Conceived and designed the experiments: TS DG. Analyzed the data: SP ZG. Wrote the paper: DG TS. Assisted with data collection/data entry: BM UM BC. Contributed to the interpretation of the results and in editing and revising the manuscript: DG TS ZG SP BM UM BC.
The authors have declared that no competing interests exist.
Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana.
Between 11/2004–07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008–04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24–4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50–6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75–6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91–0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study.
Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health.
ClinicalTrials.gov
Non-adherence and loss to follow-up in a clinical trial threatens the validity of
conclusions about the intervention. The Botswana Isoniazid Preventive Therapy (IPT)
clinical trial was conducted between November 2004 and July 2009. It was a
double-blinded, randomized, placebo-controlled clinical trial to determine whether
isoniazid taken daily for 36 months was more effective in protecting against
tuberculosis (TB) in HIV-infected adults compared to the standard-of-care in which
isoniazid was taken daily for six months. The researchers reported that participants
receiving 36 months of IPT had half the risk of TB compared to participants
receiving the 6-month regimen
While IPT reduces the incidence of TB disease among HIV and TB co-infected
individuals
Non-adherence to medication regimens is observed in clinical trials and is common
under routine program conditions. Participants may wish to stop taking the
medication or cease returning for clinic appointments. In order to better understand
what factors affected non-adherence in our study, we conducted a sub-study in which
we identified two distinct groups of non-adherent participants:participants who
refused to take the study medication but agreed to return for study visits and
participants who were lost to follow-up. Demographic characteristics and other risk
factors of these two groups were compared against those who remained adherent in the
Botswana IPT clinical trial. As an earlier analysis of trial data found that being
on antiretroviral therapy (ART) was associated with better IPT adherence
Potential participants for the clinical trial were recruited from 5 public health
clinics in Gaborone and 3 in Francistown
Participants in the current sub-study were divided into cases and controls (
Case-Non-adherent was defined as not taking the study medication due to unwillingness to take any more study medication but continuing to attend quarterly visits and seen at the last expected visit. Case-LosT to follow-up was defined as a participant who was still expected to take the study medication and receive monthly medication refills but missed the last visit by≥60 days. A control was defined as a participant who continued to be on study medication and was last seen within the expected visit window which was 7 days early or 14 days late in the 30-day study month. The median number of days since the last visit of those cases who were lost to follow-up was 396 days (range 91–1196), and 48 days (range 6–116) for the cases who were non-adherent. As the sub-study was conducted between 10/2008 AND 4/2009, 21 PARTICIPANTS HAS ALREADY COMPLETED THE RQUIRED 36 MONTHS OF OBSERVATION AND HAD VOLUNTARILY WITHDRAWN.
Rates of pharmacy refill visits among enrolled participants were determined using
a criterion of attending ≥80% of visits within six 6-month
periods (
Period after enrolment (months) | Participants enrolled at beginning of period | Attending ≥80% of clinic visits | % with detectable urine isoniazid
metabolites in 36H arm |
||
6H | 36H | Total | |||
1–6 | 1995 | 86% | 85% | 85% | - |
7–12 | 1945 | 87% | 80% | 84% | - |
13–18 | 1870 | 79% | 77% | 78% | 80%† |
19–24 | 1808 | 79% | 76% | 77% | 79%‡ |
25–30 | 1755 | 79% | 75% | 77% | 74%§ |
31–36 | 1712 | 79% | 77% | 78% | - |
|
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*Unannounced, urine samples were collected in 2006, 2007 and 2008 from 200 randomly selected participants receiving isoniazid who returned for refills. The numbers of participants and their median (range) month in the study were:194 at month 13† (5–22), 202 at month 22‡ (12–30), 195 at month 30§ (21–36). Abbreviations: 6H = six months of isoniazid daily followed by placebo; 36H = 36 months of isoniazid daily.
In order to better understand factors associated with non-adherence and loss to follow-up, a third party (a private company in Botswana) was hired to contact sub-study participants and carry out the focus group discussions, interviews and surveys. This third party was enlisted in order to reduce the risk that study participants would be less than forthcoming in their responses to questions and also to facilitate finding lost to follow-up participants. Focus group discussions and individual interviews were first conducted to provide supplemental information and to help finalize a survey that was administered during the second phase of the study (the complete questionnaire is available upon request). Native Setswana-speaking persons moderated the focus group discussions and interviews.
Group and individual interviews were conducted prior to finalizing the survey
instrument to assure that relevant questions were included. Purposeful
sampling, or selecting participants based on their ability to provide
information on the relevant subject
The survey instrument was interviewer-administered and consisted primarily of
close-ended questions. Participants (247 cases and 253 controls, see
Participants were provided explanations about the sub-study, were told that the
information they provided would be confidential, and were informed that their
participation was voluntary so they could refuse to answer any questions or
leave the focus group at any time. Verbal, not written, consent was obtained for
this sub-study because the risks were minimal and participants had already
provided written consent for the parent clinical trial. The ethics committees
agreed that verbal consent was sufficient. For the survey and interviews, if the
potential participant refused to participate and consent, this was recorded. All
participants designated as cases who participated in the group discussion or
individual interviews received a monetary reimbursement (approximately U.S.
$8.00) for their time and transportation costs. Ethical approval was
obtained from the Botswana Ministry of Health's Human Research
Development Committee and the Centers for Disease Control and
Prevention's Institutional Review Board (see
Between November 2004 and July 2006, 1995 participants were enrolled in the clinical
trial. Overall, the clinical trial had a very good adherence rate during the 3 years
of follow-up with 78% of participants adherent to at least 80%
of their scheduled visits, more than three-quarters of randomly selected
participants having detectable isoniazid metabolites in their urine (
From the dataset of October 8, 2008, we identified 247 cases and from a pool of
1370 controls, we randomly selected 253 controls (
Cases discussed their views on several topics related to adherence to the study
regimen. There were five in-person group discussions consisting of 18
individuals (11 females, 7 males) and seven individual interviews (3 females, 4
males; one face-to-face and six via telephone) for a total of 25 individuals.
Regarding their treatment by clinic staff, cases strongly expressed that the
clinical trial staff provided them with information about their health, treated
them with respect, and imbued them with a sense of empowerment. Themes
associated with barriers to trial participation included, for example, competing
commitments, side effects, and relocation (
Domain of Inquiry | Theme | Examples |
Reasons joined trial | Benefit to self | “It seemed better to prevent than to contract TB.” |
Benefit to others | “…by becoming a participant I could be able to advise other young people and discuss issues like the importance of programs like IPT with them.” | |
Referred | “…I tested positive. And they referred me to the IPT office where I started taking the treatment.” | |
Knowledge of TB | Symptoms | “It is a cough that is easily spread to other people and you lose a lot of weight.” |
Transmission | “…if you spit on the ground, it can spread to others easily.” | |
Facilitators to trial participation | Health-related | “I managed to prevent TB and I'm happy because I do not have TB. I know my status. They also check my CD4 count every time I go for monthly check ups.” |
Barriers to trial participation | Competing commitments | “The reasons were work commitments. My job was a barrier to taking the pill but the medication treated me well.” |
Side effects | I always felt like vomiting and my eyes were always itching because of the pills.” | |
Started ART | “I was taking a lot of tablets and I was always thinking I will die…so I decided to stop these ones (isoniazid).” | |
Stigma | “They (Batswana) still discriminate against people on the trial and that discrimination is what makes people drop out of the trial..” | |
Relocate | “My job contract came to an end and I had to relocate to my home village” | |
Lack of staff | “…the barriers… the one I can think of is the lack of staff.” | |
Transport | “When you are far from the clinic, the transport to the clinic becomes a problem.” | |
Inconsistent | “…when I was taking the trial medication then I started with ART I asked whether I should continue with the isoniazid and they said I could just stop isoniazid as its really not a problem.” | |
Treatment by clinic staff | Respect | “Every time I did not understand, I asked and they made sure they explained clearly in order for me to understand better.” |
Empower | “They made me realize that I can move forward. I was able to take ART without being reluctant and this trial made me build a home for my family because of my confidence.” | |
Information | “We learned a lot about TB. We have learned how one can be infected, how it can be treated, how dangerous it is and many more other things.” |
Suggestions |
More dispersed clinics |
|
Communication of trial requirements to broader community |
|
More staff |
|
Convenient times for appointments |
|
Communication |
|
Shorter trial |
|
Among the 500 cases and controls selected for this survey study, 462 completed
the survey for a response rate of 92.4% (462/500). The response rate
for the controls (252/253 or 99.6%) was higher than for the
non-adherent (127/145 or 87.6%) and lost to follow-up cases (83/102
or 81.4%) (
Compared to controls, the case non-adherent group was younger
(t = 58.2,
Compared to controls, non-adherent participants had greater odds of being male
(AOR 2.24; 95%CI 1.24–4.04) and having difficulties with
the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI
1.75–6.60), and had lower odds of being older (AOR 0.94 for each year
of age; 95%CI 0.91–0.98) (
Demographic Characteristic or Risk Factor | Adherent | Non-adherent | Lost to follow-up | |||
N (%) |
AOR (95% CI) | N (%) |
AOR (95% CI) | |||
Age (years) | Mean±SD | 37±10 | 34±7 | 0.94 (0.91, 0.98) |
35±6 | 0.99 (0.95, 1.04) |
Sex | ||||||
Female | 199 (79) | 86 (68) | Referent | 48 (58) | Referent | |
Male | 53 (21) | 41 (32) | 2.24 (1.24, 4.04) |
35 (42) | 3.08 (1.50, 6.33) |
|
Employed | ||||||
Yes | 161 (64) | 80 (63) | – | 54 (66) | – | |
No | 90 (36) | 47 (37) | – | 28 (34) | – | |
Income per month (Pula) | ||||||
0–900 | 96 (52) | 41 (43) | – | 30 (41) | Referent | |
901–2000 | 58 (31) | 35 (37) | – | 23 (32) | 1.26 (0.63, 2.52) | |
>2000 | 31 (17) | 19 (20) | – | 20 (27) | 1.03 (0.42, 2.53) | |
Education | ||||||
Primary or less | 99 (41) | 38 (31) | Referent | 18 (22) | Referent | |
Secondary | 127 (52) | 74 (60) | 0.97 (0.51, 1.85) | 50 (62) | 2.55 (1.10, 5.91) | |
Tertiary | 18 (7) | 12 (10) | 1.05 (0.39, 2.78) | 13 (16) | 2.72 (0.68, 10.80) | |
Time to get to clinic (minutes) | ||||||
<30 | 73 (29) | 33 (26) | – | 36 (44) | Referent | |
30–60 | 144 (58) | 76 (60) | – | 32 (39) | 0.64 (0.33, 1.24) | |
>60 | 32 (13) | 18 (14) | – | 14 (17) | 1.61 (0.61, 4.26) | |
Do you drink/take alcohol? | ||||||
No | 227 (90) | 104 (83) | Referent | 64 (79) | Referent | |
Yes | 25 (10) | 22 (17) | 1.55 (0.76, 3.17) | 17 (21) | 1.26 (0.51, 3.09) | |
Main reason for joining the trial | ||||||
Prevent TB | 167 (66) | 78 (61) | – | 53 (64) | – | |
Other |
85 (34) | 49 (39) | – | 30 (36) | – | |
Started on antiretroviral therapy (ART) | ||||||
Yes | 133 (53) | 76 (60) | Referent | 35 (42) | Referent | |
No | 119 (47) | 51 (40) | 0.67 (0.41, 1.10) | 48 (58) | 1.18 (0.63, 2.21) | |
Baseline CD4+ T cell count | ||||||
≥200 cells/mm3 | 173 (69) | 83 (66) | – | 56 (68) | – | |
<200 cells/mm3 | 76 (31) | 43 (34) | – | 26 (32) | – | |
When I enrolled in the trial, I understood what was expected of me | ||||||
Agree | 205 (82) | 94 (74) | Referent | 54 (66) | Referent | |
Disagree/Don't know | 45 (18) | 33 (26) | 1.65 (0.93, 2.90) | 28 (34) | 1.87 (0.93, 3.75) | |
I didn't have any difficulties with the regimen | ||||||
Agree | 231 (93) | 92 (75) | Referent | 69 (84) | Referent | |
Disagree/Don't know | 18 (7) | 30 (25) | 3.40 (1.75, 6.60) |
13 (16) | 1.46 (0.58, 3.66) | |
The isoniazid medication may be dangerous to my health | ||||||
Agree | 48 (21) | 26 (23) | – | 14 (20) | – | |
Disagree/Don't know | 180 (79) | 85 (77) | – | 57 (80) | – | |
More information about TB would help me stay with the medication | ||||||
Agree | 219 (89) | 114 (91) | – | 74 (91) | – | |
Disagree/Don't know | 26 (11) | 11 (9) | – | 7 (9) | – |
Notes. Missing values are not included; AOR = adjusted odds ratio, SD = standard deviation.
*Overall significant, i.e.
‘–’ = Not
included in multiple regression model because
Examples of other responses included:“to receive TB education”, “receive free medical care”, “to prevent TB”, “to receive incentives for taking part”, “recruited or advised to do so”, “because I am HIV positive”, “to help my country”, “to help the study succeed.”
For the variable Age, this column reflects the mean ± standard deviation of the mean (SD).
Among cases, 40/210 (19.0%) reported that they stopped the medication
because of work commitments (non-adherent 18.9%, lost to follow-up
19.3%) and 33/210 (15.7%) said they thought they had
completed the study (non-adherent 17.3%, lost to follow-up
13.3%) (
Reasons | Non-adherent N (%) | Lost to follow-up N (%) |
Work commitment | 24 (18.9) | 16 (19.3) |
Personal doctor told me to stop because of medical problems including side effects of the study medication | 10 (7.9) | 6 (7.2) |
Side effects of the study medication (but personal doctor did not tell me to stop) | 20 (15.8) | 5 (6.0) |
Stigma associated with being in the trial | 3 (2.4) | 2 (2.4) |
Relocated too far away to keep appointments | 10 (7.9) | 15 (18.1) |
Not enough transport money (does not include relocating) | 2 (1.6) | 6 (7.2) |
Completed the study (though had not) | 22 (17.3) | 11 (13.3) |
Pregnant | 3 (2.4) | 3 (3.6) |
Take too many pills | 1 (0.8) | 2 (2.4) |
Lost/forgot | 7 (5.5) | 2 (2.4) |
Other |
23 (18.1) | 4 (4.8) |
No reason provided | 2 (1.6) | 11 (13.3) |
Total | 127 (100%) | 83 (100%) |
Examples of other responses included:social problems, religious beliefs, boyfriend threw the pills away, sister flushed the pills down the toilet, pills were stolen, miscommunication, long lines at the clinic, pills increased appetite.
Adherence and retention in clinical trials are important issues because participant
non-adherence and loss to follow-up can compromise study results. Generally
speaking, patients are less adherent to treatment when they feel well, such as when
taking prophylactic treatment, than they are for a symptomatic condition
In the case-control sub-study, men had twice and thrice the odds of women to be
non-adherent or lost to follow-up, respectively. While we were unable to identify
published studies examining adherence to prophylactic therapy in large numbers of
HIV-infected adults in sub-Saharan Africa, adherence to ART has been assessed in
such populations. Among enrollees of ART programs in Côte d'Ivoire
and Kenya, men were more likely than women to be lost to follow-up
Non-adherent participants had more than three times the odds of reporting
difficulties with the regimen or not knowing if they had difficulties than controls
(rates reported were 25% in non-adherent cases vs. 7% in
controls) and although not significant in the multivariable model, participants lost
to follow-up also had higher rates (16%) of reporting these difficulties
or not knowing. Some discussion group and interview participants reported that the
study medication made them sick, lose weight, feel dizzy or tired or made their body
ache. It is well established that side-effects can greatly influence an
individual's willingness to adhere to therapy
Some associations that were significant in bivariate analysis were not significant in
the adjusted analyses but bear mentioning:distance from clinic, alcohol use, level
of education, and understanding the requirements of the study. All four factors have
been reported as barriers to adherence
Our study had several potential limitations. First, data were cross-sectional, so we cannot state that the significant factors led to a participant becoming non-adherent or lost to follow-up. Second, responses to survey questions were self-reported which may have resulted in some bias in answering questions about non-adherence, although we believe this was minimized since the study was conducted by an independent contractor and not members of the clinic staff. Third, the clinical trial staff did not have control over the independent administration of ART to study participants during their changing disease course over the 3-year study. As HIV-infected persons widely regard ART as life-sustaining and as ART consists of many additional pills and also have significant adverse effects, they may have complicated adherence to study medication. Fourth, we did not assess the personalities of the participants which could have potentially been a factor in their adherence to study medication. Fifth, because we were unable to contact 197 participants who had voluntarily withdrawn at the time the sub-study was begun, the lack of information about them may have biased our sub-study. Finally, all of the relevant and important variables may not have been captured in our survey (e.g., peer or family social support). The strengths of this study are the inclusion of group discussions and interviews to supplement the survey data, clear definitions of non-adherence and loss to follow-up, and the very high survey response rate.
Studies have shown that participant satisfaction with the clinic staff can contribute
to adherence
A Randomized, Placebo-Controlled Study of Limited vs. Continuous Isoniazid Tuberculosis Preventive Therapy for HIV-infected Persons in Botswana.
(PDF)
CONSORT checklist for
(DOC)
We would like to extend our appreciation to the study participants, the BOTUSA research nurses and the staff of Premiere Personnel–in particular Vanessa Mpho Beyleveld and Matildah Engleton–for their contributions to the adherence sub-study. We appreciate the assistance of Monicah Taylor-Jones in Atlanta with the qualitative analysis.