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HCV Natural History: recent study in women...
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.....exposed to HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany in 1978-79
"Slow Rate of Disease Progression in HCV-Positive Women"
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.
-Atif Zaman, MD, MPH
Published in Journal Watch Gastroenterology October 25, 2005
EDITORIAL by Harvey Alter (CDC)
.....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...."
Journal of Hepatology
(October 2005)
HCV natural history: The retrospective and prospective in perspective
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.
"Outcome in a hepatitis C (genotype 1b) single source outbreak in GermanyÑa 25-year multicenter study"
Journal of Hepatology Oct 2005
Manfred Wiesea, Kurt GrŸngreiffb, Wolfgang GŸthoffc, Michael Lafrenzd, Ute Oesene, Heiner Porstf, for the East German Hepatitis C Study Group
Background/Aims
The natural course of the hepatitis C virus genotype 1b (HCV-1b) infection is still unclear but important for therapeutic decisions. There are few unbiased long-term follow-up studies with known dates of infection.
Methods
Between August 1978 and March 1979, 14 HCV-1b contaminated batches of anti-D immunoglobulin had been administered to 2867 women for prophylaxis of rhesus isoimmunization throughout East Germany. We reexamined 1980 women, representing 70% of the total cohort of 15 centers.
Results
After application of the contaminated anti-D, 93% of the recipients developed an acute hepatitis C. After 25 years, 86% of the 1833 affected women still tested positive for hepatitis C virus antibodies and 46% for HCV RNA. Only nine (0.5%) had overt liver cirrhosis, 30 women (1.5%) developed precirrhotic stages and one HCC was diagnosed. Ten (0.5%) died of HCV related complications, half of these related to additional comorbidity. In the last 5 years, a continuous, but low increase of fibrotic scores was observed.
Conclusions
Young women without comorbidity may clear HCV (1b) infection in more than half of the cases, or develop mild chronic hepatitis C. We confirmed the low risk of progression to cirrhosis in this cohort within 25 years.
Introduction
Hepatitis C virus (HCV) infection is rated by the World Health Organization (WHO) and international consensus conferences as a global health problem, based on its prevalence, the high rate of chronicity, the rate of severe complications such as cirrhosis and HCC as well as the high costs of antiviral therapy and liver transplantation [1-3]. Screening measures by transfusion organizations as well as preventive measures have indeed led to a decreasing incidence of HCV infections in the industrialized world. However, the prevalence of fully-developed illnesses caused by HCV, and the subsequent mortality due to HCV are rising [4]. An evaluation of the risk of progression to cirrhosis and HCC is highly important in relationship to the need for therapy, not only for the general welfare of society but also for the individual patient. In order to make a decision for the appropriate therapy, studies of the natural course of the disease are necessary. This applies especially to aggressive and very expensive forms of therapy which are frequently burdened with side effects, e.g. interferon-ribavirin-therapy for chronic hepatitis C.
Retrospective studies on the natural history of hepatitis C assumed that HCV would lead to cirrhosis over the course of 20 years. However, more recent studies show that the progression of hepatitis C is usually slow and that only a proportion of cases develop rapidly into advanced forms of liver disease [1,5-7]. Existing studies differ widely in design with the particular concern that specialized clinics, which are the sources of some of the studies, are more likely to see patients with advanced chronic liver disease and less likely to see those without any symptoms. International consensus conferences have therefore called for further prospective studies as well documented populations, indicating that natural history studies should begin with the onset of HCV infections. Especially interesting are the rare instances in which infection begins at a known time, such as the hepatitis C outbreak in East Germany in 1978/79 [8-12]. An earlier report regarding this cohort [11] showed the lowest ever reported cirrhosis rate of only 0.4% after 20 years.
Acute course and the early period of follow-up
In the acute stage, the patients showed (at that time unknown) characteristics of an acute viral hepatitis C. One thousand two hundred and twenty-one patients (66.6%) had no, or only imperceptible complaints and often polyphasic ALT pattern [9,10]. In 458 patients, jaundice was evident; fulminant courses of hepatitis were not observed. One hundred and forty-seven women (7%) had not exhibited increased ALT levels after HCV inoculation and tested negative for HCV markers so that they were assessed as inoculated persons without signs of hepatitis.
Clinical data
After 25 years, 1141 patients (62%) of the patients complained of constitutional symptoms such as reduced exertional capacity, weakness and fatigue, abdominal distention, arthralgia, myalgia, or headaches in most cases in a intermittent manner. Sonographic examination revealed an enlargement of the liver (craniocaudal diameter >15cm) and a coarse structure on ultrasound in 343 (19%) of the cohort. Serum ALT activity was normal in 1216 (61%) of the entire cohort. Also in 176 (20%) chronic viremic women the ALT was completely normal, but fluctuating in 138 (16%) and permanently elevated in 554 (64%). Persistently normal ALT levels and no clinical and histological evidence of liver disease were presented in 14 viremic women (0.8%); they are regarded as HCV carriers. Alpha-fetoprotein as marker for hepatocellular carcinoma was elevated in 86 (5%) of the patients above the upper limit of normal, but only one of these patients had a HCC (AFP 43.5-mol/l).
HCV infection status
One thousand five hundred and seventy-three (79%) of the entire cohort were still positive for anti-HCV, and 835 (42%) for HCV RNA by PCR. Twenty-five years after acute hepatitis C, 835 (46%) of all women with documented acute hepatitis showed persistent viremia with HCV genotype 1b, including 185 (10%) who had not responded to treatment with interferon. Conversely, 1145 (54%) had cleared the virus, among them 883 (48%) spontaneously, and 115 (6%) in response to treatment with interferon. The sustained viral response to interferon treatment was surprisingly high (115/300=38%) compared to a similar cohort.
Liver histology
In the last 10 years (15-25 years after infection), liver biopsy specimens had been obtained in 537 patients, including 490 (59%) viremic women. Two hundred and twenty-one liver biopsies were carried out in the last 5 years (see Table 5). Inflammatory activity was absent in 14 (30%) of the nonviremic women and minimal (grading 1-3) in 29 (63%) of the patients. All but one of them lacked any evidence of advanced severe fibrosis. Among the 490 viremic women 254 (54%) showed chronic hepatitis of minimal grade (score 1-3), 182 (37%) of mild grade (score 4-8), and 11 (2.2%) of moderate grade (score 9-13). Mild portal fibrosis with no or rare short fibrous septa (staging score 1 or 2) was present in 270 (55%), and discrete or marked bridging fibrosis (staging 3 or 4) in 43 (9%) of the viremic women. Development of incomplete or complete cirrhosis (staging 5 or 6) was observed in 11 patients during the last 5 years, compared to two patients in the previous time. The trend of the fibrosis scores over time was significant with linear regression. Between the 10-year and the 5-year study period, only a slight increase in precirrhotic and cirrhotic scores was noted.
Final diagnoses, clinical endpoints
After 25 years, 836 HCV infected women (46%) showed a spontaneous recovery with viral clearance, normal ALT levels and/or normal liver histology. One hundred and fifteen women (6% of the total cohort) were cured successfully with interferon/ribavirin in various therapeutic schedules during the last decade.
In contrast, the rate of chronic hepatitis with persistent viremia comprised 868 (47%) women after 25 years. An apparent HCV carrier status was assessed in 14 cases (0.8%). The rate of precirrhotic and cirrhotic stages (1.6/0.5%, resp.) increased slightly in the last 5 years and one hepatocellular carcinoma was diagnosed. Comparing the results between the 20th and the 25th year in a subgroup (n=907) nine apparent carriers and 11 patients with chronic hepatitis deteriorated. The HCV related mortality was relatively low (n=7=0.35%). In additional three cases (0.15%), with severe comorbidity the HCV infection was a partial mortality factor.
Discussion
Not only patients but doctors as well need reliable information regarding the natural course of HCV infection, the former for planning their lives, the latter for a substantiated decision on whether expensive therapy with considerable side effects should be recommended to the patient. Unfortunately, despite a considerable number of publicationsÑFreeman et al. [20] found in a metaanalysis 145 studiesÑa clear answer has still yet be given. After 20 years, progression rates to cirrhosis in studies of posttransfusion hepatitis were 24 (11-37)%, in retrospective studies in Hepatology Centers 22 (18-26)%, in community based cohorts 7 (4-10)% and among blood donors 4 (1-7)%. Seeff found a cirrhosis rate of 42% in retrospective studies, of 11% in prospective studies, and of 2.1% in retrospective-prospective cohort studies [7]. Within his own posttransfusion study, there were 15% cirrhosis after 23 years, and in a study among young men over a period of 45 years, the cirrhosis rate was 5.9% [21]. An HCC was observed in 0-1.3%, and liver-associated death in 1.6-6%, within a mean follow up period of 8-14 years [22-25]. A WHO working group estimated the proportion of infected persons who develop chronic viraemic infection at 75%, the proportion of chronically infected persons who develop cirrhosis -20 years after infection at 20-40% (younger than 40 or older) and the annual rate of HCC among patients with cirrhosis at 1.6% [1]. How can such significant differences be explained? Investigations so far show that there can be no single answer on the prognosis of hepatitis C. Due to the fact that the results depend strongly on the population examined, on the study method and duration of follow up, as well as on host factors (age at infection, sex), co-factors (coinfections, alcohol), viral and transmission factors, and therefore, very variable. In most studies on chronic hepatitis C, there was a bias in favour of severe and progressive cases.
For a valid study on the natural course of hepatitis C, the following demands were set: (1) known date of infection or onset of hepatitis C, (2) inclusion of the full range of the acute virus hepatitis C, (3) no therapy influences to interfere with the natural course, (4) continuous follow-up results until recovery or up to the endpoints death or liver transplant, and (5) control group without hepatitis C.
Because of the mostly unclear onset of hepatitis C, and the course without symptoms over decades, the postulates 1 and 2 are not realised in most studies, including the Irish study on HCV infected women [13]. In contrast, the study we are describing realizes those imperatives because the exact inoculation date is known and the whole cohort inoculated is documented, as well as the full clinical course at the acute stage. The cohort includes -70% of the 2867 women exposed to contaminated anti-D immunoglobulin and is, therefore, a representative study population. Fulfilling the third postulate conflicts with ethical considerations. Refusal of indicated antiviral therapy could not be justified for ethical reasons. In our study, only 15% of the population received treatment. We think the relatively small group of patients treated only has a small influence on the progression rate, so that the results presented here reflect the natural course of HCV (1b) infection. Thirty-eight percent of our patients treated have reached a permanent response (SVR) to various interferon/peginterferon-(ribavirin) treatments carried out over the last 15 years. In our patients, the success of the therapy was significantly higher than in the Irish study, in which none of the 11 women treated obtained an SVR [17].
A complete follow up from the onset to the clinical end points and a matched control group-according to demands 4 and 5Ñis usually impossible [7]. In our study, at least the patients who have either recovered completely or have died have been documented exactly from onset to the clinical end points. This study shows, that in a representative female population with HCV (1b)-infection, the virus has been eliminated spontaneously after 25 years in 48% of all affected women. The virus elimination was significantly higher in icteric cases (66%) compared with asymptomatic courses (P<0.001; Fig. 2). This confirms that an icteric acute course expresses a strong immune response, along with a high degree of self limiting infections [16]. This observation is important for deciding therapy in case of acute icteric hepatitis C [26].
Among the clinical findings, it was noticeable that 62% of the womenÑregardless of the stage of their illness subjectively still described more or less intense symptoms.
In 61% of the women, ALT values were normal, among these 20% of chronic cases of hepatitis. These data correspond to recent studies of patients with persistently normal ALT levels [27,28].
Persisting viraemia with chronic hepatitis C was now documented in 46% of cases, clinically evident cirrhosis in 0.5% of viraemic women, and an HCC in 0.05%. Liver-associated mortality was 0.5% in viremic women (n=10); more than half of them showed significant comorbidity (chronic abuse of alcohol; one HBV superinfection with fulminant course; vascular diseases). Furthermore, most of these women were not in medical care of liver centers. Further six nonviremic women died from other causes (see Table 6). Up to now, no elevated HCV associated mortality was registered.
Altogether, the rate of progressive liver disease was astonishingly low. This is also shown by the histological findings (Table 5). The results for our study population match the findings of Poynard et al. [29], who showed in an extensive histological follow-up study, that the fibrosis patterns in patients with chronic hepatitis C are very heterogeneous: in this study there was one third of slow fibrosers who would first suffer from cirrhosis after 50 years (if at all). As in our study, this group consisted of women who were infected before the age of 40 and did not drink alcohol. The results of our study are certainly positively influenced by the young age (median 24 years), the female sex and a strong immunological response at the time of infection. The absence of other risk factors or coinfections, a low-risk lifestyle, and long-term medical care starting immediately after screening may also have contributed to the benign course. In our study population, there was still only a slight increase in precirrhotic findings after 20 years (see Fig. 3 and trend for fibrosis in Fig. 4). In addition to our earlier study, the 25-year results after this quantitatively high HCV outbreak show that a clear transition to a progressive course of hepatitis C is not evident so far.
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