor any long-term effects of in utero exposure to multiple antiretroviral agents.

Safety and pharmacokinetics of hyperimmune anti-human immunodeficiency virus (HIV) immunoglobulin administered to HIV-infected pregnant women and their newborns. Pediatric AIDS Clinical Trials Group Protocol 185 Pharmacokinetic Study Group.

The pharmacokinetics and safety of hyperimmune anti-human immunodeficiency virus (HIV) intravenous immunoglobulin (HIVIG) were evaluated in the first 28 maternal-infant pairs enrolled in a randomized, intravenous immunoglobulin (IVIG)-controlled trial of HIVIG maternal-infant HIV transmission prophylaxis. Using 200 mg/kg, mean half-life and volume of distribution (Vd) in women were 15 days and 72 mL/kg, respectively, after one and 32 days and 154 mL/kg after three monthly infusions, with stable 4 mL/kg/day clearance. Transplacental passage occurred. Newborn single-dose half-life, Vd, and clearance were 30 days, 143 mL/kg, and 4 mL/kg/day, respectively. HIVIG rapidly cleared maternal serum immune complex-dissociated p24 antigen, and plasma HIV-1 RNA levels were stable. Mild to moderate adverse clinical effects occurred in 2 of 103 maternal and 2 of 25 infant infusions. No adverse hematologic, blood chemistry, or immunologic effects were seen. HIVIG is well-tolerated in HIV-infected pregnant women and their newborns, clears antigenemia, crosses the placenta, and exhibits pharmacokinetics similar to those of other immunoglobulin preparations.

Efficacy of zidovudine and human immunodeficiency virus (HIV) hyperimmune immunoglobulin for reducing perinatal HIV transmission from HIV-infected women with advanced disease: results of Pediatric AIDS Clinical Trials Group protocol 185.

Pediatric AIDS Clinical Trials Group protocol 185 evaluated whether zidovudine combined with human immunodeficiency virus (HIV) hyperimmune immunoglobulin (HIVIG) infusions administered monthly during pregnancy and to the neonate at birth would significantly lower perinatal HIV transmission compared with treatment with zidovudine and intravenous immunoglobulin (IVIG) without HIV antibody. Subjects had baseline CD4 cell counts /=200/microL) but not with time of zidovudine initiation (5.6% vs. 4.8% if started before vs. during pregnancy; P=. 75). The Kaplan-Meier transmission rate for HIVIG recipients was 4. 1% (95% confidence interval, 1.5%-6.7%) and for IVIG recipients was 6.0% (2.8%-9.1%) (P=.36). The unexpectedly low transmission confirmed that zidovudine prophylaxis is highly effective, even for women with advanced HIV disease and prior zidovudine therapy, although it limited the study's ability to address whether passive immunization diminishes perinatal transmission.

Cérato-conjuntivite por microsporídeo em AIDS: descriçäo do primeiro caso brasileiro e revisäo da literatura / Microsporidial kerato-conjunctivitis in AIDS: description of the brazilian first case and literature review

Relato do conhecimento dos autores sobre o primeiro caso diagnosticado na América do Sul