Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors.

Some 10-20% of bleeding events in haemophilia patients with high-responding inhibitors cannot be controlled with bypassing agents. However, sequential combined bypassing therapy (SCBT) has been reported to be successful in five children. To extend this observation, a survey was undertaken by the European Haemophilia Treatment Standardisation Board (EHTSB) in children and adults. Data were collected from all centres belonging to the EHTSB network by a retrospective medical record review. SCBT courses were defined as the administration of both recombinant activated factor VIIa (rFVIIa) and activated prothrombin complex concentrate (APCC) within 12 h. A web-based database was prepared to collect data on SCBT courses in a standardized and anonymous manner from patients' files. Eleven inhibitor patients underwent SCBT (nine haemophilia A; two haemophilia B). Two children had refractory knee haemarthrosis and one, an unresponsive calf haematoma. Five adults had significant bleeds following major surgery, one had lower limb compartmental syndrome and one a post-traumatic upper limb haematoma and haemarthrosis. SCBT administration alternated one APCC dose to 1-3 rFVIIa doses: dosing intervals ranged between 3 and 6 h; APCC (20-80 U kg(-1) ) was given every 8-12 h; rFVIIa (90-270 µg kg(-1) ) was given every 3-12 h. Bleeding control was achieved in 12-24 h in all patients. SCBT was discontinued after 1-15 days. No clinical adverse events were observed, but a significant increase in D-dimer levels was seen in three/five patients who were assessed. SCBT was efficacious without adverse events; nevertheless, due to potential risks, it remains a salvage treatment. A prospective clinical trial is needed to provide further evidence.

Non-genetic risk factors and the development of inhibitors in haemophilia: a comprehensive review and consensus report.

SUMMARY: The development of inhibitors to the infused factor in patients with haemophilia is a serious clinical problem. Recent evidence suggests that alongside the strong genetic contribution to inhibitor formation, there are a number of non-genetic factors--perceived by the immune system as danger signals--which promote formation of inhibitors. This study provides a comprehensive review of clinical studies relating to these factors and also presents a survey of opinion concerning their importance and clinical influence, conducted among the members of the European Haemophilia Treatment Standardisation Board (EHTSB). Taken together, this information highlights the lack of robust data concerning the influence of several non-genetic risk factors on inhibitor development, and an urgent need for prospective, well-conducted studies that adhere to recommendations made by the European Medicines Agency (EMEA) for studying inhibitors. Based on current literature, the EHTSB formulated consensus recommendations. It is desirable to minimize intensive treatment wherever possible, given the clinical situation. Prophylaxis should be offered to all children, although we still need to determine optimal dosing with respect to inhibitor development, and age for starting treatment. Vaccinations should be given subcutaneously and concomitant factor concentrate infusions avoided. According to the board, there is no evidence in the literature supporting suggestions that the type of concentrate influences inhibitor risk; but all patients should be monitored during their first exposures. Furthermore, there is no evidence to support an association between pregnancy-related issues, breast feeding and treatment-related factors (e.g. route of administration, or use of blood components) and inhibitor development.

Searching for West Nile virus (WNV) in Greece.

West Nile virus (WNV), a mosquito-borne flavivirus, has increasingly become a concern in both America and Europe due to its complex and unpredictable lifecycle. Transfusion-associated transmission of the WNV has been well documented during the last few years. This study aimed to detect the presence of WNV in: (i) cerebrospinal fluid (CSF) specimens derived from aseptic meningitis cases in Greece and (ii) Greek blood donations. A total of 115 CSF specimens from patients suffering from aseptic meningitis and 9590 blood samples were collected from seven Greek hospitals during the periods June to October 2006 and 2007 and tested for investigational purposes. Both blood and CSF samples were tested for the presence of WNV RNA by using the PROCLEIX WNV assay. None of 115 CSF and 9590 blood donor samples was found positive according to our testing algorithms. Despite the presence of WNV in Balkan countries, WNV has not reached significant levels in Greece.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80-90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10-14 days; for liver biopsy, 70-100%, 1-7 days; tonsillectomy: 90-100%, 5-11 days; indwelling venous access device insertion: 100%, 3-10 days; circumcision: 50-60%, 2-4 days; dental surgery: 30-50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better-designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.

Pegylated interferon plus ribavirin combination therapy for chronic hepatitis C in patients with congenital coagulation disorders.

Chronic hepatitis C (CHC) and end-stage liver disease are becoming an increasingly common cause of mortality in patients with congenital bleeding disorders, especially in the HIV-coinfected group. Combination of pegylated interferon (Peg-IFN) and ribavirin has recently become the treatment of choice for CHC. In this study, we evaluated the safety and efficacy of combination therapy with Peg-IFN plus ribavirin for the treatment of CHC in human immunodeficiency virus (HIV)- and HIV+ patients with congenital bleeding disorders. Between 2000 and 2004, 50 (18-68 years old) patients with CHC (19 HIV+) from two hemophilia centers were included in the study. They were treated with weekly subcutaneous administration of Peg-INF-alpha combined with 800-1,200 mg ribavirin daily, for 24-48 weeks depending on viral genotype. Response was evaluated at weeks 12, 24, 48 (end of treatment response) and 72 had sustained virological response). Overall, 22/50 patients (43.8%) had end of treatment response and 20/50 (40%) sustained virological response. HIV- patients responded similarly to the general population (58.1%), while HIV+ patients had very low response rates (10.5%). The high rate of discontinuation (36.9%) as a result of side effects contributed to the observed low response rate in the HIV+ group. The only factor strongly associated with sustained virological response in the HIV- patients was the reduction of HCV RNA at 12 weeks (p = 0.001). Patients with viral genotypes other than 1 had higher SVR rates, but this was not found to be statistically significant. Peg-INF plus ribavirin is safe for the treatment of CHC monoinfected patients with inherited bleeding disorders, with similar response rates to nonhemophiliacs. On the contrary, in HIV coinfected hemophilic patients under highly active antiretroviral therapy it is associated with severe toxicity and very poor sustained virological response rates. Careful evaluation and several considerations are needed before starting treatment in this population.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey.

BACKGROUND: Antibodies to glycoprotein (GP) IIb-IIIa and/or HLA may render platelet transfusions ineffective to stop bleeding or to cover surgery in patients with Glanzmann's thrombasthenia (GT). Anecdotal reports suggest recombinant factor (rF)VIIa might be a therapeutic alternative in these situations. OBJECTIVES: An international survey was conducted to evaluate further the efficacy and safety of rFVIIa in GT patients. PATIENTS: We analyzed the use of rFVIIa during 34 surgical/invasive procedures and 108 bleeding episodes in 59 GT patients including 29 with current or previous antiplatelet antibodies, and 23 with a history of refractoriness to platelet transfusion. RESULTS: rFVIIa was effective in 29 of the 31 evaluable procedures, and in 77 of the 103 evaluable bleeding episodes of which eight had a recurrence. A significantly higher success rate was observed in severe bleeding episodes when an arbitrarily defined 'optimal regimen' derived from the Canadian pilot study results (> or = 80 micro g kg(-1) rFVIIa/injection, dosing interval < or = 2.5 h, three or more doses before failure declaration) was used compared with other regimens (77%; 24/31 vs. 48%, 19/40; chi(2), P = 0.010). Patients given maintenance doses had significantly fewer recurrences within 48 h of bleed cessation compared with those not given any (Fisher's exact test, P = 0.022). One thromboembolic event and one blood clot in the ureter occurring in surgical patients following prolonged continuous infusion of high-dose rFVIIa and antifibrinolytic drug use have been previously reported. CONCLUSION: rFVIIa seems a potential alternative to platelet transfusion in GT patients, particularly in those with antiplatelet antibodies and/or platelet refractoriness.

Mutations associated with genotypic resistance to antiretroviral therapy in treatment naïve HIV-1 infected patients in Greece.

The widespread use of antiviral drugs against HIV has increased the prevalence of HIV-1 resistant strains among naïve individuals due to transmission of resistant strains. The purpose of this study was to investigate the presence of HIV-1 strains harboring resistance mutations in naïve patients in Greece. Blood samples were collected from 25 individuals. The DNA sequence of protease and partial reverse transcriptase regions (codons 41-223) were obtained by direct sequencing. Our results showed the absence of any primary resistance mutations in the study population. However, we were able to identify high prevalence of sequence polymorphisms at positions in reverse transcriptase region associated mainly with resistance to NNRTIs. Moreover, in protease region several secondary mutations were detected, suggesting the higher genetic variability of this region. The clinical significance of the polymorphisms associated with reduced susceptibility to NNRTIs remains to be clarified.

Epidemiology of haemophilia in Greece: an overview.

Demographic data of the Greek haemophilia A and B population for the period 1972-1993 were analyzed. Prevalence at birth including known not-registered patients was calculated at 23.1 per 100,000 male births. However, the observed prevalence in 1993 was only 61% of the expected. Since 1975 the proportion of mild cases had significantly increased. Adjusted by age, severity and HIV status reproductive fitness of haemophiliacs was 0.62. Overall mortality was 2.6 times higher than in the general population, but 7.9 times among patients with severe haemophilia and 16.4 among HIV(+) haemophiliacs. Fifty out of 78 deaths occurred among HIV(+) patients and 28 of these were caused by AIDS. Inhibitor patients did not show excess mortality due to bleeding. Cancer mortality was equal to normal, but the number of deaths from ischaemic heart disease was 0.25 of the expected. Risk of death due to cerebral haemorrhage was 3.8 times higher in HIV(+) haemophiliacs than in HIV(-).

Genotypic characterization of human immunodeficiency virus type 1 in Greece. Multicentre Study on HIV-1 Heterogeneity.

The HIV-1 subtype distribution in 83 HIV-1-seropositive individuals living in Greece was investigated by using the heteroduplex mobility assay (HMA), DNA sequencing, and phylogenetic analysis. The results revealed that partial HIV-1 gp120 sequences from 71 (86%) patients were subtype B, 5 (6%) were subtype A, 4 were subtype D (5%), 2 (2%) were subtype C, and 1 (1%) was subtype I. The subtype I isolate was documented in an intravenous drug user. A high prevalence (90-100%) of B isolates among intravenous drug users, hemophiliacs, and homosexual men was observed, in contrast to heterosexuals, among whom non-B subtypes seemed to be common (42.9%, p < 0.001). Among the Greek population subtype B is the most frequent (94%), in contrast to the high prevalence (57%) of non-B isolates found in emigrants living in Greece (p < 0.001). A heterosexual transmission case of subtype D in a Greek individual not traveling abroad was also documented. The broad HIV-1 diversity in Greece may be explained by population movements, such as migration and traveling.

Virological and immunological response to HAART therapy in a community-based cohort of HIV-1-positive individuals.

PURPOSE: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. METHOD: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. RESULTS: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/microL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. CONCLUSION: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.

Hemostatic function and carotid artery disease.

AIM: Since conventional risk factors predict less than one half of future cardiovascular events, other factors that contribute to atherogenesis need to be evaluated. The aim of this study was to investigate whether clotting factors are associated with carotid artery disease. Furthermore, we tried to determine whether clotting factors could be used to predict the risk of cerebrovascular events in patients with internal carotid artery stenosis. METHODS: Twenty-six patients with high-grade (>70%) internal carotid artery stenosis and 43 age-matched controls were evaluated for atherogenic risk factors and hemostatic function. Laboratory tests included plasma assays of fibrinogen, tissue plasminogen activator (TPA), D-dimer, plasminogen activator inhibitor 1 (PAI-1), plasminogen and factor VII:c. Nineteen (72%) patients had history of stroke or transient ischemic attack, while the remaining 7 (28%) were asymptomatic. Statistical analysis was performed using multiple linear regression analysis. RESULTS: Carotid artery stenosis was associated with high levels of TPA (p<0.001), D-dimer (p=0.019) and PAI-1 (p<0.001). No statistically significant correlation was found between the presence of carotid artery disease and the levels of fibrinogen (p=0.28), plasminogen (p=0.96) or factor VII:c (p=0.19). As regards the clinical manifestations, none of the studied clotting factors was correlated with the history of cerebrovascular events in the patients with carotid stenosis. CONCLUSION: The results of this study show that the hemostatic system may play a role in the development of carotid artery atherosclerotic disease, while it does not seem to affect the development of symptoms in patients with carotid stenosis.

Eosinophilia in patients undergoing regular hemodialysis.

The prevalence of eosinophilia (eosinophil counts greater than 400/mm3) in 69 patients undergoing regular hemodialysis for one to 80 months was estimated as 52,2%, in a random examination. On the other hand, a retrospective chart review of 30 patients hemodialyzed at one unit between 1973 and 1981 showed that 14 of them developed either recurrent of continuous eosinophilia, while 16 never had elevated eosinophil counts over a period of 21 to 72 months. In the whole group of 30 patients, mean eosinophil count increased progressively during the first two years of hemodialysis treatment and remained unchanged thereafter. All cases of eosinophilia were observed between the years 1977 and 1981 i.e., at least two years after a change in the type of dialyzers used at this unit.

Natural course of treated and untreated chronic HCV infection: results of the nationwide Hepnet.Greece cohort study.

BACKGROUND: Interferon (IFN-alpha)-based regimens have been used with varying success in the treatment of chronic hepatitis C (CHC) for over two decades. The effect of such treatments on the natural course of CHC has been evaluated in small clinical trials with conflicting results. AIM: To investigate the natural course of IFNalpha-based-treated and untreated patients with CHC by analysing data from the HEPNET.GREECE study. METHODS: We retrospectively analysed 1738 patients from 25 Greek Centres (median age 40.1; males 57.6%; cirrhosis 9.2%), 734 untreated and 993 treated with IFNalpha-based regimens [44.7% sustained viral response (SVR)], followed-up for median 25.2 and 46.8 months, respectively. RESULTS: During follow-up, 48 patients developed liver decompensation and 24 HCC. Older age was significantly related to disease progression (HR = 2.6 per 10 years of increasing age). Stratified by baseline cirrhosis, Cox analysis showed that patients with SVR, but not without SVR, had significantly lower hazard for events compared with nontreated patients (HR = 0.16; P < 0.001), whereas the detrimental effect of older age remained highly significant. Separate group analysis demonstrated that in cirrhosis, the beneficial effect of treatment was evident even without SVR. Treatment effect interacted significantly with age, indicating that older patients, mainly noncirrhotic, gained the most benefit. CONCLUSIONS: IFNalpha-based treatment does alter the natural course of CHC. A protective effect is mostly present in patients with SVR, but older patients, at higher risk of events, gain the greatest benefit. In established cirrhosis, treatment carries a protective effect even among those without SVR.

Analytical and clinical sensitivity of the Procleix Ultrio HIV-1/HCV/HBV assay in samples with a low viral load.

BACKGROUND AND OBJECTIVES: The Procleix Ultrio human immunodeficiency virus type 1 (HIV-1)/hepatitis C virus (HCV)/hepatitis B virus (HBV) (Ultrio) assay simultaneously detects HIV-1 RNA, HCV RNA and HBV DNA in individual blood donations. The main objective of the study was to assess the analytical and clinical sensitivity of the multiplex and discriminatory probe assays in samples with a low viral load. MATERIAL AND METHODS: The VQC HIV RNA genotype B, HCV RNA genotype 1 and HBV DNA genotype A standard dilutions were tested in 26 repeats. The probability of detection by Ultrio was compared with previously obtained data of the Procleix Duplex HIV-1/HCV assay on the same reference panels. A selection of 121 anti-HIV-1, 138 anti-HCV and 190 HBsAg positive samples from patients receiving antiviral therapy were tested. The majority of patient samples had a viral load below the detection limit of the diagnostic nucleic acid test assays, which made them suitable to evaluate the performance of the multiplex and discriminatory assays on yield cases with a similar low viral load. RESULTS: The 95% and 50% detection end-points of the Ultrio assay along with the corresponding 95% confidence intervals are 53.7 (32.9-117.2) and 8.6 (6.2-12.1) geq/ml for HIV-1 RNA, 30.3 (19.0-62.4) and 5.2 (3.7-7.2) geq/ml for HCV RNA and 393.7 (147.9-6978) and 54.5 (22.4-143.8) geq/ml for HBV DNA. The analytical sensitivity of Ultrio expressed as a potency factor relative to previously obtained Duplex results on the same HIV-1 RNA and HCV-RNA standard dilutions was 1.09 (0.20-6.10) and 1.11 (0.21-5.89), respectively. The assay detected all 22 HIV-1 infected patients with viral load > 50 copies/ml, and 41 of 99 patients (41%) with viral load < 50 copies/ml, of which 23 (56%) were detected by the discriminatory assay. All 47 patients with HCV RNA load > 521 IU/ml and 10/91 polymerase chain reaction-negative patients with viral load < 50 IU/ml tested positive in Ultrio assay of which five were missed in the discriminatory test. The assay detected 53/55 HBV infected patients (96%) with viral load > 250 copies/ml and 108/135 patients (80%) with viral load < 250 copies/ml of which 17 (16%) were missed by the discriminatory test. CONCLUSIONS: The new Procleix Ultrio assay is as sensitive as the Procleix Duplex assay for HIV-1 and HCV detection meeting the requirements of universal guidelines. The ability of the assay to detect HBV DNA in low viral load samples could be useful for screening blood. Inevitable negative results of discriminatory probe assays caused by stochastic sample variation will reduce the chance of recognizing low viraemic blood donors detected by individual donation nucleic acid test.

Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data.

A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16-24 years and adults aged over 50 years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16-20 years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50 years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18-22 years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis.

Molecular epidemiology of hepatitis C virus (HCV) in Greece: temporal trends in HCV genotype-specific incidence and molecular characterization of genotype 4 isolates.

This study aimed to estimate the overall HCV genotype distribution and to reconstruct the HCV genotype-specific incidence in Greece during the recent decades. It also focused at the identification of genotype 4 subtype variability in Greek isolates. A total of 1686 chronically infected HCV patients with detectable serum HCV RNA by RT-PCR, belonging to different risk groups were studied. Amplified products from the 5'-noncoding region were typed using a commercially available assay based on the reverse hybridization principle. The HCV genotype-specific incidence was estimated using a previously described back calculation method. HCV genotype 1 was the most prevalent (46.9%) followed by genotype 3 (28.1%), 4 (13.2%), 2 (6.9%) and 5 (0.4%). A high prevalence of genotype 1 (66.3%) in haemophilia patients was recorded whereas HCV genotype 3 was found mainly among patients infected by I.V. drug use (58.2%). Data on the temporal patterns of HCV genotype-specific incidence in Greece revealed a moderate increase (1.3-1.6 times) for genotypes 1 and 4, and a decrease (1.5 times) for genotype 2 from 1970 to 1990, whereas there was a sharp (13-fold) increase for genotype 3. The molecular characterization of 41 genotype 4 HCV isolates belonging to various risk groups revealed that, subtype 4a was the most frequently detected (78%). Phylogenetic comparison of the Greek 4a isolates with all HCV-4a isolates reported worldwide so far revealed a topology which does not discriminate Greek isolates from the others. HCV-4 does not represent a recent introduction in Greece.

Progression of HIV infection in the post-HAART era among a cohort of HIV+ Greek haemophilia patients.

AIM: The study aims to describe the course of HIV-1 infection in the pre- and post-HAART period in a cohort of HIV+ haemophilia patients followed up for up to 21 years. METHODS: The cohort includes 158 haemophilic men with known seroconversion dates followed up prospectively for a median time of 12 and 5.7 years in the pre- (1980-96) and post-HAART period (1997-2003), respectively. RESULTS: The risk of developing AIDS was lowered by 56% in the post- as compared to the pre-HAART period. Of the 158 patients 69 developed AIDS in the pre-HAART period while of the 59 subjects still alive and AIDS free on 1/1/1997 six developed AIDS. The rate of PCP (12.0 cases per 1000 person-years) and NHL (5.4 cases per 1000 person-years), the most common causes of AIDS diagnosis in the pre-HAART era, were remarkably reduced in the post-HAART era (both rates: 2.8 cases per 1000 person-years). On the contrary, the corresponding risk for non-AIDS deaths was fourfold increased in the post-HAART period. Of the 38 non-AIDS related deaths in both periods, 13 occurred post-HAART. The predominant cause of non-AIDS mortality in both periods was end-stage liver disease (ESLD) (7 pre- and 4 post-HAART). The rate of non-AIDS related cancers was also increased during the post-HAART period. CONCLUSION: In this haemophilia cohort the risk of AIDS has substantially reduced in the post-HAART period, but the rate of non-AIDS mortality tended to increase. Among haemophilia subjects, due to the high rates of HCV/HIV coinfection, ESLD, the predominant cause of non-AIDS mortality, will become an increasingly important clinical problem.

HLA antigens as predictors of disease progression in HIV-infected haemophilia patients (a 22 years' follow up).

Our objective was to assess the influence of genetic factors such as HLA classes I and II antigens and other clinical and laboratory variables on the progression of HIV disease in a cohort of 118 HIV infected haemophilic subjects of Greek origin who had been typed for HLA antigens and were followed up prospectively for 22 years since seroconversion. At the end of the follow up we compared two groups of patients: 22 patients who had a fast progression to AIDS (median 6 years since seroconversion) vs. 33 patients who remained asymptomatic in stage A2 for up to 22 years (median 15 years). The results showed that the two groups did not differ significantly in age at seroconversion or baseline CD4+ T cell count. However there was a difference in the frequencies of certain HLA antigens in the two groups. The fast progressors had a higher frequency of HLA-A28, B21 and DR3, which was statistically significant (P = 0.02, 0.04, 0.05, respectively) compared to the slow progressors. These findings based on classical HLA typing techniques confirm other published observations and support the effect of genetic background in the progression of HIV infection in haemophilics.