Cohort Of Hemophiliacs Research Articles

Abstract W P392: Incidence Of Ischemic Or Hemorrhagic Non-fatal Strokes In Hemophiliac Adults And Teenage Children

Background: Persons with hemophilia are at high risk for spontaneous or prolonged bleeding, including intracranial hemorrhage. However, the incidence of ischemic or hemorrhagic stroke has not been studied in hemophiliac adults and teenage children. Methods: We analyzed data from the Second Multicenter Hemophilia Cohort Study (MHCS-II) that enrolled patients ≥13 years who had a congenital coagulation disorder [hemophilia A or B (congenital factor VIII or IX deficiency), von Willebrand's disease, or other], and who had serological or molecular evidence of HCV or HIV-1 infection. Participant’s medical history (including factor concentrate use), a targeted physical examination, and blood tests were performed at baseline and annually for three to four years. Person-years were estimated from the date of follow-up (the first blood sample) to the date of an event of interest (stroke), death, or censoring. We use Kaplan Meier analysis to estimate the probability of stroke or death in the study cohort. Results: A total of 2569 hemophiliac persons (age range = 13-88 years, men n=2431 (94.8%)) were recruited at 52 collaborating hemophilia centers in North and South America and Europe. The severity of hemophilia was classified as mild (>5%) (n=511, 19.9%), moderate (1-5%) (n=490, 19.1%) and severe (<1%) (n=1561, 60.9%) based on von Willebrand Type (type 1,2,3 respectively). A total of 1996 (77.8%) and 584 (22.8%) had received transfusions with factor VII and factor IX, respectively. A total of 4 participants developed stroke (including 1 intracerebral hemorrhage) over 4.5 year’s follow-up period with an estimated incidence of 0.034 per person 100 years. Conclusions: The rate of stroke appears to be low in adults and teenage children in a cohort of hemophiliacs with predominantly moderate and severe disease.

Decrement table and the estimation of human immunodeficiency virus (HIV) mortality rate with an application to hemophilia-associated acquired immune deficiency syndrome (AIDS)

The human immunodeficiency virus/ acquired immune deficiency syndrome(HIV/AIDS) epidemic represents the most serious public health problem in India. There is no denial of the enormity of the problem. The available surveillance data clearly indicates that HIV is prevalent in almost all parts of the country. Hence, knowledge of HIV incidence is important to formulate sensible strategies aimed at controlling the HIV/AIDS epidemic. The objective of this paper is to estimate the probability of dying in the stage of HIV (Grover and Das, 2005) in a year without passing to the state of AIDS (HIV mortality rate). Secondly, a double decrement life table approach (Biswas et al., 2006) has been followed for a cohort of hemophiliacs who were at risk of infection with the AIDS virus. This device consists essentially of two decrements: HIV positive hemophiliacs either depart from the AIDS-free group by eventually developing AIDS or by dying from other causes; those who eventually develop AIDS either remain alive with it until they die from it or die from other causes. The distribution of incubation period of AIDS is based on a two-stage parametric regression model (Brookmeyer and Goedert, 1989), proposed for the analysis of cohort of hemophiliacs. Key words: HIV mortality rate, incubation period, two-stage parametric regression model, double decrement life table, sero-positivity.

Failure of ADCC to predict HIV-associated disease progression or outcome in a haemophiliac cohort

Antibody-dependent cell-mediated cytotoxicity (ADCC) has been described in a number of virus infections and occurs in HIV infection. In spite of numerous studies on the ability of HIV-positive sera to mediate ADCC, it remains unclear whether ADCC has any functional significance. Here we examine serial serum samples from a cohort of haemophilia patients who became infected from a common source in 1984, and show that there is no significant difference in ADCC values between those who remained asymptomatic and those who progressed to disease. This study does not compare effector cell function and clinical status and does not exclude activity against different target cell lineages in vivo.

Fifteen years of Env C2V3C3 evolution in six individuals infected clonally with human immunodeficiency virus type 1

The study of the evolution of human immunodeficiency virus type 1 (HIV-1) requires blood samples collected longitudinally and data on the approximate time point of infection. Although these requirements were fulfilled in several previous studies, the infectious sources were either unknown or heterogeneous genetically. In the present study, HIV-1 env C2V3C3 (nt 7029-7315) evolution was examined retrospectively in a cohort of hemophiliacs. Compared to other cohorts, the area of interest here was the infection of six hemophiliacs by the same virus strain, that is, the infecting viruses shared an identical genome. As expected, divergence from the founder sequence as well as interpatient divergence of the predominant virus strains increased significantly over time. Based on the V3 nucleotide sequences, CCR5 usage was predicted exclusively throughout the whole period of infection in all patients. Interestingly, common patterns of viral evolution were detected in the patients of the cohort. Four amino acid substitutions within the V3 loop emerged and persisted subsequently in five (positions 305 and 308 of the HXB2 gp120 reference sequence) and six patients (positions 325 and 328 in HXB2 gp120), respectively. These common changes within the V3 loop are likely to be enforced by HIV-1 specific immune response.

Percutaneous liver biopsy in adult haemophiliacs with hepatitis C virus: safety of outpatient procedure and impact of human immunodeficiency virus coinfection on the spectrum of liver disease

Both HCV and HIV are common in haemophiliacs previously treated with non-viral-inactivated clotting factor concentrates. Because of increased bleeding risks, little data are available on the safety of percutaneous outpatient liver biopsy (LBx) and impact of HIV coinfection in this population. This study aims at reporting our experience with percutaneous LBx in a cohort of haemophiliacs infected with HCV and describe the spectrum of disease and impact of HIV coinfection. A retrospective review of consecutive patients with haemophilia and HCV who underwent percutaneous LBx was performed. All patients were positive for HCV RNA by commercial assay and received factor concentrate prior to biopsy. A total of 29 male patients (mean age 36, 24 haemophilia A, five haemophilia B, and 44% coinfected with HIV) underwent successful outpatient percutaneous LBx without bleeding complication. Histologic activity index was 6.44 with advanced fibrosis (bridging fibrosis/cirrhosis) in 31%. When patients were stratified by HIV positive (n = 13) vs. HIV negative (n = 16), coinfected patients had higher fibrosis scores and higher proportion advanced fibrosis (54% vs. 12%; P = 0.0167) with no differences in age, demographic or other laboratory parameters. Multivariate logistic regression found that HIV positivity was independently associated with advanced fibrosis (OR = 3.7; 95% CI: 1.17-11.8; P = 0.026). Outpatient percutaneous LBx can be safely performed in patients with haemophilia. Despite similar age, HIV coinfection was an independent predictor of advanced fibrosis. These data support the hypothesis that HIV accelerates fibrosis progression in those coinfected with HCV and highlights the importance of liver histology in this population.

Significance of blood analysis in hemophiliacs co-infected with human immunodeficiency virus and hepatitis viruses

To study the effect of hepatitis virus infection on cirrhosis and liver function markers in HIV-infected hemophiliacs. We have analyzed the immunological, liver function and cirrhosis markers in a cohort of hemophiliacs co-infected with human immunodeficiency virus (HIV) and hepatitis viruses. There was no difference in immunological markers among co-infected patients and patients infected with HIV only and those co-infected with one or more hepatitis virus. Although liver function and cirrhosis markers remained within a normal range, there was a worsening trend in all patients co-infected with hepatitis virus C (HCV), which was further exacerbated in the presence of additional infection with hepatitis virus B (HBV). Co-infection with HIV, HBV and HCV leads to worsening of hyaluronic acid and liver function markers. Increases in serum hyaluronic acid may be suggestive of a predisposition to liver diseases.

Nef Alleles from Human Immunodeficiency Virus Type 1-InfectedLong-Term-Nonprogressor Hemophiliacs with or without Late Disease Progression Are Defective in Enhancing Virus Replication and CD4 Down-Regulation

Infection with human immunodeficiency virus (HIV)-encoding defective nef variants may contribute to a relatively benign course of disease in a minority of long-term nonprogressors (LTNP). We have examined the functions of nef alleles from six individuals belonging to the same cohort of hemophiliacs infected with HIV-1 prior to 1985 and classified as LTNP in 1995. Three out of six individuals have progressed to HIV disease (late progressors [LP]), whereas the three remainders have maintained their LTNP status at least up to 2003. The nef alleles were obtained from both plasma virus and peripheral blood mononuclear cells of all six individuals in 1995 and 1998. The proportion of sequences containing mutations not yielding Nef expression significantly diminished in 1998 versus that in 1995. Several previously defined functional regions of intact nef alleles were highly conserved. However, the major variant obtained in 1998 from plasma RNA of five out of six individuals significantly reduced HIV infectivity/replication and impaired Nef-mediated CD4 but not major histocompatibility complex class I antigen down-modulation from the cell surface. Thus, functional alterations of the nef gene are present in both LP and LTNP, suggesting that Nef defectiveness in vitro is not necessarily associated with the long-term maintenance of LTNP status. Of interest is the fact that isolates from three out of three LP showed a dual CCR5/CXCR4 coreceptor use (R5X4), in contrast to those from LTNP, which were exclusively R5. Thus, in vivo evolution of gp120 Env to CXCR4 use appears to be associated with HIV disease progression in individuals infected with nef-defective viruses.

Trends in AIDS and Mortality in HIV-Infected Subjects With Hemophilia From 1985 to 2003

To study trends in progression to AIDS, all-cause mortality, and cause-specific mortality (AIDS-related, liver disease, and hemorrhagic complications) over calendar periods with different exposure to highly active antiretroviral therapy (HAART) in a cohort of hemophiliacs in Spain, taking into account the competing risks of the causes of death. Multicenter cohort of HIV-infected hemophiliacs. HIV seroconversion was estimated using mathematic techniques for interval-censored data from 1979 through 1985. Rates of AIDS and cause-specific death were calculated by Poisson regression, allowing for late entry, for the periods 1985 through 1992, 1993 through 1996, 1997 through 2000 (early HAART), and 2001 through 2003 (late HAART), also allowing for competing risks. Of 585 subjects, 44% were younger than 15 years of age, 82% had severe hemophilia, 86% had type A hemophilia, and the median seroconversion date was October 1982. Calendar period and age at HIV seroconversion strongly influenced AIDS and death rates. Compared with 1993 through 1996, decreases of 75% (relative risk [RR] = 0.25, 95% confidence interval [CI]: 0.14 to 0.43) and 72% (RR = 0.28, 95% CI: 0.12 to 0.63) in the RR of AIDS were observed in early and late HAART. For all-cause mortality, 72% (RR = 0.28, 95% CI: 0.18 to 0.42) and 83% (RR = 0.17, 95% CI: 0.09 to 0.33) decreases were observed by 1997 through 2000 and 2001 through 2003. For liver-related deaths, increases were observed in the late-HAART period (RR = 2.80, 95% CI: 0.94 to 8.36) compared with 1993 through 1996, but using competing risks, this RR was substantially reduced (RR = 1.70, 95% CI: 0.57 to 5.04). Major reductions in AIDS and death rates were observed from 1997 to 2003 in hemophiliacs. These survival improvements are largely attributable to decreases in AIDS-related deaths and have been accompanied by increases in liver disease death rates, which are overestimated if competing risks are not taken into account.

Histopathological Findings on Liver Biopsies (bx) Do Not Correlate with Serum Markers of Fibrosis and Necro-Inflammation in Hemophiliacs (HEM) Co-Infected with Hepatitis C (HCV) and Human Immunodeficiency Virus (HIV).

Background: Virtually all severe HEM exposed to plasma concentrates in the USA before 1985 are seropositive for HCVand HIV. HIV accelerates progression of HCV-induced chronic liver disease. HAART therapy has stabilized HIV in HEM so that end-stage liver disease is the predominant cause of death in HIV/HCV HEM. Pegylated interferon-alpha and ribavirin (IFN-R) produces significant remission in chronic HCV, and HEM with chronic HCV should benefit similarly. Liver histology is desirable to decide who should receive IFN-R since evidence of limited fibrosis with inflammation would be expected to derive the most benefit. Liver bx in HEM is fraught by significant costs of factor replacement and the small risk of significant bleeding. Thus, a surrogate marker for the information revealed by liver bx would be particularly advantageous for HEM with HCV. Diagnostic kits composed of specific and sensitive serum biochemical markers for the chronic complications of HCV are being validated as surrogates for liver bx, particularly prior to initiating IFN-R. The FibroSure assay (Labcorp, Burlington, USA) purportedly detects hepatic fibrosis and necrosis (necroinflammation) and in non-HEM cohorts appears predictive for either absent or minimal fibrosis or for advanced fibrosis/cirrhosis. The assay poorly predicts intermediate fibrosis.Patients and Methods: Histopathologic features of acute and chronic HCV and fibrosis observed from liver bx in 49 HEM were retrospectively correlated with the biochemical markers for liver fibrosis and necrosis. This was intended to determine if the FibroSure assay could substitute for liver bx in HEM. Impact of HIV/HCV co-infection on bx morphology and FibroSure results were also assessed. Trans-jugular liver bx was utilized in all HEM.Results: Of 49 HEM, 22 (44.9%) had HCV/HIV co-infection. Thirty one HEM underwent liver bx and 40 had FibroSure results. Twenty two had both liver bx and FibroSure. Only 18 had interpretable data from FibroSure. Seven of these 18 (38.9%) had morphological evidence of chronic HCV with significant fibrosis (Metavir score >2) but only 3/7 (42.8%) had FibroSure results corroborative of significant fibrosis (score of 0.48 or higher correlating with a Meatier score>2). All of these 7 HEM were co-infected. One of 18 (5.6%) HEM exhibited minimal fibrosis on liver bx but FibroSure results consistent with severe fibrosis. The 4 uninterpretable FibroSure results were from HIV/HCV HEM with opportunistic infections involving the liver but without marked fibrosis on bx. The median bx length was 1.7 cm for the entire cohort, which was adequate for representative morphological assessment. No bleeding complications occurred with transjugular liver bx.Conclusions: In this cohort of HEM, FibroSure results do not strongly correlate with the presence of severe liver fibrosis observed on bx. HIV co-infection may be responsible for this poor sensitivity since all 7 HEM with severe fibrosis on liver bx were infected with both. Trans-jugular liver bx was well tolerated and safe in HEM. In summary, our data do not support using the FibroSure assay as a sensitive or reliable surrogate marker for the extent of hepatic fibrosis in HCV/HIV co-infected HEM. Liver bx should still be considered the "gold standard" in co-infected HEM when assessing the suitability of IFN-R therapy.

Comparison of GB virus C, HIV, and HCV infection markers in hemophiliacs exposed to non-inactivated or inactivated factor concentrates

Background: Until the mandatory introduction of viral inactivation techniques of blood plasma products in the early 1980s many recipients of these products were infected with various viral pathogens. Objectives: To determine the rate of transmission of GB virus C/hepatitis G virus (GBV-C/HGV) HCV, and HIV through non-virus-inactivated clotting factor concentrates in hemophiliacs, as well as the relation between amount of administered clotting factor and risk for GBV-C/HGV infection. Study design: In this cross-sectional study, we determined retrospectively the rates of infection markers for GBV-C/HGV, HCV, and HIV in a German cohort of hemophiliacs treated with documented amounts of non-virus-inactivated clotting factor concentrates (group A) and in a second group of hemophiliacs who were treated exclusively with virus-inactivated clotting factor (group B). The presence of anti-virus antibodies was determined by ELISA. Viral RNA was detected by RT-PCR. Markers for viral infections were compared to amounts of administered non-virus-inactivated clotting factor. Results: Among hemophiliacs treated with documented amounts of non-virus-inactivated clotting factor the prevalence for GBV-C/HGV, HCV, and HIV was 40.3%, 98.6%, and 56.3%, respectively. In contrast to HIV, the rate of GBV-C/HGV infections did not increase with increasing amounts of consumed non-inactivated clotting factor. Even in the subgroup of heavily treated hemophiliacs the rate of GBV-C/HGV infection markers did not exceed 45%. Conclusions: The amount of non-virus-inactivated clotting factor is not predictive for the risk of GBV-C/HGV infection in hemophiliacs. Despite repeated parenteral exposure more than 55% of hemophiliacs were not infected with GBV-C/HGV. Our findings indicate a high frequency of host factors preventing parenteral transmission of GBV-C/HGV.

Modelling infectious disease transmission with complex exposure pattern and sparse outcome data.

We present a regression modelling framework to analyse infectious disease transmission during a time period where extensive exposure data are available, but where the outcome data are sparse. A latent variable model is used for each exposure time, allowing a straight-forward accumulation of risk for a collection of exposures for which outcome data are available. We describe an analysis of HIV infection from blood products among a cohort of haemophiliacs in Ireland between 1980 and 1985. The analysis provides estimates of the time pattern and batch effects; we show how analytical complexity such as smoothly varying coefficients or random coefficient models can be accommodated by the model. Finally, we discuss other problems where the model is applicable.

HAART and the HCV-infected liver: friend or foe?

HAART and the HCV-infected liver: friend or foe?

Iliopsoas haemorrhage in patients with bleeding disorders – experience from one centre

Iliopsoas haemorrhage in patients with bleeding disorders is a potentially life-threatening condition, with significantly associated morbidity. Despite its clinical importance, little has been published on the frequency, complications or outcomes of this entity since the advent of modern therapies for haemophilia. In a retrospective review of 297 patients with bleeding disorders followed at our centre, we identified 46 episodes of iliopsoas haemorrhage in 31 patients. Patients presented primarily with thigh, hip and/or groin pain, and frequently had flexion hip contracture, femoral nerve paresthesia, and >2 g dL(-1) haemoglobin drop. The duration of symptoms prior to seeking medical attention was 3.8 +/- 4 days. Nineteen of 155 patients (12.3%) with haemophilia A had 28 episodes of iliopsoas bleed; 52.6% of these patients had severe haemophilia. Of these 19 patients with haemophilia A who had iliopsoas haemorrhage, seven (36.8%) had an inhibitor to factor VIII (FVIII), and accounted for one-half of the bleeding episodes. Nine of 66 patients (13.6%) with haemophilia B had 15 episodes of iliopsoas haemorrhage; 22.2% of these patients had severe haemophilia, including one patient with an inhibitor to FIX who had two iliopsoas bleeds. The mean duration of therapy was 18.7 +/- 11.9 days, and the duration of hospitalization was 12.3 +/- 9.1 days. The length of hospital stay was significantly longer in patients with inhibitors, when compared with patients without inhibitors (19.1 +/- 5.8 days vs. 7.6 +/- 7.8 days; P<0.0001) with higher factor consumption, although the total duration of therapy was not significantly different. Patients with inhibitors were over-represented in the cohort of haemophiliacs with iliopsoas bleed. Patients with inhibitors who had iliopsoas bleeds remained hospitalized longer, although the duration of therapy was the same as patients with no inhibitors. There was a low frequency of recurrent bleed (2.8%).

Applying the Cox proportional hazards model for analysis of latency data with interval censoring

The latency time of an infectious disease is defined as the time from infection to disease onset. This paper applies the proportional hazards model to estimate the effect of covariates on latency when the time of disease onset is exact or right-censored but the time of infection is interval-censored. We use a Monte Carlo EM algorithm to estimate parameters of the joint distribution of infection times and latency times. At each EM iteration, exact infection times are multiply imputed from the density determined by the parameters of the infection and latency time distributions. The methodology is tested using a simulation study and is applied to data from a cohort of haemophiliacs with HIV disease.

Defective nef Alleles in a Cohort of Hemophiliacs with Progressing and Nonprogressing HIV-1 Infection

Deletion of the nef gene results in viral attenuation and confers protection against challenge with wild-type simian immunodeficiency virus in macaques. Regarding HIV-1 infection, a few long-term nonprogressors (LTNP) with nef deletions have been described. In this study, the nef genes of a group of seven LTNP and eight progressors, all belonging to the same cohort of infected hemophiliacs, were analyzed by cloning and sequencing from both virion RNA and peripheral blood mononuclear cell-associated proviral DNA. Defective nef sequences coexisted with full-length nef open reading frames in five of seven LTNP and two of eight progressors. The proportion of disrupted nef sequences within each individual was significantly higher in LTNP (ranging from 10 to 63%) than in progressors (ranging from 9 to 21%) (P = 0.013). Moreover, in-frame small deletions predicting to encode Nef were found in all RNA- and DNA-derived clones from one LTNP and four progressors. A chimeric virus in which the nef gene of NL4.3 was substituted with the nef allele containing the deletion of two alanines at position 49–50 found in two progressors showed a defective replicative capacity compared to NL4.3 virus. In summary, hemophiliacs with either progressing or nonprogressing HIV-1 infection are characterized by the presence of defective nef variants.

Patterns of Hepatitis G Viraemia and Liver Disease in Haemophiliacs Previously Exposed to Non-virus Inactivated Coagulation Factor Concentrates

Hepatitis G virus (HGV), a novel flavivirus, has been implicated as a cause of posttransfusion hepatitis. We have performed a longitudinal study in a cohort of haemophiliacs (n = 68) who previously received non-virus inactivated coagulation factor concentrates to assess both patterns of HGV viraemia and any associated liver disease. Hepatitis C virus (HCV) RNA was present in 58/68 and co-infection with human immunodeficiency virus (HIV) was present in 15/68. HGV RNA was detected in 17/68 (25%) samples from the mid-1980s. There was no association between either HIV infection (p = 0.74) or co-infection with a particular HCV genotype (p = 0.62). However, there was a relationship between HGV viraemia and the severity of haemophilia (p = 0.0004) with HGV RNA detected in 5/19, 9/16 and 3/32 patients with mild, moderate and severe haemophilia respectively. A longitudinal study was performed in 15/17 haemophiliacs with HGV viraemia using stored serum samples from the 1980s and 1990s. HGV viraemia persisted in 8/15 and cleared in 7/15 over a variable period of time. A Weibull model was constructed to estimate the duration of HGV viraemia in the study group. The 75th and 90th percentiles for the duration of HGV were estimated to be 8.7 years (95%, confidence interval 4.8-15.7) and 23.6 years (95% confidence interval 11.8-47.1) respectively. Laparoscopic liver inspection/biopsy was performed in 25/68. There was no association between severity of liver disease and HGV viraemia (p = 0.43). This study demonstrates considerable variation in patterns of HGV viraemia in haemophiliacs. We found little evidence to implicate HGV as a major cause of chronic liver disease in haemophiliacs.

Hazard Function Estimation Using B-Splines

A flexible parametric procedure is given to model the hazard function as a linear combination of cubic B-splines and to obtain maximum likelihood estimates from censored survival data. The approach yields smooth estimates of the hazard and survivorship functions that are intermediate in structure between strongly parametric and non-parametric models. A simple method is described for selecting the number and location of knots. Simulation results show favorable root mean square error compared to non-parametric estimates for both the hazard and survivorship functions. Three methods are given to calculate confidence intervals based on the delta method, profile likelihood, and bootstrap, respectively. The procedure is applied to estimate hazard rates for acquired immunodeficiency syndrome (AIDS) following infection with human immunodeficiency virus (HIV). Spline methods can accommodate complex censoring mechanisms such as those that arise in the AIDS setting. To illustrate, HIV infection incidence is estimated for a cohort of hemophiliacs in which the dates of HIV infection are interval-censored and some subjects were born after the onset of the HIV epidemic.

High prevalence of anti-HCV antibodies in a cohort of hemophiliacs from Apulia region: Low risk in patients treated with virus inactivated FVIII concentrates

High prevalence of anti-HCV antibodies in a cohort of hemophiliacs from Apulia region: Low risk in patients treated with virus inactivated FVIII concentrates

Relationship between HCV infection, liver damage and imbalance of lymphocyte subpopulations in a cohort of hemophiliacs

Relationship between HCV infection, liver damage and imbalance of lymphocyte subpopulations in a cohort of hemophiliacs

HIV infection in the Edinburgh haemophiliac cohort.

HIV infection in the Edinburgh haemophiliac cohort.