Sharon Huang

Pharmacokinetics of Saquinavir plus Low-Dose Ritonavir in Human Immunodeficiency Virus-Infected Pregnant Women

ABSTRACT The physiologic changes that occur during pregnancy make it difficult to predict antiretroviral pharmacokinetics (PKs), but few data exist on the PKs of protease inhibitors in human immunodeficiency virus (HIV)-infected pregnant women. The objective of the present study was to determine the PKs of ritonavir (RTV)-enhanced saquinavir (SQV) in HIV-infected pregnant women by an area under the curve (AUC)-targeted approach. A phase I, formal PK evaluation was conducted with HIV-infected pregnant woman during gestation, during labor and delivery, and at 6 weeks postpartum. The SQV-RTV regimen was 800/100 mg twice a day (b.i.d.), and nucleoside analogs were administered concomitantly. The SQV exposure targeted was an AUC at 24 h of 10,000 ng · h/ml. Participants were evaluated for 12-h steady-state PKs at each time period. Thirteen subjects completed the PK evaluations during gestation, 7 completed the PK evaluations at labor and delivery, and 12 completed the PK evaluations postpartum. The mean baseline weight was 67.4 kg, and the median length of gestation was 23.3 weeks. All subjects achieved SQV exposures in excess of the target AUC. The SQV AUCs at 12 h (AUC12s) during gestation (29,373 ± 17,524 ng · h/ml [mean ± standard deviation]), during labor and delivery (26,189 ± 22,138 ng · h/ml), and during the postpartum period (35,376 ± 26,379 ng · h/ml) were not significantly different. The mean values of the PK parameters for RTV were lower during gestation than during the postpartum period: for AUC12, 7,811 and 13,127 ng · h/ml, respectively; for trough concentrations, 376 and 632 ng/ml, respectively; and for maximum concentrations, 1,256 and 2,252 ng/ml, respectively (P ≤ 0.05 for all comparisons). This is the first formal PK evaluation of a dual protease inhibitor regimen with HIV-infected pregnant women. The level of SQV exposure was sufficient at each time of evaluation. These data demonstrate large variability in SQV and RTV concentrations and suggest that RTV concentrations are altered by pregnancy. These PK results suggest that SQV-RTV at 800/100 mg b.i.d. appears to be a reasonable treatment option for this population.

Pharmacokinetics and Safety of Indinavir in Human Immunodeficiency Virus-Infected Pregnant Women

ABSTRACT Human immunodeficiency virus-infected women (n = 16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy.

Pharmacokinetics of Didanosine in Antepartum and Postpartum Human Immunodeficiency Virus-Infected Pregnant Women and Their Neonates: An AIDS Clinical Trials Group Study

Didanosine (ddI) pharmacokinetics in antepartum and postpartum human immunodeficiency virus (HIV)-infected women and their neonates were studied. HIV-infected pregnant women received an intravenous (iv) ddI infusion (1.6 mg/kg/h) or an oral dose (200 mg bid or 125 mg bid) at 31 weeks antepartum and 6 weeks postpartum. Blood samples were obtained regularly up to 6 or 8 h after drug administration. The same oral dose of ddI (bid) was administered until labor began. Then, ddI was infused iv until delivery. An oral pharmacokinetic study (60 mg/m2) was conducted in infants at day 1 and at week 6 after birth. Plasma concentrations of ddI were measured by radioimmunoassay. After iv ddI administration, only the maternal plasma clearance was found to be significantly increased antepartum (1028+/-231 mL/min) versus postpartum (707+/-213 mL/min). No pharmacokinetic parameters after oral administration were significantly affected by pregnancy. The pharmacokinetics of ddI in the neonates were highly variable. We conclude that the oral ddI dose need not be adjusted during pregnancy.

Pharmacokinetics of Saquinavir-SGC in HIV-Infected Pregnant Women

Abstract Purpose: To evaluate saquinavir (SQV) pharmacokinetics, tolerance, and safety in 10 HIV-infected pregnant women between 14-32 weeks gestation. Method: This was a phase I, prospective, area-under-the-curve (AUC) targeted study. Antepartum treatment consisted of SQV 1200 mg tid, lamivudine 150 mg bid, and zidovudine 200 mg tid. The SQV targeted exposure was an 8-hour AUC (AUC8) of 3000 ng · h/mL; the study was to be halted if the first 4 participants did not achieve this AUC8. Cord blood and plasma samples were collected in neonates at birth. Results: Four women completed the SQV pharmacokinetic assessments. Exposure in all 4 patients was below the target AUC8. Median (range) AUC8 and trough (C8H) were 1672 (738-2614) ng · h/mL and 60 (<15-332) ng/mL, respectively. Oral clearance (CL/F) was 9.3 (5.1-16.6) L/h/kg and Cmax was 599 (177–953) ng/mL. Cord and neonate plasma concentrations were mostly undetectable; 1 of 5 infants was HIV-infected at 24 weeks. Conclusion: These data suggest highly variable SQV pharmacokinetics in pregnant women, and exposure at 1200 mg tid may not be adequate for longer term therapy; both the AUC8 and C8H were considerably below average. Because ritonavir has been shown to significantly increase SQV concentrations, this combination should be further explored in this population.

Effect of cessation of zidovudine prophylaxis to reduce vertical transmission on maternal HIV disease progression and survival.

Zidovudine prophylaxis is recommended to reduce perinatal HIV-1 transmission, but there are limited data on long-term effects on womens health. Pediatrics AIDS Clinical Trials Group (PACTG) 288 was a prospective observational study among US women randomized to zidovudine or placebo in PACTG 076 that was designed to evaluate and compare postpartum clinical, immune, and viral parameters between randomized treatment arms. Forty-eight percent (226/474) of eligible women enrolled in the study (mean follow-up of 4.1 years). Progression and time to AIDS or death were similar in both groups, observed in 21 (19%) zidovudine group women and 29 (25%) placebo group women (RR = 0.73, 90% CI: 0.46–1.17). No significant differences in CD4+ lymphocyte count or HIV RNA levels were detected. Genotypic zidovudine resistance was detected in 10% of 156 women (9% of zidovudine group women and 11% of placebo group women). Based on our data, ZDV monotherapy could be considered as chemoprophylaxis to reduce perinatal HIV transmission for minimally symptomatic HIV-infected pregnant women with a low viral load and normal CD4+ cell count who do not want to receive highly active antiretroviral therapy because of concern about potential side effects or who wish to reduce fetal exposure to multiple drugs during pregnancy.

The Rate of Serious Bacterial Infections Among HIV-Infected Children With Immune Reconstitution Who Have Discontinued Opportunistic Infection Prophylaxis

Objective. Receipt of highly active antiretroviral therapy is associated with a decrease in the incidence of opportunistic infections (OIs) among HIV-infected adults. The goal of Pediatric AIDS Clinical Trials Group protocol 1008 was to evaluate prospectively the incidence of serious bacterial infections (SBIs) and other OIs after discontinuation of OI and/or Pneumocystis jiroveci pneumonia (PCP) prophylaxis among HIV-infected pediatric subjects who experienced immune reconstitution while receiving stable antiretroviral therapy. Methods. HIV-infected children and adolescents, 2 to 21 years of age, who had received OI and/or PCP prophylaxis for ≥6 months were enrolled if they had sustained responses (>16 weeks before study entry) to antiretroviral therapy, with CD4+ cell percentages of ≥20% for patients >6 years of age or ≥25% for patients 2 to 6 years of age. Prophylaxis was discontinued at entry. To identify whether any correlation existed between functional immune reconstitution and protection from OIs, subjects were immunized with the hepatitis A virus vaccine. The association between the humoral immune response and the likelihood of developing an OI was evaluated. Results. A total of 235 HIV-infected subjects from 43 participating sites had a median follow-up period of 132 weeks, yielding 547 person-years of observation. Twenty SBIs were observed among 19 subjects, resulting in an incidence rate of 3.66 SBIs per 100 person-years (95% confidence interval: 2.24–5.66 SBIs per 100 person-years). Sixteen of the events were presumed bacterial pneumonia, with 4 proven SBIs. One participant experienced 2 separate pneumonia episodes, of presumed bacterial cause. Ten subjects who developed SBIs had baseline CD4+ cell counts of ≥750 cells per mm3, and 15 had CD4+ cell percentages of ≥25% at the time of their SBIs. Two subjects died as a result of non–SBI-related causes. There were no statistically significant differences in changes over time in CD4+ cell counts or CD4+ cell percentages between subjects who experienced primary end points and those who did not. There was no evidence that baseline protease inhibitor use, gender, race/ethnicity, age, or CD4+ cell count or percentage affected the time to development of a SBI. Conclusions. OI or PCP prophylaxis can be withdrawn safely for HIV-infected pediatric patients who experience CD4+ cell recovery while receiving stable antiretroviral therapy. More studies are needed to assess the association between antibody responses to neoantigens and the development of SBIs.

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

Abstract 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 μg · 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 μg/mL vs. 5.01 μg/mL, p < .05) and AUC0-24 (56.6 vs. 86.8 μg · 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.

Pharmacokinetics and Safety of Single-Dose Tenofovir Disoproxil Fumarate and Emtricitabine in HIV-1-Infected Pregnant Women and Their Infants

ABSTRACT Tenofovir (TFV) is effective in preventing simian immunodeficiency virus (SIV) transmission in a macaque model, is available as the oral agent tenofovir disoproxil fumarate (TDF), and may be useful in the prevention of mother-to-child transmission of human immunodeficiency virus (HIV). We conducted a trial of TDF and TDF-emtricitabine (FTC) in HIV-infected pregnant women and their infants. Women received a single dose of either 600 mg TDF, 900 mg TDF, or 900 mg TDF-600 mg FTC at labor onset or prior to a cesarean section. Infants received no drug or a single dose of TDF at 4 mg/kg of body weight or of TDF at 4 mg/kg plus FTC at 3 mg/kg as soon as possible after birth. All regimens were safe and well tolerated. Maternal areas under the serum concentration-time curve (AUC) and concentrations at the end of sampling after 24 h (C24) were similar between the two doses of TDF; the maximum concentrations of the drugs in serum (Cmax) and cord blood concentrations were higher in women delivering via cesarean section than in those who delivered vaginally (P = 0.04 and 0.046, respectively). The median ratio of the TFV concentration in cord blood to that in the maternal plasma at delivery was 0.73 (range, 0.26 to 1.95). Without TDF administration, infants had a median TFV concentration of 12 ng/ml 12 h after birth. Following administration of a single dose of TDF at 4 mg/kg, infant TFV concentrations fell below the targeted level, 50 ng/ml, by 24 h postdose. In HIV-infected pregnant women and their infants, 600 mg of TDF is acceptable as a single dose during labor. Low concentrations at birth support infant dosing as soon after birth as possible. Rapidly decreasing TFV levels in infants suggest that multiple or higher doses of TDF will be necessary to maintain concentrations that are effective for viral suppression.

Pharmacokinetics and Safety of Stavudine in HIV-Infected Pregnant Women and Their Infants: Pediatric AIDS Clinical Trials Group Protocol 332

This study evaluates the safety, tolerance, and pharmacokinetics of stavudine (d4T) in human immunodeficiency virus (HIV)-infected zidovudine (ZDV)-intolerant/refusing pregnant women and of single-dose d4T in their infants. Women received d4T and lamivudine (3TC) from enrollment until labor. During labor, women received oral 3TC and either intravenous or oral d4T. Infants received ZDV and 3TC for 6 weeks and a single dose of oral d4T at weeks 1 and 6. Mean maternal antenatal d4T pharmacokinetics (terminal plasma half-life [T1/2], 83.5+/-16.8 min; area under the plasma-concentration time curve [AUC0-infinity), 81.6+/-22.0 microg.min/mL; n=6) were not significantly different from those during labor (T(1/2), 87.3+/-24.7 min; AUC0-infinity, 88.1+/-16.6 microg.min/mL; n=6). Umbilical-cord and maternal plasma concentrations were not significantly different from one another. The oral clearance of d4T in infants was significantly greater at week 6 versus week 1 (6.8+/-1.0 vs. 5.6+/-1.2 mL/min/kg). There were no toxicities, in women or infants, that required discontinuation or modification of the study drug. No infants had positive HIV viral diagnostic tests. d4T with or without 3TC is a potential alternative to ZDV for HIV-infected pregnant women.

Characteristics and management of HIV-1-infected pregnant women enrolled in a randomised trial: differences between Europe and the USA

BackgroundRates of mother-to-child transmission of HIV-1 (MTCT) have historically been lower in European than in American cohort studies, possibly due to differences in population characteristics. The Pediatric AIDS Clinical Trials Group Protocol (PACTG) 316 trial evaluated the effectiveness of the addition of intrapartum/neonatal nevirapine in reducing MTCT in women already receiving antiretroviral prophylaxis. Participation of large numbers of pregnant HIV-infected women from the US and Western Europe enrolling in the same clinical trial provided the opportunity to identify and explore differences in their characteristics and in the use of non-study interventions to reduce MTCT.MethodsIn this secondary analysis, 1350 women were categorized according to enrollment in centres in the USA (n = 978) or in Europe (n = 372). Factors associated with receipt of highly active antiretroviral therapy and with elective caesarean delivery were identified with logistic regression.ResultsIn Europe, women enrolled were more likely to be white and those of black race were mainly born in Sub-Saharan Africa. Women in the US were younger and more likely to have previous pregnancies and miscarriages and a history of sexually transmitted infections.More than 90% of women did not report symptoms of their HIV infection; however, more women from the US had symptoms (8%), compared to women from Europe (4%). Women in the US were less likely to have HIV RNA levels <400 copies/ml at delivery than women enrolling in Europe, and more likely to receive highly active antiretroviral therapy, and to start therapy earlier in pregnancy. The elective caesarean delivery rate in Europe was 61%, significantly higher than that in the US (22%). Overall, 1.48% of infants were infected and there was no significant difference in the rate of transmission between Europe and the US despite the different approaches to treatment and delivery.ConclusionThese findings confirm that there are important historical differences between the HIV-infected pregnant populations in Western Europe and the USA, both in terms of the characteristics of the women and their obstetric and therapeutic management. Although highly active antiretroviral therapy predominates in pregnancy in both settings now, population differences are likely to remain.Trial registrationNCT00000869