Interferon combined with ribavirin is the standard of care for the treatment of chronic hepatitis C (hepatitis C for short) and is now widely used in clinical practice with good results. However, any therapy has its specific side effects, and interferon and ribavirin are no exception. Below we have invited Professor Miao Xiaohui from Changzheng Hospital of Second Military Medical University to talk about the common side effects of antiviral therapy for chronic hepatitis C and related management.
Chronic hepatitis C is curable, and interferon combined with ribavirin is the standard antiviral treatment regimen with a >50% maintenance response rate. However, both interferon and ribavirin have significant side effects and occur at a high rate. Some side effects may be severe, others last longer and mostly affect the patient’s quality of life during treatment; a small number of patients discontinue treatment or reduce the dose because they cannot tolerate or tolerate the side effects, resulting in treatment failure or reduced efficacy. Therefore, it is important for clinicians to understand and know how to manage these side effects.
Common adverse reactions Fever and flu-like symptoms
Fever most often appears 2 to 5 hours after interferon injection, and the body temperature is often higher than 38°C. Fortunately, fever occurs only during the initial injection in most patients and is mild and well tolerated by the second injection, although in a very small number of patients, moderate fever may persist throughout the course of treatment. In addition to fever, flu-like symptoms such as headache, muscle aches and weakness were seen in almost all patients, but most of them were tolerated, and only a few patients discontinued the drug because they could not tolerate it.
Hematologic abnormalities
Interferon can inhibit the release of blood cells from the bone marrow, resulting in a decrease in peripheral blood leukocytes and platelets, but generally does not affect hematopoietic function. A white blood cell count of no less than 2.0×109/L, a neutrophil count of no less than 0.8×109/L, and a platelet count of no less than 50×109/L is safe.
The decrease in leukocytes and platelets mostly occurs 2 weeks after interferon treatment. Some patients’ platelets stop decreasing after 4-6 weeks of treatment and can maintain relatively stable levels, and a few patients need to reduce the interferon dose or use leukocyte-raising drugs.
Hemolysis is the most common side effect of ribavirin, and the condition is often positively correlated with dosage. In severe cases, hemolytic anemia and hemolytic jaundice can result, and the hemolytic symptoms are relieved after dosage reduction. Interferon can also cause autoimmune hemolysis, but it is less common.
Hair loss
Hair loss can occur in almost all patients, but it varies in severity, mostly resulting in thinning of hair and almost never causing total hair loss. Hair loss mainly affects appearance and causes psychological disturbances, especially in female patients. Patients need to understand that hair loss can heal quickly after stopping the drug, and some patients have even seen new hair become thicker after stopping interferon.
Mental and psychological abnormalities
In mild cases, the symptoms are excitement, euphoria, insomnia, anxiety, lack of concentration, cognitive impairment, memory loss and emotional instability; in severe cases, the symptoms are personality change, mania, depression, and in more serious cases, self-harm and suicidal tendencies.
The psychiatric and psychological abnormalities caused by interferon can have different manifestations and degrees in different patients. It is worth noting that patients with pre-existing mild depression may have the opposite manifestation of psychiatric abnormalities after the use of interferon than before the use of the drug, which is often easily overlooked.
Thyroid damage
About 30% of patients with chronic hepatitis C have autoimmune phenomena or autoimmune disease, and are more likely to have autoimmune damage after interferon use, with thyroid damage being more common, occurring in about 5% of cases. Graves’ disease and Hashimoto’s thyroiditis are common complications. Massive destruction of the thyroid gland may manifest as hyperthyroidism and later as hypothyroidism.
In a small number of patients, thyroid damage is non-immune-mediated, such as “destructive thyroiditis”, which may be caused by direct interferon damage.
Fertility defects
Both interferon and ribavirin have the potential to cause birth defects, especially abnormal fetal development, which is a serious side effect.
Other side effects
Other side effects include rash, gum bleeding, retinopathy, digestive symptoms, malnutrition, weight loss, taste changes, burning pain in the mouth, decreased sexual function, menstrual abnormalities, and cardiopulmonary damage.
Prevention and management of related side effects Adequate assessment is required before treatment
1. Benefits of treatment and consequences of not treating.
Patients with chronic hepatitis C can benefit from interferon and ribavirin combination therapy as long as there are no absolute contraindications, and there is a high risk of cirrhosis and hepatocellular carcinoma if early aggressive antiviral therapy is not instituted.
2. Contraindications.
The Guidelines for the Prevention and Treatment of Chronic Hepatitis B, developed by the Chinese Medical Association’s Branch of Hepatology and Infectious Diseases, point out absolute and relative contraindications to interferon that are fully applicable to patients with chronic hepatitis C.
Absolute contraindications are: pregnancy, history of psychiatric disorders (e.g., major depression), uncontrolled epilepsy, unabated alcohol or drug abusers, uncontrolled autoimmune disease, decompensated cirrhosis, symptomatic heart disease, pre-treatment neutrophil count <1.0×109/L and platelet count <50×109/L.
Relative contraindications are: thyroid disease, retinopathy, psoriasis, previous history of depression, uncontrolled diabetes or hypertension, and total bilirubin >51 μmol/L, especially if indirect bilirubin is predominant. Considering the side effects of ribavirin, anemia should also be a relative contraindication.
3. Organ function assessment.
Interferon may aggravate hepatic impairment and therefore should be used with caution in patients with chronic hepatitis C in the decompensated phase. The dosage of interferon and ribavirin should be adjusted in patients with decompensated renal function.
Adequate communication prior to treatment
Physicians must provide patients and their families with detailed information about the side effects, consequences and management of interferon and ribavirin prior to treatment to improve patient compliance. It is important to inform both the benefits and risks of treatment and the consequences of not treating; to clarify both the incidence and severity of drug side effects and the degree of impact on quality of life, and to inform patients about the monitoring and management of side effects, especially to let patients and their families understand the controllability of side effects with a view to cooperating with treatment and improving tolerability.
Regular monitoring
Patients or their families can easily detect fever, flu-like symptoms and more serious mental and psychological abnormalities in a timely manner, but milder symptoms may be overlooked. Therefore, patients should be asked to visit the hospital for regular follow-up to assess mental and psychological status; routine blood and thyroid function tests should be included as routine monitoring items and should be reviewed regularly with a view to detecting abnormalities and providing timely treatment.
In general, an adverse reaction can be evaluated or tested within the shortest “incubation period” of its occurrence, such as blood tests 2 weeks after starting treatment and thyroid function tests every 4 weeks. Other rare and less serious side effects require careful consultation and observation by medical staff at follow-up visits.
Prompt management of
1. Fever and flu-like symptoms.
Treat accordingly according to the severity and patient’s tolerance. Antipyretic and analgesic drugs may be used before interferon injection or during high fever, while rest and plenty of fluids are sufficient for mild cases.
2. Leukocytopenia and thrombocytopenia.
If leukocytes and platelets fall below a safe threshold, the dosage of interferon must be reduced, but patients need to be aware that this may reduce the efficacy; in addition to regular or irregular injections of granulocyte colony-stimulating factor, and attention to the prevention of bacterial infections.
3. Anemia.
Reduction of ribavirin dosage is the primary measure, but also prompt detection and management of acute tubular injury due to acute hemolysis.
4. Psychiatric and psychological abnormalities.
Emphasis is placed on timely detection and timely treatment. For those with mild clinical symptoms, psychological counselling treatment can be taken to enhance the patient’s confidence and improve tolerance, which can reduce psychological abnormalities to a certain extent; for those with more severe depressive symptoms, they need to be supplemented with antidepressants (often effective about 2 weeks after use); if self-harm or suicidal tendencies appear, interferon must be discontinued immediately and closely monitored until the symptoms disappear.
5. Abnormal thyroid function.
Interferon reduction can reduce thyroid damage and control related symptoms; hypothyroidism can be treated with thyroxine tablets; whether to discontinue interferon therapy is a matter of weighing the pros and cons based on full communication with the patient; in general, thyroid function will be fully or partially restored after discontinuation of interferon.
6. Alopecia.
It is generally not necessary to manage it, but the patient should be informed of the trade-off between temporary cosmetic changes and antiviral therapy.
7. Contraception.
Family planning should not be carried out during the use of interferon and ribavirin in either sex, and conception should not occur until 6 months after discontinuation of the drug.