Anja Griffioen

Antiviral therapy for chronic hepatitis C in patients with inherited bleeding disorders: an international, multicenter cohort study

Summary.  Background: Hepatitis C is a major co‐morbidity in patients with hemophilia. However, there is little information on the efficacy of antiviral therapy and long‐term follow‐up after treatment.Objectives: To assess the effect of interferon‐based (IFN‐based) therapy on hepatitis C virus (HCV) eradication, to identify determinants associated with treatment response, and to assess the occurrence of end‐stage liver disease (ESLD) after completing antiviral therapy.Patients and methods: In a multicenter cohort study, 295 treatment‐naïve hemophilia patients chronically infected with HCV were included. The effect of therapy was expressed as sustained virological response (SVR). Determinants associated with treatment response were expressed as odds ratios (ORs). Cumulative incidence of ESLD was assessed using a Kaplan–Meier survival table.Results: Among human immunodeficiency virus (HIV) negative patients (n = 235), SVR was 29% (29/101) for IFN monotherapy, 44% (32/72) for IFN with ribavirin, and 63% (39/62) for pegylated IFN (PegIFN) with ribavirin. In patients co‐infected with HIV (n = 60), IFN monotherapy, IFN with ribavirin, and PegIFN with ribavirin eradicated HCV in 7/35 (20%), 1/2 (50%), and 11/23 (48%), respectively. SVR increased with genotype 2 and 3 [OR 11.0, 95% CI: 5.8–20.5], and combination therapy (IFN and ribavirin OR 3.7, 95% CI: 1.7–8.4), PegIFN and ribavirin (OR 4.2, 95% CI: 1.8–9.5). Up to 15 years after antiviral treatment, none of the patients with a SVR relapsed and none developed ESLD. In contrast, among unsuccessfully treated patients the cumulative incidence of ESLD after 15 years was 13.0%.Conclusions: Successful antiviral therapy appears to have a durable effect and reduces the risk of ESLD considerably.

Carrier testing in haemophilia A and B: adult carriers' and their partners' experiences and their views on the testing of young females

Summary.  This is a descriptive study, which aims to report adult carriers’ and their husbands/partners’ experiences of carrier diagnosis and their views as to how these issues should be handled for the next generation. Following an initial pilot, 105 carriers and husbands/partners responded to a postal questionnaire. Most of the adult carriers had been tested because either they or their parents wanted to know their carrier status or they had a son diagnosed with haemophilia. The respondents agreed that the main reasons for testing young potential carriers should be either a family history of severe haemophilia or that the young person or her parents wanted to know her status. Forty per cent (35/87) believed the earliest age for carrier testing should be 0–9 years, 44% (38/87) 10–15 years and 16% (14/87) ≥16 years. Respondents aged 18–39 years were more likely to be in favour of testing <2 years. If parents and teenagers disagreed, the majority of parents thought that a test should not be forced, consent refused or results withheld. Genetic counselling provides an important opportunity for parents, who want a very early genetic test, to explore their motivations and balance their desire to prepare and protect their daughter with her right to decide as a teenager.

Markers of HIV-1 disease progression in individuals with haemophilia coinfected with hepatitis C virus: a longitudinal study

BACKGROUND Low serum albumin concentration is associated with short-term survival in individuals with HIV-1. However, few investigators have assessed whether individuals with a low serum albumin concentration have delayed progression to AIDS, or survive in the long term. We aimed to assess the relation between markers of liver function and progression to AIDS and death in individuals with haemophilia infected with HIV-1 and hepatitis C virus. METHODS We measured markers of liver function and took CD4 counts every 3 months in 111 patients registered at the Royal Free Hospital Haemophilia Centre, London, UK. HIV RNA concentrations were measured yearly and then every 3-6 months from 1996. We used Coxs regression models to assess the independent prognostic value of these markers for AIDS and death. FINDINGS As a fixed covariate, albumin concentrations measured shortly after HIV-1 seroconversion were associated with risk of AIDS (relative hazard 0.91 [95% CI 0.84-1.00], p=0.04) and death (0.89 [0.82-0.96], p=0.004) over a 15-year period. These findings were independent of the CD4 count and HIV-1 RNA concentration. As a time-updated covariate, after adjustment for CD4 count and HIV-1 RNA concentrations, albumin was not associated with progression to AIDS (0.96 [0.90-1.01], p=0.13), but was strongly associated with death (0.88 [0.84-0.93], p<0.0001) in the short term. INTERPRETATION Low concentrations of albumin in individuals infected with HIV-1 could indicate a poor outlook and should therefore prompt concern at any stage of infection.

Two decades of HIV infection in a cohort of haemophilic individuals: clinical outcomes and response to highly active antiretroviral therapy.

ObjectivesMany haemophilic individuals infected with HIV died before receiving antiretroviral therapy (ART). Most who remain alive are chronically infected with hepatitis C virus (HCV), which has implications for their prognosis and choice of ART. The clinical status of a cohort of HIV-positive haemophilic men is reported together with their response to highly active antiretroviral therapy (HAART). DesignLongitudinal cohort study. SettingA comprehensive care haemophilia centre. PatientsA group of 111 haemophilic men who seroconverted to HIV in the period 1979 to 1985. ResultsThe cohort has been followed since 1979. By 30 April 1999, 57 of the 111 men had developed AIDS and 65 had died: Kaplan−Meier rates of 57.0% [95% confidence interval (CI) 46.9−67.0) and 65.1% (95% CI 52.7−77.4) by 19.5 years, respectively. AIDS rates have declined since 1997 but death rates have remained high, largely owing to deaths from non-HIV-related causes. Thirty-five patients remain alive and under follow-up at the clinic. The 28 men who had received ART had lower CD4 cell counts than the seven patients who had not received ART, but the two groups were otherwise similar. In total, 21 patients are known to have started HAART while under care at the centre. By 10−12 months after starting HAART, viral loads dropped by 2.06 log10 copies/ml and CD4 cell counts increased by 60 × 106 cells/l. In 10 out of 18 patients with viral loads initially > 400 copies/ml, a viral load below this level was attained; four had changed therapy at the time. ConclusionsWhile the decision to initiate HAART in haemophilic men should be made carefully because of the possible adverse events, our results suggest that a good response rate was achieved in this group of men.

Thrombin generation assay identifies individual variability in responses to low molecular weight heparin in pregnancy: implications for anticoagulant monitoring

Low molecular weight heparin (LMWH) given to inhibit coagulation and reduce the risk of thrombosis, is typically monitored by anti‐Xa assay. However, anti‐Xa levels may not necessarily provide an accurate measure of coagulation inhibition. Moreover, pregnancy is associated with hypercoagulability, which may compromise the efficacy of LMWH. We looked at the association between anti‐Xa levels and parameters of thrombin generation assay [TGA; area under the curve (AUC), peak height (PH) and time to peak (ttP)] using samples from 41 pregnant women receiving LMWH and 40 normal pregnant women controls. TGA results confirmed the physiological hypercoagulability of normal pregnancy (mean normalised values: AUC 119%; PH 157%; ttP 72%). Although anti‐Xa measures correlated with all three TGA parameters, this group correlation masked significant inter‐individual variability, demonstrated by the R2 value or coefficient of determination. Anti‐Xa levels contributed to 74% of variation in AUC values, 63% of variation in PH values and only 53% of variation in ttP values. The remainder reflects the contribution of patients’ intrinsic coagulation status. Hence, some patients with ‘safe’ anti‐Xa levels may potentially be under‐anticoagulated, particularly in pregnancy. Measuring coagulability directly with TGA may lower the risk of adverse events due to under‐anticoagulation in selected patients.

Influence of HIV-1 infection on GBV-C infection in multiply infected haemophilic patients

Two hundred thirteen haemophilic patients were studied for the presence of GBV‐C RNA and anti‐E2 antibodies soon after their first treatment with unsterilised factor concentrates and in their most recent sample. An assessment was made to determine whether coinfection with HIV had any effect on the progression of GBV‐C infection. All of the patients were infected with HCV and 81 patients (37%) were also infected with HIV. GBV‐C RNA was detected using the Abbott LCx™ assay and by RT‐PCR. Anti‐E2 antibodies were detected using the μPLATE Anti‐HGenv assay and by Abbott Laboratories. The HIV‐negative patients were more likely than the HIV‐positive patients to lose GBV‐C RNA between the two time points. A proportion of the patients lost their anti‐E2 antibodies over the time period, however, the majority of these were HIV‐positive. This study shows that infection with HIV does affect the progression of GBV‐C infection, however, this effect is little understood as yet. J. Med. Virol. 56:316–320, 1998.

The prognostic value of a single hepatitis C virus RNA load measurement taken early after human immunodeficiency virus seroconversion.

Hepatitis C virus (HCV) RNA loads are measured sporadically in HCV-positive individuals. However, the prognostic value of these isolated measurements for predicting progression to acquired immune deficiency syndrome (AIDS) and all-cause mortality in coinfected individuals remains unclear. In this study, the prognostic value of a single HCV RNA load measurement taken early after human immunodeficiency virus (HIV) seroconversion was investigated in a cohort of 96 male patients with inherited bleeding disorders. Dates of HIV seroconversion had been estimated for all patients, and at least 4 HCV RNA load measurements per patient were done retrospectively after HIV seroconversion. HCV RNA load stabilized at 4 years after HIV seroconversion, and this point was used for analysis. There was a significant correlation between increased age and early HCV RNA load (r=0.25; P=.01). Adjusting for HIV RNA levels, CD4 cell counts, and the age effect, HCV RNA load >5.90 log(10) copies/mL was predictive of progression to AIDS and all-cause mortality over a period of at least 15 years.

Review of a multidisciplinary clinic for women with inherited bleeding disorders

Dear Editor, Women with inherited bleeding disorders are particularly at risk of bleeding complications from the regular haemostatic challenges during menstruation and child birth. During the last decade, there has been an international research interest in women with inherited bleeding disorders and this has led to considerable progress in the identification of obstetric and gynaecological problems in these women, as well as raising the clinical awareness among their care providers. Menorrhagia is the commonest bleeding symptom in women with inherited bleeding disorders and could be the first or only presenting symptom. Child birth presents a haemostatic challenge. Thus these women require specialized and individualized care during pregnancy to include preconceptual counselling, prenatal diagnosis, and antenatal, intrapartum and postnatal care. A multidisciplinary approach has been recommended [1]. A multidisciplinary clinic was set up at the Katharine Dormandy Haemophilia Centre and Haemostasis Unit in 2002. A review of this clinic incorporating a quality of care survey was conducted covering the years 2002–2005. (This has previously been published in abstract form [2].) The healthcare professionals included a consultant haematologist (C.A. Lee), a consultant obstetrician and gynaecologist (R.A. Kadir), a haemophilia nurse specialist (D. Pollard), and a family therapist (N. Dunn). Between October 2002 and September 2005, 178 patients were seen at the clinic with 312 appointments. The most common diagnoses were carrier of haemophilia, 50 (28%), von Willebrand disease (VWD), 44 (24%), and factor XI (FXI) deficiency, 28 (16%). North London has a large population of Ashkenazi Jewish people in whom the carriage rate for FXI deficiency is 8% [3]. The most common management issues at the appointments were menorrhagia, 137 (44%), and pregnancy, 112 (36%). There were 72 women who experienced menorrhagia and after being fully assessed various treatments were offered and prescribed – in descending order of use, tranexamic acid, combined oral contraceptive pill, levonorgestrel-releasing intrauterine system [4], desmopressin, progestogens (oral cyclical or injectable), clotting factor concentrate and gonadotrophinreleasing hormone analogue with add back therapy. Uterine artery embolization, endometrial ablation, hysterectomy, and myomectomy were the surgical options offered/performed when appropriate. There were 13 women who attended preconceptual counselling, five carriers of haemophilia A; one carrier of haemophilia B; one doubtful bleeding state; three FXI deficiency, one partner with a bleeding disorder, one thrombotic disorder, and one carrier of haemophilia A with VWD. Of the 112 women seen for management of pregnancy there were 28 who wanted to discuss prenatal diagnosis, 27 who were carriers of haemophilia and one who had FXI deficiency. The options that were offered included second-trimester ultrasound scanning; analysis of free fetal DNA (ffDNA) in maternal blood [5] and first-trimester ultrasound scanning; chorion villus sampling (CVS); and amniocentesis. The majority opted for non-invasive prenatal diagnosis – eight had second-trimester ultrasound scanning and 16 ffDNA with first-trimester ultrasound scan. A CVS was performed for five women, four of whom had shown a male fetus on ffDNA. It was possible to send a quality of care survey to 111 women who attended the clinic and there was a 61% response rate – 88% valued the presence of the haematology and gynaecology professionals in the same consultation; 90% considered this model of care to be beneficial or quite beneficial; 92% felt included in the decision-making about their care; and Correspondence: Rezan A. Kadir, Haemophilia Centre and Haemostasis Unit, Royal Free Hospital, Pond Street, London, NW3 2QG. Tel.: 0207 794 0500; fax: 0207 4726759; e-mail: rezan.abdul-kadir@royalfree.nhs.uk

Comparative study of full-length and B-domain deleted factor VIII concentrates

The debate about the comparative efficacy of fulllength and B-domain deleted recombinant factor VIII (FVIII) concentrates continues owing to the lack of comparative studies of these factor concentrates. In an attempt to address the lack of adequate studies, Gruppo et al. analysed data from studies using either full-length (FL-FVIII) or B-domain deleted (BDDFVIII) FVIII concentrates [1]. In their report, our study on prophylaxis in a cohort of 41 children with either severe haemophilia A or B was included in the analysis [2]. Within our cohort of children, 32 had severe haemophilia A. Incorrectly the data from this study has been included in the FL-FVIII subgroup. In our report we did not specify the type of recombinant FVIII concentrate used for prophylaxis. Therefore, it was incorrect to assume that these 32 children received FL-FVIII concentrate. In fact 27 children were receiving FL-FVIII concentrate and five were receiving BDD-FVIII concentrate. In addition to our concerns that our study has been misquoted, we are hesitant about the conversion of median values to mean values adopted by the authors. In our study the data is from relatively small groups and did not demonstrate a normal distribution, therefore, we quoted median rather than mean values. For example, compared with a median number of joint bleeds of 0.5 bleeds/year for the two groups while on prophylaxis, the corresponding mean values for joint bleeds in the FL-FVIII and BDD-FVIII groups are 1.2 bleeds/year and 0.8 bleeds/year, respectively. The misuse of statistics would lead one to speculate that the BDD-FVIII concentrate resulted in fewer joint bleeds during prophylaxis in this group of children. If we are to make informed decisions on the best treatment for our patients we need reliable data, and ideally comparative prospective studies.