Predicting Drug Concentration-Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically-Based Pharmacokinetic Model.

Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System-specific and drug-specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration-time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration-time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development.

Transcatheter interventions in the early postoperative period after the Fontan procedure.

OBJECTIVE: To analyze the safety and clinical impact of interventional cardiac catheter procedures in the management of early postoperative problems after completion of an extracardiac Fontan procedure. BACKGROUND: The mortality after Fontan procedure has consistently decreased over the last decade. The role of interventional catheterization to address early postoperative problems in this setting has not been studied systematically. METHODS: Over a 9.7-year period, 289 patients underwent an extracardiac fenestrated Fontan procedure with two early deaths (0.7%) and takedown in four (1.4%). Twenty-seven patients (9.3%) underwent 32 interventional cardiac catheter procedures at a median interval of 12.2 (1-30) days. The median weight was 14.5 (13.5-25) kg. The case notes and procedure records were reviewed retrospectively. RESULTS: Fontan pathway obstructions were treated in 11 patients with stent implantation with good results and no complications. Stent fenestration of the Fontan circulation was performed in 16 patients with one episode of transient hemiparesis and one episode of pericardial effusion. Three patients underwent initial balloon dilatation of branch pulmonary arteries or fenestration with little effect and underwent stent treatment 6 (5-9) days later. One patient had device closure of a large atrial fenestration. In one patient, residual anterograde pulmonary blood flow was occluded using a device. There were no deaths and in-hospital course was improved in all. CONCLUSION: Interventional cardiac catheter procedures can be performed safely and effectively in the early postoperative period after Fontan completion to address hemodynamic problems. These techniques contribute significantly to achieve a very low mortality and address morbidity after Fontan completion.

Sildenafil in the management of the failing Fontan circulation.

BACKGROUND: Sildenafil is increasingly being used in the management of pulmonary arterial hypertension in the newborn. Its role in patients with congenital cardiac disease is less well defined and as yet has only been reported sporadically. AIM: Present our experience with sildenafil treatment in patients with a failing Fontan circulation. PATIENTS AND METHODS: Retrospective review of 13 symptomatic patients after Fontan palliation who received treatment with sildenafil between January, 2006 and July, 2008. RESULTS: Three patients suffered from protein-losing enteropathy, four patients presented with bronchial casts, two had severe cyanosis after fenestrated Fontan procedure, two had prolonged chylous effusions, one had a previous failure of Fontan and take-down, and one patient had arrhythmias and end-stage cardiac failure requiring conversion to an extra-cardiac Fontan. Sildenafil was used in the dosage of 1-2 milligrams per kilogram 3-4 times per day. Protein-losing enteropathy and alpha-1-antitrypsin levels improved in all three patients on sildenafil treatment. One of these patients had a concomitant catheter creation of a fenestration, as did two patients presenting with bronchial casts and both patients with persistent chylous effusions. All four patients with bronchial casts and two patients with cyanosis improved significantly on sildenafil treatment. Chylous effusions decreased after sildenafil and stent enlargement of a fenestration. There were no significant side effects requiring sildenafil withdrawal over a treatment period ranging from 2 months to 2 years. CONCLUSIONS: Sildenafil can be used safely and effectively in the treatment of patients with a failing Fontan circulation.

Hypoplastic left heart syndrome.

Hypoplastic left heart syndrome is a rare congenital heart defect in which the left side of the heart is underdeveloped. Surgical management of hypoplastic left heart syndrome has changed the prognosis of the condition that was previously regarded as fatal. We discuss surgical strategies based on staged procedures, with the right ventricle supporting both systemic and pulmonary circulation. We also discuss other management options, such as neonatal transplantation and the recent innovation of hybrid techniques. Surgical techniques and the understanding of the pathophysiology of this condition have been at the forefront of neonatal cardiac surgery and intensive care. The management of the syndrome remains a challenge because affected children grow into adolescence and adulthood posing various new problems and demands.

Transcatheter recanalization of ligated main pulmonary artery.

A 12.5-year-old boy with tricuspid atresia and quadriplegic cerebral palsy presented with increasing cyanosis after previous palliation with a cavopulmonary shunt and ligation of the main pulmonary artery (MPA). Because of severe physical disabilities he was not considered suitable for Fontan completion. He underwent successful transcatheter stent recanalization of the ligated MPA. This re-established anterograde flow to the pulmonary arteries resulting in marked improvement in saturations.

Fate of pulmonary arteries following Norwood Procedure.

OBJECTIVE: This study evaluated the requirement for surgical reoperation and catheter-based reintervention to central pulmonary arteries (CPAs) following Norwood Procedure (NP). We sought to identify the influence of various surgical techniques employed during NP on subsequent interventions. METHODS: Between 1993 and 2004, 226 patients underwent Stage II following NP. Ninety-eight patients (43%) had completion of Fontan circulation (Stage III) and a further 107 (47%) are on course for Fontan completion with 21 (9%) inter-stage deaths. During NP, the aortic arch was reconstructed without additional material (n = 91, 40%) or with a pulmonary homograft patch (n = 135, 60%). Pulmonary blood flow was supplied by modified Blalock-Taussig shunt (n = 177, 78%) or right ventricle to pulmonary artery conduit (RV-PA; n = 49, 22%). The CPAs defect was closed directly (n = 69, 31%) or with a patch (n = 157, 69%). Complete resection of coarctation was performed in 126 patients (56%). RESULTS: Ninety-seven patients (43%) required surgical reoperation to CPAs during Stage II. Actuarial freedom from reoperation was 60+/-3%, 52+/-4% and 50+/-4% at 1, 5 and 10 years, respectively. On multivariable analysis, NP with RV-PA increased risk of reoperation (LR 8.3, 5.3-13.2; p < 0.001). Forty-one patients (18%) required catheter-based reintervention on CPAs. Actuarial freedom from reintervention was 98+/-1%, 72+/-4% and 58+/-6% at 1, 5 and 10 years, respectively. CPA problems were almost exclusively limited to the proximal Left pulmonary artery. On multivariable analysis, catheter-based reintervention became more common with time. Complete resection of coarctation increased risk of reintervention (LR 3.9, 1.6-9.6; p < 0.005). Arch reconstruction and CPAs repair techniques did not affect risk of reoperation or reintervention on CPAs. CONCLUSIONS: CPA stenoses and hypoplasia need surgical attention in approximately half of all patients undergoing the NP. The need for reoperation is increased when using the RV-PA conduit technique (although the majority of these are performed as part of the Stage II procedure). Catheter reinterventions are almost exclusively confined to the left CPA and are increased when the arch is shortened by resection of the coarctation tissue at time of NP.

Experience with intraoperative ultrasound in paediatric cardiac surgery.

OBJECTIVE: Intraoperative ultrasound was introduced to evaluate the adequacy of repair after surgical repair of congenital cardiac malformations. Our purpose was to review the evolution of this technique at our centre. METHODS: We evaluated all intraoperative ultrasound studies undertaken between 1997 and 2002, reviewing the data from 1997 through 2001 retrospectively, but undertaking a prospective audit of studies undertaken from 2002 onwards. In all, we carried out a total number of 639 intraoperative ultrasound studies, from a possible 2737 cardiac operations (23.3%), using the epicardial approach in 580 (90.7%), and transoesophageal ultrasound in the other 59 patients (9.3%). Median age was 0.6 years, with an interquartile range from 0.06 to 3.6 years. RESULTS: The findings obtained using intraoperative ultrasound influenced the surgical management in 63 of the 639 patients (9.9%), suggesting the need for additional surgery in 26, adjustment of the band placed round the pulmonary trunk in 16, preoperative assessment of the cardiac malformation in 5, and confirming the need for prolonged support with cardiopulmonary bypass for impaired ventricular function in 16. There were 18 early reoperations, 5 of which may have been predicted by intraoperative ultrasound. Of the 183 studies reviewed prospectively in 2002, it was not possible to obtain the complete range of views in 8 (4.4%), while in 27 patients (14.7%), the postoperative findings using transthoracic interrogation differed from the findings obtained immediately following bypass. CONCLUSION: Intraoperative ultrasound is an important technique for monitoring the results of complex congenital cardiac surgery. The immediate recognition of significant lesions, together with multidisciplinary discussion, allows for improved management and prevention of early surgical reintervention.

Influence of surgical strategies on outcome after the Norwood procedure.

OBJECTIVE: The study objective was to identify how the evolution of surgical strategies influenced the outcome after the Norwood procedure. METHODS: From 1992 to 2004, 367 patients underwent the Norwood procedure (median age, 4 days). Three surgical strategies were identified on the basis of arch reconstruction and source of pulmonary blood flow. The arch was refashioned without extra material in group A (n = 148). The arch was reconstructed with a pulmonary artery homograft patch in groups B (n = 145) and C (n = 74). Pulmonary blood flow was supplied by a modified Blalock-Taussig shunt in groups A and B. Pulmonary blood flow was supplied by a right ventricle to pulmonary artery conduit in group C. Early mortality, actuarial survival, and freedom from arch reintervention or pulmonary artery patch augmentation were analyzed. RESULTS: Early mortality was 28% (n = 102). Actuarial survival was 62% +/- 3% at 6 months. Early mortality was lower in group C (15%) than group A (31%) or group B (31%; P <.05). Actuarial survival at 6 months was better in group C (78% +/- 5%) than group A (59% +/- 5%) or group B (58% +/- 4%; P <.05). Fifty-three patients (14%) had arch reintervention. Freedom from arch reintervention was 76% +/- 3% at 1 year, with univariable analysis showing no difference among groups A, B, and C (P =.71). One hundred patients (27%) required subsequent pulmonary artery patch augmentation. Freedom from patch augmentation was 61% +/- 3% at 1 year, and was lower in group C (3% +/- 3%) than group A (80% +/- 4%) or group B (72% +/- 5%; P <.05). CONCLUSIONS: Survival after the Norwood procedure improved after the introduction of a right ventricle to pulmonary artery conduit, but a greater proportion of patients required subsequent pulmonary artery patch augmentation. The type of arch reconstruction did not affect the incidence of arch reintervention.

Surgical aortic valvotomy in infancy: impact of leaflet morphology on long-term outcomes.

BACKGROUND: Surgical valvotomy for critical aortic stenosis in children enables relatively accurate commissurotomies to be fashioned, resulting in the formation of two or three leaflets. We hypothesized that outcomes after surgery may be best in patients in whom three leaflets are produced. METHODS: A retrospective review of infants undergoing primary surgical valvotomy at our institution during a 12-year period was carried out. Patients who had additional intracardiac defects were excluded. Clinical and echocardiographic follow-up data were analyzed. RESULTS: Fifty-four patients fulfilled the study criteria. Median age at surgery was 3 weeks (range, 0 to 51 weeks). Commissurotomy resulted in bileaflet anatomy in 41 patients (group A) and trileaflet anatomy in 13 patients (group B). Operative mortality was 5% in group A and 0% in group B (p = 1.0). In group A, 18 patients required one or more aortic valve reinterventions, including valve replacement in 8 patients. In group B, there was only one reintervention (repeat valvotomy). Kaplan-Meier analysis showed that at 10 years, comparisons of group A versus group B were as follows: actuarial survival, 85% versus 100% (p = 0.15); freedom from reintervention, 33% versus 92% (p = 0.01); freedom from aortic reoperation, 45% versus 92% (p = 0.04); and freedom from aortic valve replacement, 57% versus 100% (p = 0.07). CONCLUSIONS: Long-term outcomes after aortic valvotomy are significantly better in infants in whom surgery results in trileaflet rather than bileaflet anatomy. Preoperative evaluation of valve morphology may enable selection of a group of patients in whom results of surgery are excellent.

Timing of breast milk HIV-1 transmission: a meta-analysis.

OBJECTIVE: To define the frequency and timing of breast milk transmission of HIV-1. DESIGN: Meta-analysis of data abstracted from published literature. SUBJECTS: Participants in prospective cohort studies of MTCT of HIV-1. Cohorts were separated on the basis of breast feeding duration. INTERVENTIONS: None. MAIN OUTCOME MEASURES: HIV-1 transmission rates. RESULTS: Two thousand three hundred and seventy five HIV-1 infected women and their infants, 499 of whom breast fed, the estimated risk of breast milk HIV-1 transmission was 16% (95% CI: 9, 22%). Among breastfeeding infants, forty seven per cent of HIV-1 infections were attributable to breast feeding. Breast milk transmission risk was 21% (95% CI: 10, 33%) in cohorts with mean/median duration of breast feeding > or = 3 months and 13% (95% CI: 4, 21%) in cohorts with median duration of breast feeding < 2 months. In a separate analysis of 702 infants with prolonged duration of breast feeding, the risk of late postnatal transmission (infection occurring later than three to six months of age) was four per cent (95% CI 2, 5%). CONCLUSIONS: This analysis suggests that breast milk transmission of HIV-1 is substantial and continues throughout the postnatal period. Early cessation of breast feeding at six months would avert some but not most infant HIV-1 infections due to breast feeding. While recently published studies showing some effectiveness of antiretrovirals early during the breast feeding period are encouraging, prevention of breast milk HIV-1 transmission needs to remain a high research priority.

CCR5 promoter polymorphisms in a Kenyan perinatal human immunodeficiency virus type 1 cohort: association with increased 2-year maternal mortality.

The CCR5 chemokine receptor acts as a coreceptor with CD4 to permit infection by primary macrophage-tropic human immunodeficiency virus type 1 (HIV-1) strains. The CCR5Delta32 mutation, which is associated with resistance to infection in homozygous individuals and delayed disease progression in heterozygous individuals, is rare in Africa, where the HIV-1 epidemic is growing rapidly. Several polymorphisms in the promoter region of CCR5 have been identified, the clinical and functional relevance of which remain poorly defined. We evaluated the effect of 4 CCR5 promoter mutations on systemic and mucosal HIV-1 replication, disease progression, and perinatal transmission in a cohort of 276 HIV-1-seropositive women in Nairobi, Kenya. Mutations at positions 59353, 59402, and 59029 were not associated with effects on mortality, virus load, genital shedding, or transmission in this cohort. However, women with the 59356 C/T genotype had a 3.1-fold increased risk of death during the 2-year follow-up period (95% confidence interval [CI], 1.0-9.5) and a significant increase in vaginal shedding of HIV-1-infected cells (odds ratio, 2.1; 95% CI, 1.0-4.3), compared with women with the 59356 C/C genotype.

Comparison of techniques for HIV-1 RNA detection and quantitation in cervicovaginal secretions.

PRINCIPLES: HIV-1 in female genital secretions has been measured using swabs, Sno Strips (Akorn, Inc., Buffalo Grove, IL), and cervicovaginal lavage (CVL), but little is known regarding the comparability of these collection techniques. METHODS: We compared HIV-1 RNA detection and quantity in specimens obtained from HIV-1-seropositive women in Kenya using three sample collection techniques and three storage techniques and evaluated reproducibility in samples collected 5 days apart. Specimens were stored in no medium, freezing medium, or TRI Reagent (Molecular Research Center, Cincinnati, OH) for 2 to 15 months. RESULTS: HIV-1 RNA assays were conducted on 640 specimens from 20 antiretroviral naive women. Storage in TRI Reagent significantly enhanced detection of genital HIV-1 and yielded significantly higher mean log10 RNA levels than specimens collected in either no or freezing medium. The prevalence of HIV-1 RNA detection in TRI Reagent ranged from 50% to 80% depending on collection method and was highest in cervical swabs. Mean log10 HIV-1 RNA levels were 3.1 log10 copies/cervical swab, 2.6 log10 copies/cervical Sno Strip, 2.5 log10 copies/vaginal swab, 2.4 log10 copies/vaginal Sno Strip, 2.9 log10 copies/ml for cervicovaginal lavage (CVL) cell pellet, and 2.1 log10 copies/ml in CVL supernatant. Comparing specimens from days 1 and 6, there was significant concordance of HIV-1 RNA detection and correlation of HIV-1 RNA levels for cervical swabs, vaginal swabs, vaginal Sno Strips, and CVL cell pellets (kappa, 0.5-0.9; r, 0.5-0.9), but not for cervical Sno Strips or CVL supernatants. CONCLUSIONS: Cervical or vaginal swab, vaginal Sno Strip, and CVL collection led to reproducible measurement of genital HIV-1 RNA, despite storage for several months and international transport. Collection using swabs was simpler than Sno Strips or cervicovaginal lavage, and yielded the highest prevalence of HIV-1 RNA detection and reproducibility.

Correlates of mother-to-child human immunodeficiency virus type 1 (HIV-1) transmission: association with maternal plasma HIV-1 RNA load, genital HIV-1 DNA shedding, and breast infections.

To determine the effects of plasma, genital, and breast milk human immunodeficiency virus type 1 (HIV-1) and breast infections on perinatal HIV-1 transmission, a nested case-control study was conducted within a randomized clinical trial of breast-feeding and formula feeding among HIV-1-seropositive mothers in Nairobi, Kenya. In analyses comparing 92 infected infants with 187 infants who were uninfected at 2 years, maternal viral RNA levels >43,000 copies/mL (cohort median) were associated with a 4-fold increase in risk of transmission (95% confidence interval [CI], 2.2-7.2). Maternal cervical HIV-1 DNA (odds ratio [OR], 2.4; 95% CI, 1.3-4.4), vaginal HIV-1 DNA (OR, 2.3; 95% CI, 1.1-4.7), and cervical or vaginal ulcers (OR, 2.7; 95% CI, 1.2-5.8) were significantly associated with infant infection, independent of plasma virus load. Breast-feeding (OR, 1.7; 95% CI, 1.0-2.9) and mastitis (relative risk [RR], 3.9; 95% CI, 1.2-12.7) were associated with increased transmission overall, and mastitis (RR, 21.8; 95% CI, 2.3-211.0) and breast abscess (RR, 51.6; 95% CI, 4.7-571.0) were associated with late transmission (occurring >2 months postpartum). Use of methods that decrease infant exposure to HIV-1 in maternal genital secretions or breast milk may enhance currently recommended perinatal HIV-1 interventions.

Maternal SDF1 3'A polymorphism is associated with increased perinatal human immunodeficiency virus type 1 transmission.

Genetic polymorphisms in chemokine and chemokine receptor genes influence susceptibility to human immunodeficiency virus type 1 (HIV-1) infection and disease progression, but little is known regarding the association between these allelic variations and the ability of the host to transmit virus. In this study, we show that the maternal heterozygous SDF1 genotype (SDF1 3'A/wt) is associated with perinatal transmission of HIV-1 (risk ratio [RR], 1.8; 95% confidence interval [CI], 1.0 to 3.3) and particularly postnatal breastmilk transmission (RR, 3.1; 95% CI, 1.1 to 8.6). In contrast, the infant SDF1 genotype had no effect on mother-to-infant transmission. These data suggest that SDF1, which is a ligand for the T-tropic HIV-1 coreceptor CXCR4, may affect the ability of a mother to transmit the virus to her infant. This suggests that a genetic polymorphism in a gene encoding a chemokine receptor ligand may be associated with increased infectivity of the index case and highlights the importance of considering transmission as well as clinical outcome in designing chemokine-based therapies for HIV-1.

Subtypes of human immunodeficiency virus type 1 and disease stage among women in Nairobi, Kenya.

In sub-Saharan Africa, where the effects of human immunodeficiency virus type 1 (HIV-1) have been most devastating, there are multiple subtypes of this virus. The distribution of different subtypes within African populations is generally not linked to particular risk behaviors. Thus, Africa is an ideal setting in which to examine the diversity and mixing of viruses from different subtypes on a population basis. In this setting, it is also possible to address whether infection with a particular subtype is associated with differences in disease stage. To address these questions, we analyzed the HIV-1 subtype, plasma viral loads, and CD4 lymphocyte levels in 320 women from Nairobi, Kenya. Subtype was determined by a combination of heteroduplex mobility assays and sequence analyses of envelope genes, using geographically diverse subtype reference sequences as well as envelope sequences of known subtype from Kenya. The distribution of subtypes in this population was as follows: subtype A, 225 (70.3%); subtype D, 65 (20.5%); subtype C, 22 (6.9%); and subtype G, 1 (0.3%). Intersubtype recombinant envelope genes were detected in 2.2% of the sequences analyzed. Given that the sequences analyzed represented only a small fraction of the proviral genome, this suggests that intersubtype recombinant viral genomes may be very common in Kenya and in other parts of Africa where there are multiple subtypes. The plasma viral RNA levels were highest in women infected with subtype C virus, and women infected with subtype C virus had significantly lower CD4 lymphocyte levels than women infected with the other subtypes. Together, these data suggest that women in Kenya who are infected with subtype C viruses are at more advanced stages of immunosuppression than women infected with subtype A or D. There are at least two models to explain the data from this cross-sectional study; one is that infection with subtype C is associated with a more rapid disease progression, and the second is that subtype C represents an older epidemic in Kenya. Discriminating between these possibilities in a longitudinal study will be important for increasing our understanding of the role of specific subtypes in the transmission and pathogenesis of HIV-1.

Cell-free human immunodeficiency virus type 1 in breast milk.

Breast-feeding may be an important route of human immunodeficiency virus type 1 (HIV-1) vertical transmission in settings where it is routinely practiced. To define the prevalence and quantity of HIV-1 in cell-free breast milk, samples from HIV-1-seropositive women were analyzed by quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). HIV-1 RNA was detected in 29 (39%) of 75 specimens tested. Of these 29 specimens, 16 (55%) had levels that were near the detection limit of the assay (240 copies/mL), while 6 (21%) had >900 copies/mL. The maximum concentration of HIV-1 RNA detected was 8100 copies/mL. The prevalence of cell-free HIV-1 was higher in mature milk (47%) than in colostrum (27%, P = 0.1). Because mature milk is consumed in large quantities, these data suggest that cell-free HIV-1 in breast milk may contribute to vertical transmission of HIV-1.

Cesarean delivery in women with genital herpes in washington state, 1989-1991.

OBJECTIVE: The purpose of this study was to determine whether the proportion of cesarean deliveries in pregnant women with a history of genital herpes and no active lesions at birth is higher than that in women with no history of genital herpes, and to determine whether this risk was modified by birth facilities' underlying prevalence of cesarean delivery. METHODS: This was a retrospective survey. Women who gave birth in Washington state from 1989 to 1991 were identified from the state birth records and were classified as having clinical genital herpes during pregnancy (N = 1,094) or history of genital herpes only (N = 4,163) at delivery. Women without genital herpes (N = 5,257) were randomly selected from remaining births. RESULTS: The main outcome measure was primary cesarean delivery, excluding those performed for indications other than genital herpes. Prevalence of primary cesarean delivery was 59.5% in women with clinical herpes during pregnancy and 12.5% in women with history of herpes, both significantly different from prevalence of 11.2% in unexposed women. Age-adjusted risk for cesarean delivery among women with a history of herpes was 1.13 [95% confidence interval (CI): 0.93, 1.37]. When baseline cesarean delivery prevalence was above 20%, this risk was 1.2 (95% CI: 1.0, 1.4; P = 0.058), compared to 1.1 (95% CI: 0.9, 1.3; P = 0.186) where cesarean delivery prevalence was below 20%. CONCLUSIONS: Women with history of genital herpes appear to have a slightly elevated risk of cesarean delivery, particularly in hospital settings with baseline prevalence of primary cesarean delivery above 20%. This rate is somewhat lower than that noted in a previous survey, suggesting that practitioners are following standard guidelines. Evaluations of cesarean delivery for genital herpes in other states should be performed.

Genital shedding of human immunodeficiency virus type 1 DNA during pregnancy: association with immunosuppression, abnormal cervical or vaginal discharge, and severe vitamin A deficiency.

The presence of human immunodeficiency virus type 1 (HIV-1) in genital secretions may be a determinant of vertical HIV-1 transmission. Cervical and vaginal secretions from HIV-1-seropositive pregnant women were evaluated to determine prevalence and correlates of HIV-1-infected cells in the genital tract. HIV-1 DNA was detected by polymerase chain reaction in 32% of 212 cervical and 10% of 215 vaginal specimens. Presence of HIV-1 DNA in the cervix was associated with cervical mucopus and a significantly lower absolute CD4 cell count (354 vs. 469, P < .001). An absolute CD4 cell count <200 was associated with a 9.6-fold increased odds of cervical HIV-1 DNA detection compared with a count > or = 500 (95% confidence interval, 2.8-34.2). Detection of vaginal HIV- 1 DNA was associated with abnormal vaginal discharge, lower absolute CD4 cell count, and severe vitamin A deficiency. Presence of HIV-1-infected cells in genital secretions was associated with immunosuppression and abnormal cervical or vaginal discharge.

Mother-to-child transmission of human immunodeficiency virus type 1.

A great deal of progress has been made in our understanding of mother-to-child transmission of HIV-1. Standardization of case definitions and transmission rate calculation methodologies, and a broader array of diagnostic options for detection of infant HIV-1 infection, will enhance our ability to evaluate and compare cohorts worldwide. In the next decade, several intervention studies should be completed. Carefully designed intervention studies have the potential both to determine which interventions are effective as well as to add to our understanding of vertical transmission of HIV-1. Regional differences in vertical transmission rates reflect a variety of viral, host, and obstetric factors. Intervention strategies will probably need to be regionally designed, taking into consideration these factors. Further research on timing and correlates of vertical transmission is necessary to determine the extent to which specific clinical trials can be extrapolated to public health policy.

PIP: Research related to maternal-child transmission of human immunodeficiency virus (HIV) has been advanced by standardization of case definitions and transmission rate calculation methodologies as well as enhanced diagnostic options for detecting infant HIV-1 infection. Standardization guidelines have yielded vertical transmission rate estimates of 25-30% in developing countries and 14-25% in developed countries. Mathematical modeling suggests that 95% of infant infections occur later than the last 2 months before delivery. Serial polymerase chain reaction evaluation has identified a 7.7% risk of in utero transmission, a 17.6% risk of combined in utero and intrapartum transmission, and a 4.9% incidence of late postnatal transmission. The risk of transmission through breast feeding has been estimated at 14%, with increases with longer durations. Advanced maternal clinical HIV status, primary infection, decreased maternal cell-mediated immunity, placentitis, ascending genital infection during the peripartum period, and syncytium-inducing HIV-1 strains have been associated with higher rates of maternal-child transmission. Prematurity, lack of cellular immunity, and vitamin A deficiency may be infant risk factors. The finding in an AIDS Clinical Trial Group that zidovudine (AZT) treatment was associated with a 67.5% reduction in risk has prompted widespread use of this regimen in developed countries; however, AZT is expensive and logistically difficult to administer in most developing country contexts. Randomized clinical trials currently underway are assessing the benefits of cesarean section delivery, postpartum HIV-specific immunoglobulin administration to infants, avoidance of breast feeding or early weaning, and antenatal maternal vitamin A administration. Selected intervention strategies should be regionally designed to take into account variations in viral, host, and obstetric factors.