Exploring the Efficacy, Mechanisms, and Growth of Antiviral Medicine: A Complete
PRINCIPLES OF ANTIVIRAL THERAPY
In contrast with the variety of medicine obtainable to deal with bacte-
rial infections, the variety of antiviral medicine could be very small. The
main motive for this distinction is the problem in acquiring
selective toxicity in opposition to viruses; their replication is intimately
concerned with the conventional artificial processes of the cell. Regardless of
the problem, a number of virus-specific replication steps have been
recognized which can be the location of motion of efficient antiviral medicine
(Desk 35–1). Desk 35–2 describes the mode of motion of
antiviral medicine that block early occasions in viral replication, and
Desk 35–3 describes the mode of motion of antiviral medicine
that block viral nucleic acid synthesis. Determine 35–1 reveals the
replication of a mannequin virus and the location of motion of medicine used
to deal with varied viral infections. Determine 35–2 reveals the replica-
tion of human immunodeficiency virus (HIV) and the location of
motion of medicine used to deal with HIV an infection.
One other limitation of antiviral medicine is that they’re comparatively
ineffective as a result of many cycles of viral replication happen dur-
ing the incubation interval when the affected person is effectively. By the point
the affected person has a recognizable systemic viral illness, the virus
has unfold all through the physique and it’s too late to interdict it.
Moreover, some viruses (e.g., herpesviruses) grow to be latent
inside cells, and no present antiviral drug can eradicate them.
One other limiting issue is the emergence of drug-resistant
viral mutants. For instance, when drug-resistant mutants of
HIV emerge, it requires that drug regimens be modified. Additionally,
therapy of HIV an infection makes use of a number of medicine, usually from dif-
ferent lessons, in order that if mutants resistant to at least one drug emerge,
one other drug will nonetheless be efficient.
INHIBITION OF EARLY EVENTS
Amantadine (α-adamantanamine, Symmetrel) is a three-ring
compound (Determine 35–3) that blocks the replication of influenza
A virus. It prevents replication by inhibiting uncoating of the
virus by blocking the “ion channel” exercise of the matrix protein
(M2 protein) within the virion. Absorption and penetration happen
usually, however transcription by the virion RNA polymerase does
not as a result of uncoating can not happen. This drug particularly inhib-
its influenza A virus; influenza B and C viruses are usually not affected.
Regardless of its efficacy in stopping influenza, it isn’t broadly
utilized in america as a result of the vaccine is most popular for the
high-risk inhabitants. Moreover, most isolates have grow to be
immune to amantadine. The principle unwanted effects of amantadine are
central nervous system alterations akin to dizziness, ataxia, and
insomnia. Rimantadine (Flumadine) is a by-product of aman-
tadine and has the identical mode of motion however fewer unwanted effects.
Enfuvirtide (Fuzeon) is an artificial peptide that binds to
gp41 on the floor of HIV, thereby blocking the entry of the
virus into the cell. It’s the first of a brand new class of anti-HIV medicine
often called “fusion inhibitors” (i.e., they forestall the fusion of the
viral envelope with the cell membrane).
Maraviroc (Selzentry) blocks the binding of HIV to
CCR-5—an necessary coreceptor for these strains of HIV that
use CCR-5 for entry into the cell. The drug binds to CCR-5 and
blocks the interplay of gp120, an HIV envelope protein, to
CCR-5 on the cell floor.
Palivizumab (Synagis) is a monoclonal antibody directed
in opposition to the fusion protein of respiratory syncytial virus (RSV).
Palivizumab neutralizes RSV by binding to the fusion protein
on the floor of RSV, thereby stopping the virus from bind-
ing to receptors on the floor of respiratory tract mucosal cells.
It’s used to stop bronchiolitis and pneumonia in untimely
or immunocompromised infants.
INHIBITION OF VIRAL NUCLEIC
Inhibitors of Herpesviruses
These medicine are analogues of nucleosides that inhibit the DNA
polymerase of a number of members of the herpesvirus household
For instance, acyclovir inhibits the DNA polymerase herpes
simplex virus sorts 1 and a pair of (HSV-1 and -2) and varicella-zoster
virus however not cytomegalovirus (CMV).
1. Acyclovir—Acyclovir (acycloguanosine, Zovirax) is a guano-
sine analogue that has a three-carbon fragment instead of the
regular sugar, ribose, which has 5 carbons (see Determine 35–3).
The time period acyclo refers to the truth that the three-carbon fragment
doesn’t have a sugar ring construction (a = with out, cyclo = ring).
Acyclovir is energetic primarily in opposition to HSV-1 and -2 and
varicella-zoster virus (VZV). It’s comparatively unhazardous, as a result of it
is activated preferentially inside virus-infected cells. That is due
to the virus-encoded thymidine kinase, which phosphorylates
acyclovir way more successfully than does the mobile thymi-
dine kinase. As a result of solely HSV-1, HSV-2, and VZV encode
a kinase that effectively phosphorylates acyclovir, the drug is
energetic primarily in opposition to these viruses. It has no exercise in opposition to
CMV. As soon as the drug is phosphorylated to acyclovir monophos-
phate by the viral thymidine kinase, mobile kinases synthesize
acyclovir triphosphate, which inhibits viral DNA polymerase
way more successfully than it inhibits mobile DNA polymerase.
Acyclovir causes chain termination as a result of it lacks a hydroxyl
group within the 3′ place.
To recap, the selective motion of acyclovir relies on two
options of the drug. (1) Acyclovir is phosphorylated to acyclovir
monophosphate way more successfully by herpesvirus-encoded
thymidine kinase than by mobile thymidine kinase. It’s there-
fore preferentially activated in herpesvirus-infected cells and
a lot much less so in uninfected cells, which accounts for its comparatively
few unwanted effects. (2) Acyclovir triphosphate inhibits herpesvirus-
encoded DNA polymerase way more successfully than it does
mobile DNA polymerase. It subsequently inhibits viral DNA syn-
thesis to a a lot better extent than mobile DNA synthesis
Topical acyclovir is efficient within the therapy of main
genital herpes and reduces the frequency of recurrences whereas
it’s being taken. Nevertheless, it has no impact on latency or on the
charge of recurrences after therapy is stopped. Acyclovir is the
therapy of alternative for HSV-1 encephalitis and is efficient in
stopping systemic an infection by HSV-1 or VZV in immuno-
Acyclovir-resistant mutants have been remoted from HSV-1-
and VZV-infected sufferers. Resistance is most frequently as a consequence of
mutations within the gene encoding the viral thymidine kinase. This
ends in diminished exercise of or the entire absence of the virus-
encoded thymidine kinase.
Acyclovir is effectively tolerated and causes few unwanted effects—even
in sufferers who’ve taken it orally for a few years to suppress
genital herpes. Intravenous acyclovir could trigger renal or central
nervous system toxicity.
Derivatives of acyclovir with varied properties at the moment are
obtainable. Valacyclovir (Valtrex) achieves a excessive plasma
focus when taken orally and is utilized in herpes genitalis
and in herpes zoster. Penciclovir cream (Denavir) is used within the
therapy of recurrent orolabial herpes simplex. Famciclovir
(Famvir), when taken orally, is transformed to penciclovir and is
used to deal with herpes zoster and herpes simplex infections.
2. Ganciclovir—Ganciclovir (dihydroxypropoxymethylgua-
9, DHPG, Cytovene) is a nucleoside analogue of guanosine
with a four-carbon fragment instead of the conventional sugar,
ribose (see Determine 35–3). It’s structurally just like acyclovir
however is extra energetic in opposition to CMV than is acyclovir. Ganciclovir
is activated by a CMV-encoded phosphokinase in a course of
just like that by which acyclovir is activated by HSV. Isolates
of CMV immune to ganciclovir have emerged, principally as a consequence of
mutations within the UL97 gene that encodes the phosphokinase.
Ganciclovir is efficient within the therapy of retinitis brought on by
CMV in sufferers with acquired immunodeficiency syndrome
(AIDS) and is helpful in different disseminated infections, such
as colitis and esophagitis, brought on by this virus. The principle aspect
results of ganciclovir are leukopenia and thrombocytopenia as a
results of bone marrow suppression. Valganciclovir, which may
be taken orally, can be efficient in opposition to CMV retinitis.
3. Cidofovir—Cidofovir (hydroxyphosphonylmethoxy-
propylcytosine, HPMPC, Vistide) is an analogue of cytosine
that lacks a ribose ring. Cidofovir doesn’t need to be phos-
phorylated and subsequently isn’t depending on the motion of a
virus-encoded phosphokinase. It’s helpful within the therapy of
retinitis brought on by CMV and in extreme human papillomavirus
infections. It might be helpful within the therapy of extreme mollus-
cum contagiosum in immunocompromised sufferers. Kidney
injury is the principle aspect impact.
4. Trifluridine—(trifluorothymidine, Viroptic) is a nucleo-
aspect analogue wherein the methyl group of thymidine con-
tains three fluorine atoms as an alternative of three hydrogen atoms
(see Determine 35–3). The drug is phosphorylated to the triphos-
phate by mobile kinases and integrated into DNA. As a result of
it has a excessive frequency of mismatched pairing to adenine,
it causes the formation of defective progeny DNA and mRNA.
Nevertheless, as a result of it’s integrated into regular cell DNA as
effectively as viral DNA, it’s too poisonous for use systemically. It’s
the drug of alternative for the topical therapy of keratoconjunc-
tivitis brought on by herpes simplex virus.
Nonnucleoside inhibitors inhibit the DNA polymerase of her-
pesviruses by mechanisms distinct from the nucleoside ana-
logues described beforehand. Foscarnet is the one authorized
drug on this class at the moment.
1. Foscarnet—Foscarnet (trisodium phosphonoformate,
Foscavir), in contrast to the earlier medicine, that are nucleoside ana-
logues, is a pyrophosphate analogue (see Determine 35–3). It binds
to DNA polymerase on the pyrophosphate cleavage website and pre-
vents removing of the phosphates from nucleoside triphosphates
(dNTP). This inhibits the addition of the subsequent dNTP and, as a
consequence, the extension of the DNA strand.
Foscarnet inhibits the DNA polymerases of all herpesviruses,
particularly HSV and CMV. In contrast to acyclovir, it doesn’t require
activation by thymidine kinase. It’s helpful within the therapy
of retinitis brought on by CMV, however ganciclovir is the drug of first
alternative for this illness. Foscarnet can be used to deal with sufferers
contaminated with acyclovir-resistant mutants of HSV-1 and VZV.
Inhibitors of Human
The selective toxicity of zidovudine, lamivudine, emtricitabine,
didanosine, zalcitabine, stavudine, abacavir, and tenofovir is
based mostly on their capability to inhibit DNA synthesis by the reverse
transcriptase of HIV to a a lot better extent than they inhibit
DNA synthesis by the DNA polymerase in human cells. These
medicine are collectively referred to as nucleoside reverse transcriptase
inhibitors (NRTIs). The impact of those medicine on the replication
of HIV is depicted in Determine 35–2.
1. Zidovudine—Zidovudine (azidothymidine, Retrovir,
AZT) is a nucleoside analogue that causes chain termina-
tion throughout DNA synthesis; it has an azido group in place
of the hydroxyl group on the ribose (see Determine 35–3). It’s
significantly efficient in opposition to DNA synthesis by the reverse
transcriptase of HIV and inhibits the expansion of the virus in
cell tradition. The principle adversarial results of zidovudine are bone
marrow suppression and myopathy.
2. Lamivudine—Lamivudine (dideoxythiacytidine, Epivir,
3TC) is a nucleoside analogue that causes chain termination
throughout DNA synthesis by the reverse transcriptase of HIV.
When utilized in mixture with AZT, it is extremely efficient each
in decreasing the viral load and in elevating the CD4 cell rely.
Lamivudine can be used within the therapy of power hepatitis
B as a result of it inhibits the reverse transcriptase of hepatitis B
virus. It is without doubt one of the finest tolerated of the nucleoside inhibi-
tors, however adversarial results akin to neutropenia, pancreatitis, and
peripheral neuropathy do happen.
3. Emtricitabine—Emtricitabine (Emtriva), a by-product of
lamivudine, can be helpful and effectively tolerated. A mixture
of emtricitabine and tenofovir (Truvada) can be utilized for pre-
publicity prophylaxis for males who’ve intercourse with males as effectively
as for postexposure prophylaxis.
4. Didanosine—Didanosine (dideoxyinosine, ddI, Videx)
is a nucleoside analogue that causes chain termination dur-
ing DNA synthesis; it’s lacking hydroxyl teams on the
ribose. The administered drug ddI is metabolized to ddATP,
which is the energetic compound. It’s efficient in opposition to DNA
synthesis by the reverse transcriptase of HIV and is used to
deal with sufferers with AIDS who’re illiberal of or immune to
zidovudine. The principle adversarial results of didanosine are pan-
creatitis and peripheral neuropathy.
5. Stavudine—Stavudine (didehydrodideoxythymidine, d4T,
Zerit) is a nucleoside analogue that causes chain termination
throughout DNA synthesis. It inhibits DNA synthesis by the reverse
transcriptase of HIV and is used to deal with sufferers with superior
AIDS who’re illiberal of or immune to different authorized thera-
pies. The principle adversarial impact is peripheral neuropathy.
6. Abacavir—Abacavir (Ziagen) is a nucleoside analogue
of guanosine that causes chain termination throughout DNA
synthesis. It’s obtainable via the “expanded entry” pro-
gram to those that have failed presently obtainable drug regi-
mens. Abacavir is utilized in mixture with both a protease
inhibitor, sometimes darunavir and ritonavir, or zidovudine
plus lamivudine. The principle adversarial results are liver injury
and extreme hypersensitivity reactions. Sufferers who’ve an
HLA-B1701 allele usually tend to have a extreme hypersen-
sitivity response, akin to fever, rash, or respiratory issues,
to abacavir. Sufferers needs to be examined for this gene earlier than
being prescribed abacavir. If sufferers develop hypersensitivity
signs, abacavir needs to be instantly and completely
7. Tenofovir—Tenofovir (Viread) is an acyclic phosphonate
that’s an analogue of adenosine monophosphate. It’s a
reverse transcriptase inhibitor that acts by chain termination.
It’s authorized to be used in sufferers who’ve developed resis-
tance to different reverse transcriptase inhibitors and in these
who’re beginning therapy for the primary time. It needs to be used
together with different anti-HIV medicine. The principle adversarial
results are liver injury, lactic acidosis, and renal failure.
In contrast to the medicine described earlier, the medicine on this group are
not nucleoside analogues and don’t trigger chain termination.
The nonnucleoside reverse transcriptase inhibitors (NNRTIs)
act by binding close to the energetic website of the reverse transcriptase and
inducing a conformational change that inhibits the synthesis of
viral DNA. NNRTIs shouldn’t be used as monotherapy as a result of
resistant mutants emerge quickly. Strains of HIV resistant to at least one
NNRTI are often immune to others as effectively. NNRTIs are typi-
cally utilized in mixture with one or two nucleoside analogues.
1. Nevirapine—Nevirapine (Viramune) is often utilized in
mixture with zidovudine and didanosine. There isn’t any
cross-resistance with the nucleoside inhibitors of reverse
transcriptase described beforehand. The principle aspect impact of
nevirapine is a extreme pores and skin rash (Stevens-Johnson syndrome).
2. Delavirdine—Delavirdine (Rescriptor) is efficient in com-
bination with both zidovudine or zidovudine plus didano-
sine. The principle aspect impact of delavirdine is a pores and skin rash.
3. Efavirenz—Efavirenz (Sustiva) is efficient together
with zidovudine plus lamivudine. The most typical aspect
results are referable to the central nervous system, akin to diz-
ziness, insomnia, and complications.
4. Etravirine—Etravirine (Intelence) is a second-generation
NNRTI helpful in treatment-experienced sufferers who’ve
important viremia. It’s only when given in combi-
nation with two protease inhibitors, darunavir and ritonavir.
The most typical adversarial impact is a rash, and Stevens-
Johnson syndrome has occurred, albeit hardly ever.
5. Rilpivirine—Rilpivirine (Edurant) is a second-generation
NNRTI helpful in treatment-naïve grownup sufferers. It’s most
efficient when utilized in mixture with both tenofovir or
emtricitabine. The most typical adversarial results are depres-
sion and insomnia.
Inhibitors of Hepatitis B Virus
Adefovir (Hepsera) is a nucleotide analogue of adenosine
monophosphate that inhibits the DNA polymerase (reverse
transcriptase) of hepatitis B virus (HBV). It’s used for the treat-
ment of power energetic hepatitis brought on by this virus.
Entecavir (Baraclude) is a guanosine analogue that inhibits
the DNA polymerase (reverse transcriptase) of HBV. It has no
exercise in opposition to the DNA polymerase (reverse transcriptase) of
HIV. It’s authorized for the therapy of adults with power HBV
Lamivudine is described within the part “Inhibitors of
Telbivudine (Tyzeka) is a thymidine analogue that inhibits the
DNA polymerase (reverse transcriptase) of HBV however has no
impact on the reverse transcriptase of HIV. It’s helpful within the
therapy of power HBV an infection.
Tenofovir is described within the part “Inhibitors of Retroviruses.”
Inhibitors of Hepatitis C Virus
1. RNA polymerase inhibitors
Sofosbuvir (Sovaldi) is a uridine analogue that inhibits the RNA
polymerase of HCV. It acts as a series terminating drug. It’s
helpful within the therapy of power HCV an infection brought on by
genotypes 1, 2, 3, and 4.
Dasabuvir is a nonnucleoside inhibitor of the RNA polymerase
of HCV. Its exact mode of motion is unsure as of this writing.
It’s obtainable together with ombitasvir (an NS5A inhibi-
tor), paritaprevir (a protease inhibitor), and ritonavir (a booster
of protease inhibitor exercise). This four-drug mixture is
referred to as Viekira.
2. NS5A inhibitors
Ledipasvir is an inhibitor of NS5A, an RNA-binding protein
required for the exercise of the RNA polymerase of HCV. Ledi-
pasvir is out there together with sofosbuvir (Harvoni)
and is helpful within the therapy of power HCV an infection brought about
by genotype 1.
Ombitasvir is one other NS5A inhibitor that’s obtainable in com-
bination with dasabuvir (a polymerase inhibitor), paritaprevir
(a protease inhibitor), and ritonavir (a booster of protease
inhibitor exercise). This four-drug mixture is named Viekira.
Inhibitors of Different Viruses
Ribavirin (Virazole) is a nucleoside analogue wherein a triazole-
carboxamide moiety is substituted instead of the conventional purine
precursor aminoimidazole-carboxamide (see Determine 35–3).
The drug inhibits the synthesis of guanine nucleotides, which
are important for each DNA and RNA viruses. It additionally inhibits
the 5′ capping of viral mRNA. Ribavirin aerosol is used clini-
cally to deal with pneumonitis brought on by respiratory syncytial virus
(RSV) in infants and to deal with extreme influenza B infections.
INHIBITION OF INTEGRASE
Raltegravir (Isentress) is an integrase inhibitor (i.e., it blocks
the HIV-encoded integrase that mediates the combination of the
newly synthesized viral DNA into host cell DNA). Two addi-
tional integrase inhibitors can be found: dolutegravir (Tivicay)
and elvitegravir (Stribild).
INHIBITION OF CLEAVAGE OF
Inhibitors of Human
Members of the protease inhibitor (PI) class of medicine, akin to
saquinavir (Invirase, Fortovase), indinavir (Crixivan), ritonavir
(Norvir), lopinavir/ritonavir (Kaletra), atazanavir (Reyataz),
tipranavir (Aptivus), amprenavir (Agenerase) and its prodrug
fosamprenavir (Lexiva), darunavir (Prezista), and nelfinavir
(Viracept), inhibit the protease encoded by HIV (Determine 35–5).
The protease cleaves the gag and pol precursor polypeptides to
produce a number of nucleocapsid proteins (e.g., p24) and enzymatic
proteins (e.g., reverse transcriptase) required for viral replica-
tion. These inhibitors include peptide bonds that bind to the
energetic website of the viral protease, thereby stopping the protease
from cleaving the viral precursor. These medicine inhibit produc-
tion of infectious virions however don’t have an effect on the proviral DNA and
subsequently don’t treatment the an infection.
Monotherapy with PIs shouldn’t be used as a result of resistant
mutants emerge quickly. These medicine sometimes are prescribed
together with reverse transcriptase inhibitors, such
as zidovudine and lamivudine. Ritonavir is often utilized in
mixture with one other PI, as within the generally used com-
bination lopinavir/ritonavir (Kaletra). Ritonavir inhibits the
enzymes that metabolize the opposite PI, which successfully raises
the focus of the opposite drug (e.g., lopinavir within the Kal-
etra mixture). Ritonavir “boosts” lopinavir is the best way to
bear in mind it.
The unwanted effects of PIs embody nausea, diarrhea, and abnor-
mal fats accumulation at the back of the neck that can lead to
a “buffalo hump” look. These irregular fats deposits can
be disfiguring and trigger sufferers to cease taking the drug. The
fats deposits are a sort of lipodystrophy; the metabolic course of
by which this happens is unknown. Indinavir could cause kidney
stones; thus further water needs to be consumed to scale back the like-
lihood of stone formation.
Inhibitors of Hepatitis C Virus
Boceprevir (Victrelis), simeprevir (Olysio), telaprevir
(Incivek), and paritaprevir (element of Viekira) are PIs that
block a serine protease required for the replication of hepatitis
C virus. They’re authorized for the therapy of power
hepatitis C brought on by hepatitis C virus (genotype 1) in combi-
nation with peginterferon and ribavirin. A very powerful
adversarial impact of those medicine is anemia. Paritaprevir is an
inhibitor of HCV protease that’s obtainable together
with ombitasvir (an NS5A inhibitor), dasabuvir (a polymerase
inhibitor), and ritonavir (a booster of PI exercise). This four-
drug mixture is named Viekira.
INHIBITION OF VIRAL
The mode of motion of interferon is described in Chapter 33.
Recombinant alpha interferon is efficient within the therapy of
some sufferers with power hepatitis B and power hepatitis C
infections. Word that using alpha interferon and pegylated
alpha interferon (see subsequent paragraph) for power HCV infec-
tion has been considerably diminished because of the availability of
newer much less poisonous drug regimens. Alpha interferon additionally causes
regression of condylomata acuminata lesions brought on by human
papillomavirus and the lesions of Kaposi’s sarcoma brought on by
Pegylated interferon (peginterferon), which is alpha inter-
feron conjugated to polyethylene glycol, is used for the treat-
ment of power hepatitis B and C. The benefit of pegylated
interferon is that it has an extended half-life than unconjugated
alpha interferon and will be administered as soon as per week as an alternative
of 3 times per week.
Fomivirsen (Vitravene) is an antisense DNA that blocks the
replication of CMV. Antisense DNA is a single-stranded DNA
whose base sequence is the complement of the viral mRNA.
Antisense DNA binds to the mRNA throughout the contaminated cell and
prevents it from being translated into viral protein. Fomivirsen
is authorized for the intraocular therapy of CMV retinitis. It
is the primary and, at current, the one antisense molecule to be
authorized for the therapy of human illness.
INHIBITION OF RELEASE OF VIRUS
Oseltamivir (Tamiflu), zanamivir (Relenza), and peramivir
(Rapivab) inhibit the neuraminidase of influenza virus. This
enzyme is situated on the floor of influenza virus and is
required for the discharge of the virus from contaminated cells. Inhibi-
tion of launch of influenza virus limits the an infection by decreasing
the unfold of virus from one cell to a different. These medicine are
efficient in opposition to each influenza A and B viruses, in distinction to
amantadine, which is efficient solely in opposition to influenza A virus.
These medicine are efficient in opposition to strains of influenza virus resis-
tant to amantadine.
In most situations, the antiviral brokers described on this chapter
are used to deal with infectious illnesses. Nevertheless, there are occasions
when they’re used to stop illnesses from occurring—a
course of referred to as chemoprophylaxis. Desk 35–4 describes the
medicine used for this objective and the conditions wherein they’re
used. For extra info, see the chapters on the person