Alejandro Dorenbaum

Development of Resistance Mutations in Women Receiving Standard Antiretroviral Therapy Who Received Intrapartum Nevirapine to Prevent Perinatal Human Immunodeficiency Virus Type 1 Transmission: A Substudy of Pediatric AIDS Clinical Trials Group Protocol 316

Pediatric AIDS Clinical Trials Group protocol 316 was an international, multicenter, placebo-controlled trial comparing single-dose oral nevirapine (200 mg to mother and 2 mg/kg to infant) with placebo in human immunodeficiency virus (HIV)-infected pregnant women receiving standard antiretroviral therapy. This substudy evaluated the emergence of nevirapine-resistance mutations at 6 weeks postpartum in a subgroup of participants. Maternal risk factors for the emergence of nevirapine-resistance mutations were evaluated. Mutations associated with nevirapine resistance were detectable at delivery, prior to receipt of study drug, in 5 (2.3%) of 217 women. Fourteen (15%; 95% confidence interval, 8%-23%) of 95 women who received intrapartum nevirapine developed a nevirapine-resistance mutation 6 weeks postpartum. The most common mutation was K103N, which was present in 10 women. The risk for development of a new nevirapine-resistance mutation did not correlate with CD4 cell count or HIV-1 RNA load at delivery or with type of antepartum antiretroviral therapy. The risk of nevirapine resistance should be considered when determining the risks or benefits of intrapartum nevirapine in women receiving antepartum antiretroviral therapy.

When the Time Comes To Talk About HIV: Factors Associated With Diagnostic Disclosure and Emotional Distress in HIV-Infected Children

Objective: To determine factors related to the timing and probability of nondisclosure of HIV status to perinatally HIV‐infected children, and to explore factors associated with emotional distress in HIV‐infected children. Methods: This is a cross‐sectional study of 51 HIV‐infected children based on medical records, parent interviews, and child assessments. Results: 1) Probability of earlier age of disclosure is associated with higher child IQ (p = .04) and more family expressiveness (p = .01); 2) controlling for child age, disclosure status at time of study is associated with major life events, but not with medical status; and 3) factors associated with increased parent‐rated anxiety in HIVinfected children in univariate analyses are: HIV disclosure (p = .04), other major life events (p = .001), higher medication dose frequency (p = .01), and child age (p = .01). Increased depression is associated only with more medication doses (p = .02). Conclusion: These data indicate that higher child IQ and greater family expressiveness increase the probability of earlier diagnostic disclosure to HIV‐infected children. Factors associated with emotional distress highlight important areas of clinical attention. These data suggest that diagnostic disclosure may not necessarily minimize emotional distress, indicating the need for further evaluation of the appropriate timing and type of disclosure for pediatric HIV.

Predose infant nevirapine concentration with the two-dose intrapartum neonatal nevirapine regimen: association with timing of maternal intrapartum nevirapine dose

Objective: To evaluate cord blood and predose nevirapine concentrations in infants exposed to the two‐dose intrapartum neonatal nevirapine regimen. Methods: The authors obtained plasma samples for nevirapine assay from cord blood and just prior to the 48‐hours to 72‐hours after birth neonatal nevirapine dose from a subset of infants participating in PACTG 316, a randomized, placebo‐controlled trial of the two‐dose intrapartum neonatal nevirapine regimen added to standard antiretroviral therapy. Results: Nevirapine concentrations were measured in 109 cord blood samples and 149 predose samples. Cord blood nevirapine concentrations were below the target concentration of 100 ng/mL (10‐times the in vitro IC50 of nevirapine against wild‐type HIV) in eight (7%) of 109 infants (95% confidence interval [CI], 3%‐14%); the concentrations in six of these infants were below the assay limit of quantitation. Predose infant nevirapine concentrations were below 100 ng/mL in 23 (15%) of 149 infants (95% CI, 10%‐22%); the concentrations in 13 of these infants were below the assay limit of quantitation. Lower predose nevirapine concentrations were associated with lower cord blood concentrations and a shorter interval between maternal dosing and delivery. All but one of the infants with predose nevirapine concentrations below the assay limit of quantitation were born less than 2 hours after maternal dosing. Conclusion: Infants born less than 2 hours after maternal nevirapine dosing during labor should receive a dose of nevirapine immediately after birth in addition to the standard infant dose at 48 to 72 hours.

Sleep Disturbances in Children With Human Immunodeficiency Virus Infection

Objective. To describe the sleep patterns and level of fatigue in children and adolescents (6–18 years of age) with HIV infection, compared with ethnic-, gender-, and age-matched healthy children in the home setting. Design. Descriptive, comparative. Setting. Conducted in each childs home environment. Study Participants. Eighteen HIV-infected and 15 noninfected children completed the study. The Centers for Disease Control and Prevention HIV classifications for the 18 HIV-infected children were: A (n = 7), B (n= 6), and C (n = 5). Methods. A symptom diary was developed using a previously validated fatigue assessment scale, modified for use with children. Content validity of the diary was established with a panel of 5 experts in child development and pediatric HIV disease. Children were asked to complete the diary each morning and evening for 3 days. Each child wore a wrist actigraph during the same period. Results. The HIV-infected children had significantly more wake time after sleep onset, compared with noninfected children (13.55% vs 7.47%). The HIV-infected children had more awakenings (25.33 vs 16.71) and were awake for longer periods (3.01 vs 1.01 minutes), compared with noninfected children. By parent report, 7 HIV-infected children napped and 2 noninfected children napped, indicating greater daytime fatigue in the HIV-infected children. HIV-infected children also reported a greater level of evening tiredness (2.47 vs 1.8). Conclusions. The findings from this study suggest that sleep disturbances occur in HIV-infected children, similar to findings previously described in HIV-infected adults. Additional research is necessary to characterize the nature and patterns of sleep disturbance and fatigue related to pediatric HIV-infection, to assess the impact these may have on daily activities, and to develop strategies to improve sleep for these children.

Impact of Asthma Exacerbations and Asthma Triggers on Asthma-related Quality of Life in Patients with Severe or Difficult-to-Treat Asthma

BACKGROUND Few data are available that evaluate the relationship among asthma exacerbations, asthma triggers, and asthma-related quality of life (QoL). OBJECTIVE To evaluate the impact of asthma exacerbations and asthma triggers on QoL. METHODS Patients with severe or difficult-to-treat asthma, ages ≥ 13 years (n = 2679) from the TENOR (The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens) 3-year observational study were included. Exacerbations were defined hierarchically in descending order of severity (hospitalization, emergency department [ED] visit, steroid burst, no exacerbation) by using data from months 6 and 12. The total number (frequency) of exacerbations was assessed. Asthma-related QoL was measured at month 12 by using the Mini-Asthma QoL Questionnaire (Mini-AQLQ); self-reported asthma triggers were collected at baseline and annually. We used 1-way ANOVA to test for differences in Mini-AQLQ domain scores across asthma exacerbation severity, the total number of asthma exacerbations, and the number of asthma triggers. RESULTS A significant decrease (P < .001) in Mini-AQLQ domain scores was seen with increasing severity of asthma exacerbation (no exacerbation, steroid burst, ED visit, and hospitalization); symptom (5.5, 4.8, 4.3, and 4.2), activity (5.8, 5.2, 4.6, and 4.4), emotional (5.6, 5.0, 4.4, and 4.2), exposure (5.0, 4.5, 4.0, and 3.9); and overall (5.5, 4.9, 4.3, and 4.1). Increasing exacerbation frequency and the number of baseline asthma triggers also were associated with significant decreases in Mini-AQLQ domain scores. An increasing number of asthma triggers were associated with an increase in severity and frequency of exacerbations. CONCLUSION Avoidance of asthma triggers may reduce exacerbation rates and improve asthma-related QoL in patients with severe or difficult-to-treat asthma. Interventional studies are warranted to further explore these outcomes.

The impact of race/ethnicity on mother-to-child HIV transmission in the United States in Pediatric AIDS Clinical Trials Group Protocol 316.

Summary: The present analysis was designed to determine whether race/ethnicity was independently associated with mother-to-child HIV-1 transmission risk in subjects enrolled in a trial of 2-dose intra-partum nevirapine in combination with standard antiretroviral therapy and to determine what factors, including race/ethnicity, predicted maternal viral suppression at the time of delivery. Women enrolled in Pediatric AIDS Clinical Trials Group (PACTG) 316 from sites in the United States and Puerto Rico were included. Distribution of selected maternal disease and treatment characteristics was assessed by race/ethnicity category. Logistic regression models were fit to evaluate possible association of factors with HIV transmission and with viral load at delivery. Variables associated with the outcome at P < 0.05 level were retained in the final models. Of 1052 women randomized at PACTG sites, 891 were included in the present analysis: 572 (64%) were black; 206 (23%) were Hispanic; and 113 (13%) were white. All women who had infected infants were black or Hispanic (11/572 and 3/206, respectively), whereas none of the women identified as white had an infected infant (0/113). This difference was not statistically significant (P = 0.54). White women had higher entry CD4 cell counts and lower HIV-1 RNA at delivery than women of other races/ethnicities. Black and Hispanic women were more likely than white women to start therapy during their current pregnancy but did not initiate prenatal care later. In bivariate models that included antiretroviral type and variables that had values of P ≤ 0.25 in univariate analysis, time of antiretroviral initiation, time of prenatal care initiation, and race/ethnicity each retained significance in predicting viral suppression at delivery. Race/ethnicity remained predictive of viral suppression at delivery in a multivariate model incorporating all of these variables (P = 0.01). Higher HIV-1 RNA and lower CD4 cell counts in women identified as black or Hispanic have significant implications for the health of these women and their newborns. Race/ethnicity is significant in predicting viral suppression at the time of delivery.

Cytokine profile of a long-term pediatric HIV survivor with hyper-IgE syndrome and a normal CD4+ T-cell count

BACKGROUND An elevated IgE level and increased production of T(H2) cytokines are factors associated with poor prognosis in HIV infection. We report a pediatric long-term survivor of vertically acquired HIV infection with a normal CD4 count and a low viral burden despite the lack of antiretroviral therapy and a phenotype resembling hyper-IgE syndrome. OBJECTIVE We sought to characterize the patients T(H1) versus T(H2) cytokine profile and anti-HIV-specific immune responses. METHODS Supernatants collected from cultures of peripheral blood T cells stimulated with phorbol myristate acetate plus ionomycin were assayed for T(H1) and T(H2) cytokines by means of ELISA. Specific IgE antibodies were determined by immunoblot. HIV-specific cytotoxic T-lymphocyte responses were measured from cell lysis by fresh T cells of autologous B-lymphoblastoid cells expressing recombinant HIV proteins. RESULTS Patient CD4(+) T cells secreted significantly more T(H2) cytokines, IL-4 (P <.003) and IL-5 (P <.03), than HIV-infected and seronegative control cells. No difference was noted in T(H1) cytokine production. IgE specific for HIV gp160, p24, p17, and p66 proteins and Aspergillus fumigatus was detected in patient sera. Despite predominance of T(H2) cytokines, HIV-specific cytotoxic T-lymphocyte activity was vigorous. CONCLUSIONS The patient demonstrated predominantly T(H2) cytokine production in vitro. Unlike other patients with HIV who have hyper-IgE and increased T(H2) cytokine production, our patient has maintained HIV-specific immune responses, a low viral load, and a normal CD4 count without antiretroviral therapy. These findings support a diagnosis of primary hyper-IgE syndrome. Presence of anti-HIV-specific IgE may represent a protective mechanism against HIV replication in our patient.

Transmission of HIV-1 in Infants Born to Seropositive Mothers: PCR-Amplified Proviral DNA Detected by Flow Cytometric Analysis of Immunoreactive Beads

The diagnosis of HIV infection in newborns is established by amplification of proviral DNA using the polymerase chain reaction (PCR). We developed a nonisotopic method for heminested PCR using a biotinylated primer among sets of three oligonucleotides, each selected from the HIV long terminal repeat (LTR) and gag sequences. An internal probe incorporating digoxigenin-dUTP was also synthesized by PCR. The PCR products, hybridized with LTR region or gag region probes, were captured with streptavidin-coated magnetic beads and detected by fluorescein isothiocyanate-labeled antidigoxigenin in flow cytometric analysis. This immunoreactive bead assay (PCR-IRB) detected about three copies of HIV proviral DNA. A panel of 50 coded DNA specimens of infants previously assayed by conventional PCR and with known clinical results revealed that the PCR-IRB findings using LTR, but not gag, were in agreement. A double-blind prospective study of blood samples from 14 mother-infant pairs using the PCR-IRB amplification of LTR gave results similar to the commercial Amplicor HIV-1 PCR test and were consistent with the clinical outcomes. PCR-IRB results were positive for 11 mothers and three infants, one at birth, one at 2 weeks after birth, and one at 8 weeks after birth. PCR-IRB is a simple, reliable, specific, and automatable assay useful in the early diagnosis of perinatal HIV infection in clinical practice and regional screening programs.

Recurrent Staphylococcus aureus renal abscess in a child positive for the human immunodeficiency virus

A 10-year-old girl with the human immunodeficiency virus was found to have a Staphylococcus aureus renal abscess with perinephric extension. The abscess was drained first percutaneously and then surgically, and the patient received a 6-week course of intravenous antibiotics. Three months later, the abscess recurred, necessitating a nephrectomy. The extended morbidity and difficulty of eradicating S aureus suggest that, in immunocompromised patients, early aggressive surgical management is indicated.

Chaperone-like therapy with tetrahydrobiopterin in clinical trials for phenylketonuria: is genotype a predictor of response?

Prospectively enrolled phenylketonuria patients (n=485) participated in an international Phase II clinical trial to identify the prevalence of a therapeutic response to daily doses of sapropterin dihydrochloride (sapropterin, KUVAN(®)). Responsive patients were then enrolled in two subsequent Phase III clinical trials to examine safety, ability to reduce blood Phenylalanine levels, dosage (5-20 mg/kg/day) and response, and bioavailability of sapropterin. We combined phenotypic findings in the Phase II and III clinical trials to classify study-related responsiveness associated with specific alleles and genotypes identified in the patients. We found that 17% of patients showed a response to sapropterin. The patients harbored 245 different genotypes derived from 122 different alleles, among which ten alleles were newly discovered. Only 16.3% of the genotypes clearly conferred a sapropterin-responsive phenotype. Among the different PAH alleles, only 5% conferred a responsive phenotype. The responsive alleles were largely but not solely missense mutations known to or likely to cause misfolding of the PAH subunit. However, the metabolic response was not robustly predictable from the PAH genotypes, based on the study design adopted for these clinical trials, and accordingly it seems prudent to test each person for this phenotype with a standardized protocol.