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Management of Antiretroviral Therapy Focuses on Boosting Adherence, Minimizing Toxicities

Cheryl A. Thompson

Antiretroviral therapy against human immunodeficiency virus (HIV) has come a long way since zidovudine became available in 1987. Multiple agents with different mechanisms of action have been developed, and research has shown that the concomitant use of these drugs is the best way to reduce the amount of HIV present and increase the CD4+ T-cell count in infected patients. But as pharmacotherapy for HIV has advanced, said Lori D. Esch, clinical assistant professor at the University of Buffalo School of Pharmacy in New York, health professionals have come to recognize that there is a "disparity between drug efficacy" in clinical studies and "drug effectiveness" in practice.

"We're now appreciating that in order to make these drugs work ... the way they've been demonstrated to work in clinical studies, we need to use them appropriately," said Esch, who is also an HIV pharmaceutical care specialist at Erie County Medical Center in Buffalo. Complex regimens and undesirable adverse effects make antiretroviral therapy difficult to take as directed, she said. To optimize the available therapeutic tools, she said, practitioners—particularly pharmacists, as drug experts—must individualize antiretroviral regimens to improve patients' adherence and minimize toxicities.

Cooperation between patient and provider. Recognizing the importance of full adherence to antiretroviral therapy, HIV experts added a section on that topic to the revised treatment guidelines for adults and adolescents released in February. "Excellent adherence has been shown to increase the likelihood of sustained virologic control, which is important for reducing HIV-related morbidity and mortality," the guidelines state. "Conversely, poor adherence has been shown to increase the likelihood of virologic failure and has been associated with increased morbidity and mortality."

An updated version of "Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents" was released in February. The guidelines were developed by the Panel on Clinical Practices for Treatment of HIV Infection convened by the U.S. Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The document is available on the Web site of the HIV/AIDS Treatment Information Service.

The term "adherence," Esch said, implies that the patient has committed to stick to a regimen mutually agreed upon with the clinician. Thus, patient communication is essential to achieving high adherence to the medication regimen. An assessment of a patient's readiness to begin antiretroviral therapy is crucial, she said, because studies have shown that patients who declare up front that they cannot take the full assortment of medications tend not to. Through discussion with a patient, Esch said, a pharmacist can identify barriers to adherence and try to devise strategies to overcome them. Evaluating a patient's demographics, including age and lifestyle issues, can help a pharmacist to determine the type of support the patient will need when starting therapy.

Various drug regimens can suppress the viral load in a patient new to antiretroviral therapy, Esch said, as long as the doses are taken properly. "If you want to optimize adherence," she said, "you need to pick the regimen the patient's most likely to take."

One factor to consider when choosing drugs, said Courtney V. Fletcher, professor in the department of experimental and clinical pharmacology at the University of Minnesota in Minneapolis, is the potential for adverse effects. The practitioner should find out which adverse effects a patient is willing to endure and which the patient would prefer to avoid, he said, and choose the most suitable regimen.

Advances in drug formulation over the past few years have helped to simplify antiretroviral therapy. Whereas HIV regimens used to consist of "handfuls of pills," said Stephen C. Piscitelli, associate director of clinical pharmacology at Virco Labs in Rockville, Maryland, the use of combination products can now allow a patient to take as few as two tablets a day. Current combinations of dideoxynucleoside reverse transcriptase inhibitors include a tablet containing zidovudine, lamivudine, and abacavir and a tablet containing zidovudine and lamivudine. Unfortunately, Piscitelli said, patients whose infection does not respond to one of these regimens "have to go to something more complicated to try to get a response."

Another way to simplify drug regimens, Fletcher said, is to use a "pharmacokinetic strategy" that takes advantage of drug interactions to reduce dosing frequency. Dual protease inhibitor regimens use low doses of ritonavir to boost the plasma level of another protease inhibitor, such as indinavir. Indinavir usually must be taken every eight hours on an empty stomach, Fletcher said, but administration with ritonavir allows indinavir to be taken twice daily with food.

Once a regimen has been chosen, pharmacists play a key role in teaching patients how to take the antiretrovirals, Piscitelli said. The pharmacist must explain to the patient which drugs to store at room temperature and which to keep in the refrigerator, which ones to take with food and which on an empty stomach, which can be taken together and which must be taken at separate times, he said. By considering all of these factors, the pharmacist can help the patient devise a workable medication schedule.

Esch stressed the importance of "trying to fit the drugs into the patient's life." A twice-daily regimen may mean different things to different patients, she said, depending on each one's lifestyle. She suggested looking at a patient's daily routine to determine when the drugs can be taken most conveniently.

The products available for helping patients adhere to their medication regimens range from old-fashioned to high tech, Esch said. Traditional multisection pillboxes and scheduling cards may be sufficient to keep some patients on track. Those who require reminders can use simple beepers that go off once a day when it is time to take an easily forgotten dose or can employ more complex alarms that can be programmed to beep every time a dose should be taken.

Making the drugs more tolerable. Patients who suffer marked adverse drug effects may be less inclined to take their medications as prescribed. Since antiretroviral therapy has become a long-term undertaking, Fletcher said, "we're going to have to deal with ... a different set of toxicities now than we ... had to deal with in 1987," when a single agent was used for a short period of time. Minimizing these toxicities, some of which can be serious, has thus become an important part of managing antiretroviral therapy.

The Centers for Disease Control and Prevention has assembled articles and a video on the history of AIDS since the initial reporting of the condition 20 years ago.

One way to decrease toxicity is to start therapy later, Piscitelli said. "The method used to be 'Hit hard, hit early,'" he said, but it is unclear from clinical studies whether patients benefit more from starting antiretroviral therapy early or waiting. And the toxicities associated with long-term use have led patients to oppose even starting therapy. The revised HIV treatment guidelines reflect the shift in opinion to delaying the start of treatment. They now recommend that clinicians consider starting antiretroviral therapy in asymptomatic HIV-infected patients when the CD4+ T-cell count falls below 350 cells/mm3 or when the plasma HIV RNA level rises above 30,000 copies/mL (measured by branched DNA assay) or 55,000 copies/mL (using reverse transcriptase polymerase chain reaction [RT-PCR] assay). Previous guidelines recommended consideration of therapy for asymptomatic patients whose CD4+ T-cell count was less than 500 cells/mm3 or whose viral load was more than 10,000 copies/mL (branched DNA assay) or 20,000 copies/mL (RT-PCR assay).

Esch likes to classify the antiretroviral drugs' toxicities according to severity. The "nuisance toxicities" are uncomfortable for the patient but not life threatening; they include gastrointestinal upset and lightheadedness. The best way to manage these, Esch said, is "full disclosure to the patients of what they might expect." Because the consequences of stopping HIV therapy without medical advice can be so serious, she said, it is important for patients to know in advance what adverse effects may occur, what the symptoms mean, and what can be done about them. For example, when a young mother begins taking the nonnucleoside reverse transcriptase inhibitor efavirenz, Esch warns her that she may feel dizzy and unstable for the first few days of therapy and suggests that the woman plan to have help caring for her children until these effects subside.

More serious toxicities include lactic acidosis, dyslipidemias, loss of glucose control, and neuropathies. Practitioners should pay attention to these potential toxicities when selecting which drugs to prescribe, Esch said. This means minimizing the use of multiple drugs with the same toxicity and avoiding drugs that can exacerbate a patient's preexisting conditions, such as diabetes mellitus. Appropriate monitoring, including patient interviews and laboratory tests, can help identify toxicities early on.

When toxicities occur, Fletcher said, switching therapy is the main way to manage them. For example, a patient who has anemia during zidovudine therapy can take stavudine instead, while a patient who suffers peripheral neuropathy while taking stavudine can switch to zidovudine. This strategy can become more complicated when a patient is taking several drugs with the same toxicity, he said. "You try and see if you can identify what the offending agent might be," Fletcher said, and look for an alternative drug that has a smaller likelihood of causing the adverse effect.

In some cases, pharmacotherapy can be used to alleviate adverse effects. Esch advises patients to treat gastrointestinal adverse effects with nonprescription antidiarrheals. Fletcher said that anemia caused by zidovudine can be treated with epoetin alfa. Several studies have evaluated the use of cholesterol-lowering statins or gemfibrozil to treat the lipid abnormalities associated with antiretroviral therapy, Piscitelli said, with variable results. Atorvastatin and gemfibrozil have been found helpful in some patients, he said, but simvastatin interacts highly with the antiretrovirals. And always, he said, the addition of drugs to a regimen increases the patient's risk of toxicities and drug interactions.

Polypharmacy is a common concern in HIV therapy. In addition to antiretrovirals, HIV patients may be receiving treatment for other conditions, such as hypertension, hyperlipidemia, asthma, or chronic pain, Esch said. The combination of multiple drugs can lead to problems including duplication of therapy, drug interactions, and overlapping toxicities, she said, so medication profiles must be reviewed on a regular basis. Although many drug interactions have been studied, she said, "there certainly haven't been studies on every drug that we use in HIV [therapy]," and it is unlikely that there ever will be. Pharmacists can draw upon their knowledge of drugs' mechanisms of action and metabolism to try to predict how drugs will interact, Esch said, and then intervene to prevent the interactions.

Other ways of minimizing the toxicities associated with antiretroviral therapy are under investigation. Researchers are looking at protocols for interrupting treatment in a structured manner, Fletcher said. And relationships between drug concentrations and either efficacy or toxicity are being studied, he said, to determine whether therapeutic drug monitoring can be used to decrease toxicities or enhance the response to antiretroviral therapy.

—Tzipora Lieder

Benefits of Antiretrovirals Outweigh Adverse Effects, Say Federal Officials

Type 2 diabetes mellitus, kidney stones, wasting syndromes—these are some of the serious complications associated with the use of antiretroviral drugs to treat AIDS patients. Nevertheless, "all of these side effects can be identified and responded to and very rarely require the discontinuation of medication," said Eric Goosby, director of the Office of HIV/AIDS Policy, Department of Health and Human Services.

Goosby made this observation on May 30 during a national conference call addressing the effects that AIDS has had on the United States over the past 20 years. Joining him was Surgeon General David Satcher.

Goosby said drug therapy has made a real difference in the lives of patients with AIDS. Early in the epidemic, he said, patients could expect to live for about two years after being diagnosed with full-blown AIDS. Nowadays, Goosby sees patients who had AIDS in 1994 and "are still doing well in 2001 with continued antiretroviral therapy."

"With the use of antivirals," he said, "we have situations where, without a doubt, we are changing the natural history of the infection." Goosby noted that there is a "whole slew" of new antiviral drugs in the developmental pipeline.

Although this is good news, Satcher said it is not good enough. "It is of major concern that there are ... 300,000 people out there who are infected [with HIV] who don’t know it, and another 250,000 to 300,000 people who ... know they are infected but are still not on treatment," he said.

—Kate Traynor