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HIV & AIDS
Several other antiretrovirals adversely affect the bone marrow. Zalcitabine- with megaloblastic anemia, leucopenia, and thrombocytopenia.
47,48
Folinic
associated neutropenia has been reported in up to 17% of patients in acid is often dosed with pyrimethamine in order to decrease these effects.
clinical trials.
17–19
Didanosine, lamivudine, and delavirdine also cause Clinicians must be aware of bone marrow toxicity and exercise caution
neutropenia, but incidence rates are less than 10%.
19–22
Protease inhibitors when combining these drugs with AZT.
suppress the bone marrow as well, although at a much lower incidence
and severity. Indinavir causes neutropenia in rare cases, and is associated Sulfamethoxazole–trimethoprim (TMP/SMX), the drug of choice for the
with an anemia rate of less than 2%.
23,24
Saquinavir and nelfinavir have prophylaxis and treatment of Pneumocystis pneumonia, also affects
caused mild dose-related neutropenia in clinical trials, but this is usually not immune function. A higher than normal incidence of adverse reactions is
clinically significant.
25–27
associated with the use of TMP/SMX in patients with AIDS (up to
80%).
49–51
Patients with HIV infection have depleted intracellular
Nucleoside reverse transcriptase inhibitors (NRTIs), especially AZT, induce glutathione (GSH) concentrations, a molecule utilized by cells as a
apoptosis in the immune cell populations of HIV patients.
28,29
Viora and reducing agent for the detoxification of oxidative species—including the
colleagues found that AZT and dideoxycytidine (ddC) inhibit cell-cycle oxidative metabolites of SMX,
52–54
which has been linked to TMP/SMX
intolerance in HIV-infected patients.
53,54
Antiretroviral Drug–Drug Interactions—
In addition to the effects of the virus
Making Matters Worse
itself, iatrogenic suppression from HIV
Clinicians should use caution when considering potential drug–drug
interactions that could adversely affect immune function, particularly those
therapy, neoplasms, malnutrition, and
involving AZT. Combining AZT with agents that affect its metabolism can
some opportunistic infections can
lead to increased toxicity. Fluconazole, atovaquone, and methadone all
interfere with the clearance of AZT.
55–57
As is well known, protease inhibitors
adversely affect bone marrow cell
have the ability to inhibit cytochrome P450 (CYP) liver enzymes, which are
survival and replication.
responsible for the metabolism of many drugs.
58,59
Ritonavir is the most
potent inhibitor, but other protease inhibitors—including saquinavir,
indinavir, and nelfinavir—will also inhibit CYP3A4 to a clinically significant
degree. This inhibition has the potential to increase the exposure to drugs
progression and increase apoptosis in human peripheral blood mononuclear metabolized by this isoenzyme, which could lead to bone marrow
cells exposed to clinically relevant concentrations.
28
Several groups have also suppression if used with agents that cause this type of toxicity.
demonstrated that mitochondrial dysfunction in hematological cells is
associated with both AZT and didanosine due to the affinity of these Drugs used in combination with antiretrovirals can also increase the
agents for mitochondrial DNA polymerase gamma.
30–33
This induces an hematological toxicity of the drug independently of any pharmacokinetic
increased level of apoptosis by inducing mitochondrial membrane interactions. AZT used in combination with dapsone, clarithromycin,
hyperpolarization.
29,34
Conversely, protease inhibitors prevent AZT-induced gancyclovir, foscarnet, or TMP/SMX causes hematopoietic toxicity in animal
apoptosis.
35–38
Saquinavir, lopinavir, and indinavir increase and stabilize models due to additive toxicity.
60–64
While clarithromycin is clinically effective
mitochondrial membrane potentials, thereby protecting against apoptosis in in the treatment of MAC,
60,65
it has also been associated with a possible
activated T cells.
35
Therefore, with combination therapy, the addition of a
protease inhibitor could be beneficial not only to decrease viral replication
and mutation, but also through this direct effect on lymphocyte apoptosis.
Harm from drug exposure in patients
Immunotoxicity of Anti-infectives
infected with HIV is not exclusive to
Harm from drug exposure in patients infected with HIV is not exclusive to
antiretrovirals. Medications commonly used for prophylaxis and treatment
antiretrovirals. Medications commonly
of OI can adversely affect the bone marrow as well. For example, cidofovir
used for prophylaxis and treatment of
causes neutropenia in as many as 20% of patients using the drug for
cytomegalovirus (CMV) retinitis.
39
Use of the antiviral agent foscarnet causes
opportunistic infections can adversely
anemia, leucopenia, granulocytopenia, and thrombocytopenia.
40,41
However,
affect the bone marrow as well.
it is also associated with a much lower incidence of severe, dose-limiting
leucopenia than ganciclovir. Much of the toxicity of these agents is due to
their use in combination with AZT.
increased mortality rate in HIV-infected patients.
60,61
The use of AZT in
Agents that affect folic acid synthesis cause bone marrow toxicity and combination with ganciclovir causes an increased incidence of severe to life-
may contribute to immunosuppression in this patient population. threatening hematological toxicity. The conclusions of a study by Hochster
Severe hematological effects reported with dapsone use include and colleagues confirmed that patients receiving ganciclovir usually cannot
agranulocytosis, aplastic anemia, and hemolytic anemia;
42–44
trimetrexate tolerate the full recommended dose of AZT.
66
In a retrospective study of
causes a high rate of myelosuppression;
45,46
and pyrimethamine is associated 32 patients with HIV, combining didanosine with ganciclovir was much
18 US INFECTIOUS DISEASE 2007
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