ART initiation and predictive factors among men who have sex with men living with HIV after the implementation of new ART strategy in China: an observational cohort study


 BackgroundChina started the new antiretroviral therapy (ART) strategy since 2016, after which free ART could be provided for all people living with HIV. We aimed to understand the prevalence of ART initiation among men who have sex with men (MSM) living with HIV and to explore how ART-related perceptions, psycho-social status etc. predict ART initiation under the new strategy.MethodsA cohort study (maximum follow-up period = 578 days) was conducted in Guangzhou, China. A total of 303 ART-naïve MSM were recruited from community. Baseline information collected demographic characteristics, HIV/AIDS-related health status, ART-related perceptions, weighting of pros versus cons and psycho-social status. The outcome was ART initiation. Cox regression models were fitted for data analyses.ResultsThe prevalence of ART initiation was 83.8% of all participants and 92.6% of MSM diagnosed recently (within 30 days). In multivariate Cox regression models, HIV-positive MSM received HIV diagnosis ≤30 days were less likely to initiate ART (HR = 0.37, 95% CI: 0.28-0.49). In adjusted analyses, belief that immediate ART initiation would have more benefit for themselves associated with increased ART initiation (HRa = 1.44, 95% CI: 1.06-1.96). In the final model, weighting of pros versus cons and time since diagnosis of HIV infection remained significant.ConclusionThe prevalence of ART initiation was high among MSM living with HIV in Guangzhou. To reach the second 90% target, measures should be focused on MSM previously diagnosed. Interventions showing HIV-positives the benefits of ART were also needed.

To reach the second 90% target, measures should be focused on MSM previously diagnosed. Interventions showing HIV-positives the benefits of ART were also needed.

Background
Globally, Human immunodeficiency virus (HIV) remains to be a severe public health threat, as there are 36.9 million people living with HIV (PLWH) in 2018 [1]. China is also badly affected. As of July 2018, there were 831225 PLWH in China [2]. The HIV epidemic among men who have sex with men (MSM) remained uncontrolled in China.
Growing evidence showed that antiretroviral therapy (ART) is the key to slow down the progression to Acquired immune deficiency syndrome (AIDS) at individual level and reducing HIV transmission at population level [10][11][12]. Based on these evidences, the 90-90-90 target was set and advocated by the Joint United Nations Programme on HIV/AIDS (UNAIDS) in 2014. It aims to have 90% of PLWH knowing about their HIV sero-status, 90% of diagnosed PLWH receiving ART, and 90% of the PLWH on ART achieved viral suppression [13]. Mathematical modelling suggested that achieving this target by 2020 would end the global HIV epidemic by 2030 [14].
The World Health Organization (WHO) soon reacted and recommended all PLWH to receive ART in 2016 [15]. However, coverage of ART among HIV positive MSM was inadequate and varied greatly across regions, ranged from 1%-6.5% in some Asian countries (e.g., Thailand and Pakistan) to 78%-87.6% in Australia and Germany [4].
In response to the changes of WHO guidelines, the Chinese National ART Guideline were also updated. Since 2014, free ART was recommended to all PLWH with CD4 counts ≤500 cells/mm 3 . The guideline started to recommend free ART to all PLWH regardless of their CD4 counts since June 2016 [16]. The implementation of "treat all" shed lights of improving the ART coverage [17][18][19]. In China, the overall ART coverage has been increasing after the changes in National ART Guideline (from 67% in 2015 to 74% in 2017) [4,20]. However, HIV positive MSM reported lower ART use than other HIV-infected groups and required more attention [21]. Before the era of "treat all" (in 2013), a group of newly diagnosed HIV positive MSM in China was offered free ART regardless of their CD4 counts, only 62% of them started ART within one year [22]. Another study conducted after the implementation of "threat all" (in 2016) reported that 69.9% of HIV-positive MSM with CD4 counts >350 cells/mm 3 intended to initiate ART [23]. Longitudinal study is needed to understand predictors of ART initiation among MSM in China in the era of "treat all". Such information is important for developing effective interventions to support the implementation of the new National ART Guideline.
Perceptions related to ART were associated with behavioral intention to initiate ART among HIV-positive MSM in China. Behavioral change theories are useful in guiding the development of interventions for a particular health behavior [24]. The Health Belief Model (HBM) was one of the most commonly used behavioral theories to explain/predict health-related behaviors. It was used as framework for selecting perceptions related to ART in this study [25] The HBM has six constructs, including perceived susceptibility, perceived severity, perceived benefits, perceived barriers, cue to action, and self-efficacy [25,26]. As compared to ART initiation at a lower CD4 cell level, immediate ART initiation would have significant benefit for their sex partners (i.e., reduce risk of HIV transmission) but modest clinical benefit for themselves, while similar side effects may occur [27][28][29]. In this context, perceptions related to ART may involve weighting pros (potential benefits for oneself and others) versus cons (potential harm for oneself). In this study, we will explore whether one might be altruistic when considering pros for protecting others even if there are side-effects and limited immediate personal benefit. Weighting of pros and cons were associated with use of condom, pre-exposure prophylaxis, and HIV testing [30][31][32]. No study had investigated the association between such perception and ART initiation.
Mental health problems (e.g., depression and anxiety) are the most commonly reported comorbid conditions of PLWH [33]. Previous studies showed high prevalence of depression and anxiety among HIV positive MSM (40%) [22,34].
Mental health problems were reported to contribute to delays in ART initiation among PLWH in general and HIV-positive MSM [35][36][37]. There is strong public stigma toward PLWH [38], which is strongly associated with their mental health problems and lower utilization of health-related services [39]. A cross-sectional study among HIV positive MSM in the U.S. showed that perceived higher public stigma related to HIV infection was associated with lower uptake of ART [40]. HIV-positive MSM may also develop internalized stigma (self-stigma), which is prevalent and associated with non-disclosure of his sero-status, low self-esteem and poor mental health [41].
Its association with utilization of ART has however, not been well studied. Social support is protective of mental health problems and utilization of health-related services among MSM [42]. Cohort studies showed that better social support predict better adherence to ART and viral suppression [43,44]. However, the association between social support and ART initiation is not well-studied.
Previous studies showed that variables related to socio-demographics (e.g., age, education level), disease-related characteristics (e.g., CD4 cell counts, time since HIV infection) were associated with ART initiation among HIV-positive MSM [45,46].
These variables were also considered by this study.
This study was to investigate factors predicting of ART initiation within follow-up period among a sample of HIV-positive MSM who had never received ART in China.
Potential predictors measured at baseline included socio-demographics, diseaserelated characteristics, perceptions related to ART and psychosocial variables.

Study design
This study was conducted in Guangzhou, China. Guangzhou is the capital city of Guangdong Province with 14.5 million residents in 2017 [47].

Participants and data collection
The inclusion criteria included: 1) aged at least 18 years, 2) received confirmatory HIV diagnosis, 3) without contradiction of ART initiation, 4) had never received ART before the date of baseline survey, and 5) willing to have the research team access their ART-related information in the national HIV/AIDS comprehensive information system. Exclusion criteria included presence of: 1) major psychiatric illness (schizophrenia and bipolar disorder), and 2) not able to communicate with the interviewers.
Participants were recruited from 6 out of 11 administrative districts of Guangzhou with relatively high HIV prevalence for the survey. There are six district Center for Disease Control and Prevention (CDC) and 29 community healthcare centers (CHC) providing HIV treatment and care for PLWH. To avoid selection bias, all HIV-positive MSM on the service record of these CDC/CHC were invited to join the study. Trained staff of these CDC/CHC contacted all HIV-positive MSM on their service records through telephone and/or during their regular follow-up, screened their eligibility, briefed them about the study, and assured them refusal would not affect their right to use any services and they could quit at any time without being questioned.
Participants were asked to leave their ID number for extracting the date of ART initiation from the National HIV/AIDS Comprehensive Information System. Guarantee was made that their ID number would be kept strictly confidential, and would not appear in the questionnaire or dataset for analysis. Those who showed interest in the study were asked to visit one of these CDC/CHC. Out of 461 eligible HIV-positive MSM approached, 102 (22.1%) declined to participate in the study, and 359 (77.9%) provided written informed consent to join the study, and 303 (84.4%) completed the baseline survey. No name or personal contact was collected during the interview.

Design of the questionnaire
A panel consisting of epidemiologists, health psychologists, and CDC/CHC workers was formed to design the questionnaire. The questionnaire was tested among 15 HIV-positive MSM. Based on their feedback, discussion was made by the panel to finalize the questionnaire.

ART initiation
Using their ID number as identifiers, date of initiating ART for the first time was extracted from the national HIV/AIDS comprehensive information system. Therefore, we could access all participants' status of ART initiation within the follow-up period.
For participants who had initiated ART within the 12-month follow-up period, the observational time was the time interval between the date of baseline survey and the date for initiating ART for the first time. For those who had not initiated ART within the follow-up period, their observational time was the entire follow-up time interval.

Background characteristics of the participants measured at baseline
Participants' background information was collected, including demographic characteristics (age, marital status, education level, income level, medical insurance, household registration) and disease-related characteristics (Time since diagnosis of HIV, CD4 cell counts in the most recent episode of testing, and selfrated their health status).

Perceptions related to ART measured at baseline
Five scales were constructed for this study to assess perceptions related to ART.
They were based on the HBM.
Perceived severity of delayed ART initiation was measured by four items (e.g., 'Failure to participate in treatment in time could lead to poor treatment effect'). The Perceived Severity Scale was formed by summing up individual item scores (1=strongly disagree to 5=strongly agree). Higher scores on the scale indicated that consequences of delayed ART initiation were perceived to be more severe.
Six items (from 1=strongly disagree to 5=strongly agree) were used to measure perceived benefit of immediate ART initiation (e.g., 'Participate in ART in time can effectively improve CD4 cell counts'). The Perceived Benefit Scale was formed by summing up individual item scores. Higher score indicated that participants perceived more benefit for initiating ART immediately.
Perceived barriers of immediate ART initiation was measured by six items (e.g., 'Early treatment means you have to suffer from the side-effects for a longer time'), with the following response categories (from 1=strongly disagree to 5=strongly agree). The Perceived Barrier Scale was formed by summing up individual item scores, higher scores indicated participants perceived more barriers to initiate ART immediately.
Cues to action were measured by 2 items (e.g., 'People who are important to you (relatives or spouses) support you to participate in the treatment in a timely manner'). The Cue to Action Scale was formed by summing up individual item scores (1=strongly disagree to 5=strongly agree). Higher scores on the scale indicated more events or information from close others promoting ART initiation were perceived.
Five items were used to measure perceived self-efficacy of immediate ART initiation (e.g., 'How confident you are about participating in ART') (response categories: 1=none to 5=a great deal). The Perceived Self-Efficacy Scale was formed by summing up individual item scores, with higher score indicated perceived higher self-efficacy in initiating ART immediately. The Cronbach's α of these five scales ranged from 0.80 to 0.91.

Weighting of pros versus cons related to immediate ART initiation measured at baseline
Regarding weighting of pros versus cons related to immediate ART initiation, participants were asked to rank the overall advantages versus overall disadvantages for immediate ART (1= disadvantages prevail, 2= disadvantages and advantages are similar, 3=advantages prevail), and its benefit for themselves versus others (1=more benefits for oneself, 2=more benefits for others, 3=benefits for oneself and for others are similar, 4=not sure).

Psychosocial variables measured at baseline
Probable depression was measured by validated Chinese version of the Patient Health Questionnaire-9 (PHQ-9) [49], which has been widely used in studies targeting PLWH and MSM. Responses were reported by using a four-point Likert Scale ranging from 0 (rarely or none of the time) to 3 (most or all of the time).
Generalized anxiety disorder was measured by validated Chinese version of the 7item Generalized Anxiety Disorder Scale (GAD-7) [51] (Response categories: from 0= rarely or none of the time to 3= most or all of the time). Scores of 0-4, 5-9, and ≥10 were defined as minimal, mild, and moderate-severe anxiety symptoms. In this study, Cronbach's alpha of the GAD-7 was 0.947 [51].
Perceived social support was measured by the 12-item multidimensional scale of perceived social support (MPSSS) from three 4-item subscales (i.e., family (FA), friends (FR) and significant others (SO)) [52]. Each item is rated on a 7-point Likerttype response format, the possible scores range from 4 to 28 for each subscale [52]. Cronbach's alpha of FA, FR and SO were 0.883, 0.844 and 0.834 respectively.
Public HIV-related stigma was measured by Chinese Courtesy Stigma Subscale (CCSSs) of Public HIV-related Stigma Scale [53,54]. The subscale contains 13 items, with a 4-point ordinal response format ranging from 1 to 4. A lower score indicates the higher perceived public stigma [53]. Cronbach's alpha of CSSSs was 0.925.
Self-stigma was measured by the 9-item short version of the Self-Stigma Scale (SSS-S) [55]. Each item is rated on a 5-point Likert-type response format ranging from 1 to 5. A higher score indicates a higher level of self-perceived stigma [55].

Statistical analyses
Using background variables measured at baseline as independent variables, univariate Cox regression models were used to estimate hazard ratios (HR u ) and respective 95% confidence interval (CI). Baseline background variables with p<0.05 in such univariate analysis were used as candidates for fitting a forward stepwise

Background characteristics
Of the 303 participants, majority of them were no more than 30 years old (53.1%), currently single (69.3%), with monthly income ≤5000RMB (about 700 USD) (72.0%), having medical insurance (67.3%) and without household registration of Guangzhou (74.8%). About half of the participants had attained at least college education (45.5%).
Regarding disease-related characteristics, 62.0% received HIV diagnosis within 30 days, 55.4% had CD4 count ≤350 cell/ μL in the most recent episode of testing, and 40.3% self-rated their health status as good/very good (Table 1). HR m : hazard ratios of multivariate Cox regression models (forward) using variables with p<0.05 in univariate analysis as candidates.

ART initiation
The duration of follow-up of the participants ranged from 1 day to 578 days (median

Perceptions and psychosocial variables measured at baseline
Item responses and scale scores (Mean, SD) of perceptions related to ART based on the HBM and psychosocial variables were presented in Table 2. We also divided the participants into different categories according to the answers of each item, an additional file shows this in more detail [see Additional file 1]. Figure 1 showed that people who were diagnosed within 30 days had higher ART initiation as compared to those who were diagnosed for more than 30 days (92.6% versus 69.6%; log-rank P < 0.0001); Figure 2 showed that the cumulative rate of ART initiation was 86.9%, 81.3% and 77.3% among those with the latest CD4 cell counts below 350, 305-500, and above 500, respectively (log-rank P < 0.001).

Factors predicting ART initiation
In

Ethics approval and consent to participate
The study protocol was reviewed and approved by the Institutional Review Board (IRB) of the School of Public Health, Sun Yat-sen University, Guangzhou, China (No: participated in the study.

Consent for publication
Not applicable.

Availability of data and materials
The datasets used or analysed in the current study are available from the corresponding author on reasonable request.

Competing interests
YTH is a member of the editorial board of BMC Infectious Diseases.

Authors' contributions
WYC, ZXW and XYF were involved in study design, data collecting, paper conceptualization, data analysis, and paper writing. LHL, HFX and LRF were involved in data collecting, quality control and project administration. XD and TLY were involved in data collecting and data analysis. FY, CH, JHL and YTH were involved in study conceptualization and paper editing. JG was in charge of the study, and involved in study conceptualization, paper conceptualization, data analysis, project administration and supervision and paper editing. All authors contributed to the interpretation of the data and approved the final version for submission