Background
Despite remarkable progress in HIV prevention and treatment, there were still 1.7 million newly HIV-infected people in 2019 and 38 million people were living with HIV globally [
1]. About 23% of new adult HIV infections in 2019 were men who have sex with men (MSM) [
1]. In China, there were 1,045,000 reported cases of HIV by the end of October 2020 [
2]. Similarly, MSM accounted for 23% of new infections in 2019 [
3]. Though MSM only constituted small proportions of the general population, they are at increased risk of acquiring HIV infection.
The introduction of combination antiretroviral therapy (ART) has dramatically reduced morbidity and mortality of people living with HIV (PLWH) [
4]. Consistent and complete adherence is considered an essential requirement for PLWH on ART to avoid treatment failure, disease progression and realize its life-extending benefits. However, maintaining a high level of adherence remained a challenge in some regions. For example, a meta-analysis in China showed that the mean rate of > 95% ART adherence dropped from 81.1% at 1 week to 68.3% at 3 months or longer [
5]. A broad range of factors associated with ART adherence have been reported including individual-related factors (e.g., understanding of the adherence), treatment-related factors (e.g., adverse drug reactions), psychosocial factors (e.g., depression and stigma) and structural factors (e.g., health workers’ attitudes) [
6,
7]. However, these factors usually differed across regions and populations due to different demographic characteristics, culture and availability of resources.
As HIV cannot be eradicated yet, it is essential to know whether PLWH can maintain ART adherence over time. A study in UK and a bi-regional cohort in sub-Saharan Africa and Asia found that the risk of suboptimal adherence decreased with ART duration extended [
8,
9]. On the other hand, some prospective studies have reported the adherence to ART declined over time [
10‐
13]. However, most of these studies had short follow-up time (< 24 months), had moderate sample size (< 200), and were conducted in high-income countries (e.g., USA and Canada) before 2010. Studies conducted in different regions, having different observation periods, or measuring adherence using different methods provided conflicting results.
In China, the National Free Antiretroviral Treatment Program (NFATP) was initiated in 2002 and then scaled up rapidly [
14]. Following WHO guidelines, China regularly updated the national ART guidelines and started providing free ART to all PLWH regardless of their CD4 levels in June 2016 [
15]. Considering that standards of ART initiation and related policies changed over time, it was necessary to understand whether PLWH with different ART duration reported consistent adherence. However, to our knowledge, few studies in China examined the association between ART duration and adherence among PLWH, especially among MSM.
Therefore, this study aimed to evaluate the impact of ART duration on ART adherence, identify the trend of complete adherence based on different ART durations, and compare the factors associated with ART adherence between those on short-term (i.e., ≤ 3 years) and long-term (i.e., > 3 years) ART among MSM living with HIV in Jinan of China.
Methods
Setting and participants
This survey was conducted in an infectious diseases hospital in Jinan, Shandong Province of China from October to December in 2020. The hospital serves more than 2000 PLWH, accounting for more than 90% of PLWH in this city. Among them, MSM patients accounted for about 80%. According to ART guidelines in China, all patients need to visit the health care providers in the designated hospital at least every 3 months for medication refilling and related testing (e.g., blood and urine testing).
All eligible patients waiting for their medical visits were invited to participate in this study. Inclusion criteria included: (1) aged 18 years or above; (2) HIV-diagnosed positive and currently on ART in this hospital; (3) born biologically male; and (4) having ever had anal sex with men.
Survey procedures and data collection
The participants were recruited from the sexually transmitted infections (STI) outpatient clinic of the hospital where PLWH visited regularly for medication refilling using convenience sampling from October 19 to December 4 in 2020. Patients seeking medical visits were referred to a waiting room by the physicians and invited to participate in this study. Those who were interested received a detailed introduction of this study by trained investigators. Those who met the inclusion criteria were asked to provide written informed consents and complete a self-administrated questionnaire. When a questionnaire was completed, investigators checked immediately to identify potential logical errors and verify with the participants. All eligible participants were reimbursed 50 Chinese Yuan (CNY) (about 7.47 USD) after the verification was completed.
The self-administrated questionnaire was developed based on literature review and revised by local STI experts. The information collected included: (1) socio-demographic and risk behavioral characteristics of participants, including age, household, monthly income, education, occupation, marital status, alcohol use, drug use, and medical insurance, etc.; (2) disclosure of sex orientation and HIV status; (3) situation of ART, including year of HIV diagnosis, year of ART initiation, whether having medication reminders, whether reporting side effects, schedule and frequency of daily medication-taking, and etc.; (4) 12-item ART medication knowledge; (5) HIV treatment adherence self-efficacy, which was measured by the 12-item HIV-ASES-Chinese-Version [
16]; and (6) ART medication adherence in the past month, which was measured using two questions including “How many times have you missed ART medications in the past month” and “how often did you take medications within one hour of prescribed time in the past month”. Those who took all medications within one hour of prescribed time were defined as “complete adherence”. Otherwise, men were defined as “suboptimal adherence”.
Data management and statistical analysis
All data were double entered with Epidata 3.1, and discrepancies were checked against the raw data. Descriptive analysis was conducted to compare differences between short-term ART group (i.e. ART initiation ≤ 3 years) and long-term ART group (i.e. ART initiation > 3 years) using chi-square tests or student’s t tests. The grouping was based on current Chinese national ART guidelines released in 2016 that started providing free ART to all PLWH regardless of their CD4 levels [
15]. First, a series of univariate logistic regressions were used to determine the association between the independent variables (ART duration as continuous variable and potential covariates) and outcome variable (ART adherence). We included sex role, sex orientation and sex orientation disclosure in univariate regressions because these characteristics may be mediated by psychosocial and behavioral factors influencing ART adherence [
17,
18]. Then variables with
P-values < 0.1 in the univariate regressions were eligible for entry into the multivariable logistic regression, where adjusted odds ratio (AOR) with 95% confidence intervals (CIs) and two-side
P-values were calculated. Stepwise method was used in multivariable analysis to select variables and reduce the effect of collinearity. Simultaneously, one-side Mann–Kendall test was used to identify the trend of proportions of PLWH with complete ART adherence. In addition, subgroup analysis was conducted to compare the factors associated with ART adherence between short-term and long-term ART group.
Data management and descriptive analysis was conducted by SPSS 24.0. The logistic regressions and Mann–Kendall test were conducted by R 4.0.4.
Ethics approval
The study was conducted in accordance with the Declaration of Helsinki. This study was approved by the Ethical Review Committee of School of Public Health in Shandong University (20190210). The written informed consents were obtained from all participants.
Discussion
In this study, we investigated the impact of ART duration on ART adherence among MSM living with HIV in Jinan of China. Simultaneously, we identified the trend of proportion of PLWH with complete adherence based on different ART durations. In addition, we explored and compared factors associated with ART adherence between short-term and long-term ART group.
This study showed that participants with longer ART duration were less likely to report complete adherence, which was consistent with studies in Europe and US [
10‐
13] but inconsistent with a cohort study in Asia and Africa [
8]. However, this cohort study mainly included Southeast Asian countries where ART polices were different from China and measured adherence using visual analogue scale without considering adherence to dosing schedule. Our findings may be because the longer the ART duration, the more likely the patients feel “tired” for the treatment. Further, long-term asymptomatic status may make some patients doubt whether it is necessary to maintain complete adherence. Studies have shown that higher current CD4 level was correlated with higher likelihood of non-adherence to ART among patients on long-term ART, which indicated the patients’ patience to maintain complete adherence decreased over time [
19,
20]. In addition, NFATP in China scaled up rapidly and China entered the era of “Treat all” in 2016. Evidence showed that early initiation of ART regardless of CD4 level can lead to higher likelihood of adherence [
21]. Further, our study found that more participants on short-term ART received pre-ART adherence education via Internet (e.g., WeChat or QQ) (see Additional file
1: Table S3). These digital platforms can significantly improve interactions between patients and healthcare providers, which can effectively enhance medication self-efficacy and decrease medication-taking difficulties [
22]. Our findings indicated the importance of sustained efforts to emphasize continued adherence over time, especially for those on long-term ART.
The proportions of complete ART adherence in the past month was 75.6% in this study, which was lower than a meta-analysis in China (80.9%, 95% CI 74.7–85.9%) [
5]. This may be due to different methods of measuring adherence. Most studies only focused on missing doses and few evaluated non-adherence to dosing schedule. However, complete ART adherence involves not only avoiding missing doses, but also taking the pills at the right time and in the right way. Taking ART medications at irregular times can change its pharmacokinetic and pharmacodynamics effects, which may exacerbate the risk of treatment failure and drug resistance [
23]. Obviously, non-adherence to dosing schedule should not be neglected.
We found that alcohol use was a key barrier to complete ART adherence, which was consistent with many studies demonstrating the harmful effects of alcohol use on ART adherence and other HIV-related outcomes [
24‐
26]. Lack of medication reminder was another important barrier for both of the groups. It was noteworthy that forgetting was the most frequently cited reason of ever missing doses (see Additional file
1: Table S1). Challenges related to forgetfulness can be overcome through providing reminder services. Text messaging have been widely used and recommended by WHO for its convenience and cost-effectiveness [
27,
28].
Studies have evaluated the association between HIV status disclosure and ART adherence, but few explored the effect of sex orientation disclosure on ART adherence among MSM living with HIV [
29‐
31]. This study found that individuals who disclosed their sex orientation were less likely to report complete adherence. Traditionally, MSM were not acceptable in Chinese society even before the HIV infection [
32,
33]. Disclosure of MSM orientation may result in the increase of psychological pressure, which was reported a key barrier to ART adherence [
6]. In China, sex orientation disclosure might be even more difficult than HIV status disclosure among MSM living with HIV. Bisexual men were less likely to report complete ART adherence compared with homosexual men. This phenomenon was also observed in long-term ART subgroup. In China, adults are expected to get married at a certain age. Different from homosexual men, bisexual men with long-term ART were more likely to eventually get married with heterosexual women, which may increase anxiety and stress to keep the secrets from family members [
17,
34]. In short-term ART group, MSM who were receptive role were more likely to report complete adherence compared with insertive role. It was reported that HIV-positive gay men usually had one or more sexual problems (e.g. erectile dysfunction) [
18] and tended to be receptive role. Consequently, they may be more likely to report complete adherence to acheive viral suppression and reduce their partners’ risk of HIV acquisition. Physiological and psychological differences between receptive and insertive MSM may also influence the interpretations of this finding. In-depth interviews are needed to better reveal the phenomenon.
This study has important public health implications. First, the study indicated the importance of sustained efforts to emphasize continued adherence over time, especially for those on long-term ART. Digital platforms (e.g., WeChat and QQ) can be utilized to improve healthcare interactions. Second, the focus should be on individuals who use alcohol and do not have medication reminders. Alcohol screening and text messaging reminder services can be integrated into routine management of PLWH. Third, subgroup analysis showed that factors associated with ART adherence were not completely consistent between short-term and long-term ART group, which indicated the necessity of tailored intervention. In addition, future qualitative studies need to be conducted to further understand the psychosocial mechanism of the assocations between sexual characteristics (e.g., sex role and sex orientation) and adherence among MSM.
Although some important findings are revealed in this study, there are also limitations. First, ART adherence was measured through self-report instead of more objective measurement such as electronic monitoring, CD4 T-cell counts and HIV viral load. Due to cost and timeline, we did not collect biological samples. However, evidence showed self-report adherence was strongly associated with HIV viral load [
35]. Second, the findings may not be generalizable to all MSM living with HIV because the participants were recruited from one hospital in Jinan using convenience sampling. Finally, adherence is a complex dynamic phenomenon influenced by individual and contextual factors. Unobserved factors may confound the impact of ART duration on adherence. A long-term cohort in Chinese context is needed to monitor ART adherence in the future.
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