Adherence to Antiretroviral Therapy: A Systematic Review - Research Paper

Abstract

Following global efforts to increase antiretroviral therapy (ART) access in Sub-Saharan Africa, ART coverage among HIV-infected Cameroonians increased from 0% in 2003 to 22% in 2014. However, the success of current HIV treatment programs depends not only on access to ART, but also on retention in care and good treatment adherence. This is necessary to achieve viral suppression, prevent virologic failure, and reduce viral transmission and HIV/AIDS-related deaths. Previous studies in Cameroon showed poor adherence, treatment interruption, and loss to follow-up among HIV+ subjects on ART, but the factors that influence ART adherence are not well known. In the current cross-sectional study, patient/self-reported questionnaires and pharmacy medication refill data were used to quantify ART adherence and determine the factors associated with increased risk of non-adherence among HIV-infected Cameroonians. We demonstrated that drug side-effects, low CD4 cell counts and higher viral loads are associated with increased risk of non-adherence, and compared to females, males were more likely to forego ART because of side effects (p<0.05). Univariate logistic regression analysis demonstrated that subjects with opportunistic infections (on antibiotics) had 2.42-times higher odds of having been non-adherent (p<0.001). Multivariable analysis controlling for ART regimen, age, gender, and education showed that subjects with opportunistic infections had 3.1-times higher odds of having been non-adherent (p<0.0003), with significantly longer periods of non-adherence, compared to subjects without opportunistic infections (p = 0.02). We further showed that compared to younger subjects (40 years), older subjects (>40 years) were less likely to be non-adherent (p<0.01) and had shorter non-adherent periods (p<0.0001). The presence of depression symptoms correlated with non-adherence to ART during antibiotic treatment (r = 0.53, p = 0.04), and was associated with lower CD4 cell counts (p = 0.04) and longer non-adherent periods (p = 0.04). Change in ART regimen was significantly associated with increased likelihood of non-adherence and increased duration of the non-adherence period. Addressing these underlying risk factors could improve ART adherence, retention in care and treatment outcomes for HIV/AIDS patients in Cameroon.

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Introduction

Of the 37 million individuals worldwide living with HIV/AIDS, 25.8 million (70%) are in Sub-Saharan Africa (SSA) [1]. Since the year 2000, over 25 million people have died from HIV/AIDS, mostly in SSA [1]. With this high HIV/AIDS-related mortality, there has been global efforts to make ART more affordable and increase treatment access to more HIV-infected subjects [2]. Thanks to those efforts many more HIV-infected people in low and middle-income countries are now receiving ART. One such example is Cameroon where the number of HIV-infected subjects receiving ART increased from 28,000 in 1998 to about 200,000 in 2013 [3], the percentage of pregnant women receiving ART increased from 14% in 2009 to 61% in 2013 [4], and overall ART coverage among Cameroonians living with HIV/AIDS increased from 0% in 2003 to 22% in 2014 [5, 6].

The new World Health Organization (WHO) HIV treatment guidelines have expanded the number of people eligible for ART [7] and this expansion is expected to increase ART coverage in several countries, including Cameroon. In fact, through the "Treatment 2015" program, WHO and UNAIDS intend to mobilize support to accelerate and scale-up HIV treatment worldwide, prioritizing countries where 9 out of every 10 people have unmet ART needs [8]. Twenty of those priority countries are in SSA and include Cameroon [8].

Achieving the WHO 2020 treatment goals, and the goal of ending the AIDS epidemic as a public health threat by 2030 [7], will depend on the success of current HIV treatment programs. Such success will not only depend on access to HIV treatment, but also on good adherence to ART and retention in care, which is necessary to achieve viral suppression, to prevent viral failure, diminish viral transmission, and reduce HIV/AIDS-related deaths.

Previous studies of HIV+ subjects on ART in Cameroon showed high rates of non-adherence, treatment interruption, and loss to follow-up [9-14], and this was associated with drug resistance and virologic failure [10, 15]. However, the factors that hinder adherence to ART in Cameroon are not well known. For ART treatment programs in Cameroon to be successful, it is critical to identify barriers to adherence, then determine and implement appropriate measures to promote and improve adherence. In the current study, we used both patient self-reported questionnaires and pharmacy medication refill data to quantify adherence to ART, and to determine the factors associated with increased risk of non-adherence.

Materials and Methods

Study Design and Ethical Consideration

This cross-sectional study was part of an ongoing project aimed at analyzing the influence of HIV genetic diversity on viral neuropathogenesis in Cameroon. This study was performed in accordance with guidelines of the Helsinki Declaration and was approved by the Cameroon National Ethics Committee, as well as the Institutional Review Board of the University of Nebraska Medical Center. Written informed consent was obtained from all the participants and data were processed using unique identifiers to ensure confidentiality.

Participants

A total of 171 HIV-infected individuals were consecutively recruited between 2008 and 2015 from: 1) the HIV voluntary counseling and testing sections of the Day-care Service in the Yaounde Central Hospital; 2) the Yaounde Jamot Hospital; 3) the Efoulan District Hospital, Yaounde; and 4) the Etoug-Ebe Baptist Health Center, Yaounde. The purpose of the study and research procedures were fully explained to participants and adults at least 18 years old who gave a written consent were allowed to participate in the study. The exclusion criteria were: 1) present or past history of CNS disease unrelated to HIV, 2) head trauma, 3) current alcohol intoxication (blood alcohol content of each participant was measured using a Breathalyzer), 4) known psychiatric disease or treatment with antipsychotic drugs, and 5) ongoing systemic illness or fever (temperature of 37.5C or higher). All subjects enrolled spoke French as their primary language and interviews were conducted in French.

Demographics and Clinical Assessment

All participants provided demographic information, underwent a complete medical history, a general physical examination, and a thorough neurological assessment by neurologists at the Yaounde Central Hospital to detect any focal neurological deficit suggestive of CNS opportunistic infection, before psychometric testing. This thorough clinical assessment of each subject combined with review of his or her prior medical history and subsequent laboratory data, ensured that potential confounding factors such as existing CNS opportunistic infections (OIs) were ruled out.

HIV Serology, CD4 Cell Counts, and Viral Loads

Sample collection and all analyses were performed in the Hematology laboratory of the Yaounde University Teaching Hospital, Cameroon. Venous blood samples were collected and stored at room temperature in the outpatient clinic and analyses performed in the Hematology laboratory within 6 hours of blood collection. The HIV status of each participant was determined using the rapid immunochromatographic HIV-1/2 test (Abbott Diagnostics, Chicago, IL, USA) and the Murex HIV antigen/antibody Combination ELISA (Abbott Diagnostics), according to the manufacturer's instructions. A participant was considered HIV+ if he/she tested positive for the two tests, HIV- if negative for both tests, and discordant if positive for only one test. No discordant result was observed in this study.

Subjects' CD4 T-lymphocyte counts were quantified by flow cytometry, using a Fluorescence Activated Cell Sorting (FACS) Count Instrumentation System and the BD FACSCount CD4 reagent kit (BD Biosciences, San Jose, CA, USA), according to the manufacturer's instructions. The FACS instrument was calibrated and quality control tested before each experiment. For viral loads quantification, HIV RNA copy number in each plasma sample was quantified by reverse transcription polymerase chain reaction (RT-PCR), using Amplicor HIV-1 Monitor Test (Roche Diagnostic Systems, Pleasanton, CA), according to the manufacturer's protocol. The assay detection limit was 40 viral copies / ml.

ART Adherence Questionnaire

The adult AIDS Clinical Trial Group (ACTG) adherence questionnaire [16] was translated into French and validated through back-translation [17]. This ART adherence questionnaire has been validated in population studies in both developed [18-20] and resources limited countries [20-23], and we previously adapted and validated this French version of the ACTG questionnaire in Cameroon [17]. This questionnaire was administered to each subject by a physician (JYF) in a face-to-face interview, and the same physician recorded all interview results. Participants were administered the ACTG questionnaire items that measure adherence behavior, including adherence to ART schedule and medication instructions over the course of their treatment. The physician-administered questionnaire form included the following questions: 1) have you ever missed ART? 2) Have you ever missed ART because of medication side effects? 3) Have you ever missed ART because of excessive drugs? 4) Have you ever had difficulties taking ART at the exact time? For each question, response was categorized into 4 levels of adherence, using a Likert scale: a) never, b) rarely, c) sometimes, and d) often. It was also recorded when patients had stopped taking ART medication, and "stopped" was considered as the 5th level of adherence.

Adherence to ART Refills

The Yaounde Central Hospital has a central pharmacy that dispenses ART medication to patients receiving medical care in the Day-care Service. Each refill is recorded in the hospital computer system, including subject ID, date, and time the prescription was collected by the patient. At each refill, the patient is given a month (30 days) ART supply and instructed to come back to the pharmacy for refill at day-25 (5 days before the drug supply provided runs out). We examined the hospital pharmacy records on September 28, 2015, to identify the individuals among the 171 subjects recruited in our study that also had pharmacy refills records. Our cut-off was any subject that had been on ART for a minimum of 6...