DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

IFN can cause myelosuppression and clinical deterioration in those
with decompensated liver disease.
Remissions in chronic hepatitis B induced by IFN are sustained
in >80% of patients treated and frequently are followed by
loss of HBV surface antigen (HbsAg), histological improvement or
stabilization, and reduced risk of liver-related complications and
mortality (Lau et al., 1997). IFN may benefit some patients with
nephrotic syndrome and glomerulonephritis owing to chronic HBV
infection. Antiviral effects and improvements occur in about onehalf
of chronic hepatitis D virus (HDV) infections, but relapse is
common unless HbsAg disappears. IFN does not appear to be beneficial
in acute HBV or HDV infections.
Hepatitis C Virus. In chronic HCV infection, IFN alfa-2B monotherapy
(3 MU three times a week) is associated with an approximate 50-
70% rate of aminotransferase normalization and loss of plasma viral
RNA, but relapse rates are high, and sustained virologic remission
(absence of detectable HCV RNA) is observed in only 10-25% of
patients.
Sustained viral responses are associated with long-term histological
improvement and probably reduced risk of hepatocellular
carcinoma and hepatic failure (Coverdale et al., 2004). Viral genotype
and pretreatment RNA level influence response to treatment,
but early viral clearance is the best predictor of sustained response.
Failure to achieve an early viral response (nondetectable HCV RNA
or reduction ≥2 log 10
units compared with baseline at 12 weeks) predicts
lack of sustained viral response with continued treatment (Seeff
and Hoofnagle, 2002). Nonresponders generally do not benefit
from IFN monotherapy retreatment, but they and patients relapsing
after monotherapy often respond to combined pegylated IFN and
ribavirin treatment. IFN treatment may benefit HCV-associated
cryoglobulinemia and glomerulonephritis. IFN administration during
acute HCV infection appears to reduce the risk of chronicity
(Alberti et al., 2002).
Pegylated IFNs are superior to conventional thrice-weekly
IFN monotherapy in inducing sustained remissions in treatmentnaive
patients. Monotherapy with pegIFN alfa-2A (180 μg subcutaneously
weekly for 48 weeks) or pegIFN alfa-2B (weight-adjusted
doses of 1.5 μg/kg/week for 1 year) is associated with sustained
response in 30-39%, including stable cirrhotic patients (Heathcote
et al., 2000), and it is a treatment option in patients unable to take ribavirin.
Studies of prolonged (4 years) maintenance monotherapy
with pegylated IFNs are in progress for those not responding to IFNribavirin
combinations. A large randomized comparison of pegIFN
alfa-2A versus alfa-2B combined with ribavirin found no difference
in response rates (McHutchison et al., 2009).
The efficacy of conventional and pegylated IFNs is enhanced
by the addition of ribavirin to the treatment regimens, particularly for
genotype 1 infections. Combined therapy with pegIFN alfa-2A (180 μg
once weekly for 48 weeks) and ribavirin (1000-1200 mg/day in
divided doses) gives higher sustained viral response rates than IFNribavirin
combinations in previously untreated patients (Fried et al.,
2002). A shorter duration of therapy (24 weeks) and lower ribavirin
dose (800 mg/day) are effective in genotype 2 and 3 infections, but
prolonged therapy and higher ribavirin doses are needed for genotype
1 and 4 infections (Hadziyannis et al., 2004). Approximately
15-20% of those failing to respond to combined IFN-ribavirin will
have sustained responses to combined pegIFN-ribavirin. Histological
improvement may occur in patients who do not achieve sustained
viral responses. In patients with compensated cirrhosis, treatment
may reverse cirrhotic changes and possibly reduce the risk of hepatocellular
carcinoma (Poynard et al., 2002).
Papillomavirus. In refractory condylomata acuminata (genital warts),
intralesional injection of various natural and recombinant IFNs is
associated with complete clearance of injected warts in 36-62% of
patients, but other treatments are preferred (Wiley et al., 2002).
Relapse occurs in 20-30% of patients. Verruca vulgaris may respond
to intralesional IFN-α. Intramuscular or subcutaneous administration
is associated with some regression in wart size but greater toxicity.
Systemic IFN may provide adjunctive benefit in recurrent juvenile
laryngeal papillomatosis and in treating laryngeal disease in older
patients.
Other Viruses. IFNs have been shown to have virological and clinical
effects in various herpesvirus infections including genital HSV
infections, localized herpes-zoster infection of cancer patients or of
older adults, and CMV infections of renal transplant patients.
However, IFN generally is associated with more side effects and
inferior clinical benefits compared with conventional antiviral therapies.
Topically applied IFN and trifluridine combinations appear
active in acyclovir-resistant mucocutaneous HSV infections.
In HIV-infected persons, IFNs have been associated with
antiretroviral effects. In advanced infection, however, the combination
of zidovudine and IFN is associated with only transient benefit
and excessive hematological toxicity. IFN-α (3 MU three times
weekly) is effective for treatment of HIV-related thrombocytopenia
resistant to zidovudine therapy.
Except for adenovirus, IFN has broad-spectrum antiviral
activity against respiratory viruses in vitro. However, prophylactic
intranasal IFN-α is protective only against rhinovirus colds, and
chronic use is limited by the occurrence of nasal side effects.
Intranasal IFN is therapeutically ineffective in established rhinovirus
colds. Systemically administered IFN-α may be beneficial in early
treatment of SARS (Loutfy et al., 2003).
Ribavirin
Chemistry and Antiviral Activity. Ribavirin is a purine
nucleoside analog with a modified base and D-ribose
sugar (Figure 58–6).
Ribavirin inhibits the replication of a wide range
of RNA and DNA viruses, including orthomyxo-,
paramyxo-, arena-, bunya-, and flaviviruses in vitro. In
vitro inhibitory concentrations range from 3 to 10 μg/mL
for influenza viruses, parainfluenza viruses, and respiratory
syncytial viruses (RSV). Similar concentrations may
reversibly inhibit macromolecular synthesis and proliferation
of uninfected cells, suppress lymphocyte responses,
and alter cytokine profiles in vitro.
Mechanisms of Action and Resistance. The antiviral
mechanism of ribavirin is incompletely understood but
relates to alteration of cellular nucleotide pools and inhibition
of viral messenger RNA synthesis (Tam et al., 2002).
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CHAPTER 58
ANTIVIRAL AGENTS (NONRETROVIRAL)