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.     

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.     

Long-term immunogenicity of a plasma-derived hepatitis B vaccine in HIV seropositive and HIV seronegative hemophiliacs

Short-term studies indicate that hepatitis B vaccines are safe and satisfactorily immunogenic in hemophiliacs. The duration of immunity in these immunocompromised patients, however, is not known. To determine this, we studied 78 hemophiliacs prospectively 2, 3, and 4 years after the initial vaccination with a plasma-derived vaccine given as three monthly injections followed by a fourth booster injection at month 14. The duration of immunity clearly depended on whether the patients were infected with the human immunodeficiency virus (HIV). In HIV seronegative hemophiliacs (n = 67), there was a progressive decline in titers of antibody to the hepatitis B surface antigen (anti-HBs), but antibody was still detectable 4 years later in all of them. From the curves of decline of antibody titers, it appears that there is no need to revaccinate patients for at least 5 to 6 years. The HIV seropositive hemophiliacs (n = 11) not only started from much lower anti-HBs titers, but 5 of 11 lost anti-HBs. None of the 45 patients treated with concentrates during the postvaccination period developed serologic signs of hepatitis B, even though 6 of them had come into contact with live or inactivated hepatitis B virus as shown by the occurrence of spontaneous anamnestic antibody responses. This vaccine and schedule of vaccination afford a prolonged duration of immunity in HIV seronegative hemophiliacs, but HIV seropositive hemophiliacs have a risk of losing immunity early.     

Laboratory and clinical markers of HIV infection in a national haemophilia cohort treated with recombinant factor VIII concentrate

Over an interval of approximately six months beginning in October 1993, most haemophilia A patients in Canada were switched from a plasma-derived intermediate-purity factor VIII concentrate (ipVIII) to a recombinant factor VIII (rVIII). In order to determine the consequence of this change in therapy on progression of HIV infection, we gathered surveillance data on clinical status and CD4 and CD8 cell counts in those patients who were HIV seropositive at the time of switching concentrates. Data were recorded at the time of switchover, annually for 2 years thereafter, and retrospectively at a point 1 year prior to the switch. CD4 cells fell significantly over the study period. Multiple direct comparisons revealed that this decline was restricted to the time intervals which included the final year in which patients received intermediate-purity factor VIII concentrate (ipVIII). In the 2 year interval in which rVIII was used exclusively, there was a nonsignificant fall in CD4 cells. Changes in CD4 cells did not correlate with the intensity of exposure to either ipVIII or rVIII. CD8 cells did not fall significantly over the study period. There was no obvious reduction in the incidence of death or clinical progression over the 2 years in which rVIII was used. However, we are hopeful that the stabilizing trend in CD4 cell counts which followed the introduction of rVIII will be predictive of corresponding clinical stabilization over the coming years.     

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 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.     

Frequency of a mutated CCR-5 allele (delta32) among Italian healthy donors and individuals at risk of parenteral HIV infection

The aim of this study was to assess the frequency of a truncated allele of the CCR-5 gene (delta32) in Italy, and address its possible role in parenteral HIV transmission, as well as its influence in HIV-associated disease progression. In 371 unrelated seronegative healthy blood donors the delta32 allele frequency was 0.047; this figure was significantly different from those reported in northern America and northern Europe populations. However, delta32 allele frequency in healthy individuals did not differ significantly from that found in 54 seronegative drug users (0.065), 98 seronegative hemophiliacs (0.051), and 81 seropositive hemophiliacs (0.049). Although in seropositive hemophiliacs the wt/delta32 heterozygous genotype was associated with a trend to a slower decline in CD4+ cell counts, its presence did not seem to influence disease progression, as comparable delta32 allele frequency frequencies were found among progressing (0.042) and nonprogressing (0.111) patients. These data do not seem to support a protective role of the delta32 allele in preventing HIV infection through the parenteral route, or in influencing the natural history of the disease in this particular risk category, although the delta32 heterozygous state was associated with lower plasma viremia levels. On the other hand, the finding of non-syncytium-inducing HIV strains in the majority of delta32 heterozygous seropositive patients suggests that its presence could not be a major factor in driving a switch toward more cytopathic, T-tropic HIV strains through selective pressure in coreceptor usage.     

Factor VIII concentrates in HIV-1-positive hemophiliacs--is pure better?

39 human immunodeficiency-virus-1 (HIV-1)-positive hemophiliacs who had been regularly treated with non-virus-inactivated intermediate-purity factor VIII concentrates were divided into two groups. Group A consisted of 21 patients with a CD4/CD8 cell ratio of less than 1.0 and group B of 18 patients with a CD4/CD8 cell ratio of greater than 1.0. All patients of group A were switched to a high-purity virus-inactivated factor VIII concentrate, whereas patients of group B continued to receive the intermediate-purity concentrate. There was no significant difference in the average decline of CD4 cells between the two groups during the observation period. 9 patients of group A and 4 patients of group B developed AIDS. 5 patients of group A but 11 patients of group B remained clinically asymptomatic. We conclude that the 15-fold increase in purity of the factor VIII concentrate had no apparent beneficial effect on the CD4 cell counts in this patient group.     

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.     

Abstracts of papers on haemophilia from other journals

Incidence of factor VIII inhibitor development in hemophilia A patients treated with less pure plasma derived concentrates. de Biasi R, Rocino A, Papa, ML, Salerno E, Mastrullo L, De Blasi D.
Rapid clearance of hepatitis C virus RNA in peripheral blood mononuclear cells of patients with clotting disorders and chronic hepatitis C treated with alpha-2b interferon is not a predictor for sustained response to treatment. Peerlinck K, Willerns M, Sheng L, Nevens F, Fevery J, Yap SH, Verrnylen J.
Factor VIII gene rearrangements in patients with severe haemophilia A. Goodeve AC, Preston FE, Peake IR.
Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. Mannucci PM, Brettler DB, Aledort LM, Lusher JM, Abildgaard CF, Schwartz RS, Hurst D and the Kogenate Study Group.
The role of platelet von Willebrand factor in platelet adhesion and thrombus formation: a study of 34 patients with various subtypes of type I von Willebrand disease. Fressinaud E, Federici AB, Castaman G, Rothschild C, Rodeghiero F, Baumgartner HR, Mannucci PM, Meyer D.
Two controlled trials of rifabutin prophylaxis against Mycobacteriurn aviurn complex infection in AIDS. Nightingale SD, Cameron DW, Gordin FM, Sullam PM, Cohn DL, Chaisson RE, Eron LJ, Sparti PD, Bihari B, Kaufman DL, Stern JJ, Pearce DD, Weinberg WG, LaMarca A, Siegal FP.
Three-year randomised study of high-purity or intermediate-purity factor VIII concentrates in symptom-free HIV-seropositive haemophiliacs: effects on immune status. Seremetis SV, Aledort LM, Bergman GE, Bona R, Bray G, Brettler D, Eyster ME, Kessler C, Lau T-S, Lusher J, Rickles F.     

Factor VIII:C concentrate purified from plasma using monoclonal antibodies: human studies

Conventional clotting factor concentrates have, until recently, been "of intermediate purity," containing less than 1% of the coagulation factor, and greater than 99% extraneous plasma proteins such as fibrinogen, fibronectin, gamma globulins, and traces of many others. We report here the results of a new factor VIII concentrate that is purified from human plasma using a mouse monoclonal antibody to factor VIII:vWF in an affinity chromatography system. The resultant concentrate has an activity of between 3,000 and 5,000 U/mg protein before albumin is added as a stabilizer. Seven patients with severe hemophilia A and no inhibitor who were positive for antibody to human immunodeficiency virus (HIV) have been treated solely with this concentrate for over 24 months. Factor usage in these patients has ranged from 611 U/kg/yr to 2,022 U/kg/yr. These patients have infused approximately once per week on the average, most often for joint hemorrhages. The efficacy of the concentrate is excellent. No allergic reactions have occurred and no factor VIII antibodies have developed. In these seven patients mean CD4 counts stabilized (856 +/- 619 at screen v 778 +/- 686 at 24 months) and there was reversal of skin test anergy. In a comparison group on conventional intermediate purity concentrate chosen retrospectively decreases in mean CD4 cell counts similarly did not occur. However, the number of the comparison patients who were anergic increased over the course of the study. These observations indicate the possibility that more highly purified concentrates may stabilize immune function in HIV seropositive patients.     

Abnormalities of lymphocyte subsets are correlated with concentrate consumption in asymptomatic Italian hemophiliacs treated with concentrates made from American plasma

Eighty-three symptom-free hemophiliacs were studied clinically, serologically and by in vitro tests for cellular immunity in a geographical area in which AIDS has not yet been encountered despite the exclusive use of concentrates manufactured from American sources of plasma. Some patients showed the following abnormalities: lymphopenia (4%), decreased T-helper/T-suppressor (Th/Ts) cell ratios (49%), or both abnormalities (2%). Low Th/Ts were mostly due to absolute or, less frequently, relative increases in Ts cells. The prevalence rates for these abnormalities were the same in patients treated with factor VIII or factor IX concentrates. There was an association between the higher Ts and lower Th cells counts and the low Th/Ts ratios and greater annual consumption of factor VIII and factor IX concentrates. These results support the view that protein load might be an important pathogenetic factor in lymphocyte abnormalities in symptom-free hemophiliacs.     

TT virus is present in a high frequency of Italian hemophilic patients transfused with plasma-derived clotting factor concentrates

The prevalence of the blood-borne TT virus (TTV) in Italian hemophiliacs treated with different preparations of factor VIII was determined. Of the 178 hemophilic patients (mean age, 29 years), TTV-DNA was found in 123 (69%), in comparison to 22 of 100 (22%) blood donors (P <.0001). Of the 123 patients who tested positive for TTV, significant numbers were also infected with human hepatitis viruses and/or human immunodeficiency virus (HIV): 31% had TTV and hepatitis C virus (HCV), 22% had TTV, and at least 2 of the 4 known human blood-borne viruses tested, whereas 15% had TTV alone. The risk of acquiring TTV alone was only slightly higher in recipients of unmodified plasma factor concentrates (78%, odds ratio, 1.24; 95% confidence interval [CI], 0.27 to 5.79) than in patients treated with virus inactivated concentrates (67%), whereas the risk was significantly lower in recipients of recombinant factors (11%, odds ratio, 0.09; 95% CI, 0.01 to 0.52). Serum alanine aminotransferase (ALT) levels were elevated in 2 of 27 patients (7%) with TTV alone compared with 43 of 56 patients (77%) coinfected with TTV and HCV and compared with 16 of 21 patients (76%) with HCV alone. Taken together, these results indicate that TTV frequently infects Italian hemophiliacs treated with plasma-derived factor VIII concentrates, both unmodified and virus-inactivated. Our results do not suggest a causal effect of TTV on chronic liver disease in these patients.     

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.     

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.     

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.     

Oral Lesions among Women Living with or at Risk for HIV Infection

Purpose: Our objectives were to compare the prevalence of oropharyngeal mucosal lesions among human immunodeficiency virus (HIV) seropositive and demographically similar seronegative women, and to determine the association of oral lesions with immunosuppression, substance abuse, use of medications, and utilization of dental services.Population and Methods: Participants in a multicenter, longitudinal cohort study of HIV infection in women were evaluated at baseline by interview, physical examination, and laboratory studies.Results: Oropharyngeal pathology was found in 40% of seropositive and 23% of seronegative women. Oral candidiasis was identified in 15% of seropositive and 3% of seronegative women. Among seropositive women, history of previous oral candidiasis, lower CD4 lymphocyte counts, and current antibiotic use were associated with oral candidiasis. Hairy leukoplakia was identified in 5% of seropositive women and was significantly associated with lower CD4 lymphocyte counts. Gingival erythema and ulcerative gingivitis were found in 23% of participants overall, but were unrelated to HIV serostatus or CD4 lymphocyte count. Substance abuse, lack of dental care, and African-American race were associated with gingival pathology.Conclusion: The high prevalence of oral lesions among HIV seropositive and at-risk seronegative women underscores the need for routine oral examination and targeted treatment of this population.     

The impact of a very high-purity factor VIII concentrate on the immune system of HIV-infected haemophiliacs: a randomized, two-year comparison with a high-purity concentrate

Summary. Randomized and cohort studies have provided evidence confirming the hypothesis, based on in-vitro observations, that the use of very high-purity factor VIII (FVIII) concentrates, either immuoaffinity chromatography purified or produced by recombinant DNA technology, may slow immunological deterioration in human immunodeficiency virus (HIV)-infected haemophiliacs, while high-purity concentrates, produced by ion-exchange chromatography, did not produce a benefit. Even though these data clearly indicate that very high-purity concentrates should be preferred for the replacement therapy of HIV-positive haemophiliacs, there are little data, based on direct comparison, supporting the use of very high-purity concentrates rather than high-purity preparations, which are less expensive. In an attempt to address this issue, we prospectively compared CD4 cell counts and changes of clinical status in 18 HIV-positive haemophiliacs, randomly assigned either to receive the treatment with a very high-purity FVIII concentrate, purified by immunoaffinity chromatography, or a high-purity product, produced by ion-exchange chromatography. All patients had CD4 lymphocyte counts below 300 μL^-1, were negative for the hepatitis B surface antigen and the HIV p24 antigen, and were receiving antiretroviral treatment with Zidovudine for at least 6 months. There were no significant changes of CD4 cell counts over the 96-week follow-up period or between the two groups. No signficant differences between the two groups were detected in the occurrence of AIDS-defining diagnoses (one in each group). On the whole, no striking benefit is conferred to the immune status of asymptomatic HIV-positive haemophiliacs by using either of these high-purity and very high-purity FVIII concentrates for 96 weeks. Larger prospective randomized trials are needed to establish definitely whether it is necessary to resort to very high-purity concentrates or it is sufficient to use high-purity concentrates to slow the fall of CD4 cell counts that occurs in HIV-positive haemophiliacs. Randomized trials, based on clinical end-points, are also needed to demonstrate whether slowing the fall in CD4 cells results in clinical benefits, delaying the occurrence of AIDS.     

Hepatitis C infection in children with hemophilia A and B.

Antibodies to hepatitis C virus (anti-HCV) were quantitated in stored sera from selected groups of hemophilic children (less than or equal to 18 years of age). During the period 1987 to 1989, seropositivity rates were as follows: untransfused hemophiliacs 0% (0 of 11 cases), hemophiliacs treated exclusively with vapor-heated factor VIII or IX concentrates 0% (0 of 9 cases), hemophiliacs treated only with cryoprecipitate or single donor blood products 0% (0 of 9 cases), and hemophiliacs regularly treated with unheated or dry heat-treated factor VIII or IX concentrates 95% (21 of 22 cases). Corresponding alanine aminotransferase (ALT) results were similar: values were always below the upper limit of laboratory normal (40 U/L) in untransfused hemophiliacs, hemophiliacs treated with vapor-heated factor concentrates, or those who received only cryoprecipitate or single donor blood products. By contrast ALT values were greater than 40 U/L in 82% (18 of 22 cases) of hemophilic children regularly infused with unheated or dry heat-treated factor concentrates. Three conclusions are drawn from this data: (1) HCV is a major cause of chronic hepatitis in multitransfused hemophilic children, (2) unheated and dry heat-treated clotting factor concentrates carry a very high risk of transmitting HCV infection, and (3) clotting factor concentrates inactivated by vapor heating carry a very low and perhaps zero risk of transmitting HCV infection. These findings are of therapeutic significance for previously untransfused hemophiliacs susceptible to HCV infection.     

The impact of a very high purity factor VIII concentrate on the immune system of human immunodeficiency virus-infected hemophiliacs: a randomized, prospective, two-year comparison with an intermediate purity concentrate [see comments]

Pathophysiologic considerations as well as non-comparative clinical results suggest that very high purity concentrates may slow immunologic deterioration in human immunodeficiency virus (HIV)-infected hemophiliacs. In an attempt to evaluate this hypothesis, we prospectively compared CD4 cell counts, skin testing responses, and changes of the clinical status in 20 asymptomatic HIV-positive hemophiliacs, randomly assigned to continue the treatment with an intermediate purity concentrate or to receive a very high purity product, purified by immunoaffinity chromatography with monoclonal antibodies. In the group switched to the very high purity concentrate there was no significant change of the CD4 cell counts over the 96-week follow-up period, whereas in the group continued on the intermediate purity concentrate, a highly significant decline was detected (P less than .013). Furthermore, in the very high purity group, four of six anergic patients at entry acquired reactivity to skin testing. The results of this study clearly support the use of very high purity concentrates for the replacement therapy of HIV-infected hemophiliacs.