Alfredo Alberti, MD

NIH Consensus Development Conference on
Management of Hepatitis C: 2002 

Bethesda, Maryland
June 10-12, 2002

Acute hepatitis C is uncommon and difficult to recognize and to diagnose. The main reasons are the following: a) the incidence of new infections with HCV has greatly decreased during the past decade in all civilized countries; b) acute hepatitis C is often mild and asymptomatic; c) there is no specific diagnostic test to identify acute infection with HCV and to distinguish it from reactivation phases that may occur in chronic infection. As a consequence, acute hepatitis C has been difficult to study and there is still limited information about its natural history and optimal management strategies. Early studies, which were conducted mainly in cases with acute post-transfusion NANB (Type C) hepatitis, indicated that this condition has an extremely high propensity to become chronic. On the basis of these observations, and of the data on the treatment of chronic hepatitis C with interferon, a number of studies have been conducted since the early 1990s to assess whether interferon therapy could prevent chronic outcome of acute hepatitis C.

Seventeen studies on the treatment of acute HCV infection with interferon have been published either as full papers (13) or as letters/abstracts (4), including 7 randomised controlled trials, 5 controlled but not randomised trials, and 5 studies without an untreated control group. Of these latter, 2 were randomised trials in which different treatment schedules were compared. In all these studies interferon (alfa or beta) monotherapy was used; there are no available reports on the treatment of acute hepatitis C with interferon plus ribavirin combination therapy or with the pegylated interferons. Overall, 295 treated patients and 162 untreated cases with acute hepatitis C have been included, with a sample size of 6–97 patients in each individual study. Analysis of the 17 published reports reveals great heterogeneity with respect to: (1) inclusion criteria and patients characteristics (for example, some studies included asymptomatic cases seen during prospective surveillance of transfused or otherwise exposed patients while others included only symptomatic cases identified clinically; 7 studies were conducted in PTH cases, 6 in patients with non-transfusion related hepatitis C, and 4 included a mixture of the two subgroups);(2) timing of treatment initiation (early or delayed treatment after infection or after clinical onset); (3) type of interferon used (interferon alfa: 12 studies, interferon beta: 5 studies); (4) dose and schedule of administration (total cumulative dose ranging from 8.4 MU to 780 MU, with daily administration in 4 studies, tiw administration in 10 studies, and daily induction followed by tiw administration in 3 studies); (5) duration of post-treatment followup (ranging from 6 to 36 months); (6) end points of biochemical (ALT) response only: 5 studies; biochemical (ALT) and virological (HCV-RNA) response: 12 studies.

Pooling all data from the 17 studies, an end-of-therapy biochemical (ETR-ALT) and virological (ETR-HCV-RNA) response was seen in 76 percent (range 15–100 percent) and in 82 percent (37–100 percent) of treated patients and in 24 percent (10–44 percent) and in 10 percent (0–20 percent) of untreated patients, respectively. A sustained biochemical (SR-ALT) and virological (SR-HCV-RNA) response was seen in 61 percent (25–100 percent) and 62 percent (37–100 percent) of treated patients and in 26 percent (16–50 percent) and 12 percent (0–20 percent) of untreated cases, respectively.  

Results of RCTs

Among the 7 RCTs published, 4 were conducted in PTH cases with an identical schedule of 3 MU tiw of interferon alpha given for 12 weeks. These 4 studies were homogeneous and could be pooled together in a recent meta-analysis (Cochrane review). According to the results of this analysis, the ETR-HCV-RNA was 42 percent (95 percent CI 30–56 percent) with interferon vs. 4 percent (0–13 percent) with no treatment (p<0.00001), while SR-HCV-RNA was 32 percent (21–46 percent) with IFN vs. 4 percent (0–13 percent) without therapy (p= 0.00007). IFN therapy was associated with 45 percent (31–59 percent, p=0.00001) and 29 percent (14–44 percent, p=0.0002) increase in ETR-HCV-RNA and SR-HCV-RNA, respectively, compared with no treatment.

These results prove that interferon therapy is associated with a significant reduction of chronicity when given to patients with post-transfusion acute hepatitis C, even using a relatively low dose for a relatively short period. However, around 2/3 of the patients treated with this regimen still developed chronic infection.

Other Studies

Other studies have used more aggressive treatment schedules with higher IFN dosages and longer periods of administration, and these approaches have usually resulted in higher rates of sustained virological response. Unfortunately, most of these studies were conducted without a randomised untreated control group. Furthermore, many of them included patients with acute symptomatic hepatitis C often acquired through a non-transfusion source. In these cases, rates of spontaneous resolution of acute hepatitis C might be significantly higher than in asymptomatic cases with PTH. In studies where 5–10 MU of interferon were given daily for 4–12 weeks or up to ALT normalization, followed by the same or a lower IFN dose given tiw for 20–40 additional weeks, rates of sustained virological response reached 83 to nearly 100 percent. In other studies, conducted in similar patient cohorts treated with lower doses of IFN (3–6 MU tiw for 3–6 months), rates of sustained virological response were between 37 and 64 percent. In one study comparing different regimes of daily beta IFN, there was a clear dose dependent effect on sustained response rates. In those studies where an untreated control (although not randomised) group was included for comparison, rates of spontaneous resolution were usually lower (8–21 percent) although a statistically significant difference was rarely obtained due to the small number of patients included. These results indicate that high rates of sustained virological response (24 week SR) can be achieved in acute hepatitis C with IFN monotherapy, in a setting where the expected rate of spontaneous resolution can be estimated around 10–40 percent.

Predictors of Response

Pre-treatment HCV-RNA levels were reported in 5 studies. In 3 of them there was a statistically significant correlation with sustained virological response that was higher with lower viraemia. Interestingly, this association was lost when high dose IFN (5–10 MU daily) schedules were used. The HCV genotype was reported in 7 studies, but in only 2 of them was there a significant association between the HCV type and response (better with HCV2/3 and worse with HCV1).

Tolerability Profile

Detailed description of side/adverse effects seen during therapy has been reported only in 7 studies, with a total of 145 treated patients. The tolerability profile of IFN therapy was very similar to that usually observed when treating patients with chronic hepatitis C. Therapy was well tolerated also in patients with jaundice or very high ALT levels. No ALT flares or deterioration of liver function were observed during therapy, apart from one single patient treated with 10MU daily who developed “acute lobular hepatitis” after HCV-RNA clearance and required a short period of steroid treatment. Overall, the available data do not indicate higher rates of IFN associated side/adverse effects or unexpected adverse effects in patients with acute hepatitis C when compared with what is reported in patients treated for chronic hepatitis C.

Unsolved Issues and Conclusions

Whom to treat: Acute HCV infection may be seen in individuals with minimally elevated or completely normal ALT and serum HCV-RNA positivity following known exposure or needle-stick injury or in sick patients with symptomatic acute hepatitis C, exemplified by very high ALT levels and jaundice. Available data would indicate that the effect of IFN therapy is independent of the clinical phenotype, although more data is needed to better define outcomes with and without therapy in different patient subgroups and to determine safety of therapy in severely ill cases.

When to start therapy: Immediate treatment of all cases with acute HCV infection means giving unnecessary therapy to those who would have recovered spontaneously. A strategy of delaying therapy by 2–3 months after diagnosis should allow giving treatment only to patients with a high risk of chronic outcome. This approach might be particularly rational in those subgroups of patients in which a high rate of spontaneous recovery is expected, such as children, young adults (particularly women), and patients with jaundice. It remains to be defined whether delaying therapy could reduce its efficacy due to HCV quasispecies expansion towards a more heterogeneous and resistant virus population, as the infection evolves into chronicity. Available data, albeit limited, tends to suggest that delaying therapy by 2–3 months does not compromise the probability of a favorable response to interferon.

How to treat: The optimal schedule in terms of risk/benefit and cost/effectiveness ratio is far from having been defined. Available data would indicate that the minimum requirement for obtaining a significant benefit compared to untreated patients is to use 3 MU tiw for at least 12 weeks. With such a regimen, however, only between 30 and 40 percent of treated patients develop a sustained virological response. More aggressive regimens, based on induction with daily IFN (5 to 10 MU) followed by tiw therapy for 4–6 months, may allow the achievement of a sustained virological response (24 week SVR) in almost 100 percent of the cases. On the basis of these findings, studies with the PEG-IFNs are urgently needed. Combination therapy with addition of ribavirin might not be essential to treat most cases of acute hepatitis C, but this also needs to be explored in clinical trials.

Long-term benefit of treatment: More prolonged followup of patients with acute hepatitis C treated with interferon is needed. Most published studies refer to sustained virological response at 24 weeks after therapy. Studies on the natural history of acute hepatitis C have indicated the need for an accurate and prolonged virological followup to predict long-term outcomes as transient phases of HCV-RNA negativity occur after acute phase in patients with chronic evolution of hepatitis C. Furthermore, long-term clinical outcomes should be accurately modeled in treated and untreated patients considering the low rate of clinically relevant chronicsequelae seen during the first two decades of infection with HCV. Nevertheless, if a near 100 percent eradication of HCV can be achieved with IFN therapy in acute infection, it seems quite difficult not to believe that this result should transfer into significant clinical benefit in many of the patients.

References

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