William Borkowsky

A Multicenter Trial of Oral Zidovudine in Children with Advanced Human Immunodeficiency Virus Disease

BACKGROUND AND METHODS Zidovudine has been shown to be an effective antiretroviral treatment in adults with human immunodeficiency virus (HIV) infection. We examined the safety of zidovudine and the tolerance of and therapeutic response to the drug in 88 children with advanced HIV disease. During a 24-week outpatient trial, zidovudine (180 mg per square meter of body-surface area per dose) was given by mouth every six hours and serial measurements were made of clinical, immunologic, and virologic indexes. Children who completed 24 weeks of treatment were permitted to continue receiving zidovudine. RESULTS Of the 88 children (mean age, 3.9 years; range, 4 months to 11 years), 61 completed the initial 24-week trial, and 49 continued to receive zidovudine for up to 90 weeks (median follow-up, 56 weeks). The patients generally tolerated zidovudine well. One or more episodes of hematologic toxicity occurred in 54 children (61 percent)--anemia (hemoglobin level, less than 75 g per liter) in 23 children (26 percent) and neutropenia (neutrophil count, less than 0.75 x 10(9) per liter) in 42 (48 percent). Many of these abnormalities resolved spontaneously, but 30 children required transfusions or a modification of the dose of zidovudine. Only three children had to stop receiving the drug because of hematologic toxicity. Kaplan-Meier analysis demonstrated that the probability of survival was 0.89 after 24 weeks and 0.79 after 52 weeks. There was marked improvement in weight gain, cognitive function (mainly in children less than 3 years old), serum and cerebrospinal fluid concentrations of p24 antigen, and the proportion of cerebrospinal fluid cultures negative for HIV. CD4+ lymphocyte counts (mean at base line, 0.263 x 10(9) per liter) improved during the first 12 weeks, although the improvement was not sustained through the 24th week. CONCLUSIONS Zidovudine in a dose of 180 mg per square meter every six hours can be safely administered to children with advanced HIV disease. The resultant clinical, immunologic, and virologic improvements in children are similar to those reported with zidovudine in adults.

Susceptibility of Human Th17 Cells to Human Immunodeficiency Virus and Their Perturbation during Infection

BACKGROUND Identification of the Th17 T cell subset as important mediators of host defense and pathology prompted us to determine their susceptibility to human immunodeficiency virus (HIV) infection. METHODS AND RESULTS We found that a sizeable portion of Th17 cells express HIV coreceptor CCR5 and produce very low levels of CCR5 ligands macrophage inflammatory protein (MIP)-1alpha and MIP-1beta. Accordingly, CCR5(+) Th17 cells were efficiently infected with CCR5-tropic HIV and were depleted during viral replication in vitro. Remarkably, HIV-infected individuals receiving treatment had significantly reduced Th17 cell counts, compared with HIV-uninfected subjects, regardless of viral load or CD4 cell count, whereas treatment-naive subjects had normal levels. However, there was a preferential reduction in CCR5(+) T cells that were also CCR6 positive, which is expressed on all Th17 cells, compared with CCR6(-)CCR5(+) cells, in both treated and untreated HIV-infected subjects. This observation suggests preferential targeting of CCR6(+)CCR5(+) Th17 cells by CCR5-tropic viruses in vivo. Th17 cell levels also inversely correlated with activated CD4(+) T cells in HIV-infected individuals who are receiving treatment. CONCLUSIONS Our findings suggest a complex perturbation of Th17 subsets during the course of HIV disease potentially through both direct viral infection and virus indirect mechanisms, such as immune activation.

Bacterial infections in human immunodeficiency virus-infected children.

A retrospective review of 71 children infected with human immunodeficiency virus cared for over a 3.5-year period revealed that 44 of 71 (63%) required a bacterial culture and 27 of 71 (37%) had bacteriologically documented infection. There were 125 episodes in 27 patients. Pneumonia (24 of 125 (19%)), upper respiratory tract syndromes (23 of 125 (19%)), urinary tract infection (24 of 125 (19%)) and wound infection (12 of 125 (10%)) were the most common syndromes identified. Bacteremic infections occurred in 35 of 125 (28%), and in 17 of 125 (14%) no other primary source could be identified. Pneumococci (11 of 35 (31%)) and Salmonella (4 of 35 (11%)) were the most common blood isolates; however, a wide spectrum of Gram-positive and Gram-negative pathogens were recovered. Bacterial pneumonia directly contributed to the death of 4 patients, in whom pneumonia caused by Pneumocystis carinii (2), cytomegalovirus (1) or varicella-zoster virus (1) also coexisted, respectively. Absolute T4 counts less than 400 and depressed lymphocyte-proliferative responses to diphtheria and tetanus toxoids, Candida antigen and pokeweed mitogen correlated with the occurrence of bacterial infection in human immunodeficiency virus-infected children. Although bacterial infections are a frequent cause of morbidity in human immunodeficiency virus-infected children, they are usually treatable.

Varicella-zoster virus infections in children infected with human immunodeficiency virus.

Primary varicella-zoster (VZ) infection in eight children with perinatally acquired human immunodeficiency virus infection tended to be severe, prolonged, complicated by bacterial infections and in one case fatal. Depletion of CD4-lymphocytes was associated with chronic and recurrent VZ infection. In some patients convalescent VZ antibody titers were low and did not correlate with recurrence of VZ lesions. Administration of acyclovir appeared to be beneficial in suppressing VZ in human immunodeficiency virus-infected children with primary or recurrent VZ infection.

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.

Virologic and Immunologic Outcomes after 24 Weeks in HIV Type 1-Infected Adolescents Receiving Highly Active Antiretroviral Therapy

BACKGROUND Adolescents represent the fastest growing demographic group of new human immunodeficiency virus (HIV) infections in the United States. At present, there is little information available about their response to therapy. METHODS We studied 120 adolescents infected via high-risk behaviors who began receiving highly active antiretroviral therapy (HAART), to determine their virologic and immunologic response to therapy. RESULTS Subjects were enrolled at 28 sites of the Pediatric Acquired Immunodeficiency Syndrome Clinical Trials Group. After 16-24 weeks of HAART, 59% of subjects had reproducible undetectable virus loads, according to repeat measurements (virologic success). As enumerated by flow-cytometric analysis, increases in levels of CD4 helper cells (both naive and memory) and decreases in levels of CD8 suppressor cells were observed. Partial restoration of some immunologic parameters for patients who did not achieve virologic success was also observed, but to a more limited extent than for adolescents with virologic success. Adherence to HAART was the only predictor of achieving undetectable virus loads. CONCLUSIONS Adolescents have the capacity to improve their immunologic status with HAART. Lower than expected success in virologic control is related to lack of adherence, and efforts to improve treatment outcome must stress measures to assure adherence to medication.

Erythrocyte Adenosine Deaminase Deficiency without Immunodeficiency: EVIDENCE FOR AN UNSTABLE MUTANT ENZYME

Inherited deficiency of the purine salvage enzyme adenosine deaminase (ADA) gives rise to a syndrome of severe combined immunodeficiency (SCID). We have studied a 2.5-yr-old immunologically normal child who had been found to lack ADA in his erythrocytes during New York State screening of normal newborns. His erythrocytes were not detectably less deficient in ADA than erythrocytes of ADA(-)-SCID patients. In contrast, his lymphocytes and cultured long-term lymphoid cells contained appreciably greater ADA activity than those from patients with ADA(-)-SCID. This residual ADA activity had a normal molecular weight and K(m) but was markedly unstable at 56 degrees C. His residual erythrocytes-ADA activity also appeared to have diminished stability in vivo. ADA activity in lymphoid line cells of a previously reported erythrocyte-ADA-deficient!Kung tribesman was found to contain 50% of normal activity and to exhibit diminished stability at 56 degrees C. ATP content of erythrocytes from both partially ADA-deficient individuals was detectably greater than normal (12.3 and 6.1 vs. normal of 2.6 nmol/ml packed erythrocytes). However, the dATP content was insignificant compared to that found in erythrocytes of ADA(-)-SCID patients (400-1,000 nmol/ml packed erythrocytes). The New York patient, in contrast to normals, excreted detectable amounts of deoxyadenosine, but this was <2% of deoxyadenosine excreted by ADA(-)-SCID patients. Thus, the residual enzyme in cells other than erythrocytes appears to be sufficient to almost totally prevent accumulation of toxic metabolites.

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.

Antibody responses to bacterial toxoids in children infected with human immunodeficiency virus

Infection with human immunodeficiency retrovirus (also known as HTLV III, LAV,. and ARV) can produce a spectrum of immunologic perturbations ranging from no obvious deficit to severe combined acquired immune deficiency. Adults with acquired immune deficiency syndrome are likely to have lymphopenia and severe cell-mediated immunodeficiency, with a dramatic deficiency of helper T cells. Adults also have hypergammaglobulinemia and diminished capacity to produce antibody after primary or booster immunizations? Even asymptomatic HIV-infected adults have defective B-lymphocyte function as measured by a variety of in vitro assays. 2 In chiidren, HIV infection produces a similar spectrum of immunologic perturbations. A recent study of sick children with AIDS has demonstrated blunted antibody responses to bacteriophage phi X174 after prinmry and secondary immunizations. In addition, class switching (IgM to IgG) was generally absent and antibody responses to pneumococcal vaccine and tetanus toxoid were also diminished? We examined 17 children with HIV infection, who had received at least three immunizations with diphtheriatetanus-pertussis vaccine, for the presence of humoral and ceil-mediated immune responses to diphtheria and tetanus toxoids. These children had neither, a history of opportunistic infection nor biopsy-proved lymphocytic interstitial proliferation at the time of study. METHODS

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.