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Hepatitis C virus (HCV) antibodies are detected in up to 1.5% of blood donors worldwide and HCV is estimated to infect at least 4 million people in the USA alone.1 HCV is probably the commonest cause of liver disease and hepatocellular carcinoma in the developed world and has become the leading reason for liver transplantation in many centres. HCV is thought to be the aetiological factor in the majority of cases of mixed cryoglobulinaemia in which HCV RNA is concentrated in high titre in cryoprecipitates.2Conversely, up to 54% of patients with HCV infection have detectable cryoglobulins, which are associated with symptoms in roughly 25%, most commonly including cutaneous manifestations and arthralgias but much less often glomerulonephritis and neurological abnormalities.3 Although some studies have noted a correlation between the severity of liver disease and the level of cryoglobulins in serum, this has not been a consistent observation.
In this issue (see page 122), Cresta and colleagues studied 87 patients with HCV related liver disease prospectively. Forty three of the patients had detectable cryoglobulins, associated with symptoms in 12 (28%). All patients were treated with 3 million units of interferon (IFN) α for six months, at the end of which time the biochemical, virological and immunological (disappearance of cryoglobulins) responses were 57%, 34%, and 40%, respectively. Sustained responses six months after completion of treatment were seen in 21%, 18% and 14% of patients, respectively, and were independent of the presence of cryoglobulins at entry. Immunological responses were associated with resolution of cutaneous and joint symptoms but neither neurological nor renal abnormalities and notably, all patients (n=6) with a sustained immunological response also had a sustained virological response. Rates of initial and sustained responses tended to be higher (non-significantly) for asymptomatic patients and a long term sustained response was seen in only one patient with symptomatic cryoglobulinaemia. Factors predicting a response to IFN-α included male sex, genotype 2 or 3 and low viral load; however, the latter did not seem to affect response in patients with cryoglobulins. The authors concluded that the presence of cryoglobulins did not affect the response to treatment with IFN-α and the simultaneous clinical, immunological and virological responses provide further evidence for an aetiological role for HCV in mixed cryoglobulinaemia. Treatment IFN was tolerated well by all patients and no one had to be withdrawn from the study because of side effects.
The observed response rate in this series is comparable with previous studies, which have documented response rates in 42–73% of patients with cryoglobulinaemia treated with IFN-α and a disappointingly low long term response in 0–22% of patients.4-7 It is difficult to compare and reach a general conclusion from this group of studies as the clinical and immunological parameters of response are not comparable between the groups. Moreover, the treatment regimen, including dose, frequency and duration of therapy, differed in all the studies. However, some important clinical issues have been tackled by other authors. Many studies had a 10–14% dropout rate because of intolerable side effects, with one study noting a deterioration in renal and neurological symptoms while on treatment, whereas other patients required a reduction in dose. These problems were not encountered by Cresta and colleagues, perhaps because of the lower dose of IFN-α used. Other comparable observations were the association of genotype 2 with response to treatment, the poor response of neurological symptoms in general and the tendency (though not significant) for symptomatic patients to respond less well than asymptomatic ones. Although not a universal finding, immunological responses tend to mirror viral responses, implying that the success of IFN-α relies on its anti-viral action rather than effects on immune function.
Marginal improvements in the long term responses have been achieved with higher doses of IFN-α and a longer duration of treatment, as observed by Casato and colleagues6 and Adinolfi and coworkers7 who treated their patients for 12 months, obtaining long term response rates of 16 and 22%, respectively. It is likely that the addition of ribavirin to IFN-α will improve the virological response further, as already documented in patients with HCV associated liver disease.8 ,9 A proportion of patients in previous studies has responded when treated with IFN-α monotherapy for a second time; this group may now be more suitably treated with combination therapy with which long term response rates of 49% have been achieved in relapsers receiving combination therapy as opposed to only 5% with monotherapy.10
Although IFN therapy is still the most extensively used antiviral agent for chronic HCV infection, it is far from ideal and the search continues for more effective antiviral agents and combination treatment.
In the meantime, what lessons can be learnt from this and similar studies? Firstly, that the presence or absence of circulating cryoglobulins cannot be used to identify patients with more severe liver disease nor to identify those more likely to respond to IFN-α. Secondly, that patients with cryoglobulinaemia and associated symptoms could be considered for treatment irrespective of the severity of liver disease as there is a reasonable expectation of symptomatic relief following a virological response. Resolution of the less common but more severe complications (nephrological and neurological) is less likely however. Thirdly, should we continue to look for cryoglobulinaemia? Probably not, except where symptoms or biochemical findings suggest they are clinically relevant as in most instances cryoglobulin-aemia is of little clinical importance. Finally, what do we know of the mechanisms that underlie the formation of cryoglobulins and their association with HCV rather than—for example, hepatitis B virus infection? So far, very little.
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