Hepatitis C infection in children with haemophilia: a pilot study

Many haemophilia patients were infected with hepatitis C virus (HCV) in childhood after transfusion with inadequately or non-virus inactivated clotting factor products. Limited information is available on the clinical course of HCV infection in children. To assess the clinical consequences of hepatitis C in these young patients we performed a pilot study of 31 patients with haemophilia, infected with HCV before the age of 13. Current median age was 20 years. Nineteen (61%) patients had chronic hepatitis C, whereas the remaining 12 patients spontaneously cleared HCV. The median duration of infection was 17 years. Among patients chronically infected with HCV, an enlarged liver and/or spleen on ultrasound was present in 59%, whereas 63% had abnormal aminotransferases and/or gamma-GT values. In conclusion, 39% of the patients infected in childhood cleared HCV spontaneously. The majority of the patients with chronic hepatitis C had ultrasound and/or laboratory abnormalities and these findings may be associated with the presence of chronic liver disease.     

Hepatitis C virus infection in USA: an estimate of true prevalence

The recent National Health and Nutrition Examination Survey (NHANES) sampled only the civilian, non‐institutionalized population of USA and may have underestimated the prevalence of hepatitis C virus (HCV) in this country. We searched the database MEDLINE, the Bureau of Justice Statistics, Center for Medicare and Medicaid and individual states Department of Corrections for all epidemiological studies regarding the prevalence of HCV in populations not sampled by the NHANES survey namely the incarcerated, homeless, nursing home residents, hospitalized and those on active military duty. Because of their relatively low frequency in the NHANES sample, we also expanded our search to include healthcare workers and long‐term dialysis patients. Although included in the NHANES sample, we also performed searches on drug users (injection and non‐injection) and veterans to confirm the findings of the NHANES study. Based on the prevalence of studies identified meeting our inclusion criteria, our most conservative estimates state that there at least 142 761 homeless persons, 372 754 incarcerated persons and 6805 persons on active military duty unaccounted for in the NHANES survey. While the NHANES estimates of drug users (both injection and non‐injection) appear to be reasonable, the survey seems to have underestimated the number of HCV‐positive veterans. Our most conservative estimates suggest that there are at least 5.2 million persons living with HCV in USA today, approximately 1.9 million of whom were unaccounted for in the NHANES survey.     

Hepatitis C in haemophilia: lights and shadows

Summary.  Hepatitis C is a major cause of morbidity and mortality in haemophiliacs who received clotting factor concentrates before the availability of virus-inactivated factors in the mid-1980s. Early studies gave conflicting indications as to the severity of hepatitis C (originally termed non-A non-B hepatitis), as mild, slowly progressive hepatitis was documented in several infants and young adults with haemophilia who were examined with repeat liver biopsies, whereas more progressive hepatitis and cirrhosis was documented in others. One major point of dispute was whether these discrepancies could in part be accounted for by epidemiological differences among studies, as hepatitis C acquired early in life may initially run a benign course and later worsen owing to spontaneous recrudescence of hepatitis or interference with such comorbidity factors as alcohol abuse or infection with the human immunodeficiency virus (HIV). In the mid 1990s, the latter infection overshadowed hepatitis C as a cause of death in this patient population. Because hepatocellular carcinoma is emerging as an important complication in haemophiliacs with long-standing hepatitis C virus (HCV) infection who survived HIV infection, and because of recent advances in treating HIV, morbidity and mortality associated with chronic hepatitis C have regained emphasis amongst haemophiliacs. The development of newer interferon-based therapies provides an opportunity for modifying the natural history of HCV infection in a substantial number of haemophilic patients.     

Hepatitis C infection and outcomes in the Scottish haemophilia population

Patients with bleeding disorders previously frequently became infected with hepatitis C virus. We identified the number of patients infected in Scotland and assessed several aspects of the outcomes of HCV infection and its treatment comparing these with cohorts infected for other reasons. We calculated the number of individuals infected in Scotland (cohort A) starting with the total number of patients treated in Scottish haemophilia centres registered on the UKHCDO database between 1970 and 1989. Cases were then removed or added based on additional information from centre records. A second cohort B, consisted of 255 patients from cohort A and 47 patients HCV infected outside Scotland, but with follow‐up data from Scottish centres around their HCV infection. We estimate that 455 patients with bleeding disorders became infected by coagulation factor provided by NHS Scotland. In 302 individuals with documented HCV infection, rates of natural clearance (17.4%), genotype spread (64% genotype 1) and responses to antiviral therapy (14.5% with monotherapy; 38.8% with combination therapy) were similar to those in other cohorts. Thirty‐four liver biopsies were performed without adverse event and liver transplantation has been performed in 11 patients, seven for liver failure, four for hepatocellular carcinoma. Around 455 patients with bleeding disorders became HCV infected in Scotland before 1989. The natural history of HCV infection and responses to treatment are similar to those in other HCV‐infected cohorts. Liver transplantation has been used successfully for the treatment of end‐stage liver failure and hepatocellular carcinoma.     

Hepatitis C genotypes in Australian haemophilia patients

Background: Differences in the hepatitis C virus (HCV) genotype influence the severity of HCV related liver disease and response to interferon therapy. HCV infection is frequent in Australian haemophilia patients who have been exposed repeatedly to multiple HCV genotypes through non HCV virally inactivated clotting factor concentrates. The distribution of the various HCV genotypes in Australian haemophilia patients is unknown. Aim: To examine the HCV genotype distribution and clinical features of HCV associated liver disease in Australian haemophilia patients. Methods: Forty patients with bleeding disorders who were known to be both HCV antibody and polymerase chain reaction (PCR) positive were evaluated by direct sequencing of the PCR products for the HCV genotype. Results: Genotype 1 was found in 65% of patients (26/40), type 2 in 5% (2/40) and type 3 in 30% (12/40). No genotypes 4 to 6 were found. There was no association between the HCV genotype and the severity of haemophilia, alanine transaminase levels, or the presence of portal hypertension. Unlike European, Asian and American studies where the majority of type 1 infection is subclass lb, in Australian haemophilia patients it is subclass la (73% - 19/26) which may have a better prognosis and response to interferon. Conclusions: Despite patients with haemophilia being exposed to multiple HCV genotypes, it appears that there is no selection advantage of one genotype over another. Australian haemophilia patients with HCV have a different genotype distribution to that reported in other countries and care should be observed in interpreting non Australian studies concerning HCV.     

Hepatitis C virus quasispecies in the natural course of HCV-related disease in patients with haemophilia

Patients with haemophilia show high prevalence of hepatitis C infection but low rate of progressive liver disease when they are not co-infected with HIV. The balance between host immune system and hepatitis C virus (HCV) variability seems to play a major role in the evolution of the HCV-related disease. To address this point we have studied, in a group of selected patients with haemophilia, the composition and in some cases the evolution, of the highest variable envelope gene within the hypervariable region 1 (HVR1) of the HCV, which is the region more directly exposed to the host immune response. Five of 12 patients show a very high homogeneity of the HVR1 and four of those had severe progressive liver disease. These results seem to confirm the major role of the immunity in driving the variability of the HCV rather than the high degree of different HCV strains to which haemophiliacs have been in touch with, during their long-term replacement therapy. Our results seem in keeping with other studies on different type of patients, where a low degree of quasispecies variability has been demonstrated in relationship with the progression and the severity of their liver disease.     

Hepatitis C seropositivity in HIV-negative children with severe haemophilia

Summary. With the advent of new viral inactivation and purification methods for factor concentrates in the 1980s, transmission of both HIV-1 and hepatitis viruses has been significantly decreased. However, on routine annual testing of the paediatric population at the New England Hemophilia Center (NEHC), several children were noted to be hepatitis C (HCV) seropositive. Thus, a retrospective review of children with severe haemophilia was undertaken. Twenty-six children (median age: 7.5 years) under the age of 12 were identified. All were HIV-1 seronegative and had received hepatitis B immunization. Of these, 22 had received factor concentrate. Four children had no documented HCV serostatus, and seven were HCV seropositive using a second-generation ELISA. Transfusion products were reviewed and stored serum samples were evaluated using a second-generation ELISA to identify the approximate date of seroconversion with positive tests confirmed by RIBA analysis. Three children became seropositive before 1989 using factor concentrates with early viral attenuation procedures. Two children who seroconverted after 1991 received only monoclonal affinity purified factor concentrate that was either pasteurized or solvent/detergent treated. There was no evidence of horizontal or nosocomial viral transmission. We are unable to prove causality with the factor concentrates used by these children. Continued surveillance with sensitive measures for detection of HCV in persons with haemophilia using plasma-derived factor concentrate is necessary.     

Hepatitis C virus infection: prevalence,predictor variables and prevention opportunities among drug users in Italy

Summary. The study assessed rates and predictor variables of hepatitis C virus (HCV) infection among drug users receiving pharmacological treatment for opiates addiction.
There was a large cohort study in 16 public centres for drug users in north-eastern Italy, with data collected by standardized face-to-face interviews between February 2001 and August 2001.
Of 1095 participants, 74.2% were HCV seropositive. Anti-HCV status was independently associated with duration of drug use of over 10 years, injecting as a route of drug administration, and hepatitis B virus (HBV) and human immunodeficiency virus (HIV) seropositivity. Further statistical analysis was conducted by dividing the subjects on the basis of the duration of heroin use: more or <10 years. In the multivariate analyses, route of drug administration and HBV status were associated with HCV seropositivity among both groups. Less education was associated with HCV among the shorter term drug users. HIV status and having a sexual partner with a history of drug use were associated with HCV seropositivity among the longer term drug users.
Half of the short-term heroin users were still HCV seronegative when starting treatment, suggesting opportunities for reducing new HCV infections. Remarkable was the relationship between vaccination for hepatitis B and HCV serostatus. Being HBV seropositive was strongly associated with being HCV seropositive. But heroin users who had been vaccinated for HBV were not significantly more likely to be HCV seropositive than heroin users who were HBV seronegative. HBV vaccination does not provide biological protection against HCV; however, vaccinating heroin users against HBV may help to create a stronger pro-health attitude among heroin users, leading to a reduction in HCV risk behaviour.     

The natural history and antiviral treatment of hepatitis C in haemophilia

People with haemophilia who received non-virucidally treated large-pool clotting factor before 1986 were infected with hepatitis C virus (HCV), previously referred to as non-A, non-B hepatitis. Approximately one-tenth of patients have been shown to clear infection naturally and shown persistently negative HCV PCR. Patients have been infected with genotypes 1, 2 and 3 reflecting the plasma donors in Northern Europe and the United States. Several studies have shown that HCV mono-infection has a very slow progression. Co-infection with human immunodeficiency virus (HIV), however, can hasten the progression to cirrhosis and liver failure. Genotype 1 and older age at first infection also increase the progression rate. Candidates with detectable HCV RNA are candidates for therapy. The combination of standard interferon-alpha and ribavirin doubles the effectiveness of interferon-alpha alone and is the current standard of care for the treatment of chronic hepatitis C. The duration of therapy depends on the genotype and level of viraemia. Patients with genotypes 2 or 3 should have 6 months' therapy while those with genotype 1 and > 2 million copies mL-1 should have 1 year of therapy. Pegylated interferon is an emerging therapy. Patients co-infected with HIV, in whom treatment has stabilized the HIV infection, may be able to tolerate therapy for HCV infection. Liver transplantation is indicated for patients with haemophilia who have decompensated hepatitis C infection.     

Hepatitis G virus RNA and its relation to hepatitis C infection in adult haemophilic patients

The prevalence of hepatitis C virus (HCV) infection and hepatitis G virus (HGV) RNA were studied in 50 adult haemophilic patients who had received commercial clotting factors prior to 1980. HGV RNA was detectable in 6/50 patients (12%); 49/50 (98%) had antibody to HCV and 40/49 (82%) of these were viraemic with detectable HCV RNA; 5/6 patients with detectable HGV RNA had co-existing HCV infection and viraemia. The HGV PCR products from all six patients were directly sequenced and all were shown to be similar to that of HGV but more diverse from that of GB virus C. One patient who had persistent abnormal liver function tests had detectable HGV RNA but no evidence of hepatitis B or C. The presence of HGV RNA in the absence of hepatitis B and C infection indicates that this virus is capable of independent transmission. Independent response to interferon was demonstrated in one patient with co-infection who lost HGV but not HCV after interferon therapy.     

Effect and side-effects of alpha interferon treatment in haemophilia patients with chronic hepatitis C

To evaluate the effect and side-effects of alpha interferon 2B (IFN) treatment in haemophilia patients with chronic hepatitis C (positive HCV antibody test, positive HCV-RNA test and ALT levels >2.5 × upper limit of normal) eight HIV and HBs-ag negative haemophilia patients were treated with IFN for 26 weeks in a dosage of 5 mega units (MU) daily for 2 weeks, 2.5 MU daily for 4 weeks and 1.5 MU 3 times a week for 20 weeks. Patients who were transient or non-responders after 26 weeks of IFN therapy were treated for 2.5 years with 5 MU IFN three times a week. At the end of 3 years follow-up, four patients were considered complete responders (HCV-RNA negative) with complete and sustained ALT normalization and disappearance from HCV-RNA from blood, two patients only showed a transient response and two patients were non-responders.
All patients experienced the common side-effects of IFN treatment. Two patients complained about feelings of depression and impotence. For both this was the reason to stop IFN treatment. In one patient, IFN treatment was stopped 90 weeks after start of therapy because of persistent fatigue. In another patient the dosage was adjusted because of a decrease in platelet count.
No effect of IFN on bleeding frequency and chronic arthopathy was seen.
We conclude that the clinical effects and side-effects of IFN therapy in patients with haemophilia and chronic hepatitis C are comparable with those of non-haemophilia patients with chronic hepatitis C. Haemophilia patients can be treated for chronic hepatitis C infection in the same way as patients without haemophilia.     

Hepatitis C testing practices and prevalence in a high‐risk urban ambulatory care setting

Summary. Approximately 3.2 million persons are chronically infected with the hepatitis C virus (HCV) in the U.S.; most are not aware of their infection. Our objectives were to examine HCV testing practices to determine which patient characteristics are associated with HCV testing and positivity, and to estimate the prevalence of HCV infection in a high‐risk urban population. The study subjects were all patients included in the baseline phase of the Hepatitis C Assessment and Testing Project (HepCAT), a serial cross‐sectional study of HCV screening strategies. We examined all patients with a clinic visit to Montefiore Medical Center from 1/1/08 to 2/29/08. Demographic information, laboratory data and ICD‐9 diagnostic codes from 3/1/97–2/29/08 were extracted from the electronic medical record. Risk factors for HCV were defined based on birth date, ICD‐9 codes and laboratory data. The prevalence of HCV infection was estimated assuming that untested subjects would test positive at the same rate as tested subjects, based on risk‐factors. Of 9579 subjects examined, 3803 (39.7%) had been tested for HCV and 438 (11.5%) were positive. The overall prevalence of HCV infection was estimated to be 7.7%. Risk factors associated with being tested and anti‐HCV positivity included: born in the high‐prevalence birth‐cohort (1945–64), substance abuse, HIV infection, alcohol abuse, diagnosis of cirrhosis, end‐stage renal disease, and alanine transaminase elevation. In a high‐risk urban population, a significant proportion of patients were tested for HCV and the prevalence of HCV infection was high. Physicians appear to use a risk‐based screening strategy to identify HCV infection.     

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.     

Hepatitis C virus antibody-positive patients with HIV infection have a high risk of insulin resistance: a cross-sectional study

Objective

The aim of the study was to characterize and compare insulin resistance (IR) in hepatitis C virus (HCV)‐antibody (Ab)‐positive and HCV‐Ab‐negative patients with HIV infection.

Methods

This was a single‐centre cross‐sectional study of 1041 HIV‐infected patients (373 HCV‐Ab‐positive; 167 with detectable plasma HCV RNA). Metabolic and anthropometric assessments were performed, including measurement of IR using the homeostasis model for assessment of insulin resistance (HOMA‐IR).

Results

The prevalence of IR (i.e. a HOMA‐IR score ≥3.8) was significantly higher in HCV‐Ab‐positive than in HCV‐Ab‐negative patients (47.7 vs. 32.7%; P<0.0001). On multivariable linear regression analysis, the following variables were associated with HOMA‐IR score, expressed as an estimate of the percentage variation (Est.): high‐density lipoprotein cholesterol (per 0.3 mmol/L increase: Est.–4.1; P=0.01), triglycerides (per 0.1 mmol/L increase: Est. 0.6; P<0.001), alcohol intake (Est. ?12.4; P=0.002), sedentary lifestyle (Est. 14.7; P<0.001), CD4 T‐cell count in the highest quartile, i.e. ≥690 cells/μL (Est. 20.7; P=0.002), body mass index in the highest quartiles, i.e. ≥22.54 kg/m² (Est. 30.5–44.7; P<0.001), waist‐to‐hip ratio in the highest quartile, i.e. >1 (Est. 30.2; P<0.001) and HCV‐Ab positivity (Est. 24.4; P<0.001).

Conclusions

Our data confirm that HCV‐Ab positivity is an independent risk factor for IR. Management aimed at correcting known risk factors for IR should be implemented.     

Combination therapy with ribavirin and interferon in a cohort of children with hepatitis C and haemophilia followed at a pediatric haemophilia treatment center

Nearly all children with bleeding disorders who received factor concentrates prior to the late 1980s were infected with hepatitis C. Treatment of adults infected with hepatitis C with combination therapy consisting of ribavirin and interferon has shown sustained response rates of 30-60%. Little data is available on the response of children infected with hepatitis C treated with combination therapy, especially those with bleeding disorders. We wish to report a single paediatric haemophilia treatment center's results of treatment of adolescents with haemophilia and hepatitis C infection with combination therapy. All patients followed at the haemophilia treatment center with hepatitis C, who were human immunodeficiency virus (HIV) negative and had a measurable hepatitis C viral load were eligible. Study patients received at least 6 months of 3 MU interferon-alpha via subcutaneous injection three times per week and 1000 mg day(-1) of ribavirin. Eleven patients agreed to participate in the study. Three patients had an un measurable viral load after 6 months of combination therapy. All three completed 12 months of medication and continued to remain free of hepatitis C for 12 months after discontinuation of therapy. Side-effects of combination therapy were significant but tolerable. The sustained response rate in this study is similar to the historical response rate seen in adults but less than the other reported response rates seen in children treated with combination therapy. Given the toxicity of combination therapy, and natural history of hepatitis C infection in children, consideration of a liver biopsy to evaluate disease progression prior to considering antiviral medications is warranted.     

Treatment of chronic hepatitis C in patients with haemophilia: a review of the literature

Summary. Chronic hepatitis C is a major cause of morbidity and mortality in haemophilia patients. In contrast to studies in the general population, the studies of antiviral therapy in haemophilia patients are limited and often include small numbers of patients. A review of the literature was performed to assess the efficacy of interferon (IFN)‐based therapy for patients with haemophilia chronically infected with hepatitis C virus (HCV). Studies were identified by electronic searches (Medline, Embase) and hand searches in references of key articles. Data of the included studies were pooled, and responses to therapy were stratified according to treatment regimen, HIV co‐infection status, and treatment history. The main outcome was a sustained virological response (SVR) defined as absence of HCV RNA both at the end of treatment and 24‐week post‐treatment. Thirty‐five studies were identified that included 1151 patients. After pooling the data of included patients, the SVR in HIV‐negative treatment naïve patients was 22% for IFN monotherapy, 43% for IFN and ribavirin, and 57% for pegylated IFN and ribavirin, respectively. Re‐treatment with IFN and ribavirin of those who failed to respond to previous IFN monotherapy was successful in 33%. In HCV/HIV‐coinfected patients, response to IFN monotherapy was 8% and to IFN combined with ribavirin 39%. Responses to IFN‐based therapy in patients with haemophilia have been improved over time and are nowadays approximately 50–60%. However, data on haemophilic HCV/HIV‐coinfected patients and in patients who failed to respond to previous therapy are limited and future studies in these specific patient population are necessary.     

Hepatitis delta virus infection prevalence,diagnosis and treatment in the Middle East: A scoping review

Hepatitis D virus (HDV) infection is a global public health concern, especially because of its unique existence in the presence of hepatitis B virus infection. HDV infection is estimated to affect 12 million people globally. Having a clearer understanding of its prevalence in all regions of the world is essential for helping direct preventive and early interventional treatment. This mini-review assessed the literature over the last 10 years to determine the prevalence, diagnostic means and treatment guidelines available for HDV in the Middle East. The search found limited data available in 21 articles, of which 18 were studies focused on Iran. Prevalence rates ranged dramatically among the countries, and none of the 12 countries included in the search had specific HDV guidelines. This review highlights the urgent need for more precise data for the Middle East region to help establish early diagnosis and treatment options for HDV.     

Splenectomy and antiviral treatment for thrombocytopenic patients with chronic hepatitis C virus infection

Summary. Thrombocytopenic patients with chronic hepatitis C virus (HCV) infection are poor candidates for antiviral treatment with interferon (IFN), but no standard treatment for thrombocytopenia has yet been established. We evaluated the safety of splenectomy and its efficacy for the initiation and continuation of antiviral therapy. From March 2003 to April 2006, 10 patients (mean age 62.5 years) with HCV‐related cirrhosis, low platelet count (≦106 000/mm³) and splenomegaly (spleen size ≧10 cm) underwent splenectomy. Platelet counts significantly increased at 4–8 weeks after splenectomy [pre: 64 200 ± 6900/mm³vs post 209 000 ± 40 600/mm³ (P = 0.004)]. No severe operative complications were observed. All patients subsequently received antiviral therapy. Of the eight patients who were infected with HCV genotype 1 and had a high viral load (≧100 KIU/mL), four received combination therapy with pegylated IFNα‐2b plus ribavirin, and the other four received standard IFNα‐2b plus ribavirin. One patient infected with HCV genotype 2 and another with HCV genotype 1 and a low viral load (<100 KIU/mL) were treated with pegylated IFNα‐2a. Six patients achieved sustained virologic response (SVR). Among four patients who failed to achieve SVR, one was given retreatment with pegylated IFN plus ribavirin, and the other three received low‐dose long‐term IFN therapy. Although this study was small, the treatment results were similar to those for patients without thrombocytopenia and suggested that splenectomy would not reduce the antiviral efficacy of IFNα‐based treatment.     

Viral clearance occurs very early during the natural resolution of hepatitis C virus infection in persons with haemophilia

We studied spontaneous hepatitis C virus (HCV) RNA clearance in 12 haemophilic patients. In their earliest anti-HCV positive samples, HCV RNA was undetectable in eight patients (66%), positive by polymerase chain reaction (PCR) but negative by branched-DNA (bDNA) in three others, and quantifiable by bDNA (4839 IU/mL) in only one patient. In contrast, in earliest anti-HCV positive samples from eight matched controls who had persistent viremia, HCV RNA was quantifiable by bDNA in seven (P = 0.0008) and at higher levels (range 4644-678 515 IU/mL; median 43 532 IU/mL). From initial HCV infection, HCV RNA cleared in 7 months or less in four patients and in 1-2 years in six others. HCV persisted for 5 years before clearance in the absence of repeated exposure in one patient. We conclude that HCV clearance usually but not always occurs within 1-2 years after infection and is more likely in those with lower than in those with higher early viral loads.