Spontaneous Viral Clearance of Hepatitis C

It is one of the minor miracles of life that stuff happens, good as well as bad. Good and bad things happen when sick people are taking a medicine. Good and bad things happen when sick people are not taking a medicine. Some people get better without any outside help or interference. Therein lies the part of the problem of understanding evidence: it isn't about whether good or bad things happen, but whether they happen more or less often, and in whom.

Hepatitis C is devoutly to be avoided, but if you have the virus, it can, in some people, be cleared without any outside help. A systematic review [1] tries to explore whether there is an underlying rate at which the virus is cleared, and some of the problems.

A relatively simple MEDLINE search sought studies that were longitudinal assessments of hepatitis C infection, with at least one follow up assessment within two years of diagnosis, RNA measurements for virus reported for all study subjects, and studies in patients untreated for acute hepatitis C infection during follow up. Studies that included treated and untreated were included where results for untreated individuals were reported separately.

Clearance of infection was defined on a universally applied basis of hepatitis C RNA assessment, whatever criteria had been used in the original article.

Studies included 19 series of acute hepatitis C, nine of post-transfusional hepatitis C, and three of sero-incident cases. Studies ranged from four to 67 individuals, with an average of 22 per study (682 individuals). Follow up ranged from six to 157 months. The time at which clearance was measured was between six and 48 months, but most were 12 months or longer.

Clearance rates varied from 0% to 80% (Figure 1); there was greater variation in smaller studies. Overall the clearance rate was 26%, and the largest study with 67 individuals was close to this. Studies of acute hepatitis C had a higher rate of spontaneous clearance (31%) than post-transfusional studies (18%). Women had a higher clearance rate (42%) than men (20%).

First, it is comforting to know that bad things can clear up on their own accord, and a timely reminder that our bodies can have sufficient natural defences to overcome all sorts of nasty things. Marvellous thing, evolution. Second, it is nice to know that natural laws keep on working: here it was the random play of chance in tiny studies, with the greatest variability in clearance rates seen in studies with fewer than 20 individuals.

But no real aggregation around the mean was occurring in most of the studies, and larger ones would be needed to be sure of this result. Even at studies of 40 people there was considerable variability, between 10% and 50%. The best current guess is that spontaneous clearance of hepatitis C virus will have occurred in about 1 in 4 people infected with it after a year or more.

There is also a lesson here about small trials. What we are looking at in this study is the equivalent of a placebo group in a clinical trial – what happens when we use an inactive treatment. But in this case there was no placebo, and no reason to magic up a “placebo effect”. If the “placebo effect” was low, any therapy might look brilliant (50% clearance versus 10%, say), but if the “placebo effect” was high, any therapy would probably look ineffective. So much of the evidence we see depends on small numbers that it can be worrying.

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