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

tubing with ribavirin. Techniques to reduce environmental exposure
of healthcare workers are recommended.
Systemic ribavirin causes dose-related reversible anemia
owing to extravascular hemolysis and suppression of bone marrow.
Associated increases occur in reticulocyte counts and in serum
bilirubin, iron, and uric acid concentrations. High ribavirin triphosphate
levels may cause oxidative damage to membranes, leading to
erythrophagocytosis by the reticuloendothelial system. About 20%
of chronic HCV infection patients receiving combination IFN-ribavirin
therapy discontinue treatment early because of side effects. In
addition to IFN toxicities, oral ribavirin increases the risk of fatigue,
cough, rash, pruritus, nausea, insomnia, dyspnea, depression, and
particularly, anemia. Preclinical studies indicate that ribavirin is teratogenic,
embryotoxic, oncogenic, and possibly gonadotoxic. To prevent
possible teratogenic effects, up to 6 months is required for
washout following cessation of long-term treatment (Glue, 1999).
Bolus intravenous infusion may cause rigors.
Pregnant women should not directly care for patients receiving
ribavirin aerosol (FDA pregnancy Category X).
Ribavirin inhibits the phosphorylation and antiviral activity of
pyrimidine nucleoside HIV reverse-transcriptase inhibitors such as
zidovudine and stavudine but increases the activity of purine nucleoside
reverse-transcriptase inhibitors (e.g., didanosine) in vitro. It
appears to increase the risk of mitochondrial toxicity from didanosine
(Chapter 59).
Therapeutic Uses. Oral ribavirin in combination with injected
pegIFN alfa-2A or -2B has become standard treatment for chronic
HCV infection (Reddy et al., 2009; Seeff and Hoofnagle, 2002).
Ribavirin monotherapy for 6-12 months reversibly decreases
aminotransferase elevations to normal in ~30% of patients but does
not affect HCV RNA levels. Combination therapy with pegIFN alfa-
2A and oral ribavirin (500 mg, or 600 mg if weight is >75 kg, twice
daily for 24-48 weeks) increases the likelihood of sustained biochemical
and virologic responses to ~56% depending on genotype
(Fried et al., 2002). The combination is superior to IFN or pegIFN
monotherapy and combinations of pegIFN alfa-2 and ribavirin in
both treatment-naive patients and those not responding to, or relapsing
after, IFN monotherapy. A longer duration of therapy (48 weeks)
appears necessary in those with genotype 1 infections, whereas
24 weeks’ therapy is adequate in genotype 2 and 3 infections
(Hadziyannis et al., 2004). Combined ribavirin and pegIFN alfa-2A
or -2B is effective in achieving sustained viral responses in a minority
of HCV/HIV co-infected patients (Reddy et al., 2009). Combined
therapy has been used in the management of recurrent HCV infection
after liver transplantation.
Ribavirin aerosol is approved in the U.S. for treatment of
RSV bronchiolitis and pneumonia in hospitalized children.
Aerosolized ribavirin (usual dose of 20 mg/mL as the starting solution
in the drug reservoir of the small particle aerosol generator unit
for 18 hours’ exposure per day for 3-7 days) may reduce some illness
measures, but its use generally is not recommended (Committee on
Infectious Diseases, American Academy of Pediatrics, 2003). No
consistent beneficial effects on duration of hospitalization, ventilatory
support, mortality, or long-term pulmonary function have been
found. High-dose, reduced-duration therapy (60 mg/mL in the drug
reservoir of the small particle aerosol generator unit for 2 hours
three times daily) has been used. Aerosol ribavirin combined with
intravenous immunoglobulin appears to reduce mortality of RSV
infection in bone marrow transplant and other highly immunocompromised
patients (Ghosh et al., 2000).
Intravenous and/or aerosol ribavirin has been used occasionally
in treating severe influenza virus infection and in the treatment
of immunosuppressed patients with adenovirus, vaccinia, parainfluenza,
or measles virus infections. Aerosolized ribavirin is associated
with reduced duration of fever but no other clinical or
antiviral effects in influenza infections in hospitalized children.
Intravenous ribavirin decreases mortality in Lassa fever and has
been used in treating other arenavirus-related hemorrhagic fevers.
Intravenous ribavirin is beneficial in hemorrhagic fever with renal
syndrome owing to Hantavirus infection but appears ineffective in
hantavirus-associated cardiopulmonary syndrome or SARS. Oral
ribavirin has been used for the treatment and prevention of
Crimean-Congo hemorrhagic fever and treatment of Nipah virus
infections (Mardani et al., 2003). Intravenous ribavirin is investigational
in the U.S.
Drugs for Hepatitis B Virus Infection
Unlike hepatitis C virus, hepatitis B virus is transcribed
into DNA that can be integrated into host chromosomal
DNA and is capable of establishing lifelong chronic
infection in ~10% of patients. Those with chronic HBV
may develop active hepatitis that can lead to fibrosis
and cirrhosis, but all such individuals have a greatly
increased incidence of hepatocellular carcinoma.
Interferon, or a combination of interferon and ribavirin,
can cure patients with chronic infection but is
associated with a high rate of side effects, often leading
to premature treatment discontinuation. Several antiretroviral
nucleoside or nucleotide analog polymerase
inhibitors, including lamivudine, telbivudine, and tenofovir,
have potent anti-HBV activity and have provided
a popular alternative therapy: chronic suppressive oral
single agent or combination treatment. These regimens
are much better tolerated than IFN-containing regimens
but are not usually curative.
Adefovir
Chemistry and Antiviral Activity.Adefovir dipivoxil (9-[2-
[bis[(pivaloyloxy)methoxy]phosphinyl]methoxyl]ethyl
]adenine, bis-POM PMEA) is a diester prodrug of adefovir,
an acyclic phosphonate nucleotide analog of
adenosine monophosphate (Figure 58–6).
It is inhibitory in vitro against a range of DNA
and RNA viruses, but its clinical use is limited to HBV
infections (De Clercq, 2003). Inhibitory concentrations
for HBV range from 0.2 to 1.2 μM in cell culture, and
it is active against lamivudine-resistant HBV strains.
Oral adefovir dipivoxil shows dose-dependent inhibition
of hepadnavirus replication in animal models. In
vitro combinations of adefovir and lamivudine or other
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CHAPTER 58
ANTIVIRAL AGENTS (NONRETROVIRAL)