Obstacles to Treatment Success
Until it is possible for individuals with HIV to safely stop taking antiretrovirals, those who have started treatment must continue for the foreseeable future. Many factors contribute to the success or failure of a long-term treatment regimen. Among the most basic of these are the health care provider's ability to prescribe drugs correctly and the individual's ability to adhere to the prescribed regimen.
This June, a national survey by Johns Hopkins University and the University of California at San Francisco of 476 physicians found that between January and March of 1998, 25% of treatment-
Another concern was highlighted in a study presented in September at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) by Bonnie Purdy, Pharm.D., and colleagues, of the Albany Medical Center (abstract I-169). The researchers found that health care providers frequently prescribed medications incorrectly. One hundred prescribing errors in 81 patients were documented over a 31-month period. The most common mistakes were over- or under-
Seventy-three percent of errors were considered serious or severe and 21% were noted as clinically significant. The mistakes appeared to result from the increasing complexity of treatment regimens and error rates increased from 2% in 1996 to 7% in 1997 to 14% in the first seven months of 1998. Dr. Purdy stated that interns (first-year residents) wrote most of the prescriptions. This suggests that not only do less experienced health care providers prescribe treatments that are not consistent with the recommended guidelines, but when writing up the prescription orders, there is a potential for further errors in dosing or administration.
Another factor that affects the outcome of a treatment regimen is the patient's own capacity for adherence. At ICAAC, Margaret Chesney, Ph.D., from the University of California at San Francisco, reported on several different methods employed to track adherence (mini-
Patient self-report is perhaps the simplest technique. It does overestimate adherence. However, it tends to be 99% accurate when a patient reports nonadherence and should be considered seriously. Since patients may experience memory problems, it is most effective when focused on the recent past. Computer-
Pill counts and assays of plasma drug levels are not particularly useful measures of adherence. Pill counts usually underestimate nonadherence. Plasma drug levels generally only measure the last dose taken, especially if the drug has a short half-life. (A novel approach for monitoring long-term drug levels in hair was presented by a French group. There was a correlation between high indinavir levels in hair samples and complete virologic response -- abstract A-71).
Dr. Chesney discussed what is perhaps the most effective method of measuring adherence last. This technique uses an electronic monitoring system or MEMS cap. A computer chip is placed in the cap of the medication bottle. The time and date is recorded each time the bottle is opened and is counted as one dose taken. The major drawback with MEMS is that more than one dose may be taken out of the bottle at a time to be used throughout the day. This will only be recorded as one dose. The system is also expensive and requires specific software for interpretation. A useful feature of MEMS is that the computer chip generates a chart of each patient's adherence by day and time that can then be plotted against viral load fluctuations.
A study presented by Kathleen Melbourne, Pharm.D., of the University of Rhode Island, compared monitoring adherence with MEMS to patient self-report in 50 participants (abstract I-175). Both methods showed a high level of patient adherence (over 90%) with prescribed medication doses over a three-month period. However, patient self-
Factors Affecting Adherence
Several studies at ICAAC attempted to unravel the factors that affect an individual's ability to consistently comply with rigid medication schedules. One such study, presented by David Paterson, M.D., of the Veterans Administration (VA) Medical Center in Pittsburgh, PA, assessed adherence to a protease inhibitor-
In this group, active depression was associated with poor adherence. Another VA Medical Center in Columbia, South Carolina, reported similar findings in a six-month prospective study conducted in 48 participants (abstract I-215). Higher depression scores correlated with lower adherence and higher viral loads.
Interestingly, the total number of pills per day that a regimen requires was not associated with adherence. Median adherence was equivalent in the twice-
The English study found that the impact of drug and alcohol use was great, with 29% of the cohort reporting missing one-fifth of their doses because they were "too stoned or drunk to take their medications."
The researchers also reported a connection between increasing time on treatment and decreasing adherence. Only half of participants who were 100% compliant for less then two years, remained so after two years. This May, a national survey conducted on 665 HIV-
Correlation between Adherence and Viral Load
Emerging data are confirming an association between adherent behavior and enhanced viral suppression. (Although it is unclear if patients with detectable viral loads are less adherent because they are discouraged by a poor virologic response and unmotivated to continue rigid dosing schedules or whether poor adherence on their part led to the detectable viral loads.) Successful adherence has been traditionally defined as 80% of doses taken. This may not be sufficient for protease inhibitor-
Median baseline CD4 count was 296 and 31% of the 45 study participants had viral loads below 400 copies/ml. Participants with greater than 95% adherence (defined as missing 1 dose in 20), had the best chance of achieving a viral load below 400 copies/ml at three months follow-up. The chances of virologic failure increased as more doses were missed. The differences between the categories were highly statistically significant.
Mark Shelton, of the State University of NY at Buffalo, reported a similar trend in a larger group of 295 patients who self-reported adherence during clinic visits (abstract I-170). Viral load was significantly lower among those with greater adherence with a direct relationship between number of missed doses and viral load. In addition, the proportion of patients with undetectable viral load was highest among those who reported no missed doses (45% of the group reported perfect adherence).
A study presented at the Retrovirus Conference in Chicago in February by Pablo Tebas, M.D., from Washington University in St. Louis, Missouri, determined that among 66 participants studied for at least six months, 75% were adherent to 85% or more of the drug regimen (abstract 149). Adherence to one drug correlated well with adherence to other drugs in the regimen and with the likelihood of a patient having a complete virologic response. In the study group, response to the regimen was similar across all stages of HIV disease. Patients with more advanced disease were as likely as patients with early infection to be adherent to their treatment regimens.
Finally, in a late breaker ICAAC presentation by Julio Montaner, M.D., of St. Pauls's Hospital, Vancouver, patient data from three clinical trials were analyzed to assess the effect of adherence on the duration of virologic suppression (abstract LB 10). Study subjects were classified as nonadherent if they took less than 75% of their medications prior to one or more visits. All participants had viral loads below 1,000 copies/ml at the start of the analysis period. After 48 weeks of treatment, over 80% of the adherent participants remained below 1,000 copies/ml, compared to about 50% of the nonadherent participants. This difference was statistically significant. In this population, adherent behavior increased the likelihood of maintaining virologic suppression.
Improving the Odds
It is difficult to determine average adherence to combination therapy in a "real world" setting because of the relatively inexact measuring techniques utilized and the lack of standardized classifications of levels of adherence. However, it is apparent that the more adherent a person is to his or her regimen, the more likely he or she is to experience durable and effective viral load suppression (90% adherence seems to be the emerging gold standard).
Poor adherence appears to be more closely associated with factors such as depression and active alcohol and drug use than with number of pills or frequency of doses. These conditions should be diagnosed and treated in conjunction with, or prior to, the initiation of antiretroviral therapy. Many of those who are expected to adhere to treatment do not, so physicians should negotiate a treatment plan to which their patient commits, provide specific education and monitor their patients' on-going experiences. Finally, interventions to assist in the long-term maintenance of adherence are crucial. Even a viral load below the limit of detection may not be enough incentive to keep taking pills ad infinitum. It would be worthwhile for HIV-
1. Sackett DL and Snow JS. Compliance in Health Care. Baltimore: Johns Hopkins University Press, 1979, page 18.
2. Gallant J and Block D. Journal of the International Association of Physicians in AIDS Care. May 1998; 4(5):32-5.