Sharon Nachman

Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America

Samir K. Gupta, Joseph A. Eustace, Jonathan A. Winston, Ivy I. Boydstun, Tejinder S. Ahuja, Rudolph A. Rodriguez, Karen T. Tashima, Michelle Roland, Nora Franceschini, Frank J. Palella, Jeffrey L. Lennox, Paul E. Klotman, Sharon A. Nachman, Stephen D. Hall, and Lynda A. Szczech Divisions of Infectious Diseases and Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis; Division of Nephrology, Johns Hopkins University, School of Medicine and Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland; Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, and Division of Nephrology and Hypertension and Division of Infectious Diseases, Department of Pediatrics, State University of New York, Stony Brook; Division of Nephrology, Department of Medicine, University of Texas Medical Branch, Galveston; Division of Nephrology, Department of Medicine, San Francisco General Hospital and Positive Health Program at San Francisco General Hospital and the UCSF AIDS Research Institute, Department of Medicine, University of California at San Francisco; Division of Infectious Diseases, Department of Medicine, The Miriam Hospital, Brown Medical School, Providence, Rhode Island; Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, and Duke Clinical Research Institute and the Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Grady Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia

Evaluation of Tuberculosis Diagnostics in Children: 1. Proposed Clinical Case Definitions for Classification of Intrathoracic Tuberculosis Disease. Consensus From an Expert Panel

There is a critical need for improved diagnosis of tuberculosis in children, particularly in young children with intrathoracic disease as this represents the most common type of tuberculosis in children and the greatest diagnostic challenge. There is also a need for standardized clinical case definitions for the evaluation of diagnostics in prospective clinical research studies that include children in whom tuberculosis is suspected but not confirmed by culture of Mycobacterium tuberculosis. A panel representing a wide range of expertise and child tuberculosis research experience aimed to develop standardized clinical research case definitions for intrathoracic tuberculosis in children to enable harmonized evaluation of new tuberculosis diagnostic technologies in pediatric populations. Draft definitions and statements were proposed and circulated widely for feedback. An expert panel then considered each of the proposed definitions and statements relating to clinical definitions. Formal group consensus rules were established and consensus was reached for each statement. The definitions presented in this article are intended for use in clinical research to evaluate diagnostic assays and not for individual patient diagnosis or treatment decisions. A complementary article addresses methodological issues to consider for research of diagnostics in children with suspected tuberculosis.

CYP2B6 genetic variants are associated with nevirapine pharmacokinetics and clinical response in HIV-1-infected children

Background:Cytochrome P450 2B6 (CYP2B6)-G516T genotype is associated with altered activity of hepatic CYP2B6 and efavirenz pharmacokinetics, but the relationship between the CYP2B6-G516T genotype and nevirapine (NVP) pharmacokinetics in plasma and cerebrospinal fluid (CSF) is limited. Methods:In 126 children who received NVP and protease inhibitors from PACTG 366 and 377 cohorts, CYP2B6 and ATP-binding cassette, sub-family B, member 1 (ABCB1) gene polymorphisms were analyzed using real-time PCR. Plasma NVP pharmacokinetics and clinical data were collected and levels of NVP in CSF were evaluated in children with HIV-related neurologic diseases. Results:NVP oral clearance in children with the CYP2B6-516-T/T genotype (homozygous variant, n = 14) was 1.6 l/h per m2, which was significantly decreased compared to 2.3 l/h per m2 in those with the -G/G (wild type, n = 49, P = 0.002) and 2.1 l/h per m2 in those with the -G/T genotype (heterozygous variants, n = 63, P = 0.008). Furthermore, children with the -T/T genotype had a significant increase in CD4+ T-cell percentage (+9.0%) compared with those with the -G/G (+3.2%, P = 0.01) and -G/T genotype (+5.0%, P = 0.04) from baseline to week 12. The same trend continued at week 24. Although ABCB1-C3435T genotypes did not affect plasma NVP pharmacokinetics (P = 0.39), the NVP CSF: plasma ratios were significantly higher in children with the ABCB1-3435-C/T or -T/T genotypes (0.62, n = 9) in comparison with those with the ABCB1-3435-C/C genotype (0.43, n = 5) (P = 0.01). Conclusions:The CYP2B6-G516T genotype alters NVP pharmacokinetics and the immunologic response to NVP-containing HAART regimens in children. These data suggest that the CYP2B6-G516T is an important genetic variant that alters the pharmacokinetics and response to HAART regimens containing NVP.

Primary isoniazid prophylaxis against tuberculosis in HIV-exposed children

BACKGROUND The dual epidemic of human immunodeficiency virus (HIV) and tuberculosis is a major cause of sickness and death in sub-Saharan Africa. We conducted a double-blind, randomized, placebo-controlled trial of preexposure isoniazid prophylaxis against tuberculosis in HIV-infected children and uninfected children exposed to HIV during the perinatal period. METHODS We randomly assigned 548 HIV-infected and 804 HIV-uninfected infants (91 to 120 days of age) to isoniazid (10 to 20 mg per kilogram of body weight per day) or matching placebo for 96 weeks. All patients received bacille Calmette-Guérin (BCG) vaccination against tuberculosis within 30 days after birth. HIV-infected children had access to antiretroviral therapy. The primary outcome measures were tuberculosis disease and death in HIV-infected children and latent tuberculosis infection, tuberculosis disease, and death in HIV-uninfected children within 96 to 108 weeks after randomization. RESULTS Antiretroviral therapy was initiated in 98.9% of HIV-infected children during the study. Among HIV-infected children, protocol-defined tuberculosis or death occurred in 52 children (19.0%) in the isoniazid group and 53 (19.3%) in the placebo group (P=0.93). Among HIV-uninfected children, there was no significant difference in the combined incidence of tuberculosis infection, tuberculosis disease, or death between the isoniazid group (39 children, 10%) and the placebo group (45 children, 11%; P=0.44). The rate of tuberculosis was 121 cases per 1000 child-years (95% confidence interval [CI], 95 to 153) among HIV-infected children as compared with 41 per 1000 child-years (95% CI, 31 to 52) among HIV-uninfected children. There were no significant differences in clinical or severe laboratory toxic effects between treatment groups. CONCLUSIONS Primary isoniazid prophylaxis did not improve tuberculosis-disease-free survival among HIV-infected children or tuberculosis-infection-free survival among HIV-uninfected children immunized with BCG vaccine. Despite access to antiretroviral therapy, the burden of tuberculosis remained high among HIV-infected children. (Funded by the National Institutes of Health and Secure the Future; ClinicalTrials.gov number, NCT00080119.).

Cryptococcosis in Children with AIDS

We compiled the clinical and immunologic features of Cryptococcus neoformans infections in human immunodeficiency virus (HIV)-infected children from 1985 to 1996 in a retrospective case series. Thirty cases of cryptococcosis were identified. These children had a median age of 9.8 years, a median CD4+ cell count of 54/microL at the time of diagnosis, and either a culture positive for C. neoformans or cryptococcal antigen in serum or cerebrospinal fluid. Sixty-three percent of the cases occurred in children vertically infected with HIV and in children between 6 and 12 years of age. The clinical and laboratory characteristics of this pediatric cohort were similar to those of adults with AIDS and cryptococcosis. On the basis of a subset of the cases, a 10-year point prevalence of cryptococcosis among children with AIDS of approximately 1% was estimated.

Neuropsychological functioning and viral load in stable antiretroviral therapy-experienced HIV-infected children

Objective. Neuropsychological functioning and its correlation with viral load were investigated for previously treated HIV-infected children who underwent a change in treatment regimen. Methods. Thirteen age-appropriate measures of cognitive, neurologic, and behavioral functioning were administered to 489 HIV-infected children who were aged 4 months to 17 years and had been treated previously for at least 16 weeks with antiretroviral therapy. These clinically and immunologically stable children were randomized onto 1 of 7 drug treatment combinations, 6 of which included a protease inhibitor (PI), and evaluated prospectively for 48 weeks with respect to changes in neuropsychological performance and viral load. Results. Neuropsychological functioning was significantly poorer at baseline for the HIV-infected children as compared with established norms for their age. Children with higher viral load had poorer cognitive, both-hands fine-motor, and neurologic signs at baseline, but single-hand fine-motor and behavioral functioning were not correlated with viral load. After 48 weeks of treatment with PI-containing combination therapy, there was significant improvement in only the vocabulary score. Neuropsychological changes did not differ among the 6 PI-containing combination regimens. At week 48, even children with a viral load response below the level of detection (RNA ≤400 copies/mL) still showed poorer neuropsychological functioning compared with established norms. Conclusion. Poor neuropsychological functioning was seen for HIV-infected children and was worse for children with higher viral loads. Only 1 measure of neuropsychological functioning showed improvement after treatment with PI-containing combination therapy, and the extent of that improvement was relatively minor. Treatment strategies for children with HIV disease need to be reevaluated so that they consider restoration of neuropsychological functioning in addition to lowering the viral load.

Combination nucleoside analog reverse transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-experienced HIV-infected children : Week 24 results of a randomized controlled trial-PACTG 377

One hundred eighty-one antiretroviral-experienced, protease inhibitor-naive, clinically stable HIV-infected children between 4 months and 17 years of age were randomly assigned to receive one of four combination regimens to evaluate the change in plasma HIV RNA, safety, and tolerance when changing antiretroviral therapy to a protease inhibitor-containing combination regimen. All four regimens contained stavudine; in addition children received nevirapine plus ritonavir, lamivudine plus nelfinavir, nevirapine plus nelfinavir, or lamivudine plus nevirapine plus nelfinavir. Twelve additional children chose to receive stavudine plus lamivudine plus nelfinavir, with nelfinavir given bid, rather than tid as for the main regimens. Overall, 51% (89/176; 95% CI 43-58%) of the children on the randomized portion of the study had an HIV RNA response (< or =400 copies/ml) on at least two of the three HIV RNA determinations taken at Weeks 8, 12, and 16. At Week 24 the proportion of children with an HIV RNA response still on initial therapy was 47% (83/176; 95% CI 40-55%) and ranged from 41 to 61% for the four randomized treatment arms. Rash was frequently seen (27%) on the treatment arms containing nevirapine. At Week 24 64% (7/11, 95% CI 31-89%) of the children on the bid nelfinavir combination regimen were still on initial therapy with an HIV RNA response as compared with 46% (23/50; 95% CI 32-61%) on the corresponding tid nelfinavir combination regimen. A change in antiretroviral therapy to a protease inhibitor-containing regimen was associated with a virological response rate of approximately 50% for this patient population.

Shedding of Live Vaccine Virus, Comparative Safety, and Influenza-Specific Antibody Responses after Administration of Live Attenuated and Inactivated Trivalent Influenza Vaccines to HIV-Infected Children

HIV-infected children (N=243), >or=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV). The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection. Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection. LAIV should be further evaluated for a role in immunizing HIV-infected children.

Effect of HIV Infection Status and Anti-Retroviral Treatment on Quantitative and Qualitative Antibody Responses to Pneumococcal Conjugate Vaccine in Infants

Serotype-specific antibody concentration and opsonophagocytic activity (OPA) were evaluated after 3 doses of pneumococcal conjugate vaccine. Groups included human immunodeficiency virus (HIV)-positive infants with CD4(+) cell percentages > or =25% who initiated immediate antiretroviral treatment (the HIV+/ART+ group) or whose antiretroviral treatment was deferred until clinically or immunologically indicated (the HIV+/ART- group). Immune responses were also evaluated in HIV-noninfected infants born to HIV-seronegative (M-/I-) or HIV-positive mothers (M+/I-). Antibody concentrations were similar between HIV+/ART+ and HIV+/ART- infants. However, antibody concentrations were lower in M-/I- infants than in M+/I- infants. Nevertheless, M-/I- infants had superior OPA responses, compared with those in HIV+/ART+ infants, who in turn had better OPA responses, compared with those in HIV+/ART- infants.

Immunogenicity, safety, and predictors of response after a pneumococcal conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children receiving highly active antiretroviral therapy

Background: The immunogenicity and safety of 2 doses of pneumococcal conjugate vaccine (PCV) and 1 dose of pneumococcal polysaccharide vaccine (PPV) were evaluated in human immunodeficiency virus (HIV)-infected children receiving highly active antiretroviral therapy (HAART). Methods: Children 2 to <19 years, receiving stable HAART for ≥3–6 months, with HIV RNA PCR <30,000–60,000 copies/mL, received 2 doses of PCV and 1 dose of PPV at sequential 8-week intervals. Antibodies to pneumococcal serotypes (STs) 1 (PPV only) and 6B, 14, 19F, and 23F (PCV and PPV) were measured by ELISA. Results: Two hundred sixty-three subjects were enrolled, of whom 225 met criteria for inclusion in the primary dataset. Antibody concentrations were low at entry, despite previous PPV in 75%. After vaccination, 76%–96% had concentrations ≥0.5 &mgr;g/mL and 62–88% ≥1.0 &mgr;g/mL to the 5 STs (geometric mean concentrations [GMCs] = 1.44–4.25 &mgr;g/mL). Incremental gains in antibody concentration occurred with each vaccine dose. Predictors of response included higher antibody concentration at entry, higher immune stratum (based on nadir CD4% before HAART and CD4% at screening), lower entry viral RNA, longer duration of the entry HAART regimen, and age <7 years. Response was more consistently related to screening CD4% than nadir CD4%. Seven percent had vaccine-related grade 3 events, most of which were local reactions. Conclusions: Two PCVs and 1 PPV were immunogenic and safe in HIV-infected children 2 to <19 years who were receiving HAART. Responses were suggestive of functional immune reconstitution. Immunologic status based on nadir and, especially, current CD4% and control of HIV viremia were independent determinants of response.