Evaluating the Impact of Educational Interventions on Use of Highly Active Antiretroviral Therapy and Adherence Behavior in Indian Human Immunodeficiency Virus Positive Patients: Prospective Randomized Controlled Study

Radhakrishnan Rajesh1*, Sudha Vidyasagar2, Danturulu Muralidhar Varma3, Vasudeva Guddattu4 and Ansar Hameed5 1Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India 2Professor & Head of the Department of Medicine, Kasturba Medical College, Manipal University, Manipal 576 104, Karnataka, India 3Associate Professor, Department of Medicine, Kasturba Medical College, Manipal University, Manipal 576 104, Karnataka, India 4Asst Professor, Department of Statistics, Manipal University, Manipal 576 104, Karnataka, India 5Department of Pharmacy Practice, Manipal College of Pharmaceutical Sciences, Manipal University, Manipal 576 104, Karnataka, India


Introduction
Currently 1,672,875 patients in India have been registered in Human Immunodeficiency Virus (HIV)/ Acquired Immunodeficiency Syndrome (AIDS) care at 358 active Antiretroviral Therapy (ART) centres as on Sept 2012 [1]. Highly Active Antiretroviral Therapy (HAART) has led to greater longevity by reducing HIV-related morbidity and mortality. HIV-infected patients treated with HAART have been known to cause short term and long term Adverse Drug Reactions (ADRs). In India, there is a lack of awareness and inadequate knowledge about use of HAART, due to lack of individual Educational Intervention (EI) leading to a greater degree of intentional or nonintentional poor adherence to ART and HIV treatment failure [2]. Unfortunately, up to 25% of HIV-infected patients discontinue their initial HAART treatment within the first eight months due to ADRs [3].
Understanding of Knowledge, Attitude, Belief, and Practice (KABP) in HIV-infected patients is a pre-requisite to develop effective EI [12]. Awareness and adequate training about HAART safety is very important among HIV infected patients for early recognition of symptoms associated with ADRs to HAART and to maintain good adherence [13]. In HIV/AIDS care, HAART medication adherence has been defined as the ability of the person living with HIV/AIDS to be involved in understanding, starting, continuing, managing, and maintaining a prescribed HAART to control viral HIV replication and to improve immune function [14]. Physicians and pharmacist play a key role to develop an individual educational program for HIV infected patients in order to improve HAART adherence and effectiveness of HIV treatment, that includes information such as factors that limits adherence, patient's social support from family and friends, understanding of HIV disease, home situation, work and daily schedules. The aims of this study were to evaluate the impact of EIs on use of HAART and to evaluate its effect on HAART adherence behavior in Intervention Care Group (ICG) in comparison with Standard Care Group (SCG).

Study setting
This study was a prospective, randomized, controlled, interventional study conducted at Kasturba Hospital, Manipal from August 2009 to May 2012. The University Ethics Committee of Manipal University approved this study.

Study population
HIV-infected patients of either sex who were receiving HAART at least one month were included in the study. HIV-infected patients who were receiving HAART along with traditional medicines practiced in India like ayurveda, yoga, naturopathy, unani, siddha and homeopathy were excluded from the study.

Sample size and randomization
Sample size was calculated by using the formula Where n=sample size z α is the percentile value of standard normal distribution for type I error fixed at 5%. z β is the percentile value of standard normal distribution for 80% power c d is the Cohen's d effect size defined as the ratio of difference in mean percentage KAPB scores between ICG and SCG groups to pooled standard deviation of the percentage change. Where percentage change in KAPB scores is defined as percentage change=100*(post score-pre score)/pre score. A pilot study of 10 subjects revealed the estimate of Cohen's d to be 0.36, 0.45, 0.39 and 0.42 for KAPB scores. From this we had chosen Cohen d value of 0.36 for calculating sample size as it yields maximum sample size of 120 in each group. After the baseline pre-KABP responses a block, randomization within 60 blocks of random length of size 4 was used to assign the patients to receive either ICG or SCG.

Study Questionnaire and Study Design
A validated questionnaire about KABP was used [15,16]. Questionnaire was translated to local language Kanada, and back translated to English to ensure consistency. A change in the order and phrasing of the questions was made after discussion with the clinicians.
Twenty five questions included knowledge towards use of ART, HIV disease and its mode of transmission, common adverse effects of ART, awareness about adherence and its importance, what needs to be done while experiencing adverse effects to ART, attitude and beliefs about ART.

Assessment of the baseline Pre-KABP responses questionnaire
HIV positive patients, who meet the inclusion criterion, were enrolled into the study. Before randomization, each of Pre-KABP questions were assessed with all enrolled patients at the baseline to explore their KABP concerning use of ART and Pre-KABP responses were documented.

Educational interventions
The ICG participated in an EI program provided by the pharmacist addressing the benefits associated with use of HAART that are currently used to treat HIV infection, while the SCG received usual standard care. The pharmacist intervention included the provision of a three educational components consisting of provision of Patient Information Leaflets (PIL) on antiretroviral drugs, ART related counseling and awareness of ADRs to ART by using a validated pictograms [17]. For illiterate patients under ICG, education was provided in the presence of a patient representative or a literate family member as agreed by the patient. During the follow-up visits, the same patient representative/ literate family member accompanied the study patient. The intervention visits was conducted every 4 weeks for a period of 16 weeks of follow-up.

Patient information leaflet (PIL)
Validated PIL on antiretroviral drugs at our own centre was used. Information included in the PIL was about the HIV following facts:

ART related adherence counseling & awareness of ADRs
During the educational program, patients under ICG were provided with ART related adherence counseling & awareness to ADRs to ART under privacy. The counseling on antiretroviral drugs usage, awareness about adherence and its importance and safety aspects of ART was explained by using visual aids. Validated pictograms of ADRs to ART was also used as a counseling tool to improve patient's knowledge towards understanding of adverse effects of ART in both illiterate and literate patients in order to promote awareness of ADRs to ART for early identification and prevention of ADRs [17].

Follow-up visits and assessment of the Post-KABP responses
In both groups, post KABP questionnaires were re-administered at the end of 16 weeks and post-KABP responses was documented. Correct responses to pre-KABP questionnaires and post-KABP questionnaires were compared between both groups after intervention and standard care in ICG and SCG groups respectively.

HAART adherence assessment
After individual assessment of the post-KABP responses of ICG and SCG, HAART adherence was assessed by asking the patient if he/ she has missed any doses of ART and also by checking the bottle/ blister packet form both groups. Percentage of adherence from self-report was calculated by using the formula [18]. The estimated level of adherence was graded into three grades [less than 80%=12 doses missed in a period of 30 days], (80-95% =3 to 12 doses missed in a period of 30 days) and {greater than 95 % =< 3 doses missed in a period of 30 days} as per the National AIDS Control Organization (NACO) guidelines [19].

Statistical analysis
Frequencies with percentage were used to summarize demographic characteristics, pre and post KABP responses of SCG and ICG. Mean ± Standard deviation was used to summarize total correct response in KABP domains. Repeated-measures Analysis of Variance (RANOVA) was used for the comparison of pre and post total KABP responses between ICG and SCG. Chi-square test was used to compare antiretroviral adherence outcomes across ICG and SCG. The patient was considered as good adherent for HAART if he or she reported ≥ 95% of the estimated level of adherence of the prescribed HAART regimen. All statistical calculations were performed using Statistical Package for Social Science (SPSS) Version 17.0. P-value of < 0.05 was considered as statistically significant.

Results
During the study period, 256 HIV positive patients were enrolled among these, 16 patients were excluded because they were on traditional medicines. Only 240 HIV-infected patients with HAART were included in the study, of whom 120 (89 [74.2%] men's, 31 [25.8%] women's) were randomly assigned to the ICG. In SCG, 120 (99 [82.5%] men's, 21 [17.5%] women's) were assigned. Majority of the patients in both group had baseline CD4 + T-cell count ≤ 350 cells/µl. About 52.6% of the patients in ICG were between the age of 21-40 years, in SCG 42.5% were between the age of 21-40 years.
Compared with the SCG post-KABP responses, ICG post-KABP responses after EI and counseling on antiretroviral therapy was increased with correct responses for all categories of knowledge based questionnaires. Comparing correct responses to questionnaires for how HIV disease transmitted, the ICG increased from 94 at baseline pre-KABP responses to 120 in the post-KABP responses, while the SCG increased from 84 to 104, respectively. Overall intervention was also associated with an increase in the percentage of correct responses to all knowledge based questionnaires of post-KABP responses between SCG and ICG as summarized in Table 2.
When the patients were asked about attitude to be taken while experiencing an adverse effect to antiretroviral therapy, post-KABP responses in ICG 120(100%) reported that they will contact physician immediately, compared with the post-KABP responses in SCG118 (98.3%). Of the patients in ICG post-KABP responses, 116(96.7%) agreed that they should not miss a dose of ART compared with the post-KABP responses in SCG 93(77.5%).
In the ICG, EI was also associated with an increase in the percentage of correct responses toward attitude of ART compared with the post-KABP responses in SCG such as 118 ( Greater than two years 7(5.9) 11(9.1)  patients' responses to the attitude-based questionnaires are mentioned in Table 3.
The effect of the intervention on belief and practice was also associated with an increase in the percentage of correct responses during post-KABP analysis compared with the SCG. Frequency distribution of the patients' responses to the beliefs and practice based questionnaires are mentioned in Table 4. Table 5 presents the results of Repeated-measures analysis of variance test of pre and post KABP between SCG and ICG. It shows that mean ± standard deviation significantly increased in patients in the ICG while it is just increased in patients in the SCG and the difference in change of mean ± standard deviation was statistically significant (p<0.001) between pre and post KABP scores in both groups.
In HAART adherence assessment, the proportion of adherent patients became significantly higher in the ICG at {Greater than 95% of adherence 81(67.5%), [p<0.001], 80 to 95% of adherence 33 (27.5%), [p<0.001], less than 80% of adherence 6(5%), [p<0.001]} compared to the proportion of adherent patients in SCG at{Greater than 95% of adherence 58(48.3%), 80 to 95% of adherence 52(43.3%), less than 80% of adherence 10(8.4%). Table 6 shows the details of changes in adherence behavior outcomes between SCG and ICG in a prospective, controlled study for evaluation of EIs on safe use of HAART. During the study period there were no loss to follow-up in both groups and no deaths were reported. Figure 1 shows the flow of participants through the randomized study.

Discussion
In this randomized controlled study comparing EI and usual standard care to evaluate the impact of EI on safe use of HAART and adherence outcomes in HIV-infected positive patients who received adherence counseling to ART, demonstrating the impact of this EI with greater than 95% of adherence outcomes. Studies demonstrated that HIV-infected patients who received EI had obtained significant improvement in adherence [20][21][22][23][24]. Our study results also show similar positive significant association of greater than 95% of adherence outcomes to HAART in ICG patients (67.5%, p<0.001) after having received EIs on adherence counseling in comparison with SCG.
Several studies also suggest for EI design to promote positive attitude and practice of HIV/AIDS care [28][29][30]. In the present study, before EI, patients who were on long term HAART had experienced adverse effects to ART, but failed to express their adverse effects to physician due to negative attitude of fear, social stigma and finally resulted in intentional non-adherence to HAART. After EI on HAART related information and counseling, these patients have shifted from negative attitude to more positive attitudes towards use of HAART and reflects in significant association between EI and positive attitude towards use of antiretroviral therapy in comparison with SCG patients.
Mini et al. study showed the impact of pharmacist provided education was found effective in improving medication adherence behavior in HIV/AIDS patients with limitation of having no control group and their study was not certain that pharmacist provided education alone improved adherence behavior [31]. Whereas our study demonstrated that EI provided by pharmacist in ICG patients reported an increase in greater than 95% of adherence (p<0.001) in comparison with control group of SCG patients showing that the impact of pharmacist provided EIs on safe use of HAART were positively associated with adherence behavior to HAART in Indian HIV-infected patients.
In the ICG, EI was associated with increased queries at the time of ART related counseling, either to continue or discontinue ART once they feel better. Before counseling, patients felt that once their symptoms improve there is no need for ART medications. After educational counseling, by citing different examples patients understood that ART should be continued regularly and showed positive changes in patient's perception of continuing ART even when their symptoms subsided during their follow-up visits. These finding demonstrated that counseling could learn to change for positive attitude for adherence to HAART. Findings of positive attitude for adherence to HAART were accordance with study conducted by Chesney et al. and Wagner et al. [32,33].
Our results show that, EI provided by the pharmacist also created an opportunity for HIV-infected patients to know the role of their HAART, with names of combination medications under HAART, dose and frequency. Before EI, patients were not even familiar with brand names of ART and patients' beliefs about ART were not clear because of misunderstanding of the role of HAART. After education, patients were able to retain ART related information they learned during counseling session which helped them to communicate in an easy way to clinician regarding their usage of HAART regimens, with dose and frequency during their follow-up visits. The patient's beliefs about safe use of HAART increased after our EI. These indicate that patient's learned the role of HAART than what they knew at the beginning. These are in agreement with Korb-Savoldelli et al. and Metsch et al. demonstrating that EI on medication instructions positively modify patient's beliefs which in turn can lead to a change in patient's medication adherence behavior [34,35].
During this study, ICG patients received PIL on antiretroviral drugs. The post-intervention questionnaires about the importance of PIL showed a score of 73.3%, which demonstrates that provision of PIL increased the amount of information to be followed for use of ART such as, ART should be continued as prescribed by the clinician, ART should not be stopped, and should be continued, patients understood that HAART is life saving medication as detailed in the PIL. This supports Dowse et al. and Kessels et al. studies [36,37]. However, in our study, 15% of patients in ICG, after post-interventions were not happy to carry PIL. This is due to the fact that these patients had a negative beliefs that carrying the PIL on antiretroviral drugs can cause a risk of revealing their HIV status to others thereby they felt that oral information provided during EIs on ART was encouraging for them for the management of HIV disease.
In our study, awareness of adverse effects to ART in ICG patients who were prescribed on HAART regimens, individually educated and counseled about adverse effects of ART most likely to occur using validated pictograms and PIL. Overall, study patients under ICG, following the EI reported good knowledge and positive attitudes towards understanding of adverse effects of ART in both illiterate and literate patients. Awareness of adverse effects to ART among these patients impacts greatly with its association to manage early adverse effects of ART treatment, improved self-efficacy skills and HAART adherence behavior. These are in agreement with Dowse et al. and Wolf et al. studies demonstrating that awareness of ART side effects using pictograms, PIL and visual images have been shown to improve patients' knowledge, particularly in low-literate groups [38,39]. Our recent study showed an association between medication adherence outcomes and ADRs to HAART in Indian HIV positive patients demonstrating the  need for EI, to promote awareness for adverse effects of ART for the early identification of sign and symptoms of ADRs [40].

Conclusion
In this study EI showed a very good positive impact on patients' knowledge, attitude positively modified their beliefs about their ART and effectively increased antiretroviral medication adherence greater than 95%. EI to ART confirm that there is large scope to promote adherence to HAART in HIV patients who have negative beliefs, social stigma and intentional non-adherence behavior.