Direct-acting antivirals reduce cryoglobulinemia in hepatitis C

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Treatment with direct-acting antivirals not only cures people of hepatitis C, but can also rapidly reduce the severity of one of the most troublesome extrahepatic manifestations of the disease, a study published this month shows.

Although studies of direct-acting antivirals show that newly-licensed combinations can cure hepatitis C in 90 to 95% of people, there is less information about the extent to which curing hepatitis C leads to improvements in the health of the liver or resolution of symptoms such as cryoglobulinemia.

Cryoglobulinemia is the presence of complexes of abnormal antibodies and proteins, which cluster in the blood vessels, in the kidneys or joints (vasculitis) causing skin lesions (purpura), pain in the joints of the hands and legs and damage to peripheral nerves (peripheral neuropathy). The presence of mixed cryoglobulins in the kidneys can lead to inflammation and kidney damage (glomerular nephritis) and the loss of kidney function over time.



A drug that acts against a virus or viruses.

sustained virological response (SVR)

The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24).

direct-acting antiviral (DAA)

Modern drugs for the treatment of hepatitis C, which work directly against the hepatitis C virus. They stop the virus from reproducing by blocking certain steps in its lifecycle.


Damage to the nerves.

pegylated interferon

Pegylated interferon, also known as peginterferon, is a chemically modified form of the standard interferon, sometimes used to treat hepatitis B and C. The difference between interferon and peginterferon is the PEG, which stands for a molecule called polyethylene glycol. The PEG does nothing to fight the virus. But by attaching it to the interferon (which does fight the virus), the interferon will stay in the blood much longer. 

Mixed cryoglobulinemia may be detected in up to half of people with hepatitis C, but in most people the condition does not cause symptoms. About one in twenty people with hepatitis C develop symptoms. There is some evidence that cryoglobulinemia increases the risk of developing cirrhosis.

Symptomatic disease as a result of cryoglobulinemia – especially kidney disease – is considered a reason to take hepatitis C treatment, regardless of the extent of liver damage. In the past, responses to treatment with pegylated interferon and ribavirin have been poor with a high rate of adverse events. Researchers from Massachusetts General Hospital and Brigham and Women’s Hospital, Boston, have now reported the first case series of 12 people with symptomatic cryoglobulinemia treated with direct-acting antivirals.

Half had cirrhosis and half had experienced failure of at least one previous course of interferon-based hepatitis C treatment. The duration of cryoglobulinemia ranged from six months to 17 years and eight of the twelve had multiple symptoms associated with cryoglobulinemia. Fifty-eight per cent had glomerulonephritis, 50% had purpura and 50% had arthralgia. One third had peripheral neuropathy. Of those with kidney damage, all had hypertension and five had active glomerulonephritis (two were in remission). All of those with active glomerulonephritis had an EGFR (creatinine clearance) < 60, indicating moderate impairment of kidney function. Three patients had severe proteinuria, although none were diabetic. Six of the seven had received some form of immunosuppressive therapy prior to direct-acting antiviral therapy in order to manage the glomerulonephritis.

The twelve patients received sofosbuvir-based therapy without interferon. Eight received sofosbuvir and simeprevir; four received sofosbuvir and ribavirin, in almost all cases for 12 weeks. Ten of the twelve achieved a sustained virologic response (SVR12). The remaining two patients experienced virologic relapse after completing treatment. Post-treatment cryoglobulin levels were available for nine patients; median levels fell from 1.5% to 0.5%, with cryoglobulin disappearing altogether in four patients. In most cases cryoglobulin levels had declined to their greatest extent within a median of 4.6 months of treatment initiation, although in one case levels continued to decline for up to one year. Cryoglobulin levels rebounded in one of the patients who experienced virologic relapse, and also became detectable at a low level once more in a patient who achieved a sustained virologic response.

Kidney function improved in all patients after treatment, although eGFR remained below 60 in three people. Proteinuria improved in all patients for whom before and after measurements were available, including one who did not achieve SVR 12, and in this case eGFR remained low at 33mL/min after completing treatment. This patient also needed to continue immunosuppressive treatment for glomerulonephritis after direct-acting antiviral treatment.

Four patients experienced a complete resolution of symptoms after treatment. In a further three patients at least one symptom resolved, with joint pain and neuropathy more likely to persist after treatment. There was no correlation between changes in cryoglobulin level or cryoglobulin detectability and resolution of symptoms.

Direct-acting antiviral treatment was well tolerated; one patient was hospitalised for hyperkalemia and one patient discontinued treatment at week 10 due to anxiety and insomnia, but both achieved SVR12.

Comparing their findings to a historic cohort of patients with cryoglobulinemia who had been treated with pegylated interferon and ribavirin, the researchers found a very low rate of sustained virologic response (10%), a high rate of treatment discontinuation (50%), lack of improvement in symptoms and lack of change in cryoglobulin levels.


Sise ME et al. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology 63(2): 408-417, 2016.