Adherence to Protease Inhibitor Therapy and Outcomes in Patients with HIV Infection

Improved therapeutic strategies, including the introduction of protease inhibitors, have led to a striking decrease in HIV-related morbidity and mortality (1, 2). It is widely believed that adherence to an antiretroviral regimen is central to the likelihood that a patient will derive sustained benefit from therapy (3, 4). Conventional wisdom holds that two groups of patients are currently experiencing clinical and virologic failure. The first group consists of patients who have received multiple different antiretroviral drugs over a prolonged period of time and who may be infected predominantly with HIV strains that are resistant to multiple drugs. The second group comprises patients who adhere poorly to their antiretroviral regimen. The two groups are not mutually exclusive: Patients with suboptimal adherence may be more likely to have antiretroviral drugresistant HIV infection. The potential public health importance of adherence to therapy in prevention of transmission of drug-resistant virus has also been emphasized (5). Patients with suboptimal adherence to antiretroviral therapy and poor adherence to use of safer-sex practices, such as use of condoms, may infect others with their own antiretroviral drugresistant virus. Anecdotal experience suggests that physicians may be unwilling to prescribe combination antiretroviral therapy to patients whom they perceive to be at high risk for poor adherence (6). Given the critical importance of adherence to therapy to patient outcome, secondary prevention of HIV infection, and willingness of providers to prescribe therapy, we prospectively investigated the association between protease inhibitor adherence and patient outcome, factors related to adherence, and the accuracy of physicians' prediction of patient adherence. We used a microelectronic monitoring system to assess adherence to antiretroviral therapy. Methods Study Sample The study was conducted at the HIV clinics of the Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, and University of Nebraska Medical Center, Omaha, Nebraska. The HIV physicians at these clinics were primary care providers for the study patients. Each site also had a dedicated HIV nurse coordinator. From August 1997 to March 1999, we enrolled consecutive patients with HIV infection who were already receiving a protease inhibitor (experienced patients) or who were to begin taking a protease inhibitor (naive patients). Exclusion criteria were inability to give informed written consent; expectation of continued use of a medication organizer to include protease inhibitors; and residence in a nursing home, jail, or hospice, where medications were dispensed at least daily. Collection of Baseline Data At baseline, a study investigator used medical chart review to complete a 52-item questionnaire for each patient. The questionnaire covered demographic information (age, sex, ethnicity, risk factors for HIV infection, educational and employment status, income), medical history (years known to be HIV infected; opportunistic infections; history of schizophrenia, depression, or bipolar affective disorder), and medication use (name, dose, and frequency of all antiretroviral agents, other antimicrobials, and other prescription therapies). The enrolling physician assessed use of illegal drugs and nonprescription therapies (including herbal or alternative therapies) by interview. Alcohol abuse was assessed by using the CAGE questionnaire (cutting down, annoyance with criticism, guilty feelings, and use of eye-opener drinks) (7). Information about use of adherence aids (such as personal reminders by significant others or timers, alarms, or other devices) was specifically sought. The investigator asked study patients if they felt that their current symptoms were attributable to HIV infection, the antiretroviral medications, or both. In addition, patients were asked whether they agreed with such health beliefs as Do you think your antiretroviral therapy will make you live longer? At baseline, each patient completed the Beck Depression Inventory and the General Health Questionnaire (8, 9), well-validated measures of psychiatric morbidity that have been widely used in patients with HIV infection (9-11). Patients completed the inventories as a written task without the assistance of a physician or clinic nurse. At baseline, we used the following question to elicit a prediction of adherence to protease inhibitor therapy from the patient's primary HIV physician and clinic nurse: Do you think that the patient is compliant with antiretroviral therapy, that is, taking greater than 80% of the prescribed doses of antiretroviral medications? This prediction was made after collection of the baseline information but before actual measurement of adherence using the microelectronic monitoring system had begun. Collection of Follow-up Data Every 3 months for the duration of the study, the study participants were asked whether any of the following had changed since their previous visit: employment, use of alcohol or illegal drugs, residence, attribution of symptoms to the antiretroviral therapy or HIV infection, and changes in medications. Patients completed a new Beck Depression Inventory and General Health Questionnaire. The primary HIV physician determined whether the patient had developed an opportunistic infection in the past 3 months. Laboratory Testing At baseline and every 3 months for the duration of the study, HIV RNA levels were measured by using the Roche Amplicor System (Roche Diagnostics, Nutley, New Jersey) and CD4 lymphocyte subpopulation assays were performed. Assessment of Adherence Adherence was measured by using the Medication Events Monitoring System (MEMS) (Aprex, Union City, California). The MEMS TrackCap system consists of standard medication bottles that have a pressure-activated microprocessor in the cap (12). The microprocessor records each opening and lists the date, time, and duration of opening. The information on medication dosing is retrieved by scanning the cap over a purpose-built communicator module. The information is then stored in a database provided by Aprex. Although the MEMS TrackCap system cannot prove consumption of the drug by the patient, prolonged deception by patients has been shown to be unlikely (13). Patients were provided with a MEMS TrackCap bottle for each prescribed protease inhibitor (including refrigerated ritonavir capsules). Use of the MEMS TrackCaps system was not possible for patients who were prescribed ritonavir from August 1998 onward because ritonavir capsules were no longer available. The patients could use their regular medication organizer for all other medications. The caps were scanned each time the patient presented to the HIV clinic. Patients were specifically instructed not to take extra doses out at any time (for example, not to take out an extra dose in the morning for consumption at lunchtime). Patients were offered small pill bottles that could be easily carried in a coat pocket. Adherence rates were defined as the number of doses recorded by the MEMS TrackCap divided by the total number of doses prescribed during the monitoring period. To evaluate the effect of dosing frequency on adherence, dosing interval errors were defined as medication doses taken at a time other than that prescribed (that is,<9 hours or>15 hours after the previous dose of a medication prescribed every 12 hours or<5 hours or>11 hours after the previous dose of a medication prescribed every 8 hours) (12). Definitions of Virologic and Clinical Outcomes Virologic failure was defined as an HIV RNA level greater than 400 copies/mL at the last study visit. Changes in CD4 lymphocyte counts were calculated as the difference between the count at the baseline visit and the count at the final study visit. Opportunistic infections were defined according to Centers for Disease Control and Prevention criteria (14). Hospitalization for all causes was recorded as the number of nights spent in any acute-care hospital; nursing homes and drug or alcohol rehabilitation facilities were excluded. Mortality was defined as all-cause mortality at any time during the study period. Statistical Analysis All data was entered into a computerized database, PROPHET Statistics Version 6.0 (AB Tech Corp., Charlottesville, Virginia). The chi-square or Fisher test was used to compare categorical variables. Continuous variables were examined by using the t-test or the MannWhitney test. Baseline and follow-up values were compared by using the paired t-test or the Wilcoxon signed-rank test. To examine the relation between two continuous measures, a best-fit line was obtained. The slope of this line was then tested against the null hypothesis of a slope of zero. The Pearson correlation coefficient was also calculated. Cox proportional-hazards regression was used to evaluate the relation between adherence and time to virologic failure. In the Cox model, predictor variables found to be significant (P<0.1) in univariate analysis were added to the model. Logistic regression models were used to assess the effects of multiple variables on adherence. Factors were entered into the regression model if they were found by univariate analysis to be significantly associated (P<0.1). To analyze time to return of detectable HIV RNA for patients with an undetectable viral load at baseline, KaplanMeier survival curves were computed for less than 95% adherence and 95% or greater adherence and were compared by using the MantelCox test. The McNemar test was used to compare the predictions of the clinical nurses and physicians. Ethical Considerations The study was approved by the institutional review boards of the two study centers. Patients were fully informed that their adherence to protease inhibitor therapy was being measured by using the MEMS TrackCap system. Results Patient Characteristics Of 99 patients enrolled in the study, 6 withdrew before follow-up data were collected (4