C. A. Lee

Assessing health-related quality-of-life in individuals with haemophilia.

The objectives of this study were to analyse current levels of health‐related quality‐of‐life (HR‐QoL) in individuals with severe haemophilia and to assess the scope for these levels to improve. To do this, 249 individuals with severe, moderate and mild haemophilia were asked to complete Medical Outcomes Study (MOS) Short‐Form 36 (SF‐36) and EuroQol (EQ‐5D) questionnaires. Access was also gained to two appropriate normative data sets. The results from these questionnaires showed that HIV status, history of orthopaedic surgery and bleeding frequency in the previous calendar year were not strong predictors of HR‐QoL for individuals with severe haemophilia. However, for the majority of scales, age was found to be a strong predictor of HR‐QoL for this patient group. The results from the analysis also showed that compared to individuals with moderate/mild haemophilia and the UK male normative population, individuals with severe haemophilia generally recorded poorer levels of HR‐QoL. These results suggest, therefore, that individuals with severe haemophilia have reduced levels of HR‐QoL compared to individuals with moderate/mild haemophilia and the general population, irrespective of differences in age. The results also suggest that the scope for primary prophylaxis to increase HR‐QoL in individuals with severe haemophilia is significant.

The Illness Perceptions and Treatment Beliefs of Individuals with Severe Haemophilia and their Role in Adherence to Home Treatment

The majority of individuals in the UK with severe haemophilia treat themselves at home with clotting factor. The aim of this study was to examine patients beliefs about their haemophilia, their beliefs regarding treatment with clotting factor and to assess whether relationships existed between these factors and adherence to home treatment. Patient beliefs were assessed by posting individuals with severe haemophilia A and B ( n = 104) the Illness Perceptions Questionnaire (IPQ) and the Beliefs about Medicines Questionnaire (BMQ). The final analysis was based on 65 questionnaires yielding a response rate of 63%. Adherence to the frequency and to the amount of each clotting factor dose was assessed for individuals treating prophylactically and the amount of each clotting factor dose for those only treating on-demand. Adherence scores were calculated by comparing individual patient treatment records with recommended regimens. Regression analysis indicated that perceptions of illness identity and treatment necessity explained a significant amount of the variance in adherence to frequency of prophylactic infusions and that illness identity was associated with the adherence to the amount of each prophylactic dose. Further regression analysis also showed that the amount of each dose of clotting factor administered on-demand was associated with perceptions regarding the necessity of treatment. Analysis with a combined measure of adherence to dose amount indicated that patients treating on-demand or with prophylaxis who under treated, recorded significantly lower perceptions of illness consequence than individuals who were fully adherent or who over-treated. The results suggest that assessing illness perceptions, especially beliefs regarding identity , consequence and necessity of treatment, may play a valuable role in identifying which individuals are least likely to adhere to treatment.

Assessing the effectiveness and cost‐effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrand's disease

Abstract. Miners AH, Sabin CA, Tolley KH, Lee CA (Royal Free Hospital School of Medicine, London; University Hospital Queens Medical Centre, Nottingham; and Royal Free Hampstead NHS Trust, London, UK). Assessing the effectiveness and cost‐effectiveness of prophylaxis against bleeding in patients with severe haemophilia and severe von Willebrands disease. J Intern Med 1998; 244: 515–22.

Cytomegalovirus (CMV) infection, CD4+ lymphocyte counts and the development of AIDS in HIV-1-infected haemophiliac patients

After a maximum of 11 years (median 8·3 years) from the time of HIV seroconversion. 25 out of 59 (42%) of CMV‐seropositive haemophiliacs had progressed to AIDS, as opposed to eight out of 50 (16%) CMV scroncgatives. The age‐adjusted relative risk for AIDS among CMV scropositives was 2·4 (P= 003). In order to determine how this adverse effect is mediated, the mean rate of decline in serial CD4+ lymphocyte counts was studied. CD4+ lymphocyte counts tended to decline more rapidly in CMV seropositives than in seronegatives (−0·087 ± 109/l per annum versus‐0·082 ± 109/l per annum), but this difference did not reach statistical significance. The average CD4+ lymphocyte count at the lime of HIV seroconversion was estimated to be similar in CMV seropositives and negatives, because in HIV‐l‐ncgative haemophiliacs the CD4+ counts were virtually identical, after adjustment for age (0·94 ± 10+/l and 0·97 ± 109/l. respectively). The median CD4+ cell count at which AIDS developed was higher in the CMV‐seropositive group (0·07 ± 109/l) than in the seronegative group (0·04 ± 109/l). but this difference did not reach statistical significance. We conclude from these findings that the adverse effect of CMV is not wholly mediated via a more rapid loss of CD4+ cells. We discuss other processes that may be mediated by CMV, such as a functional deficiency of residual CD4+ cells, or dissemination of HIV in other organs, which may be important in determining the earlier onset of AIDS among CMV‐seropositive subjects.

Primary prophylaxis for individuals with severe haemophilia: how many hospital visits could treatment prevent?

Abstract. Miners AH, Sabin CA, Tolley KH, Lee CA (Royal Free Hospital School of Medicine, London; University of Nottingham, Nottingham; and Royal Free Hampstead NHS Trust, London, UK). Primary prophylaxis for individuals with severe haemophilia: how many hospital visits could treatment prevent? J Intern Med 2000; 247: 493–499.

The changing patterns of factor VIII (FVIII) and factor IX (FIX) clotting factor usage in a comprehensive care centre between 1980 and 1994

The annual amount of clotting factor used by patients at the Royal Free Haemophilia Centre increased significantly from 4 million iu in 1980 to over 15 million iu by 1994 (P < 0.0001). In order to assess the reasons for this increase, data on concentrate usage over this period were retrospectively collected for patients who had Haemophilia or von Willebrand’s disease. Only patients who were registered exclusively at the Centre were included in the study. In total, 498 patients met the inclusion criterion. The median age of the cohort on 1 January 1980 was 21 (range < 1–69) years. During the period there were 88 births and 45 deaths. The majority of patients had Haemophilia A (55%). The median follow‐up period per patient was 2.1 (range 0–14.8) years. Despite adjusting for increases in the number of patients and changes in body weight, statistically significant increases in clotting factor usage were detected for some subgroups of patients, in particularly for those with severe Haemophilia A and B and from the late 1980s onwards, for patients with von Willebrand’s disease. Two reasons for this increase in clotting factor usage were identified as being the introduction of improved products and prophylaxis. However, the increased cost of clotting factor provision that has resulted from these changes in treatment policy should not be analysed in isolation but should be balanced off against cost decreases in other areas and against increases in the effectiveness of treatment.

Setting research priorities to improve cost-effectiveness estimations of primary prophylaxis with clotting factor for people with severe haemophilia

Summary.u2002 Primary prophylaxis with clotting factor is the clinical treatment of choice for people with severe haemophilia, as evidence suggests it can prevent the onset and progression of joint‐ and muscle‐related problems caused by bleeding episodes. However, the major limitation of this approach is that it requires considerably more clotting factor compared with treating on‐demand. Thus, there is a need to establish its cost‐effectiveness. The aim of this paper is to review the published evidence on the cost‐effectiveness of prophylaxis and to highlight areas for future research that would decrease the uncertainty around these findings.

Development and evaluation of ELISAs for factor XIIIA and XIIIB subunits in plasma

Severe, congenital deficiency of factor XIII is extremely rare. However, a moderate reduction in the plasma level of the functional subunit (factor XIIIA) and also to a lesser extent of the carrier subunit (factor XIIIB), and a decrease in the XIIIA:B subunit ratio, have recently been reported in patients with the inflammatory bowel disorder Crohns disease, particularly during clinical relapse. In order to accurately monitor patients, sensitive, reliable assays for the two subunits of factor XIII are required. We report here the development and validation of ELISAs for these components. The assays are identical except in respect of the specificity of the polyclonal antiserum used as starting material, both of which are commercially available. The antisera are purified by n-octanoic acid precipitation and portions of these purified immunoglobulins are used as coating antibodies. The remaining portions are biotinylated and used with streptavidin and horse-radish peroxidase as tracer antibodies. A normal range (n = 24) was established for factor XIIIA (mean 95 range 60-130 U/dl) and for factor XIIIB (mean 99 range 60-130 U/dl). There were no significant differences between the ELISA and electroimmunodiffusion assays either for factor XIIIA (means +/- 1 standard deviation 95 +/- 15.9 and 89 +/- 22.7 respectively) or for factor XIIIB (99 +/- 18.3 and 106 +/- 23.4 respectively). These assays have been in routine use for six months, during which time two further antisera purifications and biotinylations have been carried out without significant problems of reproducibility or stability.

Assessing the relationship between productivity levels and severity of haemophilia

In this study, we assessed whether severity of haemophilia was associated with levels of productivity. Productivity levels were assessed by sending a ‘time‐use’ questionnaire to 228 individuals with mild, moderate and severe haemophilia. The results showed that, after adjusting for differences in age and HIV serostatus, there were no differences between individuals with severe and mild/moderate haemophilia in terms of completed levels of education, employment status, absenteeism from work over the previous 2u2003weeks, the number of hours each week spent performing unpaid tasks and how efficiently individuals performed these tasks. The data did suggest, however, that a significantly larger proportion of individuals with severe haemophilia (32%) required help from family or friends to perform routine household tasks each week than individuals with mild/moderate haemophilia (13%). In conclusion, it is possible that individuals with severe haemophilia have similar levels of productivity compared to individuals with mild/moderate haemophilia or that treatment with secondary prophylaxis has helped to reduce differences between the two patient groups.

CD4 lymphocyte count as predictor of drug expenditure in a cohort of anti‐HIV seropositive haemophiliacs

The CD4 lymphocyte counts of 76 haemophilic patients who acquired HIV infection from unsterilised clotting factor concentrate were measured and the cost of all drugs used to treat each patient calculated. A rapid rise in drug costs was seen as patients CD4 counts approached 0.2×109/L, the level at which zidovudine treatment and prophylaxis against Pneumocystis carinii are started. The relationship between decline in CD4 counts and cost of drugs was found to be linear. The authors conclude that it is possible to use CD4 counts to predict future drug costs.