Acute hepatitis C is a rare diagnosis in clinical practice nowadays because most patients with this condition are either asymptomatic or perhaps do not feel sufficiently ill to seek medical advice(2). Acute hepatitis C was once common after transfusion of contaminated blood, but with the advent of scrupulous blood screening, the condition is now often seen following needle-stick injuries and in intravenous drug users (IVDU).

Hepatitis CV is currently responsible for 10-20% of all cases of acute hepatitis seen in clinical practice. The natural history of acute hepatitis C has been well documented in several retrospective and prospective studies. These studies have shown that 25% of individuals who contract HCV clear the infection spontaneously as evidenced by the loss of HCV RNA and in 10% the concomitant loss of HCV serologic markers, and the remaining 75% progress to chronic hepatitis C(7). Of all patients who developed acute hepatitis C, 3.5% subsequently died of liver-related disease and an additional 15-30% of living patients developed cirrhosis. Thus severe progressive disease develops in 15-20% of patients with acute hepatitis C(8). The remaining 55% of patients will continue to have stable and apparently non-progressive disease. Because of the short duration of follow-up (10-20 years in most trials), the long-term outcome of those patients with stable disease is at present unknown(7,9).

Traditionally, the course of acute hepatitis C is believed to run for approximately 6 months. If HCV infection persists beyond this period, chronic hepatitis C is said to be present. This is because spontaneous clearance of HCV is rare after 6 months (10). Figure 2 illustrates the time sequences of antibody seroconversion and viraemia that follows acute infection with HCV. The understanding of these sequences helps in the diagnosis of acute hepatitis C and in the interpretation of the results of antibody and HCV-RNA PCR results. Acute hepatitis C can be confidently diagnosed when there is a recognizable time point of exposure (e.g. needle-stick injury) preceded by negative HCV RNA PCR and followed by the development of HCV viraemia (positive PCR) and ultimately the development of antibody seroconversion detectable by either Enzyme Immunoassay (EIA) or Recombinant Immunoblot Assay (RIBA). This however is rarely seen except during monitoring following needle-stick injuries. Acute hepatitis C may also be considered a strong possibility when a subject who is PCR positive but antibody negative later develops antibody seroconversion. Patients with multiple time exposure points (e.g active IVDU) who are positive for both antibody and PCR are not generally considered to have acute hepatitis C as most of these subjects are chronic carriers.

Figure 2:  Time sequence of virological and biochemical markers of HCV infection following exposure to HCV

Other less common indicators of acute hepatitis C infection include the detection of fluctuating HCV RNA levels over a period of three months, the presence of very low viral loads and intermittently positive HCV PCR, all occurring within a period of weeks in a patient who may have already developed antibodies to HCV.

The treatment of acute hepatitis C, like that of chronic hepatitis C, progressed over the years from interferon monotherapy to combination therapy. The initial experience with interferon monotherapy in acute hepatitis was summarized in three consecutive metanalyses(11-13). The first metanalysis, reported by Camma et al(11), established the efficacy of interferon mono-therapy in acute hepatitis C and documented that such treatment produced significantly better virological responses than no treatment. The second metanalysis showed that the therapeutic benefit of interferon can be achieved even when shorter courses (6 weeks) were used as compared to long (12 weeks) courses(12). Furthermore, increasing the dose of interferon produced even better virological responses. The third metanalysis showed that a 3-month course of interferon achieved a sustained virological response (SVR) in 32% of patients with acute hepatitis C as compared to 4% in untreated patients(13). However, these metanalyses have not provided data on the long-term efficacy of interferon therapy in patients with acute hepatitis C, a fact referred to in a recent Cochran Database Systemic Review(14). An excellent review of therapies in acute hepatitis was included in the 2002 National Institutes of Health (NIH) consensus development centre on the management of acute hepatitis C(15). The authors of this review noted that a virological response of 62% can be achieved with interferon in patients with acute hepatitis as compared to 12% in untreated controls. There is evidence that increasing the dose of interferon can achieve superior virological response and that delaying such treatment for 8-12 weeks after onset of disease does not influence the outcome of treatment(15-18).

Three uncontrolled trials focused on the use of pegylated interferon in the treatment of acute hepatitis C(19-21). In the largest of these trials(19), 40 patients with acute hepatitis C were randomized to receive either pegylated interferon plus ribaverin or pegylated interferon alone. The pegylated interferon plus ribaverin produced an SVR of 85% as compared to 80% in patients treated with pegylated interferon only. A similar SVR was achieved (83%) in the small series reported by Scotto et al (21). In the series reported by Sanatonio et al(20) 15 out of 16 patients (94%) treated with pegylated interferon alfa-2b (dose 1.5 ug/kg/weekfor 24 weeks) achieved SVR which was sustained 6months and 12 months after completion of treatment. Based on this data, both standard and pegylated interferon are equally effective in treatment of acute hepatitis. An SVR of 80-95% is achievable with either drug..

The optimal dose of standard interferon therapy in acute hepatitis C is debatable. Indeed several different interferon regimes have been explored. When standard interferon dose of 3 MIU three times per week was used to treat acute hepatitis C, the SVR achieved was 30-70%. Jackel et al(17) used an induction phase of 5 MIU of interferon given daily for 4 weeks followed by three times weekly for a further 20 weeks if HCV RNA PCR is still positive after the induction phase. They reported an SVR of 100% with similar SVR rates in patients infected with different genotypes of HCV. The SVR obtained with interferon monotherapy seems long-lasting. None of the 31 patients treated by Wiegand et al(22) who achieved an SVR with interferon relapsed after a median follow up of 135 weeks (range 52-224 weeks). Furthermore, none of their patients developed clinical evidence of liver disease and all but one maintained normal ALT levels during the follow up period.

It is not often possible to predict the outcome of acute hepatitis C. Because acute hepatitis C may resolve spontaneously and because interferon has well established profile of side effects, it is reasonable to attempt to select patients with acute hepatitis C who are likely to benefit from interferon therapy. Several prognostic factors have been studied but unfortunately none proved a reliable marker of spontaneous clearance. Thus some studies identified female gender and symptomatic status as markers of spontaneous clearance of HCV infection(9,10,23,24) while others associated genotype 2 and 3 and the progressive decline of HCV RNA load over the first month with favorable outcome of acute hepatitis C(10,24,25).

It may therefore be of practical importance to adapt a “wait and see” policy for longer periods in patients with acute hepatitis C who are symptomatic or jaundiced and those who are infected with genotypes 2 and 3 as they are likely to clear HCV spontaneously, and to offer treatment earlier to other groups of patients who are at risk of becoming chronic carriers. Treatment with either standard interferon or pegylated interferon can be used to treat acute hepatitis C and this treatment is often started at 12 weeks if viraemia persists. If standard interferon is used, perhaps induction regimen is preferable in view of the higher SVR it achieves. Treatment should ideally be continued for a total of 24 weeks. If pegylated interferon is used, the dose is the same as that used in chronic hepatitis C. It does appear that combination therapy with interferon and ribaverin is not more effective than interferon monotherapy in acute hepatitis C.

An SVR is achieved in only 10-20% of patients with chronic hepatitis treated with standard interferon alone, and in only 30-40% of those treated with standard interferon plus ribaverin(26,27). Furthermore, some patients who clear HCV infection during antiviral therapy relapse at a later stage after completion of treatment and become viraemic again. Thus there is a fairly large pool of patients with chronic hepatitis C who had failed or relapsed after antiviral therapy. Re-treatment of these patients with standard interferon alone, even if given at high dosages and for prolonged periods, has been shown to be ineffective and largely unsuccessful(28,29). Similarly combination therapy with standard interferon plus ribaverin in patients who previously failed interferon monotherapy has not been effective, achieving an SVR in only 8-15% of cases(29). It has been estimated that, in patients who had previously failed interferon treatment, at least 15 patients need to be re-treated with standard interferon plus ribaverin in order to achieve one SVR(30). On the other hand, induction regimens with high–dose daily interferon plus ribaverin have yielded higher SVR rates (25-30%) in previous treatment failures(31,32). At least one trial have shown that the SVR achieved with high-dose daily interferon plus ribaverin (33%) was not statistically different from that achieved with standard interferon plus ribaverin (23%, p=0.17)(30).

The current gold standard therapy for naïve previously untreated patients with chronic hepatitis C is a combination of pegylated interferon plus ribaverin. Pegylated interferon has the advantage over standard interferon of having longer half life; hence a once weekly administration and of higher blood levels; hence a more efficacious preparation. Such combination has been shown to yield an overall SVR of 50%, an SVR of 45-50% in patients infected with genotype 1 and SVR of over 80% in patients infected with genotypes 2 and 3(33,34). Data on the use of pegylated interferon and ribaverin in patients who had previously failed antiviral therapy is limited at present. Preliminary analyses from on-going trials focusing on this issue are encouraging(35,36,37). The interim results of the “lead-in” phase of the HALT-C trial have recently been published(38). The trial was designed to examine the clinical and histological benefits of long-term treatment with pegylated interferon in patients with advanced fibrosis and / cirrhosis who had previously failed antiviral therapy. Although the initial virological response assessed at 20 weeks of treatment with pegylated interferon plus ribaverin was 35%, only 18% subsequently sustained their early virological response. The cohort studied in this trial included patients with multiple poor risk factors (patients with genotype 1, patients with cirrhosis, older patients) who have previously failed either interferon alone of combination interferon plus ribaverin therapy. It is therefore not unexpected that a low SVR was obtained.

Several prognostic factors have been identified which appear to increase the SVR rates in patients with chronic hepatitis C who had failed previous antiviral therapy. These include: previous treatment with interferon monotherapy alone, HCV genotype 2 and 3 and an initial viral load of more than 1.5 x 106 IU/ml. Patients with these favorable prognostic factors may be considered for antiviral therapy with pegylated interferon plus ribaverin. Whether long term maintenance treatment with pegylated interferon will affect the long term outcome of non responders and relapsers remains to be seen. There are no therapeutic options at present for patients who fail pegylated interferon plus ribaverin combination.

Most of the currently available guidelines on the management of chronic hepatitis C have stressed the importance of elevated ALT levels in selecting patients for treatment with interferon and ribaverin(39-42). Patients with normal ALT levels are frequently denied potentially effective antiviral treatment(43,44). Yet a significant proportion of patients with chronic hepatitis C have persistently normal ALT levels. Screening of blood donors, many of whom have no symptoms and no previous history of liver disease, has shown that approximately 25% of patients with chronic hepatitis C infection have persistently normal ALT levels(45,46). It has been estimated that in general, at least 20% of patients with chronic hepatitis C have normal ALT levels(47). In published trials, where selection bias is relevant, the reported prevalence of normal ALT in patients with HCV infection have varied between 8% and 46%(47,48). The definition of normal ALT levels remains a controversial issue. Indeed the criteria used to define normal ALT ranges have varied from one study to another. In most reported trials however, a normal ALT level is defined as: two or more normal ALT levels obtained at intervals of at least one month apart over a 6-month period preceding antiviral therapy(49,50).

Patients with chronic hepatitis C and normal ALT levels are generally considered to have mild liver disease on histological grounds, even though the histological changes have varied widely(51,52). A recent European Collaborative Study(48) showed that 85% of patients with chronic hepatitis C and persistently normal ALT levels had mild liver disease (Stage 0-1 fibrosis in the METAVIR scoring system with only 15% showing moderate (Stage 2) or advanced (Stage 3-4) fibrosis. In contrast, mild histological changes are seen in only 25% of patients with elevated ALT levels and advanced fibrosis in a further 25%, Figure 3. The reported prevalence of cirrhosis in patients with chronic hepatitis C and normal ALT levels have varied from 0.5% to 20%(47,49,50,52). Despite this varied histological picture, the rate of progression in the histological changes to fibrosis and cirrhosis is generally much slower in patients with normal ALT as compared to those with abnormal ALT.
 

Patients with chronic hepatitis C and normal ALT levels have not in the past been considered good candidates for antiviral therapy. This view dates back to the days of interferon monotherapy when the SVR obtained with this treatment were so low that the benefit of such treatment in these patients was questioned. Furthermore, such treatment was considered potentially harmful since some patients with mild hepatitis developed “ALT flares” ” manifested by an increase in the ALT levels, usually to less than 10 times the upper limit of normal, when given antiviral therapy(53). These observations and the fact that most patients with normal ALT levels have histologically mild disease have prompted the recommendations that such patients should not be treated.

There are many reasons why patients with chronic hepatitis C and persistently normal ALT levels should not be denied antiviral therapy. First, interferon monotherapy is now outdated and the current standard treatment for chronic hepatitis, a combination of pegylated interferon plus ribaverin, is far more effective than standard interferon monotherapy. Several trials have documented that the SVR rates achieved with pegylated interferon plus ribaverin in patients with normal ALT levels were comparable to those achieved in patients with raised ALT levels (53-55). Second, there is weak association between ALT levels and the severity of histological changes on liver biopsy(56) indicating that a decision to treat these patients should not be made solely on the basis of ALT levels. Whilest it is recognized that the majority of patients with normal ALT will have histologically mild disease, as many as 20% of these patients may have advanced fibrosis or cirrhosis on the initial biopsy. The distribution of histological changes and other viral and host characteristics in patients with normal and elevated ALT are summarized in Table 1. There is clear evidence that ALT levels, although commonly used in clinical practice as a marker of liver damage, are neither a reliable predictor nor correlate with the severity of histological damages in liver biopsy. Third, the earlier concern about “ALT flares” occurring in patients with mild hepatitis C when given antiviral therapy, have not been substantiated. Even when they occur, ALT flares are often mild, transient and unsustainable(54,55). Finally, there may be other overriding reasons for antiviral therapy in patients with normal ALT to demand antiviral therapy irrespective of their liver biopsy results or their ALT levels. Examples include symptomatic patients, health workers or patients with extra-hepatic manifestations of HCV infection such as cryoglobulinaemia. Concerns regarding transmission of HCV to family and friends is another reason some patients may demand antiviral therapy.
 

Combination therapy using ribaverin plus either standard interferon or pegylated interferon are effective in treatment of patients with HCV infection and normal ALT. Studies in which standard interferon plus ribaverin were used have shown that an SVR of 30-46% can be achieved in these patients(54,55), an SVR that is comparable to that achieved with the same combination in patients with elevated ALT (Figure 4). Higher doses of standard interferon and longer duration of treatment, usually for 48 weeks, are often needed to achieve this SVR in patients infected with HCV Genotype 1 and 4.

 

The therapeutic efficacy of pegylated interferon plus ribaverin in patients with chronic hepatitis C with normal ALT has been examined in a pivotal trial reported by Zeuzem et al(57). In this trial, over 500 patients with chronic hepatitis C and persistently normal ALT levels were randomized into three groups: Group A (Received peginterferon alfa-2a, 180 ug/week plus ribaverin 800 mg /d for 24 weeks, n=212), Group B (same treatment but for 48 weeks, n=210) and Group C (received no treatment). The SVR rates achieved in the treatment groups are summarized in Table 2. In this trial, the factors that significantly and independently influenced the outcome were: the HCV genotype, the duration of treatment and the baseline viral load, although the latter only influenced the outcome in patients infected with HCV Genotype 1. The adverse events reported in this trial were generally mild in severity and were typical of those previously reported in association with pegylated interferon and ribaverin combination.
 

The historical view that patients with chronic hepatitis C with persistently normal ALT should not be considered for antiviral therapy is now out of date. The present evidence dictates that such patients should be managed on an individual case basis. Several issues should be considered and taken into account when considering antiviral therapy in such patients, including liver biopsy results, genotype, patient’s age, wishes and concerns, symptomatic status and co-morbidity. The NIH and the American Association for the Study of Liver Disease (AASLD) recommend that patients with chronic hepatitis and increased risk of developing cirrhosis should receive antiviral therapy implying that liver biopsy and not ALT levels should form the basis for decision making. Whilest it is recognized that patients with moderate-severe hepatitis C should clearly be treated with pegylated interferon and ribaverin regardless of their ALT levels, the place of antiviral therapy in patients with mild hepatitis and normal ALT remains uncertain.

Patients with mild hepatitis

The severity of liver disease due to HCV infection is classified histologically into mild, moderate and severe. The classification is based on the amount of fibrosis and the grade of necroinflammatory changes observed in liver biopsies. Mild hepatitis is characterized by the presence of no or minimal fibrosis limited to the portal area with no periportal spread. This corresponds to F0 / F1 in most proposed scoring systems(58-60) and to chronic persistent hepatitis in the old classification system. Moderate hepatitis (F2) usually shows portal and periportal fibrosis while severe hepatitis (F3-F4) is a pre-cirrhotic stage with bridging fibrosis and incomplete regenerative nodules. These later stages correspond to chronic active hepatitis in the previously used classification.

An understanding of the natural history of mild chronic hepatitis, particularly with regards to fibrosis progression, is central to decision making regarding antiviral therapy. As there are no reliable and specific markers of liver fibrosis that can be used to monitor fibrosis progression, liver biopsy is currently the gold standard for assessment of fibrosis progression. There is evidence to indicate that mild hepatitis C is not as a benign condition as we led to believe. The observations that patients with mild hepatitis C tend to be younger and have shorter duration of infection compared to those with more severe disease indicate that mild hepatitis C has the potential to progress to more advanced disease. Hui et al(61) have shown that 32.1% of patients with mild hepatitis C had on repeated liver biopsy fibrosis progression over a period of 6 years. In a similar study(62), 39% of patients with mild hepatitis C showed worsening of fibrosis, 37% showed no change and 24% seemed to improve over a mean follow up period of 44 months. Of those with worsening fibrosis, 25% had fibrosis score increased by at least 2 points and 10% of those without cirrhosis on the initial liver biopsy showed histological progression to cirrhosis. The results from these studies and from others(63-66) indicate fibrosis progres- sion does occur at least in some patients with mild hepatitis, (Figure 5).
 

As fibrosis progression is not a universal finding among patients with mild hepatitis C, identifying prognostic factors associated with such progression becomes an important issue. Serum ALT levels emerged as the most predictive prognostic factor in these circumstances. Hui et al(61) have shown that fibrosis progression was observed in 22.5% of patients with mild hepatitis C and normal ALT levels whereas 41.5% of those with elevated ALT had fibrosis progression. In a similar study, Ghany et al(62) showed the rate of fibrosis progression expressed as units/year was 0.05 in patients with mild hepatitis C and near normal ALT levels as compared to 0.95 in those with elevated ALT levels. The degree of fibrosis and the amount of necro-inflammatory changes on the initial liver biopsy is also an important prognostic factor (Figure 6). Progression to more advanced fibrosis only occurred in patients with mild hepatitis C in whom the initial liver biopsy showed F1 fibrosis score whereas none of those with F0 had fibrosis progression(61). In an other study, the mean index of fibrosis progression was 0.02 / year in patients with mild hepatitis C and normal ALT levels and F0 score, 0.11 /year in those with normal ALT and F1 score, 0.15 /year in those with raised ALT and F0 score and 0.16 / year in those with raised ALT and F1 scores(67). Several other prognostic factors beside serum ALT levels and the fibrosis score on the initial liver biopsy may increase the risk of progression of mild hepatitis to more severe disease. These include: coinfection with HBV/HIV, alcohol intake and age at infection with HCV(68,69).

Thus patients with mild chronic hepatitis C and normal ALT have a low rate of disease progression to warrant antiviral therapy and it may be prudent to adapt a wait and see policy in this group with periodic liver biopsies. Indeed mathematical modeling of disease outcome and cost –effectiveness studies have shown that antiviral therapy in these patients is not cost-effective(70). On the other hand, patients with mild hepatitis C and elevated ALT are at significant risk of developing cirrhosis and its complications and should be considered for antiviral therapy if there are no contraindications to this treatment. It has been hypothesized that patients with mild hepatitis C may respond better to antiviral therapy with higher SVRs than those with more severe disease(71,72). However a recent study have shown that the SVRs obtained in patients with mild hepatitis C are similar to those achieved in patients with more advanced disease (73). As such, when treatment is indicated in patients with mild hepatitis C, a combination of pegylated interferon and ribaverin should be used.
 

Summary:

References:

73. Wright M, Fortan D, Main J et al. Treatment of histologically mild hepatitis C virus infection with interferon and ribaverin: A multicentre randomized controlled trial. J Viral Hepatitis 2005; 12: 58-66.