John Moye

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.

RISK FACTORS FOR PERINATAL TRANSMISSION OF HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 IN WOMEN TREATED WITH ZIDOVUDINE

BACKGROUND Maternal, obstetrical, and infant-related factors associated with the risk of perinatal transmission of human immunodeficiency virus type 1 (HIV-1) were identified before the widespread use of zidovudine therapy in pregnant women. The risk factors for transmission when women and infants receive zidovudine are not well characterized. METHODS We examined the effects of maternal, obstetrical, and infant-related characteristics and maternal virologic and immunologic variables on the risk of perinatal transmission of HIV-1 among 480 women and their infants, all of whom received zidovudine. The women and infants were participating in a phase 3 trial of passive immunoprophylaxis for the prevention of perinatal transmission. RESULTS In univariate analyses, the risk of perinatal transmission was associated with each of the following: decreased maternal CD4+ lymphocyte counts at base line; decreased maternal HIV p24 antibody levels at base line and delivery; increased maternal HIV-1 titer at base line and delivery; increased maternal HIV-1 RNA levels at base line and delivery; and the presence of chorioamnionitis at delivery. In multivariate analyses, the only independent risk factor was the maternal HIV-1 RNA level at base line (odds ratio for transmission, 2.4 per log increase in the number of copies; 95 percent confidence interval, 1.2 to 4.7; P=0.02) and at delivery (odds ratio, 3.4; 95 percent confidence interval, 1.7 to 6.8; P=0.001). There was no perinatal transmission of HIV-1 among the 84 women who had HIV-1 levels below the limit of detection (500 copies per milliliter) at base line or the 107 women who had undetectable levels at delivery. CONCLUSIONS Among pregnant women and their infants, all treated with zidovudine, the maternal plasma HIV-1 RNA level was the best predictor of the risk of perinatal transmission of HIV-1. Antiretroviral therapy that reduces the HIV-1 RNA level to below 500 copies per milliliter appears to minimize the risk of perinatal transmission as well as improve the health of the women.

The Relationship between Serum Human Immunodeficiency Virus Type 1 (HIV-1) RNA Level, CD4 Lymphocyte Percent, and Long-Term Mortality Risk in HIV-1—Infected Children

Association of human immunodeficiency virus type 1 (HIV-1) RNA level, CD4 cell percent, and mortality was examined in stored sera from 254 infected children in an intravenous immunoglobulin infection prophylaxis trial. Ninety-two children (36.2%) died (41 during the study, 51 during long-term follow-up). The geometric mean baseline HIV-1 RNA level was 104,626 copies/mL, and the mean CD4 cell percent was 25%. Relative risk of death (RR) was 2.1 if the baseline RNA level was >100,000 copies/mL (95% confidence interval [CI], 1.4-3.0) and was 3.0 if the baseline CD4 cell percent was <15% (95% CI, 2.2-4.0). If RNA levels increased after baseline, the RR was 1.8 (95% CI, 1.3-2.6), and if the CD4 cell percent dropped to <15%, the RR was 2.8 (95% CI, 1.6-4.9). In a multivariate model, both baseline RNA level and CD4 cell percent were independently associated with mortality risk. In a time-dependent model, the RR per log 10 increase in HIV-1 RNA copy numbers was 2.8 (95% CI, 2.1-3.6) and per 5 percentage point decrement in CD4 cell percent was 1.3 (95% Cl, 1.2-1.5). Both variables should be considered for in decision-making regarding therapy and evaluation of antiretroviral response.

Short-term risk of disease progression in HIV-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis.

BACKGROUND Data on the short-term risk of disease progression in HIV-1-infected children are needed to address the question of when to begin combination antiretroviral therapy. We estimated 12-month risks of progression to AIDS and death, by age and most recent measurement of CD4 T-cell percentage (CD4%) or viral load, in children receiving no antiretroviral therapy or zidovudine monotherapy only. METHODS We undertook a meta-analysis of individual longitudinal data for 3941 children from eight cohort studies and nine randomised trials in Europe and the USA. Estimates of risk were derived from parametric survival models. FINDINGS 997 AIDS-defining events were recorded over 7297 person-years of follow-up in the analysis of CD4%, and 284 events over 2282 person-years in the viral load analysis, corresponding to 568 deaths (9087 person-years) and 129 deaths (2816 person-years), respectively. In children older than 2 years, risk of death increased sharply when CD4% was less than about 10%, or 15% for risk of AIDS, with a low and fairly stable risk at greater CD4%. Children younger than 2 years had worse outlook than older children with the same CD4%. Risk of progression increased when viral load exceeded about 10(5) copies per mL, although this association was more gradual compared with CD4%. Both markers had independent predictive value for disease progression; CD4% was the stronger predictor. INTERPRETATION This information is important for paediatricians making decisions, and for researchers designing trials, about when to initiate or restart antiretroviral therapy.

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 </=500/microL (22% had counts <200/microL) and required zidovudine for maternal health (24% received zidovudine before pregnancy). Transmission was associated with lower maternal baseline CD4 cell count (odds ratio, 1.58 per 100-cell decrement; P=.005; 10.0% vs. 3.6% transmission for count <200 vs. >/=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 studys ability to address whether passive immunization diminishes perinatal transmission.

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.

Iodine Status in Pregnant Women in the National Children's Study and in U.S. Women (15–44 Years), National Health and Nutrition Examination Survey 2005–2010

BACKGROUND This report presents iodine data from National Health and Nutrition Examination Survey (NHANES) and from a sample of pregnant women in the National Childrens Study (NCS) Vanguard Study. METHODS Urinary iodine (UI) was measured in a one third subsample of NHANES 2005-2006 and 2009-2010 participants and in all 2007-2008 participants age 6 years and older. These measurements are representative of the general U.S. population. UI was also measured in a convenience sample of 501 pregnant women enrolled in the NCS initial Vanguard Study from seven study sites across the United States. RESULTS NHANES median UI concentration in 2009-2010 (144 μg/L) was significantly lower than in 2007-2008 (164 μg/L). Non-Hispanic blacks had the lowest UI concentrations (131 μg/L) compared with non-Hispanic whites or Hispanics (147 and 148 μg/L, respectively). The median for all pregnant women in NHANES 2005-2010 was less than adequate (129 μg/L), while third trimester women had UI concentrations that were adequate (median UI 172 μg/L). Third trimester women participating in the NCS similarly had an adequate level of iodine intake, with a median UI concentration of 167 μg/L. Furthermore, NCS median UI concentrations varied by geographic location. CONCLUSIONS Dairy, but not salt, seafood, or grain consumption, was significantly positively associated with median UI concentration in women of childbearing age. Pregnant women in their third trimester in the NHANES 2005-2010 had adequate median UI concentrations, but pregnant women in NHANES who were in their first or second trimesters had median UI concentrations that were less than adequate. Non-Hispanic black pregnant women from both the NHANES 2005-20010 and the NCS consistently had lower UI median concentrations than non-Hispanic whites or Hispanics.

Performance characteristics of HIV-1 culture and HIV-1 DNA and RNA amplification assays for early diagnosis of perinatal HIV-1 infection.

A plasma HIV-1 RNA amplification assay (RNA assay), a quantitative peripheral blood mononuclear cell (PBMC) microculture (culture), and a PBMC HIV-1 DNA amplification assay (DNA assay) were compared for diagnosis of HIV-1 infection in infants receiving zidovudine in Pediatric AIDS Clinical Trials Group protocol 185; assays were performed for all 24 infected and 100 uninfected infants. HIV-1 infection was defined as ≥2 positive cultures or positive antibody to HIV-1 at ≥18 months. Cultures were performed at birth and 6 and 24 weeks of age; DNA and RNA assays were performed on cryopreserved specimens. The sensitivity of culture and DNA and RNA assays at birth was 20.8%, 10.5%, and 26.7%, respectively. At older ages, sensitivity typically exceeded 80%, remaining highest for the RNA assay (>85%). Assay specificity was >99%. Positive predictive values exceeded 93% for each assay at each age; negative predictive values were highest (>90%) for the RNA assay. At birth (P < 0.005) and age 6 weeks (P < 0.001), a significantly larger proportion of infected infants were identified by means of the RNA assay than by the other assays. The diagnostic performance of the RNA assay matched or exceeded that of culture and the DNA assay. Given that RNA assays require less blood volume and yield rapid results, our study adds to existing data suggesting that RNA assays may be used for early diagnosis of HIV-1 infection in infants.

Urinary concentrations of environmental phenols in pregnant women in a pilot study of the National Children's Study

Environmental phenols are a group of chemicals with widespread uses in consumer and personal care products, food and beverage processing, and in pesticides. We assessed exposure to benzophenone-3, bisphenol A (BPA), triclosan, methyl- and propyl parabens, and 2,4- and 2,5-dichlorophenol or their precursors in 506 pregnant women enrolled in the National Childrens Study (NCS) Vanguard Study. We measured the urinary concentrations of the target phenols by using online solid-phase extraction-isotope dilution high performance liquid chromatography-tandem mass spectrometry. NCS women results were compared to those of 524 similar-aged women in the National Health and Nutrition Examination Survey (NHANES) 2009-2010, and to 174 pregnant women in NHANES 2005-2010. In the NCS women, we found significant racial/ethnic differences (p<0.05) in regression adjusted mean concentrations of benzophenone-3, triclosan, 2,4- and 2,5-dichlorophenol, but not of BPA. Urinary 2,4- and 2,5-dichlorophenol concentrations were highly correlated (r=0.66, p<0.0001). Except for BPA and triclosan, adjusted mean concentrations were significantly different across the 7 study sites. Education was marginally significant for benzophenone-3, triclosan, propyl paraben, and 2,5-dichlorophenol. Urinary concentrations of target phenols in NCS pregnant women and U.S. women and pregnant women were similar. In NCS pregnant women, race/ethnicity and geographic location determined urinary concentrations of most phenols (except BPA), suggesting differential exposures. NCS Main Study protocols should collect urine biospecimens and information about exposures to environmental phenols.

Recombinant CD4-IgG2 in Human Immunodeficiency Virus Type 1—Infected Children: Phase 1/2 Study

The use of recombinant CD4-IgG2 in pediatric human immunodeficiency virus type 1 (HIV-1) infection was evaluated by single and multidose intravenous infusions in 18 children in a phase 1/2 study. The study drug was well tolerated, and dose proportionality was observed in terms of area under time-concentration curve and peak serum concentration. Acute decreases of >0.7 log(10) copies/mL in serum HIV-1 RNA concentration were seen in 4 of the 6 children treated with 4 weekly 10 mg/kg doses. At 14 days after treatment, 3 children had sustained reductions in serum HIV-1 RNA; the other children had rebounded to baseline levels or above. By 28 days after therapy, the peak HIV-1 cellular infectious units was reduced in all 6 children, including the 2 who had experienced an earlier transient increase in values. Thus, recombinant CD4-IgG2 treatment of HIV-1-infected children appears to be well tolerated and capable of reducing HIV-1 burden.