Journal of Gerontological Nursing

Geropharmacology 

Recognizing and Preventing Drug Interactions in Older Adults with HIV

Susan M McLennon, MSN, ARNP-CS; Rachel Smith, MSN, FNP-CS; Joanne J Orrick, PharmD, BCPS

Abstract

Older adults face the added challenge of drug interactions among HIV and AIDS medications and those used to treat conditions associated with aging.

Abstract

Older adults face the added challenge of drug interactions among HIV and AIDS medications and those used to treat conditions associated with aging.

The U.S. population who are infected with human immunodeficiency virus (HIV) is aging, largely because of improved efficacy of antiretroviral medications and treatment regimens. In addition, from 1991 to 1996, new acquired immune deficiency syndrome (AIDS) cases among adults older than 50 were diagnosed at twice the rate found among those ages 13 to 39 (Centers for Disease Control [CDC], 1998). This 22% increase in the 50-years-and-older population of HIV-infected individuals accounts for 15% of the entire AIDS population, or 66,200 cases (Ory& Mack, 1998).

Predictably, diseases associated with aging, such as vascular disease, hypertension, hyperlipidemia, depression, gastroesophageal reflux disease, and impotence, are also being diagnosed and treated in older dults who are infected with HIV. Thus, a significant potential exists for drug interactions between the medications used in the treatment of HIV and AIDS - including highly active antiretroviral therapy (HAART) and medications used to prevent and treat opportunistic infections - and those used to treat the common conditions of aging (Szirony, 1999). Because so few providers are expert at managing both HIV-related and general medical conditions, individuals with HIV usually obtain health care from both an infectious disease specialist and a primary care provider (Lieberman, 2000).

Table

TABLE 1ANTIRETROVIRAL DRUG CLASSIFICATION, DOSAGE, AND ADVERSE EFFECTS

TABLE 1

ANTIRETROVIRAL DRUG CLASSIFICATION, DOSAGE, AND ADVERSE EFFECTS

This division of care adds to the difficulty of choosing and monitoring these multiple medications. Nurses must take into account the risk for potentially harmful drug interactions. This article is intended as a guide for gerontological nurses facing these complexities. The general goals of HAART therapies and the mechanisms of drug interaction are discussed briefly. The remainder of the article is devoted to a detailed discussion of interactions that may occur with specific combinations of antiretroviral medications and medications used to treat conditions commonly associated with aging.

GOAL OF HIV THERAPY

The primary goal of therapy in HIV infection is to prolong life through maximal suppression of HIV replication. This goal is achieved by using an individualized combination of antiretroviral agents designed to minimize side effects while maximizing effectiveness and quality of life (Bartlett & Gallant, 2000). Combinations of antiretroviral agents attack the virus at multiple sites via different mechanisms. This treatment optimally results in both a reduced viral load (VL) to less than 50 copies/mL and an increased CD4+ cell count to a minimum of 350 cell/mm3, but preferably to within the normal range of 500 to 1,400 cells/mm (CDC, 2002; Szirony, 1999). Thus, a greater VL and lower CD4+ cell count results in an increased risk for opportunistic infections.

According to the most recent guidelines for the use of antiretroviral agents, there are three different options for initiating treatment in individuals who have not been treated with antiretrovirals previously. The options include combining two nucleoside reverse transcriptase inhibitors (NRTIs) with a single protease inhibitor (PI), with a combination of PIs, or with a nonnucleoside reverse transcriptase inhibitor (NNRTI) (CDC, 2002). Consult the Department of Health and Human Services guidelines for specific recommendations at http://www.aidsinfo.nih.gov. The CD4+ cell count and the VL are the recommended laboratory tests for disease staging, prediction of progression, monitoring response to the treatment regimen, and therapeutic decision-making related to treatment and prophylaxis for opportunistic infections (Bartlett & Gallant, 2000). Viral load indicates the actual amount of virus in the blood and is usually measured with the HIV RNA polymerase chain reaction assay (Bartlett & Gallant, 2000).

MECHANISMS OF DRUG INTERACTIONS

Drug interactions can be classified into two major categories: pharmacodynamic and pharmacokinetic. Pharmacodynamic interactions alter or increase the pharmacological effect of one or more of the drugs on the body. If the result is additive therapeutic efficacy, then the interaction is beneficial. For example, choosing combinations of antiretrovirals from different classes increases the potency of the regimen. If, however, therapeutic antagonism or additive adverse effects caused by overlapping toxicities occurs, the interaction can be detrimental. Pharmacokinetic interactions, which are more common, alter the concentration of active drug in the body. Pharmacokinetic interactions can affect the drug absorption, distribution, metabolism, or excretion (Dresser, Spence, & Bailey, 2000; Piscitelli & Galliano, 2001).

Pharmacokinetic interactions involving either induction or inhibition of the metabolism of a drug occur frequently and can have clinically significant results. Induction results from an increase in the synthesis of drug-metabolizing enzymes and can decrease the plasma concentration of the drug, adversely affecting therapeutic efficacy. Drug metabolism inhibition results in increased plasma concentrations of the drug, an effect that can be beneficial if it enhances the therapeutic efficacy of drugs with poor bioavailability.

One example of this beneficial effect is the use of ritonavir to increase plasma concentrations of saquinavir hard gel capsules (Invirase®). In fact, Invirase should not be used without ritonavir because of its poor bioavailability. Ritonavir is commonly combined with other PIs, such as saquinavir soft gel capsules (Fortovase®), indinavir, and amprenavir to decrease pill burden and potentially improve adherence to therapy. However, drug metabolism inhibition may also increase adverse effects, thus becoming detrimental (Piscitelli & Galliano, 2001).

For drugs hepatically metabolized, the cytochrome P450 (CYP) enzymes account for the majority of the oxidative metabolism. More than 12 families of CYP enzymes exist in humans. The CYP 1, 2, and 3 are responsible for the majority of the oxidative metabolism of these drugs. The CYP3A4 enzyme is one of the most important enzymes involved in drug metabolism and drug interactions because it is responsible, in total or in part, for metabolizing 60% of oxidized drugs. Other important CYP subfamilies include CYPl A2, CYP2C9, CYP2C19, and CYP2D6 (Dresser et al., 2000).

Table

TABLE 2INTERACTIONS OF ANTIRETROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

TABLE 2

INTERACTIONS OF ANTIRETROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

Table

TABLE 2INTERACTIONS OF ANTIRE1ROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

TABLE 2

INTERACTIONS OF ANTIRE1ROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

ANTIRETROVIRAL THERAPY AND DRUG INTERACTIONS

Currently there are three classifications of antiretroviral agents: NRTIs, PIs, and NNRTIs. The usual adult dosages and common adverse effects of the Food and Drug Administration-approved antiretroviral agents are listed in Table 1.

NRTIs

The NRTIs inhibit viral replication through competitive inhibition of the reverse transcriptase enzyme, thereby preventing the formation of viral DNA from RNA. All of the NRTIs, with the exception of abacavir, undergo renal elimination and, therefore, are not involved in CYPmediated drug interactions common with the NNRTI and PI classes. Abacavir and alcohol are metabolized by alcohol dehydrogenase; therefore, individuals taking abacavir should be discouraged from consuming alcohol because of the increased risk for adverse effects.

Because of the magnesium buffer in the non-enteric-coated formulation of didanosine (Videx®), didanosine is also involved in pharmacokinetic interactions that can decrease the absorption of other medications, such as fluoroquinolones, dapsone, delavirdine, indinavir, and itraconazole. The timing of the administration of agents whose absorption is affected by the magnesium-containing buffer should be adjusted according to the manufacturer's recommendations. Alternatively, the enteric-coated formulation of didanosine (Videx EC®) can be used instead as a way to avoid these interactions. Tenofovir has been shown to increase systemic levels of the buffered and enteric-coated formulation of didanosine. The dose of didanosine should be decreased to 250 mg QD when combined with tenofovir (Kearney, 2003).

Most of the interactions involving other NRTIs - zidovudine, didanosine, stavudine, and zalcitabine - are pharmacodynamic interactions involving additive toxicity with other agents having a similar adverse effect profile. Zidovudine interacts with agents such as ganciclovir, antineoplastic agents, and flucytosine to create an additive bone marrow suppressive effect. Zalcitabine, stavudine, and didanosine can interact with drugs such as isoniazid, cisplatin, vincristine, pentamidine, hydralazine, and phenytoin to create an additive neurotoxic effect. Zalcitabine, stavudine, and didanosine can also interact with other drugs such as alcohol, pentamidine, valproic acid, loop diuretics (e.g., furosemide and thiazide diuretics) leading to an increased risk of pancreatitis.

NNRTIs

The NNRTIs inhibit viral replication through noncompetitive inhibition of the reverse transcriptase enzyme. All of the NNRTIs are metabolized by the CYP3A4 enzyme. Table 2 summarizes the most common potential drug interactions between NNRTIs and other medications that may be used in individuals with HIV. In general, the NNRTIs require routine monitoring for signs of hepatic toxicity.

PIs

The PIs are the most potent of the antiretrovirals, especially when used in combination with each other, and are responsible for the largest number of drug interactions. They prevent viral replication by preventing cleavage of the core viral proteins, leading to the formation of a noninfectious virion (Phair & Murphy, 1997). The PIs are metabolized by the CYP3A4 enzyme system and also may inhibit those enzymes. Ritonavir is the most potent inhibitor of the CYP3A4 enzyme system. Additionally, ritonavir and Kaletra® are metabolized, in part, by the CYP2D6 isoenzyme, and inhibit the enzymes CYP2D6, 2C19,2A6, 1A2, and 2El. Nelfinavir is also metabolized in part by the enzymes CYP2C19, 2D6,2C9,and2El.

Ritonavir is used in combination with other PIs to increase bioavailability, ease administration requirements, and decrease pill burden, which often requires dose adjustments. The PIs may also induce hyperglycemia, requiring routine blood glucose monitoring in all individuals using these agents. Additionally, insulin adjustments may be necessary in individuals with insulin-dependent diabetes mellitus. Individuals using PIs require routine monitoring for signs of hepatic toxicity. Monitoring is individualized depending on hepatic function and historical information, such as previous liver disease.

TREATMENT FOR CHRONIC DISEASE IN CONJUNCTION WITH ANTIRETROVIRAL THERAPY

All antiretroviral drugs have adverse effects that may be potentiated by the simultaneous use of other drugs. Thus, it is important for health care providers to be aware of all prescription and nonprescription medications their patients are taking. Particular care should be taken to elicit information about herbal products and other nontraditional remedies individuals may be using. Because older adults are at risk for age-related decline in drug metabolism and elimination, interactions between HAART and other medications used to treat chronic disease are more likely to occur in that population than in younger populations. Table 2 lists potential drug interactions between PIs and NNRTIs and medications used to treat conditions common in aging populations.

Many individuals with HPV use over-the-counter drugs, herbal products, and other complementary therapies in an attempt to boost immune function, improve memory, relieve fatigue, and alleviate other symptoms caused by HIV infection and treatments. However, little information is available to guide nurses about interactions between HAART and herbal products or other unregulated medications. Thus, providers should use caution when such interactions are possible. For example, St. John's Wort, an herbal product commonly used to treat depressive symptoms, may interact with PIs to decrease the blood levels of the PIs by as much as 81%, allowing the virus to proliferate (Phair & King, 2000). For the same reason, grapefruit juice should not be consumed at the same time as PIs (Phair & King, 2000).

Individuals receiving HAART may experience lipid abnormalities, a condition also common in many older adults. Lipodystrophy and lipid elevations have been found to increase the risk for cardiac disease in individuals with HIV infection (Phair & King, 2000). Hyperlipidemia should be treated in accordance with the intervention criteria listed in the guidelines of the National Cholesterol Education Program (Dube, Sprecher, & Henry, 2000). The fibrates gemfibrizol, fenofibrate, and Clofibrate are appropriate choices for treating isolated hypertriglyceridemia.

If therapy with a 3-hydroxy-3methylglutaryl-coenzyme A (HMGCoA) reductase inhibitor, or "statin," is required, pravastatin or fluvastatin may be used at standard doses. Alternatively, atorvastatin can be used, though individuals should be started on low doses (e.g., 5 mg to 10 mg per day) that should be titrated slowly, and the individuals should be carefully monitored for signs and symptoms of rhabdomyolysis (CDC, 2002). Lovastatin and simvastatin should not be used with the NNRTIs or PIs because of the risk of substantially increasing the level of statin and, thus, the risk for serious complications such as rhabdomyolisis. When using PIs, lipid profiles should be monitored at baseline and every 3 to 6 months thereafter (Steinhart, Orrick, & Simpson, 2002).

Impotence is common in older men with HIV. This condition may occur as a result either of complications of aging or of the 30% to 50% reduction in testosterone levels associated with HIV infection (Dolin, Masur, & Saag, 1999). Sildenafil (Viagra®), metabolized by the CYP3A4 enzyme system, is commonly prescribed for erectile dysfunction. Protease inhibitors may interact with sildenafil to elevate systemic sildenafil levels through inhibition of metabolism. Therefore, when sildenafil is given in combination with any PI, the maximum recommended dose is 25 mg in a 48-hour period (Phair & King, 2000). Caution should also be exercised in prescribing the NNRTIs delavirdine or ef avirenz in combination with sildenafil because of the potential for a similar interaction.

Affective disorders, such as depression and anxiety, may be encountered in older HIV-infected individuals. Antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are often prescribed for depression; however, many of these drugs are metabolized via hepatic enzyme pathways, thus increasing the risk for interaction and toxicity with HAART. The levels of some SSRIs may be increased or decreased by agents that inhibit or induce the enzymes CYP3A4 or CYP2D6. Inhibition of SSRI metab- \ olism by agents such as the PIs and! the NNRTIs efavirenz and delavir- I dine can lead to increased levels of SSRI and an increased risk of SSRI i toxicity (e.g., the serotonin syndrome). Reduced levels of SSRIs I caused by induction of metabolism by agents such as efavirenz or nevirapine may lead to decreased efficacy, requiring dosage increases of the SSRIs. Conversely, some of the SSRIs can inhibit the metabolism of the PIs and NNRTIs, leading to increased levels of these drugs and the potential for toxicity. Paroxetine may be less likely than other SSRIs to interact with PIs or NNRTIs. There is insufficient information to make specific recommendations regarding dosage adjustments of the SSRIs and antiretrovirals when used concomitantly. Because the clinical significance of these drug interactions is not known, caution and close monitoring is recommended.

In addition, the antidepressant venlafaxine should be used with caution because it was shown to substantially decrease levels of indinavir (Levin et al., 2001). The mechanism of this interaction is not known and it is not known whether this interaction will occur between venlafaxine and other antiretrovirals. Tricyclic antidepressants, such as amitryptiline, can be used to treat depression or peripheral neuropathy in individuals with HIV. These agents are metabolized by the CYP2D6 enzyme. Therefore, their therapeutic levels may be increased by the PIs ritonavir and Kaletra, thus increasing the risk for signs of toxicity such as arrhythmias. Additionally, because of aging metabolism, elderly individuals may be at a higher risk for TCA-related toxicity. For this reason, these agents should be used cautiously - particularly in older adults taking ritonavir or Kaletra.

Benzodiazpines are commonly prescribed for older adults with HIV who experience anxiety. The benzodiazepines midazolam and triazolam should not be used with the any of the PIs or with the NNRTIs delavirdine or efavirenz because these agents inhibit the metabolism of the benzodiazepines, thus increasing the risk of adverse effects. Clinicians should consider the use of anti-anxiety agents less likely to interact with these antiretrovirals, such as lorazepam, oxazepam, or temazepam (Phair & King, 2000; Tseng & Fois, 1999).

Gastroesophageal reflux and gastritis are often seen in older adults. The use of antiretrovirals may also cause adverse gastrointestinal effects such as nausea, diarrhea, and reflux. Antacids (e.g., Turns®); histamine2 receptor blockers (H-2 blockers) famotidine, ranitidine, and nizatidine; or a proton pump inhibitor such as lansoprazole, omeprazole, or pantoprazole, may help control symptoms. However, all of these agents may also decrease the absorption of the NNRTI delavirdine, which requires an acid environment for adequate absorption. Delavirdine should thus be taken 1 hour before or 1 hour after antacids. Because of their suppression of acid production, chronic use of H-2 blockers or proton pump inhibitors in combination with delavirdine should be avoided if possible.

Atherosclerosis associated with aging may increase the risk for heart disease and hypertension. The antiarrhythmic agents flecainide, propafenone, quinidine, and amiodarone and the beta-adrenergic blockers propranolol, metoprolol, and timolol are metabolized by the enzyme CYP2D6. Thus, caution should be taken when setting the dosages of these medications when they are used in combination with the PIs ritonavir and Kaletra because of the risk of increased levels and toxicity.

The calcium channel blockers verapamil and diltiazem and the dihydropyridines (e.g., nicardipine, nifedipine, and nitrendipine) are metabolized by the enzyme CYP3A4 (Phair & King, 2000). The NNRTIs delavirdine and efavirenz and all of the PIs may potentially inhibit the CYP3A4 enzyme, leading to increased levels and toxicity of these medications. Providers should consider using alternative agents for individuals using these antiretrovirals. If one of these agents must be used, extreme caution should be exercised and individuals should be monitored for toxicity.

IMPLICATIONS FOR NURSES

Reasons cited in the literature for the increase in the number of new HIV cases among adults older than 50 are increased sexual activity, fewer preventive educational efforts targeted to this population as compared to younger populations, and delayed testing or late diagnosis. It is a common societal myth that older adults are not sexually active. In fact, older adults are living longer and healthier lives than any previous generation and many are engaging in risky sexual behaviors. Older adults are less likely to use preventive measures and may be more likely to use commercial sex workers than younger adults (Lieberman, 2000).

Women, in particular, are especially at risk when participating in unprotected sexual activity, because of an aging immune system coupled with vaginal tissue thinning (CDC, 1998; Gordon & Thompson, 1995; Lieberman, 2000; Woolery, 1997). Therefore, as the baby boomers age during the next 20 years, it is predicted that the population of older adults diagnosed with HTV will continue to increase.

Gerontological nurses will thus be confronted with increasing numbers of older adults seeking medical care for the chronic conditions associated with aging, concomitantly taking drugs for HTV infection. Nurses can facilitate effective coordination of care and prevention of potentially harmful drug interactions through communication with the clients' infectious disease specialists or other health care providers and through increasing their knowledge about the dynamics of, and anticipating, potentially harmful drug interactions.

The field of HIV/AIDS disease management is changing rapidly, largely because of persistent and successful research in the area of drug treatment. Tables 1 and 2 were compiled from a variety of resources. Web addresses have been provided in the Sidebar for readers interested in accessing the most current information.

REFERENCES

  • Bartlett, J.G., & Gallant, J.E. (2000). Medical management of HIV infection. Baltimore, MD: Johns Hopkins University, Department of Infectious Disease.
  • Centers for Disease Control and Prevention (CDC). (1998). AIDS among persons aged > 50 years: United States, 1991-1996. Morbidity and Mortality Weekly Report, 47(2), 21.
  • Centers for Disease Control and Prevention (CDC). (2002). Guidelines for using antiretroviral agents among HIV infected adults and adolescents: Recommendations from the panel on clinical practice for treatment of ?G?". Morbidity and Mortality Weekly Report, 51(RR07), 1-55.
  • Dolin, R., Masur, H., & Saag, M.S. (1999). AIDS therapy. New York: Churchill Livingstone.
  • Dresser, G.K-, Spence, J.D., & Bailey, D.G. (2000). Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clinical Pharmacokinetics, 38, 41-57.
  • Dube, M.P., Sprecher, Dn & Henry, WKn Aberg, J.A., Tornarti, F.J., Hodis, H.N., Schauten, J., Levin, J., Meyers, G., Zakin, R., Nevin, T., Currier, J.S., & the Adult AIDS Clinical Trial Group. (2000). Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus receiving antiretroviral therapy: Recommendations of the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group. Clinical Journal of Infectious Disease, 31, 1216-1224.
  • Gordon, S.M., & Thompson, S. (1995). The changing epidemiology of human immunodeficiency virus infection in older persons. Journal of the American Geriatrics Society, 43, 7-9.
  • Kearney, B.P., Isaacson, E., Sayre, J., Namami, H., & Cheng, A. (2003). Didanosine and tenofovirDF drug-drug interaction. Assessment of didanosine dose reduction [Abstract #553]. Presented at the 10th annual Conference on Retroviruses and Opportunistic Infections, Boston, MA.
  • Levin, G.M., Nelson, L.A., DeVane, CL., Preston, S.L., Eisele, G., & Carson, S.W. (2001 ). A pharmacokinetic drug-drug interaction study of venlafaxine and indinavir. Psychopharmacology Bulletin, 35, 62-71.
  • Lieberman, R. (2000). HIV in older Americans: An epidemiologic perspective. Journal of Midwifery and Womens Health, 45,176-181.
  • Ory, M.G., & Mack, K.A. (1998). Middle-aged and older people with AIDS: Trends in national surveillance rates, transmission routes, and risk factors. Research on Aging, 20, 652-665.
  • Phair, J.P., & King, E. (Eds.). (2000). HIV/AIDS annual update. New York: Medscape.
  • Phair J.P., & Murphy, R.L. (1997). Contemporary diagnosis and management of HIV/ AIDS infections. Handbooks in Health Care: Newtown, PA.
  • Piscitelli, S.C., & Galliano, K.D. (2001). Interactions among drugs for HIV and opportunistic infections. New England Journal of Medicine, 344, 984-996.
  • Steinhart, CS., Orrick, J.J., & Simpson, K. (2002). HIV/AIDS pHmary care guide. Gainesville, FL: University of Florida, Florida AIDS education training center.
  • Szirony, TA. (1999). Infection with HTV in the elderly population. Journal of Gerontological Nursing, 25, 25-31.
  • Tseng, AXn & Fois, M (1999). Significant interactions with new antiretrovirals and psychotropic drugs. Armals of Pharmacotherapy, 33, 461-73.
  • Woolery, WA. (1997). Occult HIV infection: Diagnosis and treatment of older patients. Geriatrics, 52,51-61.

TABLE 1

ANTIRETROVIRAL DRUG CLASSIFICATION, DOSAGE, AND ADVERSE EFFECTS

TABLE 2

INTERACTIONS OF ANTIRETROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

TABLE 2

INTERACTIONS OF ANTIRE1ROVIRAL DRUGS WITH OTHER MEDICATIONS COMMONLY USED WITH OLDER PATIENTS

10.3928/0098-9134-20030401-05

Sign up to receive

Journal E-contents