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HCV natural history in the west & developing world: The retrospective and prospective in perspective
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EDITORIAL
Journal of Hepatology
Oct 2005
Harvey Alter
Department of Transfusion Medicine, Clinical Center, NIH, Bethesda, MD, USA
"........... It is estimated that 170 million persons worldwide are chronically infected with HCV, most of whom reside in developing nations....even if only 10% of such individuals advance to cirrhosis, the global burden of this infection is staggering. Thus HCV, like HIV, is a disease of two worlds....."
Article Outline
The key word in this Editorial, 'iatrogenic,' is derived from the Greek 'iatros' meaning physician and 'genic' meaning 'produced by' or 'related to.' In addition, in current usage, an iatrogenic occurrence must be unintended. Thus, the Merriam Webster definition of iatrogenic is, 'induced 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 'experiments 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 'a 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 'cured' 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 'Tale of Two Cities' and we must address them both with equal measure.
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