Page 398 - Review of Medical Microbiology and Immunology ( PDFDrive )

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mebooksfree.com mebooksfree.com mebooksfree.com indinavir, nelfinavir, ritonavir, saquinavir, tipranavir, and a 387 mebooksfree.com
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CHAPTER 45 Human Immunodeficiency Virus
prolonging life, improving quality of life, and reducing viral
load but does not cure the chronic HIV infection (i.e., rep-
combination of lopinavir and ritonavir). Protease inhibitors
when combined with nucleoside analogues are very effec-
lication of HIV within CD4-positive cells continues indefi-
nitely). Discontinuation of HAART almost always results in
tive in inhibiting viral replication and increasing CD4 cell
counts and are commonly used in HAART regimens. Lopi-
viremia (a return of the viral load to its pretreatment set
point) and a fall in the CD4 count.
navir inhibits the degradation of lopinavir thereby
increasing the concentration of lopinavir. A briefer way of
Nucleoside/Nucleotide Reverse Transcriptase
saying that is ritonavir “boosts” lopinavir.
Inhibitors (NRTIs) navir and ritonavir are given in combination because rito-
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Mutants of HIV resistant to protease inhibitors can be a
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Table 45–3 describes six nucleoside reverse transcriptase
significant clinical problem. Resistance to one protease
inhibitors (abacavir, didanosine, emtricitabine, lamivudine,
inhibitor often conveys resistance to all; however, the com-
stavudine, and zidovudine) and a single nucleotide reverse
transcriptase inhibitor (tenofovir). These drugs are charac-
lopinavir (Kaletra), is effective against both mutant and
terized by not having a 3′ hydroxyl group on the ribose ring
nonmutant strains of HIV. Also, darunavir is effective
and therefore are chain-terminating drugs. They inhibit
against many strains of HIV that are resistant to other pro-
HIV replication by interfering with proviral DNA synthesis
tease inhibitors. Mutants of HIV resistant to both protease
by reverse transcriptase. They cannot cure an infected cell
inhibitors and reverse transcriptase inhibitors have been
of an already integrated copy of proviral DNA. Additional
recovered from patients.
information on these “nucleoside analogue” drugs and the
A major side effect of protease inhibitors is abnormal
other antiretroviral drugs can be found in Chapter 35. Note
that zalcitabine (Hivid), an NRTI analogue of cytosine, is
back of the neck (Figure 45–6). The fat deposits in the
no longer available. fat deposition in specific areas of the body, such as the
back of the neck are said to give the person a “buffalo
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Two main problems limit the use of NTRIs: the emer-
hump” appearance. These abnormal fat deposits are a
gence of resistance and adverse effects. The main adverse
type of lipodystrophy; the metabolic process by which
effects are described in Table 45–3. For example, the long-
term use of zidovudine (ZDV) is limited by suppression of
infrequently used because of toxicity and nelfinavir is no
the bone marrow leading to anemia and neutropenia. This
longer recommended.
hematotoxicity is due to the inhibition of the mitochondrial
Treatment for acute HIV infection with two reverse
DNA polymerase. Nevertheless, ZDV is used in postexpo-
transcriptase inhibitors and a protease inhibitor is often
sure prophylaxis and to prevent vertical transmission from
used. With this regimen, the viral load drops below the
mother to fetus. Lamivudine and its analogue emtricitabine
level of detection, CD4 cell counts rise, and CD8 activity
have the same mechanism of action as ZDV but are better
tolerated, and one or another is a common component of
HAART. Abacavir is also commonly used. Patients who
have an HLA-B1701 allele are more likely to have a severe
hypersensitivity reaction to abacavir. Patients should be
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tested for this gene before being prescribed abacavir.
Nonnucleoside Reverse Transcriptase Inhibitors
Table 45–3 describes five nonnucleoside reverse transcrip-
tase inhibitors (delavirdine, efavirenz, etravirine, nevirap-
ine, and rilpivirine) that are effective against HIV. Unlike
the NRTIs, these drugs are not base analogues. Efavirenz
(Sustiva) and nevirapine (Viramune) are the most com-
monly used drugs in this class. Efavirenz is a common
component of HAART regimens, especially a single pill
containing efavirenz, tenofovir, and emtricitabine (Atri-
pla). Nevirapine is often used to prevent vertical transmis- FIGURE 45–6 Lipodystrophy—note enlarged fat pad on back
sion of HIV from mother to fetus. Both nevirapine and
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mebooksfree.com mebooksfree.com mebooksfree.com of neck. This is known as a “buffalo hump” and is an adverse effect of mebooksfree.com
efavirenz can cause skin rashes and Stevens-Johnson
syndrome.
the protease inhibitor class of antiretroviral drugs. (Reproduced with
Protease Inhibitors
permission from Wolff K, Johnson R. Fitzpatrick’s Color Atlas & Synopsis
Table 45–3 describes the currently available protease inhib-
of Clinical Dermatology. 6th ed. New York: McGraw-Hill, 2009. Copy-
itors (amprenavir atazanavir, darunavir, fosamprenavir,
right © 2009 by The McGraw-Hill Companies, Inc.)
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