Henry Pollack

Latent Tuberculosis Diagnosis in Children by Using the QuantiFERON-TB Gold In-Tube Test

BACKGROUND. The QuantiFERON-TB Gold test was the first blood test to be approved for the diagnosis of latent tuberculosis infection. Although it has been shown to be sensitive and specific in adults, limited data on its performance in children are available. METHODS. This was a prospective study of children receiving health care in New York, New York. Each child was assessed for risk factors for Mycobacterium tuberculosis infection, underwent tuberculin skin testing, and had a QuantiFERON-TB Gold In-Tube test performed. The concordance between tuberculin skin test and QuantiFERON-TB Gold In-Tube test results was calculated, and the results were analyzed according to the likelihood of exposure to M tuberculosis. RESULTS. Data for 207 children with valid tuberculin skin test and QuantiFERON-TB Gold In-Tube test results were analyzed. There was excellent correlation between negative tuberculin skin test results and negative QuantiFERON-TB Gold In-Tube test results; however, only 23% of children with positive tuberculin skin test results had positive QuantiFERON-TB Gold In-Tube test results. Positive QuantiFERON-TB Gold In-Tube test results were associated with increased likelihood of M tuberculosis exposure, and interferon γ levels were higher in children with known recent exposure to M tuberculosis, compared with children with older exposure histories. Younger children produced lower interferon γ levels in response to the mitogen (phytohemagglutinin) control used in the QuantiFERON-TB Gold In-Tube test, but indeterminant results were low for children of all ages. Performance characteristics were similar across all age groups. CONCLUSION. The QuantiFERON-TB Gold In-Tube test is a specific test for M tuberculosis exposure in children, with performance characteristics similar to those for adults residing in regions with low levels of endemic disease. Concerns about test sensitivity, especially for children <2 years of age, will require additional prospective long-term evaluation.

High sustained virologic response rates in children with chronic hepatitis C receiving peginterferon alfa-2b plus ribavirin

BACKGROUND & AIMS Pegylated interferon (PEG-IFN) alfa-2b plus ribavirin (RBV) is the standard of care for adults with chronic hepatitis C but was not approved for the treatment of children at the time of this study. The aim of this study was to evaluate the efficacy and safety of PEG-IFN alfa-2b plus RBV in children. METHODS Children and adolescents ages 3-17 years were treated with PEG-IFN alfa-2b (60microg/m(2)/week) plus RBV (15mg/kg/day). The duration of therapy was 24 weeks for genotype (G) 2 and G3 patients with low viral load (<600,000IU/ml) and 48 weeks for G1, G4, and G3 with high viral load (>or=600,000IU/ml). The primary end point was sustained virologic response (SVR), defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after completion of therapy. RESULTS SVR was attained by 70 (65%) children. Genotype was the main predictor of response: G1, 53%; G2/3, 93%; G4, 80%. SVRs were similar in younger and older children. Baseline viral load was the main predictor of response in the G1 cohort. No new safety signals were identified, and adverse events (AEs) were generally mild or moderate in severity. Dose was modified because of AEs in 25% of children; 1 child discontinued because of an AE (thrombocytopenia). No serious AEs related to study drugs were reported. CONCLUSION Therapy with PEG-IFN alfa-2b plus RBV in children and adolescents with chronic hepatitis C offers favorable efficacy, reduced injection frequency, and an acceptable safety profile.

Human Immunodeficiency Virus Type 1- and Cytomegalovirus-Specific Cytotoxic T Lymphocytes Can Persist at High Frequency for Prolonged Periods in the Absence of Circulating Peripheral CD4+ T Cells

ABSTRACT CD4+ T cells are thought to be critical in the maintenance of virus-specific CD8+ cytotoxic T-cell (CTL) responses. In human immunodeficiency virus type 1 (HIV-1) infection, a selective decline in HIV-1-specific CTL as the CD4+ T-cell count decreases has been reported. Using HLA-peptide tetrameric complexes, we show the presence at high frequency of HIV-1- and cytomegalovirus-specific CD8+ T cells when the peripheral CD4+ T-cell count was low or zero in three HIV-1-infected patients. No direct virus-specific CD8+-mediated effector activity was seen in these subjects, suggesting antigen unresponsiveness, although tetramer-sorted cells could be expanded in vitro in the presence of interleukin-2 into responsive effector cells. Thus, virus-specific CD8+ T cells can be maintained in the peripheral circulation at high frequency in the absence of circulating peripheral CD4+ T cells, but these cells may lack direct effector activity. Strategies designed to overcome this antigen unresponsiveness may be of value in therapies for the treatment of AIDS.

Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to <18 years) with chronic hepatitis B.

This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment‐naive and treatment‐experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV‐treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo‐treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV‐treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV‐associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment‐related adverse events were reported for 12% of ADV‐treated and 10% of placebo‐treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment‐naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. Conclusion: ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years. (HEPATOLOGY 2008.)

Increased transmission of vertical hepatitis C virus (HCV) infection to human immunodeficiency virus (HIV)-infected infants of HIV- and HCV-coinfected women.

The transmission of perinatal hepatitis C virus (HCV) infection was studied retrospectively in 62 infants born to 54 HCV- and human immunodeficiency virus (HIV)-coinfected women enrolled in a prospective natural history study of HIV transmission. Infant HCV infection was assessed by nested RNA polymerase chain reaction. The overall rate of vertical HCV transmission was 16.4% (9/62). Most HCV-infected children did not develop antibodies to HCV. The rate of HCV infection was higher among HIV-infected infants (40%) than among HIV-uninfected infants (7.5%; odds ratio, 8.2; P = .009). This difference in transmission was not related to differences in maternal HCV load, as measured by branched DNA assay, or mode of delivery. Why HIV-infected infants of HCV- and HIV-coinfected women have significantly higher rates of perinatal HCV transmission remains to be elucidated. The rate of HCV transmission in HIV-uninfected infants of HCV- and HIV-coinfected women is similar to that reported for infants born to HIV-seronegative mothers.

Correlation of perinatal transmission of human immunodeficiency virus type 1 with maternal viremia and lymphocyte phenotypes

OBJECTIVE To determine whether maternal transmission of human immunodeficiency virus (HIV) is correlated with increased quantities of HIV, decreased frequencies of CD4+ T cells, or increased levels of CD8+ T cells in the transmitting mother. METHODS Peripheral blood obtained from HIV-infected women at different times during pregnancy was used to measure quantitative cell-associated HIV-1 and CD3+CD4+ and CD3+CD8+ proportions; the plasma was used to perform measurements of quantitative viremia by culture and subsequently to measure quantitative HIV-1 ribonucleic acid levels. These measurements were analyzed with respect to their association with HIV transmission to the baby, which occurred in one fourth of the cases. The children were also studied to determine whether HIV-1 was detected near birth or not until 1 to 8 weeks of life. RESULTS Increased clonal frequencies of HIV-1-infected peripheral blood mononuclear cells were found in mothers of infected children; fivefold fewer cells were required for a positive culture result (median cell numbers of 10(4.5) vs 10(5.2); p = 0.008). Higher frequencies of infected cells were seen in mothers of babies with evidence of infection at birth than in mothers of infected babies without evidence of infection at birth (p < 0.05). Plasma viremia was measured in 10% of cultures without regard to whether the mothers transmitted virus to their babies. Increased levels of ribonucleic acid as detected by the branched-chain DNA method were measurable more often (45% vs 17%) in the mothers of infected children than in mothers of uninfected children. Proportions of CD4+ and CD8+ T cells were indistinguishable in these two groups of women. CONCLUSIONS Increased viremia was present in mothers who transmitted HIV to their offspring. This variable could be used to select women at highest risk of transmitting HIV to their offspring for treatment to decrease the HIV burden five-fold.

Cell-mediated and humoral immune responses in children infected with human immunodeficiency virus during the first four years of life

OBJECTIVES To determine whether cell-mediated and humoral immune responses to recall antigens develop in children infected with the human immunodeficiency virus (HIV) and, if so, whether these responses are retained. METHODS Children infected with HIV and uninfected children born to mothers infected with HIV were compared with respect to lymphoproliferative responses to recall antigens and protective levels of antibody to bacterial toxoids during the first 4 years of life. RESULTS Children infected with HIV who were enrolled in a prospective study of the natural history of the infection were relatively normal (1) in their lymphoproliferative responses to diphtheria toxoid, tetanus toxoid, and Candida, and (2) in their ability to make protective diphtheria and tetanus antitoxins during the first 2 years of life. During the next 2 years, attrition was noted in both lymphoproliferative and humoral responses. Attrition in response was not necessarily correlated with declining numbers of helper T cells. CONCLUSIONS These results suggest that both cellular and humoral immune responses develop early in life in most children infected with HIV, while they remain relatively well both clinically and immunologically. Previously reported severe immune deficits in these children were probably attributable to advanced clinical disease when they were first studied.

Role of Imiquimod and Parenteral Meglumine Antimoniate in the Initial Treatment of Cutaneous Leishmaniasis

BACKGROUND Cutaneous leishmaniasis is a serious public health problem in the developing world. The main therapeutic agent--pentavalent antimony, developed >50 years ago--is expensive, often accompanied by severe adverse effects, and complicated by the emergence of drug resistance. Better therapies are urgently needed. In the present pilot study, we compared the use of imiquimod, an immunomodulatory molecule, to the use of meglumine antimoniate alone and in combination for the initial treatment of cutaneous leishmaniasis. MATERIALS AND METHODS Patients with newly diagnosed cutaneous leishmaniasis were enrolled from a single referral center in Lima, Peru, from August 2005 through October 2005. Patients were randomly assigned to 1 of 3 treatment groups and received either imiquimod 7.5% cream administered topically every other day for 20 days, intravenous meglumine antimoniate administered at a dosage of 20 mg/kg per day every day for 20 days, or combination therapy with both intravenous meglumine antimoniate and imiquimod 7.5% cream. Patients were evaluated weekly and at 1 and 3 months after treatment. Patients who had healed lesions at 3 months were considered to be clinically cured. RESULTS Although several patients showed initial resolution of symptoms with imiquimod treatment alone, all of these patients experienced relapse after treatment discontinuation. Four (57%) of 7 patients treated with meglumine antimoniate alone and 7 (100%) of 7 patients treated with combination therapy were cured. Combination therapy was not only more effective than the other 2 treatments (P<.05) but also led to faster healing and better cosmetic results. CONCLUSION Combination therapy with imiquimod and meglumine antimoniate is a promising regimen for the initial treatment of cutaneous leishmaniasis that warrants additional larger studies.

Changes in Frequency of HIV-1—Specific Cytotoxic T Cell Precursors and Circulating Effectors after Combination Antiretroviral Therapy in Children

Combination antiretroviral therapy has had a major role in reducing human immunodeficiency virus type 1 (HIV-1) plasma viral loads in HIV-1-infected adults but a variable effect in infants, in whom complete viral suppression appears to be less readily achieved. In adults, after the reduction in plasma viremia, there is a decrease in the numbers of circulating cytotoxic T cell (CTL) effectors and precursors in the majority of patients. This longitudinal study assessed the effect of combination drug therapy on the frequency of HIV-1-specific CTL responses in 8 HIV-1-infected children. Following treatment, the frequency of HIV-1-specific CTL responses initially increased, especially in children with incomplete viral suppression but with increasing CD4+ cell counts. In children with complete viral suppression, the frequency of HIV-1-specific CTL responses decreased, suggesting that viral replication is required to maintain CTL responses in the systemic circulation.

Impaired early growth of infants perinatally infected with human immunodeficiency virus: Correlation with viral load

OBJECTIVE To evaluate the effect of viral load on the early growth of infants infected with human immunodeficiency virus (HIV). METHODS Plasma concentrations of p24-antigen and HIV ribonucleic acid were measured retrospectively and correlated with growth parameters for the first 18 months of life in a cohort of 47 term infants born to HIV-infected mothers prospectively enrolled in a study of perinatal HIV transmission. Comparisons of the mean weight and length of the 18 HIV-infected and 29 uninfected infants for each interval and across intervals were made. Viral load was correlated with standard deviation scores. Infants were stratified by high and low viral load during the first 6 months of life. RESULTS At birth, no difference in weight and length was observed between HIV-infected and uninfected infants. Between birth and 6 months of age, the infected infants grew less rapidly than the uninfected infants, a finding temporally associated with an exponential increase in HIV viremia. The linear growth of infected infants remained consistently less than that of the uninfected infants after 6 months of life, although the differences were no longer statistically significant and tended to decrease with age in parallel with declines in viral load. The median plasma concentration of HIV ribonucleic acid was significantly higher at 3, 6, 12, and 18 months in infected infants in whom growth failure developed. Infants who had a high viral load in the first 6 months of life were significantly more likely to have severe growth failure. Though the mean SD for weight of the infected infants was always less than that of the uninfected infants, the differences were small and not significant. CONCLUSIONS Our results confirm the observation that stunting is an early frequent finding in perinatal HIV infection. The deleterious effect of HIV on linear growth appears to be correlated with the level of postnatal HIV viremia, although the exact mechanism of this association remains to be elucidated.