GMHC Treatment Issues 1994 Aug 10; 8(7): 3
People with HIV commonly take several medications at the same
time to fight both HIV and its related conditions. These drugs
can interact with each other, leading to more toxic side
effects and reduced effectiveness. Last month's Treatment
Issues (July 1992; volume 8, no. 6) presented the first part of
this article, surveying antiretroviral drugs, drugs for
pneumocystis pneumonia and antifungal drugs. We conclude this
month with drugs for mycobacteria (TB and MAC), cytomegalovirus
TB and MAC Drugs
1. INH (Isoniazid): INH is the mainstay in the treatment and
prevention of tuberculosis. Its main toxicities are hepatitis
and peripheral neuropathy. Liver damage seems to be more common
in persons over the age of 35, those who consume a lot of
alcohol and those who also are taking rifampin for TB. Liver
enzyme levels in the blood must be monitored when INH is taken
along with rifampin and/or pyrazinamide, a combination used for
treating active TB. INH is usually discontinued when liver
enzyme test results are five times the upper limit of normal,
signaling severe liver inflammation.
Peripheral neuropathy is also common with INH, but can be
avoided if it is taken along with vitamin B6 (pyridoxine).
Aluminum-containing antacids can decrease the absorption of INH
and reduce the compound's effect. INH on the other hand can
inhibit liver enzymes that metabolize certain drugs, leading to
increased blood levels of such medications as Dilantin,
Tegretol, Coumadin, theophylline and the benzodiazepines
Skin flushes due to inhibition of histamine metabolism by INH
occur in some patients who eat certain fishes or cheeses while
receiving the drug. Finally, the body metabolizes INH more
quickly in the presence of alcohol and steroid medications
(prednisone). This could result in decreased effectiveness.
2. Rifampin and rifabutin: These anti-TB and anti-MAC drugs are
fraught with potential drug- drug interactions. Physicians must
administer them extremely carefully in order to achieve their
therapeutic effects and avoid interfering with other,
concurrent therapies. Several studies have found rifampin to
have a greater incidence of side effects among HIV-positive
patients as compared to HIV-negative controls.
Rifampin decreases the blood levels of such common drugs as
ketoconazole, dapsone, atovaquone, fluconazole,
corticosteroids, oral contraceptives, cyclosporine, Coumadin,
methadone, theophylline, levothyroxine, digoxin, quinidine and
propanolol. If possible, these drugs' blood concentrations
should be monitored when patients take them along with
rifampin. Dosages require upward adjustment in most cases in
order to maintain effectiveness. Rifabutin seems to have fewer
drug-drug interactions than rifampin, yet like INH can change
liver enzyme production and thus alter the metabolism of the
drugs mentioned in the previous section. In addition, lowered
blood levels of AZT have been observed in rifabutin trials for
3. Ciprofloxacin: This drug is used for the treatment of MAC
and multi-drug resistant TB. Concomitant administration of
antacids that contain aluminum or magnesium hydroxide (Mylanta
or Amphogel) can lead to the formation of insoluble chelates
that prevent the drug's absorption, reducing its level in the
blood. Another drug that decreases the absorption of
ciprofloxacin is sucralfate, a stomach ulcer remedy that should
not be taken along with ciprofloxacin. Ciprofloxacin in
contrast can increase the absorption and blood levels of
theophylline (an asthma remedy). Theophylline blood levels
should be monitored, and its dosage may require reduction to
4. Clarithromycin: Decreased AZT blood levels have occurred
with this MAC drug, but the clinical significance of this
reduction are unknown. Clarithromycin can increase theophylline
and Tegretol blood levels, resulting in added toxicity form
these drugs. Another MAC drug, rifabutin has recently been
shown to lower clarithromycin levels.
4. Clofazimine: This is another drug for MAC. It can decrease
the rate of rifampin absorption and thus reduce its effects. In
addition, it lowers Dilantin levels, which has led to
1. Ganciclovir (Cytovene): Ganciclovir's main toxicity is bone
marrow suppression leading to low neutrophil and platelet
counts. Drugs with similar effects on the bone marrow should
not in general be prescribed at the same time unless the
benefits are felt to outweigh the risks. These include AZT,
amphotericin, pyrimethamine, amphotericin, dapsone,
flucytosine, imipenem-cilastatin, pentamidine, Bactrim,
vinblastine, vincristine and adriamycin. Fortunately, the
advent of agents like G-CSF (Neupogen) that help increase white
blood cell production has made it possible to administer
ganciclovir together with many of these drugs without running
the risk of bone marrow suppression. G-CSF is usually started
when the total neutrophil count is at 750 or below and
continued until the count is near or above the normal range.
Another drug-drug interaction seen with ganciclovir and
imipenem- cilastatin, an antibiotic used to treat severe
bacterial infections, is seizures.
Oral ganciclovir has been reported to be associated with an
increased risk of pancreatitis if administered in association
Foscarnet can cause kidney dysfunction, reduced blood levels of
calcium and phosphorus, anemia and nausea. The necessity of
avoiding other kidney-damaging drugs, pentamidine,
aminoglycoside antibiotics and amphotericin B, needs to be
underscored. If these drugs are prescribed concomitantly with
foscarnet, then patients must undergo hydration with
intravenous fluid (usually saline).
Hydration may also prevent the formation of the penile ulcers
occasionally noted with foscarnet, which are due to the local
irritant effect of the drug in the urine. Another observed
interaction is that of foscarnet and pentamidine together can
lower blood calcium levels, a condition that can lead to
seizures and spasms.
1. Pyrimethamine: Pyrimethamine in combination with
sulfadiazine is the mainstay for the treatment of
toxoplasmosis. Unfortunately its most important toxicity is
bone marrow suppression (causing neutropenia and
thrombocytopenia), and it can interact with other drugs that
also harm the bone marrow. In order to save the bone marrow
from the toxic effects of the drug, which are predominantly
from depression of the normal metabolism of folate caused by
the combined action of pyrimethamine and sulfa drugs, folinic
acid (or calcium leucovorin) is given along with pyrimethamine.
2. Atovaquone and Clindamycin: See the section on PCP in part
Drug-drug interactions are a complex system of effects that
arise when patients receive several drugs concurrently.
Individuals with HIV disease often require multiple drugs to
combat different opportunistic infections, to treat the
underlying HIV infection or for treatment of symptoms
(antacids, pain medications etc.). This puts them at high risk
of using drugs which interact with each other with the end
result being a less than desired effect or increased toxicity
and adverse effects.
Ways of coping with these interactions include more frequent
blood tests of drug concentrations, adjusting the dosage of the
drug if it is known to have a lower blood level in the presence
of the second drug, or avoiding combinations that interact,
which last can be achieved by substituting drugs with similar
therapeutic activity but lacking the interaction. For example,
substituting fluconazole for ketoconazole when a patient is
also receiving ddI will sidestep the issue of ketoconazole
malabsorption induced by the buffer in the ddI formulation.
Fluconazole does not require acidity for its absorption.
Sometimes no alternatives are available, and interacting
substances must be administered together. Repeated blood tests
may then be the only way to detect early signs of compound drug
effects on organs like the bone marrow and the kidney.
Alternatively, the dosages of the interacting drugs may be
adjusted, and physicians can add drugs such as G-CSF to avoid
the combined toxicities.
1 Soriano E, et al. AIDS. 1988; 2(6):429-32.
2 Narang P, et al. Eighth International Conference on
AIDS. Amsterdam, 1992; abstract PoB 3888.
3 Hafner R. personal communication.
4 Cone LA, et al. Clinical Infectious Diseases. 1992;
5 Lee BL, et al. Clinical Infectious Diseases. 1992;
6 Youle MS, et al. The Lancet. 1988; 1(8600):1455-6.
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