Page 285 - Review of Medical Microbiology and Immunology ( PDFDrive )

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PART III Basic Virology
274
of severe molluscum contagiosum in immunocompro-
ovudine are bone marrow suppression and myopathy.
mised patients. Kidney damage is the main side effect.
4. Trifluridine—(trifluorothymidine, Viroptic) is a
2. Lamivudine—Lamivudine (dideoxythiacytidine,
Epivir, 3TC) is a nucleoside analogue that causes chain
nucleoside analogue in which the methyl group of thymi-
dine contains three fluorine atoms instead of three hydro-
gen atoms (see Figure 35–3). The drug is phosphorylated
scriptase of HIV. When used in combination with AZT, it
is very effective both in reducing the viral load and in
to the triphosphate by cellular kinases and incorporated
into DNA. Because it has a high frequency of mismatched termination during DNA synthesis by the reverse tran-
elevating the CD4 cell count. Lamivudine is also used in
the treatment of chronic hepatitis B because it inhibits the
pairing to adenine, it causes the formation of faulty prog-
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eny DNA and mRNA. However, because it is incorpo-
reverse transcriptase of hepatitis B virus. It is one of the
rated into normal cell DNA as well as viral DNA, it is too
best tolerated of the nucleoside inhibitors, but adverse
toxic to be used systemically. It is the drug of choice for
neuropathy do occur.
the topical treatment of keratoconjunctivitis caused by
herpes simplex virus.
3. Emtricitabine—Emtricitabine (Emtriva), a derivative
of lamivudine, is also useful and well tolerated. A combi-
Nonnucleoside Inhibitors
nation of emtricitabine and tenofovir (Truvada) can be
Nonnucleoside inhibitors inhibit the DNA polymerase of
used for preexposure prophylaxis for men who have sex
herpesviruses by mechanisms distinct from the nucleoside
analogues described previously. Foscarnet is the only
4. Didanosine—Didanosine (dideoxyinosine, Videx,
approved drug in this class at this time.
ddI) is a nucleoside analogue that causes chain termina-
1. Foscarnet—Foscarnet (trisodium phosphonoformate, with men as well as for postexposure prophylaxis.
tion during DNA synthesis; it is missing hydroxyl groups
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Foscavir), unlike the previous drugs, which are nucleoside
on the ribose. The administered drug ddI is metabolized
analogues, is a pyrophosphate analogue (see Figure 35–3).
to ddATP, which is the active compound. It is effective
It binds to DNA polymerase at the pyrophosphate cleav-
age site and prevents removal of the phosphates from
HIV and is used to treat patients with AIDS who are
nucleoside triphosphates (dNTP). This inhibits the addi-
intolerant of or resistant to zidovudine. The main adverse
tion of the next dNTP and, as a consequence, the exten-
effects of didanosine are pancreatitis and peripheral
sion of the DNA strand.
neuropathy.
Foscarnet inhibits the DNA polymerases of all herpesvi-
5. Stavudine—Stavudine (didehydrodideoxythymidine,
ruses, especially HSV and CMV. Unlike acyclovir, it does
not require activation by thymidine kinase. It is useful in
termination during DNA synthesis. It inhibits DNA syn-
the treatment of retinitis caused by CMV, but ganciclovir is
thesis by the reverse transcriptase of HIV and is used to
the drug of first choice for this disease. Foscarnet is also
treat patients with advanced AIDS who are intolerant of
used to treat patients infected with acyclovir-resistant d4T, Zerit) is a nucleoside analogue that causes chain
or resistant to other approved therapies. The main
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mutants of HSV-1 and VZV.
adverse effect is peripheral neuropathy.
Inhibitors of Retroviruses
logue of guanosine that causes chain termination during
Nucleoside Inhibitors
DNA synthesis. It is available through the “expanded
The selective toxicity of zidovudine, lamivudine, emtric-
access” program to those who have failed currently avail-
itabine, didanosine, zalcitabine, stavudine, abacavir, and
able drug regimens. Abacavir is used in combination with
tenofovir is based on their ability to inhibit DNA synthesis
either a protease inhibitor, typically darunavir and ritona-
by the reverse transcriptase of HIV to a much greater
vir, or zidovudine plus lamivudine. The main adverse
extent than they inhibit DNA synthesis by the DNA poly-
effects are liver damage and severe hypersensitivity reac-
merase in human cells. These drugs are collectively called
tions. Patients who have an HLA-B1701 allele are more
nucleoside reverse transcriptase inhibitors (NRTIs). The
likely to have a severe hypersensitivity reaction, such as
effect of these drugs on the replication of HIV is depicted
in Figure 35–2.
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should be tested for this gene before being prescribed
1. Zidovudine—Zidovudine (azidothymidine, Retrovir,
abacavir. If patients develop hypersensitivity symptoms,
AZT) is a nucleoside analogue that causes chain termina-
abacavir should be immediately and permanently
tion during DNA synthesis; it has an azido group in place
discontinued.
of the hydroxyl group on the ribose (see Figure 35–3). It
7. Tenofovir—Tenofovir (Viread) is an acyclic phospho-
is particularly effective against DNA synthesis by the
nate that is an analogue of adenosine monophosphate.
reverse transcriptase of HIV and inhibits the growth of
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