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This study used a well characterized cohort of human immunodeficiency virus type 1 (HIV-1)-infected hemophiliacs to define the relationship between the SDF1-3'A allele, the plasma HIV-1 coreceptor tropism, and the natural history of HIV-1 disease. Subjects heterozygous or homozygous for the SDF1-3'A allele experienced higher rates of decline in CD4+ T cell counts over time than did those without the allele (P=.009). Moreover, they had an increased risk of progression to acquired immunodeficiency syndrome and death, a relationship that persisted even when baseline plasma HIV-1 RNA levels and CD4+ T cell counts or CCR5 Delta 32 and CCR2-64I genotype were controlled for. This relationship was even stronger in a subgroup of subjects for whom tropism data were available. Subjects with the SDF1-3'A allele were also more likely to have detectable X4-tropic viruses (P=.012), and, when tropism was included in the survival analyses, the effect of the SDF1-3'A allele on disease progression was no longer significant. Therefore, the increased frequency of X4-tropic viruses in subjects carrying the SDF1-3'A allele may explain the observed adverse effect that this allele has on the natural history of HIV-1 disease. Copyright © 2005 Infectious Diseases Society of America [ABSTRACT FROM AUTHOR]

Objectives: To describe the Indiana Hemophilia and Thrombosis Center (IHTC) surgical database, its key components, and exploratory analyses of surgeries conducted between 1998 and 2019., Methods: Surgical data across bleeding disorders collected retrospectively (1998-2006) and prospectively (2006-2019) were analyzed. Perioperative hemostasis, complications, and surgical plan deviations were compared by bleeding disorder diagnosis and data collection period., Results: Within the 21-year period, 3246 procedures were conducted in 1413 patients with a diagnosis of von Willebrand disease (vWD), hemophilia A (HA), hemophilia B (HB), and other bleeding disorders. Majority of the procedures were minor (63.3%), and median number of surgeries per patient was 1 (range: 1-22). Adequate perioperative hemostasis was achieved in 90.9%, complications occurred in 13.6%, and surgical plan deviations occurred in 31.3% of procedures. Inadequate perioperative hemostasis and surgical plan deviations occurred more frequently in procedures involving HB compared with other bleeding disorders. Complications were not significantly different across bleeding disorders (p = .164). The prospective data collection period was associated with higher rates of hemostatic efficacy (92.4% vs. 88.3%; p < .001), complications (14.3% vs. 12.3%; p < .001), and plan deviations (34.2% vs. 25.1%; p < .001)., Conclusion: The surgical database is an important resource in surgical management in patients with bleeding disorders. Further evaluation will facilitate use for the development of predictive models and principles of care., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Spontaneous clearance of acute hepatitis C virus (HCV) infection is associated with single nucleotide polymorphisms (SNPs) on the MHC class II. We fine-mapped the MHC region in European (n = 1,600; 594 HCV clearance/1,006 HCV persistence) and African (n = 1,869; 340 HCV clearance/1,529 HCV persistence) ancestry individuals and evaluated HCV peptide binding affinity of classical alleles. In both populations, HLA-DQβ1Leu26 (p value Meta = 1.24 × 10 -14 ) located in pocket 4 was negatively associated with HCV spontaneous clearance and HLA-DQβ1Pro55 (p value Meta = 8.23 × 10 -11 ) located in the peptide binding region was positively associated, independently of HLA-DQβ1Leu26. These two amino acids are not in linkage disequilibrium (r 2 < 0.1) and explain the SNPs and classical allele associations represented by rs2647011, rs9274711, HLA-DQB1 ∗ 03:01, and HLA-DRB1 ∗ 01:01. Additionally, HCV persistence classical alleles tagged by HLA-DQβ1Leu26 had fewer HCV binding epitopes and lower predicted binding affinities compared to clearance alleles (geometric mean of combined IC 50 nM of persistence versus clearance; 2,321 nM versus 761.7 nM, p value = 1.35 × 10 -38 ). In summary, MHC class II fine-mapping revealed key amino acids in HLA-DQβ1 explaining allelic and SNP associations with HCV outcomes. This mechanistic advance in understanding of natural recovery and immunogenetics of HCV might set the stage for much needed enhancement and design of vaccine to promote spontaneous clearance of HCV infection., Competing Interests: Declaration of interests J.C.P. has received research grant support to her institution from Gilead Sciences, Merck, and Abbvie and has served on an advisory board for Gilead Sciences and Theratechnolgies. S.H.M. have received speaker fees from Gilead Sciences not related to this work. A.H.K. serves on the Data Monitoring Committee for Kintor Pharmaceutical., (Copyright © 2022. Published by Elsevier Inc.)

Background: Spontaneous clearance of acute hepatitis C virus (HCV) infection is more common in women than in men, independent of known risk factors., Methods: To identify sex-specific genetic loci, we studied 4423 HCV-infected individuals (2903 male, 1520 female) of European, African, and Hispanic ancestry. We performed autosomal, and X chromosome sex-stratified and combined association analyses in each ancestry group., Results: A male-specific region near the adenosine diphosphate-ribosylation factor-like 5B (ARL5B) gene was identified. Individuals with the C allele of rs76398191 were about 30% more likely to have chronic HCV infection than individuals with the T allele (OR, 0.69; P = 1.98 × 10-07), and this was not seen in females. The ARL5B gene encodes an interferon-stimulated gene that inhibits immune response to double-stranded RNA viruses. We also identified suggestive associations near septin 6 and ribosomal protein L39 genes on the X chromosome. In box sexes, allele G of rs12852885 was associated with a 40% increase in HCV clearance compared with the A allele (OR, 1.4; P = 2.46 × 10-06). Septin 6 facilitates HCV replication via interaction with the HCV NS5b protein, and ribosomal protein L39 acts as an HCV core interactor., Conclusions: These novel gene associations support differential mechanisms of HCV clearance between the sexes and provide biological targets for treatment or vaccine development., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Clearance of acute infection with hepatitis C virus (HCV) is associated with the chr19q13.13 region containing the rs368234815 (TT/ΔG) polymorphism. We fine-mapped this region to detect possible causal variants that may contribute to HCV clearance. First, we performed sequencing of IFNL1-IFNL4 region in 64 individuals sampled according to rs368234815 genotype: TT/clearance (N = 16) and ΔG/persistent (N = 15) (genotype-outcome concordant) or TT/persistent (N = 19) and ΔG/clearance (N = 14) (discordant). 25 SNPs had a difference in counts of alternative allele >5 between clearance and persistence individuals. Then, we evaluated those markers in an association analysis of HCV clearance conditioning on rs368234815 in two groups of European (692 clearance/1 025 persistence) and African ancestry (320 clearance/1 515 persistence) individuals. 10/25 variants were associated (P < 0.05) in the conditioned analysis leaded by rs4803221 (P value = 4.9 × 10 -04 ) and rs8099917 (P value = 5.5 × 10 -04 ). In the European ancestry group, individuals with the haplotype rs368234815ΔG/rs4803221C were 1.7× more likely to clear than those with the rs368234815ΔG/rs4803221G haplotype (P value = 3.6 × 10 -05 ). For another nearby SNP, the haplotype of rs368234815ΔG/rs8099917T was associated with HCV clearance compared to rs368234815ΔG/rs8099917G (OR: 1.6, P value = 1.8 × 10 -04 ). We identified four possible causal variants: rs368234815, rs12982533, rs10612351 and rs4803221. Our results suggest a main signal of association represented by rs368234815, with contributions from rs4803221, and/or nearby SNPs including rs8099917.

Variation in the risk and severity of many autoimmune diseases, malignancies and infections is strongly associated with polymorphisms at the HLA class I loci. These genetic associations provide a powerful opportunity for understanding the etiology of human disease. HLA class I associations are often interpreted in the light of 'protective' or 'detrimental' CD8 + T cell responses which are restricted by the host HLA class I allotype. However, given the diverse receptors which are bound by HLA class I molecules, alternative interpretations are possible. As well as binding T cell receptors on CD8 + T cells, HLA class I molecules are important ligands for inhibitory and activating killer immunoglobulin-like receptors (KIRs) which are found on natural killer cells and some T cells; for the CD94:NKG2 family of receptors also expressed mainly by NK cells and for leukocyte immunoglobulin-like receptors (LILRs) on myeloid cells. The aim of this study is to develop an immunogenetic approach for identifying and quantifying the relative contribution of different receptor-ligand interactions to a given HLA class I disease association and then to use this approach to investigate the immune interactions underlying HLA class I disease associations in three viral infections: Human T cell Leukemia Virus type 1, Human Immunodeficiency Virus type 1 and Hepatitis C Virus as well as in the inflammatory condition Crohn's disease., Competing Interests: BD, LB, JL, CT, JA, GK, SK, SD, JG, BA No competing interests declared

Background: A significant fraction of women with an impaired factor VIII or IX gene in the X chromosome, carriers of haemophilia, will have clotting factor activities corresponding to those seen in males with non-severe haemophilia, hence, experience an increased bleeding tendency. Data describing the long-term joint outcomes among carriers are limited. We compared the age at onset, frequency of joint-related diagnoses as well as joint surgery and related hospitalizations among carriers of haemophilia with sex- and birthdate-matched controls from the general population., Methods: Carriers of haemophilia born 1941-2008 were identified through the haemophilia treatment centres' (HTCs) databases and the National Patient Register of Sweden. For each carrier, we included up to five individuals using the Swedish population register as comparisons. Data for the period 1987-2008 were obtained., Results: Among 539 potential carriers identified, 213 had a known factor activity. Carriers with reduced factor activity and those with unknown factor activity had received their first joint-related diagnosis at a significantly earlier age than their comparisons. The same subgroups showed an overall 2.3- and 2.4-fold higher hazard for joint-related diagnoses compared with the general population. In addition, the hazards of joint-related outpatient hospitalization were 3.2-fold (95% CI: 1.2, 9.1) and 2.5-fold (95% CI: 1.6, 3.7). This was not observed for those with normal factor activity., Conclusion: Carriers of haemophilia suffer a significant risk for joint comorbidities. This risk seems to correlate to the factor activity. Our findings underline the importance of regular clinical follow-up of carriers at HTCs., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry., Methods: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed., Results: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10 -50 ) and the MHC locus 6p21.32 (P = 1.15 × 10 -21 ). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10 -07 ). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants., Conclusions: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection., (Copyright © 2019. Published by Elsevier Inc.)

Killer cell immunoglobulin-like receptors (KIRs) are expressed predominantly on natural killer cells, where they play a key role in the regulation of innate immune responses. Recent studies show that inhibitory KIRs can also affect adaptive T cell-mediated immunity. In mice and in human T cells in vitro, inhibitory KIR ligation enhanced CD8 + T cell survival. To investigate the clinical relevance of these observations, we conducted an extensive immunogenetic analysis of multiple independent cohorts of HIV-1-, hepatitis C virus (HCV)-, and human T cell leukemia virus type 1 (HTLV-1)-infected individuals in conjunction with in vitro assays of T cell survival, analysis of ex vivo KIR expression, and mathematical modeling of host-virus dynamics. Our data suggest that functional engagement of inhibitory KIRs enhances the CD8 + T cell response against HIV-1, HCV, and HTLV-1 and is a significant determinant of clinical outcome in all three viral infections., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Approximately three quarters of acute hepatitis C (HCV) infections evolve to a chronic state, while one quarter are spontaneously cleared. Genetic predispositions strongly contribute to the development of chronicity. We have conducted a genome-wide association study to identify genomic variants underlying HCV spontaneous clearance using ImmunoChip in European and African ancestries. We confirmed two previously reported significant associations, in the IL28B/IFNL4 and the major histocompatibility complex (MHC) regions, with spontaneous clearance in the European population. We further fine-mapped the association in the MHC to a region of about 50 kilo base pairs, down from 1 mega base pairs in the previous study. Additional analyses suggested that the association in MHC is stronger in samples from North America than those from Europe.

Introduction: The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development., Aim: To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors., Methods: The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA., Results: Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects., Conclusion: Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population., (© 2016 John Wiley & Sons Ltd.)

Haemophilia A is a congenital bleeding disorder characterised by recurrent haemorrhages into the major joints. Haemophilic arthropathy is a well-established outcome of recurrent joint bleeding; however, it is clear that multiple factors determine the extent and severity of its occurrence. We sought to identify genetic factors related to abnormalities in range of motion (ROM) in the knees, ankles and elbows in a cohort of children and adolescents with haemophilia A not treated primarily with regular prophylaxis. Using data from the Haemophilia Growth and Development Study, we examined associations between 13,342 genetic markers and ROM scores measured at six-month intervals for up to seven years. As a first step, ordered logistic regression models were fit for each joint separately. A subset of SNP markers showing significant effects (p<0.01) on the right and left sides for at least two joints were included in a full model fit using a multivariate generalised linear mixed model assuming an ordinal response. The models contained all ROM scores obtained at all visits. Twenty-five markers analysed in the full model showed either increased or decreased risk of ROM abnormalities at the p<0.001 level. Several genes identified at either the first or second stage of the analysis have been associated with arthritis in a variety of large studies. Our results support the likelihood that risk for haemophilic arthropathy is associated with genetic factors, the identification of which holds promise for further advancing the individualisation of treatment.

Studies of determinants of development of inhibitory Abs to factor VIII in people with hemophilia A indicate a complex process involving multiple factors. The Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort was formed to extend our understanding of the genetic background of risk. The study group contains 833 subjects from 3 independent cohorts: brother pairs and singletons with and without a history of inhibitors, as well as 104 brother pairs discordant for inhibitor status. Using an Illumina iSelect platform, 13 331 single-nucleotide polymorphisms from 1081 genes, primarily immune response and immune modifier genes, were typed. Each cohort was analyzed separately with results combined using a meta-analytic technique. After adjustment for potential confounders, 53 single-nucleotide polymorphisms were found to be significant predictors of inhibitor status using the criteria of odds ratios in the same direction in all cohorts or allowing for a 20% interval around an odds ratio = 1 in 1 of the 3 and significant in at least 2. Of the 53 markers, 13 had meta P < .001. Eight of the 53 were significant predictors among the discordant pairs. Results support the complexity of the immune response and encourage further research with the goal of understanding the pathways involved.

Unlabelled: Chinese translation, Background: Hepatitis C virus (HCV) infections occur worldwide and either spontaneously resolve or persist and markedly increase the person's lifetime risk for cirrhosis and hepatocellular carcinoma. Although HCV persistence occurs more often in persons of African ancestry and persons with genetic variants near interleukin-28B (IL-28B), the genetic basis is not well-understood., Objective: To evaluate the host genetic basis for spontaneous resolution of HCV infection., Design: 2-stage, genome-wide association study., Setting: 13 international multicenter study sites., Patients: 919 persons with serum HCV antibodies but no HCV RNA (spontaneous resolution) and 1482 persons with serum HCV antibodies and HCV RNA (persistence)., Measurements: Frequencies of 792 721 single nucleotide polymorphisms (SNPs)., Results: Differences in allele frequencies between persons with spontaneous resolution and persistence were identified on chromosomes 19q13.13 and 6p21.32. On chromosome 19, allele frequency differences localized near IL-28B and included rs12979860 (overall per-allele OR, 0.45; P = 2.17 × 10-30) and 10 additional SNPs spanning 55 000 base pairs. On chromosome 6, allele frequency differences localized near genes for HLA class II and included rs4273729 (overall per-allele OR, 0.59; P = 1.71 × 10-16) near DQB1*03:01 and an additional 116 SNPs spanning 1 090 000 base pairs. The associations in chromosomes 19 and 6 were independent and additive and explain an estimated 14.9% (95% CI, 8.5% to 22.6%) and 15.8% (CI, 4.4% to 31.0%) of the variation in HCV resolution in persons of European and African ancestry, respectively. Replication of the chromosome 6 SNP, rs4272729, in an additional 745 persons confirmed the findings (P = 0.015)., Limitation: Epigenetic effects were not studied., Conclusion: IL-28B and HLA class II are independently associated with spontaneous resolution of HCV infection, and SNPs marking IL-28B and DQB1*03:01 may explain approximately 15% of spontaneous resolution of HCV infection.

Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII (FVIII) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene (F8) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen (HLA) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified (N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products (N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual., (© 2012 Blackwell Publishing Ltd.)

Killer cell immunoglobulin-like receptors (KIRs) influence both innate and adaptive immunity. But while the role of KIRs in NK-mediated innate immunity is well-documented, the impact of KIRs on the T cell response in human disease is not known. Here we test the hypothesis that an individual's KIR genotype affects the efficiency of their HLA class I-mediated antiviral immune response and the outcome of viral infection. We show that, in two unrelated viral infections, hepatitis C virus and human T lymphotropic virus type 1, possession of the KIR2DL2 gene enhanced both protective and detrimental HLA class I-restricted anti-viral immunity. These results reveal a novel role for inhibitory KIRs. We conclude that inhibitory KIRs, in synergy with T cells, are a major determinant of the outcome of persistent viral infection.

Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.

Interleukin-10 (IL-10) is a pleiotropic cytokine with both immunosuppressive and immunostimulatory functions. Its roles in infections and autoimmunity may have resulted in selective pressures on polymorphisms within the gene, leading to genomic coexistence of several semi-conserved haplotypes involved with diverse pathogen interactions during genomic evolution. Previous studies focused either exclusively on promoter haplotypes or on individual SNPs. We genotyped 21 single nucleotide polymorphisms in the human IL10 gene and examined this variation compared to other mammalian species sequences. Haplotype heterogeneity in human populations is centered around 'classic' 'proximal' promoter polymorphisms: -592, -819 and -1082. High-producing GCC haplotypes are by far the most numerous and diverse group, the intermediate IL-10 producing ACC-inclusive haplotypes seem to be related most closely to the ancestral haplotype, and the ATA-inclusive haplotypes cluster a separate branch with strong bootstrap support. We looked at associations of corresponding haplotypes with HIV progression. A haplotype trend regression confirmed that individuals carrying the low-producing ATA-inclusive haplotypes in European Americans progress to AIDS faster, and most likely explain the role of IL10. Our findings are consistent with the hypothesis that existing polymorphisms in this gene may reflect a balance of historic adaptive responses to autoimmune, infectious and other disease agents.

Unlabelled: Resistance mutations to hepatitis C virus (HCV) nonstructural protein 3 (NS3) protease inhibitors in <1% of the viral quasispecies may still allow >1000-fold viral load reductions upon treatment, consistent with their reported reduced replicative fitness in vitro. Recently, however, an R155K protease mutation was reported as the dominant quasispecies in a treatment-naïve individual, raising concerns about possible full drug resistance. To investigate the prevalence of dominant resistance mutations against specifically targeted antiviral therapy for HCV (STAT-C) in the population, we analyzed HCV genome sequences from 507 treatment-naïve patients infected with HCV genotype 1 from the United States, Germany, and Switzerland. Phylogenetic sequence analysis and viral load data were used to identify the possible spread of replication-competent, drug-resistant viral strains in the population and to infer the consequences of these mutations upon viral replication in vivo. Mutations described to confer resistance to the protease inhibitors Telaprevir, BILN2061, ITMN-191, SCH6 and Boceprevir; the NS5B polymerase inhibitor AG-021541; and to the NS4A antagonist ACH-806 were observed mostly as sporadic, unrelated cases, at frequencies between 0.3% and 2.8% in the population, including two patients with possible multidrug resistance. Collectively, however, 8.6% of the patients infected with genotype 1a and 1.4% of those infected with genotype 1b carried at least one dominant resistance mutation. Viral loads were high in the majority of these patients, suggesting that drug-resistant viral strains might achieve replication levels comparable to nonresistant viruses in vivo., Conclusion: Naturally occurring dominant STAT-C resistance mutations are common in treatment-naïve patients infected with HCV genotype 1. Their influence on treatment outcome should further be characterized to evaluate possible benefits of drug resistance testing for individual tailoring of drug combinations when treatment options are limited due to previous nonresponse to peginterferon and ribavirin.

Hepatitis B virus (HBV) infection remains a serious global health problem despite the availability of a highly effective vaccine. Approximately 5% of HBV-infected adults develop chronic hepatitis B, which may result in liver cirrhosis or hepatocellular carcinoma. Variants of interleukin-10 (IL10) have been previously associated with chronic hepatitis B infection and progression to hepatocellular carcinoma. Single nucleotide polymorphisms (SNP; n = 42) from the IL10, IL19 and IL20 gene regions were examined for an association with HBV infection outcome, either chronic or recovered, in a nested case-control study of African Americans and European Americans. Among African Americans, three nominally statistically significant SNP associations in IL10, two in IL20, and one haplotype association were observed with different HBV infection outcomes (P = 0.005-0.04). A SNP (rs1518108) in IL20 deviated significantly from Hardy-Weinberg equilibrium in African Americans, with a large excess of heterozygotes in chronic HBV-infected cases (P = 0.0006), which suggests a strong genetic effect. Among European Americans, a nominally statistically significant SNP association in IL20 and an IL20 haplotype were associated with HBV recovery (P = 0.01-0.04). These results suggest that IL10 and IL20 gene variants influence HBV infection outcome and encourage the pursuit of further studies of these cytokines in HBV pathogenesis.

Subject reports of efficacy of treatment of haemophilia-related joint bleeding are by definition subjective, yet are often the primary outcome in studies comparing therapies. Verbal descriptors such as effective, partially effective, poorly effective, not effective are treated as dichotomous or categorical variables in analyses, lowering the statistical power relative to that which might be achieved with a continuous variable. The aims of this study were to examine reports of pain recorded on a 100-mm visual analogue scale (VAS) during the course of joint bleeding; determine whether pain varied by treatment period among pairs reporting discordant outcomes on a verbal scale (one product effective, the other not effective); test whether the two products under study were equivalent with respect to VAS scores; and evaluate their relationship to verbal reports of efficacy. Data from the international, prospective, randomized, crossover FEIBA NovoSeven Comparative study of two bypassing agents used for treatment of 96 bleeding episodes in 48 participants were examined. VAS scores were associated with verbal descriptors of efficacy at every time point, and were equivalent between treatment periods. There were differences in mean scores at time points at which participants rated one treatment effective, the other not effective. As a continuous variable, the VAS score may have more power than a dichotomous variable and when used with verbal descriptions of efficacy can improve the overall accuracy of assessment. This report highlights an important consideration in the selection of outcome measurement that can be generalized to other haemophilia treatment research.

Inhibitory antibodies to factors VIII or IX have the potential to affect a broad range of outcomes among people with hemophilia; however, their possible effect on growth and maturation has not been explored. We evaluated skeletal maturation (bone age), pubertal progression, serum testosterone levels, height velocity, and stature in the multicenter Hemophilia Growth and Development Study. A total of 333 children and adolescents (mean age, 12.4 years) were enrolled from 1989 to 1990 and followed for 7 years. Of these, 18% (n = 60) had a history of inhibitors. Bone age among HIV(-) adolescents with a history of inhibitors lagged 9 or more months behind those without inhibitors at every age from 12 to 15 years. Those with a history of inhibitors were older at every Tanner stage transition, attained a lower maximum growth velocity, and their serum testosterone levels were significantly lower compared with those without inhibitors. Delays were greater among HIV(+) patients with a history of inhibitors compared with those without inhibitors; however, the differences were generally small and not statistically significant. The results of this investigation underscore the importance of monitoring the growth and maturation of children and adolescents with hemophilia, particularly those with inhibitors.

Thrombocytopenia is a common finding among HIV-1-infected individuals. In addition to their function in hemostasis, platelets have been found to play a role in host immune defenses and to directly interact with HIV-1. To explore the role of platelets in HIV-1 infection, we examined the relationship between platelet number and the natural history of HIV-1 disease in the well-characterized Hemophilia Growth and Development Study cohort. In a multivariate analysis platelets were found to be inversely related to plasma HIV-1 RNA with increasing platelets associated with lower plasma HIV-1 RNA levels (p < 0.001). Despite this, increasing platelet count was independently associated with enhanced risk of progression to AIDS and death (p < 0.001 for both). While there may be multiple explanations for these novel observations, they do generate hypotheses related to the potential influence platelets may have on the natural history of HIV-1 disease.

Background: Human immunodeficiency virus type 1 (HIV-1) coreceptor tropism, the ability of the virus to enter cells via CCR5 or CXCR4, is a viral characteristic mediated by the envelope gene. The impact of coreceptor tropism on the natural history of HIV-1 infection has not been fully explored., Methods: Coreceptor tropism was measured using a recombinant virus single-cycle assay on plasma specimens obtained at baseline from 126 children and adolescents in the Hemophilia Growth and Development Study cohort who were enrolled from 1989 through 1990 and underwent follow-up through 1997., Results: Detectable CXCR4-using virus at baseline was associated with a lower baseline CD4(+) T cell count and a higher plasma HIV-1 RNA level. In addition, it independently predicted a greater decrease in CD4(+) T cell count over time (P<.001) and was associated with a 3.8-fold increased risk of progression to clinical AIDS., Conclusions: This study demonstrates that coreceptor tropism, as assessed by this single-cycle assay, independently influences the natural history of HIV-1 disease.

A study of major joint outcomes, specifically range of motion and synovitis, was conducted with data from a subset of adolescents enrolled in the prospective Hemophilia Growth and Development Study (HGDS). Clinical observations were carried out over a 7-year period from 1989 to 1996. A secondary aim was to gain insight into factors that might influence decisions regarding maintaining or discontinuing prophylaxis during early adulthood. Twenty-nine participants (median age 17.4 at entry) were included. Median follow-up was 7 years (range: 4.8-7.7). Range of motion (ROM) and synovitis in six major joints (knees, elbows and ankles), were evaluated by physical examination every 6-12 months. At the baseline observation, 73.6% of joints showed no ROM abnormalities or synovitis, and all joints were normal in 11 patients. Of the 11 participants, 54.5% developed abnormalities and 28.1% of normal joints at baseline became abnormal during the follow-up. Ankles were the most severely affected and had persistent progression during late adolescence and adulthood. Elbows and knees did not show progression after the first few years of the follow-up. The progression of haemophilic arthropathy in adolescents and young adults varies from individual to individual and also in the site of affected joints. In view of this, the decision regarding discontinuation of prophylaxis in patients with haemophilia should be individualized.

The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.

Hepatitis C virus (HCV) is an infectious blood-borne pathogen that usually persists as a chronic infection. However, approximately 15% of the time, patients can clear the virus, indicating that host differences could be critical in determining the course of HCV infection. The inflammatory response is crucial to resolving or failing to resolve an acute HCV infection. Some previous reports have implicated interleukin 10 (IL10) polymorphisms with successful anti-HCV therapy and natural viral clearance. We tested 54 single nucleotide polymorphisms (SNPs) in the IL10 region (+/-300 kb and 24 within the IL10 gene itself), which contains 13 genes including the IL10 immunomodulatory paralogs IL19, IL20, and IL24, for association with HCV clearance vs persistence. SNPs from two haplotype block regions, one at IL10 and the other from IL19/IL20, were associated with HCV clearance in African Americans (91 clearance cases and 183 chronically infected matched controls; P=0.05-0.002) while with expectation-maximization algorithm-reconstructed haplotypes, these associations remained (P=0.05-0.002). However, no significant associations were detected in European Americans (108 clearance and 245 chronic). Our results indicate that variants of the immunomodulatory IL10 and IL19/IL20 genes may be involved in natural clearance of HCV in the African-American population.

The aim of the study is to determine the causes and frequency of hospitalization in HIV-negative boys and adolescents with haemophilia and evaluate their impact on academic achievement. One hundred and twenty-six HIV-negative boys and adolescents were followed prospectively from 1989-96, at 14 comprehensive haemophilia treatment centres. One hundred and fifteen participants with haemophilia A or B were included in the investigation. These participants contributed an average of 57.8 months of follow-up. There were 203 hospitalizations in 65 participants and 50 participants were never hospitalized. Haemarthroses and soft tissue bleeds accounted for 46 and 44 causes of hospitalization. Central line infection was the third most common cause. Participants with inhibitor had the majority of central line infections and hospitalizations. Intracranial haemorrhage resulted in five hospitalizations in two participants. Other causes of bleeding accounted for 22% of hospitalizations. The median number of hospitalizations per year was 0.18. Duration of hospital stay was significantly related to lower spelling scores. Acute and chronic joint problems and soft tissue bleeds still account for the majority of hospitalizations. Positive inhibitor status was associated with higher numbers of hospitalizations and central line infections. Academic achievement was affected, to some degree, by length of hospital stay.

Purpose: To analyse the risk factors for infection associated with central venous access device (CVAD) use in children with haemophilia., Methods: Risk factors for CVAD infection among patients with congenital haemophilia who had had a CVAD implanted at a single institution were evaluated utilizing the following variables: age at CVAD placement, age at end of study, number of days with a CVAD, percentage of lifetime with a CVAD, and history of inhibitor., Results: Fifty-nine patients had a total of 97,936 (median 1768 days per patient) CVAD days in the study period. The median age at CVAD placement was 2.7 years (range 0-14.0). Twenty-six (44%) patients reported CVAD infections during the study period from January 1993 to October 2000. Twenty-four patients had their CVAD replaced, 17 (71%) of whom reported having infections and seven (29%) of whom had a history of inhibitor. The strongest predictor for having any infections was inhibitor status (P=0.16), although none of the risk factors had statistically significant effects. Among the 26 patients reporting infections, 42% had more than one CVAD-related infection. Seven patients had multiple infections involving the same organism. The mean rate of infection was 0.45 per 1000 catheter days, with a 95% confidence interval of 0.33-0.60. Those with a history of inhibitor had an infection rate of 0.66 compared with 0.38 per 1000 catheter days (P=0.09) for those without a history of inhibitor. Patients who were older (greater than the median age of 2.7) at CVAD placement had a lower rate of infection (0.29 vs. 0.65, P<0.01) compared with those < or =2.7 years. Adjustment for inhibitor status had little impact on these results. For the group as a whole, the median time to first infection was 1977 days from CVAD placement. Patients who were older at CVAD placement or study exit had lower relative hazards of infection (P=0.05 and P=0.09 respectively), while those who had inhibitors had a higher but not statistically significant relative hazard of 1.88 (P=0.13)., Conclusions: These data reveal that while considerable numbers of patients develop CVAD-related infection, the interval between catheter placement and infection can be quite long. In addition, the earlier in life a CVAD is placed, the higher the risk of infectious complications, as evidenced by the tendency towards a higher infection rate. Measures to prevent CVAD-related infection might be focused on very young patients who appear to be at higher risk.

Objective: To quantify practice effects associated with annual administrations of WISC-R and WAIS-R in children and adolescents with and without hemophilia., Methods: Participants were young men (age: 7-19; 80 with hemophilia, 30 siblings) enrolled in the Hemophilia Growth and Development Study. Participants with hemophilia completed age-appropriate Wechsler scales at baseline and at four annual follow-ups; the siblings, at baseline and one 2-year follow-up. Regression analyses were used to quantify average changes in scores, adjusting for variables related to test performance., Results: Consecutive annual evaluations were free of significant practice effects for 4 years with the Verbal Scale and for 2 years with the Performance Scale. VIQ decreased, and PIQ increased over time. Baseline VIQ was related to changes in VIQ; baseline PIQ and number of test-specific retests were related to changes in PIQ., Conclusions: The findings support use of Wechsler scales for annual evaluations to monitor cognitive development in children and adolescents.

Objectives: We characterized a population-based cohort of school-aged children with severe hemophilia with respect to type of treatment, on-demand versus prophylaxis, and frequency of bleeding episodes in the year before enrollment. We also investigated the association between hemophilia-related morbidity, measured by number of bleeding episodes in the year before enrollment, and academic performance after adjustment for other factors known to have an effect on achievement. Finally, we explored the mechanisms for the association between bleeding episodes and academic achievement., Study Design: This study was a multicenter investigation of boys 6 to 12 years old with severe factor VIII deficiency (clotting factor level <2%) receiving care in US hemophilia treatment centers. Children with a history of inhibitor, severe developmental disorder, significant psychiatric disorder, or insufficient fluency in English were excluded from the study. On-demand treatment was defined as administration of clotting factor on the occurrence of a bleeding episode. Prophylactic therapy was defined as a course of regular infusions for >2 months with a goal of preventing bleeding episodes. Academic achievement was measured by the Wechsler Individual Achievement Test. Quality of life was measured by the Child Health Questionnaire. Of particular interest was the Physical Summary (PhS) measure of the Child Health Questionnaire. The type of information captured by the PhS includes limitations in physical activity, limitations in the kind or amount of schoolwork or social activities the child engaged in, and presence of pain or discomfort., Results: One hundred thirty-one children were enrolled, a median center recruitment rate of 77%. The mean age of the participants was 9.6 years, and approximately half of the participants had completed less than the fourth grade at the time of enrollment. Sixty-two percent of the children were on prophylaxis at enrollment, and 9% had previously been on prophylaxis but were currently on on-demand therapy. Two groups were defined: ever treated with prophylaxis and never treated with prophylaxis. For those ever treated, treatment duration ranged from 2.7 months to 7.7 years, with one half of the children treated with prophylaxis for >40% of their lifetimes; 29% had always been on on-demand therapy. Children in both treatment groups were similar with respect to age, clotting factor level, parents' education, and IQ. The median number of bleeding episodes experienced in the year before enrollment for the cohort as a whole was 12. The median number of bleeding episodes in children on prophylaxis at enrollment was significantly lower than in children on on-demand therapy (6 vs 25.5). The mean achievement scores were within the average range of academic performance: reading, 100.4; mathematics, 101.6; language, 108.1; writing, 95.4; and total achievement, 102.5. When children were categorized as above or below the study group median by number of bleeding episodes, those who had a low number of bleeding episodes (< or =11) had better total achievement (104.4 vs 100.6) and mathematics (103.6 vs 99.6) than children in the higher bleeding episode category (> or =12) after adjusting for child's IQ and parents' education. Treatment with prophylaxis per se was not associated with better test scores, but children who had been treated on a regimen of long-term prophylaxis (>40% of lifetime) and reported < or =11 bleeding episodes in the year before enrollment had significantly higher scores in total achievement (104.9 vs 100.6), mathematics (105.2 vs 99.6), and reading (104.0 vs 98.6) than all other children reporting > or =12 bleeding episodes in the same time period. Increased school absenteeism and hemophilia-related limitations in physical functioning among children with greater frequency of bleeding episodes were proposed as the mechanisms for lower scores. The number of bleeding episodes was positively correlated with school absenteeism (Spearman correlation = 0.23), and children with more school absences had lower scores in mathematics, reading, and total achievement, even after adjusting for the child's IQ and parents' education. Children with fewer bleeding episodes also had better PhS scores than children in the high bleeding episode category (48.4 vs 41.3). The mean PhS for children in the low bleeding episode group (48.4) was similar to that of the general US population (50), but the mean PhS for children in the higher bleeding episode group was almost a full standard deviation lower than the mean for the general US population. PhS scores were positively related to reading and total achievement scores after adjusting for IQ and parents' education. Of interest and concern was a group of children who were reportedly being treated with prophylaxis during the year before enrollment (N = 18) but whose bleeding events were not optimally suppressed. These children were 3 times as likely (33.3% vs 11.1%) to be receiving < or =2 infusions per week as children on prophylaxis who reported < or =11 bleeding episodes during the same period. A review of the sites of bleeding reported for the 18 children revealed that 12 (66.6%) experienced > or =25% of their bleeding episodes in the same joint., Conclusions: Each child should have the opportunity to achieve his or her potential. Control of a chronic disorder must include this important goal as well as the more commonly identified medical outcomes. This study has identified an important association between the number of bleeding episodes experienced and academic achievement in a cohort of school-aged children with severe hemophilia. The data support the assertion that therapeutic care programs in this population must not be evaluated only in terms of financial cost to achieve adequate musculoskeletal outcomes. Also significant are the individual and societal benefits of increased academic accomplishments if adequate suppression of hemorrhagic events can be attained. The number of bleeding episodes experienced, regardless of treatment regimen, should be followed to optimize the child's academic outcome.

Objective: The investigation examined the associations of plasma human immunodeficiency virus (HIV) RNA and CD4(+) T lymphocytes with height, weight, skeletal maturation, testosterone levels, and height velocity for hemophilic children and adolescents with HIV infection in the Hemophilia Growth and Development Study., Study Design: Two hundred seven participants were evaluated over 7 years., Results: A threefold increment in baseline plasma HIV RNA was associated with a 0.98-cm decrease in height and a 1.67-kg decrease in weight; 100-cells/microL decrements in baseline CD4(+) were associated with a 2.51-cm decrease in height and a 3.83-kg decrease in weight. Participants with high plasma HIV RNA (>3125 copies/mL) experienced significant delay in achieving maximum height velocity and lower maximum velocity compared with those with low viral load. The high CD4(+) (>243)/low plasma HIV RNA group had earlier age at maximum height velocity compared with the other 3 groups and higher maximum height velocity compared with the low CD4(+)/high plasma HIV RNA and low CD4(+)/low plasma HIV RNA groups. Decrements in CD4(+) were associated with decreases in bone age and testosterone level., Conclusions: CD4(+) and HIV RNA were important in predicting growth outcomes.

The effect of human immunodeficiency virus (HIV) infection on response to measles, mumps, and rubella revaccination in children and adolescents with hemophilia was evaluated. Antibody levels of measles, mumps, and rubella were assayed at baseline and two annual examinations in 207 HIV-positive and 126 HIV-negative hemophiliacs participating in the Hemophilia Growth and Development Study (HGDS). Response to revaccination was analyzed for participants whose antibody levels were below the cut-off at the start of a year-long observation period. Among HIV-positive participants, antibody levels were below cut-off in 52 subjects for measles, in 71 for mumps, and in 96 for rubella. Among HIV-negative participants, antibody levels were low in 23 subjects for measles, in 23 for mumps, and in 31 for rubella. For measles and mumps antigens, revaccination was associated with a significant increase in redraw antibody levels for HIV-negative participants. Although there was an increase in the mean measles titers for revaccinated HIV-positive participants, it was not significant. Revaccination was associated with an increase in rubella antibodies in HIV-positive and HIV-negative participants. Revaccination with measles and mumps was associated with an increase in antibody levels in HIV-negative participants but not in HIV-positive participants. Both HIV-positive and HIV-negative participants responded to rubella revaccination with an increase in antibody levels.

Objective: This analysis was undertaken to evaluate the etiology and sequelae of 2- to 5-mm focal white matter hyperintensities on T2-weighted MR images of some participants enrolled in the Hemophilia Growth and Development Study (HGDS)., Materials and Methods: The HGDS is a multicenter study of the growth and development, neurological, neuropsychological, and immune functioning of a cohort of children and adolescents, 62% of whom were infected with HIV through the use of clotting factor concentrates, and their non-hemophiliac, non-HIV infected male siblings. The current investigation was conducted with all three groups of HGDS participants: HIV-positive hemophiliacs (n = 207), HIV-negative hemophiliacs (n = 126), and their siblings (n = 47). Magnetic resonance imaging was performed at each center, with a variety of 0.3 to 1.5 T instruments. Standard examinations included 5-mm-thick T1-weighted sagittal and axial images, intermediate, and T2-weighted axial images. A study of abnormalities of the coagulation system known to be associated with thrombotic events was conducted among a subgroup of participants (n = 51) from eight centers., Results: Lesions were not associated with hemophilia-related factors, immune function, hematologic, or neurologic factors. There were no associations between the presence of white matter lesions and defects of coagulation in any of the assays completed., Conclusion: The 2- to 5-mm focal white matter hyperintensities on T2-weighted MR images of the brain were incidental findings in our study population.

This longitudinal study examines differences in hepatitis B immune titres in children and adolescents with haemophilia to determine if they are dependent on how immunity was acquired (vaccination or natural infection), and whether they are related to the child's HIV status and/or are influenced by HIV disease progression. Serologic titres (HBcAb, HBsAb) and HBsAg were measured prospectively at baseline, and at years 1, 2 and 3 of follow-up in 126 HIV- and 207 HIV+ children and adolescents with haemophilia. Analyses were performed to assess the impact of HIV status on the measured titres, and for HIV+ subjects to examine the association with CD4+ lymphocyte counts and p24 antigen status. The results show that HIV+ children were more likely than HIV- children to lose vaccine-induced immunity as indicated by the loss of HBsAb. There was an increased risk of losing HBsAb with higher CD4+ counts and younger age. Re-immunization was not successful in seven of eight HIV+ children. Two subjects (one HIV+, one HIV-) entered the study HBsAg- but became HBsAg+ over the course of follow-up. Seven HIV+ subjects lost natural immunity as indicated by the loss of HBcAb. The loss of either HBsAb or HBcAb in HIV--subjects was negligible to absent. In conclusion, because of the loss of immunity in HIV+ children the viral safety of factor replacement concentrates for these children is an important consideration. HIV- children rarely lose immunity, therefore frequent measures of HBsAb are not necessary.

As part of the Hemophilia Growth and Development Study (HGDS), we investigated the relationship between HIV-associated immune dysfunction and delayed pubertal development in a cohort of 333 boys and adolescents with moderate or severe hemophilia who were between the ages of 6 and 19 years at study entry in 1989. Sixty-two percent of the cohort was infected with HIV in the late 1970s and early 1980s through exposure to contaminated clotting factor concentrates. The cohort was observed during follow-up at 6-month intervals; measurements taken at each follow-up visit included Tanner stage and CD4+ cell count. This analysis of data from the first 4 years of follow-up revealed statistically significant delays in pubertal development associated with increasing levels of immune dysfunction. Our results emphasize the importance of following pubertal development in HIV-infected adolescent boys since delays in maturation may reflect underlying disease progression.

Data from the Hemophilia Growth and Development Study (HGDS) were used to evaluate the association between hemophilia morbidity, measured by abnormalities in coordination and gait (CG), and intellectual ability and academic achievement. The CG abnormalities observed in the HGDS participants (n = 333) were primarily due to hemophilia-related morbidity. Although HGDS participants performed within the average range for age on measures of intellectual ability, there were meaningful differences between CG outcomes at baseline and throughout the 4 years of study. Participants without CG abnormalities consistently achieved higher scores than those with CG abnormalities on Reading, Spelling, and Arithmetic subtests of the Wide Range Achievement Test-Revised. Our findings suggest that lowered achievement is related to the functional severity of hemophilia.

The Hemophilia Growth and Development Study (HGDS) is a multicenter longitudinal study of 333 male children and adolescents with moderate or severe hemophilia, ranging in age from 6 to 19 at entry. Sixty-two percent of the cohort was infected with human immunodeficiency virus (HIV) in the late 1970s and early 1980s through exposure to contaminated clotting factor concentrates. The HGDS has followed this cohort since 1989. HGDS subjects have blood drawn twice each year for t-lymphocyte subsets, with fresh blood shipped overnight to a central laboratory. T-lymphocyte subsets from the same blood draw are often determined locally as well. To evaluate interlaboratory variation, we examined the comparability of pairs of local and central results for CD4+ absolute counts and percents. Ninety-four pairs of absolute counts and 73 pairs of percent CD4 + results were available. We calculated concordance correlation coefficients, which evaluate the agreement between two readings from the sample by measuring the variation from the 45 degrees line through the origin. Absolute counts were square root transformed. Comparability of the pairs was high for both absolute counts and percents (0.93 and 0.92, respectively). Agreement was high whether we determined the CD4+ counts and percents centrally, using fresh samples received the day after the examination (0.95, 0.95), or from specimens that were frozen upon receipt and batched for later testing (0.90, 0.87). We conclude that when a centrally processed CD4+ result is unavailable because of shipping problems or loss of specimens, a study may reasonably accept a CD4+ result completed locally, if validity checks indicate good comparability. In the HGDS, the data provided by the local laboratories were of comparable quality to those provided by the central laboratories.

Objective: To determine the effects of human immunodeficiency virus (HIV) infection on children's development by identifying neurological and environmental variables associated with neuropsychological measures of cognitive development in HIV-seronegative (HIV-) and HIV-seropositive (HIV+)children and adolescents with hemophilia., Methods: Participants (N = 298; 60% HIV+) were males ages 7-19 years enrolled in the Hemophilia Growth and Development Study (HGDS). Least squares modeling was used to determine whether there was a difference at baseline in mean neuropsychological test scores by HIV status, age, and neurological baseline findings, adjusting for selected environmental and medical history variables., Results: The participants were within age expectations for general intelligence. Variables associated with lowered neuropsychological performance included academic problems, coordination and/or gait abnormalities, parents' education, and previous head trauma., Conclusions: Hemophilia-related morbidity has a subtle adverse influence on cognitive performance. HIV infection was not associated with neuropsychological dysfunction in this group even when MRI abnormalities were present.

Background: Boys and young men with hemophilia treated with factor infusions before 1985 had a substantial risk of acquiring the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome. This study was designed to assess the effects of HIV and hemophilia per se on neurological function in a large cohort of subjects with hemophilia, and to investigate the relationships between neurological disease and death during follow-up., Methods: Three hundred thirty-three boys and young men (207 HIV seropositive and 126 HIV seronegative) were evaluated longitudinally in a multicenter, multidisciplinary study. Neurological history and examination were conducted at baseline and annually for 4 years. The relationship between neurological variables, HIV serostatus, CD4+ cell counts, and vital status at the conclusion of the study was examined using logistic regression models., Results: The risks of nonhemophilia-associated muscle atrophy, behavior change, and gait disturbance increased with time in immune compromised HIV-seropositive subjects compared with HIV seronegative or immunologically stable HIV-seropositive subjects. The risk of behavior change in immune compromised HIV-seropositive hemophiliacs, for example, rose to 60% by year 4 versus 10% to 17% for the other study groups. Forty-five subjects (13.5%), all of whom were HIV seropositive, died by year 4. Subjects who died had had increased risks of hyperreflexia, nonhemophilia-associated muscle atrophy, and behavior change., Conclusions: These results indicate that immune compromised, HIV-seropositive hemophiliacs have high rates of neurological abnormalities over time and that neurological abnormalities were common among subjects who later died. By contrast, immunologically stable HIV-seropositive subjects did not differ from the HIV-seronegative participants. Hemophilia per se was associated with progressive abnormalities of gait, coordination, and motor function.

Unlabelled: Growth and pubertal development in hemophilic males, age 6-19 years at baseline, were evaluated over a 3.5-year period in 207 HIV-positive and 126 HIV-negative subjects as part of the Hemophilia Growth and Development Study., Methods: Thyroid function, insulin-like growth factor I (IGF-1) levels, bone age, cranial magnetic resonance image normality, CD4+ counts, and serum testosterone levels of study participants were measured at baseline. An extensive endocrine evaluation was performed in subjects who demonstrated declines in height for age (measurement <5th percentile with two pervious heights >10th percentile), who had not achieved Tanner stage 4 level of pubertal development by age 15 years or who had abnormal growth velocity, which included assessment of peak stimulated growth hormone response after clonidine stimulation, 12-hour growth hormone profiles, and serum beta carotene levels (triggered protocol)., Results: For almost the entire group (-99%), thyroid function tests were normal for age. IGF-1 levels were normal for 93% of the cohort. A total of 120 subjects, 89 HIV-positive and 31 HIV-negative, had an abnormality of growth, pubertal development, or both; 34 (11.1%) HIV-positive and 4 (3.6%) HIV-negative subjects had declines in height (p = .001), 20 (23.3%) HIV-positive and 5 (15.8%) HIV-negative subjects had not achieved Tanner stage 4 by 15 years of age (p = .372) and 59 (43.4%) HIV-positive and 23 (25.6) HIV-negative subjects had abnormal growth velocity (p < 0.001). Among subjects with abnormal height or growth velocity, the HIV-positive group had significantly lower mean age-adjusted testosterone levels than did the HIV-negative group (p = .030). Within the HIV-positive group, older subjects with abnormal height or growth velocity had significantly lower mean bone age than subjects of similar age without growth abnormalities (p = .0092). Extensive testing was done in 39 patients (32 HIV-positive, 7 HIV-negative). Half of the HIV-positive subjects had mean 12-hour growth hormone levels <3 ng/ml, 47% had peak stimulated levels <10 ng/ml, 28% had peak spontaneous values <10 ng/ml, and 38% had low levels of IGF-1. In the HIV-positive cohort, there was no difference in the rate of abnormalities of growth hormone secretion between those with CD4+ counts > or = or <200 cells/mm3 and between those subjects that met the 1987 Centers for Disease Control (CDC) surveillance definition of AIDS. In the subset of HIV-positive patients with abnormal peak growth hormone levels after clonidine stimulation, growth hormone response correlated positively with CD4+ count (r = .657, p = .0056) and beta carotene concentration (R = .596, p = .0192)., Conclusions: The results of this longitudinal study suggest that abnormalities of growth and pubertal development, particularly an abnormal growth velocity, are common in HIV-infected hemophilic boys and adolescents. These abnormalities might serve as indicators of the presence of HIV infection in this at-risk population. Since thyroid function tests and IGF-1 levels were normal, the etiology of growth impairment in HIV infection does not appear to be secondary to inadequate caloric intake or acquisition, or severe illness such as that caused by recurrent or persistent infection. Rather, HIV infection appears to lead to diminished growth hormone production or release and decreased androgen secretion, even before the development of AIDS and immunocompromise. These results provide a rationale for trials of treatment with growth hormone or androgens in patients with abnormalities of endocrine function.

Whether a shift from a type I (cell mediated) immune profile occurs with progressive HIV-related immune dysfunction is a matter of heated debate. We analyzed data for 333 HIV antibody-positive (HIV+) and -negative (HIV-) hemophilic children/adolescents, to examine whether the relationships among immunologic parameters and vaccine-related serology supported a shift with advancing HIV infection. In stepwise logistic regression analysis of HIV+ children's data, anergy to a panel of delayed hypersensitivity skin test antigens was positively associated with serum immunoglobulin A (IgA) levels (p = 0.012) and CD8+ cell counts (p = 0.021) and negatively associated with CD4+ cell counts (p = 0.002). Modeling supported anergy as a positive correlate of log IgA level (p = 0.046) and CD4+ lymphocyte count as a negative correlate, for HIV+ participants only (p < 0.0001). For mumps, the proportion of vaccinated HIV+ participants with protective IgG antibody titers was higher among those with CD4+ lymphocyte counts < 200 cells/mm3 (p = 0.058). For HIV+ participants < 14 years of age, this same trend was seen for measles and rubella, but was not seen in any age group for bacterial vaccine antigens. The intercorrelations among skin test anergy, CD4+ lymphocyte counts, serum IgA levels, and viral vaccine antigen-related serologic titers for HIV+ participants are consistent with an association between progressive HIV-related immune dysfunction and a predominance of type II (humoral immunity) or Type 0 (mixed immunity), relative to type I, lymphocyte profiles.

As part of the Hemophilia Growth and Development Study, we investigated the impact of human immunodeficiency virus (HIV) infection on statural growth, weight gain, and skeletal and sexual maturity in more than 300 boys with moderate to severe hemophilia, of whom 62% were infected with HIV. Age-adjusted height and weight were reduced in the HIV-infected subjects (p < 0.001). However, mean weight for height and triceps skin-fold thickness of the infected-boys closely resembled those of the uninfected group. In HIV-infected boys, height for age was positively related to the CD4+ lymphocyte count when the count was < 200 cells/mm3. Age-adjusted serum testosterone levels did not differ by HIV status, but in the infected participants the mean age-adjusted bone age was significantly reduced (p = 0.038) and the distribution of Tanner stages, adjusted for age, differed significantly (p = 0.003). The probability of advancing one or more Tanner stages in the first study year was significantly slowed in HIV-infected boys more than 14 years of age (p = 0.0003). We conclude that linear growth was significantly impaired in boys with hemophilia and HIV infection, but the wasting of malnutrition was not found. The delays in bone age and pubertal maturation strongly suggest that part of the growth failure seen in acquired immunodeficiency syndrome can be attributed to pubertal delay. We speculate that the lack of demonstrable difference in age-adjusted testosterone concentrations might reflect subtle differences in the pattern of secretion of testosterone or in the concentration of sex-hormone binding globulin.