Adherence to Antiretroviral Therapy in Turkey: Results from the ACTHIV-IST Study Group

Abstract

Maintaining optimal adherence to antiretroviral therapy (ART) is essential for optimizing the management of HIV infection. The aim of this study is to explore ART adherence rates in Turkey. Included in this study were a total of 263 HIV-infected patients followed up by the ACTHIV-IST (ACTion against HIV in Istanbul) Study Group affiliated with four tertiary hospitals. The study population included patients 18 years of age or older who were on ART for over 12 months. Adherence was assessed by the medication possession ratio (MPR) calculated for each patient using data (a list of all drugs dispensed within the previous year for that patient) obtained from pharmacy medication records. In addition, patients completed a self-report questionnaire addressing missed doses and the AIDS Clinical Trials Group (ACTG) adherence questionnaire. The study was reviewed and approved by the Ethics Committee of Cerrahpasa Medical Faculty. Patient ages ranged from 19 to 71 years. Two hundred and thirty-one patients were male (88%). Two hundred and twenty-four patients (85%) had optimal adherence (MPR ≥95%). During the course of ART, 236 patients (90%) reported no missed doses in the past 4 days of their treatment, whereas 206 patients (78%) reported no missed doses in the past month. Simply forgetting was the most common reason for nonadherence. MPR was associated with virologic rebound. Major factors affecting adherence were being female, taking antituberculosis drugs, having an opportunistic infection, being able to take all or most of the medication as directed, and being aware of the need to take medication exactly as instructed to prevent the development of drug resistance. Adherence to ART measured by MPR and self-report surveys is relatively high in Turkey when compared with other countries, which probably led to high ART success rates.

Introduction

Since the introduction of combination antiretroviral therapy in the 1990s, decreasing levels of mortality and morbidity have been observed in HIV-infected patients.¹ However, as there is no cure for HIV at present, treatment is lifelong.² Successful HIV treatment largely depends on the adherence of patients to antiretroviral therapy (ART).³ ART nonadherence is associated with increased plasma HIV RNA levels, viral resistance development, and increased morbidity and mortality.^3
–5 Adherence should be maintained at a minimum of 95%.⁶ However, it must be taken into consideration that this much-cited study is outdated. Newer drugs, with longer half-lives, higher resistance barriers, and better overall pharmacokinetics, such as darunavir (DRV), may allow a higher noncompliance.⁷

Currently, there is no consensus on the optimal method to estimate adherence to ART.⁸

Several self-report methods, pharmacy adherence measures (PAMs), and electronic drug monitoring methods are widely used to evaluate adherence in clinical trials and observational studies.⁹ Electronic monitoring is the most objective method, but its use is limited by relatively high cost and inconvenience.^9
–11 Unlike patient self-report methods, PAMs are objective and convenient for routine use and may be calculated from information available in medical and pharmacy records. PAMs are classified into three categories: medication possession ratio (MPR), pill count, and pill pick-up.¹² The self-reported feedback questionnaire is still the most commonly used method due to its low cost and simplicity.¹³

Various factors affecting ART adherence have been identified, including primarily substance use, depression, lack of family and social support, side effects of medication, and stigmatization and discrimination.^14
–16

Turkey has one of the lowest HIV/AIDS seroprevalence rates in the world. According to data from the Turkish Ministry of Health in November 2015, about 11,109 people were living with HIV/AIDS in Turkey.¹⁷ HIV/AIDS was first diagnosed in three patients in Turkey in 1985, with a progressive increase in the annual number of cases during the following years.^18,19

A meta-analysis of studies on ART adherence found that 77% of patients in Africa achieved adequate adherence of 95% compared with 55% of patients in North America.¹⁴ Countries in Eastern Europe and in Asia were reported to achieve higher rates of adherence.¹⁴ In the present study, our aim was to investigate the level of ART adherence and causes of nonadherence in Turkey, a country with low HIV seroprevalence.

Methods

The study was conducted cross-sectionally by the ACTHIV-IST (ACTion against HIV in Istanbul) Study Group. A total of 263patients who had received ART for at least 12 months from March 2014 to March 2015 were enrolled. Adherence was measured by a self-report questionnaire, by the AIDS Clinical Trials Group (ACTG) adherence questionnaire and by MPR.

Ethics statement

The study was reviewed and approved by the Ethics Committee of Cerrahpasa Medical Faculty in Istanbul, Turkey. Written consent was obtained from all subjects before initiation of the study.

Study population

The study was conducted at four tertiary hospitals affiliated with the ACTHIV-IST Study Group in Istanbul, Turkey. Patients 18 years of age or older with a diagnosis of HIV/AIDS were enrolled if they were competent and willing to complete study questionnaires, if they were able to speak and understand Turkish, and if they had received treatment for at least 1 year. Pregnant women and patients with concomitant illnesses (dementia, or severe psychiatric or neurological conditions) that could potentially affect the study results were excluded from the study.

Study adherence measures

As an initial method, MPR was calculated for each patient using data (a list of all drugs dispensed within the previous year for that patient) obtained from pharmacy medication records.

MPR = Sum of the number of days'—in which drugs were supplied within the past 12 months (days)/12 months (365 days).

Second, a simple, self-report questionnaire consisting of four questions on medication use was administered to patients. Patients were asked to report whether they had missed a tablet during the past 4 days, within the past 1 week, within the past month, and within the past 3 months. Patients responding “no” to all questions were considered “adherent,” whereas patients responding “yes” to any of the four questions were considered “suboptimally adherent.” As a third method, patients were asked to complete the ACTG Adherence Baseline Questionnaire and the ACTG Adherence Follow-Up Questionnaire provided free of charge by the Center for AIDS Prevention Studies (AIDS Research Institute, University of California, San Francisco, CA). ACTG adherence questionnaires have been used extensively to measure self-reported adherence to ART internationally. In the ACTG questionnaires, patients are asked to apply 1 of 4 options—“never,” “rarely,” “sometimes,” or “often,”—to 14 different reasons for missing a dose (Likert format). This self-report questionnaire included factors relating to missed dosing, substance use and frequency, and sociodemographic characteristics.

The linguistic validation of the Turkish version was done by HIVEND (HIV Enfeksiyonu Derneği). The questionnaires were translated into Turkish and subsequently back translated by a panel of independent experts. After the pretesting and cognitive interviewing process, minor changes were made. The final version was checked and approved by HIVEND's scientific committee.

Patients' epidemiological data, CD4 count, and HIV-RNA levels were obtained from their medical files. The viral loads of the patients were recorded at the time of the questionnaire. A viral load >200 copies per milliliter was considered virologic rebound (VR).

The drugs history of the patients included the nucleoside analogues Tenofovir/Emtricitabine (TDF/FTC), Zidovudine/Lamivudine (ZDV/3TC) or Abacavir/Lamivudine (ABC/3TC), the non-nucleoside analogue agent Efavirenz (EFV), and the protease inhibitors Lopinavir/Ritonavir (LPV/RTV) or DRV/Ritonavir (RTV).

Statistical analyses

Descriptive statistics included the mean, standard deviation, median, lowest and highest frequencies, and ratio values. The Kolmogorov–Smirnov test was used to assess the distribution of the variables. Quantitative data were analyzed using the independent sample t-test, and qualitative data were analyzed using a chi-square test. The SPSS 22.0 software package was used for all statistical analyses. A p-value of <.05 was considered statistically significant.

Results

A total of 263 patients with a mean age of 40 years (ranging from 19 to 71) were enrolled in the study, of whom 231 were males (87.8%). See the flow chart describing participant numbers (Fig. 1).

FIG. 1.

Patient consort flowchart of the study.

Patient sociodemographic characteristics are shown in Table 1. The mean CD4 count of patients was 505 cells/mm³ (range: 2–1,450).

Table 1.

Baseline Characteristics of Patients

Age (years), mean ± SD	41.0 ± 11.0
Duration of treatment (months), mean ± SD	34.1 ± 21.9
CD4 cell count (cells/mm³), median ± SD	484 ± 268
Viral load (copies/ml), median ± SD	116.409 ± 554,504
Gender, n (%)
Female	32 (12.2)
Male	231 (87.8)
Employment status, n (%)
Unemployed	48 (18.3)
Employed	173 (65.8)
Retired	21 (8.0)
Housewife	21 (8.0)
Marital status, n (%)
Married	116 (44.1)
Single	127 (48.2)
Widow–widower	20 (7.6)
Education level, n (%)
11th Grade or less	102 (38.8)
High school graduate	67 (25.5)
University	94 (35.7)
Previous use of cotrimoxazole
Yes	39 (14.8)
No	224 (85.2)
Previous use of antituberculosis drugs
Yes	5 (1.9)
No	258 (98.1)
Opportunistic infections
Yes	26 (9.9)
No	237 (90.1)
Use of concomitant drugs^a
Yes	70 (26.6)
No	193 (73.4)
Travel to treatment center takes
Less than 1 h	149 (56.7)
More than 1 h	114 (43.3)

Medical drugs: antihypertensive, antidiabetic, analgesic drugs.

SD, standard deviation.

Table 2 shows adherence as assessed by self-reporting, MPR, and ACTG questionnaires.

Table 2.

Adherence Assessment Through Self-Reported Rates of Missing Tablets, Medication Possession Ratio, and AIDS Clinical Trials Group

MPR median ± SD, range of value	0.99 ± 0.086	0.33–1
MPR	N	%
<%95	39	14.8
>%95	224	85.2
Missing tablets
Within past 4 days
Yes	27	10.3
No	236	89.7
Within past 1 week
Yes	32	12.2
No	231	87.8
Within last month
Yes	57	21.7
No	206	78.3
Within past 3 months
Yes	70	26.6
No	193	73.4
ACTG
When was the last time you missed taking any of your medications?
Never skipped medications or not applicable	144	54.8
More than 3 months ago	42	16.0
1–3 Months ago	8	3.0
2–4 Weeks ago	19	7.2
1–2 Weeks ago	24	9.1
Within the past week	26	9.9

ACTG, AIDS Clinical Trials Group; MPR, medication possession ratio.

Table 3 provides the reasons cited for nonadherence as reported by patients through the ACTG questionnaire. Simply forgetting was the most common reason (41%) for nonadherence. Other common reasons included being away from home (29%), experiencing a change in daily routine (23%), and falling asleep or sleeping through dose time (20%).

Table 3.

Reasons for Nonadherence as Determined by AIDS Clinical Trials Group

	ACTG Nonadherent
	n (119)	%
In the past month, how often have you missed taking your medications because you:
Were away from home	34	29
Were busy with other things	22	18
Simply forgot	49	41
Had too many pills to take	10	8
Wanted to avoid side effects	8	7
Did not want others to notice you taking medication	16	13
Had a change in daily routine	27	23
Felt like the drug was toxic/harmful	6	5
Fell asleep/slept through dose time	24	20
Felt sick or ill	9	8
Felt depressed/overwhelmed	15	13
Had problem taking pills at specified times (with meals, on empty stomach, etc.)	14	12
Ran out of pills	11	9
Felt good	11	9

The nonadherence rate indicated by MPR was significantly greater among patients with VR compared with patients without VR (p < .05). Nonadherence rates estimated by self-reported measures and by the ACTG questionnaire did not differ significantly between patients with or without VR (p > .05) (Table 4).

Table 4.

Adherence in Patients with Virologic Rebound as Determined by Medication Possession Ratio, Self-Reported Measures, and AIDS Clinical Trials Group

	Virologic rebound
	Virologic rebound		Virologic suppression
	n	%	n	%	P
MPR (<95%)
Nonadherent	13	33.3	26	66.7	.000
Adherent	26	11.6	198	88.4	.000
Self-reported
Nonadherent	14	20.0	56	80.0	.155
Adherent	25	13.0	168	87.0	.155
ACTG adherence
Nonadherent	21	17.6	98	82.4	.242
Adherent	18	12.5	126	87.5	.242

Bolded values are statistically significant.

Chi-square test.

Distributions of patient age, education level, and employment status were not significantly different between MPR adherent and nonadherent groups and between ACT adherent and nonadherent groups (p > .05). The MPR nonadherent group and the ACT nonadherent group had significantly higher percentages of female patients compared with the MPR adherent group and the ACT adherent group (p < .05) (Table 5).

Table 5.

Potential Factors Influencing Adherence to Antiretroviral Therapy as Determined by Medication Possession Ratio and AIDS Clinical Trials Group

	MPR nonadherent Mean ± SD/n (%)	MPR adherent Mean ± SD/n (%)	p	ACTG nonadherent Mean ± SD/n (%)	ACTG adherent Mean ± SD/n (%)	p
Age (years)	40.2 ± 12.7	41.1 ± 10.7	.489	40.6 ± 12.7	41.3 ± 12.7	.645
Gender
Female	11 (28.2)	21 (9.4)	.001	21 (17.6)	11 (7.6)	.013
Male	28 (71.8)	203 (90.6)	.001	98 (82.4)	133 (92.4)	.013
Education level
11th Grade or less	21 (53.8)	81 (36.2)	.109	53 (44.5)	49 (34.0)	.216
High school graduate	8 (20.5)	59 (26.3)		28 (23.5)	39 (27.1)
Undergraduate	10 (25.6)	84 (37.5)		38 (31.9)	56 (38.9)
Employment status
Unemployed	9 (23.1)	39 (17.4)	.698	25 (21.0)	23 (16.0)	.490
Employed	24 (61.5)	149 (66.5)		74 (62.2)	99 (68.8)
Retired/housewife	6 (15.4)	36 (16.1)		20 (16.8)	22 (15.3)
CD4
<200	9 (23.1)	38 (17.0)	.067	21 (17.6)	26 (18.1)	.760
200–350	21 (53.8)	90 (40.2)		48 (40.3)	65 (45.1)
>350	9 (23.1)	96 (42.9)		48 (40.3)	53 (36.8)

Bolded values are statistically significant.

The MPR nonadherent group had a significantly lower percentage of patients who reported that they were “sure that if they do not take this medication exactly as instructed, the HIV in their body will become resistant to HIV medications” compared with patients in the MPR adherent group (Table 6).

Table 6.

Potential Factors Influencing Adherence to Antiretroviral Therapy as Determined by Medication Possession Ratio and AIDS Clinical Trials Group

	MPR nonadherent		MPR adherent			ACTG nonadherent		ACTG adherent
	n	%	n	%	p	n	%	n	%	p
Previous use of ART regimen(s)	11	28	38	17	.096	28	24	21	15	.064
Use of cotrimoxazole	7	18	32	14.3	.552	20	17	19	13	.412
Use of antituberculosis drugs	1	3	4	1.8	.743	5	4	0	0	.013
Opportunistic infection	7	18	19	8.5	.068	17	14	9	6	.030
Use of concomitant drugs	7	18	63	28.1	.184	39	33	31	22	.040
Travel to treatment center takes
Less than 1 h	19	49	130	58.0	.279	69	58	80	56	.693
More than 1 h	20	51	94	42.0		50	42	64	44	.693
Are you sure that
You will be able to take all or most of the study medication as directed?
Not sure	0	0	3	1.3	.467	3	3	0	0	.055
Sure	39	100	221	98.7		116	97	144	100	.055
The medication will have a positive effect on your health?
Not sure	0	0	5	2.2	.346	3	3	2	1	.503
Sure	39	100	219	97.8		116	97	144	99	.503
If you do not take this medication exactly as instructed, the HIV in your body will become resistant to HIV medications?
Not sure	6	1	8	3.6	.002	11	9	3	2	.010
Sure	33	85	216	96.4		108	91	141	98	.010
In general, are you satisfied with the overall support you get from your friends and family members?	30	77	178	79.5	.719	89	75	119	83	.119
To what extent do your friends or family members help you remember to take your medication?	31	79	150	67.0	.119	81	68	100	69	.810

Bolded values are statistically significant.

Independent sample t-test/chi-square test.

ART, antiretroviral therapy.

The ACT nonadherent group was found to have a significantly higher proportion of patients who were taking antituberculosis drugs, experiencing opportunistic infections, and taking concomitant medication in comparison to the ACTG adherent group (p < .05). Furthermore, the ACT nonadherent group also showed a significantly lower proportion of patients who reported that they were “able to take all or most of the study medication as directed” versus the ACT adherent group. The ACT nonadherent group also had a significantly lower percentage of patients who reported that they were “sure that if they do not take this medication exactly as instructed, the HIV in their body will become resistant to HIV medications” in comparison to the ACT adherent group (Table 6).

Discussion

This is the first study to have investigated adherence to ART in Turkey. In this study, although we found that Turkey had a higher adherence rate compared with rates reported in other Asian countries, it was similar to the adherence rate reported by Wasti et al. in Nepal.^14,15 The high rate of adherence found in Turkey may be explained by the ease of access to ART drugs nationwide, the coverage of these drugs by reimbursement programs for all patients, and the lack of a contribution fee requested from patients for examination and treatment. Other reasons may include the use of self-report measures and MPR as study methods and the inclusion of patients who were provided full care and followed at outpatient clinics.

In the present study, we used three different methods to evaluate adherence to ART and compared the results with VR data. As with similar studies, both MPR and the other PAMs were consistent with virologic failure and VR.^{12,20

–24} Thus, MPR may assist in identifying patients currently at risk of VR. MPR is thus predictive in this study, and although it was not shown to be predictive for future outcomes, it can be used to assess adherence as it is a simple and inexpensive method.

Consistent with previous studies, simply forgetting was found to be the most common reason for ART nonadherence (41%).^25,26 Other common reasons included being away from home (29%), experiencing a change in daily routine (23%), and falling asleep or sleeping through dose time (20%).^25,26

Adverse drug effects have been cited as a major reason for nonadherence in some studies.^14,26 However, “wanting to avoid side effects” was cited as a reason for nonadherence only by 7% of patients in the present study. While treatment cost is the key barrier to seeking treatment in other developing countries, it did not emerge as a reason for nonadherence in Turkey because ART is provided through public health insurance to all patients who need it.

Although education level has been reported to be correlated with adherence in several studies,^14,15,27 age, education level, and employment status were not associated with adherence in the current study. Cauldbeck et al. found that education level did not have any effect on adherence, lending support to our findings.²⁸ This result may be explained by a high level of awareness of ART among the study patients (Table 6).

Adherence rates were lower among females compared with males. This is an important finding that has been shown in only a few previous studies¹⁵ and that may be explained by the poor sociocultural status of women in Turkey. Women have a disadvantaged position in many areas of life compared with men in Turkey, which is a developing country. Acceptance of an HIV diagnosis by women is far more difficult than by men, and women have greater concerns about being stigmatized. Another reason might be women's greater responsibilities for daily household chores.

This study was limited to hospitals located in Istanbul, and study data may not be considered representative of the current situation in other parts of Turkey. However, Istanbul, which comprises more than one-fifth of the general population, is Turkey's most populous city and is home to people of different backgrounds from all geographic regions. Additionally, since a substantial proportion of people infected with HIV live in Istanbul, it is our belief that the study data can be extrapolated to the Turkish population in general.

In the current study, the following factors were found to be significantly associated with ART adherence: female sex, use of antituberculosis drugs, opportunistic infections, sureness that all or most of the study medication can be taken as directed, awareness of that drug resistance could develop if the medication is not taken exactly as instructed, and use of concomitant drugs.

In conclusion, adherence to ART, as measured by MPR and self-report survey questionnaires, is relatively high in Turkey when compared with other countries, which has probably led to Turkey's high ART success rates.

Footnotes

Acknowledgments

This study was supported by the Gilead Sciences Turkey Fellowship Program and HIVEND (Istanbul, Turkey). The authors would like to thank Dr. Berna Ozelgun, MD for her kind efforts and contribution in proofreading of the article.

Author Disclosure Statement

No competing financial interests exist.

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