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AIDS Drug Interactions: Part II


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 and toxoplasmosis.

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 (Valium, Ativan).

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.[1] 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 MAC prophylaxis.[2] 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 prevent toxicity.

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.[3] 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 breakthrough seizures.[4] Anti-CMV Drugs 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.[5] Oral ganciclovir has been reported to be associated with an increased risk of pancreatitis if administered in association with ddI.

2. Foscarnet: 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.[6] Anti-toxoplasmosis Drugs 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 one.

Conclusion 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; 15(6):1066-8.

5 Lee BL, et al. Clinical Infectious Diseases. 1992; 14(3):773-9.

6 Youle MS, et al. The Lancet. 1988; 1(8600):1455-6.

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Copyright © 1994 -Gay Men's Health Crisis, Publisher. All rights reserved to Gay Men's Health Crisis (GMHC) Treatment Issues. Reproduced with permission. Treatment Issues is published twelve times yearly by GMHC, INC. Noncommercial reproduction is encouraged. Subscription lists are kept confidential. GMHC Treatment Issues, The Tisch Building, 119 West 24th Street, New York, NY 10011 Email GMHC. Visit GMHC

Information in this article was accurate in August 10, 1994. The state of the art may have changed since the publication date. This material is designed to support, not replace, the relationship that exists between you and your doctor. Always discuss treatment options with a doctor who specializes in treating HIV.