FACTORS AFFECTING ADHERENCE TO ANTIRETROVIRAL THERAPY IN HIV POSITIVE INJECTION DRUG USERS (IDUs) AND NON-IDUs

The study of adherence to antiretroviral therapy among HIV positive Injection Drug Users (IDUs) has been largely neglected. Many clinicians believe that this group is too unreliable to take these medications, particularly in the early stage of their recovery from drug abuse when they are vulnerable to relapse. This is the first study of its kind to compare medication adherence rates between HIV positive injection drug users and non-users. The medication adherence among IDUs and non-IDUs was compared in an HIV infected population (n=143) who were currently on antiretroviral therapy. The factors affecting medication adherence were also examined in the same population. Data on demographics, clinical characteristics, mood status, physical functioning and social support was obtained. Medication adherence was measured using the "Temptation to skip antiretroviral medication scale" and "Percent of doses missed in the past week, month and three months". Multiple T-tests conducted on the data revealed that IDUs and non-IDUs had no distinction in medication adherence behavior (p<0.05). Therefore, further group difference analyses such as multiple T-tests and Chi-Square tests were done on all other independent variables to look for possible confounders.

( ( ACKNOWLEDGEMENTS As is the case with any research, this project is the result of the collaborative effort, guidance and support of many people. To acknowledge a few and leave out the rest would be inequitable. Having said that, it would be impossible to name every person that has contributed towards this venture. Nonetheless, I wish to express my sincere gratitude towards some unique individuals without whose help this project would have never reached fruition.
To begin with, I would like to profoundly thank my major advisor, Dr. Cynthia Willey, for her invaluable and timely advice. She was the one who introduced me to the exciting field of Epidemiology. She was always there to encourage and assist me whenever I felt that I had reached a dead end. I am truly grateful to Dr. Norman Campbell for his constant support both inside and outside the academic field. It has been a pleasure and an honor to interact and work with you. Thank you for watching over me. Adherence, often used interchangeably with compliance, is the act, action, or quality of being consistent with administration of prescribed medications [Altice FL et al, Ann Intern Med, 1998]. Non-adherence may mean not taking medication at all, taking reduced amounts, not taking doses at prescribed frequencies or intervals, or not matching medication to food requirements [Altice FL et al, Ann Intern Med, 1998].
Critical data on exactly how much adherence to antiretroviral therapy is enough, and how little is too little, are lacking [Sherer R, JAMA, 1998]. However, the association between poor adherence and virologic failure with resistance has been clearly established [Sherer R, JAMA, 1998;Montaner Jet al, 1996].
Adherence to HIV therapies presents special issues that result from the biology of HIV, the magnitude of therapeutic effort, and the changing demography of HIV infection [Altice FL et al, Ann Intern Med, 1998]. The replication of the virus is rapid and highly error-prone, resulting in great species diversity and new drug-resistant mutants unless replication is completely suppressed. Cross-resistance among drugs within a therapeutic class limits future treatment options. Thus, the development and transmission of antiretroviral-resistant species carries potentially disastrous public health consequences. In theory, if patients are 100% adherent to potent combination therapy, viral replication will most likely be halted and development of drug-resistant mutants is unlikely. However, in patients who intermittently or irregularly take drugs, the likelihood of selection of mutants that are resistant to drugs increases, a consequence of both continuing viral replication and selective automicrobial pressure [Friedland G, JAMA, 1998]. Thus, improvement in adherence is thought to be key to preventing the emergence of drug-resistant viruses that compromise therapeutic benefit and may be transmitted to others. The cost of interventions to enhance adherence is minimal compared with the cost of the therapies themselves and should be weighed against the costs to individual patients and to society resulting from compromised therapeutic benefit [Altice FL et al, Ann Intern Med, 1998].
The study of adherence to antiretroviral therapy among HIV positive injection drug users (IDUs) has been largely neglected. Many clinicians believe that this group is too unreliable to take these medications, particularly in the early stage of their recovery from drug abuse when they are vulnerable to relapse [Bangsberg D et al, JAMA, 1997;Malow RM et al, Psyc Serv, 1998]. However, no studies have clearly demonstrated this association. Several complex factors influence adherence to antiretroviral medications in HIV positive IDUs. In order to develop interventions that would maximize adherence to antiretroviral therapy in IDUs, it is essential to consider the factors affecting adherence in this group of people.
This study will determine if IDUs are less adherent than non-IDUs towards HIV therapies and will identify factors associated with adherence.

B. Determinants of Adherence
Over the years, researchers have determined several factors associated with medication adherence in general. These factors can be broadly categorized as patient characteristics, clinical characteristics and psychological and emotional characteristics.
Patient Characteristics: Sociodemographic variables such as age, sex, education, income, race and ethnicity have shown some correlation with adherence but not consistently and not at significant levels Davis, 1968;Haynes et al, 1979]. Majority of the studies on medication adherence show no association between noncompliance and lower socioeconomic status, poor education and older age . Social support is probably the most important factor among patient characteristics associated with adherence [Friedland G, 1998].
Clinical Characteristics: Haynes (1979) has commented after critically reviewing the literature that there are few obvious associations between disease features and compliance. The one association between illness and nonadherence that is consistently reported is that when patients get better from an illness they are less likely to adhere to the treatment [Heinzelman, 1962;Johnson, 1973;Prien & Caffey, 1977].
Psychological and Emotional Characteristics: These are said to play a greater role in determining medication adherence than demographic characteristics. One of the important characteristics in this group is Mood Status.
Mood Status: A level of anxiety either too low or too great may well be related to noncompliance [Evans L et al, Drugs, 1983]. Studies in HIV suggest that psychosocial stress associated with the illness adversely affects the quality of life in HIV patients [Fawzy et al, 1989;Holland et al, 1985;Solomon et al, 1989] To summarize, many factors have been associated with medication adherence, including patient characteristics, clinician-patient relationship, type of disease, treatment regimen, and clinical setting Ickovics JR, et al, 1997]. Gender, age, race, socioeconomic status, educational level, and a history of past substance use are not predictors of poor adherence to treatment, although active drug or alcohol use are [Sherer R, 1998;Klaus BD, 1997]. Adherence improves with a relationship with a trusted, accessible physician; this is particularly critical for the care of ID Us [Sherer R, 1998;O' Connor PG, 1994]. Asymtomatic and chronic diseases are less likely to have high rates of adherence, and complex treatment regimens decrease adherence ]. The organization of clinical services can affect adherence, including availability of expertise, linkages with drug treatment and mental health services, flexibility in the hours of operation, and the presence of nonjudgmental and supportive staff Morse EV, 1991].
Compared with therapies for other chronic diseases, which are often forgiving of lapses in adherence, HIV therapy is unforgiving ]. This is because, under the selective pressure conferred by imperfect adherence to antiretroviral therapy, drug-resistant mutants rapidly emerge.

C. Assessment of Adherence
There is no ideal method to assess drug compliance. Four methods, commonly used to measure compliance, are as follows:  [Norell SE, Soc Sci Med, 1981 ]. When compared with other measures the interview tends to overestimate adherence [Dunbar J, 1984]. A review conducted by Adams and Soumerai states that in 87% of 37 comparisons, self-reported adherence rates exceeded the objective rates, resulting in a median overestimation of adherence of 27% [Adams AS et al, 1999]. Using face-to-face interviews for patients' reports about medication-taking behavior have been found to get higher quality information than do survey instruments [Ickovics JR et al, 1997].
Pill Count: Corrigan and Strauss described the method of counting tablets to determine patient medication behavior in 1936 in a study of iron treatment for anemia . Since then, several techniques based on the same principle have been described. This method involves a comparison of the medicine left in the patient's bottle and the quantity that should have been left if the medication had been taken. Though this method is being used extensively, it is not believed to be very accurate. Patients may empty the pillbox, or take all the remaining pills before their clinic visit [Gray L et al, 1998].
Drug Assay: The accuracy of this method depends in part on the half-life of the drug [Gray L et al, 1998]. This means that it depends on how soon the drug reaches the systemic circulation so as to be detected in a drug assay. Longer-acting indicators have been used, but testing will show only past ingestion and not frequency or dosing interval. These studies are very inconvenient and can be expensive. Patient-to-patient variability is another disadvantage of this method. Some patients may object to having their blood specimen taken, regarding this as unnecessary and intrusive. Again the value of assessing compliance in this way depends greatly on the reliability of the method by which the drug is identified or quantified in body fluids ].

Medication Event Monitoring System (MEMS):
This method provides a computer chip in the cap of the medicinal bottle. Information is recorded each time the bottle is opened. Data from the MEMS allows calculation of 1) the compliance rate, 2) prescribed frequency, and 3) prescribed interval. This method also does not directly measure whether the medication was taken by the patient; hence the accuracy of this method is suspect [Gray L et al, 1998]. A study of adherence in patients on antiretroviral therapy revealed that while the overall compliance rate was 82% to 86%, more detailed measures of the fraction of doses taken at the prescribed daily interval (55-77%) and fraction of doses taken at the prescribed dosing interval (27%) were lower [Friedland G, JAMA 1997].

Veterans' Affairs Medical Center in Providence, RI, which currently provides care
to approximately 60 HIV seropositive men.
For the purposes of this study, we were interested only in persons taking antiretroviral medications. Therefore two subjects who were on a protease inhibitor alone were dropped from the study population. This reduced the population size to 143 subjects.

B. Data Collection
Patients meeting the above criteria who visited one of the three sites were asked to fill out a standardized questionnaire. The patients were told that the questionnaire was about how they think and feel about the HIV related medications that they were taking, and about different strategies that people use to take their medications. They were given the choice of filling out the questionnaire at home and mailing it in or returning it to the clinic, or filling it out at the clinic. They were also told that they would each receive a gift certificate of $20 after they had filled out the questionnaire.
The data was collected during the year 1996-97. Similarly, scores on questions a, e, g and i were added to get the raw score of each individual on Vitality, Energy or Fatigue. Finally, transformed scores on each of the two measures were obtained by using the following formula: Transformed scale= (actual score -lowest possible score)* 100 Possible raw score range Social support: Support in the form of financial support and emotion support was assessed using the following two questions: 1. How many of your family or friends can you count on for emotional support?
2. How many of your family or friends can you count on for financial help?
D. Assessment of Medication Adherence: Two measures were used to assess medication adherence. They are as follows: 1. Temptation to skip medication: This scale was developed to measure the selfreported likelihood of non-compliance (Willey, C et al, manuscript in progress The correction consists of adjusting the significance level by correcting for the number of tests. The adjusted significance level is alpha/k, where alpha is the desired significance level and k is the number of hypotheses being tested.

RESULTS
A total of 145 patients were enrolled in the study. One hundred and forty three (143) patients were on antiretroviral therapy, which comprised the study population. As seen from Only 13% (19/136) patients had T-cell counts less than fifty. More than half the study sample (66%) had been diagnosed as HIV positive for a period of 5 years or more.
Descriptive statistics for the mood status variables of the study population are given in Table 3. The median score on both the General mental health variable and the Vitality, energy or fatigue variable was 0.392 and the values ranged from 0 to 1.
Only 4% (5/143) patients reported having very severe bodily pain in the past four weeks. Thirty three percent (47/143) patients reported that pain had not interfered with their normal work in the past four weeks [ Table 4].
As seen from Table 5, the median value for number of persons giving emotional support was 8 and it ranged from 0 to 60. The median value for number of persons giving financial support was 3 and it ranged from 0 to 22.
A. Table 6 summarizes the results of the Multiple T-tests carried out on all the continuous IVs to check for group differences between the two groups -IDUs and Non-IDUS: The variables age (p=0.0127), years of education (p=0.0373) and general mental health (p=0.0084) were found to be significantly different between IDUs and non-IDUs at the 0.05 level of significance.
B. Injection drug users and non-users showed no significant differences in medication adherence at the p value of less than 0.05 on the temptation to skip medication due to side effects, due to lack of social support, when feeling good, and the total scale. Neither did they show significantly different medication adherence behavior (a=0.05) when measured using percent of doses missed during past week, during the past month and during the past three months.
D. Table 9 summarizes the results of multiple ANCOV As for the Temptation to skip medication due to side effects scale and the variable of primary interest (IDU/non-IDU): The ANCOVAs were found to be non-significant at the p-value of 0.05.
E. Table 10 summarizes the results of multiple ANCOV As for the Temptation to skip medication due to lack of social support scale and the variable of primary interest (IDU/non-IDU): The ANCOVAs were found to be non-significant at the p-value of 0.05 .

22
F. Table 11 summarizes the results of multiple ANCOV As for the Temptation to skip medication when feeling good scale and the variable of primary interest (IDU/non-IDU): The ANCOVAs were found to be non-significant at the p-value of 0.05 G. Table 12 summarizes the results of multiple ANCOV As for the Temptation to skip medication Total scale and the variable of primary interest (IDU/non-IDU): The ANCOVAs were found to be non-significant at the p-value of 0.05.
H. Table 13 summarizes the results of multiple ANCOV As for the Percent of doses missed during the past week and the variable of primary interest (IDU/non-IDU): The ANCOV As were found to be non-significant at the p-value of 0.05.
I. Table 14 summarizes the results of multiple ANCOV As for the Percent of doses missed during the past month and the variable of primary interest (IDU/non- The ANCOVAs were found to be non-significant at the p-value of 0.05. J. Table 15 summarizes the results of multiple ANCOV As for the Percent of doses missed during the past three months and the variable of primary interest (IDU/non-IDU): 23 The ANCOV As were found to be non-significant at the p-value of 0.05.
K. Table 16 summarizes the results of multiple ANCOV As for the Health Model using health related variables as covariates versus IDU/Non-IDU: The ANCOV As were found to be non-significant at the p-value of 0.05.
L. Table 17 summarizes the results of multiple ANCOV As for the Full Model using all the independent variables as covariates versus IDU/Non-IDU: The ANCOVAs were found to be non-significant at the p-value of 0.05.

DISCUSSION
This study examined differences in adherence to antiretroviral therapy among HIV positive injection drug users and non-injection drug users. Two measures of medication adherence were employed for this purpose. They were ' Temptation to skip medication' (due to side effects, due to lack of social support, when feeling good, and Total scale) and ' Percent of doses missed' (during the past week, during the past month, and during the past three months).

A. Differences in medication adherence among IDUs and non-IDUs:
Interestingly, there were found to be no significant differences m medication adherence between IDUs and non-IDUs for this study population on any of the adherence measures used. This result is in absolute opposition to what has been hypothesized by several clinicians in the past, who believe that HIV positive IDUs are less adherent to their medication regimens than non-users. This disparity was thought to be due to confounding variables in the data, which in all probability could be masking the relationship between medication adherence and injection drug use.

F. Differences in support variables among IDUs and non-IDUs:
No differences were seen in support variables between IDUs and non-IDUs.
All the variables that showed significant differences between IDUs and non-IDUs were thought of as being possible confounders.
Hence, the relationship between medication adherence and injection drug use was again examined after controlling for all the variables that showed significant differences between the two groups (ID Us & non-ID Us) of individuals.
However, no significant differences were found between IDUs and non-IDUs on any of the measures of medication adherence, even after controlling for the possibly confounding factors.

G. Limitations:
The limitations of this study include use of cross-sectional and self-reported data, small sample size and skewed data (probably due to selection bias). In addition, there is no gold standard to measure compliance and researchers are still debating over the acceptable range of values for compliance rates in the case of HIV positive patients.
Self reported data: People may be inaccurate in reporting their behavior. There may be multiple factors influencing them in terms of their ability and desire to provide a valid response. These factors may include clarity of questions, setting, memory, literacy and mood status.

Measurement:
Although there seems to be no gold standard or satisfactory way to measure medication adherence, the questionnaire has been designed to cover every aspect of the patients' moods, disease status, demographics, temptations, etc. which can help us in determining the factors affecting medication adherence to the best of our ability.
Selection Bias: The data obtained from the questionnaires were found to be very compliant. This could be the result of selection bias due to which only the more compliant HIV positive individuals filled out the survey questionnaires.

CONCLUSIONS
The objective of this study was to compare medication adherence rates in injection drug users and non-users. This study is the first of its kind to compare medication adherence between HIV positive injection drug users and non-injection drug users.
This study reported no significant differences in medication adherence between injection drug users and non-users. While in the past researchers have held the belief that there exists a negative relationship between injection drug use and medication adherence, no study has been carried until now which actually compares medication adherence rates between IDUs and non-IDUs. indicate that although injection drug users are no less adherent than non-users, they are not being given the optimum treatment required due to erroneous beliefs about their ability to comply with complex medication regimens.
( However, the results of this study cannot be generalized to the entire population due to limitations such as cross-sectional, self-reported data and small sample size. In addition, it could be due to selection bias that this study found no differences in medication adherence between IDUs and non-IDUs.

SECTION I BACKGROUND WFORMATION
The first section of this questionnaire asks about your background.
-Please circle or fill in the correct response for each question. (1/4-9) (1/10-11) ( We would like to ask you about each medicine that you are currently taking. Pleasefill out the following 2 page medicationformfor each medicine that you checked on the above list.  . .

MEDICATION #3
M EDICIN E NAME _ _ _ _ _ _ _ __ _ _ _ _ _ l. This medicine is for:  If you are taking more than one antiviral medication NOW. please answer these questions for the medicine that ts most dlfficu.Ufor .you to take, andjill in the name of that medicine here (9/1-201 If you have discontinued your antiviral medication. please answer these ques· tions for the medicine that you took most recently. andfiU in the name of that medicine here (9/21-40l Taking medications as directed (the prescribed amount taken at the right time) is not alway~ easy. At one time or another most people simply forget to take a dose of their medication. and sometimes .people discontinue taking their medications for a while. The following Is a llst of possible advan-"tages and disadvantages of taking antiviral medications as directed .
For each numbered statement. please mark one box with an ·x:to rate HOW .IMPORTANT that statement ts to you when you are thinking about whether to take your anliuirol medication as directed. 14. I worry that taking.all the doses that are presi::rtbed might not be good for me.
16. I worry that the antiviral medication Is doing more harm than good.
18. It may be hard on my system. if I take my antlviiaI medication as directed. ..
Sometimes people take their medlcatlons as directed for n while, and then stop taking them for a while.
-The following 2 questions are about h ow you are Lalcing your anliuiral medication RIGHT NOW.
21. Do you consistently take your antiviral medication as directed? ("as directed" means takJng your medication at the right lime and taking the prescribed amounl) ..... 22. How long have you been taking your antiviral medication as directed?
(10/l) a. 0-3 months b. 4-6 months c. 6-12 months d. more than 12 months Now here arc some situations that might affect whether you take your antiviral medication for HIV Infection as directed.
For.each situation. please ritark one box with an "X" to rate HOW TEMPTED you would be to skip your antiviral medication or talce a dose which is different from the one prescribed.
24. When you are anxious about side effects.
26. When you wonder whether you really need your medication.
28. When you experience minor side effects. 34. When your medical condition doesn't seem that bad. -46. When your family or friends don't seem Interested In whether you take your medication.

When
· 48. When your Insurance doesn•t cover the cost of your medication.
50. When you worry that taking too many medications might be bad for your health.
52. When you worry that the chemicals in the medication might harm or hurt your body.       -!J you have discontinued your antHnfective medication. please answer these questions for the medicine that you took most recently, andf tU in the name of that medicine here (11/28-47) Taking medications as directed (the prescribed amount taken at the light time) Is not always easy.
At one time or another most people simply f9rget to take a dose of their medication. and sometimes people discontinue taking their medications for a while. Tue following ls a list of poSslble advantages and disadvantages of taking anti-infective medications as directed .
..... For each numbered statement. please mark one box with an ·r to rate HOW IMPORTANT that statement is to you when you are thinking about whether to tal<e your 011ti·in[ective medication as directed.   harm or hurt your body. · The following statements represent some thoughts and experiences that people have when they are taking anti-Infective medications on a regular basis. Think about your thoughts ;nd experiences during the past month.
_. For each numbered statement please mark one.box with an ·;x:to best desaibe HOW OFTEN that thought occurs or has occurredfor you during the past month.    -If you are taJdng more than one protease Inhibitor medication NOW. please answer these questions for the medlc!ne that ls most dl.ffii;:ultfor you to take. andfiU ln the name of that medicine here (13/1-201 -If you have discontinued your protease lnhibitor medication. please answer these questions for the medicine that you took most recently. and fill in the name of that medicine here (13/21-40) Taking medications as directed (the prescribed amount taken at the right time) ls not always easy.

VERT OFTEN
At one tlme or another most people simply forget to take a dose of their medication. ahd sometimes people discontinue taking their medlcatlons for a while. The following ls a list of possible advantages ·· and disadvantages of taking protease lnhlbltor medications as dlrected.
-+-For each numbered statement. please. mark one box with an ·r to rate HOW .IMPORTANT that statement is to you when you are thinking about whether to take your protease Inhibitor medication as directed.   Sometimes people take their medications as directed for a while, and then stop taking them for a while.
-Thefollowing 2 ques tions are about how you are ta1cing your protease inhibitor m edication RIGHT NOW.
2 L Do you consistently take your protease Inhibitor medication as directed? ("as directed· means taking your medication at the right Ume and taking the prescribed amount) (  46. When your family or friends don't seem Interested In whether you take your medication.
48. When your Insurance doesn't cover the cost of your medication.
50. When you worry that taking too many medications might be bad for your health.     12. Sometimes lt ls difficult to take prescnbed medicine all the time. During the past week, how many_tlmes did you miss a dose of MEDICATION 4? (16/58-59] 13. During the past month, about how many times did you miss a dose of MEDICATION 4? (16/60-61] 14. Durtng the past three months, about how many tiIµes did you miss a dose MEDICATION 4?  15. Please check any slde effect(s) you are having that you believe ai:e caused by this medicine: Legend: A = 1 obs, B = 2 obs, etc .