antiviraldrugsforvirusesotherthanhumanimmunodeficiencyvirus
antiviraldrugsforvirusesotherthanhumanimmunodeficiencyvirus
antiviraldrugsforvirusesotherthanhumanimmunodeficiencyvirus
ANTIVIRAL THERAPIES
Raymund R. Razonable, MD
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
viral thymidine kinase (TK) and subsequently by human en- crystals. Acyclovir crystalline nephropathy is more com-
zymes. Acyclovir-triphosphate serves as a competitive sub- mon when acyclovir is given as a rapid infusion (reaching
strate for viral DNA polymerase, and its incorporation into serum concentrations >25 μg/mL)15 and in patients with
the DNA chain results in termination of viral replication. dehydration and preexisting renal impairment.16 Adequate
Acyclovir is approved for the treatment of primary and hydration, a slower rate of infusion, and dosing based on
recurrent genital HSV infection (Table 1).2,4,5 Topical acy- renal function may reduce this risk. Reversible neuro-
clovir may be used to treat genital herpes, but the oral for- logic symptoms such as delirium and seizures may occur
mulation is generally recommended6; IV acyclovir is used rarely in elderly people and those with renal impairment;
for severe cases.1,4 Suppressive therapy with oral acyclovir this toxicity has been associated with high serum acy-
is also indicated to reduce the incidence of recurrent geni- clovir concentrations15 and high CSF levels of its metabo-
tal herpes.4,7 lite 9-carboxymethoxymethylguanine.17-19 Other adverse
Oral acyclovir is modestly efficacious against orolabial effects are gastrointestinal symptoms, myelosuppression,
herpes. In immunocompetent individuals, orolabial herpes and rash.3,20,21
is often self-limited, and antiviral treatment is generally not Acyclovir-resistant HSV has been reported, especially
recommended.7 However, oral acyclovir may be indicated in immunocompromised patients.22-24 Resistance occurs by
for severe cases, for those with recurrent orolabial herpes, selection of viral mutants that are deficient in TK (which
and in those who are immunocompromised.7,8 results in an inability to activate acyclovir) or that have al-
Intravenous acyclovir is the first-line treatment for tered DNA polymerase with reduced affinity to acyclovir-
HSV encephalitis9 and should be started as soon as the triphosphate.23
disease is suspected clinically. Magnetic resonance im-
aging of the brain typically demonstrates temporal lobe BRIVUDIN
involvement, and diagnosis is confirmed by detection of Brivudin is a 5ʹ-halogenated thymidine nucleoside analogue
HSV DNA in the CSF. Major studies have evaluated the that is highly active against HSV-1 and VZV.25,26 Brivu-
efficacy of 10 days of acyclovir treatment for HSV en- din is phosphorylated by viral TK and cellular kinases to
cephalitis; however, the recommended duration of treat- brivudin-triphosphate, which serves as a competitive in-
ment in the clinical setting is 2 to 3 weeks because shorter hibitor of viral DNA polymerase, thereby terminating
durations have been associated with relapse.10 The treat- viral DNA synthesis. It is available in some countries for
ment duration may be further prolonged in immunocom- the treatment of herpes zoster and herpes simplex. How-
promised patients.8 ever, concerns about its toxicity halted its clinical develop-
Acyclovir is also approved by the US Food and Drug ment in the United States. Its metabolite, bromovinyluracil,
Administration (FDA) for the treatment of VZV11,12; how- irreversibly inhibits dihydropyridine dehydrogenase, which
ever, young immunocompetent patients with zoster may regulates nucleoside metabolism. Coadministration with 5-
not require treatment if the lesions are localized and have fluorouracil has resulted in lethal bone marrow toxicity and
been present for more than 72 hours. Intravenous acyclovir severe gastrointestinal toxicity.25,26
is recommended for patients with disseminated zoster dis-
ease or visceral involvement. Acyclovir treatment of zoster CIDOFOVIR
reduces duration of viral shedding, formation of new le- Cidofovir is a nucleoside analogue used for the treatment
sions, and short- and long-term neuralgia.13 Therapy should of CMV, other herpesviruses, and other DNA viral infec-
be started early, but even delayed initiation of acyclovir may tions.27 It is available as an IV formulation, and an oral
still be beneficial in immunocompromised patients. Short- prodrug of cidofovir (known as $.9) is under clinical
course prednisone may be added as an adjunct to acyclovir development.28 This investigational lipid ester formulation
treatment of zoster to improve quality of life, especially in of cidofovir has enhanced bioavailability, resulting in im-
elderly patients. proved 50% inhibitory concentrations.28 Direct intraocular
Acyclovir has been used in the treatment of acute retinal injection of cidofovir is contraindicated due to ocular hy-
necrosis (which is associated with HSV or VZV), eczema potony.27 Serum cidofovir concentrations decline rapidly
herpeticum, and oral hairy leukoplakia due to EBV. Oral after IV infusion, with a half-life of 2 hours; however, the
acyclovir is used to prevent HSV during the early period intracellular half-life of active cidofovir-diphosphate is as
after transplant in patients not receiving ganciclovir or val- long as 65 hours. Cidofovir is eliminated by glomerular
ganciclovir prophylaxis.14 filtration and tubular secretion; probenecid reduces its ex-
Acyclovir is generally well tolerated. However, IV acy- cretion by blocking tubular secretion.29,30
clovir may cause reversible nephrotoxicity in 5% to 10% of Cidofovir is phosphorylated by cellular kinases into
patients because of intratubular precipitation of acyclovir cidofovir-diphosphate, a competitive substrate for viral
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
TABLE 1. Continueda,b,c
Virus Clinical disease Drug name (route) Recommended dosage Comments
CMV Preemptive therapy Valganciclovir (oral) 900 mg orally twice daily CMV replication is detected by weekly
(continued) for asymptomatic CMV surveillance using PCR or pp65
CMV infection antigenemia
in transplant Preferred drug for the treatment of
recipients asymptomatic CMV infection in solid
organ and hematopoietic stem cell
transplant recipients
Ganciclovir (IV) 5 mg/kg IV every 12 h Less preferred than valganciclovir because
of the logistics of IV administration
Oral ganciclovir should not be used for
treating active CMV infection
CMV retinitis in Valganciclovir (oral) Induction: 900 mg orally twice For sight-threatening retinitis, use in
HIV-infected daily for 14-21 d combination with ganciclovir intraocular
patients Maintenance: 900 mg orally once implant (see below)
daily until immune reconstitution
Ganciclovir (IV) Induction: 5 mg/kg IV every 12 h For sight-threatening retinitis, use in
for 14-21 d combination with ganciclovir intraocular
Maintenance: 5 mg/kg IV every implant (see below)
24 h until immune reconstitution
Ganciclovir One sustained-release intravitreal Replace every 6-8 mo until immune
(intraocular implant (4.5 mg/implant) reconstitution
implant) every 6-8 mo Use in combination with systemic
ganciclovir (or valganciclovir) because of
the systemic nature of CMV disease
Foscarnet (IV) Induction: 90 mg/kg every 12 h Second-line therapy
OR Indicated for ganciclovir-resistant CMV
60 mg/kg every 8 h disease
Maintenance: 90-120 mg/kg every High risk of nephrotoxicity and electrolyte
24 h abnormalities
Cidofovir (IV) Induction: 5 mg/kg per dose once Alternative treatment of CMV disease
weekly for 2 doses Indicated for ganciclovir-resistant CMV
Maintenance: 5 mg/kg every 2 wk disease
High risk of nephrotoxicity; requires
concomitant hydration and probenecid use
CMV disease other Valganciclovir (oral) Induction: 900 mg orally twice
than retinitis daily for 14-21 d
in HIV-infected Maintenance: 900 mg orally once
patients daily until immune reconstitution
Ganciclovir (IV) Induction: 5 mg/kg IV every 12 h Preferred for severe disease (eg,
for 14-21 d pneumonitis, encephalitis) and for those
Maintenance: 5 mg/kg IV every with poor intestinal absorption
24 h until immune reconstitution
Foscarnet (IV) Induction: 90 mg/kg every 12 h Second-line therapy
OR Indicated for ganciclovir-resistant CMV
60 mg/kg every 8 h disease
Maintenance: 90-120 mg/kg every High risk of nephrotoxicity and electrolyte
24 h abnormalities
Cidofovir (IV) Induction: 5 mg/kg per dose once Alternative treatment for CMV disease
weekly for 2 doses Indicated for ganciclovir-resistant CMV
Maintenance: 5 mg/kg every 2 wk disease
High risk of nephrotoxicity; requires
concomitant hydration and probenecid use
a
CMV = cytomegalovirus; HIV = human immunodeficiency virus; IV = intravenous; PCR = polymerase chain reaction.
b
Doses are given for persons with normal renal function. Please consult individual drug’s package insert for dose adjustments in persons with impaired
renal function.
c
No antiviral drugs have been approved for the treatment of Epstein-Barr virus or human herpesviruses 6, 7, and 8.
DNA polymerase, thereby halting viral DNA synthesis.27 to ganciclovir.32 Because activation of cidofovir does not
The major clinical indication for cidofovir is the treatment rely on viral kinases, it retains activity against CMV with
of CMV retinitis in HIV-infected patients (Table 1).31 Ci- the UL97 mutation and HSV with the TK mutation.33 Re-
dofovir is also used as rescue therapy for immunocompro- sistance to cidofovir occurs when the virus develops muta-
mised patients with CMV disease resistant or unresponsive tions in the DNA polymerase gene (ie, $.76- gene
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
mutations).33 Cidofovir has also been used off-label for increased intraocular pressure and inflammation. Blurred
various illnesses, such as acyclovir-resistant HSV disease, vision, conjunctival hemorrhage, retinal detachment, and
condyloma acuminatum, BK virus–associated hemor- retinal edema are other adverse effects.55-57
rhagic cystitis, JC virus–associated progressive multifocal
leukoencephalopathy, and other infections due to double- FOSCARNET
stranded DNA viruses.34-47 Foscarnet is a nonnucleoside pyrophosphate analogue that is
Nephrotoxicity is the most common serious adverse ef- given intravenously for the treatment of herpesviruses.58 Its
fect of cidofovir.27 The incidence and severity of nephrotox- pharmacokinetic profile is complicated by a high incidence
icity may be reduced by hydration and probenecid.48 Blood of nephrotoxicity and by its deposition and subsequent grad-
cell counts should be monitored to assess myelosuppression, ual release from bone.58 Its half-life depends on the duration
and ophthalmological surveillance is recommended because of therapy; in patients with normal renal function, the plas-
of the risk of ocular hypotony, uveitis, and iritis.49,50 ma half-life is about 2 to 4 hours, but terminal half-lives up
to about 8 days may occur when it has accumulated in bones.
FAMCICLOVIR Foscarnet is excreted through glomerular filtration.
Famciclovir is a diacetyl 6-deoxy analogue of penciclovir. Foscarnet selectively inhibits pyrophosphate binding on
Oral famciclovir is rapidly absorbed and achieves a bio- viral DNA polymerases, thus suppressing HSV-1, HSV-2,
availability of 77%.51 Famciclovir is metabolized into pen- and CMV replication. It is also active against VZV, HHV-6,
ciclovir, reaching peak plasma penciclovir concentrations and EBV.59 Unlike ganciclovir, foscarnet does not require
within 1 hour. Because of extensive hepatic metabolism, intracellular conversion to active triphosphate, thus main-
virtually no famciclovir is detectable in plasma.51 Famci- taining activity against herpesviruses with TK or UL97 ki-
clovir is excreted renally as penciclovir and its 6-deoxy nase mutations.33
precursor.9 Foscarnet is approved for the treatment of CMV ret-
Famciclovir is active against HSV-1, HSV-2, and VZV, initis in patients with AIDS.58 It has been used to treat
and, to a lesser extent, against EBV. Its mechanism of ac- other CMV diseases in immunocompromised patients,
tion is through penciclovir; penciclovir triphosphate in- especially those unable to tolerate ganciclovir and those
hibits herpes DNA synthesis by acting as a substrate for infected with ganciclovir-resistant virus.60,61 Foscarnet is
viral DNA polymerase. The major clinical indications for also used for treating acyclovir-resistant mucocutaneous
famciclovir use are treatment of herpes zoster, recurrent HSV and VZV in immunocompromised patients.58 On
genital herpes,52 and recurrent herpes labialis.53 Famciclo- rare occasion, it has been used for prevention of CMV
vir can also be used as suppression therapy to reduce the in transplant recipients; however, its toxicity limits this
risk of recurrent genital herpes as well as oral treatment of clinical indication.60,61
uncomplicated varicella in HIV-infected patients. Nephrotoxicity is the most common serious adverse ef-
The most common adverse effects of famciclovir are fect of foscarnet, affecting 30% of patients. It is caused
headache and nausea.54 Rare adverse events include jaun- by deposition of foscarnet crystals in the glomerular cap-
dice, rash, pruritus, somnolence, and confusion.54 Acute re- illary lumen.62,63 Foscarnet may cause myelosuppression,
nal failure has occurred in patients taking inappropriately with anemia as the most common effect. It can chelate bi-
high doses of famciclovir. valent metal ions and may lead to reductions in ionized
calcium. Other electrolyte disturbances are hypokalemia,
FOMIVIRSEN hypomagnesemia, and hypophosphatasemia, which could
Fomivirsen is a 21-nucleotide phosphorothionate oligo- manifest as paresthesias, cardiac dysrhythmias, and neu-
nucleotide complementary to messenger RNA (mRNA) of rologic symptoms, including seizures.64 Patients should be
the immediate-early region of CMV.55-57 Its antiviral prop- hydrated to prevent nephrotoxicity, and electrolyte abnor-
erty is exerted by antisense inhibition of target gene ex- malities should be corrected to avoid cardiac and neuro-
pression. Other potential mechanisms of antiviral activity logic complications.
include its nonspecific interactions with viral particles that
may prevent adsorption or lead to inhibition of enzymes GANCICLOVIR
required for viral DNA synthesis. Ganciclovir is an acyclic 2ʹ-deoxyguanosine analogue for
Fomivirsen is given intravitreally. Its main indication the management of CMV.65 It is available in oral and par-
is the treatment of CMV retinitis in patients with AIDS enteral formulations. Oral ganciclovir is poorly absorbed,
who have not benefited from or are intolerant of standard with a bioavailability of only 5%.65 Management of active
CMV therapies, or whose virus is resistant to ganciclovir CMV disease is therefore with IV ganciclovir or its oral
and foscarnet.55-57 The main adverse effect of fomivirsen is valyl prodrug valganciclovir. Intravitreal ganciclovir im-
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
transplant recipients.78 Although ganciclovir is the back- identical to those underlying ganciclovir resistance, ie,
bone for CMV prevention in transplant recipients, the through mutations in the 6- gene, which encodes for
efficacy of valacyclovir prophylaxis for CMV preven- CMV kinase, and the 6- gene, which encodes for CMV
tion was demonstrated in kidney transplant recipients.78 DNA polymerase.71
However, valacyclovir has not been proven effective for
preventing CMV in heart, liver, lung, pancreas, and small VIDARABINE
bowel transplant recipients. Vidarabine, a purine nucleoside obtained from 4USFQUPNZ
The adverse effects of valacyclovir are similar to DFTBOUJCJPUJDVT was historically used for treating HSV and
those of acyclovir. At very high doses, neurotoxicity VZV. Acyclovir has since become the preferred drug for
characterized by confusion, hallucinations, and seizures these conditions.90 Vidarabine is currently available only
may occur,78 especially in elderly patients and in those as an ophthalmic solution for treating recurrent epithelial
with dehydration and renal disease. The mechanism of keratitis and acute keratoconjunctivitis.90 Once phosphor-
resistance for valacyclovir is identical to that of acyclovir ylated into its active form, vidarabine inhibits viral DNA
(TK mutation); however, achieving higher serum acyclo- polymerase. Adverse effects of ophthalmic vidarabine in-
vir levels with valacyclovir could reduce the risk of resis- clude irritation, pain, photophobia, lacrimation, and occlu-
tance compared with oral acyclovir. sion of the lacrimal duct.90
VALGANCICLOVIR
ANTIVIRAL DRUGS FOR INFLUENZA
Valganciclovir is the L-valyl ester prodrug of ganciclovir.
Oral valganciclovir is well absorbed and converted to gan- M2 INHIBITORS
ciclovir by first-pass intestinal or hepatic metabolism.79 The Amantadine. Amantadine is a symmetric tricyclic
bioavailability of ganciclovir after valganciclovir adminis- amine that inhibits replication of influenza A virus by im-
tration is about 60%, and peak plasma concentrations are pairing the function of the membrane protein M2.91 Present
achieved in 1 to 3 hours.80,81 Valganciclovir is eliminated only in influenza A virus, M2 is an acid-activated ion chan-
renally as ganciclovir.80,82 nel required for nucleocapsid release.91 Amantadine is well
Valganciclovir exerts its antiviral activity in the form absorbed after oral administration. It has an elimination
of ganciclovir-triphosphate, which inhibits viral replica- half-life of 11 to 15 hours and is excreted by glomerular
tion by serving as a competitive substrate for CMV DNA filtration and tubular secretion.
polymerase. Valganciclovir was first approved by the FDA Amantadine is effective for treating susceptible influ-
for treatment of CMV retinitis in patients with AIDS.83 For enza A virus infection.91 It results in a more rapid func-
immediate sight-threatening lesions, valganciclovir is used tional recovery and reduces the duration of fever and other
in combination with an intravitreal ganciclovir implant. symptoms by about 1 day, if given within 48 hours of dis-
Valganciclovir is also used for preventing CMV disease in ease onset.91 Amantadine is effective as prophylaxis for
high-risk CMV donor-positive/recipient-negative recipi- preventing symptomatic influenza A infection in exposed
ents of kidney, heart, or kidney-pancreas transplants.61,84 persons.92,93 It is usually given for 14 days or for at least
In the United States, valganciclovir is not approved for 7 days after the last confirmed illness. Seasonal influenza
preventing CMV disease in liver recipients because of a vaccination, however, remains the preferred method for
higher incidence of tissue-invasive CMV disease in pa- prevention.
tients who received valganciclovir vs oral ganciclovir Amantadine is generally well tolerated. Among its ad-
prophylaxis. In other countries, valganciclovir is used for verse effects are mild neurologic symptoms such as anxi-
preventing CMV disease in all solid organ transplant re- ety, disorientation, and headache, especially in elderly pa-
cipients. It has recently gained approval for the preven- tients and those taking neuroaffective drugs. Emergence
tion of CMV disease in pediatric heart and kidney trans- of amantadine resistance has limited its use in the clinical
plant recipients. It can also be used to preemptively treat setting.94,95 Amantadine resistance, characterized by amino
asymptomatic CMV infection in transplant recipients.85-88 acid substitutions in the M2 protein, emerges within 2 to
Valganciclovir was recently demonstrated to be as effec- 4 days of treatment. Because of widespread resistance,
tive as IV ganciclovir for treating mild to moderate CMV amantadine is no longer recommended for empiric treat-
disease in transplant recipients.86,87,89 ment of influenza.94,95 M2 mutation confers cross-resistance
Bone marrow suppression is the most common adverse with rimantadine.
effect of valganciclovir. Gastrointestinal manifestations, Rimantadine. Rimantadine is a symmetric tricyclic
such as diarrhea, nausea, and vomiting, may be observed. amine that inhibits influenza virus.93 It is well absorbed af-
Resistance to valganciclovir occurs through mechanisms ter oral administration, reaching peak plasma concentration
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
in 3 to 5 hours. Rimantadine undergoes extensive hepatic oseltamivir, but not to zanamivir.104 Oseltamivir resistance
metabolism before it is excreted in the urine. among influenza B viruses occurs less frequently.105
The mechanism of action of rimantadine is similar to Zanamivir. Zanamivir is an inhaled neuraminidase in-
that of amantadine; it inhibits the ion channel function of hibitor that is used for the treatment and prophylaxis of
M2, thereby inhibiting viral uncoating. Rimantadine is indi- influenza A and B viruses.106 Zanamivir is not available
cated for prevention and treatment of influenza A virus93; orally since it is poorly absorbed.106 Inhaled zanamivir pro-
however, its clinical utility is currently limited by drug duces high concentrations in the respiratory tract where in-
resistance.96,97 A few trials that compared amantadine and fluenza virus infection occurs. About 4% to 20% of inhaled
rimantadine suggested similar efficacy; however, neu- zanamivir is absorbed systemically, producing peak serum
rologic adverse events are less severe and frequent with concentrations at 1 to 2 hours. The absorbed drug is not
rimantadine. metabolized and is excreted unchanged in the urine, while
the unabsorbed drug is excreted in the feces.106
NEURAMINIDASE INHIBITORS The mechanism of action of zanamivir is similar to osel-
Oseltamivir. Oseltamivir phosphate is a prodrug of osel- tamivir, by inhibiting neuraminidase, which is essential
tamivir carboxylate, which is an inhibitor of neuraminidase for release of newly formed viral particles from infected
that is essential in the replication of influenza A and B vi- cells.106 For treatment, zanamivir is given by inhalation
ruses.98 Oral oseltamivir is well absorbed and reaches peak twice daily for 5 days, with the therapy begun within 48
serum concentrations in 1 hour. Bioavailability of oseltam- hours after symptom onset. Zanamivir can be given once
ivir phosphate is at least 75%. The prodrug oseltamivir daily for 10 days as postexposure prophylaxis of influenza
phosphate undergoes extensive hepatic metabolism via A and B in household or close contacts. Zanamivir pro-
ester hydrolysis. More than 99% of active oseltamivir car- phylaxis during community outbreaks may be given for 28
boxylate is excreted renally. days. Zanamivir has occasionally been given IV to treat
Oseltamivir carboxylate, the active drug metabolite, critically ill patients with influenza.107,108
selectively blocks viral neuraminidase, thereby preventing Inhaled zanamivir is well tolerated.106 Acute broncho-
the release of virus from infected cells.98 Oseltamivir is ap- spasm with decline in respiratory function has been re-
proved for the treatment of children (≥1 year) and adults ported; a bronchodilator should be available if given as
with influenza A or B viral infections.98 Treatment should treatment for patients with underlying pulmonary disease.
start within 48 hours of disease onset and continue for 5 Other adverse effects include headache and gastrointestinal
days. Oseltamivir is as effective as the other neuraminidase symptoms. Hypersensitivity reactions and neuropsychiat-
inhibitor, zanamivir, in reducing the febrile period during ric adverse effects occur rarely.109
infection with influenza A (H1N1), influenza A (H3N2),
and influenza B virus.99
ANTIVIRAL DRUGS FOR HEPATITIS AND
Oseltamivir is also used for postexposure prophylaxis
OTHER VIRUSES
against influenza A and B, including pandemic strains.
For this indication, oseltamivir should be started within 48 INTERFERONS
hours of exposure and continued daily for at least 10 days or Interferons (IFNs) are naturally occurring proteins pro-
for up to 6 weeks during an outbreak. A systematic review duced in response to viral infection.110 The 3 major classes
reported no statistically significant difference between osel- of IFNs are α, β, and γ; IFN-α and IFN-β are further classi-
tamivir and zanamivir prophylaxis for preventing symptom- fied as type I, whereas IFN-γ is type II.110 Available only in
atic influenza among immunocompetent adults.100 parenteral formulation, more than 80% of a subcutaneous
The most common adverse effects of oseltamivir are (SC) or intramuscular dose of IFN-α is absorbed.110 After
nausea, vomiting, diarrhea, abdominal pain, insomnia, and an intramuscular injection, peak IFN concentrations occur
vertigo. Neuropsychiatric adverse effects, including de- within 4 to 8 hours and return to baseline levels in 16 to 24
lirium, abnormal behavior, and hallucinations, have been hours.110 Pegylation, which is the process of attachment of
reported. Oseltamivir-resistant influenza A virus has been IFN to a large inert polyethylene glycol, markedly reduces
reported.101-103 Mutations in the neuraminidase gene, such as the rate of absorption and excretion of IFN and therefore
R292K101 and H274Y,98 account for oseltamivir resistance. increases its plasma concentration.111 For example, after an
Surveillance conducted during the 2009 H1N1 influenza SC dose of peginterferon α-2b, the peak serum concentra-
pandemic detected sporadic and infrequent incidence of tion occurs in 15 to 44 hours, high concentrations are main-
oseltamivir-resistant pandemic (H1N1) 2009 influenza vi- tained for 48 to 72 hours, and the mean terminal half-life
rus. All resistant viruses had neuraminidase mutations (most is about 40 hours.110 In contrast, the peak serum concentra-
commonly H275Y mutation) that conferred resistance to tion of peginterferon α-2a is reached in 72 to 96 hours after
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
an SC dose, and the mean terminal half-life is 160 hours.110 infected with HIV is 24 weeks (for hepatitis C virus [HCV]
Interferon-α undergoes extensive renal catabolism, and genotype 2 or 3) or 48 weeks (for HCV genotype 1).
negligible amounts of IFN are excreted in the urine. For patients coinfected with HIV and HCV, the rate of
Interferons have multiple overlapping biological activi- intolerance to a combination regimen of IFN-α and riba-
ties, including antiviral, antiproliferative, and immunoreg- virin is higher and the rate of sustained virologic response
ulatory functions. After binding to receptors, IFNs initiate (SVR) lower than in patients infected with HCV alone.131-133
a cascade of events that lead to various cellular responses, Use of peginterferon-α resulted in a higher SVR rate than
such as inhibition of virus replication, suppression of cell use of IFN-α.131,133 The APRICOT study reported an SVR
proliferation, enhancement of the phagocytic activity of rate of 40% for patients treated with peginterferon-α
macrophages, and augmentation of the specific cytotoxic- plus ribavirin, compared with 20% for those treated with
ity of lymphocytes for target cells. peginterferon-α monotherapy, and 12% for those treated
Interferons have been used in treating multiple viral in- with IFN-α plus ribavirin.132 A lower SVR rate to combi-
fections and are most commonly used for treating chronic nation peginterferon-α plus ribavirin therapy was observed
viral hepatitis.112 Interferon-α was the first drug approved in patients coinfected with HCV genotype 1 (29%) than
for treatment of compensated liver disease due to CHB; with HCV genotypes 2 and 3 (62%).132,133 Guidelines for
it is not approved for treating acute hepatitis B. For CHB, the management of HIV and HCV coinfection have been
IFN α-2a or α-2b is given parenterally, depending on dos- published recently.130 In general, the guidelines recommend
ing schedule, for 4 to 6 months or up to 48 weeks.112,113 combination therapy with peginterferon-α and ribavirin for
Interferon was most effective in patients with recently 48 weeks.
acquired hepatitis B virus (HBV), high pretreatment lev- Interferons are generally not recommended in acute
els of alanine aminotransferase (ALT), and low levels of viral hepatitis, but treatment of acute HCV with IFN-α
HBV DNA. Subcutaneous peginterferon-α is as effective has resulted in a more rapid resolution of viremia and re-
or slightly more effective than SC IFN-α.114 Likewise, SC duced progression to chronic hepatitis.134,135 The American
peginterferon-α may be more effective than lamivudine in Association for the Study of Liver Diseases recommends
hepatitis B e antigen (HBeAg)–positive and HBeAg-nega- either IFN-α or peginterferon-α for at least 6 months for
tive patients with CHB,115-117 and the addition of lamivudine acute HCV if infection persists for 2 to 4 months after
to peginterferon-α did not significantly enhance efficacy.118 diagnosis.
Interferon-α is effective in patients with HBV and hepati- Interferons are also approved as intralesional therapy
tis D virus coinfection,119 although they are less responsive for condyloma acuminatum of genital and perianal areas.136
than patients infected with HBV alone.120 Guidelines for the Intralesional injection ensures relatively high concentra-
management of CHB in HIV-infected patients were recently tions of IFN at the local site of infection, but occurrence
published121,122; for patients not requiring anti-HIV therapy, of systemic adverse effects suggests its absorption from
peginterferon-α for 12 months is considered a therapeutic this site. Currently, HSV is generally treated with acyclo-
option. Lamivudine and the other antiviral nucleos(t)ides vir, but beneficial responses to topical IFN-α have been re-
for the treatment of HBV often have anti-HIV properties ported for genital herpes137 and HSV keratitis.90 Beneficial
and may result in the development of HIV resistance if giv- responses to IFN-α have been reported for HIV-associated
en as monotherapy in HBV-HIV coinfected patients. progressive multifocal leukoencephalopathy138; however,
Interferon-α-2a and -2b are approved for the treatment these findings are debatable because IFN-α may not pro-
of chronic hepatitis C (CHC); however, they are not ap- vide added benefits when used with highly active antiretro-
proved for acute hepatitis C. A meta-analysis found that viral therapy.139
IFN-α for at least 12 months had the best risk-benefit ratio Most patients receiving IFN may develop flulike symp-
for patients with CHC.123 Once-weekly peginterferon-α was toms, which appear to be dose-related, are more likely to
more effective than IFN-α given 3 times weekly in patients occur at the start of treatment, and typically respond to
with CHC.124-126 However, combination therapy with IFN-α acetaminophen. Among the more serious adverse effects
and oral ribavirin is more effective than either drug used are neuropsychiatric disorders (eg, depression and homi-
alone.127 Combining oral ribavirin with peginterferon-α cidal and suicidal ideation), neurologic disturbances (eg,
may be more effective than combining it with IFN-α.128,129 confusion and seizures), myelosuppression (neutropenia
Therefore, the British Society for Gastroenterology and the [most commonly] and aplastic anemia [rarely]), cardiovas-
American Association for the Study of Liver Diseases130 cular disorders (eg, arrhythmias), endocrine disorders (eg,
recommends once-weekly SC peginterferon-α combined thyroid disorders), and pulmonary disorders (eg, dyspnea
with oral ribavirin as the first line of treatment of CHC. The and pneumonitis).140-142 Patients at risk for developing de-
recommended duration of treatment of CHC in patients not pression are those with preexisting mood and anxiety dis-
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
orders, those with a history of major depression, and those virin is usually given by the aerosol route, which delivers
receiving higher doses of IFN-α or undergoing long-term high concentrations at the site of infection.152 Oral ribavirin
treatment regimens. Selective serotonin reuptake inhibi- has also been used with good outcomes.153 Ribavirin has
tors have been used successfully to treat patients with been used, off-label, for the treatment of HSV, influenza,
IFN-associated depression, allowing therapy to be con- severe acute respiratory syndrome coronavirus,154,155 La
tinued,143 and as a pretreatment to prevent its occurrence Crosse encephalitis,156 Nipah encephalitis,157 Lassa fever,158
in high-risk patients.144 Other adverse effects are altered hemorrhagic fever with renal syndrome,159 Crimean-Congo
liver function,145 renal insufficiency,146 and gastrointesti- hemorrhagic fever,160,161 Bolivian hemorrhagic fever,162 and
nal manifestations.147 hantavirus pulmonary syndrome.163
Aerosolized ribavirin can cause sudden deterioration
RIBAVIRIN of respiratory function and cardiovascular effects. Precipi-
Ribavirin, a synthetic nucleoside analogue of guanine, is tation of inhaled ribavirin may occur in ventilatory tub-
available in oral, aerosolized, and IV formulations. Oral ings. Hemolytic anemia occurs commonly,154 and ribavirin
ribavirin is absorbed extensively, but its bioavailability is should not be given to patients with preexisting medical
only 65% because of first-pass metabolism. Peak plasma conditions exacerbated by ribavirin-induced hemolysis,
ribavirin concentrations occur within 1 to 2 hours after oral including significant cardiac disease or hemoglobinopa-
dose.148 Peak plasma concentrations increase over time and thies. Severe depression, suicidal ideation, and relapse of
are 6 times higher after 4 weeks of treatment. Administra- drug abuse may occur, and ribavirin is contraindicated in
tion of aerosolized ribavirin leads to high concentrations in patients with a history of, or existing, psychiatric disorders.
the respiratory tract, with some ribavirin absorbed systemi- Significant teratogenic and/or embryocidal effects have
cally. Ribavirin is mainly excreted in the urine.149 been observed in animals exposed to ribavirin. Ribavirin
The mechanism of action of ribavirin is known to be is therefore contraindicated in pregnant women and their
diverse but is not completely understood. It may be a com- male partners, and it is recommended that patients use 2
petitive inhibitor of cellular enzymes because its antiviral forms of contraception and avoid pregnancy during therapy
activity is reversed by guanosine. Its triphosphorylated and for 6 months thereafter.
form, ribavirin triphosphate, is a potent competitive inhibi-
tor of inosine monophosphate dehydrogenase, influenza vi- NUCLEOS(T)IDE ANALOGUES FOR CHB
rus RNA polymerase, and mRNA guanylyltransferase. As a In addition to IFN, several nucleos(t)ide analogues are
result of this competitive inhibition, intracellular guanosine available for the treatment of CHB (Table 2). With the
triphosphate pools are markedly reduced and viral nucleic exception of telbivudine, these drugs possess anti-HIV
acid and protein synthesis are inhibited. Ribavirin does not properties, serving as inhibitors of the HIV reverse tran-
alter viral attachment, penetration, or uncoating, nor does scriptase inhibitors. The specific mechanism of their anti-
it induce IFN production. HBV property is through competitive inhibition of HBV
Ribavirin inhibits multiple viruses in vitro. Among the DNA polymerase. Because of their anti-HIV properties,
susceptible DNA viruses are herpesviruses, adenoviruses, it is highly recommended that CHB patients considered
and poxviruses. Susceptible RNA viruses include HCV, for treatment with these drugs be tested for HIV infection,
Lassa virus, influenza, parainfluenza, measles, mumps, and monotherapy with these drugs should be avoided for
RSV, and HIV. However, no correlation has been found HIV-infected patients to reduce the risk of HIV resistance.
between ribavirin's in vitro activity and its activity against Hepatitis B virus may also develop resistance to these
human infections. drugs, usually after prolonged exposure, and this risk may
Oral ribavirin is approved for use, in combination with be reduced by a strategy of combination antiviral thera-
IFN-α or peginterferon-α, for the treatment of CHC. How- pies. The exact duration of anti-HBV treatment is not de-
ever, it is not effective when given as monotherapy.150,151 The fined, and HBV relapse often occurs after discontinuation
duration of treatment, and sometimes its dose, may be dic- of treatment. Severe exacerbation of hepatitis may also
tated by HCV genotype. Treatment for infections with HCV occur on discontinuation of these drugs; hence, monitor-
genotype 1, and probably with genotype 4, should generally ing for hepatotoxicity should be performed after stopping
continue for 48 weeks, whereas those with genotype 2 or 3 treatment. Lactic acidosis may occur with nucleos(t)ide
may be treated for 24 weeks. Treatment of HCV in patients analogues, and the drugs should be withdrawn if there is a
coinfected with HIV should be for 48 weeks.150,151 rapid increase in ALT levels, progressive hepatomegaly or
Ribavirin is approved for the treatment of RSV in chil- steatosis, or acidosis.
dren, including hematopoietic stem cell transplant recipi- Adefovir. Adefovir dipivoxil is an acyclic nucleotide
ents. When used for the treatment of RSV pneumonia, riba- analogue of adenosine monophosphate.164 Oral adefovir
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
Lamivudine 100 mg orally once daily Nucleoside analogue of cytosine Lactic acidosis rtM204V/I is most frequent
Myopathy
Rebound hepatitis
Telbivudine 600 mg orally once daily Synthetic thymidine nucleoside analogue Myopathy rtM204I is most frequent
No activity against HIV Peripheral neuropathy mutation; others include
Lactic acidosis rtL80I/V, rtA181T,
Rebound hepatitis rtL180M, and rtL229W/V
Tenofovir 300 mg orally once daily Acyclic nucleoside phosphonate diester Nephrotoxicity Not well-defined; rtN236T
analogue of adenosine monophosphate Lactic acidosis is suggested but not yet
One of the most potent anti-HBV drugs Rebound hepatitis confirmed
a
HBV = hepatitis B virus; HIV = human immunodeficiency virus.
b
All drugs inhibit hepatitis B replication by acting as a competitive substrate for the HBV DNA polymerase. All drugs except telbivudine have anti-HBV
properties, and all patients with chronic hepatitis B who are considered for treatment should be screened for HIV.
c
A common toxicity of the nucleos(t)ide analogues is lactic acidosis, with the potential to cause increases in serum alanine aminotransferase levels and
hepatomegaly.
dipivoxil is rapidly absorbed and converted to adefovir. Its tenofovir in HIV/HBV–coinfected patients. Emtricitabine
oral bioavailability is about 59%. Excretion of the drug is is very similar to lamivudine, and cross-resistance between
by glomerular filtration and active tubular secretion. these drugs is common. Emtricitabine may be more po-
Adefovir is converted intracellularly by cellular kinases tent than lamivudine; however, it should not be used as
to its active metabolite, adefovir diphosphate, which com- monotherapy because of high rates of resistance devel-
petitively inhibits HBV DNA polymerase.165 Although opment.170 The rate of emtricitabine resistance among
adefovir has the distinction of being the least potent among patients with HBV monoinfection is 18% at 96 weeks.170
currently available anti-HBV drugs, it has been used in Adverse effects are reportedly uncommon and include
adults with decompensated liver disease, or with compen- mild to moderate headache, nausea, diarrhea, and rash.170
sated liver disease with evidence of active viral replication, Entecavir. Entecavir, a nucleoside guanosine ana-
persistently elevated ALT levels, and histologic evidence of logue,171 is considered one of the most potent agents for
active inflammation and fibrosis.164 the treatment of patients with CHB, including those re-
The major adverse effect of adefovir is nephrotoxicity, sistant to lamivudine.172 Oral entecavir is extensively
including proximal renal tubular dysfunction and Fanconi absorbed: peak plasma concentrations occur in 30 to 90
syndrome. Gastrointestinal symptoms, such as nausea, di- minutes, and oral bioavailability is almost 100%. Despite
arrhea, and abdominal pain, may be observed. Adefovir re- low plasma concentrations, entecavir maintains its poten-
sistance, characterized by the rtN236T mutation, gradually cy by the long intracellular half-life of its active metabo-
increases over time to 11%, 18%, and 29% at year 3, 4, lite entecavir triphosphate. Entecavir is mainly excreted
and 5, respectively.166-169 To minimize the risk of resistance, by glomerular filtration and active tubular secretion.
adefovir is used in combination with other drugs such as The mechanism of action of entecavir is somewhat
lamivudine.165 However, concomitant use with the related unique because it inhibits 3 specific functions of the
drug tenofovir disoproxil fumarate is not recommended be- HBV DNA polymerase: priming of the HBV DNA poly-
cause of the augmented risk of nephrotoxicity. merase, reverse transcription of the negative strand from
Emtricitabine. Emtricitabine is an analogue of cytidine. the pregenomic mRNA, and synthesis of positive-strand
Although not currently approved for the treatment of CHB, HBV DNA.172 Entecavir is approved for the treatment of
emtricitabine has been used clinically in combination with CHB, at a dose of 0.5 mg orally once daily for nucleoside
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
treatment–naive patients, and a dose of 1 mg orally once Telbivudine-triphosphate inhibits HBV by competitive
daily for patients with a history of HBV viremia while inhibition of viral DNA polymerase. Oral telbivudine is
receiving lamivudine, those with lamivudine- or telbivu- approved for the treatment of CHB in patients with com-
dine-resistant mutations, and those with decompensated pensated liver disease and evidence of active viral replica-
liver disease.173 In randomized trials of HBeAg-positive tion, persistently increased serum ALT concentrations, and
and HBeAg-negative patients, entecavir demonstrated histologic evidence of active liver inflammation and fibro-
better outcomes than lamivudine, with improvement in sis.180,181 It is considered more effective than lamivudine
histologic responses, higher percentages of HBV DNA and adefovir.182,183 Compared with lamivudine, telbivudine
suppression, and normalization or improvement of ALT was associated with a higher degree of reduction in HBV
levels. DNA levels; however, no significant differences were found
Adverse effects of entecavir are generally mild and in- in ALT level normalization, loss of HBeAg, or anti-HBe
clude headache, fatigue, nausea, diarrhea, and insomnia. seroconversion.
Entecavir has a high barrier to resistance and requires at The most common adverse effects reported for telbivu-
least 3 mutations for phenotypic resistance. Entecavir re- dine are dizziness, fatigue, gastrointestinal symptoms,
sistance requires a baseline rtM204V/I and rtL180M mu- and rash. Unique adverse effects are peripheral neurop-
tation plus either rtT184S/A/I/L, rtS202G/C, or rtM250L. athy and myopathy with elevation in creatine kinase lev-
Among nucleoside-naive patients, the rate of entecavir els. Telbivudine treatment should be discontinued if ei-
resistance is less than 1% after 5 years, but patients with ther peripheral neuropathy or myopathy is diagnosed. The
preexisting rtM204V/I have a higher rate of entecavir re- rate of resistance to telbivudine is 25% after 96 weeks of
sistance (51%) after 5 years.173 treatment.
Lamivudine. Lamivudine is a nucleoside analogue of Tenofovir. Tenofovir disoproxil fumarate, an acyclic
cytosine. Oral lamivudine provides bioavailability of about nucleoside phosphonate diester analogue of adenosine
85%, and peak serum concentrations occur in 1.0 to 1.5 monophosphate, is considered one of the most potent anti-
hours. Hepatic metabolism is low, and up to 70% is ex- HBV drugs. In oral form, it is rapidly absorbed and con-
creted unchanged by the kidneys.174 verted to tenofovir, reaching peak plasma concentrations in
Lamivudine is phosphorylated intracellularly into its ac- 1 to 2 hours.184 Oral bioavailability, which is only 25% in
tive 5´-triphosphate metabolite, lamivudine triphosphate. the fasting state, can be enhanced when taken with a high-
When the active metabolite is incorporated into viral DNA fat meal. The terminal elimination half-life of tenofovir is
by HBV polymerase, it results in DNA chain termination. 12 to 18 hours, and it is excreted mainly by active tubular
Lamivudine was the first drug to be used as an al- secretion and glomerular filtration.184
ternative to IFN-α for the treatment of CHB.175,176 In a Tenofovir disoproxil fumarate is a prodrug that requires
double-blind study involving about 350 patients with CHB, diester hydrolysis for conversion to tenofovir. Subsequent
lamivudine was associated with substantial histologic im- phosphorylation by cellular enzymes forms tenofovir
provement, HBeAg antibody seroconversion, and ALT nor- diphosphate, which competes with the natural substrate
malization.177 However, relapses are common once treat- deoxyadenosine 5ʹ-triphosphate for incorporation into the
ment is discontinued.178 viral DNA strand.
The adverse effects of lamivudine are mild and include Tenofovir is used for the treatment of CHB. In a ran-
abdominal pain, nausea, and headache. The clinical utility domized trial comparing tenofovir and adefovir, a higher
of lamivudine is limited by the rapid development of anti- percentage of patients receiving tenofovir achieved HBV
viral resistance. Lamivudine shares with the L-nucleosides DNA level suppression. In HBeAg-positive patients, the
the primary resistance mutation, rtM204V/I, which occurs biochemical response was higher with tenofovir; however,
easily and confers cross-resistance. After 4 years of lamiv- the anti-HBe seroconversion rates and histologic responses
udine monotherapy, rtM204V/I resistance develops in up were similar for adefovir and tenofovir.185-188
to 70% and 90% of patients with HBV monoinfection and The adverse effects of tenofovir include gastrointestinal
HIV/HBV coinfection, respectively. symptoms, dizziness, fatigue, and headache. Renal toxici-
Telbivudine. Telbivudine is a synthetic thymidine ties, including nephritis, proximal renal tubulopathy (in-
nucleoside analogue. Unlike other anti-HBV drugs, tel- cluding Fanconi syndrome), and renal failure, have been
bivudine has no activity against HIV. Oral telbivudine is associated with tenofovir.189-193
well absorbed and achieves peak plasma concentrations Primary tenofovir resistance mutations have not been
after about 3 hours. It is mainly excreted by glomerular well defined. Although viruses with rtN236T are not resis-
filtration, with a terminal elimination half-life of 30 to 50 tant to tenofovir, they have a slower response than do wild-
hours.179 type viruses. One study reported rtA194T as a tenofovir re-
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
sistance mutation; however, this pattern was not confirmed tivariable stepwise logistic regression analysis, the baseline
in other studies. factors associated with SVR were boceprevir use, previous
relapse (compared with previous nonresponder), low viral
PROTEASE INHIBITORS FOR THE TREATMENT OF CHC load at baseline, and absence of cirrhosis.196
The current standard treatment of CHC is peginterferon-α Boceprevir (800 mg 3 times daily) was approved by the
in combination with ribavirin for 24 weeks (for HCV geno- FDA as the first HCV protease inhibitor for the treatment
type 2 or 3) or 48 weeks (for HCV genotype 1). The major of CHC, specifically for genotype 1; it should be combined
aim of treatment is to achieve SVR, which is defined as with peginterferon and ribavirin. The most common ad-
undetectable HCV RNA at 24 weeks after completion of verse effects of boceprevir are flulike illness, fatigue, nau-
treatment. A combination regimen of peginterferon-α and sea, dysgeusia, and anemia.194 The addition of boceprevir
ribavirin results in SVR rates between 38% and 46%, and nearly doubled the rate of anemia compared with the use
the rate is even lower among black patients. Hence, ma- of standard peginterferon and ribavirin therapy, with many
jor efforts have been made to develop novel therapies for patients requiring the use of erythropoietin.195
CHC. Recently, 2 serine protease inhibitors were approved Telaprevir. Telaprevir is an orally available inhibitor
as novel therapies for CHC due to genotype 1 infection. specific to the HCV nonstructural 3/4A serine protease.197 It
The addition of serine protease inhibitors to the backbone inhibits HCV replication by binding reversibly to nonstruc-
therapies of peginterferon-α and ribavirin will emerge as tural 3 serine protease. After oral administration, telaprevir
the standard of care for the HCV genotype 1 infection, both achieves peak plasma concentrations in 4 to 5 hours. It is
in treatment-naive and treatment-experienced patients. metabolized primarily in the liver and it has an elimination
Boceprevir. Boceprevir is a linear peptidomimetic keto- half-life of 4 to 5 hours. Most of the drug is excreted in the
amide serine protease inhibitor that was recently approved feces.
for the treatment of CHC, particularly for genotype 1.194 Early-phase studies demonstrated the potent anti-HCV
It is available in oral formulation, and the time to peak properties of telaprevir.198-200 In a recent phase 3 inter-
concentration after oral administration is 2 hours. Food en- national randomized double-blind placebo-controlled
hances its absorption. Boceprevir is metabolized primarily clinical trial, the addition of telaprevir to the standard
in the liver. It has an elimination half-life of 3 hours and is treatment of peginterferon-ribavirin was associated with
excreted mostly in the feces.194 significantly higher SVR rates compared with standard
Boceprevir exerts anti-HCV properties by binding re- peginterferon-ribavirin alone in a cohort of 1088 patients
versibly to the HCV nonstructural 3 protein, ultimately with previously untreated HCV genotype 1 infections.201
inhibiting viral replication. In a recently conducted phase Specifically, the group of patients who received 12 weeks
3 international randomized placebo-controlled trial that en- of telaprevir combined with peginterferon-ribavirin, fol-
rolled previously untreated black and nonblack adults with lowed by peginterferon-ribavirin for 12 weeks (if HCV
HCV genotype 1 infection (SPRINT-2 [serine protease in- RNA was undetectable at weeks 4 and 12) or 36 weeks
hibitor therapy 2] trial), the addition of boceprevir for 22 (if HCV RNA was still detectable at weeks 4 and 12),
weeks or 44 weeks to standard therapy (peginterferon-α- had SVR rates of 75% vs 44% with standard therapy.201
2b and ribavirin) resulted in significantly higher SVR rates The SVR rates were also significantly higher compared
compared with standard therapy alone for the nonblack with standard therapy among patients who received only 8
cohort (67% and 68% vs 40%, respectively) and the black weeks of telaprevir combined with peginterferon-ribavirin
cohort (42% and 53% vs 23%, respectively).195 The rela- (69% vs 44%).201 In the second randomized phase 3 trial
tive increases in SVR rates for the nonblack cohort were that evaluated telaprevir in treatment-experienced patients
68% and 70%, respectively, compared with the standard with HCV genotype 1 infection, the addition of telaprevir
therapy.195 to the standard treatment regimen of peginterferon-α and
The HCV RESPOND-2 (Retreatment with HCV Ser- ribavirin was associated with significantly higher SVR
ine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2) rates compared with the standard regimen of peginterfer-
trial evaluated boceprevir for the treatment of patients who on-ribavirin alone.202
had experienced a relapse or who had not achieved SVR Collectively, these studies indicate that the addition of
to peginterferon-ribavirin treatment.196 In this random- telaprevir to standard peginterferon-ribavirin therapy can
ized open-label trial that enrolled 403 patients, the SVR significantly improve SVR rates in treatment-naive pa-
rates were significantly higher for patients who received tients infected with HCV genotype 1 and in those who did
peginterferon-ribavirin plus boceprevir treatment for 32 not benefit from initial treatment with peginterferon-α-2a
weeks (59%) or 44 weeks (66%) compared with standard and ribavirin. As a result of these findings, the FDA ap-
peginterferon-ribavirin treatment alone (21%).196 In a mul- proved telaprevir (750 mg 3 times daily) for this treatment
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
indication. The most common adverse effects are anemia, 7. Cernik C, Gallina K, Brodell RT. The treatment of herpes simplex infec-
tions: an evidence-based review. "SDI*OUFSO.FE. 2008;168:1137-1144.
neutropenia, leukopenia, and rash.201 In one study, 41% 8. Zuckerman R, Wald A. Herpes simplex virus infections in solid
to 60% of patients reported some kind of rash.199 Rashes organ transplant recipients. "N+5SBOTQMBOU. 2009;9(suppl 4):S104-S107.
can be mild to severe, and Stevens-Johnson syndrome and 9. De Clercq E. Antivirals for the treatment of herpesvirus infections. J
"OUJNJDSPC$IFNPUIFS 1993;32(suppl A):121-132.
drug rash with eosinophilia and systemic symptoms have 10. Valencia I, Miles DK, Melvin J, et al. Relapse of herpes encephalitis
been reported. Telaprevir therapy should be discontinued after acyclovir therapy: report of two new cases and review of the literature.
if these dermatologic complications occur, especially in /FVSPQFEJBUSJDT. 2004;35:371-376.
11. Balfour HH Jr, Kelly JM, Suarez CS, et al. Acyclovir treatment of vari-
cases of severe rash or even mild to moderate rash if ac- cella in otherwise healthy children. +1FEJBUS. 1990;116:633-639.
companied by systemic symptoms. The mechanism under- 12. Wallace MR, Bowler WA, Murray NB, Brodine SK, Oldfield EC III.
lying rash development is unknown.199 Fatigue, pruritus, Treatment of adult varicella with oral acyclovir: a randomized, placebo-con-
trolled trial. "OO*OUFSO.FE. 1992;117:358-363.
and gastrointestinal sympotoms (eg, nausea, diarrhea, and 13. Wood MJ, Kay R, Dworkin RH, Soong SJ, Whitley RJ. Oral acyclovir
taste disturbance) may also be observed.199 therapy accelerates pain resolution in patients with herpes zoster: a meta-anal-
ysis of placebo-controlled trials. $MJO*OGFDU%JT. 1996;22:341-347.
14. Other herpesviruses: HHV-6, HHV-7, HHV-8, HSV-1 and -2, VZV. "N
CONCLUSION +5SBOTQMBOU. 2004;4(suppl 10):66-71.
15. Bean B, Aeppli D. Adverse effects of high-dose intravenous acyclovir in
This review has highlighted the pharmacokinetics, mecha- ambulatory patients with acute herpes zoster. +*OGFDU%JT. 1985;151:362-365.
16. Perazella MA. Crystal-induced acute renal failure. "N + .FE. 1999;
nisms of action, clinical indications, and adverse effects of 106:459-465.
clinically available drugs for the management of viruses 17. Helldén A, Lycke J, Vander T, Svensson JO, Odar-Cederlof I, Stahle
other than HIV. The currently available antiviral drugs tar- L. The aciclovir metabolite CMMG is detectable in the CSF of subjects with
neuropsychiatric symptoms during aciclovir and valaciclovir treatment. +"OUJ
get 3 main groups of viruses: herpes, hepatitis, and influ- NJDSPC$IFNPUIFS. 2006;57:945-949.
enza viruses. The antiviral therapeutic armamentarium has 18. Ernst ME, Franey RJ. Acyclovir- and ganciclovir-induced neurotoxic-
evolved over the years and is rapidly expanding. Some of ity. "OO1IBSNBDPUIFS. 1998;32:111-113.
19. Wade JC, Meyers JD. Neurologic symptoms associated with paren-
the “old” antiviral drugs retain their clinical utility for most teral acyclovir treatment after marrow transplantation. "OO*OUFSO.FE. 1983;
infections, such as acyclovir for herpes simplex virus and 98:921-925.
ganciclovir for CMV. However, other of these “old” anti- 20. Buck ML, Vittone SB, Zaglul HF. Vesicular eruptions following acyclo-
vir administration. "OO1IBSNBDPUIFS. 1993;27:1458-1459.
viral drugs (eg, amantadine and rimantadine for influenza 21. Amos RJ, Amess JA. Megaloblastic haemopoiesis due to acyclovir.
virus infections) have lost their clinical utility because of -BODFU. 1983;1:242-243.
the rapid and widespread development of resistance. This 22. Danve-Szatanek C, Aymard M, Thouvenot D, et al. Surveillance net-
work for herpes simplex virus resistance to antiviral drugs: 3-year follow-up. J
serves as a catalyst for the development of novel therapies $MJO.JDSPCJPM. 2004;42:242-249.
and, more importantly, should urge the medical community 23. Bacon TH, Levin MJ, Leary JJ, Sarisky RT, Sutton D. Herpes simplex
to use these drugs optimally in the clinical setting. Indeed, virus resistance to acyclovir and penciclovir after two decades of antiviral
therapy. $MJO.JDSPCJPM3FW. 2003;16:114-128.
increased resistance has been observed to the neuramini- 24. Malvy D, Treilhaud M, Bouee S, et al. A retrospective, case-con-
dase inhibitors for the treatment of influenza viruses and trol study of acyclovir resistance in herpes simplex virus. $MJO *OGFDU %JT.
the nucleos(t)ide analogues for the treatment of CHB. As 2005;41:320-326.
25. Superti F, Ammendolia MG, Marchetti M. New advances in anti-HSV
novel therapies develop (eg, the serine protease inhibitors chemotherapy. $VSS.FE$IFN. 2008;15:900-911.
for the treatment of CHC), care must be taken to optimize 26. De Clercq E. Discovery and development of BVDU (brivudin)
their use so that the clinical life span of these drugs is not as a therapeutic for the treatment of herpes zoster. #JPDIFN 1IBSNBDPM.
2004;68:2301-2315.
abbreviated by the development of resistance. 27. Lea AP, Bryson HM. Cidofovir. %SVHT. 1996;52:225-230.
28. Lanier R, Trost L, Tippin T, et al. Development of CMX001 for the
treatment of poxvirus infections. 7JSVTFT. 2010;2:2740-2762.
REFERENCES 29. Wolf DL, Rodriguez CA, Mucci M, Ingrosso A, Duncan BA, Nickens
1. Corey L, Fife KH, Benedetti JK, et al. Intravenous acyclovir for the DJ. Pharmacokinetics and renal effects of cidofovir with a reduced dose of
treatment of primary genital herpes. "OO*OUFSO.FE. 1983;98:914-921. probenecid in HIV-infected patients with cytomegalovirus retinitis. J Clin
2. Nilsen AE, Aasen T, Halsos AM, et al. Efficacy of oral acyclovir in the 1IBSNBDPM. 2003;43:43-51.
treatment of initial and recurrent genital herpes. -BODFU. 1982;2:571-573. 30. Cundy KC. Clinical pharmacokinetics of the antiviral nucleotide ana-
3. Serota FT, Starr SE, Bryan CK, Koch PA, Plotkin SA, August CS. Acy- logues cidofovir and adefovir. $MJO1IBSNBDPLJOFU. 1999;36:127-143.
clovir treatment of herpes zoster infections: use in children undergoing bone 31. Kendle JB, Fan-Havard P. Cidofovir in the treatment of cytomegaloviral
marrow transplantation. JAMA. 1982;247:2132-2135. disease. "OO1IBSNBDPUIFS. 1998;32:1181-1192.
4. Gupta R, Warren T, Wald A. Genital herpes. -BODFU. 2007;370:2127- 32. Cherrington JM, Fuller MD, Lamy PD, et al. In vitro antiviral suscep-
2137. tibilities of isolates from cytomegalovirus retinitis patients receiving first- or
5. Reichman RC, Badger GJ, Mertz GJ, et al. Treatment of recurrent gen- second-line cidofovir therapy: relationship to clinical outcome. + *OGFDU %JT.
ital herpes simplex infections with oral acyclovir: a controlled trial. JAMA. 1998;178:1821-1825.
1984;251:2103-2107. 33. Jabs DA, Enger C, Forman M, Dunn JP; The Cytomegalovirus Retinitis
6. Luby JP, Gnann JW Jr, Alexander WJ, et al. A collaborative study of and Viral Resistance Study Group. Incidence of foscarnet resistance and cido-
patient-initiated treatment of recurrent genital herpes with topical acyclovir or fovir resistance in patients treated for cytomegalovirus retinitis. "OUJNJDSPC
placebo. +*OGFDU%JT. 1984;150:1-6. "HFOUT$IFNPUIFS. 1998;42:2240-2244.
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
34. Snoeck R, De Clercq E. Role of cidofovir in the treatment of DNA virus 59. Balfour HH Jr, Fletcher CV, Erice A, et al. Effect of foscarnet on quanti-
infections, other than CMV infections, in immunocompromised patients. $VSS ties of cytomegalovirus and human immunodeficiency virus in blood of per-
0QJO*OWFTUJH%SVHT. 2002;3:1561-1566. sons with AIDS. "OUJNJDSPC"HFOUT$IFNPUIFS. 1996;40:2721-2726.
35. Cha S, Johnston L, Natkunam Y, Brown J. Treatment of verruca vul- 60. Kotton CN, Kumar D, Caliendo AM, et al. International consensus
garis with topical cidofovir in an immunocompromised patient: a case report guidelines on the management of cytomegalovirus in solid organ transplanta-
and review of the literature. 5SBOTQM*OGFDU%JT. 2005;7:158-161. tion. 5SBOTQMBOUBUJPO. 2010;89:779-795.
36. Lamoth F, Pascual M, Erard V, Venetz JP, Nseir G, Meylan P. Low-dose 61. Humar A, Snydman D. Cytomegalovirus in solid organ transplant re-
cidofovir for the treatment of polyomavirus-associated nephropathy: two case cipients. "N+5SBOTQMBOU. 2009;9(suppl 4):S78-S86.
reports and review of the literature. "OUJWJS5IFS. 2008;13:1001-1009. 62. Jacobson MA, Causey D, Polsky B, et al. A dose-ranging study of daily
37. Toro JR, Sanchez S, Turiansky G, Blauvelt A. Topical cidofovir for maintenance intravenous foscarnet therapy for cytomegalovirus retinitis in
the treatment of dermatologic conditions: verruca, condyloma, intraepithelial AIDS. +*OGFDU%JT. 1993;168:444-448.
neoplasia, herpes simplex and its potential use in smallpox. %FSNBUPM $MJO. 63. Beaufils H, Deray G, Katlama C, et al. Foscarnet and crystals in glo-
2003;21:301-309. merular capillary lumens. -BODFU. 1990;336:755.
38. Lalezari JP, Drew WL, Glutzer E, et al. Treatment with intravenous (S)- 64. Lor E, Liu YQ. Neurologic sequelae associated with foscarnet therapy.
1-[3-hydroxy-2-(phosphonylmethoxy)propyl]-cytosine of acyclovir-resistant "OO1IBSNBDPUIFS. 1994;28:1035-1037.
mucocutaneous infection with herpes simplex virus in a patient with AIDS. J 65. Nichols WG, Boeckh M. Recent advances in the therapy and prevention
*OGFDU%JT. 1994;170:570-572. of CMV infections. J Clin Virol. 2000;16:25-40.
39. Bryant P, Sasadeusz J, Carapetis J, Waters K, Curtis N. Successful treat- 66. Frank KB, Chiou JF, Cheng YC. Interaction of herpes simplex virus-
ment of foscarnet-resistant herpes simplex stomatitis with intravenous cidofo- induced DNA polymerase with 9-(1,3-dihydroxy-2-propoxymethyl)guanine
vir in a child. 1FEJBUS*OGFDU%JT+. 2001;20:1083-1086. triphosphate. +#JPM$IFN. 1984;259:1566-1569.
40. Kopp T, Geusau A, Rieger A, Stingl G. Successful treatment of an 67. Razonable RR, Paya CV. The impact of human herpesvirus-6 and -7
aciclovir-resistant herpes simplex type 2 infection with cidofovir in an AIDS infection on the outcome of liver transplantation. -JWFS 5SBOTQM. 2002;8:651-
patient. #S+%FSNBUPM. 2002;147:134-138. 658.
41. Garvey L, Thomson EC, Taylor GP. Progressive multifocal leukoen- 68. Spector SA, Weingeist T, Pollard RB, et al; AIDS Clinical Trials Group;
cephalopathy: prolonged survival in patients treated with protease inhibitors Cytomegalovirus Cooperative Study Group. A randomized, controlled study
and cidofovir: a case series. "*%4. 2006;20:791-793. of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in
42. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for pro- patients with AIDS. +*OGFDU%JT. 1993;168:557-563.
gressive multifocal leukoencephalopathy in AIDS. "*%4. 2002;16:1791-1797. 69. Drew WL, Ives D, Lalezari JP, et al; Syntex Cooperative Oral Ganciclo-
43. Razonable RR, Aksamit AJ, Wright AJ, Wilson JW. Cidofovir treatment vir Study Group. Oral ganciclovir as maintenance treatment for cytomegalovi-
of progressive multifocal leukoencephalopathy in a patient receiving highly rus retinitis in patients with AIDS. /&OHM+.FE. 1995;333:615-620.
active antiretroviral therapy. Mayo Clin Proc. 2001;76:1171-1175. 70. Gane E, Saliba F, Valdecasas GJ, et al; Oral Ganciclovir International
44. Segarra-Newnham M, Vodolo KM. Use of cidofovir in progressive mul- Transplantation Study Group. Randomised trial of efficacy and safety of oral
tifocal leukoencephalopathy. "OO1IBSNBDPUIFS. 2001;35:741-744. ganciclovir in the prevention of cytomegalovirus disease in liver-transplant
45. Viallard JF, Lazaro E, Ellie E, et al. Improvement of progressive multi- recipients [published correction appears in -BODFU 1998;351(9100):454].
focal leukoencephalopathy after cidofovir therapy in a patient with a destruc- -BODFU. 1997;350:1729-1733.
tive polyarthritis. *OGFDUJPO. 2007;35:33-36. 71. Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Emergence
46. Cesaro S, Hirsch HH, Faraci M, et al. Cidofovir for BK virus-associ- of drug-resistant cytomegalovirus in the era of valganciclovir prophylaxis:
ated hemorrhagic cystitis: a retrospective study. $MJO*OGFDU%JT. 2009;49:233- therapeutic implications and outcomes. $MJO5SBOTQMBOU. 2008;22:162-170.
240. 72. Sarisky RT, Bacon TH, Boon RJ, et al. Profiling penciclovir susceptibil-
47. Kottke MD, Parker SR. Intravenous cidofovir-induced resolution of ity and prevalence of resistance of herpes simplex virus isolates across eleven
disfiguring cutaneous human papillomavirus infection. +"N"DBE%FSNBUPM. clinical trials. "SDI7JSPM. 2003;148:1757-1769.
2006;55:533-536. 73. Bacon TH, Boyd MR. Activity of penciclovir against Epstein-Barr vi-
48. Kazory A, Singapuri S, Wadhwa A, Ejaz AA. Simultaneous develop- rus. "OUJNJDSPC"HFOUT$IFNPUIFS. 1995;39:1599-1602.
ment of Fanconi syndrome and acute renal failure associated with cidofovir. J 74. Spruance SL, Rea TL, Thoming C, Tucker R, Saltzman R, Boon R;
"OUJNJDSPC$IFNPUIFS. 2007;60:193-194. Topical Penciclovir Collaborative Study Group. Penciclovir cream for the
49. Ambati J, Wynne KB, Angerame MC, Robinson MR. Anterior uveitis treatment of herpes simplex labialis: a randomized, multicenter, double-blind,
associated with intravenous cidofovir use in patients with cytomegalovirus placebo-controlled trial. JAMA. 1997;277:1374-1379.
retinitis. #S+0QIUIBMNPM. 1999;83:1153-1158. 75. Acosta EP, Fletcher CV. Valacyclovir. "OO 1IBSNBDPUIFS. 1997;31:
50. Tseng AL, Mortimer CB, Salit IE. Iritis associated with intravenous ci- 185-191.
dofovir. "OO1IBSNBDPUIFS. 1999;33:167-171. 76. Spruance SL, Tyring SK, DeGregorio B, Miller C, Beutner K; Valaci-
51. Gill KS, Wood MJ. The clinical pharmacokinetics of famciclovir. Clin clovir HSV Study Group. A large-scale, placebo-controlled, dose-ranging trial
1IBSNBDPLJOFU. 1996;31:1-8. of peroral valaciclovir for episodic treatment of recurrent herpes genitalis.
52. Faro S. A review of famciclovir in the management of genital herpes. "SDI*OUFSO.FE. 1996;156:1729-1735.
*OGFDU%JT0CTUFU(ZOFDPM. 1998;6:38-43. 77. Pergam SA, Limaye AP. Varicella zoster virus (VZV) in solid organ
53. Chacko M, Weinberg JM. Famciclovir for cutaneous herpesvirus in- transplant recipients. "N+5SBOTQMBOU. 2009;9(suppl 4):S108-S115.
fections: an update and review of new single-day dosing indications. $VUJT. 78. Lowance D, Neumayer HH, Legendre CM, et al; International Valacy-
2007;80:77-81. clovir Cytomegalovirus Prophylaxis Transplantation Study Group. Valacyclo-
54. Saltzman R, Jurewicz R, Boon R. Safety of famciclovir in pa- vir for the prevention of cytomegalovirus disease after renal transplantation. N
tients with herpes zoster and genital herpes. "OUJNJDSPC "HFOUT $IFNPUIFS. &OHM+.FE. 1999;340:1462-1470.
1994;38:2454-2457. 79. Razonable RR, Paya CV. Valganciclovir for the prevention and treat-
55. Grillone LR, Lanz R. Fomivirsen. %SVHT 5PEBZ #BSD . 2001;37: ment of cytomegalovirus disease in immunocompromised hosts. &YQFSU 3FW
245-255. "OUJ*OGFDU5IFS. 2004;2:27-41.
56. Vitravene Study Group. A randomized controlled clinical trial of intra- 80. Brown F, Banken L, Saywell K, Arum I. Pharmacokinetics of valgan-
vitreous fomivirsen for treatment of newly diagnosed peripheral cytomegalo- ciclovir and ganciclovir following multiple oral dosages of valganciclovir in
virus retinitis in patients with AIDS. "N+0QIUIBMNPM. 2002;133:467-474. HIV- and CMV-seropositive volunteers. $MJO 1IBSNBDPLJOFU. 1999;37:167-
57. Highleyman L. Fomivirsen. #&5". 1998;29:31. 176.
58. Chrisp P, Clissold SP. Foscarnet: a review of its antiviral activity, phar- 81. Wiltshire H, Hirankarn S, Farrell C, et al. Pharmacokinetic profile of
macokinetic properties and therapeutic use in immunocompromised patients ganciclovir after its oral administration and from its prodrug, valganciclovir, in
with cytomegalovirus retinitis. %SVHT. 1991;41:104-129. solid organ transplant recipients. $MJO1IBSNBDPLJOFU. 2005;44:495-507.
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
82. Caldes A, Colom H, Armendariz Y, et al. Population pharmacokinetics 106. Freund B, Gravenstein S, Elliott M, Miller I. Zanamivir: a review of
of ganciclovir after intravenous ganciclovir and oral valganciclovir administra- clinical safety. %SVH4BG. 1999;21:267-281.
tion in solid organ transplant patients infected with cytomegalovirus. "OUJNJ 107. Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for osel-
DSPC"HFOUT$IFNPUIFS. 2009;53:4816-4824. tamivir-resistant 2009 H1N1 influenza [letter]. /&OHM+.FE2010;362(1):88-
83. Martin DF, Sierra-Madero J, Walmsley S, et al. A controlled trial of val- 89.
ganciclovir as induction therapy for cytomegalovirus retinitis. /&OHM+.FE. 108. Kidd IM, Down J, Nastouli E, et al. H1N1 pneumonitis treated with
2002;346:1119-1126. intravenous zanamivir. -BODFU. 2009;374:1036.
84. Paya C, Humar A, Dominguez E, et al. Efficacy and safety of valgan- 109. Gravenstein S, Johnston SL, Loeschel E, Webster A. Zanamivir: a
ciclovir vs. oral ganciclovir for prevention of cytomegalovirus disease in solid review of clinical safety in individuals at high risk of developing influenza-
organ transplant recipients. "N+5SBOTQMBOU. 2004;4:611-620. related complications. %SVH4BG. 2001;24:1113-1125.
85. Khoury JA, Storch GA, Bohl DL, et al. Prophylactic versus preemptive 110. Zeuzem S, Welsch C, Herrmann E. Pharmacokinetics of peginterferons.
oral valganciclovir for the management of cytomegalovirus infection in adult 4FNJO-JWFS%JT. 2003;23(suppl 1):23-28.
renal transplant recipients. "N+5SBOTQMBOU. 2006;6:2134-2143. 111. Pedder SC. Pegylation of interferon alfa: structural and pharmacoki-
86. Snydman DR. Use of valganciclovir for prevention and treatment of netic properties. 4FNJO-JWFS%JT. 2003;23(suppl 1):19-22.
cytomegalovirus disease [editorial]. $MJO*OGFDU%JT. 2008;46:28-29. 112. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heath-
87. Einsele H, Reusser P, Bornhauser M, et al. Oral valganciclovir leads to cote J. Effect of alpha-interferon treatment in patients with hepatitis B e
higher exposure to ganciclovir than intravenous ganciclovir in patients follow- antigen-positive chronic hepatitis B: a meta-analysis. "OO*OUFSO.FE. 1993;
ing allogeneic stem cell transplantation. #MPPE. 2006;107:3002-3008. 119:312-323.
88. Len O, Gavalda J, Aguado JM, et al. Valganciclovir as treatment for 113. Haria M, Benfield P. Interferon-alpha-2a: a review of its pharmacologi-
cytomegalovirus disease in solid organ transplant recipients. $MJO*OGFDU%JT. cal properties and therapeutic use in the management of viral hepatitis. %SVHT.
2008;46:20-27. 1995;50:873-896.
89. Asberg A, Humar A, Rollag H, et al. Oral valganciclovir is noninferior 114. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. )FQBUPMPHZ.
to intravenous ganciclovir for the treatment of cytomegalovirus disease in solid 2009;50:661-662.
organ transplant recipients. "N+5SBOTQMBOU. 2007;7:2106-2113. 115. Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B. J
90. Wilhelmus KR. Therapeutic interventions for herpes simplex virus epi- 7JSBM)FQBU. 2005;12:333-345.
thelial keratitis. $PDISBOF%BUBCBTF4ZTU3FW. 2008;CD002898. 116. Lau GK, Piratvisuth T, Luo KX, et al. Peginterferon alfa-2a, lamivu-
91. De Clercq E. Antiviral drugs in current clinical use. J Clin Virol. dine, and the combination for HBeAg-positive chronic hepatitis B. /&OHM+
2004;30:115-133. .FE. 2005;352:2682-2695.
92. Tappenden P, Jackson R, Cooper K, et al. Amantadine, oseltamivir and 117. Marcellin P, Lau GK, Bonino F, et al. Peginterferon alfa-2a alone,
zanamivir for the prophylaxis of influenza (including a review of existing guid- lamivudine alone, and the two in combination in patients with HBeAg-negative
ance no. 67): a systematic review and economic evaluation. )FBMUI5FDIOPM chronic hepatitis B. /&OHM+.FE. 2004;351:1206-1217.
"TTFTT. 2009;13(11):iii,ix-xii, 1-246. 118. Janssen HL, van Zonneveld M, Senturk H, et al. Pegylated Interferon
93. Betts RF. Amantadine and rimantadine for the prevention of influenza alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic
A. 4FNJO3FTQJS*OGFDU. 1989;4:304-310. hepatitis B: a randomised trial. -BODFU. 2005;365:123-129.
94. Krumbholz A, Schmidtke M, Bergmann S, et al. High prevalence of 119. Farci P, Mandas A, Coiana A, et al. Treatment of chronic hepatitis D
amantadine resistance among circulating European porcine influenza A vi- with interferon alfa-2a. /&OHM+.FE. 1994;330:88-94.
ruses. +(FO7JSPM. 2009;90:900-908. 120. Farci P, Roskams T, Chessa L, et al. Long-term benefit of interferon
95. Higgins RR, Eshaghi A, Burton L, Mazzulli T, Drews SJ. Differential alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis.
patterns of amantadine-resistance in influenza A (H3N2) and (H1N1) isolates (BTUSPFOUFSPMPHZ. 2004;126:1740-1749.
in Toronto, Canada. J Clin Virol. 2009;44:91-93. 121. Soriano V, Puoti M, Bonacini M, et al. Care of patients with chronic
96. Hayden FG, Hay AJ. Emergence and transmission of influenza A vi- hepatitis B and HIV co-infection: recommendations from an HIV-HBV Inter-
ruses resistant to amantadine and rimantadine. $VSS5PQ.JDSPCJPM*NNVOPM. national Panel. "*%4. 2005;19:221-240.
1992;176:119-130. 122. Alberti A, Clumeck N, Collins S, et al. Short statement of the first Eu-
97. Hayden FG, Sperber SJ, Belshe RB, Clover RD, Hay AJ, Pyke S. Re- ropean Consensus Conference on the treatment of chronic hepatitis B and C in
covery of drug-resistant influenza A virus during therapeutic use of rimanta- HIV co-infected patients. +)FQBUPM. 2005;42:615-624.
dine. "OUJNJDSPC"HFOUT$IFNPUIFS. 1991;35:1741-1747. 123. Poynard T, Leroy V, Cohard M, et al. Meta-analysis of interferon ran-
98. Ward P, Small I, Smith J, Suter P, Dutkowski R. Oseltamivir (Tamiflu) domized trials in the treatment of viral hepatitis C: effects of dose and duration.
and its potential for use in the event of an influenza pandemic. +"OUJNJDSPC )FQBUPMPHZ. 1996;24:778-789.
$IFNPUIFS. 2005;55(suppl 1):i5-i21. 124. Zeuzem S, Feinman SV, Rasenack J, et al. Peginterferon alfa-2a in pa-
99. Sugaya N, Tamura D, Yamazaki M, et al. Comparison of the clinical tients with chronic hepatitis C. /&OHM+.FE. 2000;343:1666-1672.
effectiveness of oseltamivir and zanamivir against influenza virus infection in 125. Perry CM, Jarvis B. Peginterferon-alpha-2a (40 kD): a review of its use
children. $MJO*OGFDU%JT. 2008;47:339-345. in the management of chronic hepatitis C. %SVHT. 2001;61:2263-2288.
100. Khazeni N, Bravata DM, Holty JE, Uyeki TM, Stave CD, Gould 126. Heathcote EJ, Shiffman ML, Cooksley WG, et al. Peginterferon alfa-
MK. Systematic review: safety and efficacy of extended-duration antiviral 2a in patients with chronic hepatitis C and cirrhosis. / &OHM + .FE. 2000;
chemoprophylaxis against pandemic and seasonal influenza. "OO*OUFSO.FE. 343:1673-1680.
2009;151:464-473. 127. Brok J, Gluud LL, Gluud C. Ribavirin plus interferon versus interferon
101. Kiso M, Mitamura K, Sakai-Tagawa Y, et al. Resistant influenza for chronic hepatitis C. $PDISBOF%BUBCBTF4ZTU3FW2010;(1):CD005445.
A viruses in children treated with oseltamivir: descriptive study. -BODFU. 128. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a
2004;364:759-765. plus ribavirin for chronic hepatitis C virus infection. / &OHM + .FE. 2002;
102. de Jong MD, Tran TT, Truong HK, et al. Oseltamivir resistance during treat- 347:975-982.
ment of influenza A (H5N1) infection. /&OHM+.FE. 2005;353:2667-2672. 129. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-
103. Le QM, Kiso M, Someya K, et al. Avian flu: isolation of drug-resistant 2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial
H5N1 virus. /BUVSF. 2005;437:1108. treatment of chronic hepatitis C: a randomised trial. -BODFU. 2001;358:958-
104. Dharan NJ, Gubareva LV, Meyer JJ, et al. Infections with oseltami- 965.
vir-resistant influenza A(H1N1) virus in the United States. JAMA. 2009; 130. Ghany MG, Strader DB, Thomas DL, Seeff LB. Diagnosis, management,
301:1034-1041. and treatment of hepatitis C: an update. )FQBUPMPHZ. 2009;49:1335-1374.
105. Hatakeyama S, Sugaya N, Ito M, et al. Emergence of influenza B vi- 131. Carrat F, Bani-Sadr F, Pol S, et al. Pegylated interferon alfa-2b vs
ruses with reduced sensitivity to neuraminidase inhibitors. JAMA. 2007;297: standard interferon alfa-2b, plus ribavirin, for chronic hepatitis C in HIV-
1435-1442. infected patients: a randomized controlled trial. JAMA. 2004;292:2839-2848.
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
132. Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon 156. McJunkin JE, Khan R, de los Reyes EC, et al. Treatment of severe La
Alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected Crosse encephalitis with intravenous ribavirin following diagnosis by brain
patients. /&OHM+.FE. 2004;351:438-450. biopsy. 1FEJBUSJDT. 1997;99:261-267.
133. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus 157. Chong HT, Kamarulzaman A, Tan CT, et al. Treatment of acute Nipah
ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV- encephalitis with ribavirin. "OO/FVSPM. 2001;49:810-813.
coinfected persons. /&OHM+.FE. 2004;351:451-459. 158. McCormick JB, King IJ, Webb PA, et al. Lassa fever: effective therapy
134. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepati- with ribavirin. /&OHM+.FE. 1986;314:20-26.
tis C with interferon alfa-2b. /&OHM+.FE. 2001;345:1452-1457. 159. Huggins JW, Hsiang CM, Cosgriff TM, et al. Prospective, double-blind,
135. Santantonio T, Fasano M, Sinisi E, et al. Efficacy of a 24-week course of concurrent, placebo-controlled clinical trial of intravenous ribavirin ther-
PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after apy of hemorrhagic fever with renal syndrome. +*OGFDU%JT. 1991;164:1119-
failure of spontaneous clearance. +)FQBUPM. 2005;42:329-333. 1127.
136. Eron LJ, Judson F, Tucker S, et al. Interferon therapy for condylomata 160. Fisher-Hoch SP, Khan JA, Rehman S, Mirza S, Khurshid M, McCor-
acuminata. /&OHM+.FE. 1986;315:1059-1064. mick JB. Crimean Congo-haemorrhagic fever treated with oral ribavirin. -BO
137. Leung DT, Sacks SL. Current recommendations for the treatment of DFU. 1995;346:472-475.
genital herpes. %SVHT. 2000;60:1329-1352. 161. Mardani M, Jahromi MK, Naieni KH, Zeinali M. The efficacy of oral
138. Huang SS, Skolasky RL, Dal Pan GJ, Royal W III, McArthur JC. Sur- ribavirin in the treatment of Crimean-Congo hemorrhagic fever in Iran. Clin
vival prolongation in HIV-associated progressive multifocal leukoenceph- *OGFDU%JT. 2003;36:1613-1618.
alopathy treated with alpha-interferon: an observational study. + /FVSPWJSPM. 162. Kilgore PE, Ksiazek TG, Rollin PE, et al. Treatment of Bolivian
1998;4:324-332. hemorrhagic fever with intravenous ribavirin. $MJO*OGFDU%JT. 1997;24:718-
139. Geschwind MD, Skolasky RI, Royal WS, McArthur JC. The relative 722.
contributions of HAART and alpha-interferon for therapy of progressive mul- 163. Prochoda K, Mostow SR, Greenberg K. Hantavirus-associated acute
tifocal leukoencephalopathy in AIDS. +/FVSPWJSPM. 2001;7:353-357. respiratory failure. /&OHM+.FE. 1993;329:1744.
140. Renault PF, Hoofnagle JH, Park Y, et al. Psychiatric complica- 164. Dando T, Plosker G. Adefovir dipivoxil: a review of its use in chronic
tions of long-term interferon alfa therapy. "SDI*OUFSO.FE. 1987;147:1577- hepatitis B. %SVHT. 2003;63:2215-2234.
1580. 165. Rivkin AM. Adefovir dipivoxil in the treatment of chronic hepatitis B.
141. Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms as- "OO1IBSNBDPUIFS. 2004;38:625-633.
sociated with hepatitis C and interferon19 alpha: a review. "N+1TZDIJBUSZ. 166. Marcellin P, Chang TT, Lim SG, et al. Adefovir dipivoxil for the treat-
2000;157:867-876. ment of hepatitis B e antigen-positive chronic hepatitis B. / &OHM + .FE.
142. Midturi J, Sierra-Hoffman M, Hurley D, Winn R, Beissner R, Carpen- 2003;348:808-816.
ter J. Spectrum of pulmonary toxicity associated with the use of interferon 167. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Adefovir dipiv-
therapy for hepatitis C: case report and review of the literature. $MJO*OGFDU%JT. oxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N
2004;39:1724-1729. &OHM+.FE. 2003;348:800-807.
143. Levenson JL, Fallon HJ. Fluoxetine treatment of depression caused by 168. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term ther-
interferon-alpha. "N+(BTUSPFOUFSPM. 1993;88:760-761. apy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. /&OHM+
144. Musselman DL, Lawson DH, Gumnick JF, et al. Paroxetine for the pre- .FE. 2005;352:2673-2681.
vention of depression induced by high-dose interferon alfa. / &OHM + .FE. 169. Delaney WE. Progress in the treatment of chronic hepatitis B: long-
2001;344:961-966. term experience with adefovir dipivoxil. + "OUJNJDSPC $IFNPUIFS. 2007;
145. Durand JM, Kaplanski G, Portal I, Scheiner C, Berland Y, Soubey- 59:827-832.
rand J. Liver failure due to recombinant alpha interferon. -BODFU. 170. Lim SG, Ng TM, Kung N, et al. A double-blind placebo-controlled
1991;338:1268-1269. study of emtricitabine in chronic hepatitis B. "SDI*OUFSO.FE. 2006;166:49-
146. Averbuch SD, Austin HA III, Sherwin SA, Antonovych T, Bunn PA Jr, 56.
Longo DL. Acute interstitial nephritis with the nephrotic syndrome following 171. Sims KA, Woodland AM. Entecavir: a new nucleoside analog for
recombinant leukocyte a interferon therapy for mycosis fungoides. /&OHM+ the treatment of chronic hepatitis B infection. 1IBSNBDPUIFSBQZ. 2006;26:
.FE. 1984;310:32-35. 1745-1757.
147. Agesta N, Zabala R, Diaz-Perez JL. Alopecia areata during interferon 172. Matthews SJ. Entecavir for the treatment of chronic hepatitis B virus
alpha-2b/ribavirin therapy. %FSNBUPMPHZ. 2002;205:300-301. infection. $MJO5IFS. 2006;28:184-203.
148. Wade JR, Snoeck E, Duff F, Lamb M, Jorga K. Pharmacokinetics of 173. Scott LJ, Keating GM. Entecavir: a review of its use in chronic hepatitis
ribavirin in patients with hepatitis C virus. #S + $MJO 1IBSNBDPM. 2006;62: B. %SVHT. 2009;69:1003-1033.
710-714. 174. Johnson MA, Moore KH, Yuen GJ, Bye A, Pakes GE. Clinical pharma-
149. Kramer TH, Gaar GG, Ray CG, Minnich L, Copeland JG, Connor JD. cokinetics of lamivudine. $MJO1IBSNBDPLJOFU. 1999;36:41-66.
Hemodialysis clearance of intravenously administered ribavirin. "OUJNJDSPC 175. Dienstag JL, Perrillo RP, Schiff ER, Bartholomew M, Vicary C, Rubin
"HFOUT$IFNPUIFS. 1990;34:489-490. M. A preliminary trial of lamivudine for chronic hepatitis B infection. /&OHM
150. Gish RG. Treating HCV with ribavirin analogues and ribavirin-like +.FE. 1995;333:1657-1661.
molecules. +"OUJNJDSPC$IFNPUIFS. 2006;57:8-13. 176. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as ini-
151. Gluud LL, Marchesini E, Iorio A. Peginterferon plus ribavirin for tial treatment for chronic hepatitis B in the United States. / &OHM + .FE.
chronic hepatitis C in patients with human immunodeficiency virus. "N+(BT 1999;341:1256-1263.
USPFOUFSPM. 2009;104:2335-2341. 177. Lai CL, Chien RN, Leung NW, et al; Asia Hepatitis Lamivudine Study
152. Ventre K, Randolph AG. Ribavirin for respiratory syncytial virus infec- Group. A one-year trial of lamivudine for chronic hepatitis B. /&OHM+.FE.
tion of the lower respiratory tract in infants and young children. $PDISBOF 1998;339:61-68.
%BUBCBTF4ZTU3FW. 2007;CD000181. 178. Honkoop P, de Man RA, Heijtink RA, Schalm SW. Hepatitis B reactiva-
153. Pelaez A, Lyon GM, Force SD, et al. Efficacy of oral ribavirin in lung tion after lamivudine. -BODFU. 1995;346:1156-1157.
transplant patients with respiratory syncytial virus lower respiratory tract in- 179. Zhou XJ, Ke J, Sallas WM, Farrell C, Mayers DL, Pentikis HS. Pop-
fection. +)FBSU-VOH5SBOTQMBOU. 2009;28:67-71. ulation pharmacokinetics of telbivudine and determination of dose adjust-
154. Knowles SR, Phillips EJ, Dresser L, Matukas L. Common adverse ment for patients with renal impairment. + $MJO 1IBSNBDPM. 2009;49:725-
events associated with the use of ribavirin for severe acute respiratory syn- 734.
drome in Canada. $MJO*OGFDU%JT. 2003;37:1139-1142. 180. Kim JW, Park SH, Louie SG. Telbivudine: a novel nucleoside analog
155. Muller MP, Dresser L, Raboud J, et al. Adverse events associated with for chronic hepatitis B. "OO1IBSNBDPUIFS. 2006;40:472-478.
high-dose ribavirin: evidence from the Toronto outbreak of severe acute respi- 181. Jones R, Nelson M. Novel anti-hepatitis B agents: a focus on telbivu-
ratory syndrome. 1IBSNBDPUIFSBQZ. 2007;27:494-503. dine. *OU+$MJO1SBDU. 2006;60:1295-1299.
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.
ANTIVIRAL THERAPIES
182. Lai CL, Gane E, Liaw YF, et al. Telbivudine versus lamivudine 193. Zimmermann AE, Pizzoferrato T, Bedford J, Morris A, Hoffman R,
in patients with chronic hepatitis B. / &OHM + .FE. 2007;357:2576- Braden G. Tenofovir-associated acute and chronic kidney disease: a case of
2588. multiple drug interactions. $MJO*OGFDU%JT. 2006;42:283-290.
183. Chan HL, Heathcote EJ, Marcellin P, et al. Treatment of hepatitis B e 194. Foote BC, Spooner LM, Belliveau PP. Boceprevir: a protease inhibitor
antigen positive chronic hepatitis with telbivudine or adefovir: a randomized for the treatment of chronic hepatitis C [Epub ahead of print August 9, 2011].
trial. "OO*OUFSO.FE. 2007;147:745-754. "OO1IBSNBDPUIFS doi:10.1345/aph.1P744.
184. Kearney BP, Flaherty JF, Shah J. Tenofovir disoproxil fumarate: clini- 195. Poordad F, McCone J Jr, Bacon BR, et al. Boceprevir for untreated
cal pharmacology and pharmacokinetics. $MJO1IBSNBDPLJOFU. 2004;43:595- chronic HCV genotype 1 infection. /&OHM+.FE. 2011;364:1195-1206.
612. 196. Bacon BR, Gordon SC, Lawitz E, et al. Boceprevir for previously
185. Grim SA, Romanelli F. Tenofovir disoproxil fumarate. "OO1IBSNBDP treated chronic HCV genotype 1 infection. / &OHM + .FE. 2011;364:1207-
UIFS. 2003;37:849-859. 1217.
186. Gallant JE, Deresinski S. Tenofovir disoproxil fumarate. $MJO *OGFDU 197. Pawlotsky JM, Chevaliez S, McHutchison JG. The hepatitis C virus
%JT. 2003;37:944-950. life cycle as a target for new antiviral therapies. (BTUSPFOUFSPMPHZ. 2007;132:
187. Wong SN, Lok AS. Tenofovir disoproxil fumarate: role in hepatitis B 1979-1998.
treatment. )FQBUPMPHZ. 2006;44:309-313. 198. Sarrazin C, Kieffer TL, Bartels D, et al. Dynamic hepatitis C virus ge-
188. Reijnders JG, Janssen HL. Potency of tenofovir in chronic hepatitis B: notypic and phenotypic changes in patients treated with the protease inhibitor
mono or combination therapy? +)FQBUPM. 2008;48:383-386. telaprevir. (BTUSPFOUFSPMPHZ. 2007;132:1767-1777.
189. Gitman MD, Hirschwerk D, Baskin CH, Singhal PC. Tenofovir-induced 199. McHutchison JG, Everson GT, Gordon SC, et al. Telaprevir with
kidney injury. &YQFSU0QJO%SVH4BG. 2007;6:155-164. peginterferon and ribavirin for chronic HCV genotype 1 infection. /&OHM+
190. Gupta SK. Tenofovir-associated Fanconi syndrome: review of the .FE. 2009;360:1827-1838.
FDA adverse event reporting system. "*%41BUJFOU$BSF45%4. 2008;22:99- 200. Hézode C, Forestier N, Dusheiko G, et al. Telaprevir and peginterferon
103. with or without ribavirin for chronic HCV infection. / &OHM + .FE. 2009;
191. Schmid S, Opravil M, Moddel M, et al. Acute interstitial nephritis 360:1839-1850.
of HIV-positive patients under atazanavir and tenofovir therapy in a ret- 201. Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for pre-
rospective analysis of kidney biopsies. 7JSDIPXT "SDI. 2007;450:665- viously untreated chronic hepatitis C virus infection. / &OHM + .FE. 2011;
670. 364:2405-2416.
192. Kapitsinou PP, Ansari N. Acute renal failure in an AIDS patient on teno- 202. Zeuzem S, Andreone P, Pol S, et al. Telaprevir for retreatment of HCV
fovir: a case report. +.FE$BTF3FQPSUT. 2008;2:94. infection. /&OHM+.FE. 2011;364:2417-2428.
The contributions to the Symposium on Antimicrobial Therapy are a CME activity. For CME
credit, see the link on our Web site at mayoclinicproceedings.com.
For personal use. Mass reproduce only with permission from Mayo
a Clinic Proceedings.