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Patient Compliance and Issues Related to Dosage and Administration

Patient Compliance

Patient compliance with recommended regimens (even when asymptomatic) is essential to the potential benefits of antiretroviral therapy. Adherence to antiretroviral regimens is an important determinant of both the degree and duration of virologic suppression. Excellent adherence has been shown to increase the likelihood of sustained virologic control, which is important for reducing HIV-associated morbidity and mortality. Poor adherence has been shown to increase the likelihood of virologic failure and can lead to the development of resistance and limit the effectiveness of antiretroviral therapy. There is evidence that nonadherence in patients receiving HAART is the strongest predictor of failure to achieve suppression of viral load to levels below the limits of detection. Several studies have shown that 90-95% of the doses in the antiretroviral regimen must be taken for optimal suppression, and lesser degrees of adherence are more often associated with virologic failure.

HIV-associated morbidity and mortality

A variety of factors may impact patient compliance with recommended antiretroviral regimens and/or compromise the effectiveness of the regimens, and these factors should be discussed with all patients. Factors that can impact patient compliance and/or antiretroviral efficacy include the complexity of the regimen (e.g., frequency of dosing, large number of doses and drugs required each day), dietary restrictions, palatability of the drugs, intercurrent illness that may affect GI absorption or require additional therapies (e.g., wasting, anorexia), adverse effects associated with the antiretroviral agents or other drugs the patient is receiving, drug interactions among the antiretroviral agents and/or with other drugs the patient is receiving (e.g., antimycobacterial agents), and adverse patient conditions or behaviors (e.g., depression or emotional crisis, active alcohol or substance abuse).

At the time antiretroviral therapy is initiated, patients should be advised of the importance of adhering to the recommended regimen. No patient should be automatically excluded from consideration for antiretroviral therapy simply because they exhibit a behavior or characteristic that may result in nonadherence. Instead, the likelihood of patient compliance to a complex drug regimen should be discussed and determined by the individual patient and clinician before therapy is initiated. To achieve the level of compliance necessary for effective therapy, clinicians are encouraged to utilize strategies for assessing and assisting adherence that have been developed in the context of chronic treatment for other serious diseases. Intensive patient education regarding the critical need for compliance should be provided, specific goals of therapy should be established with mutual agreement, and a long-term treatment plan should be developed with the patient. Intensive follow-up is necessary to assess compliance with the regimen and to continue patient counseling for the prevention of sexual and drug injection-related transmission. The guidelines published by the Panel on Clinical Practices for Treatment of HIV Infection (available at http://www.aidsinfo.nih.gov) should be consulted for additional information on strategies to improve compliance with antiretroviral regimens, including patient-related strategies, clinician-related strategies, and regimen-related strategies.

Once- and Twice-Daily Regimens

Once- or twice-daily antiretroviral therapy is desirable for patient convenience and compliance, especially since nonadherence to less convenient regimens may impact development of resistance during therapy. Based on currently available agents, antiretroviral regimens that involve twice-daily dosing are now feasible for most patients and these regimens have been evaluated in clinical studies. Although once-daily regimens are appropriate when the pharmacokinetic profiles of the antiretroviral agents support once-daily administration, long-term data are lacking for once-daily regimens and longer follow-up is needed to support routine use of these regimens. In addition, there are concerns about the possible consequences of missed doses with once-daily antiretroviral regimens since this might affect acquired resistance during therapy.

Antiretrovirals that are labeled by the US Food and Drug Administration (FDA) for twice-daily dosing include abacavir, amprenavir, didanosine, enfuvirtide, fosamprenavir, lamivudine, the fixed combination of lopinavir and ritonavir, nelfinavir, nevirapine, stavudine, zidovudine, the fixed combination of lamivudine and zidovudine (Combivir®), and the fixed combination of abacavir, lamivudine, and zidovudine (Trizivir®). In addition, twice-daily regimens of amprenavir (with low-dose ritonavir), fosamprenavir (with low-dose ritonavir), indinavir (with low-dose ritonavir), or saquinavir liquid-filled (soft gelatin) capsules (with low-dose ritonavir) are recommended. Although ritonavir is labeled for use in a twice-daily regimen, experts no longer recommend use of full-dose ritonavir as the sole HIV protease inhibitor in antiretroviral regimens because of GI toxicity associated with this dosage.

Based on pharmacokinetic data, NRTIs that can be administered once daily include didanosine, emtricitabine, lamivudine, and tenofovir disoproxil fumarate; some experts suggest that abacavir has the potential for once-daily administration but further study is needed. Efavirenz is the only NNRTIs currently recommended for once-daily administration; although nevirapine has potential for use in once-daily regimens. Atazanavir is the only HIV protease inhibitor currently labeled for once-daily administration, although once-daily regimens of amprenavir or fosamprenavir with low-dose ritonavir have received FDA approval. Saquinavir with low-dose ritonavir also has the potential for once-daily administration but further study is needed.

Administration Instructions

The fact that some antiretrovirals can be administered without regard to meals (abacavir, amprenavir, delavirdine, efavirenz, emtricitabine, fosamprenavir, lamivudine, nevirapine, stavudine, tenofovir, zalcitabine, zidovudine) while others should preferably be given with a meal (atazanavir, lopinavir and ritonavir, nelfinavir, ritonavir, saquinavir) or in the fasting state (didanosine, indinavir) to maximize bioavailability should be considered when selecting an antiretroviral regimen.Regimens requiring an empty stomach numerous times daily may be difficult for patients with wasting, and regimens requiring high fat intake may be difficult for patients with lactose intolerance or fat aversion.

All drugs in the antiretroviral regimen should be started simultaneously (ideally within 1 or 2 days of each other). Sequential introduction of individual drugs in an effort to increase patient compliance should be avoided since incomplete suppression of viral replication may result in emergence of resistance. While dose escalation regimens are recommended when initiating ritonavir or nevirapine therapy and, in some cases, ritonavir and saquinavir regimens, all other drugs should be initiated using usually recommended dosages.

Underdosing or irregular dosing should be avoided since this may result in less than optimal suppression of HIV and increase the risk of emergence of resistant strains and disease progression. To the extent possible, antiretroviral regimens should be simplified by reducing the number of daily doses and by minimizing drug interactions and adverse effects.

Patients receiving antiretroviral therapy must be evaluated continuously for toxicity and disease progression. If an antiretroviral agent must be discontinued for an extended period of time because of intolerable adverse effects, drug interactions, unavailability of a particular drug, or first trimester of pregnancy, it has been suggested that it may be advisable to discontinue all antiretroviral agents simultaneously, rather than continuing the antiretroviral regimen using only 1 or 2 of the agents, to minimize the potential for emergence of resistant HIV.

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