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Direct-Acting Antivirals Reduce Cryoglobulinemia in People with Hepatitis C


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 extra-hepatic manifestations of the disease, a study published in the February edition of Hepatology shows.

Although studies of direct-acting antivirals show that newly licensed interferon-free combinations can cure hepatitis C in 90% to 95% of patients, 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.

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 1 in 20 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, response to treatment with pegylated interferon and ribavirin has been poor with a high rate of adverse events. Researchers from Massachusetts General Hospital and Brigham and Women’s Hospital in Boston have now reported the first case series of 12 people with symptomatic cryoglobulinemia treated with direct-acting antivirals.

Half of the patients had liver cirrhosis and half had experienced failure of at least one previous course of interferon-based hepatitis C treatment. The duration of cryoglobulinemia ranged from 6 months to 17 years, and 8 of the 12 had multiple symptoms associated with cryoglobulinemia. 58% had glomerulonephritis, 50% had purpura, 50% had arthralgia, and one-third had peripheral neuropathy.

Of those with kidney damage, all had hypertension and 5 had active glomerulonephritis (2 were in remission). All of those with active glomerulonephritis had an eGFR (creatinine clearance) <60, indicating moderate impairment of kidney function; 3 patients had severe proteinuria, although none were diabetic. 6 of 7 had received some form of immunosuppressive therapy prior to direct-acting antiviral therapy in order to manage the glomerulonephritis.

The 12 patients all received sofosbuvir-based therapy without interferon: 8 received sofosbuvir (Sovaldi) and simeprevir (Olysio) and 4 received sofosbuvir and ribavirin, in almost all cases for 12 weeks. After treatment and follow-up, 10 of the 12 achieved a sustained virological response (SVR12). The remaining 2 patients experienced viral relapse after completing treatment.

Post-treatment cryoglobulin levels were available for 9 patients; median levels fell from 1.5% to 0.5%, with cryoglobulin disappearing altogether in 4 patients. In most cases cryoglobulin levels had declined to their greatest extent within a median of 4.6 months after treatment initiation, although in one case levels continued to decline for up to a year. Cryoglobulin levels rebounded in one of the patients who experienced virological relapse, and also became detectable at a low level once more in a patient who achieved SVR.

Kidney function improved in all patients after treatment, although eGFR remained below 60 in 3 people. Proteinuria improved in all patients for whom before and after measurements were available, including one who did not achieve SVR12; in this case eGFR remained low at 33 mL/min after completing treatment. This patient also needed to continue immunosuppressive treatment for glomerulonephritis after direct-acting antiviral treatment.

There were 4 patients who experienced a complete resolution of symptoms after treatment. In a further 3 patients at least 1 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; 1 patient was hospitalized for hyperkalemia and 1 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 response (10%), a high rate of treatment discontinuation (50%), lack of improvement in symptoms, and lack of change in cryoglobulin levels.



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