|
||||||||||||||||||||||||||||||||||||||||||||||||
NSD: normal spontaneous delivery; n.t.: not tested; CI: cutoff index. **This assay was done using the preserved sample. HCV RNA was measured by *branched DNA assay, **real time PCR, ***qualitative PCR. |
(1) the duration of HCV infection; (2) the presence of cofactors for development of liver fibrosis (such as male gender, ethnicity, older age at infection, heavy alcohol intake, HIV or chronic hepatitis B virus (HBV) co-infection, diabetes, obesity, and hepatic steatosis); (3) access to HCV therapy and a favorable treatment response; and (4) competing mortality risk (such as HIV and illicit drug-related overdose).
The generally slowly progressive nature of chronic HCV, with limited advanced liver disease in the initial 10 to 15 years of infection (even in those individuals with cofactors for fibrosis development), means that duration of HCV infection and its surrogate, age, are key determinants of mortality risk.
Thus, a 50-year-old individual with 30 years chronic HCV is likely to have a higher HCV-related mortality risk, even in the absence of liver disease cofactors, than a 30-year-old individual with 5 to 10 years infection and several cofactors. However, the 50-year-old individual with 30 years infection, with heavy alcohol intake, obesity, and regular cannabis smoking (recently shown to be a liver fibrosis cofactor) will be at particularly high risk.
Out of 100 people that contract the infection, 75–85 people will develop chronic infection, 60–70 people will develop chronic liver disease, five to 20 people will develop cirrhosis over the course of their chronic infection and one to five people will die of complications including hepatocellular carcinoma (HCC).
The introduction of anti‐D immunoglobulin has proved extremely effective in the management of rhesus haemolytic disease, with deaths attributed to rhesus immunization falling dramatically from 46 per 100 000 births before 1969 to 1.6 per 100 000 in 1990.17 While intravenous immunoglobulin was thought to be a relatively safe product,18 there have been two reported epidemics of hepatitis C as a result of its use. Two distinct cohorts of Irish women became infected following exposure to contaminated anti‐D immunoglobulin in 1977/8 and 1991/3, respectively.1 Intravenous anti‐D immunoglobulin was implicated in the large scale transmission of hepatitis C in the former East Germany in 1978.19
Production of anti‐D immunoglobulin in Ireland was commenced by the Blood Transfusion Service Board (BTSB) in 1970. Freeze‐dried intravenous anti‐D immunoglobulin was prepared from plasma containing a high concentration of anti‐D antibody procured in Ireland by the Hoppe method.20 The Hoppe method was refined in 1972, with the main objective of increasing the volume of anti‐D produced. The 1972 method replaced the process of ethanol precipitation with an ultrafiltration step, and also involved a quarantine period of 6 months before using plasma for the preparation of anti‐D. Hoppe believed that by pooling and fractionating only those plasmas which had been stored at least 6 months at −40°C provided a further safeguard against transmitting hepatitis. He believed that storing the plasma until the donor had been examined and repeatedly tested would provide further protection. However, modification of the Hoppe method21 in 1972 was not implemented by the Irish BTSB.
We have studied women who were primipara and received contaminated anti‐D immunoglobulin post delivery in 1977/8. This represents a unique group of patients for whom the source and time of infection are clearly defined. While mindful of the relatively small size of the study group, we have found no evidence of either an increased risk of miscarriage or an adverse effect on subsequent pregnancies. Indeed in the general population, the incidence of spontaneous miscarriage has been estimated at 15–20% of all pregnancies,22 as compared with just 12.4% in the study group. Our study indicates that obstetric intervention and mode of delivery (including normal vaginal delivery, forceps/vacuum delivery and caesarean section) is not significantly influenced by the presence of HCV infection. Our study also shows that HCV infection does not increase the risk of obstetric complications and obstetric interventions.
The favourable outcome of pregnancy and the low transmission rate of HCV may be explained partially by the endogenous production of interferon (IFN). Evidence of this production is indicated by findings from a number of studies. For example, the human placenta has been demonstrated to be a site of IFN manufacture.23 Interferon activity has also been detected in human amniotic fluid,24,,25 in placental blood26 and in perfused placenta.27 Immunohistochemical studies have demonstrated IFNs in feto‐placental units.28
Vertical transmission of HCV occurred in one pregnancy in the study group. While we noted two major congenital abnormalities in the affected group, the number of cases is too small to test any hypothesis as to the possible role of HCV infection.
Mother-to-child vertical transmission of HCV is reported to occur in 3-10% of cases, mostly in the late intrauterine period, at delivery or in the peri-natal period. Many factors have been reported to influence the transmission rate, including maternal high viral load, labour duration, newborn gender, premature membrane rupture and genotype. The role of elective cesarean section to reduce mother-to-child transmission rates is debated and controversial and the guidelines of the European Association for the Study of the Liver (EASL) does not recommend cesarean section to prevent HCV vertical transmission...........
The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection
The aim of this study was to investigate some of the unresolved issues regarding the natural history of HCV infection in a representative subgroup of women (with chronic infection or spontaneous self limited infection) derived from the Irish cohort. The clinical and histological status of these women was investigated at the time of diagnosis in 1994/95 and after 4–5 years of follow up (21/22 years after inoculation). Other features investigated included: symptomalogy, psychosocial impact of HCV infection, extrahepatic manifestations, and HLA class II associations.
This study investigated the natural course of HCV genotype 1b infection in a representative subgroup of a larger homogenous cohort (n=795) who were infected with HCV via contaminated anti-D immunoglobulin in 1977.5 The 87 women with chronic HCV infection and 68 with spontaneous viral clearance described in this study shared similar ethnic origin, sex, demographic characteristics, duration of disease, mode of acquisition, viral genotype, and lacked other possible causes of liver disease. A benign course of HCV infection, lack of disease progression, and low incidence of extrahepatic manifestations were observed in women with chronic HCV infection after a 22 year period.
This benign and non-progressive course of chronic HCV infection was reflected clinically in the mildly elevated serum ALT activity at presentation (17 years after inoculation) (mean 50.6 (31) IU/l) and after five years of follow up (mean 51 (37.5) IU/l). Similarly, the mild histological activity observed at presentation was reflected in the mean HAI and fibrosis scores of 4.1 (1.4) and 1.1 (1.3), respectively. Histological deterioration was not observed after a five year follow up period as the mean follow up HAI and fibrosis scores were 4.1 (1.2) and 1.0 (1.0), and 22.7% (10/44) of biopsies even showed a spontaneous reduction in HAI score.19 Cirrhosis or hepatocellular carcinoma was not observed on the first or subsequent liver biopsy. These results confirm the findings of fellow investigators on Irish anti-D patients showing lack of disease progression over similar time spans but conflict with other studies observing significant fibrosis, cirrhosis, and advanced liver disease within 20 years of disease duration.6 19-26 Several variables have been suggested to influence the progression of HCV, including older age at infection and diagnosis, male sex, excess iron, increased alcohol consumption, and coinfection with hepatitis B virus and human immunodeficiency virus.27-33 Mode of transmission is also thought to be important as patients infected via transfusion receive a more infectious inoculum while those who acquire HCV via anti-D immunoglobulin receive a partially attenuated virus.34 The relatively young age (late 20s) of the women in this study at infection, together with the mode of transmission, and absence of excess alcohol consumption, iron on liver biopsy, and coinfection with other viruses probably contributes to the favourable outcome observed in this unique cohort.
Sixty eight females considered to have spontaneous viral clearance were also investigated in this study. Of these, 32 (47.1%) were still antibody positive 18 years after inoculation. Debate exists as to whether these individuals have truly resolved infection or actually have current infection undetectable in serum but detectable in liver (as viral levels have been demonstrated to be 104-fold higher in the liver than in serum). Furthermore, it has been demonstrated in two separate studies that antibody positive serum PCR patients have similar clinical, histological, and virological profiles as serum PCR positive individuals.35-39 In this study, the mean serum ALT was significantly lower in PCR negative women compared with PCR positive women (p=0.000) (table 3). Similarly, the mean HAI and fibrosis scores of the 27 (40%) PCR negative women who underwent liver biopsy were also significantly lower than those of PCR positive women (p=0.000) (table 3). Furthermore, HCV RNA was not detectable in liver biopsies from serum PCR negative women but was detectable in biopsies from all serum PCR positive women, thus providing evidence that the negative serum PCR status is indeed a true reflection of cleared past infection. Steatosis was however observed at a higher frequency in PCR negative liver biopsies (48%v 10.3% in PCR positive biopsies; p=0.000). In a recent study of a larger group of serum PCR negative individuals, we have demonstrated that 63.6% (21/33) were overweight or obese, as determined by calculation of body mass index, and the histological findings of these women were more suggestive of non-specific reactive changes, steatosis, or non-alcoholic steatohepatitis rather than chronic HCV.40
The 68 women with viral clearance described in this study represent a subgroup of a much larger group with spontaneous viral clearance. The findings from the total infected cohort from 1977 (n=704) may therefore indicate that more individuals spontaneously clear HCV than previously reported, as 314 (45%) of the original cohort were antibody positive but PCR negative for HCV RNA when tested in 1994.4 5Moreover, an additional 74 recipients of 1977 contaminated anti-D volunteered a history of jaundice shortly post partum and are now known to test both antibody and PCR negative.5 In this (table 1) and in another Irish study, a history of acute icteric hepatitis after inoculation has been demonstrated to be associated with spontaneous viral clearance.41 Why such a large proportion of women spontaneously cleared infection while the remainder went on to develop chronic HCV is unclear as the difference in disease outcome cannot be accounted for by differences in age, sex, source/duration of infection, size of inoculum, or alcohol consumption. These findings may therefore suggest that immune-host factors play an important role in the spontaneous clearance of HCV, and in this study the class II DRB1*01 allele was significantly increased in women with spontaneous viral clearance compared with those with chronic HCV infection. These results confirm the findings of a previous study on a larger cohort of these patients and also the findings of two other studies of separate groups of women from the same homogenous cohort.14 42 43
A wide spectrum of extrahepatic manifestations has been traditionally ascribed to chronic HCV infection, with varying strengths of association. The best described of these include cryoglobulinaemia, sicca complex, autoimmune thyroiditis, membranoproliferative glomerulonephritis, and porphyria cutanea tarda.44-46 In our experience, cryoglobulinaemia is the most common of these HCV associated autoimmune disorders. Our observed prevalence rate of 12.7% among PCR positive patients and 0% among PCR negative patients further supports the role of the HCV virus in the pathogenesis of cryoglobulinaemia. In keeping with observations made in Britain, type 3 cryoglobulinaemia was the predominant type.47 However, we have previously demonstrated that Irish anti-D/HCV patients without cryoglobulinaemia were as likely to experience significant fatigue as those with cryoglobulinaemia.15 Tranet al reported a high prevalence of thyroid autoantibodies among patients with chronic HCV infection but did not include the known prevalence rate in healthy controls for comparison.48 The well conducted Wickham survey designed 20 years ago and recently updated provided an ideal sex matched population in the community for this purpose.16 17 Our surprising finding of significantly less autoimmune thyroid disease among the PCR positive population compared with that observed in the Wickham survey does not support the earlier investigators' claims. The observed prevalence rate of thyroid autoantibodies among our PCR negative group may mirror the prevalence among healthy women in the community. Indeed, current studies have failed to establish an association between autoimmune thyroid disease and hepatitis C.49 50 It is likely that the only significance of thyroid autoantibodies in patients with HCV lies in their positive predictive value for interferon associated thyroid dysfunction.51
Glomerulonephritis and HCV dermopathy, including porphyria cutanea tarda and lichen planus, and antibodies to liver-kidney microsome 1 were not detected in this study group.
Initially the symptom profile of the PCR positive and negative women presented in this study (PCR positive patients were found to have fewer complaints of fatigue and arthralgia than PCR negative patients at presentation) was contrary to what might be expected, but when calendar year was taken into account there were no differences in complaints of fatigue between the two groups. This observation, together with the psychological profile of 66 of these women, suggested that when suddenly diagnosed with chronic HCV the identity of this illness as chronic, infectious, and associated with intravenous drug misuse may have caused great concern to the infected women. The impact of such a diagnosis on psychological well being may have been even further compounded by the high legal profile related to this patient group.5 While accepting the uniqueness of this patient cohort, recent studies in other patient cohorts have also documented problems in quality of life and mental health.52-54
In conclusion, this study investigated the natural course of HCV infection in a homogenous cohort almost half of whom now have spontaneous viral clearance. A benign course of HCV genotype 1b infection, lack of disease progression, and low incidence of extrahepatic manifestations was observed in women with chronic HCV after a 22 year period. The host HLA class II DRB1*01 allele was found to be associated with spontaneous viral clearance which supports the notion that host factors may play an important role in disease outcome. Finally, although the outcome of HCV infection was favourable, this study also demonstrated that the diagnosis of HCV was a very stressful event for these women who reported high levels of psychological distress and poor quality of life. It is hoped that longer term follow up of this unique cohort may further provide valuable information regarding the natural course of HCV infection.
One can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection
Most data on the natural history of hepatitis C virus (HCV) infection are retrospective and suggest that progression to cirrhosis occurs during 20 to 30 years. In this prospective study, researchers reported 25-year outcomes in a cohort of women in East Germany who acquired HCV infection from a single-source outbreak of contaminated anti-D immunoglobulin in 1978 and 1979.
Researchers reexamined 1980 women from 15 medical centers (70% of the initial cohort). Mean age at infection was 24; 9.7% of women were obese, and 2.6% had diabetes. Only 3% drank more that 40 g of alcohol daily, and 42% did not drink alcohol at all.
After 25 years, 62% of patients complained of constitutional symptoms, such as headaches, myalgias or arthralgias, and fatigue. Overall, 54% had cleared the virus (48% spontaneously and 6% in response to interferon). Only 9 patients (0.5%) had developed overt cirrhosis, 30 patients (1.5%) had developed advanced fibrosis, and 1 patient had developed hepatocellular carcinoma. Of the 10 patients who had died of HCV-related complications, half had comorbidities (e.g., alcohol abuse). The rate of disease progression increased slightly between the 20-year and the 25-year follow-up evaluations: During these last 5 years, six women developed cirrhosis, and nine developed advanced fibrosis.
Comment: In this unique cohort of HCV patients with known dates of infection, the overall rate of disease progression during 20 years was low. However, because the women had few comorbidities and minimal alcohol consumption, the outcomes cannot be generalized to all HCV patients. The rate of progression to cirrhosis increased during the last 5 years of the study.
The key word in this Editorial, Ôiatrogenic,' is derived from the Greek Ôiatros' meaning physician and Ôgenic' meaning Ôproduced by' or Ôrelated to.' In addition, in current usage, an iatrogenic occurrence must be unintended. Thus, the Merriam Webster definition of iatrogenic is, Ôinduced inadvertently by a physician, surgeon, medical treatment or diagnostic procedure'. Two almost identical and temporally related inatrogenic events involving HCV-contaminated lots of Rh immunoglobulin occurred in Ireland and Germany in the late 1970's. Thousands of women were inadvertently infected with HCV and these Ôexperiments in nature' have, through diligent investigation and long-term follow-up, provided enormous insights into the natural history of HCV infection.
The long-term outcomes of HCV infection have had differing interpretations during the decades since the predecessor virus, non-A, non-B, was first recognized [1]. In the 1970's, non-A, non-B hepatitis (NANBH) was viewed by many as an asymptomatic illness of minor consequence; some considered it merely a non-specific transaminitis. However, as these cases were followed prospectively, it became clear that as many as 20% evolved into cirrhosis [2]. This dramatic outcome stimulated clinical interest in NANBH and in the 1980's increasingly dire reports of severe outcomes emerged. In a now classic study by Tong et al. [3] 46% of post-transfusion hepatitis cases had biopsy evidence of cirrhosis and 11% had hepatocellular carcinoma. However, this and similar severe outcome data in the 1980's, reflected referral bias rather than worsening prognosis. Because of early treatment trials and the emergence of specialized hepatitis centers, the most severe cases of NANBH were being referred and then reported. This is not to impugn the relevance of these observations because Ôa case of cirrhosis is a case of cirrhosis' whether it is found prospectively or retrospectively and confirms that dire outcomes can be part of the natural history of HCV infection. However, such retrospective studies do not provide perspective on the proportion of infected individuals who will manifest these severe outcomes over the lifetime of their infection. In the early 90's, after the monumental cloning of HCV by Houghton and associates [4] and the development of sensitive assays to detect antibody to HCV [5], it became possible to introduce an alternate study design (retrospective-prospective) that allowed testing of unselected samples from decades-old serum repositories and then recall of infected patients and controls to assess outcomes over intervals that that extended from 20 to 45 years. These retrospective-prospective studies, free of selection bias, provided several key insights into the natural history of HCV infection. First, it was observed that the spontaneous recovery rate was higher than previously reported and might approach 25% in adults [6]. Other cohort studies have shown spontaneous recovery rates in children [7] and in some adults [8] to be as high as 45-55%, respectively. The other major finding of retrospective-prospective studies that included liver biopsy data was that the incidence of cirrhosis after approximately 20 years was lower than 15% and sometimes less than 5% and that HCV-related mortality over 20 years only marginally differed from that in uninfected controls [6]. In one, albeit small, study of persons infected as young military recruits, the frequency of cirrhosis after almost 50 years was only 6% [9]. Hence, the outcome of hepatitis C, both in terms of spontaneous recovery and severity, tended to ameliorate as one studied defined cohorts rather than referral cases.
The ideal study to assess HCV natural history is one in which the onset of infection is precisely defined, the infection emanates from a single identified source, where case ascertainment is high, the study population is large, and where follow-up is prospective, comprehensive and of long-duration. Such an idealized combination of study parameters is very difficult to achieve since acute HCV infection is rarely identified, since large common-source outbreaks are unusual and since long-term prospective studies are difficult to support. The iatrogenic outbreaks of hepatitis C related to contaminated Rh immune globulin, though tragic in their occurrence, provide almost all the elements of the perfect natural history study. This is well exemplified in the 25-year follow-up data of Wiese and co-workers [10]. Basically in 1978-79, 14 batches of HCV (genotype 1b)-contaminated Rh immunoglobulin were administered to 2867 women in East Germany. The investigators were able to trace and then follow 1980 women representing 70% of the exposed cohort. Importantly, there was no selection of participants based on outcome, but solely on whether they could be located and were willing to participate in the study. The major findings in this study are highly relevant to HCV natural history assessment and can be summarized as follows: (1) 7% of those with a documented parenteral exposure did not manifest either biochemical or serologic evidence of HCV infection; it is unclear why this sizeable proportion were protected from this highly infectious inoculum and further genetic, molecular and immunologic study of these patients is warranted; (2) of 1718 untreated subjects, a remarkable 49% (836 patients) spontaneously recovery from their HCV infection as evidenced by normal ALT and the absence of HCV RNA; (3) the spontaneous recovery rate was higher in patients who were jaundiced during their acute hepatitis compared to those who were symptomatic but anicteric and those who were asymptomatic (66% vs., 46% vs. 45%, respectively; P<0.001); (4) of the 868 (51%) who developed chronic hepatitis C, 683 were untreated allowing for assessment of natural history over the 25-year duration of the study. Over this prolonged span, only 9 (1.3%) developed cirrhosis, 1 (0.1%) developed HCC and 30 (4.4%) had significant fibrosis that might evolve to cirrhosis; HCV-related mortality was 0.35%; (5) Although <5% progressed to severe fibrosis between years 15 to 25, the trend to escalating severity with increasing time from disease onset was significant by linear regression analysis.
As an epidemiologic aside, in the absence of an iatrogenic transmission, it is now quite rare in Germany or other industrialized nations to be exposed to HCV because the blood supply has been protected, because occupational exposures have been minimized and because sexual and perinatal transmissions are rare. New HCV infections in the developed world are now almost exclusively in persons who put themselves at risk through shared needle exposures in the course of intravenous drug abuse. Further prevention is more a sociologic issue than a medical issue. The situation is different in developing nations where traditional risks are still prevalent.
In sum, from the study of Wiese et al. [10] and a similar study in Ireland [11], one can conclude that a woman infected with HCV in her mid-20's has a near 50% chance of spontaneous recovery and in those with persistent infection, there is only a 5% probability of developing bridging fibrosis, cirrhosis or HCC during the first 25 years of infection. These relatively benign outcomes are quite encouraging, but this population represents a best-case scenario because of the young age and general good health at the onset of infection, and the rarity of co-morbid factors. Risk might increase slightly in males and would increase significantly in those infected at ages beyond 40, those with immunodeficiency states, those with excessive alcohol intake and perhaps those with high body mass index. Nonetheless, the 25-year outcome in the natural history of HCV infection is one of higher than expected spontaneous recovery and lower than predicted morbidity and mortality. In addition, one can now anticipate that 50% of those with genotype 1 or 4 infection and 80% of those with genotype 2 or 3 infection can be Ôcured' by combination treatment with pegylated interferon and ribavirin. Hence, if one conservatively assumes a 25% spontaneous clearance rate, a mild, non-progressive course in 20% of those chronically infected and a 50% sustained treatment response, one can estimate that in immune-competent persons acutely infected with HCV, the probable lifetime risk of severe liver disease will be less than 30%. This percentage will continue to diminish as therapies improve. While these numbers are encouraging and give reasonable hope to the individual patient who has access to treatment, they do not address the global burden of HCV infection. It is estimated that 170 million persons worldwide are chronically infected with HCV, most of whom reside in developing nations and many of whom may be coinfected with HIV and/or HBV and have very limited access to treatment. Even if only 10% of such individuals advanced to cirrhosis, the global burden of this infection is staggering. Thus HCV, like HIV, is a disease of two worlds, one where new infections are rare and effective treatments are available and one where high population density, inadequate preventive strategies and inaccessible treatments maintain HCV as a common disease with devastating consequences. It is a ÔTale of Two Cities' and we must address them both with equal measure.
After HCV acute infection an average 50-85% of patients will not clear the virus, with higher rates in HIV-co-infected subjects, and will therefore remain chronically infected with plateau or fluctuating viremia detectable in the blood. The remaining 15-50% will gradually show a decrease and final disappearance of the virus from the blood, usually within 3 months from infection [15,16]. The complex mechanisms regulating virus clearance and persistence are still not completed understood, but probably imply both host and virus factors. The role of ethnicity has not been proved. On the contrary, sexual transmission of HCV and HBV co-infection might favor viral clearance, probably due to limited inoculum and viral interference, respectively [17]. From the virological perspective, the higher the genetic diversity of the infecting virus, the higher the probability that the immune response will not be able to control its replication, resulting in chronic infection, while a narrow quasispecies spectrum is more likely associated to viral clearance [18]. Of note, similar to hepatitis B infection but without genomic integration, it has been recently demonstrated that HCV may replicate in the liver in the absence of detectable viral level in the blood , a condition sometimes referred to as “occult C hepatitis”, with lower potential for progressive disease [19].
In the setting of persistent hepatitis C viremia, liver fibrosis is the consequence of chronic inflammation leading to the final distortion of hepatic architecture and impairment of liver microcirculation and cell functions. The main consequence of chronic HCV infection is the progression to cirrhosis, often clinically silent apart from non-specific symptoms such as fatigue, upper right quadrant pain or, sometimes, arthralgia and myalgia, until severe complications develop.
In most cases, abnormal ALT values are the only clinical aspecific findings of the disease, only representing a marker of hepatocellular dysfunction. In particular, a direct correlation between the degree of ALT elevation and stage of the HCV-related disease is often lacking as a significant cytolytic activity is not a surrogate marker of disease severity [20] as well as normal ALT does not always mean an healthy liver. Population-based studies indicate that up to 30%-40% of individuals with chronic HCV have persistently normal ALT values when serially tested. However, significant liver disease, with active inflammation and/or at least significant fibrosis, is biopsy-proven in about 20% of HCV carriers with normal ALT [21].
Chronic hepatitis C is the most common cause of cirrhosis and the most common indication for liver transplantation in Europe, North and South America, Australia and Japan. The risk of developing cirrhosis ranges from 5% to 25% over periods of 25-30 years [22].
Environmental and host factors can increase the risk and/or accelerate the natural course of HCV-related disease. Multiple studies have shown that alcohol consumption, in particular a daily intake greater than 40-50 g, is one of the most influential factor driving fibrosis progression in patients with HCV. Age at time of infection also plays a role: the estimated probability of progression is significantly higher in patients that were infected at an older age (> 40 years) [23]. Also, a recent and large analysis of published studies suggests that early acquisition of HCV in childhood is rarely associated to a severe future course of the disease [24]. Other factors that affect the progression of hepatic fibrosis include male gender, the degree of inflammation and fibrosis on the liver biopsy, co-morbidities such as immunosoppression or metabolic condition such as non-alcholic steatohepatitis, obesity and insulin resistance [20].
In addition, co-infection with HBV or HIV are significant risk factors for liver fibrosis. Approximately 4 to 5 million subjects with chronic hepatitis C are co-infected with HIV. Highest co-infection rates are observed among injection drug users (IDU): in the USA and in Europe, among HIV-infected IDU, HCV prevalence may be as high as 70-90 %. Paradoxically, the longer life-expectancy offered to HIV-infected patients by HAART permits slow-acting HCV-related liver injury to emerge as a significant cause of morbidity and mortality in HIV-HCV co-infected patients. Furthermore, the progression rate to cirrhosis and end-stage liver disease is accelerated in HIV co-infected patients: they have a twofold increased rate of cirrhosis compared to HCV mono-infected individuals [25], particularly when HIV associated immune-depression progresses.
The mechanisms underlying accelerated liver disease in HIV-HCV co-infected patients are not completely understood, possibly including direct HCV effects on hepatocytes and hepatic stellate cells as well as immunological alterations such as immune activation, apoptosis and impaired HCV specific T-cell response [26]. Furthermore, liver toxicity of anti-retroviral drugs and the burden of metabolic diseases may contribute to a faster progression of liver fibrosis in HIV-HCV co-infected patients.
Conversely, the role of HCV on the natural history of HIV infection continue to be debated and contrasting evidence exist [27,28].
HCV replication has been observed in extra-hepatic tissues, such as bone marrow, the central nervous system, endocrine glands, lymph nodes, spleen, monocytes, macrophages and skin cells. HCV is also often associated with profound alterations in the host immune system, resulting in immunological abnormalities and even autoimmune disease such as mixed cryoglobulemia (MC), rheumatoid factor (RF) production, B cell lymphoproliferative disorders that may progress to non–Hodgkin lymphoma, and others. Cryoglobulins are immunoglobulins that precipitate in the cold and are classified into three groups, based on Ig clonality. Type I cryoglobulins are usually associated with lymphoproliferative disorders, including myeloma and Waldenstrom macroglobulinemia, and usually consist of monoclonal IgM or IgG, rarely IgA. Type II cryoglobulins are composed of polyclonal IgG and monoclonal IgM, usually characterizing the condition known as essential MC that is often associated with HCV. Type III MC is also characterized by RF activity, although polyclonal IgG and polyclonal IgM exist. The incidence of HCV infection in MC ranges from 40% to 90%, with geographical variations [29]. The high incidence of disease among Mediterranean people and the association of certain human leukocyte antigen (HLA) supports that genetic factors play a role in the disease. The clinical picture is characterized by the skin manifestations ranging from purpura of lower limbs to chronic torpid skin ulcers, more frequent in the sovramalleolar regions. Skin reactions include Raynaud’s phenomenon, livedo reticularis, urticaria, and edema. Arthralgias more frequently involve the hands and the knees symmetrically. Renal injury may complicate MC in almost 30% of cases and involvement of the nervous system from 17% to 60%. Peripheral sensory-motor neuropathy can represent the first clinical sign of cryoglobulinemia.
The natural course of HCV infection remains controversial. The German HCV (1b)-contaminated anti-D cohort provides an ideal population to investigate the natural course of HCV infection in a large and homogenous cohort of young women from the date of HCV inoculation.
Our previous follow-up studies at 20 years and 25 years after infection suggested slow fibrosis progression rates in this unique cohort.
The aim of our prospective community-based multicenter study was to re-evaluate the liver disease progression in 718 patients of the original anti-D cohort at 35 years after infection.
Patients with self-limited HCV infection (n=189) were compared to those who failed to eliminate the virus spontaneously (n=529), comprising patients who were treatment naive (n=197) or achieved a sustained virological response (SVR, n=149) respectively failed to clear the virus (non-SVR, n=183) after antiviral therapy.
In the overall cohort, 9.3% of patients showed clinical signs of liver cirrhosis at 35 years after infection. Liver disease progression largely depended on the HCV infection status. The highest proportion of patients with clinical signs of end-stage liver disease was observed in the non-SVR group (15.3%), whereas decreased cirrhosis rates were detected in the SVR group (6%) and in patients with self-limited HCV infection (1.1%, p=6.2x10−6).
Overall survival was significantly enhanced following SVR compared to treatment naive patients or non-SVR (p=0.027).
Conclusion: The present study provides further evidence for a mild but significant disease progression at 35 years after infection in the German HCV (1b)-contaminated anti-D cohort. Patients with self-limited HCV infection or SVR after antiviral treatment were protected from progressive liver disease and showed the best clinical long-term outcome.
The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.
Chien-Jen Chen, ScD, and researchers from the Genomic Research Center in Taipei, Taiwan, enrolled more than 23,000 adults in Taiwan in their study and followed them from 1991 to 2008. Blood samples were collected at study entry and at follow-up health examinations. Researchers found increased mortality from liver-and non-liver-related diseases—including cancers of the esophagus, prostate, and thyroid, as well as circulatory and renal diseases—among those infected with HCV. Mortality was higher in HCV-infected participants with detectable serum levels of HCV RNA, indicating they had active infections; subjects with previous infections who only had HCV antibodies, but not HCV RNA, in their blood did not have increased mortality on follow-up. The study, published in the Journal of Infectious Diseases and available online, found increased mortality in patients with chronic HCV infection—that is, with detectable levels of HCV genetic material, or RNA, in their blood—suggesting that chronic HCV infections, even in people who have no symptoms, can lead to increased mortality from liver disease or a variety of other causes. The findings highlight the importance of people getting tested for HCV antibodies and for active HCV infection—and of evaluating patients for antiviral treatment when they are found to have an active HCV infection, even when they feel well.
Patients with chronic hepatitis C and advanced hepatic fibrosis were less likely to die from any cause or from liver-related issues after achieving sustained virologic response to interferon-based therapy in a recent study
In an international, multicenter study, researchers evaluated 530 patients with chronic HCV and cirrhosis or advanced fibrosis (defined as Ishak scores between 4 and 6), who received interferon-based treatment between 1990 and 2003. Incidence of all-cause or liver-related mortality, liver failure, hepatocellular carcinoma (HCC) and liver transplant was recorded over a median of 8.4 years of follow-up.
Sustained virologic response (SVR) occurred in 36% of cases, including 125 participants who achieved SVR with initial treatment and 67 who experienced SVR with retreatment after a median of 5.8 years.
During follow-up, 113 participants died, including 13 who achieved SVR. Investigators noted a significant difference in the 10-year cumulative all-cause mortality rates for the groups (8.9% for patients who achieved SVR vs. 26% for those who did not, P<.001).
Liver-related death occurred in three SVR cases and 70 non-SVR cases, and liver transplant was not required for patients who achieved SVR. Transplant was necessary for 46 patients without SVR (including 13 who subsequently died). Researchers calculated 10-year cumulative liver transplant or liver-related mortality incidence rates of 27.4% for patients who did not achieve SVR and 1.9% who did. HCC occurred in seven SVR cases and 76 non-SVR cases, for cumulative incidence rates of 5.1% and 21.8%, respectively. Four SVR patients experienced liver failure compared with 111 without SVR, with incidence rates of 2.1% and 29.9%, respectively (P<.001 for all comparisons).
Multivariate analysis indicated associations between SVR and reduced risk for all-cause (HR=0.26, 0.14-0.49) and liver-related mortality or liver transplant (HR=0.06, 0.02-0.19). Patients who achieved SVR also were less likely to develop HCC (aHR=0.19, 0.08-0.44) or liver failure (aHR=0.07, 0.03-0.20) (95% CI for all).
“Our study indicates that SVR was associated with improved overall survival in patients with chronic HCV infection and advanced hepatic fibrosis,” the researchers concluded. “In addition, we were able to further establish and quantify the risk reduction of HCC, liver failure and liver-related mortality or liver transplantation in patients with SVR.”
The initial 5 of 10 patients treated with antiviral therapy in 1986 at the NIH for chronic HCV achieved an SVR and had both biochemical and histological evidence of improvement in the year following treatment. These five patients have now been followed up for more than 20 years and remain HCV RNA-negative and have normal or near-normal serum enzyme levels.
Liver biopsies on these patients 10 years after initial therapy showed resolution of the disease activity and regression of fibrosis in some. After this initial study, patients at the NIH were enrolled in various therapeutic trials for chronic hepatitis C. As of 2003, a total of 103 patients had achieved an SVR, all in response to interferon-based therapy. The duration of subsequent follow-up in these 103 patients varied from a few months to as long as 23 years. In this cohort, three patients relapsed, and the remaining 100 patients had markedly improved liver tests at the time of follow-up evaluation and none had clinical evidence of advanced cirrhosis, hepatic decompensation or end-stage liver disease.
These findings indicate that an SVR from interferon-based therapies for chronic HCV is usually durable and associated with improvement in biomarkers of disease, a favourable long-term prognosis and lack of evidence of progression of liver disease.
Similar findings after SVR in chronic HCV have been published in other cohorts. However, the current analysis extends this experience to more than 20 years after therapy. Importantly, while patients who achieved an SVR did not develop progressive liver disease, at least one case of HCC still occurred. In this cohort, one patient who had cirrhosis before treatment developed HCC despite having had an SVR 12 years previously. The occurrence of HCC after SVR has been reported in several cohorts, although the rate of liver cancer appears to be far less than occurs among untreated patients with advanced fibrosis or cirrhosis due to chronic hepatitis C. Such findings suggest that patients with an SVR should continue to have regular surveillance for HCC if they had histological evidence of cirrhosis before treatment.
A shortcoming of this study is the lack of a control group of patients with chronic hepatitis C who were not treated or a comparison group of patients who were treated but did not achieve an SVR. However, it was not feasible or considered ethical to randomise patients to therapy vs. no therapy and follow them for an indefinite period. In early controlled trials of interferon for hepatitis C, some patients were not treated for the initial 1–2 years after randomisation. However, the controls from those studies were subsequently offered therapy on an open-label basis and some achieved an SVR and are a part of this analysis. Since 1992 and the approval of interferon as therapy of hepatitis C, all large 'controlled' trials of treatment have compared one interferon-based regimen to another and patients were not given placebo or randomised to no therapy.
Another approach to assessment of the possible benefit of an SVR is to compare patients who achieve an SVR to those who relapse or do not respond. However, multiple studies have shown that patients who have an SVR have a durable loss of HCV RNA and are less likely to have advanced fibrosis or cirrhosis. For these reasons, such comparisons require careful balancing of risk factors. Among the 262 patients treated in at this centre, the majority of the non responders were retreated at one time or another, with differing regimens and often at different institutions.
Use of transient elastography, a non-invasive marker for hepatic fibrosis, suggested that 41% of the cohort had residual evidence of fibrosis at the time of last follow-up 3–23 years after SVR. The elevated elastography scores were not associated with residual abnormalities of serum aminotransferase levels but were more likely to be abnormal in patients who had advanced fibrosis or cirrhosis before treatment.
This suggests that some degree of fibrosis persists despite the resolution of disease activity as assessed by serum enzymes. Slight decreases in platelet counts at the time of final follow-up also correlated with the initial liver histology. Elastography scores were not available from before treatment, but improvements in other markers of advanced disease (platelet count, direct bilirubin, immunoglobulin levels) suggest that SVR may be associated with subsequent improvement in portal hypertension and perhaps partial regression of fibrosis. These findings suggest that the greatest benefit from successful eradication of HCV may be in non-cirrhotic patients, but that even patients with advanced disease, gain a benefit from treatment.
In summary, with continued follow-up of patients with chronic hepatitis C for up to 23 years after achieving sustained clearance of HCV RNA, progressive liver disease was not seen. Among patients who had advanced fibrosis and cirrhosis before being treated, evidence from platelet counts and transient elastography suggested the persistence of some degree of hepatic fibrosis and a low but continued risk for HCC.
The natural history of hepatitis C virus infection differs between women and men. Women demonstrate a slow rate of disease progression until menopause. Older women are more likely to develop fibrosis and are less responsive than younger women to pegylated interferon and ribavirin. Women of childbearing age have higher rates of sustained virologic response, but current therapies are contraindicated during pregnancy. Vertical transmission of hepatitis C virus occurs, but data supporting recommendations for prevention of mother-to-infant transmission are limited.
Women also manifest slower progression to two major chronic HCV infection complications, cirrhosis and hepatocellular carcinoma. In a cohort of 376 Irish women chronically infected with HCV from contaminated anti-D immunoglobulin, only 1.9% had progressed to histological cirrhosis after a mean of 17 years following exposure. The low rate of fibrosis progression was confirmed in a 25-year follow-up study of 167 women, of whom 1.2% developed histological cirrhosis. Male sex was identified as an independent risk factor for developing hepatocellular carcinoma in several studies. This sex-specific predilection for complications of liver disease is not completely understood. Some experts posit that higher estrogen states exert a protective effect on the liver. Animal models suggest that estrogen suppresses hepatic fibrosis, and a recent in vitro study proposed that estrogen inhibits the production of HCV virions. Multiparous women exhibit lower stages of fibrosis than nulliparous women, and fibrosis progression accelerates after menopause. In observational studies, women who received hormone therapy (HT) appeared to have a slower progression to fibrosis; however, the benefits of HT in women with HCV have not been established. HT appears to be safe in women with liver disease when indicated for other reasons.
