Beneficial effect of successful HCV treatment in patients with inherited bleeding disorders, assessed by liver stiffness measurements

Hepatitis C infection is a major comorbidity in patients with inherited bleeding disorders. Successful antiviral treatment leads to a reduction in liver fibrosis, as shown by liver biopsies. Liver stiffness measurement (LSM) is a non-invasive method of assessing liver fibrosis. The aim of this cohort study was to evaluate the long-term effect of successful antiviral treatment, using LSM, in HCV-infected patients with inherited bleeding disorders. The LSM were performed in 2005 (LSM 1) and 2009 (LSM 2) in 39 patients who were successfully treated for HCV. The change in liver fibrosis between LSM 1 and 2 was assessed. The median duration of HCV infection was 28.8 years. A total of 22 patients (56%) underwent successful antiviral treatment before LSM 1 (group 1), and 17 patients between LSM 1 and LSM 2 (group 2). The median time since antiviral treatment was 8.8 years in group 1 and 2.5 years in group 2. In group 1, the median results of LSM 1 and 2 were similar (6.0 vs. 5.6 kPa, P-value 0.36), so overall, patients remained stable. In three patients in this group, all treated more than 15 years ago, an increase of liver stiffness was shown. Group 2 showed a significant improvement in median LSM results (10.3 vs. 6.1 kPa, P-value <0.01), with decrease of liver stiffness in 82%. Even after a long HCV infection duration, successful antiviral treatment led to a significant improvement of fibrosis, measured by LSM, mainly in the first few years after completing treatment.     

Liver biopsy in Irish hepatitis C-infected patients with inherited bleeding disorders

The majority of patients receiving plasma-derived clotting factor concentrates between 1970s and the mid-1980s are now hepatitis C positive. The progression of hepatitis C is extremely variable and there is frequently a poor correlation among liver biochemistry, viral load and the stage of liver disease. Liver biopsy remains the only definitive way of staging fibrosis and grading necroinflammatory activity. Concerns have been expressed about the safety of the procedure; however, with modern regimes for the correction of coagulopathy in patients with inherited bleeding disorders, normal haemostasis may be maintained during the peribiopsy period. We performed 21 liver biopsies between 1984 and 1997 on patients with factor VIII (FVIII) or IX (FIX) deficiency and von Willebrand's Disease (VWD). Four had concomitant human immunodeficiency virus (HIV) infection, five were thrombocytopenic and one had a prolonged prothrombin time (PT). Haemostasis was achieved using an intermittent bolus of factor concentrate or continuous infusion regimens. One patient with VWD received Desmopressin (DDAVP). There were no bleeding episodes associated with biopsy. We suggest that liver biopsy is a safe procedure in patients with inherited bleeding disorders when the coagulopathy is fully corrected. It is the only definitive method of staging the extent of fibrosis associated with hepatitis C infection, and it is this that defines prognosis.     

Side effects of desmopressin in patients with bleeding disorders

Introduction: Desmopressin is frequently used in patients with bleeding disorders because of its prohaemostatic effects. In recent years desmopressin use increased due to reported high incidence of inhibitors in mild haemophilia after clotting factor infusion and the rising costs of clotting factor concentrates. The safety and frequency of side effects have hardly been assessed in well‐designed studies. Aim: We therefore prospectively evaluated side effects of desmopressin in a large unselected cohort of bleeding disorder patients, who received a desmopressin test dose. Methods: Blood was drawn prior to, one, three, six and 24 h after desmopressin. Primary outcome was change in serum sodium, haematocrit, serum‐ and urine osmolality, body weight and vital signs. Self‐reported side effects were evaluated as secondary outcome. Results: In total, 108 patients were included, median age 30 years, the majority of whom had von Willebrand disease type 1 (76%). A significant change in water balance parameters was observed. Four patients (4%) had hyponatraemia (≤135 mmol L^?1) after 24 h but no severe hyponatraemia occurred (≤125 mmol L^?1). After infusion, 41 (38%) patients were hypotensive (≤90 mmHg SBP and/or ≤60 mmHg DBP) and 10 (9%) presented with tachycardia (>100 min^?1). However, none of these effects sustained at 24 h. Infusion was discontinued in one patient because of tachycardia, nausea and malaise. Self‐reported side effects included: headache, fatigue, flush and dizziness. Conclusion: Observed side effects correspond with the known antidiuretic and vasomotor effects of desmopressin. Changes in parameters were temporary and not clinically relevant. In conclusion, our study supports desmopressin use as a safe treatment option in patients with various bleeding disorders.     

Correlation of transient elastography with APRI and FIB‐4 in a cohort of patients with congenital bleeding disorders and HCV or HIV/HCV coinfection

Summary. Patients with inherited bleeding disorders frequently suffer from chronic hepatitis C virus (HCV) mono‐ or human immunodeficiency virus (HIV)/HCV coinfection. Non‐invasive markers for liver fibrosis are warranted for these patients. We tested a large cohort of haemophilic patients with HCV mono‐ or HIV/HCV coinfection for correlation of transient elastography (TE) with two simple surrogate markers of liver fibrosis and for differences in fibrosis stages according to these markers. We prospectively enrolled HCV‐positive patients with congenital bleeding disorders with or without HIV coinfection. Liver function tests and platelet counts were determined and TE was performed. Aspartate aminotransferase‐to‐platelet ratio index (APRI) and a simple index called FIB‐4 were calculated and results were correlated with TE. A total number of 174 patients were included (23% HCV, 36% HIV/HCV coinfected, 33% with cleared HCV and 8% with ongoing HIV but cleared HCV). TE correlated significantly with APRI and FIB‐4 (r = 0.60; P < 0.001 and r = 0.54; P < 0.001 respectively). This correlation was pronounced in patients with ongoing HCV infection (r = 0.67; P < 0.001 and r = 0.60; P < 0.001). Prediction of advanced fibrosis resulted in concordance rates >80% with combinations of TE plus APRI and APRI plus FIB‐4. HIV/HCV coinfected patients did not present with advanced fibrosis stages when compared with HCV‐monoinfected patients. Combinations of two non‐invasive markers may significantly reduce the number of liver biopsies in patients with bleeding disorders and advanced liver fibrosis. Furthermore, our data support previous studies that observed a favourable outcome in patients with HIV/HCV and a preserved immune function in times of highly active antiretroviral therapy.     

Hepatitis C virus genotypes among patients with thalassemia and inherited bleeding disorders in Markazi province, Iran

Hepatitis C virus (HCV) genotypes, multiple genotypes infection and HCV seroprevalence were investigated among 98 thalassemia patients and 76 haemophiliacs in Markazi province, Iran. HCV antibody was detected in 5 (5.1%) of the first group and 33 (43.4%) of the latter. Risk factors associated with anti-HCV antibody were also determined. Anti-HCV positivity in thalassemiacs were related to the number of blood transfusion units, splenectomy and duration of thalassemia. Analysis of risk factors in haemophiliacs revealed that seropositivity was significantly associated with duration of transfusion (P =0.009) and severity of disease (P = 0.000). The prevalence of HCV antibody in thalassemia subjects dropped from 8.1% to 0% after implementation of anti-HCV screening (1996). It was found that higher prevalence of HCV antibody in haemophiliacs (43.4%) compared with thalassemia patients (5.1%) correlated with clotting factor concentrates. Of the 34 seropositive haemophilia patients, HCV RNA was detected in 23 (67.7%). HCV genotype distribution was one in 50%, three in 18.2%, two in 4.54% and mixed in 27.3% (1 + 2 in 9.1%, 1 + 3 in 4.54%, 1 + 4 in 9.2% and 2 + 3a in 4.54%) cases. Among the five anti-HCV-positive thalassemiacs, two (40%) were positive for HCV RNA and one sample was found to be subtype 3a. This study confirms that multitransfused patients in Markazi province had similar genotype distribution as those previously reported form some other regions of Iran. Considering the possibilities of HCV mixed genotype among patients with haemophilia and thalassemia, accuracy and precision should be highly concerned in the detection of genotypes and their subsequent treatment.     

Occurrence, course and risk factors of depression during antiviral treatment for chronic hepatitis C in patients with inherited bleeding disorders: a prospective study

Summary.  Treatment of hepatitis C virus (HCV) consists of pegylated interferon (IFN)-α and ribavirin for 24 or 48 weeks. An important side-effect of IFN-α is depression. The occurrence, course and risk factors of depression during antiviral treatment were studied prospectively in HCV patients with inherited bleeding disorders. The Beck Depression Inventory, indicating no, mild, moderate or severe depression, was administered to 47 patients before starting therapy, after 4, 12, 24 and 48 weeks of treatment, and 4 weeks after cessation of therapy. At baseline, five patients (11%) had mild depression. Depression worsened during treatment in three of these patients. In all five patients, (mild) depression persisted 4 weeks after treatment. Of the remaining 42 patients, 23 (55%) developed depression during treatment (14 mild, eight moderate and one severe), mostly (78%) during the first 12 weeks. Four weeks after cessation of treatment, three of 23 patients still had mild depression. The only independent risk factor for development of depression was a history of depression or other psychiatric problems (odds ratio 9.7). For patients with inherited bleeding disorders, depression is a significant, mostly transient, problem during HCV treatment. We recommend close monitoring of patients, especially those with previous psychiatric problems, to ensure adequate detection and treatment of depression during antiviral therapy.     

Liver biopsy in patients with inherited disorders of coagulation and chronic hepatitis C

Liver biopsy plays a pivotal role in the management of patients with a variety of liver diseases, including chronic hepatitis C virus. The major risk of the procedure is the potential for significant haemorrhagic complications. Although the data are limited, the procedure does not appear to pose excessive risk to the patient with inherited disorders of coagulation, provided that adequate haemostasis can be achieved prior to the liver biopsy. This requires close coordination of care between the hepatologist and the haematologist. Indications for liver biopsy should be the same in patients with haemophilia as in other populations.     

Hepatitis G virus infection in patients with bleeding disorders

Eighty-two patients with bleeding disorders registered with our centre were screened for infection with hepatitis G virus (HGV). 80 patients were positive for hepatitis C (HCV) antibodies, 66 of whom (83%) were HCV PCR positive. 11 patients (13%) were HGV RNA-positive, a similar prevalence rate to that of other studies of patients with bleeding disorders who received factor concentrates prior to the introduction of viral inactivation procedures. There was no significant difference in histological activity index (HAI) between the 10 HGV RNA-positive and the 31 HGV RNA-negative patients who underwent liver biopsy for assessment of HCV infection (median HAI scores 5.5, range 2–10 and four, range 0–10 respectively, P  = 0.07). One patient in each group had established cirrhosis. In patients who underwent HCV quantitation there was no significant difference in HCV viral titre between HGV RNA-positive and negative patients (median HCV titre in HGV RNA-positive patients 2.10 × 10⁵ DNA copies /ml ( n  = 8) range 4.17 × 10² to 4.17 × 10⁶, median HCV titre in HGV RNA-negative patients 3.33 × 10⁵ ( n  = 31) range 1.00 × 10³ to 6.67 × 10⁶, P  = 0.68). In this study there was no evidence that individuals co-infected with HGV and HCV have more severe liver disease than those infected with HCV alone.     

Liver stiffness measurements to assess progression of fibrosis in HCV‐infected patients with inherited bleeding disorders

Summary. Hepatitis C is a major co‐morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non‐invasive way of assessing the extent of liver fibrosis. This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement of LSM results of more than 2 kPa. These results are comparable with those of paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM.     

Access to primary dental care for patients with inherited bleeding disorders

Patients with inherited bleeding disorders (IBD) can face difficulty in accessing primary dental care either due to disease-specific or patient-related barriers. This can lead to poor oral health and increase the need for more invasive dental treatment. This study aimed to highlight actual and perceived barriers that IBD patients from the East London area were experiencing. It also gives an overview of the experience history of the General Dental Practitioners (GDPs) treating these patients. Information was gathered via pre-designed surveys as part of a service development audit. A total of 105 anonymous patient surveys and 50 GDP surveys were completed between December 2010 and July 2011. The patient survey highlighted more patients to be affected by patient-related than disease-specific barriers to access dental care. The GDP survey identified that just under half of GDPs questioned were not confident in the dental management of patients with bleeding disorders. Identifying misconceptions and barriers to access primary dental care will enable further development of our shared-care approach between General Dental Services, Hospital or Community Dental Services and Haemophilia Centre, optimizing regular preventative advice and follow ups to prevent dental disease and invasive dental treatment requiring haemostatic treatment.     

Deep venous thrombosis screening in patients with inherited bleeding disorders and central venous catheters

Summary. Children with inherited bleeding disorders often require central venous catheters (CVCs). Although CVCs are known to be complicated by deep venous thrombosis (DVT), little is known about the timeline of DVT development or risk of post‐thrombotic syndrome (PTS). The aim of this study was to determine the timeline and confirm the incidence of thrombosis in patients with bleeding disorders who have CVCs. In 2002, we instituted a screening programme to monitor for CVC‐related complications in children with haemophilia and von Willebrand disease. This is a retrospective review of this cohort. All children with CVC followed up between 1 January 2000 and 1 June 2009 were evaluated for DVT every 24 months with contrast venography and Doppler sonography. An institutional PTS severity scale was utilized at each visit. Thirty‐six patients had 37 CVCs placed. Thirty patients had imaging studies, with DVT observed in 14 (47%). Most cases of DVT were diagnosed at the first venogram (median CVC duration 26 months). There were no abnormal ultrasound results. Sixteen patients (44%) had clinical findings consistent with PTS, including 10 (71%) with an abnormal venogram. Dilated chest wall veins appeared to be more strongly associated with underlying DVT (positive predictive value of 0.8) than arm circumference discrepancy. Successful transition to use of peripheral veins occurred at a median of 11 months after abnormal venograms. CVC‐related DVT is common in children with inherited bleeding disorders and likely occurs earlier than previously thought. Clinical signs of PTS are also common, but long‐term sequelae and severity of PTS are not known.     

Viral markers and use of factor products among Finnish patients with bleeding disorders

In the seventh national voluntary cross-sectional survey (in 1999) of Finnish patients with haemophilia A or B, type 3 von Willebrand disease or factor XIII deficiency, a plasma sample was received from 193 patients (67%). The samples were tested for hepatitis B and C, human immunodeficiency virus (HIV) and human T-cell leukaemia virus (HTLV) antibodies. Fifty-one percent of the patients were hepatitis C antibody positive and 34% hepatitis B core antibody positive. None of the patients had antibodies against HIV or HTLV. Eighteen percent of the patients had an elevated alanine aminotransferase activity. Abnormal alanine aminotransferase was significantly associated with hepatitis C seropositivity. No new seroconversions were detected among the haemophiliacs or patients with type 3 von Willebrand disease when compared with the last two surveys in 1993 and 1996, and there was no seroconversion in sole users of solvent/detergent-treated factor products. Currently, 32% of the patients use prophylactic factor treatment as their principal mode of therapy, particularly the younger patients with severe forms of the bleeding diseases.     

Clinical outcome of interferon and ribavirin combination treatment in hepatitis C virus infected patients with congenital bleeding disorders in Iran

Summary.  Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in patients with inherited bleeding disorders. The results of interferon and ribavirin combination therapy have been reported in a limited number of clinical trials on these patients. Peginterferon is a costly treatment. Conventional interferon and ribavirin therapy is still the main available and affordable antiviral therapy in some countries. The goal of this study was to assess the effectiveness and safety of interferon alfa-2b plus ribavirin in HIV seronegative, non-alcoholic, non-cirrhotic, naïve subjects with congenital coagulopathy. Between May 2003 and August 2007, 103 haemophiliacs were treated consecutively with standard inclusion and exclusion criteria, with interferon alfa-2b (PDferon B^®) 3MIU three times a week subcutaneously plus ribavirin, for 24–48 weeks, with appropriate dose adjustments. They were all scheduled to have serial visits and laboratory tests. Among 7(6.8%) female and 96(93.2%) male haemophiliacs, 11(10.68%) cases did not complete the study because of psychological side effects. With intent-to-treat analysis, end-of-treatment response was 63.1%, and sustained virological response (SVR) was 56.3%. There was a significant correlation between SVR and genotype, baseline HCV viral load, rapid virological response, early virological response and BMI. A decrease in the haemoglobin level of two patients required ribavirin dose reduction. One developed thrombocytopenia at the end of treatment, but none had neutropenia. Hypothyroidism was observed in two patients. Interferon plus ribavirin combination therapy in HCV-infected haemophilic patients is well tolerated and treatment outcomes appear to be similar to those seen in the general population.     

Quantification of hepatitis C virus in patients treated with peginterferon-alfa 2a plus ribavirin treatment by COBAS TaqMan HCV test

Summary. Extremely low levels of serum hepatitis C virus (HCV) RNA can be detected by COBAS TaqMan HCV test. To investigate whether the COBAS TaqMan HCV test is useful for measuring rapid virological response (RVR) and early virological response (EVR) to predict sustained virological response (SVR), we compared the virological response to PEG‐IFN‐alfa 2a plus RBV in 76 patients infected with HCV genotype 1 when undetectable HCV RNA by the COBAS TaqMan HCV test was used, with those when below 1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test was used, which corresponded to the use of traditional methods. Among the 76 patients, 28 (36.8%) had SVR, 13 (17.1%) relapsed, 19 (25.0%) did not respond, and 16 (21.0%) discontinued the treatment due to side effects. The positive predictive values for SVR based on undetectable HCV RNA by COBAS TaqMan HCV test at 24 weeks after the end of treatment [10/10 (100%) at week 4, 21/23 (91.3%) at week 8 and 26/33 (78.7%) at week 12] were superior to those based on <1.7 log IU/mL HCV RNA [17/19 (89.4%) at week 4, 27/38 (71.0%) at week 8, and 27/43 (62.7%) at week 12]. The negative predictive values for SVR based on <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test [46/57 (80.7%) at week 4, 37/38 (97.3%) at week 8, and 32/33 (96.9%) at week 12] were superior to those based on undetectable HCV RNA [48/66 (72.7%) at week 4, 46/53 (86.7%) at week 8, and 41/43 (95.3%) at week 12]. The utilization of both undetectable RNA and <1.7 log IU/mL HCV RNA by COBAS TaqMan HCV test is useful and could predict SVR and non‐SVR patients with greater accuracy.     

HCV treatment with pegylated interferon and ribavirin in patients with haemophilia and HIV/HCV co-infection

Summary.  Individuals with haemophilia are frequently infected with both human immunodeficiency virus (HIV) and hepatitis C virus (HCV); however, limited evidence is currently available regarding the efficacy of HCV treatment with pegylated interferon and ribavirin in this patient population. The aim of this study was to review HCV treatment outcomes in a cohort of patients with haemophilia and HIV/HCV co-infection. A retrospective, single centre review of 13 consecutive patients treated with pegylated interferon and ribavirin was performed. All patients were male with haemophilia A and a median age of 43 (range 27–62) at initiation of HCV therapy. Nine of 13 (69%) patients had genotype (gt1) 1 HCV (3 × gt3, 1 × gt4). Twelve of 13 (92%) were receiving ART, with a mean CD4+ count of 428 cells μL⁻¹ (range 175–928 cells μL⁻¹) at initiation of HCV therapy. Six of 11 (55%) patients achieved EVR (3 × gt1, 2 × gt3, 1 × gt4) at 12 weeks, 4/13 (31%) had EOTR (2 × gt1, 2 × gt3) and 1/13 (8%) achieved sustained virological response (1 × gt1). Seven of 11 (64%) patients normalized ALT during therapy wherein mean ALT fell from 101 to 76 U L⁻¹. Only 1/13 (8%) patients discontinued therapy prematurely due to side effects. CD4+ cell counts and HIV viral load remained stable during HCV treatment, with a mean 437 cells μL⁻¹ and <50 copies mL⁻¹ at 48 weeks respectively. Patients in our cohort with haemophilia and HCV/HIV co-infection responded poorly to HCV treatment. Alternative HCV treatment strategies need to be considered in patients with haemophilia and HIV/HCV co-infection.