Hepatitis C seropositivity in HIV-negative children with severe haemophilia

Summary. With the advent of new viral inactivation and purification methods for factor concentrates in the 1980s, transmission of both HIV-1 and hepatitis viruses has been significantly decreased. However, on routine annual testing of the paediatric population at the New England Hemophilia Center (NEHC), several children were noted to be hepatitis C (HCV) seropositive. Thus, a retrospective review of children with severe haemophilia was undertaken. Twenty-six children (median age: 7.5 years) under the age of 12 were identified. All were HIV-1 seronegative and had received hepatitis B immunization. Of these, 22 had received factor concentrate. Four children had no documented HCV serostatus, and seven were HCV seropositive using a second-generation ELISA. Transfusion products were reviewed and stored serum samples were evaluated using a second-generation ELISA to identify the approximate date of seroconversion with positive tests confirmed by RIBA analysis. Three children became seropositive before 1989 using factor concentrates with early viral attenuation procedures. Two children who seroconverted after 1991 received only monoclonal affinity purified factor concentrate that was either pasteurized or solvent/detergent treated. There was no evidence of horizontal or nosocomial viral transmission. We are unable to prove causality with the factor concentrates used by these children. Continued surveillance with sensitive measures for detection of HCV in persons with haemophilia using plasma-derived factor concentrate is necessary.     

Evidence for the aetiological role of blood-borne virus infections in causing reduced lectin-induced T-cell proliferation in haemophilic boys

Summary T-lymphocyte function, as expressed by polyclonal proliferation to lectin mitogens phytohaemagglutinin and concanavalin A, has been studied in a normal control population and three groups of haemophilic boys: group 1, HIV and HCV seronegative and treated only with a single heat-treated factor VILT (FVITI) concentrate; group 2, HIV seronegative but HCV seropositive; group 3, all HIV and HCV seropositive. Groups 2 and 3 have been previously treated with unheated and heated FVIII concentrate. Group 1 boys (HIV/HCV uninfected) showed no significant reduction in lymphocyte proliferation when compared with a control population. Group 2 and 3 boys showed an impaired response to these mitogens compared to group 1 boys and the control group. There was no relationship between FVIII concentrate received and proliferative response. The absence of immune modulation in haemophilic boys who have not acquired HIV and HCV infection implicates chronic blood-borne virus infections as the major contributory factors to impaired lymphocyte proliferative responses seen in haemophiliacs treated with large-pool concentrates. The presence of virus infections, such as HCV, may account for similar lymphocyte function abnormalities observed in previously described cohorts.     

The spectrum of human immunodeficiency virus infection in patients with factor IX deficiency (Christmas disease)

Early reports suggested that hemophiliacs with factor IX deficiency (Christmas Disease) may be at less risk for developing the acquired immunodeficiency syndrome (AIDS) than patients with classic hemophilia. We evaluated 12 factor IX deficient patients for clinical and immunologic abnormalities related to infection with the human immunodeficiency virus (HIV). Antibody to HIV was not detected in these patients prior to 1982. By 1985, 66 percent (eight of 12) patients were seropositive. All three concentrates available commercially before 1985 were associated with seropositivity. Furthermore, seropositive hemophiliacs had received on average significantly more factor IX concentrate than seronegative hemophiliacs (27,825 +/- 17,976 (S.D.) versus 1,250 +/- 1,500 factor units/year, (p less than 0.02). Half of the seropositive individuals had generalized lymphadenopathy with splenomegaly. Two seropositive patients have developed AIDS, one with cryptococcal meningitis and another with a large cell immunoblastic lymphoma. Infection with HIV has occurred with high frequency in hemophiliacs who received unmodified factor IX concentrates.     

Antibodies to HIV in Israeli hemophiliacs: relationship between serological profile and disease development

We studied 66 Israeli hemophiliacs for antibodies to HIV in blood samples collected between 1978 and 1985. By May 1985, 2 had AIDS, 2 had ARC, 4 had lymphadenopathy with some immunologic dysfunction, and 58 were asymptomatic. Antibodies to HIV were detected in 40 (60.6%) patients, including all 8 with disease. Presence of HIV antibodies was significantly associated with receipt of non-heat-treated commercial factor VIII concentrates (NHT fac VIII) between 1980 and 1983. Thirty-eight of 45 (84.44%) patients treated with NHT fac VIII developed antibodies to HIV, compared to 1 of 16 (6.25%) treated with cryoprecipitates and fresh plasma only. Of 40 seropositive patients, 1 (2.5%) had antibodies by 1980, 4 (10%) by 1982, 14 (35%) by 1983, 10 (25.0%) by 1984, and 11 (27.5%) by May 1985. The decline in the rate of seroconversion can be attributed to the replacement of NHT fac VIII concentrate with heat-inactivated factor VIII (HT fac VIII) concentrate by November 1983. As of January 1984 only HT fac VIII was administered. Twenty-nine multitransfused thalassemia patients as well as 20 healthy Israeli blood donors were seronegative to HIV. All 40 (100%) seropositive hemophiliacs had antibodies to viral env gene encoded gp120/gp160 antigens. Twenty-four (60.05%) also had antibodies to viral gag gene encoded p24 and/or p55 antigens. While antibodies to gp120/160 persisted during the follow-up time, a loss of antibodies to p24/55 was observed in 5 of 16 (31.25%) seropositive patients from whom multiple samples were available. gp120/160 positive, p24/55 negative hemophiliacs had significantly lower absolute T-helper cell counts and reversed Th/Ts ratios when compared to gp120/160 p24/55 seropositive patients. Four of the 16 (25.0%) asymptomatic gp120/160 positive, p24/55 negative patients developed overt disease within 15 months of the last blood collection. The data suggest that exposure to HIV antigens is widespread among hemophiliacs in Israel, and can be attributed to receipt of NHT fac VIII concentrates prior to 1984. Antibodies to gp120/160 are of the most important diagnostic value while loss of antibodies to p24/p55 may be of prognostic value.     

Serological and virological markers of human parvovirus B19 infection in patients with haemophilia

Clotting factor concentrates prepared from human plasma are a potential route of parvovirus B19 (B19) infection in patients with coagulation disorders. However, it is not clear whether B19 transmits and persistently infects patients with haemophilia, especially those with HIV infection. We examined serological and virological markers of B19 in samples from 40 patients with haemophilia who had been receiving several brands of clotting factor concentrates. All of them were anti-B19 IgG seropositive and anti-B19 IgM seronegative. The levels of anti-B19 IgG were significantly higher in haemophiliacs than in healthy donors, whereas there was no difference between the level of anti-B19 IgG in haemophiliacs with HIV infection and those without HIV infection. Moreover, there was no difference between the level of anti-B19 IgG in haemophiliacs receiving recombinant factor VIII and that in those receiving plasma-derived clotting factors. Although by using polymerase chain reaction (PCR) B19 DNA was detected at very low levels (< 40 DNA copies mL⁻¹, in 3 out of 40 haemophiliacs, persistent B19 infection was negligible.     

Clinical analysis of 4 Chinese hemophiliacs with human immunodeficiency virus infection

Human immunodeficiency virus (HIV-is) now considered the causative agent of acquired immunodeficiency syndrome(AIDS). A high risk of AIDS has been reported among patients with hemophilia who received lyophilized commercial factor VIII and IX concentrates of American origin. In a prevalence survey conducted from September to December 1985, HIV antibodies were found in all the 4 patients with hemophilia treated with the batch number W87307, 955 I.U. of American commercial factor VIII concentrate supplied by Armour pharmaceutical Company U.S.A. One of the seropositive patients developed AIDS-related complex (ARC) and died of cerebral hemorrhage. The other three sero-positive patients had abnormalities in cell mediated immunity; among them two developed left lumbosacral radiculopathy and hemorrhagic herpes zoster and one remains well so far.     

Cytolytic activity against mycobacterial antigens: differences between haemophiliacs with and without HIV infection

Summary Although asymptomatic haemophiliacs have been shown to have abnormalities of their immune response, independent of HIV, clinical evidence of significant immunosuppression is limited. The only clinical report has been an outbreak of M. tuberculosis in which a group of haemophilic boys appeared unduly susceptible to infection. These boys are now all HIV seropositive. Along with a group of HIV seronegative children with coagulation disorders and non-haemophilic HIV seropositive men, these boys have been restudied to examine immune response to PPD. The HIV seropositive haemophilic boys that had had M. tuberculosis infection had reduced cytolytic response to PPD pulsed macrophages comparable to the non-haemophilic HIV seropositive men. The HIV seronegative children with coagulation disorders showed a reduction in cytolytic activity at low effector:target ratios compared to normal controls. In vitro studies showed that exogenous factor VIII concentrate could inhibit cytolytic activity to PPD pulsed macrophages. The possible role of chronic blood-borne virus infection and factor VIII concentrates in the original outbreak are discussed.     

Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. The Kogenate Study Group

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2- microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.     

PCR analysis of HIV-1 sequences and differential immunological features in seronegative and seropositive haemophiliacs

We have compared the immunological features of two matched groups of seronegative and seropositive haemophilia A individuals. Both groups were exposed from 1981 to 1985 to comparable amounts and batches of FVIII concentrates not subjected to virus inactivation procedures, and had therefore a 100% probability of receiving HIV-contaminated material. The presence of proviral HIV-1 sequences was evaluated by PCR in the DNA from peripheral blood lymphocytes and/or monocytes. After hybridization with specific probes, DNA from all seropositive haemophiliacs revealed HIV sequences; no HIV sequences were observed from the DNA of seronegative patients, even after two rounds of amplification, thus suggesting that these patients were not affected by a latent HIV infection. Seronegative/PCR- and seropositive/PCR+ patients showed a normal and reduced number of CD4+ lymphocytes, and a slight and marked increase of CD8+ cells respectively. Activated T cells expressing the HLA-DR antigen were elevated in both groups. Interestingly, a significant reduction of circulating CD56+/CD3- NK lymphocytes was observed only in seropositive haemophiliacs, whereas NK lymphocytes with CD56+/CD3+ phenotype were within normal levels in both groups. In seropositive patients no correlation was found between the number of CD4+ and CD56+/CD3- lymphocytes. The marked reduction of CD56+/CD3- lymphocytes observed in seropositive haemophiliacs in addition to the CD4+ cell depletion may represent a key pathogenetic factor which facilitates the onset and/or the progression of HIV-1 infection in haemophiliacs, and is related to the capacity of HIV to infect NK cells.     

1986 update of HIV seroprevalence, seroconversion, AIDS incidence, and immunologic correlates of HIV infection in patients with hemophilia A and B

A cohort of 181 patients with hemophilia A (149) and hemophilia B (32) cared for at the Hemophilia Center of Western Pennsylvania was followed to determine human immunodeficiency virus (HIV) seroprevalence, seroconversion rate, and clinical and immunologic correlates of HIV infection. By December 1986, 82 (45%) were HIV seropositive, and of these, ten (12%) had developed AIDS, 28 (34%) had symptomatic HIV infection (CDC class III, IV), of whom 14 (17%) had AIDS-related complex (ARC), and 44 (54%) had asymptomatic HIV infection (CDC class II). The HIV seropositive group included 82% of those treated with factor VIII concentrate (97% severe, 5% moderate), 48% of those treated with factor IX concentrate (92% severe, 8% moderate), 10% of those treated with cryoprecipitate (67% severe, 33% moderate), and none of those treated with fresh frozen plasma. Based on 77 serially sampled HIV seropositive hemophiliacs (1977 to 1986), peak seroconversion occurred in 1982, with 14% (11 of 77) occurring since 1984. With increasing time from seroconversion, both T4 lymphocyte number and function (the latter measured by growth in soft agar [T colony assay]) progressively declined; T4 number declined to 135 +/- 26/mm3 (SEM), and colony count declined 1193 +/- 537 (control 3851 +/- 387) by 5 years after seroconversion. In those developing AIDS, total T4 fell below 100/mm3 (33 +/- 8/mm3) at diagnosis. In this cohort, the overall AIDS incidence is 5.5% (12% among the HIV seropositive) and in those seropositive 5 or more years, the AIDS incidence approaches 32%.     

HIV Transmission by Seronegative Blood Components: Report of 2 Probable Cases

HIV seroconversion was reported in 2 haemophiliacs after having corrective orthopaedic surgery. They received solvent-detergent/heat-treated factor VIII concentrate, HIV-seronegative cryoprecipitate and fresh frozen plasma during the course of surgery. HIV seroconversion was found on days 31 and 71 after surgery. It is highly probable that the infections were acquired by transfusions of seronegative blood components. In countries with a relatively low prevalence of HIV infection, transmission of HIV by transfusion of derivatives of seronegative blood is occasionally reported as a rare complication of blood transfusion [1–3]. In Thailand the prevalence of HIV infection and the incidence of new infections in the general population and in blood donors has recently increased dramatically (fig. 1) [4–5]. As a result of these components prepared from HIV-seronegative blood donations pose a significant hazard to recipients because of the risk of viraemia during the ‘window period’ of HIV infection. Here we report HIV infection in 2 haemophilia patients treated with HIV-seronegative (using Fujirebio agglutination or second-generation Abbott ELISA) cryoprecipitate and fresh frozen plasma in 1991, prepared locally from single-unit donations. All donors were voluntary. Anti-HIV was tested in every unit of donor blood before processing to blood components. Although not proven, it is highly probable that the infections were acquired by transfusions of seronegative blood components.     

High prevalence and high titers of LAV/HTLV-III antibodies in healthy hemophiliacs in the midwestern United States

Twenty-eight patients from the Nebraska Regional Hemophilia Center were studied for the prevalence and titers of antibodies to lymphadenopathy-associated virus/human T cell lymphotropic virus type III (LAV/HTLV-III) and for clinical symptoms of possible progression to the acquired immune deficiency syndrome (AIDS). Ten of 18 (56 percent) patients with hemophilia A who were frequently treated with commercial factor VIII concentrate were seropositive for LAV/HTLV-III antibodies as determined by immunofluorescent study and Western blot testing. Of the four factor VIII-deficient patients who were seronegative, one had received only heat-treated factor VIII concentrates, two had received only cryoprecipitate, and one had received no transfusions since 1983. None of the patients treated only with factor IX concentrate, volunteer donor plasma, or cryoprecipitate had LAV/HTLV-III antibodies. In nine of 10 seropositive hemophiliacs, titers of serum antibodies to LAV/HTLV-III ranged from 1:1,280 to 1:10,240, indicating a strong immune response against LAV/HTLV-III antigens and/or persistent infection with the virus. Serum from seropositive hemophiliacs interacted on Western blot testing with all the major LAV/HTLV-III polypeptides, including envelope proteins gp 42 and gp 120. Despite the possible exposure to LAV/HTLV-III during the past four years, none of the patients in this group had symptoms suggestive of progression towards AIDS. Whether or not immunity to the AIDS retrovirus developed in this group of patients remains to be determined.     

Antibodies reactive with human T cell leukemia viruses in the serum of hemophiliacs receiving factor VIII concentrate

The third member of the family of T cell leukemia viruses (HTLV III) has been proposed as the primary etiologic agent of the acquired immunodeficiency syndrome (AIDS). A high risk of AIDS has been reported among patients with hemophilia, particularly those with factor VIII deficiency who receive commercial clotting factor concentrates. In a prevalence survey conducted between September 1982 and April 1984, initial serum samples from 74% of hemophiliacs who had ever been treated with commercial factor VIII concentrate, 90% of those frequently treated with factor VIII concentrate, and 50% of those treated with both factor VIII and factor IX concentrates had antibodies reactive against antigens of HTLV III, compared with none of the hemophiliacs treated only with factor IX concentrate or volunteer donor plasma or cryoprecipitate. Two of the seropositive patients have developed AIDS-related illnesses, and a third patient died of bacterial pneumonia. One initially seronegative patient developed antibodies against HTLV III during the study and is currently well. The predominant antibody specificities appear directed against p24 and p41, the presumed core and envelope antigens of HTLV III, suggesting that factor VIII concentrate may transmit the p24 and p41 antigens of HTLV III. However, the presence of infectious retroviruses in clotting factor concentrates and the effectiveness of screening and viral neutralization procedures remain to be determined.     

Immunological effects of intermediate purity clotting factor concentrates: failure to affect lymphocyte activation in vivo

Concern has been expressed that intermediate purity clotting factor concentrates may cause immunological abnormalities in haemophilic patients, distinct from those related to HIV infection. Early reports of lymphocyte dysfunction in anti-HIV seronegative haemophiliacs pointed to activation of their lymphocytes; a potential cause of CD4 + ve lymphocyte decline in anti-HIV seropositive patients. Recent reports have suggested that the use of high purity FVIII concentrates might retard the rate of decline in CD4 + ve lymphocytes in haemophiliacs infected with the HIV virus.
Expression of markers of acute and chronic activation of T and B lymphocytes was measured in heavily treated anti-HIV seronegative haemophiliacs using two-colour flow cytometry. No T or B lymphocyte stimulation was observed. Cellular markers of activation were absent and CD4 + ve lymphocyte counts and serum IgG levels were normal. Anti-HIV seropositive haemophiliacs showed T and B cell activation consistent with HIV infection. The extent of lymphocyte activation in individual patients was unrelated to the type, amount or frequency of FVIII received.
These findings do not support the hypothesis that lymphocytes of haemophiliacs are affected directly by the regular administration of intermediate purity concentrates so as to accelerate the progression of HIV disease.     

HIV-serology and lymphocyte subsets in relation to therapy and clinical development in haemophiliacs

389 Swedish patients with haemophilia A, B or von Willebrand's disease were examined for HIV-1 antibodies. T-cell subsets were measured in 260 of them. HIV-1 antibodies were found in 98 of these patients. Of the 199 patients with severe or moderate haemophilia A, 44% were seropositive. They had seroconverted between 1979 and 1983. HIV-1-seropositive patients had significantly decreased numbers of CD4 cells and increased numbers of CD8 cells. The seronegative haemophilia A patients had significantly increased numbers of CD8 cells. The T-cell subsets were followed for a median of 40 months in 73 seropositive patients. All groups of patients, at different clinical stages, showed decreasing numbers of CD4 cells. The most pronounced decrease was seen in the patients who developed AIDS, followed by the group which developed HIV-related signs or symptoms. HIV antigen in serum and antibody pattern in Western blot and ELISA were followed in 89 patients. HIV-1 antigen was present and p24 antibodies were lacking in 11% and 13% of asymptomatic subjects, in 13% and 20% of patients with persistent generalized lymphadenopathy, in 33% and 38% of patients with other HIV-related signs or symptoms and in 5/6 of the AIDS patients, respectively. In conclusion, the decrease of CD4 cells and the presence of HIV antigen and/or absence of p24 antibodies were found to be prognostic markers for HIV disease.     

Antibodies against hepatitis C in a population of Swedish haemophiliacs and heterosexual partners

The prevalence of antibodies against hepatitis C virus in 160 Swedish patients with haemophilia or related coagulation disorders and 13 heterosexual partners was assessed by means of an ELISA method. A high prevalence of HCV antibodies was found in haemophiliacs with chronic hepatitis (87%), with HIV-antibodies (87%), with severe form of the coagulopathy (81%), and among those who at any point had received factor concentrates without viral inactivation (79%) or of foreign origin (84%). On the other hand, none of the partners were seropositive, indicating a low risk of sexual transmission.     

The use of intermediate-purity clotting factor concentrates and HIV disease progression in men with haemophilia

Summary. On the basis of evidence from the immune systems of patients with haemophilia infected with HIV, patients in the UK have been switched to high-purity clotting factor concentrates. However, there is very little information currently available on the effect of intermediate-purity clotting factor concentrates on progression of HIV disease. Among 99 HIV-positive men with severe factor VIII deficiency registered at The Royal Free Hospital Haemophilia Centre, a 100 IU kg^-1 increase in the yearly amount of concentrate received did not appear to be associated with more rapid progression to AIDS, death or to a low CD4 count. However, the use of total concentrate usage may mask a more subtle effect of specific concentrate contaminants on the progression of HIV disease.     

Prevalence of human immunodeficiency virus type 1 DNA in hemophilic men and their sex partners. Hemophilia-AIDS Collaborative Study Group

Polymerase chain reaction (PCR) was used to detect human immunodeficiency virus (HIV)-1 DNA in peripheral blood mononuclear cells to assess in hemophilic men whether any were HIV-seropositive but uninfected or seronegative but infected and in seronegative sex partners of seropositive hemophilic men whether any were infected. Of 40 seropositive men, 38 (95%) were PCR-positive; one was PCR-indeterminate and one PCR-negative. None of 41 seronegative men who used only donor-screened, virus-inactivated coagulation factor products were PCR-positive. However, two of six who received noninactivated products were PCR-positive; one had low T-helper cell counts and died of unrelated causes and the other had seroconverted 11 mo later. PCR with a second primer pair also detected HIV-1 DNA in these two men. None of 25 seronegative female sex partners of seropositive men, including six men with AIDS and seven with AIDS-related symptoms, were PCR-positive. These data suggest that most seropositive hemophilic men are HIV-infected; whether some are infected with defective virus remains to be resolved as does the infection status of seropositive PCR-negative men. Identification of two seronegative PCR-positive men supports the possibility that HIV-1 DNA can be detected before seroconversion.     

Immunological studies in HIV seronegative haemophiliacs: relationships to blood product therapy

Immunological studies were performed on a group of 44 haemophilia A and 15 haemophilia B patients who were treated exclusively with blood products manufactured by the Scottish National Blood Transfusion Service (SNBTS). All patients were HIV seronegative throughout the study. Of the haemophilia A patients 14 (32%) had CD4+ lymphocyte subset counts less than or equal to 0.5 x 10(9)/l, compared with one (6%) haemophilia B patient and four (8%) controls. The percentage of activated T cells was greater than 5% in 19/33 (57%) with haemophilia A, 5/9 (55%) haemophilia B and 14/50 (28%) of control subjects. beta 2 microglobulin values greater than or equal to 2.0 mg/l were observed in 19 (43%) haemophilia A and four (26%) haemophilia B patients, compared with one (2%) control. No significant increases in serum interleukin-2 receptor concentrations were observed in 15 haemophilia A and one haemophilia B patients. Significantly elevated levels of IgG, IgM and IgA were observed in the haemophilia A group, but elevation of immunoglobulins was restricted to the IgG class in the haemophilia B group. Of the haemophilia A patients 16/30 (53%) and 6/11 (54%) haemophilia B patients had depression of cell-mediated immunity (CMI) as assessed by delayed-type hypersensitivity responses to intradermally injected recall antigens. There was no correlation between factor VIII or factor IX usage and changes in lymphocyte subsets, beta 2 microglobulin, and immunoglobulin levels. There was, however, a strong correlation between annual factor VIII usage and the degree of depression of CMI for those with haemophilia A but not for those with haemophilia B. No correlation between alterations in the immune parameters and disturbance of liver function tests was observed in either haemophilia A or haemophilia B patients. We conclude that alloantigen or non-HIV viral exposure due to repeated administration of factor concentrates brings about alterations in the immune response, and that these changes are more marked following exposure to intermediate purity factor VIII compared with factor IX concentrate.     

Association of changes in monocyte antigen presentation and cytokine production in haemophilic boys with treatment and blood-borne virus infection

Summary Aspects of monocyte function (antigen presentation and cytokine production (e.g. IL-1, IL-6) have been studied in a normal control population and three groups of haemophilic boys: group 1 HIV and HCV seronegative and treated only with a single heat-treated factor VIII (FVIII) concentrate; group 2 HIV seronegative but HCV seropositive; group 3 all HIV and HCV seropositive. Groups 2 and 3 have been previously treated with unheated and heated FVIII concentrate. Group 1 boys (HIV/HCV uninfected) showed no significant reduction in monocyte antigen presentation function nor IL-1 or IL-6 production when compared with a control population. Group 2 boys (HCV infected) showed a reduced monocyte antigen presentation activity (P< 0.05), but no significant reduction in IL-1 or IL-6 production. Group 3 boys (HIV and HCV infected) showed a significantly reduced monocyte antigen presentation activity (P < 0.001) and an impairment of IL-1 and IL-6 production (P lt 0.05). A significant reduction of IL-1 and IL-6 production was only seen in the HIV and HCV infected haemophilic boys, implicating HIV as an aetiological agent. In contrast, reduced monocyte antigen presentation activity was seen in haemophilic boys with both HIV and HCV infection or HCV alone. The HIV and HCV seronegative boys had normal antigen presentation. The absence of immune modulation in haemophilic boys that have not acquired HIV and HCV infection suggests that chronic blood-borne virus infections as contributory to immune modulation seen in haemophiliacs with virus infections.