Carmen D. Zorrilla

Maternal levels of plasma human immunodeficiency virus type 1 RNA and the risk of perinatal transmission

BACKGROUND The importance of plasma levels of human immunodeficiency virus type 1 (HIV-1) RNA in pregnant women in relation to the other factors known to influence the risk of transmission of infection to their infants is incompletely defined. We studied the relation of maternal plasma HIV-1 RNA levels to the risk of perinatal transmission and the timing of transmission. METHODS We measured plasma HIV-1 RNA serially in 552 women with HIV-1 infection who had singleton pregnancies. The status of infection in their infants was assessed by culture of blood and further classified as early (if a culture of blood obtained within the first two days of life was positive) or late (if a culture of blood obtained in the first seven days of life was negative but subsequent cultures were positive). The rates of transmission at various levels of maternal plasma HIV-1 RNA were analyzed by tests for trend, with adjustment for covariates by stratification and logistic regression. RESULTS Increasing geometric mean levels of plasma HIV-1 RNA were associated with increasing rates of transmission: the rate was 0 percent among women with less than 1000 copies per milliliter (0 of 57), 16.6 percent among women with 1000 to 10,000 copies per milliliter (32 of 193), 21.3 percent among women with 10,001 to 50,000 copies per milliliter (39 of 183), 30.9 percent among women with 50,001 to 100,000 copies per milliliter (17 of 55), and 40.6 percent among women with more than 100,000 copies per milliliter (26 of 64) (P<0.001). The treatment status of one woman was unknown. The highest rate of transmission was among women whose plasma HIV-1 RNA levels exceeded 100,000 copies per milliliter and who had not received zidovudine (19 of 30 women, 63.3 percent). Neither higher HIV-1 RNA levels early in pregnancy nor higher levels late in pregnancy were associated with the timing of infection in the infants. CONCLUSIONS In pregnant women with HIV-1 infection the level of plasma HIV-1 RNA predicts the risk but not the timing of transmission of HIV-1 to their infants.

Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy

Data from 2543 HIV-infected women were analyzed to correlate antiretroviral therapy (ART) used during pregnancy with maternal and pregnancy outcomes. ART was analyzed according to class of agents used and according to monotherapy versus combination ART containing neither protease inhibitors (PIs) nor nonnucleoside reverse transcriptase inhibitors versus highly active ART. Timing of ART was classified according to early (recorded at or before 25-week gestation study visit) and late (recorded at 32-week gestation or delivery visit) use. Maternal outcomes assessed included hematologic, gastrointestinal, neurologic, renal, and dermatologic complications; gestational diabetes; lactic acidosis; and death. Adverse pregnancy outcomes assessed included hypertensive complications; pre-term labor or rupture of membranes; preterm delivery (PTD); low birth weight; and stillbirth. Logistic regression analyses controlling for multiple covariates revealed ART to be independently associated with few maternal complications: ART use was associated with anemia (odds ratio [OR] = 1.6, 95% confidence interval [CI]: 1.1-2.4), and late use of ART was associated with gestational diabetes (OR = 3.5, 95% CI: 1.2-10.1). Logistic regression analyses revealed an increase in PTD at <37 weeks for 10 women with late use of ART not containing zidovudine (ZDV; OR = 7.9, 95% CI: 1.4-44.6) and a decrease in adverse pregnancy outcomes as follows: late use of ART containing ZDV was associated with decreased risk for stillbirth and PTD at <37 weeks (OR = 0.06, 95% CI: 0.02-0.18; OR = 0.5, 95% CI: 0.3-0.8, respectively), and ART containing nucleoside reverse transcriptase inhibitors but not ZDV during early and late pregnancy was associated with decreased risk for PTD at <32 weeks (OR = 0.3, 95% CI: 0.2-0.7). Benefits of ART continue to outweigh observed risks.

Risk factors for in utero and intrapartum transmission of HIV.

Objective: To identify predictors of in utero and intrapartum HIV-1 transmission in infants born in the Women and Infants Transmission Study between 1990 and 2000. Methods: In utero HIV-1 infection was defined as an infant with the first positive HIV-1 peripheral blood mononuclear cell culture and/or DNA polymerase chain reaction assay at 7 days of age or younger; intrapartum infection was defined as having a negative HIV-1 culture and/or DNA polymerase chain reaction assay at 7 days of age or younger and the first positive assay after 7 days of age. Results: Of 1709 first-born singleton children with defined HIV-1 infection status, 166 (9.7%) were found to be HIV-1 infected; transmission decreased from 18.1% in 1990-1992 to 1.6% in 1999-2000. Presumed in utero infection was observed in 34% of infected children, and presumed intrapartum infection, in 66%. Among infected children, the proportion with in utero infection increased over time from 27% in 1990-1992 to 80% (4 of 5) in 1999-2000 (P = 0.072). Maternal antenatal viral load and antiretroviral therapy were associated with risk of both in utero and intrapartum transmission. Controlling for maternal antenatal viral load and antiretroviral therapy, low birth weight was significantly associated with in utero transmission, while age, antenatal CD4+ cell percentage, year, birth weight, and duration of membrane rupture were associated with intrapartum transmission. Conclusion: Although there have been significant declines in perinatal HIV-1 infection over time, there has been an increase in the proportion of infections transmitted in utero.

HIV-1 genotypic zidovudine drug resistance and the risk of maternal-infant transmission in the women and infants transmission study.

ObjectivesAlthough the treatment of pregnant women and their infants with zidovudine (ZDV) has been remarkably effective in preventing the perinatal transmission of human HIV-1, many potentially preventable infections still occur. To examine whether the risk of perinatal infection is increased among women who carry ZDV-resistant HIV-1, the role of genotypic ZDV resistance in perinatal transmission was evaluated. MethodsThe reverse transcriptase (RT) region of clinical isolates from culture supernatants of 142 HIV-1-infected women enrolled in the Women and Infants Transmission Study (WITS), who had been treated with ZDV during pregnancy was sequenced. Results from genotypic sequencing were linked to demographic, laboratory, and obstetrical databases, and the magnitude of association of having consensus drug-resistant HIV-1 RT mutations with transmission was estimated. ResultsTwenty-five per cent (34/142) of maternal isolates had at least one ZDV-associated resistance mutation. A lower CD4 cell percentage and count (P  = 0.0001) and higher plasma HIV-1 RNA (P  = 0.006) were associated with having any ZDV resistance mutation at delivery. Having any RT resistance mutation [odds ratio (OR): 5.16; 95% confidence interval (CI): 1.40, 18.97; P  = 0 0.01], duration of ruptured membranes [OR: 1.13 (1.02, 1.26) per 4 h duration; P  = 0.02], and total lymphocyte count [OR: 1.06 (1.01, 1.10) per 50 cells higher level; P  = 0.009] were independently associated with transmission in multivariate analysis. ConclusionMaternal ZDV resistant virus was predictive of transmission, independent of viral load, in these mothers with moderately advanced HIV-1 disease, many of whom had been treated with ZDV before pregnancy.

mode of Delivery and Postpartum Morbidity Among Hiv-infected Women: The Women and Infants Transmission Study

Summary: Cesarean delivery before onset of labor and rupture of membranes (i.e., scheduled cesarean delivery) is associated with a lower risk of vertical transmission of HIV. The following a priori hypotheses were tested: among HIV‐infected women, scheduled cesarean delivery is associated with a higher risk of postpartum morbidity, longer hospitalization, and a higher risk of rehospitalization than spontaneous vaginal delivery. Postpartum morbidity occurred following 178 of 1,186 (15%) of deliveries during 1990 to 1998 in The Women and Infants Transmission Study. The most commonly reported postpartum morbidity events were: fever without infection, hemorrhage or severe anemia, endometritis, urinary tract infection, and cesarean wound complications. Several time trends were observed: the median duration of ruptured membranes decreased (p < .001), intrapartum antibiotic use increased (p < .001), the median antepartum plasma HIV RNA concentration decreased (p < .001), and the incidence of any postpartum morbidity decreased (p = .02). With spontaneous vaginal delivery as the reference category, both scheduled (odds ratio [OR] = 4.69; 95% confidence interval [95% CI], 2.03‐10.84), and nonscheduled (OR, 2.50; 95% CI, 1.24‐5.04) cesarean deliveries were associated with fever without infection; with urinary tract infection (OR, 3.79; 95% CI 1.04‐13.85; OR, 3.86; 95% CI, 1.55‐9.60, respectively), and with any postpartum morbidity (OR, 3.19; 95% CI 1.69‐6.00; OR, 4.10; 95% CI, 2.71‐6.19, respectively). Nonscheduled cesarean deliveries were more likely to be complicated by endometritis (OR, 6.98; 95% CI, 3.53‐13.78). Adjusted ORs relating mode of delivery and each of the outcomes (fever without infection, urinary tract infection, endometritis, and any postpartum morbidity) were similar to unadjusted ORs. Results of this analysis indicate scheduled cesarean delivery is associated with an increased risk of any postpartum morbidity and, specifically, postpartum fever without infection. The potential for postpartum morbidity with scheduled cesarean delivery should be considered in light of possible adverse events associated with other interventions to decrease the risk of vertical transmission of HIV. Counseling of HIV‐infected pregnant women regarding scheduled cesarean delivery as a possible intervention to decrease maternal‐infant transmission of HIV should include discussion of these results, as well as new data as they become available, regarding the incidence and severity of postpartum morbidity events among HIV‐infected women according to mode of delivery.

Cell-associated genital tract virus and vertical transmission of human immunodeficiency virus type 1 in antiretroviral-experienced women.

To determine the association between genital tract shedding of human immunodeficiency virus (HIV) type 1 and vertical transmission, a case-control substudy was conducted within the Women and Infants Transmission Study. Antenatal cervicovaginal lavage specimens were assessed for HIV-1 RNA in the supernatant and HIV-1 RNA and DNA in cell pellets. Multivariate analyses compared 26 women who transmitted HIV to their infants with 52 women who did not; 33% received combination antiretroviral therapy, and 65% received monotherapy. Adjusted odds ratios (ORs) for the presence (OR, 3.42; 95% confidence interval [CI], 0.76-15.4; P=.11) and titer (OR, 1.66; 95% CI, 0.93-2.99; P=.09) of HIV-1 DNA suggested that there is an independent association with vertical transmission. When analyses were restricted to vaginal and nonelective cesarean deliveries, each one-log increase in mean titer of HIV-1 DNA was associated with a significantly higher risk of transmission (OR, 2.28; 95% CI, 1.09-4.78; P=.03). The cell-associated genital tract compartment is important in the pathophysiology and prevention of vertical HIV-1 transmission.

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.

Prevalence of human immunodeficiency virus-associated cognitive impairment in a group of Hispanic women at risk for neurological impairment.

Human immunodeficiency virus (HIV)-associated cognitive impairment, a significant cause of morbidity, affects up to 30% of HIV-infected people. Its prevalence doubled as patients began to live longer after the introduction of highly active retroviral therapy. Women are now one of the fastest growing groups with acquired immunodeficiency syndrome (AIDS) in the United States and Puerto Rico, but relatively little is known about the prevalence and characteristics of cognitive dysfunction in HIV-infected women. In this study the authors investigated its prevalence in a group of HIV-1—seropositive Hispanic women in Puerto Rico. Forty-nine women with a nadir CD4 cell count of ≤500 cells/mm3 were enrolled. Cognitive impairment was defined according to the American Academy of Neurology criteria for HIV dementia as modified to identify an “asymptomatic cognitively impaired” group. Observed prevalence was compared with prevalence in other populations in United States, Europe, and Australia. Differences in clinical markers and neuropsychological test performance among the cohort stratified by cognitive impairment were tested. Cognitive impairment was observed in 77.6% (38/49) of cases; asymptomatic cognitive impairment in 32.7% (16/49); minor cognitive motor disorders in 16.3% (8/49); and HIV-associated dementia (HAD) in 28.6% (14/49). Cognitive impairment did not correlate with age, CD4 cell count, viral load, or treatment modality. The cross-sectional prevalence of HIV-associated cognitive impairment was 77.6% (28.6% for HAD). These findings should enhance awareness of the prevalence of HIV-associated cognitive impairment, both clinically apparent and “asymptomatic,” in Hispanic women and lead to improvements in areas such as education and compliance and to reevaluation of treatment interventions.

Multicenter review of protease inhibitors in 89 pregnancies

Context: Despite the success of highly active antiretroviral therapy, the optimal approach for preventing perinatal HIV‐1 transmission is not known. Objective: A retrospective survey was conducted at six centers in the United States and Puerto Rico from January 1997 to October 1998 to evaluate the effects of protease inhibitor use during pregnancy on maternal and infant safety, prematurity rate, and frequency of perinatal HIV‐1 transmission. Results: In the study, 91 live infants, including 3 sets of twins, and 1 neonate who died shortly after birth were born to 89 women. HIV perinatal transmission rate in this series was 0 (95% confidence interval [CI], 0%‐3%). Prematurity rate was 19.1%, comparable to rates in earlier reports of HIV‐1‐infected women. In multiple regression analysis, only cocaine use and premature rupture of membranes were associated with prematurity (p = .03 and .008, respectively). The gestational week during which the protease inhibitors were initiated was not found to be significantly associated with prematurity. Adverse maternal, obstetric, and infant events possibly related to protease inhibitors were uncommon. Conclusions: Protease inhibitors appeared generally safe in mothers and infants in this series. No perinatal HIV‐1 transmission occurred. Further prospective, controlled studies are needed to define the optimal management of HIV‐1 in 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.