In clinical trials, approximately 10–15% of patients discontinue
PegIFN/RBV therapy due to AEs; however, in clinical practice,
the rate of treatment withdrawal has been reported to be
substantially higher.
In addition, dose reduction of PegIFN and/or RBV owing to AEs
is necessary in 25–40% of patients (especially in elderly and in
those with low baseline hemoglobin level). Importantly, dose
reduction should be implemented at the earliest possible stage,
when slight signs of AEs are noted. Combination therapy should
then be prolonged to ensure the full scheduled doses of therapy.
Regional and global variability exists in the nature of AEs and
in the strategies employed to mitigate their impact (Sulkowsky
2011).
Influenza-like symptoms (such as fatigue, headache, fever,
and rigors) occur in virtually all patients after the first doses of
PegIFN, but usually subside after the first month of treatment.
Dermatologic effects (alopecia, dermatitis) and gastrointestinal
symptoms (nausea, diarrhea) are also very frequent. The most
prevailing severe AEs are
– hematologic
– neuropsychiatric
– autoimmune
Anemia occurrs in more than 30% of treated patients. Usually,
the lowest hemoglobin (Hb) values are recorded 6-8 weeks after
22 | Hepatitis C Treatment
treatment initiation and stay at the same level throughout the
remaining therapy period, up to 48 weeks. Severe anemia, with
hemoglobin levels <10 g/dL, occur in approximately 10 - 15% of
patients. IFN induces bone marrow suppression, while RBV cause
hemolytic anemia. Recently, genome-wide association studies
have identified an inherited genetic polymorphism at
chromosome 20, in the inosine triphosphatase gene (SNPs:
rs1127354 and rs7270101), as predictive for RBV induced anemia
(Fellay 2010). The presence of A/A and A/C vs. C/C genotypes
predicts protection from RBV induced hemolytic anemia during
the early stages of treatment.
The management of anemia follows several successive steps:
– RBV dose reduction by 200-400 mg/day, when Hb level
decreases between 8.5 - 10 g /dl;
– Discontinuation of RBV when Hb level declines to <8.5g/dl;
– Epoetin administration in patients with early onset of
anemia, in order to prevent treatment interruption. Use of
recombinant human erythropoietin-stimulating agents has
been associated with higher SVR rates and with reduced
dropout rates (Sulkowski 2009).
RBV induced anemia can precipitate occult coronary artery
disease, especially in older patients (due to age related reduction
in creatinine clearance). An accurate estimation of the
glomerular filtration rate and the administration of a lower dose
of RBV are recommendable in elderly patients.
Neutropenia (with absolute neutrophil count – ANC less than
1.5 x109/mL) and thrombocytopenia (less than 50 000
cells/mm3) are also common. Consequently, eligibility for
treatment may be restricted in patients with advanced liver
cirrhosis.
The following decision tree is recommended for the
management of neutropenia and thrombocytopenia:
– PegIFN dose reduction, when ANC< 750 cells/mm3 and
platelets count < 50,000 cells/mm3;
– treatment discontinuation, when ANC < 500 cells/mm3 and
platelets count< 25,000 cells/mm3. If neutrophils or platelets
Antiviral Therapy: The Basics | 23
counts go up, treatment can be restarted, but at a reduced
Peg IFN dose;
– use of stimulating factors (i.e. Filgastrim™ - granulocyte
macrophage colony stimulating factor or Eltrombopag™ -an
oral thrombopoietin receptor agonist) is not routinely
recommended in clinical practice, except for patients with
cirrhosis.
Neuropsychiatric symptoms such as depression, irritability,
insomnia, and, occasionally, aggressive behavior are some of the
most debilitating AEs of PegIFN therapy, occurring in
approximately 20% to 30% of patients after the first month of
treatment. Interventions may require an initial dose reduction,
followed by permanent discontinuation of IFN in the case of
persistently severe or worsening symptoms. In most cases, the
neuropsychiatric symptoms resolve after PegIFN
discontinuation. A multidisciplinary approach, including medical
treatment (administration of antidepressants – especially
serotonin uptake inhibitors and benzodiazepines, when
required) and psychiatric counseling is needed in order to
reduce the psychiatric side effects of antiviral therapy.
Autoimmune disorders involve most commonly the
development of autoimmune thyroiditis, but HCV infection has
been also related to mixed cryoglobulinemia, thyroid
dysfunction and papillary thyroid cancer. There is ample
evidence showing that 7–11% of HCV-infected patients have
thyroid dysfunction (frequently consistent with hypothyroidism,
with increases in thyroid-stimulating hormone -TSH and
decreases in free thyroxin -T4 -mean values) prior to the
initiation of treatment. This percentage goes up to 15-20%, once
combined PegIFN/RBV therapy is initiated. Thyroid function
should be monitored routinely before and during treatment,
with TSH and T4 levels measured every 12 weeks while on
therapy and again at 6 months after the end of treatment.
Specific therapy may be needed to maintain a euthyroid state.
A series of other side effects are reported at lower rates, such as
pulmonary (cough, dyspnea), cardiovascular (cardiomyopaty,
24 | Hepatitis C Treatment
hypertension, supraventricular arrhythmias and myocardial
infarction) and ocular (retinal abnormalities).
Usually, but not always, these side effects reverse within a
short period after the end of therapy. Extreme caution is
however recommended in patients with preexisting chronic
obstructive pulmonary disease, diabetes mellitus prone to
ketoacidosis, severe myelosuppression, and/or coagulation
disorders (including thrombophlebitis and pulmonary
embolism). RBV may cause birth defects and/or death of the
unborn infant. Pregnancy must be avoided in female patients
and in female partners of male patients.
Recognition and effective management of AEs are critical
components of the successful treatment of CHC. Additional
measures include life style modification (hypocaloric diet,
physical exercise) in order to decrease the BMI and to prevent
weight gain. There are reports suggesting the beneficial effects
of insulin sensitizers (Metformin™- to reduce hepatic
gluconeogenesis and Pioglitazone™ -to sensitize insulin
receptors and mobilize visceral fat to subcutaneous tissues). A
series of hepatoprotective drugs and antioxidants (vitamin E,
betaine, silymarin and β-carotine) inhibit the toxic effects of free
radicals and prevent the synthesis of proinflammatory cytokines
that promote steatosis (El-Zayadi 2009). Excessive alcohol use
could reduce the likelihood of therapy response and abstinence
should be recommended before and during treatment
PegIFN/RBV therapy due to AEs; however, in clinical practice,
the rate of treatment withdrawal has been reported to be
substantially higher.
In addition, dose reduction of PegIFN and/or RBV owing to AEs
is necessary in 25–40% of patients (especially in elderly and in
those with low baseline hemoglobin level). Importantly, dose
reduction should be implemented at the earliest possible stage,
when slight signs of AEs are noted. Combination therapy should
then be prolonged to ensure the full scheduled doses of therapy.
Regional and global variability exists in the nature of AEs and
in the strategies employed to mitigate their impact (Sulkowsky
2011).
Influenza-like symptoms (such as fatigue, headache, fever,
and rigors) occur in virtually all patients after the first doses of
PegIFN, but usually subside after the first month of treatment.
Dermatologic effects (alopecia, dermatitis) and gastrointestinal
symptoms (nausea, diarrhea) are also very frequent. The most
prevailing severe AEs are
– hematologic
– neuropsychiatric
– autoimmune
Anemia occurrs in more than 30% of treated patients. Usually,
the lowest hemoglobin (Hb) values are recorded 6-8 weeks after
22 | Hepatitis C Treatment
treatment initiation and stay at the same level throughout the
remaining therapy period, up to 48 weeks. Severe anemia, with
hemoglobin levels <10 g/dL, occur in approximately 10 - 15% of
patients. IFN induces bone marrow suppression, while RBV cause
hemolytic anemia. Recently, genome-wide association studies
have identified an inherited genetic polymorphism at
chromosome 20, in the inosine triphosphatase gene (SNPs:
rs1127354 and rs7270101), as predictive for RBV induced anemia
(Fellay 2010). The presence of A/A and A/C vs. C/C genotypes
predicts protection from RBV induced hemolytic anemia during
the early stages of treatment.
The management of anemia follows several successive steps:
– RBV dose reduction by 200-400 mg/day, when Hb level
decreases between 8.5 - 10 g /dl;
– Discontinuation of RBV when Hb level declines to <8.5g/dl;
– Epoetin administration in patients with early onset of
anemia, in order to prevent treatment interruption. Use of
recombinant human erythropoietin-stimulating agents has
been associated with higher SVR rates and with reduced
dropout rates (Sulkowski 2009).
RBV induced anemia can precipitate occult coronary artery
disease, especially in older patients (due to age related reduction
in creatinine clearance). An accurate estimation of the
glomerular filtration rate and the administration of a lower dose
of RBV are recommendable in elderly patients.
Neutropenia (with absolute neutrophil count – ANC less than
1.5 x109/mL) and thrombocytopenia (less than 50 000
cells/mm3) are also common. Consequently, eligibility for
treatment may be restricted in patients with advanced liver
cirrhosis.
The following decision tree is recommended for the
management of neutropenia and thrombocytopenia:
– PegIFN dose reduction, when ANC< 750 cells/mm3 and
platelets count < 50,000 cells/mm3;
– treatment discontinuation, when ANC < 500 cells/mm3 and
platelets count< 25,000 cells/mm3. If neutrophils or platelets
Antiviral Therapy: The Basics | 23
counts go up, treatment can be restarted, but at a reduced
Peg IFN dose;
– use of stimulating factors (i.e. Filgastrim™ - granulocyte
macrophage colony stimulating factor or Eltrombopag™ -an
oral thrombopoietin receptor agonist) is not routinely
recommended in clinical practice, except for patients with
cirrhosis.
Neuropsychiatric symptoms such as depression, irritability,
insomnia, and, occasionally, aggressive behavior are some of the
most debilitating AEs of PegIFN therapy, occurring in
approximately 20% to 30% of patients after the first month of
treatment. Interventions may require an initial dose reduction,
followed by permanent discontinuation of IFN in the case of
persistently severe or worsening symptoms. In most cases, the
neuropsychiatric symptoms resolve after PegIFN
discontinuation. A multidisciplinary approach, including medical
treatment (administration of antidepressants – especially
serotonin uptake inhibitors and benzodiazepines, when
required) and psychiatric counseling is needed in order to
reduce the psychiatric side effects of antiviral therapy.
Autoimmune disorders involve most commonly the
development of autoimmune thyroiditis, but HCV infection has
been also related to mixed cryoglobulinemia, thyroid
dysfunction and papillary thyroid cancer. There is ample
evidence showing that 7–11% of HCV-infected patients have
thyroid dysfunction (frequently consistent with hypothyroidism,
with increases in thyroid-stimulating hormone -TSH and
decreases in free thyroxin -T4 -mean values) prior to the
initiation of treatment. This percentage goes up to 15-20%, once
combined PegIFN/RBV therapy is initiated. Thyroid function
should be monitored routinely before and during treatment,
with TSH and T4 levels measured every 12 weeks while on
therapy and again at 6 months after the end of treatment.
Specific therapy may be needed to maintain a euthyroid state.
A series of other side effects are reported at lower rates, such as
pulmonary (cough, dyspnea), cardiovascular (cardiomyopaty,
24 | Hepatitis C Treatment
hypertension, supraventricular arrhythmias and myocardial
infarction) and ocular (retinal abnormalities).
Usually, but not always, these side effects reverse within a
short period after the end of therapy. Extreme caution is
however recommended in patients with preexisting chronic
obstructive pulmonary disease, diabetes mellitus prone to
ketoacidosis, severe myelosuppression, and/or coagulation
disorders (including thrombophlebitis and pulmonary
embolism). RBV may cause birth defects and/or death of the
unborn infant. Pregnancy must be avoided in female patients
and in female partners of male patients.
Recognition and effective management of AEs are critical
components of the successful treatment of CHC. Additional
measures include life style modification (hypocaloric diet,
physical exercise) in order to decrease the BMI and to prevent
weight gain. There are reports suggesting the beneficial effects
of insulin sensitizers (Metformin™- to reduce hepatic
gluconeogenesis and Pioglitazone™ -to sensitize insulin
receptors and mobilize visceral fat to subcutaneous tissues). A
series of hepatoprotective drugs and antioxidants (vitamin E,
betaine, silymarin and β-carotine) inhibit the toxic effects of free
radicals and prevent the synthesis of proinflammatory cytokines
that promote steatosis (El-Zayadi 2009). Excessive alcohol use
could reduce the likelihood of therapy response and abstinence
should be recommended before and during treatment
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