Treatment of haemophilia in the United Kingdom 1981-1996.
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Data Collection↗
Biomedical subjects
C R Rizza
Publications and source records attributed to C R Rizza.
Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C. UK Haemophilia Centre Directors' Organisation.
BACKGROUND: Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS: We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS: Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION: There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.
Adult↗
Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. UK Haemophilia Centre Directors' Organisation.
BACKGROUND: Greater age at infection with HIV-1 is known to be associated with shorter time to development of AIDS, but the size of the differences between people infected in infancy and those infected in old age has not been examined in a single large population of patients with death as an endpoint. We, therefore, investigated the role of age at seroconversion in the entire UK population of haemophiliacs. METHODS: We studied 1216 HIV-1-infected haemophilia patients in the UK who were registered with the National Haemophilia Register and were alive on Jan 1, 1985. Their estimated ages at HIV-1 seroconversion ranged from 8 months to 79 years. FINDINGS: 10 years after seroconversion 67% (95% Cl 64-69) of the population were still alive. Survival was strongly related to age at seroconversion (86% [82-90], 72% [68-76], 45% [39-51], and 12% [5-21] at 10 years among those patients who seroconverted at ages < 15, 15-34, 35-54, and > or = 55). This steep age-gradient in survival was not explained by deaths expected in the absence of HIV infection or by confounding with other factors such as haemophilia type or severity. The age-gradient was steeper for survival (ie, time from HIV-1 infection to death) than for time to diagnosis of AIDS, partly because survival after an AIDS diagnosis was poorer in older patients, and there was also a substantial increase in mortality among HIV-infected patients who did not satisfy the formal AIDS definition and this increase was greater in older patients. INTERPRETATION: Age at infection with HIV-1 is a more important determinant of survival than has previously been appreciated. Age should, therefore, be considered in future studies of disease progression, and studies that compare people infected at different ages should provide insight into the biology of the immune response to HIV-1.
Acquired Immunodeficiency Syndrome↗
Mortality before and after HIV infection in the complete UK population of haemophiliacs. UK Haemophilia Centre Directors' Organisation.
During 1977-91, 6,278 males diagnosed with haemophilia were living in the UK. During 1979-86, 1,227 were infected with the human immunodeficiency virus (HIV-1) as a result of transfusion therapy (median estimated seroconversion date, October 1982). Among 2,448 with severe haemophilia, the annual death rate was stable at 8 per 1,000 during 1977-84; during 1985-92 death rates remained at 8 per 1,000 among HIV-seronegative patients but rose steeply in seropositive patients, reaching 81 per 1,000 in 1991-92. Among 3,830 with mild or moderate haemophilia, the pattern was similar, with an initial death rate of 4 per 1,000 in 1977-84, rising to 85 per 1,000 in 1991-92 in seropositive patients. During 1985-92, there were 403 deaths in HIV seropositive patients, whereas 60 would have been predicted from rates in seronegatives, suggesting that 85% of the deaths in seropositive patients were due to HIV infection. Most of the excess deaths were certified as due to AIDS or to conditions recognized as being associated with AIDS.
Adolescent↗
Low risk of sexual transmission of hepatitis C virus.
Sexual transmission of hepatitis C virus (HCV) was studied between 104 anti-HCV positive index cases (99 haemophilic men, five women) who have attended the Oxford Haemophilia Centre and 104 (98 female, 6 male) longstanding sexual partners. Ninety-one percent of the index cases were HCV RNA positive by the polymerase chain reaction (PCR) and 56% were anti-human immunodeficiency virus (HIV) positive. Three (2.9%) sexual partners (each a female partner of a different HCV RNA positive haemophilic man) were anti-HCV, and HCV RNA, positive. All had other risk factors for HCV infection. Of 59 partners who were tested for anti-HIV four (7%) were positive and only one of these was also anti-HCV positive. There was no association between HIV positivity in the index cases and HCV positivity in their partners. Our results confirm a low risk of sexual transmission of HCV.
Adult↗
Analysis of factor VIII mRNA reveals defects in everyone of 28 haemophilia A patients.
Haemophilia A is a mutationally heterogeneous disease caused by defects in the large and complex factor VIII gene. Recent studies examining the putative promoter, all exons and most intron/exon boundaries have failed to detect mutations in half the patients with severe disease leading to hypotheses such as mutations in remote controlling regions or even in genes other than factor VIII. We have amplified the factor VIII gene (putative promotor, coding region and polyadenylation/cleavage signal region) in 8 fragments from reverse transcribed mRNA and genomic DNA. Any mutation is then located by chemical mismatch detection and characterised by direct sequencing. This rapid and efficient method has been fully successful and has revealed an unusual cluster of mutations causing severe disease. Of the 28 patients we have reported, 5 had mild or moderate disease and all had a missense mutation. Twenty-three patients were severely affected and 13 of these had different detrimental mutations that were fully characterised at the genomic DNA level. The remaining 10 patients all had mRNA with exon 22 not contiguous to exon 23. Since all exons were normal and so were the splice sites of intron 22, the mutation in these patients should be in the regions of intron 22 that were not screened. These results prove that all haemophilia A cases are due to mutations of the factor VIII gene where, unexpectedly, intron 22 seems to be the target of approximately 40% of the mutations causing severe haemophilia A.
Amino Acid Sequence↗
Confirmation of viral safety of dry heated factor VIII concentrate (8Y) prepared by Bio Products Laboratory (BPL): a report on behalf of U.K. Haemophilia Centre Directors.
Twenty-seven factor VIII deficient patients who had previously not been treated with blood or blood products were studied after infusion of a total of 24 batches of NHS factor VIII (8Y) concentrate produced by Bio-Products Laboratory, Elstree. Follow-up was carried out according to guidelines laid down by the International Society for Thrombosis and Haemostasis. Serial estimations of amino transferase level carried out over a 26-week period revealed no elevation of these enzymes attributable to hepatitis. Studies of various virological markers found no evidence of infection with hepatitis C, hepatitis B or HIV following transfusion. This confirms a previous finding that severe dry heating of factor VIII at 80 degrees C for 72 h seems to reduce the risk of transmitting hepatitis C from approximately 90% to a rate of 0-11%.
Adult↗
Factor VIII gene explains all cases of haemophilia A.
Using an mRNA-based method to examine haemophilia A mutations we provide an explanation for the puzzling report that half of the mutations causing severe disease are not detected by analysis of the putative promoter, exons, and most exon/intron boundaries of the factor VIII gene. An unusual cluster of mutations involving regions of intron 22 not examined earlier leads to defective joining of exons 22 and 23 in the mRNA and caused haemophilia A in 10/24 severely affected UK patients.
Electrophoresis, Agar Gel↗
Human immunodeficiency virus variants that escape cytotoxic T-cell recognition.
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Amino Acid Sequence↗
Human immunodeficiency virus genetic variation that can escape cytotoxic T cell recognition.
In a longitudinal study of HIV seropositive patients, there were fluctuations in the specificity of cytotoxic T cells for the virus. This was matched by variability in proviral gag DNA epitope sequences in the lymphocytes of these patients. Some of these viral variants are not recognized by autologous T cells. Accumulation of such mutations in T-cell antigenic targets would provide a mechanism for immune escape.
Amino Acid Sequence↗
Detection of three novel mutations in two haemophilia A patients by rapid screening of whole essential region of factor VIII gene.
In an attempt to replace the existing, DNA-based, 50% effective, carrier and prenatal diagnoses of haemophilia A with the 100% successful direct detection of defective genes, a new procedure was developed to screen and identify mutations in all the essential regions of the factor VIII gene (putative promoter, coding sequence, and the cleavage and polyadenylation region). Genomic DNA and cDNA obtained by reverse transcription of the "leaky" mRNA found in peripheral lymphocytes were amplified by means of the polymerase chain reaction to yield a set of eight segments comprising the essential gene sequences. The segments were then screened individually for mutations by the amplification mismatch detection method, which detects and locates any type of sequence discrepancy between the test DNA and the control probe by cleavage of the probe at the site of mismatches. Two haemophilia A patients were studied. The first showed two single-base changes: one (substitution of tryptophan 2229 by cysteine in the C2 domain) is the probable cause of the disease, since it affects a conserved residue of factor VIIIa, whereas the other (the conservative substitution of aspartic acid at position 1241 by glutamic acid) occurs in a domain (B) irrelevant to factor VIII activity. The second patient showed a complete failure of pre-mRNA splicing due to a single-base substitution that changes the obligatory AG acceptor splice site of intron 5 to GG. The method characterises the gene defect in 10 days or less and should lead to the rapid accumulation of information on the molecular biology of haemophilia A.
Adult↗
A less severe form of Haemophilia B Leyden.
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Base Sequence↗
Time from infection with HIV to onset of AIDS in patients with haemophilia in the UK.
The two-stage parametric regression model of Brookmeyer and Goedert has been adapted and fitted to data on the development of AIDS in haemophiliacs in the UK who are seropositive for HIV. The risk of developing AIDS by a given time following seroconversion increases with increasing age at seroconversion. It is likely that the risk increases smoothly with age, although the data have been analysed in three age categories, and it is estimated that by seven years after seroconversion 6 per cent of patients aged under 25 at seroconversion, 20 per cent of those aged 25-44 and 34 per cent of those aged 45 or more have developed AIDS. For a given age at seroconversion the annual risk of developing AIDS increases with increasing time after seroconversion, and at seven years the annual risks of developing AIDS during the next year in the three age groups are estimated to be 2 per cent for those aged less than 25 at seroconversion, and 10 and 11 per cent respectively for those aged 25-44 and 45 or more.
Acquired Immunodeficiency Syndrome↗
An HIV-1 and HIV-2 cross-reactive cytotoxic T-cell epitope.
The HLA-B27-restricted HIV gag cytotoxic T-lymphocyte (CTL) epitope, 265-279, is highly conserved amongst HIV-1 isolates, only one, HIV-1ELI, having a single amino acid substitution. Over the same region HIV-2 differs by five amino acids. As a broadly cross-protective AIDS vaccine should protect against infection from all isolates of HIV-1 and HIV-2, we tested CTL specific for the HIV-1 265-279 epitope with peptide analogues from HIV-1ELI, HIV-2 and two simian immunodeficiency virus (SIV) isolates, and with recombinant vaccinia viruses expressing the respective gag genes, to determine whether there was any cross-reactivity for this CTL epitope. CTL from the HIV-1-infected donor could recognize the HIV-1ELI peptide, the HIV-2 peptide and recombinant vaccinia virus-infected target and one of the two SIV peptide-treated targets. Epitopes that exhibit such cross-reactivity may be valuable in vaccine design.
Amino Acid Sequence↗
Incidence of AIDS and excess of mortality associated with HIV in haemophiliacs in the United Kingdom: report on behalf of the directors of haemophilia centres in the United Kingdom.
OBJECTIVE--To estimate the cumulative incidence of AIDS by time since seroconversion in haemophiliacs positive for HIV and to examine the evidence for excess mortality associated with HIV in those who had not yet been diagnosed as having AIDS. DESIGN--Analysis of data from ongoing national surveys. SETTING--Haemophilia centres in the United Kingdom. PATIENTS--A total of 1201 men with haemophilia who had lived in the United Kingdom during 1980-7 and were positive for HIV. INTERVENTION--None. END POINTS--Diagnosis of AIDS; death in those not diagnosed as having AIDS. MEASUREMENTS AND MAIN RESULTS--Estimation of cumulative incidence of AIDS and number of excess deaths in seropositive patients not diagnosed with AIDS. Median follow up after seroconversion was 5 years 2 months. Eight five patients developed AIDS. Cumulative incidence of AIDS five years after seroconversion was 4% among patients aged less than 25 at first test positive for HIV, 6% among those aged 25-44, and 19% among those aged greater than or equal to 45. There was little evidence that type or severity of haemophilia or type of factor VIII or IX that had caused HIV infection affected the rate of progression to AIDS. Mortality was increased among those who had not been diagnosed as having AIDS, especially among those with "AIDS related complex." Thirteen deaths were observed among 36 patients diagnosed as having AIDS related complex against 0.65 expected, and 34 deaths in 1080 other patients against 22.77 expected; both calculations were based on mortality rates observed in haemophiliacs in the United Kingdom in the late 1970s. CONCLUSIONS--Rate of progression to AIDS depended strongly on age. There is a substantial burden of fatal disease among patients positive for HIV who have not been formally diagnosed as having AIDS.
Acquired Immunodeficiency Syndrome↗
HIV-1 gag-specific cytotoxic T lymphocytes defined with recombinant vaccinia virus and synthetic peptides.
Current candidate vaccines fail to protect primates against challenge with human immunodeficiency virus (HIV) in the presence of antibody responses; this underlines the importance of studying cell-mediated immunity to HIV and identifying specific epitopes that stimulate cytotoxic T lymphocytes (CTL). Using a recombinant vaccinia virus to express the gag protein of HIV-1 we found HLA class-I-restricted gag-specific CTL in thirteen out of fifteen healthy HIV seropositive patients. We then used short synthetic peptides in the lysis assay to screen for gag CTL epitopes. In one patient we have identified a peptide in p24 that is recognized by CTL in association with HLA-B27. This peptide, and further peptide sequences defined by these methods, could be incorporated in vaccines designed to induce cell-mediated immunity against HIV.
Acquired Immunodeficiency Syndrome↗
Evidence linking familial thrombosis with a defective antithrombin III gene in two British kindreds.
Using DNA probes in a structural study of the antithrombin III gene locus we found no evidence of gene deletion in two British kindreds with inherited antithrombin III deficiency. However, linkage analysis between a common DNA polymorphism and the antithrombin III deficiency trait showed that the defect lies at or close to the antithrombin III structural gene. The lod score for linkage within the larger Scottish kindred was 3.1 (theta = 0). These results are consistent with previously published data suggesting that mutation of the antithrombin III structural gene is the cause of inherited antithrombin III deficiency in some families.
Antithrombin III↗