Acute hepatitis C: to treat or not to treat

Individuals recently infected with the hepatitis C virus are regarded as having acute disease.¹ When such an infection lasts more than 6 months, the disease is considered chronic. This distinction, although arbitrary, was chosen because most patients who are destined to clear the infection do so within this timeframe.² Most new cases of hepatitis C occur in injecting drug users, men who have sex with men, and patients exposed during medical procedures.^{3, 4} Two-thirds of cases have an asymptomatic presentation. However, spontaneous resolution of acute hepatitis C occurs in 10–50% of patients and is most common in young people, women, and patients who present with jaundice, as well as in individuals with a specific polymorphism of IL28B that encodes for interferon λ, a type III interferon with antiviral activity.^{5, 6, 7, 8} Once the infection becomes chronic, spontaneous resolution is very rare.⁹ Patients with chronic hepatitis C are at risk of progression to cirrhosis, end-stage liver disease, and hepatocellular carcinoma.¹⁰

The rationale for treatment of acute hepatitis C is to reduce the risk of progression to chronic infection, to treat at a time when response rates are high compared with the chronic phase, and to restrict spread of infection. However, whether all cases of acute hepatitis C need to be treated at initial presentation is controversial. Immediate treatment unnecessarily exposes patients who might spontaneously clear the infection to the substantial side-effects of therapy, whereas delayed treatment might decrease the chance of treatment response.

Katja Deterding and colleagues report the results of a randomised open-label non-inferiority trial¹¹ in The Lancet Infectious Diseases that aimed to assess immediate versus delayed treatment in patients with acute hepatitis C. 132 patients with symptomatic or asymptomatic acute hepatitis C were recruited at 72 centres in Germany. Symptomatic patients were randomly allocated at presentation to receive immediate treatment with pegylated interferon alfa-2b 1·5 μg for 24 weeks or delayed treatment with pegylated interferon alfa-2b 1·5 μg in combination with weight-based ribavirin (>10·6 mg/kg) for 24 weeks after an observation period of 12 weeks. Asymptomatic patients received immediate treatment with pegylated interferon alfa-2b 1·5 μg for 24 weeks. The primary endpoint of the study was the proportion of individuals who tested negative for hepatitis C virus RNA 24 weeks after discontinuation of treatment—known as a sustained virological response (SVR), and the standard metric for assessment of long-term viral eradication and cure. In the intention-to-treat analysis, 37 (67%) of 55 symptomatic participants who were treated immediately achieved an SVR. By delaying therapy, 11 (21%) of 52 symptomatic participants spontaneously cleared the infection and a further 17 (33%) responded to treatment, leading to 27 patients (54%) with an SVR (difference 13·7% [95% CI −4·6 to 32·0], exceeding the non-inferiority margin of 10%; p=0·071). Of concern, 14 symptomatic patients in the immediate treatment group (25%) and 22 in the delayed-treatment group (42%) were either lost to follow-up or dropped out of the study. A secondary analysis, restricted to patients who completed the protocol-specified treatment and follow-up, showed no difference in the proportion of patients who obtained an SVR (37 [90%] of 41 patients who completed immediate treatment vs28 [93%] of 30 patients who completed deferred treatment or observation; p=0·322). The different treatment regimens used in the trial and the high dropout rate adversely affected the interpretation of the results.

So how should acute hepatitis C be managed? The body of evidence supports treatment during the acute phase but the optimum regimen and timing of initiation or duration of therapy have not been firmly established.^{12, 13} Management should take into account the nature of the presentation and preferences of the patient. A wait-and-see approach might be appropriate for symptomatic patients—starting therapy within 12 weeks if the patient does not clear the infection spontaneously. For asymptomatic patients, consideration should be given to immediate initiation of treatment; alternatively, IL28Bgenotype testing might be ordered, and a wait-and-see approach used if patients have the favourable genetic trait. The present study suggests that pegylated interferon alfa-2b monotherapy for 24 weeks should be adequate for most patients if treatment is started immediately; shorter durations might be possible perhaps if ribavirin is included in the regimen. For patients who choose to delay therapy, initial treatment with the combination of pegylated interferon alfa-2b and ribavirin might be preferable because some patients could already be in transition to chronic infection.

Deterding and colleagues’ study,¹¹ which was done across 72 sites for 6 years, shows the challenges of studying a disease with an asymptomatic presentation and a population with substantial retention issues. Realistically, more studies assessing pegylated interferon alfa-2b are unlikely to provide the answers we need. Thankfully, the management dilemmas might become irrelevant with the availability of safer and more effective therapies than pegylated interferon alfa-2b. ^{14, 15} This development might allow either approach (delayed or immediate treatment) to be undertaken without compromising response rates, putting an end to the ongoing debate of whether to treat or not to treat acute hepatitis C.