Viral load as a predictor of progression of chronic hepatitis C?†‡ (2005)

The long-term sequelae following exposure to the hepatitis C virus (HCV) is a product of outcome of the two phases of the infection: first, whether or not acute hepatitis spontaneously resolves; and second, if virus persists, whether or not the established chronic hepatitis remains stable or progresses. A characteristic of acute HCV infection is its low rate of viral loss, presumably a consequence of a blunted innate immune response to the virus through multiple mechanisms.1 This has prompted efforts to seek features associated with or predictive of viral persistence. Of several identified features, age at initial infection plays a crucial role. Whereas 75% to 85% of older infected persons (usually considered to be >40 years of age) do not lose virus,2 spontaneous resolution occurs in almost 50% of younger infected persons.3, 4 Other items that correlate with failure to recover include male sex, African-American heritage, specific human leukocyte antigen subtypes and polymorphisms, and intrinsic or induced immunosuppression.5 There is scant evidence that either viral load or genotype effect spontaneous resolution. HCV, hepatitis C virus; ESLD, end-stage liver disease; NASH, nonalcoholic steatohepatitis; HTLV-II, human lymphotropic virus type II. The issue shifts from acute to chronic hepatitis C when HCV infection persists for 6 or more months. Concern about the high frequency of chronic hepatitis and its implications has prompted numerous attempts to determine its natural course using several strategies.6 The process has been difficult because both acute and chronic hepatitis C are usually asymptomatic conditions, and the course of chronic hepatitis C is extremely protracted.7 Available data suggest, however, that the course is quite variable. Some people develop slowly advancing liver disease, culminating in end-stage liver disease (ESLD) or hepatocellular carcinoma; some die early with but not from ESLD because of other associated morbidities; and some, perhaps the majority, persist with HCV infection but remain alive and well with stable liver disease, dying ultimately from non-liver disease–related causes. Accurate information on lifetime outcome, therefore, requires many years of careful study, well in excess of two decades. Currently, the anticipated lifetime outcome derives from predictions based on modeling or data extrapolation from natural history studies of only moderate length.8, 9 Accordingly, like the studies performed in regard to viral resolution, efforts have been directed at seeking host-, environmental-, or viral-related features that may portend progression of established chronic hepatitis C. Current thinking is that host-related features play the predominant role. Thus, similar to the acute hepatitis C situation, age at infection seems to be a primary determinant of disease progression, since cirrhosis rates are far lower, at an equivalent time after infection, among infants or young women10, 11 than among those infected at older ages.2, 12, 13 Also, cirrhosis rates are higher in men than women and among immunosuppressed than nonimmunosuppressed persons. Interestingly, African Americans infected with HCV seem to have a slower rate of disease progression than infected Caucasians.14 Other important host-related factors include the co-existence of certain infections (e.g., hepatitis B, HIV, and schistosomiasis), and superimposed nonalcoholic steatohepatitis (NASH), or diabetes.15, 16 By far the leading extraneous factor is concurrent chronic alcoholism. In a classical study by Poynard and coworkers, items identified by multivariate analysis to be associated with fibrosis progression were male sex, age >40 years, and alcohol consumption of >50 g/day.17 In that study, as in a number of others, neither viral load nor viral genotype was found to be associated with liver disease progression. Contradictory data regarding the effect of viral load, however, are reported in this issue of HEPATOLOGY by Hisada et al.18 In this study, which involved 6,570 injection drug users infected with HCV, some of whom were co-infected with HIV and some with human lymphotropic virus type II (HTLV-II), they examined and contrasted the impact of both pre-morbid HCV RNA levels and specific HCV protein antibodies between 84 individuals who had died from ESLD and 301 randomly selected living individuals infected with HCV, stratified by sex, race, and HIV and HTLV-II status. They found the relative hazard of death from ESLD to be unassociated with HCV antibody intensities, but that its rate increased with higher HCV RNA levels. They also noted a significant association between ESLD and nonblack race but found that ESLD was unrelated to alcohol consumption, sex, or HIV co-infection. They thus conclude that among persons with chronic hepatitis C, the HCV RNA level is a predictor of death from ESLD. There have been a number of previous attempts to examine the impact of the serum concentration of HCV RNA on liver disease severity by relating it to the degree of alanine aminotransferase (ALT) activity and the extent of histopathological abnormality.19-36 Most have been single, cross-sectional studies that have not, however, tracked the long-term significance of the findings, as was done in the study reported in this issue of HEPATOLOGY. The results have been varied: the majority found no relationship whatsoever with liver disease severity19-29; some identified increased hepatic inflammation without an impact on fibrosis30-32; and a few identified increasing histological severity with increasing levels of virus.33-36 One recent, compelling study measured and found a positive correlation between serum and liver levels of HCV RNA, but neither level correlated with either ALT activity or histological abnormality.27 Similarly, in another recent study that found a strong correlation between HCV RNA and core antigen levels, no association was identified between the levels of these two viral markers and fibrosis, necro-inflammation, or steatosis on liver biopsy, viral genotype, ALT concentration, or alcohol consumption.28 So, what accounts for the findings by the present authors of a strong association between HCV RNA levels and ESLD, given that the weight of evidence seems to contradict this relationship? Indeed, if their findings are valid it would suggest, as the authors note, that lowering viral load with antiviral treatment may decrease advancement to ESLD, even if virus cannot be eliminated. Possible explanations for these discrepancies are that either the conclusions of previous studies or those of the present study are erroneous, or that both are correct and the variation is accounted for by diverse study populations. Alternatively, disagreement among the differing studies might stem from utilization of serological assays of differing sensitivities or from faulty data interpretation. All subjects in the present study were injection drug users; some were immunocompromised by co-infection with HIV and HTLV II and others possibly by factors peculiar to this population, such as additional infections, co-morbidities, or nutritional deficits. In contrast, most previous studies involved patients with a lesser likelihood of immune compromise. Conceivably, the higher HCV RNA levels might result from the induced immune deficiency, which itself accounts for the liver disease progression. Indeed, as is widely accepted and even referred to by the authors, HCV is not considered a cytopathic agent, further supporting the likelihood that it is the immune compromise rather than the viral load that is responsible for inducing progression of chronic liver disease. Additional evidence for this view is that other HCV-infected groups who are immunosuppressed, such as those co-infected with HIV, those who have received kidney or liver transplants, or those with agammaglobulinemia, display a high HCV viral load and a high likelihood of progressing to ESLD. Thus, the immune dysregulation itself could account for both the raised viral load and the liver disease progression. The issue thus becomes the difference between cause and effect. Regarding relative sensitivities of the serological assays, most previous studies were performed in the early- to mid-1990s, since which time technology has markedly improved; clearly, the present study cannot be criticized on this account. Regarding the varied sophistication of data analysis, the present study also cannot be faulted on this score, although the statistical analyses were highly complex and indeed difficult to easily digest. Of some concern, however, was the reliance of these authors for diagnosis of ESLD on the National Death Index, well known to be far from accurate.37 Another issue to consider is the report by the authors that HIV was not associated with ESLD when adjusted for HCV viral level in multivariate analyses, and that death from AIDS was not associated with HCV RNA. This must be viewed in the context of the time of the study, which occurred prior to the introduction of highly active antiretroviral therapy (HAART). At that time, most deaths resulted from the HIV infection, an outcome that has changed with the advent of HAART; currently, most deaths are due to ESLD. Since progression to cirrhosis generally requires the passage of 20 to 30 years, and the present study began approximately 8 years ago, it is feasible that many study participants already had severe underlying chronic liver disease at study initiation. This raises the issue of lead-time bias. Nevertheless, the findings of these authors cannot be dismissed and are clearly of importance regarding the question of therapy. However, it seems premature to recommend therapy with the implied aim of “reducing viral load” in order to prevent or reduce ESLD until further studies are undertaken using a prospective approach with serial viral level measurements and probably repeat liver biopsies. The basis for progression of chronic hepatitis C is not only of theoretical importance but also has biologic relevance. Since there are those that cannot presently be cured, it is important to identify and ameliorate factors that cause progressive liver disease. Relevant studies are in progress.