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1.
Genes Immun ; 5(4): 261-6, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15029237

ABSTRACT

The polymorphic MHC class I chain-related A (MICA) gene encodes a ligand that has different binding affinities for the NKG2D activating receptor of CD8+ T cells and natural killer (NK) cells. We hypothesized that MICA heterogeneity would affect recovery from hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. To test the hypothesis, we initially typed known MICA polymorphisms for 228 persons who cleared HCV infection and 442 persons with persistent hepatitis C matched on other factors affecting viral persistence. Although MICA(*)015 was detected more than two-fold more often in persons with viral clearance (odds ratio 0.36, 95% confidence interval=0.19, 0.80), it occurred in fewer than 5% of the study population. In a similar analysis of 442 persons with chronic hepatitis B and 768 matched controls who recovered, MICA(*)015 was detected in 2.0% of persons with chronic hepatitis B and only 0.9% of controls. No significant associations were detected with other MICA polymorphisms. While further investigation may reveal a structural basis of the MICA(*)015 associations, these data provide little support for the hypothesis that differential distribution of MICA alleles substantially affects recovery from HCV and HBV infections.


Subject(s)
Hepatitis B/metabolism , Hepatitis C/metabolism , Histocompatibility Antigens Class I/metabolism , Hepacivirus/immunology , Hepacivirus/metabolism , Hepatitis B/immunology , Hepatitis B virus/immunology , Hepatitis B virus/metabolism , Hepatitis C/immunology , Histocompatibility Antigens Class I/immunology , Humans , NK Cell Lectin-Like Receptor Subfamily K , Polymorphism, Genetic , Receptors, Immunologic/metabolism , Receptors, Natural Killer Cell
2.
Haemophilia ; 9(3): 261-8, 2003 May.
Article in English | MEDLINE | ID: mdl-12694515

ABSTRACT

Activated prothrombin complex concentrates have been used to treat bleeding episodes for patients who have developed an inhibitor to factor VIII (FVIII). FEIBA-Vh (FVIII bypassing activity, FEIBA) has been used since 1970 for this purpose and with FVIII for immune tolerance programmes. Studies have not been presented to show the safety and efficacy of FEIBA when given over a long period of time to prevent haemophilic arthropathy with bleeding into the joints of these patients. This study was undertaken to ascertain the outcome of haemophilic arthropathy with FEIBA prophylaxis. Data were collected on seven patients with known long-standing high-titre FVIII inhibitors given FEIBA prophylaxis for 3-6(1/2) years. Patients were given 50-100 units of FEIBA three to four times weekly. A functional joint evaluation revealed some degree of arthropathy already present in all patients at time of prophylaxis initiation. Safety was measured by medical status, evidence of thrombosis, life-threatening bleeding and inhibitor titre. Efficacy was measured for joint outcome by a functional physical therapeutic scale. At the conclusion of the study, efficacy was mixed as all of the joints for which the patients were placed on prophylaxis had progressed and developed synovitis. Two patients had a functional improvement in their arthropathy, and all were functional enough to attend regular school. The product was deemed safe for long-term use, as there were no complications of therapy with no thrombosis, no life-threatening bleeding episodes and no anamnesis caused by FEIBA alone. Inhibitor titres fell in all patients over the course of the study. Total product usage ranged from approximately 9373-15,571 U kg(-1) year(-1). FEIBA is safe for long-term prophylaxis when given in the recommended dosage for an extended period of time. Efficacy to prevent arthropathy could not be seen as all patients had some degree of arthropathy at time of prophylaxis initiation. An additional study needs to be performed using FEIBA before arthropathy has developed.


Subject(s)
Blood Coagulation Factors/therapeutic use , Hemarthrosis/prevention & control , Hemophilia A/drug therapy , Child , Child, Preschool , Drug Administration Schedule , Factor VIII/antagonists & inhibitors , Follow-Up Studies , Hemarthrosis/etiology , Hemarthrosis/physiopathology , Hemophilia A/blood , Hemophilia A/complications , Humans , Male , Retrospective Studies , Severity of Illness Index
3.
J Acquir Immune Defic Syndr ; 26(5): 466-72, 2001 Apr 15.
Article in English | MEDLINE | ID: mdl-11391167

ABSTRACT

Coinfection with hepatitis C virus (HCV) and HIV-1 is common in patients with hemophilia and in intravenous drug users. Little, however, is known about the relation between HIV-1 and HCV coinfection and the effects on HCV clearance and pathogenesis. We examined data from 207 HIV-1-infected and 126 HIV-1-uninfected patients with hemophilia enrolled in the multicenter Hemophilia Growth and Development Study. Participants were observed during prospective follow-up for approximately 7 years with annual measurements of alanine aminotransferase (ALT), CD4+ cells, and HCV and HIV-1 RNA levels. Clearance of HCV was more likely to occur in those uninfected with HIV-1 (14.3 versus 2.5%; odds ratio [OR] 4.79; 95% confidence interval [CI], 1.63-14.08, p =.005) and was more common with decreasing age (OR, 1.23; 95% CI, 1.04-1.47; p =.017). HCV RNA levels were higher throughout the 7 years of follow-up in those HIV-1-infected (p <.001). In the HIV-1-infected participants, baseline CD4+ cells were inversely related to HCV RNA with every 100-cell increase associated with a 0.19 log10 copy/ml decrease in HCV RNA (p =.002), and HIV-1 and HCV RNA levels were directly related (p =.008). Increasing HCV RNA levels were also associated with significantly higher ALT levels regardless of HIV-1 infection status. These results demonstrate that HIV-1/HCV co-infection is associated with a reduced likelihood of HCV clearance and that higher levels of HCV RNA are associated with increased hepatic inflammation.


Subject(s)
HIV Infections/virology , HIV-1/physiology , Hemophilia A/complications , Hemophilia A/virology , Hepacivirus/physiology , Hepatitis C/virology , Adolescent , Adult , Alanine Transaminase/blood , Anti-HIV Agents/therapeutic use , CD4 Lymphocyte Count , Child , Cohort Studies , HIV Infections/complications , HIV Infections/drug therapy , Hepatitis C/complications , Humans , RNA, Viral/blood , Viral Load
4.
Am J Hematol ; 66(2): 92-8, 2001 Feb.
Article in English | MEDLINE | ID: mdl-11421305

ABSTRACT

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.


Subject(s)
Antibodies/blood , HIV Seropositivity/immunology , Hemophilia A/therapy , Immunotherapy, Active , Viral Vaccines/immunology , Adolescent , Anti-HIV Agents/administration & dosage , CD4-Positive T-Lymphocytes/cytology , Child , Cohort Studies , HIV Seronegativity/immunology , Humans , Lymphocyte Count , Measles Vaccine/administration & dosage , Measles Vaccine/immunology , Mumps Vaccine/administration & dosage , Mumps Vaccine/immunology , Rubella Vaccine/administration & dosage , Rubella Vaccine/immunology , Statistics, Nonparametric , Viral Load , Viral Vaccines/administration & dosage
5.
J Infect Dis ; 184(1): 16-21, 2001 Jul 01.
Article in English | MEDLINE | ID: mdl-11398104

ABSTRACT

A broad, vigorous CD4 T cell response, mediated by class II human leukocyte antigens (HLAs), favors hepatitis C virus (HCV) clearance. HLA-DQB1*0301 has been associated with viral clearance in an ethnically homogeneous cohort. To validate this association and to identify other class II associations in an ethnically varied cohort, molecular class II HLA typing was performed on 200 HCV clearance and 374 matched persistently infected subjects. HLA-DQB1*0301 was weakly associated with viral clearance in combined ethnic groups (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.53-0.97) but was stronger in black subjects. In white subjects, viral clearance was associated with DRB1*0101 (OR, 0.32; 95% CI, 0.17-0.60) and its DQB1*0501 haplotype, whereas viral persistence was associated with DRB1*0301 (OR, 2.36; 95% CI, 1.23-4.52) and its DQB1*0201 haplotype. These results support a role for class II alleles in the immune response to HCV and underscore the importance of studying genetic associations in an ethnically diverse cohort.


Subject(s)
Black People/genetics , Hepacivirus/immunology , Hepatitis C/immunology , Histocompatibility Antigens Class II/genetics , White People/genetics , Adult , Alleles , Cohort Studies , Disease Progression , Female , HLA-DQ Antigens/genetics , HLA-DQ Antigens/immunology , HLA-DQ beta-Chains , HLA-DR Antigens/genetics , HLA-DR Antigens/immunology , HLA-DRB1 Chains , Haplotypes , Humans , Male
6.
Pediatrics ; 107(4): E56, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11335777

ABSTRACT

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.


Subject(s)
CD4 Lymphocyte Count/statistics & numerical data , CD4-Positive T-Lymphocytes/immunology , Growth/physiology , HIV Infections/blood , HIV/chemistry , Hemophilia A/diagnosis , RNA, Viral/blood , Adolescent , Age Determination by Skeleton/methods , Age Factors , Body Height/immunology , Body Height/physiology , Body Weight/immunology , Body Weight/physiology , CD4-Positive T-Lymphocytes/chemistry , Child , Growth/immunology , HIV/immunology , HIV Infections/immunology , Hemophilia A/blood , Hemophilia A/physiopathology , Humans , Male , RNA, Viral/immunology , Regression Analysis , Testosterone/blood
7.
J Infect Dis ; 183(4): 589-95, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11170984

ABSTRACT

Hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) coinfection is common in hemophiliacs and injection drug users. To assess the interaction between HCV load and HIV-1 disease progression, we examined 207 HIV-1/HCV-coinfected patients. Patients were followed prospectively for approximately 7 years, and annual measurements of CD4(+) cell counts and HCV and HIV-1 loads were obtained. Survival analysis was used to define the independent effects of HCV load on HIV-1 progression. After controlling for CD4(+) cell count and HIV-1 RNA level, every 10-fold increase in baseline HCV RNA was associated with a relative risk (RR) for clinical progression to acquired immunodeficiency syndrome (AIDS) of 1.66 (95% confidence interval [CI], 1.10-2.51; P=.016) and an RR for AIDS-related mortality of 1.54 (95% CI, 1.03-2.30; P=.036). These findings emphasize the need for further research regarding the use of HIV-1- and HCV-specific therapy in coinfected individuals.


Subject(s)
HIV Infections/complications , Hemophilia A/virology , Hepacivirus/physiology , Hepatitis C/complications , Viral Load , Adolescent , Adult , CD4 Lymphocyte Count , Child , Disease Progression , HIV Infections/mortality , HIV Infections/virology , HIV-1/physiology , Hepatitis C/virology , Humans , Prospective Studies , RNA, Viral/blood
8.
J Acquir Immune Defic Syndr ; 21(4): 317-25, 1999 Aug 01.
Article in English | MEDLINE | ID: mdl-10428111

ABSTRACT

We have investigated the effects of plasma HIV RNA, CD4+ T lymphocytes and chemokine receptors CCR5 and CCR2b on HIV disease progression in hemophiliacs. We prospectively observed during follow-up 207 HIV-infected hemophiliacs in the Hemophilia Growth and Development Study. Plasma HIV RNA was measured on cryopreserved plasma from enrollment using the Chiron Corporation bDNA (version 2.0) assay. Genoytpe variants CCR2b-641 and CCR5-delta32 were detected using standard molecular techniques. Those with the mutant allele for CCR2b, and to a lesser extent CCR5, had lower plasma HIV RNA, and higher CD4+ T lymphocytes than did those without these genetic variants. After controlling for the effects of plasma HIV RNA and CD4+ T lymphocytes, those with the CCR2b mutant allele compared with those wild-type, had a trend toward a lower risk of progression to AIDS, adjusted relative hazard of 1.94 (95% confidence interval [CI], 0.9-4.18; p = .092), and AIDS-related death, relative hazard 1.97 (95% CI, 0.98-4.00; p = .059). We conclude that plasma HIV RNA, CD4+ T lymphocytes, and CCR genotypes are correlated, and the protective affect of CCR2b against HIV disease progression is not completely explained by plasma HIV RNA or CD4+ T-lymphocyte number.


Subject(s)
HIV Infections/complications , HIV Infections/virology , HIV-1 , Hemophilia A/complications , Acquired Immunodeficiency Syndrome/complications , Adolescent , Adult , CD4 Lymphocyte Count , Child , Cohort Studies , Genetic Variation , Genotype , HIV Infections/immunology , HIV-1/isolation & purification , Humans , Male , Prospective Studies , RNA, Viral/blood , Receptors, CCR2 , Receptors, CCR5/genetics , Receptors, Chemokine/genetics , Receptors, Cytokine/genetics
9.
Cancer Epidemiol Biomarkers Prev ; 8(4 Pt 1): 293-6, 1999 Apr.
Article in English | MEDLINE | ID: mdl-10207631

ABSTRACT

Human endogenous retrovirus K10 (HERV-K10) env and gag expression has been detected in placenta, embryonic tissue, and cell lines. By transfection, these sequences have been expressed in insect cells and developed into serological assays, revealing HERV-K10 antibodies in patients with testicular cancer. Patients with AIDS are at an increased risk for testicular cancer and frequently reactivate latent infections. We postulated that HERV-K10 seroprevalence might be increased with HIV infection or AIDS. Stored, frozen serum samples from 52 patients with testicular cancer (8 patients with HIV and 30 patients with samples near the time of diagnosis) and 84 controls (40 patients with HIV) were diluted 1:40 and tested by immunofluorescence against SF158 cells transfected with HERV-K10 env [ENV1.9(+)] or gag (pACGAG). Seroprevalence rates were compared cross-sectionally in cases and controls, excluding those with indeterminate results (3 of 30 cases and 7 of 84 controls), and also were examined longitudinally in the cases before or after diagnosis of testicular cancer. Seroprevalence to HERV-K10 Env or Gag was 17 of 27 testicular cancer patients (63%) around the time of diagnosis, compared to 4 of 77 controls (5%; P < 0.0001). Seroprevalence was similar (50% to 60%) with seminoma, teratocarcinoma, or embryonal carcinoma, and it was not increased with HIV infection in either cases (33%) or controls (3%). HERV-K10 antibodies were detected in 12 of 19 cases (63%) more than 6 months before seminoma diagnosis, as well as in four cases with residual or recurrent malignancy more than 1 month after initial diagnosis. Thus, HERV-K10 antibodies are detected frequently with testicular cancer and seem to resolve rapidly with effective therapy of the malignancy. Antibody reactivity also occurs in approximately 5% of controls, perhaps because of nonspecific or cross-reactive epitopes. HIV and AIDS were not associated with HERV-K10 antibodies, thus, leaving their higher risk of testicular cancer unexplained.


Subject(s)
Acquired Immunodeficiency Syndrome/immunology , Antibodies, Viral/analysis , Gene Products, gag/immunology , Retroviridae/immunology , Seminoma/immunology , Testicular Neoplasms/immunology , Acquired Immunodeficiency Syndrome/epidemiology , Adult , Aged , Case-Control Studies , Cross-Sectional Studies , Fluorescent Antibody Technique , Gene Products, gag/genetics , HIV Antibodies/analysis , HIV Infections/epidemiology , HIV Infections/genetics , HIV Infections/immunology , Humans , Male , Middle Aged , Retroviridae/genetics , Risk Assessment , Seminoma/epidemiology , Seminoma/genetics , Sensitivity and Specificity , Seroepidemiologic Studies , Testicular Neoplasms/epidemiology , Testicular Neoplasms/genetics
10.
Science ; 282(5395): 1907-11, 1998 Dec 04.
Article in English | MEDLINE | ID: mdl-9836644

ABSTRACT

The CCR5 gene encodes a cell surface chemokine receptor molecule that serves as the principal coreceptor, with CD4, for macrophage-tropic (R5) strains of human immunodeficiency virus-type 1 (HIV-1). Genetic association analysis of five cohorts of people with acquired immunodeficiency syndrome (AIDS) revealed that infected individuals homozygous for a multisite haplotype of the CCR5 regulatory region containing the promoter allele, CCR5P1, progress to AIDS more rapidly than those with other CCR5 promoter genotypes, particularly in the early years after infection. Composite genetic epidemiologic analyses of genotypes bearing CCR5P1, CCR5-Delta32, CCR2-64I, and SDF1-3'A affirmed distinct regulatory influences for each gene on AIDS progression. An estimated 10 to 17 percent of patients who develop AIDS within 3.5 years of HIV-1 infection do so because they are homozygous for CCR5P1/P1, and 7 to 13 percent of all people carry this susceptible genotype. The cumulative and interactive influence of these AIDS restriction genes illustrates the multigenic nature of host factors limiting AIDS disease progression.


Subject(s)
Acquired Immunodeficiency Syndrome/physiopathology , HIV-1 , Promoter Regions, Genetic , Receptors, CCR5/genetics , Receptors, Chemokine , Receptors, Cytokine/genetics , Acquired Immunodeficiency Syndrome/genetics , Acquired Immunodeficiency Syndrome/mortality , Alleles , Chemokine CXCL12 , Chemokines, CXC/genetics , Cohort Studies , Disease Progression , Genes, Dominant , Genes, Recessive , Genetic Predisposition to Disease , Genotype , HIV Infections/genetics , HIV Infections/physiopathology , Haplotypes , Heterozygote , Homozygote , Humans , Proportional Hazards Models , Receptors, CCR2 , Risk Factors , Survival Rate
12.
Science ; 277(5328): 959-65, 1997 Aug 15.
Article in English | MEDLINE | ID: mdl-9252328

ABSTRACT

The critical role of chemokine receptors (CCR5 and CXCR4) in human immunodeficiency virus-type 1 (HIV-1) infection and pathogenesis prompted a search for polymorphisms in other chemokine receptor genes that mediate HIV-1 disease progression. A mutation (CCR2-64I) within the first transmembrane region of the CCR2 chemokine and HIV-1 receptor gene is described that occurred at an allele frequency of 10 to 15 percent among Caucasians and African Americans. Genetic association analysis of five acquired immunodeficiency syndrome (AIDS) cohorts (3003 patients) revealed that although CCR2-64I exerts no influence on the incidence of HIV-1 infection, HIV-1-infected individuals carrying the CCR2-64I allele progressed to AIDS 2 to 4 years later than individuals homozygous for the common allele. Because CCR2-64I occurs invariably on a CCR5-+-bearing chromosomal haplotype, the independent effects of CCR5-Delta32 (which also delays AIDS onset) and CCR2-64I were determined. An estimated 38 to 45 percent of AIDS patients whose disease progresses rapidly (less than 3 years until onset of AIDS symptoms after HIV-1 exposure) can be attributed to their CCR2-+/+ or CCR5-+/+ genotype, whereas the survival of 28 to 29 percent of long-term survivors, who avoid AIDS for 16 years or more, can be explained by a mutant genotype for CCR2 or CCR5.


Subject(s)
Acquired Immunodeficiency Syndrome/genetics , HIV Infections/genetics , HIV-1 , Mutation , Receptors, Chemokine , Receptors, Cytokine/genetics , Receptors, HIV/genetics , Acquired Immunodeficiency Syndrome/immunology , Acquired Immunodeficiency Syndrome/mortality , Acquired Immunodeficiency Syndrome/virology , Black People , Cohort Studies , Disease Progression , Genotype , HIV Infections/immunology , HIV Infections/mortality , HIV Infections/virology , Haplotypes , Heterozygote , Humans , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Polymorphism, Single-Stranded Conformational , Proportional Hazards Models , Receptors, CCR2 , Receptors, CCR5 , Survival Analysis , White People
13.
Haemophilia ; 3(2): 154-6, 1997 Apr.
Article in English | MEDLINE | ID: mdl-27214728
14.
Article in English | MEDLINE | ID: mdl-8797689

ABSTRACT

We studied the characteristics and temporal trends of AIDS- associated non-Hodgkin's lymphoma (AIDS-NHL) in individuals with hemophilia. Prospective data were collected on 33 HIV-positive hemophiliacs with AIDS-NHL enrolled in the Hemophilia Malignancy Study (HMS), of whom 21 had primary and 12 had secondary or subsequent AIDS-defining illnesses, and analyzed for frequency and temporal trends. As compared with primary AIDS- NHL, secondary AIDS-NHL occurred at an older mean age, 37 versus 29 years (p = 0.12); at a lower mean CD4 count, 46 versus 154 (p = 0.07); after a longer period of immunosuppression (CD4 < 200/microl), 41 versus 16 months (p = 0.03); and with shorter median survival, 2 versus 7 months (p = 0.09). The presence of EBV in tumor tissue was associated with shorter survival, 1 versus 7 months (p = 0.17). Between 1981 and 1988 and 1989 and 1994, the proportion of primary AIDS diagnoses that were AIDS-NHL changed minimally, 4.6 versus 6.1%, whereas there were significant decreases in Pneumocystis carinii pneumonia (PCP, p = 0.02) and wasting (p = 0.07), and an increase in Candida (p = 0.004). These findings confirm that an increasing proportion of AIDS-NHL in hemophiliacs are occurring as secondary or later AIDS diagnoses, and they are associated with prolonged duration of immunosuppression.


Subject(s)
Acquired Immunodeficiency Syndrome/complications , Acquired Immunodeficiency Syndrome/diagnosis , Hemophilia A/complications , Lymphoma, AIDS-Related/complications , Lymphoma, AIDS-Related/diagnosis , Lymphoma, Non-Hodgkin/complications , Lymphoma, Non-Hodgkin/diagnosis , AIDS-Related Opportunistic Infections/complications , AIDS-Related Opportunistic Infections/diagnosis , Adult , Hemophilia A/virology , Humans , Neoplasms/complications , Neoplasms/diagnosis , Prospective Studies
15.
JAMA ; 276(2): 105-10, 1996 Jul 10.
Article in English | MEDLINE | ID: mdl-8656501

ABSTRACT

OBJECTIVE: To determine if the long-term incidence of the acquired immunodeficiency syndrome (AIDS) is related to human immunodeficiency virus type 1 (HIV-1) RNA levels measured early in HIV-1 infection. DESIGN: Epidemiologic cohort study. SETTING: Five hemophilia treatment centers in the United States. SUBJECTS: A total of 165 subjects with hemophilia and HIV-1 infection (age at HIV-1 seroconversion, 1-66 years) followed from 1979 to 1995. METHODS: The HIV-1 RNA level was measured by polymerase chain reaction over a range of 200 to 1 million or more HIV-1 RNA copies/mL in archived serum specimens collected 12 to 36 months (median, 27 months) after the estimated date of HIV-1 seroconversion. Kaplan-Meier methods were used to examine the risk of AIDS and proportional hazards models were used to estimate relative hazards. RESULTS: The HIV-1 RNA values were similar in subjects younger than 17 years at seroconversion (median, 5214 copies/mL) and those 18 to 34 years old (median, 4693 copies/mL), but higher in those 35 years or older (median, 12069 copies/mL) (P = .02 compared with each younger group). At 10 years after seroconversion, the proportions of subjects with AIDS were 72% among subjects with 100,000 or more HIV-1 RNA copies/mL measured 12 to 36 months after HIV-1 seroconversion (n = 9), 52% among subjects with 10,000 to 99,999 copies/mL (n = 55), 22% among subjects with 1000 to 9,999 copies/mL (n = 82), and 0% among subjects with fewer than 1000 copies/mL (n = 19) (P < .001). The age-adjusted relative hazard for AIDS for subjects with 10,000 or more copies/mL was 14.3 (95% confidence interval, 1.9-105.6) compared with subjects with fewer than 1000 copies/mL. CONCLUSIONS: The HIV-1 RNA level during early chronic HIV-1 infection is a strong, age-independent predictor of clinical outcome; low levels define persons with a high probability of long-term AIDS-free survival.


Subject(s)
Acquired Immunodeficiency Syndrome/mortality , HIV Seropositivity/blood , HIV-1/genetics , RNA, Viral/blood , Acquired Immunodeficiency Syndrome/blood , Acquired Immunodeficiency Syndrome/complications , Adolescent , Adult , Age Factors , Aged , Child , Child, Preschool , Cohort Studies , Disease Progression , HIV Seropositivity/complications , HIV Seropositivity/mortality , Hemophilia A/complications , Humans , Infant , Longitudinal Studies , Middle Aged , Polymerase Chain Reaction , Prognosis , Proportional Hazards Models , Survival Analysis , Time Factors
16.
Am J Hematol ; 51(4): 324-7, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8602635

ABSTRACT

Heteroduplex analysis of polymerase chain reaction (PCR)-amplified factor IX (FIX) sequences in eight hemophilia B pedigrees localized the causative hemophilia mutation to a single exon in each case. Subsequent PCR-based direct DNA sequence analysis identified two novel FIX mutations and six recurrent mutations. Three of the eight pedigrees represent sporadic hemophilia B, and direct mutation analysis facilitated hemophilia carrier diagnosis in each case.


Subject(s)
DNA Mutational Analysis , Factor IX/genetics , Genetic Carrier Screening , Hemophilia B/genetics , Nucleic Acid Heteroduplexes/analysis , Nucleic Acid Hybridization , Point Mutation , Female , Haplotypes/genetics , Humans , Male , Polymerase Chain Reaction
17.
Am J Hematol ; 49(3): 201-6, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7604813

ABSTRACT

Persons with hemophilia or other HIV-1 risk factors may be more likely to have idiopathic CD4+ T-lymphocytopenia (ICL). We determined the frequency of ICL in prospectively followed cohorts of HIV-1 seronegative hemophilic men and seronegative female sex partners of HIV-1 infected hemophilic men, and examined factors potentially associated with ICL. Seven of 304 (2.3%) seronegative hemophilic men and one of 160 (0.6%) female partners met the ICL definition, but the condition resolved for two of the men and for the sole female partner. All five men with persistent ICL had lymphocytopenia (< 1,200 total lymphocytes/microliters) and < 300 total CD4+ lymphocytes/microliters; only one had a low CD4+ percentage. On the most recent measurement, 14.5% of the 304 seronegative hemophilic men had lymphocytopenia. Compared with matched hemophilic controls, men with persistent ICL more often had a history of liver disease (3/5 cases, 0/21 controls, P = 0.007) or splenomegaly (3/5 cases, 4/21 controls; P = 0.04), but not severe hemophilia, greater clotting factor concentrate exposure, high alanine aminotransferase levels, hepatitis B virus antigenemia, or detectable hepatitis C virus RNA in plasma. All five cases and 20/21 controls had antibodies to hepatitis C virus present in their serum. In this cohort of hemophilic men, ICL was related to lymphocytopenia associated with liver disease rather than selective loss of CD4+ lymphocytes.


Subject(s)
CD4-Positive T-Lymphocytes , HIV Seropositivity , Hemophilia A/complications , Lymphopenia/complications , Sexual Partners , Acquired Immunodeficiency Syndrome/complications , Adult , Case-Control Studies , Female , HIV Seronegativity , Hepacivirus/immunology , Hepatitis Antibodies/blood , Humans , Liver Diseases/complications , Male , Middle Aged , Prospective Studies , Splenomegaly
18.
J Infect Dis ; 172(1): 228-31, 1995 Jul.
Article in English | MEDLINE | ID: mdl-7797917

ABSTRACT

Blood samples were obtained from 16 hemophiliacs who had a 50%-94% defined risk of human immunodeficiency virus (HIV) type 1 infection on the basis of treatment history and from 14 controls not at risk for HIV infection. HIV-1 was not detected in any of 12 patient samples by cocultivation nor in 14 patient samples by the polymerase chain reaction. Peripheral blood cells from 7 seronegative hemophiliacs at highest risk of seroconversion (94%) were less susceptible to HIV-1 infection in vitro than were cells from healthy controls (P < .025, one-tailed Wilcoxon rank sum test). In contrast, the susceptibility to HIV-1 infection of lymphocytes from 6 seronegative hemophiliacs at moderate risk (50%-56%) of seroconversion did not differ from that of cells from controls or from high-risk hemophiliacs. Therefore, prolonged periods of seronegative HIV-1 infection are not common in this high-risk population. In addition, among hemophiliacs there may exist heterogeneity in susceptibility to HIV-1 infection in vitro and in vivo.


Subject(s)
HIV Infections/epidemiology , HIV Seronegativity , HIV Seropositivity/immunology , HIV-1 , Hemophilia A/complications , Adult , CD4 Lymphocyte Count , CD8-Positive T-Lymphocytes/immunology , Disease Susceptibility , Factor IX/analysis , Factor VIII/analysis , HIV Infections/transmission , HIV-1/genetics , HIV-1/isolation & purification , Hemophilia A/blood , Hemophilia A/immunology , Humans , Lymphocyte Count , Male , Polymerase Chain Reaction , Risk Factors
19.
Blood ; 85(8): 2091-7, 1995 Apr 15.
Article in English | MEDLINE | ID: mdl-7718880

ABSTRACT

Transfusions purportedly induce dysfunction of cell-mediated immunity in sickle cell anemia (SCA). We studied hematologic and lymphocytic indices in 173 human immunodeficiency virus (HIV)-negative subjects with SCA and 131 black controls. Children aged 1 to 7 years with SCA had leukocyte counts and percentages of granulocytes, monocytes, natural killer cells, and T-cell markers (CD2+CD11b+, CD4+CD26+, CD4+CD29+) that were significantly higher than those for control children. Percent total lymphocytes was decreased for this age group, but the total number of lymphocytes and T and B cell counts were similar to controls. Platelets were not increased. Adolescents (aged 8 to 17 years) and adults (aged > or = 18 years) with SCA had increased total leukocytes and monocytes and lymphocytes counts that remained level instead of decreasing, as did comparably aged controls. Lymphocyte subsets typically increased in count, but their percentage remained similar to children. The exception was CD56+ cell counts, which were increased in adolescents and adults. No lymphocytic subset change suggested impaired cellular immunity, and none could be related to transfusion. Prophylactically transfused patients had higher granulocyte counts, but these may arise from the complications of SCA itself.


Subject(s)
Anemia, Sickle Cell/blood , Blood Transfusion , Immunophenotyping , Leukocytosis/etiology , Lymphocyte Subsets , Adolescent , Adult , Age Factors , Anemia, Sickle Cell/complications , Anemia, Sickle Cell/immunology , Antigens, CD/analysis , Child , Child, Preschool , Cohort Studies , Female , HIV Seronegativity , Humans , Immunocompetence , Infant , Lymphocyte Count , Male , Prospective Studies
20.
Transfusion ; 35(3): 204-8, 1995 Mar.
Article in English | MEDLINE | ID: mdl-7878711

ABSTRACT

BACKGROUND: Vapor-heated human factor VII concentrate and human factor IX complex are both obtained from prothrombin complex, undergo similar methods of manufacture, and are subjected to an identical two-step vapor-heating process for virus inactivation. STUDY DESIGN AND METHODS: Intermediate-purity vapor-heated human factor VII concentrate and vapor-heated human factor IX complex were monitored for safety with regard to viral infection in the context of an International Factor Safety Study, a prospective study that follows the revised recommendations from the International Congress of Thrombosis and Hemostasis (ICTH). Because the rarity of the respective hereditary deficiencies would have made separate analyses unrealizable, the results were combined for the final analysis. Entry required that patients have no history of transfusion with any blood derivative. After the first infusion of the study drug, patients were monitored for 6 months for the development of non-A, non-B hepatitis (NANBH) and infection with hepatitis B virus (HBV) and for 15 months for infection with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). An event was defined as a positive result on any test for any infection. An alanine aminotransferase level more than 2.5 times the upper limit of normal on two consecutive occasions was defined as an event for NANBH. HBV infection was monitored with tests for three different HBV markers: the HBV surface antigen, antibody against the HBV surface antigen, and antibody against HBV core antigen. HCV and HIV infection were monitored with tests for HCV and HIV antibodies. RESULTS: The 25 patients who completed the study (1 has not completed the study and 1 dropped out) received a total of 434 infusions comprising 17 different production lots of the concentrates. Twenty patients were analyzable for NANBH and 25 for HCV and HIV infection. Since most patients had been given HBV vaccination, only 4 patients were analyzable for this end point. None of the patients showed evidence of having developed an event. These data satisfy ICTH criteria when the products are considered together, but vapor-heated factor VII concentrate does not qualify alone because there were only five patients in this group. CONCLUSION: Vapor-heated factor VII concentrate and vapor-heated factor IX complex are associated with a low risk of viral infection. Preliminary results are also presented, indicating that the concentrates are safe with regard to inhibitor development.


Subject(s)
Factor IX/therapeutic use , Factor VII/therapeutic use , Hemophilia B/drug therapy , Hot Temperature , Virus Diseases/prevention & control , Virus Diseases/transmission , Adult , Aged , Aged, 80 and over , Female , HIV Infections/prevention & control , HIV Infections/transmission , Hepatitis B/prevention & control , Hepatitis B/transmission , Hepatitis C/prevention & control , Hepatitis C/transmission , Humans , Infant , Infant, Newborn , Male , Plasma/virology , Risk Factors , Volatilization
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