Book on hepatitis from page 266 to 271

Book on hepatitis from page 266 to 271

266  Hepatology 2012
psychiatrist. One important risk factor for the development of psychotic symptoms
is a history of drug use.
Although history of major depression or suicide attempts is considered a
contraindication for interferon-based therapy, treatment of patients with pre-existing
psychiatric disorders can be initiated in close collaboration with an experienced
psychiatrist in a well-controlled setting (Schaefer 2004, Schaefer 2007).
It must be mentioned that so far there is no systematic experience with
combination of the recently approved HCV protease inhibitors and antidepressants.
While the new antiviral drugs telaprevir or boceprevir do not induce specific
psychiatric side effects, drug-drug interactions may complicate the use of
antidepressants and sleep medications.
Preemptive therapy with antidepressants
One double-blind randomised study with patients with malignant  melanoma
demonstrated that 14 days of pre-treatment with 20 mg paroxetine per day reduced
the incidence of depression during interferon therapy significantly (Musselmann
2001). Pre-treatment with paroxetine also had a positive effect on the development
of fears, cognitive impairments and pain during interferon treatment, but not on
symptoms such as fatigue, sleep disturbances, anhedonia and irritability (Capuron
2002). A recent prospective controlled trial with  HCV-infected patients
demonstrated that pre-treatment with citalopram significantly reduced depression
during the first 6 months of antiviral therapy in patients with psychiatric illness
compared to controls (Schaefer 2005). Furthermore, prophylactic treatment with
SSRIs was shown to reduce the severity of depressive symptoms in patients who
had suffered from severe depression during previous treatment of hepatitis C with
interferon α (Kraus 2005). A recent trial confirmed a protective effect of preemptive
initiation of treatment with antidepressants before starting interferon-based therapy
in cases of elevated depression scores (Raison 2007). However, three other trials
could not show significant effects on reduction of depressive symptoms nor overall
incidence of major depression, although these trials were either small in size or had
short observation times (Morasco 2007, Morasco 2010, Diez-Quevedo 2010). In
summary, current data support the view that all patients with pre-existing depressive
symptoms should receive a prophylactic treatment with antidepressants. However,
larger prospective controlled studies are needed in order to answer the question if
antidepressants should be given before antiviral plus interferon-based therapy,
independent of pre-existing psychiatric disorders.
Sleep disturbances
Patients who have difficulties in falling asleep can be treated with zopiclone or
trimipramine. Zolpidem may be used for patients with interrupted or shortened sleep
patterns. Although the risk of addiction is markedly reduced compared with other
benzodiazepines, only small amounts of zoplicon or zolpidem should be prescribed
at a time and therapy should be limited to the period of interferon-based therapy. As
sleeping disorders can be an early symptom of depression, it is also important to
assess the possible presence of other depressive symptoms when considering the use
of sleeping aids.
Management of Adverse Drug Reactions  267
Hematological and immunologic effects
Interferon-based therapy is accompanied by a marked drop in white blood cells in
general, neutrophils and absolute, although not relative, CD4+ cell count. This
change of the cellular immune system does not result in an increased number of
serious infections even in HIV-coinfected patients (Fried 2002,  Manns 2001,
Torriani 2004). In general, the incidence of serious infections is low (<5%) in
patients on interferon-based therapy.
G-CSF increases neutrophils in patients treated with interferon-based therapies.
However G-CSF has not been proven to have a clinical benefit in clinical trials for
this purpose and its use is off-label. Hemolytic anemia induced by ribavirin is
further aggravated by the myelosuppressive effect of interferon inhibiting
compensatory reticulocytosis (De Franceschi 2000). As a consequence, anemia (<10
g/dl) is reported in up to 20% of patients (Hadziyannis 2004). In severe cases of
anemia dose reduction of ribavirin is required. In rare cases red blood cell
transfusion may be necessary. Erythropoietin can be successfully used to correct the
ribavirin-induced anemia at least partially and to avoid ribavirin dose reduction or
red blood cell transfusions. In addition erythropoietin use was associated with an
improved quality of life. However, prospective controlled trials have not shown a
positive effect on the efficacy of hepatits C therapy in patients who take
erythropoietin (Afdahl 2004,  Pockros 2004,  Shiffman 2007). At present,
erythropoietin is not approved for correction of ribavirin-induced anemia in
hepatitis C therapy.
Mild to moderate thrombocytopenia is frequently seen in patients with advanced
liver fibrosis and may complicate interferon-based therapy. Reduction of interferon
dosing may be indicated to reverse severe thrombocytopenia. In studies
eltrombopag has been used successfully to increase platelet count in patients with
hepatitis C associated thrombocytopenia (McHutchison 2007). In recent trials
eltrombopag even increased efficacy of hepatitis C treatment in cirrhotic patients,
although the occurrence of portal vein thrombosis was observed in a number of
patients cautioning its widespread use (Afdhal 2011).
Skin disorders and hair loss
Some skin disorders such as lichen ruber planus, necrotising vasculitis or porphyrea
cutanea tarda are associated with hepatitis C infection. The effects of hepatitis C
therapy are often not well-studied and based only on information gathered through
cohorts (Berk 2007).
Interferon and ribavirin therapy may have an effect on the skin itself including dry
skin, itching, eczema and new or exacerbated psoriasis. Ointments with rehydrating
components, urea or steroids can be used depending on the nature of the skin
disorders. In severe cases a dermatologist should be involved. In particular, eczema
and psoriasis may last substantially longer than the treatment period with interferon-based therapy.
Local skin reactions to the injection of pegylated interferon are common and
usually present as red indurations lasting days to weeks. Repeated injections at the
same site may cause ulcers and should be avoided. Hypersensitivity reactions to
pegylated interferons are reported anecdotally.
Hair loss is frequent, usually appearing after the first months of therapy and
continuing for some weeks after the cessation of therapy. Alopecia is very rare and
268  Hepatology 2012
hair loss is usually fully reversible, although the structure of the hair may be
different after therapy.
Adverse events with telaprevir and boceprevir
Triple combination therapy of pegylated interferon, ribavirin plus one of the newer
HCV protease inhibitors telaprevir or boceprevir is standard of care for the
treatment of most genotype 1 patients. This treatment provides better efficacy, but
also new challenges for adherence and management of adverse events. In general all
adverse events caused by interferon and ribavirin remain, however some may be
accentuated or new adverse events may occur.
In addition, boceprevir and telaprevir are simultaneous inducers and inhibitors of
multiple enzymes of the cytochrome P450 system. For this reason, drug-drug
interactions are not easy to predict and involve frequently used drugs such as
sedatives, antidepressants, antibiotics, immunosuppressants, oral corticosteroids,
statins and calcium channel blockers. As this is an evolving area, for updated
information, the website  www.hep-druginteractions.org  should be checked
regularly.
Boceprevir and telaprevir have to be taken three times a day with food or a fat-containing meal, respectively. Pill burden is high with 12 pills for boceprevir and 6
for telaprevir. Dosing and taking the medication not fasting are crucial for efficacy.
Boceprevir or telaprevir doses should never be reduced in case of toxicities, but
rather discontinued or kept at the standard dose. Reducing the dose of these HCV
protease inhibitors will result in treatment failure due to lower drug exposure.
Frequent adverse events seen with telaprevir are itching and rash, with the first
occurring in the majority of patients. Itching can be orally treated with
antihistamines, e.g., cetirizine, but efficacy seems limited. Rash is usually mild to
moderate while serious skin reactions seem to be rare. Discontinuation is rarely
necessary. Use of corticosteroid-based ointments, e.g., betamethasone 0.1% together
with rehydrating and/or urea-containing creams are the treatments of choice for
rash. For a serious case of psoriasis a consultation of an experienced dermatologist
is advisable. Anal symptoms ranging from discomfort to pain and bleeding are also
common. Depending on the severity, local therapy with a zinc paste or
corticosteroid ointments are used.
A more frequent and more pronounced anemia than what is seen with interferon
plus ribavirin may require dose adjustment of ribavirin or red blood cell transfusion.
The use of erythropoietin for mitigation of anemia is not approved, but can be tried
where reimbursement is possible.
Nausea and diarrhea are frequently seen in patients on telaprevir and may require
symptomatic therapy (Hézode 2009,  McHutchison 2009,  McHutchison 2010,
Marcellin 2010).
With boceprevir, anemia is the most important adverse event requiring dose
adjustment of ribavirin or red blood cell transfusion in a considerable number of
patients. Dysgeusia is another frequent complaint that resolves upon discontinuation
(Bacon 2011, Poordad 2011).
Management of Adverse Drug Reactions  269
Adherence
Adherence data from retrospective analyses suggest that at least 80% of the
cumulative doses of ribavirin and interferon should be taken by patients as a
prerequisite for treatment success. Cumulative doses of less than 80% were
associated with a steep drop in sustained virologic response (Camma 2005).
Another surrogate of adherence is the premature treatment discontinuation rate,
which usually ranges from 10–15% with pegylated interferon and ribavirin (Fried
2002, Manns 2001).
The added mandatory intake of food as a complication of HCV protease inhibitors
has heightened the adherence concerns.
Despite these increased complications, discontinuation rates in the triple-therapy
arms were only slightly higher in the registration trials, leading to the approval of
boceprevir and telaprevir, indicating a better management of drug-related toxicities
(Bacon 2011, Marcellin 2010, McHutchinson 2010, Poordad 2011).
Conclusion
In summary, the toxicity of interferon-based therapy plus ribavirin is considerable
and requires active management and profound knowledge, particularly about the
management of psychiatric adverse events.
The first generation of HCV protease and polymerase inhibitors will improve the
efficacy of therapy, in particular in HCV genotype 1 patients, but at the cost of
increased toxicities during therapy. Early assessment and robust management of
adverse events may prevent premature treatment discontinuations and improve the
efficacy of hepatitis C therapy.
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