Barriers and facilitators of Pre-exposure Prophylaxis (PrEP) intention among Chinese men who have sex with men

Despite strengthened to increase in a highly effective HIV prevention tool, has recently been included in Action Plan of and To inform future PrEP implementation, this study aims to identify the barriers and facilitators of PrEP intention among MSM in China.


Introduction
Despite strengthened efforts on HIV prevention and control, new HIV infections continue to increase among men who have sex with men (MSM) in China due to the presence of multiple sex partners and unprotected sex. HIV prevalence among MSM populations ranged from 5.0-20%, while incidence was reported between 1.6-6.6% [1,2]. Similar trends were also observed in other countries in South-East Asia [3].
Pre-exposure prophylaxis (PrEP), which involves individuals at high risk of HIV taking HIV anti-retrovirals such as Truvada (tenofovir/emtricitabine) (TDF/FTC), is highly effective at preventing HIV acquisition [4]. Clinical trials have demonstrated that taking oral TDF/FTC daily decreases HIV risk by up to 99% when adherence is high [4,5]. In addition to evidence from clinical trials, a prospective cohort study in Australia showed that PrEP implementation was associated with a rapid decline of HIV incidence among MSM at the population level [6]. A mathematical modeling study of Chinese MSM demonstrated that PrEP would be an important and cost-effective biomedical intervention if added to the existing HIV prevention programs in China [7]. Therefore, as part of a combination prevention approach, PrEP implementation has been included in the latest Five-Year Action Plan of HIV Prevention and Control by the Chinese government.
Due to its robust e cacy in preventing HIV infection in high-risk men and women, oral TDF/FTC has been approved by the FDA in the US and other countries since 2012. However, the uptake rate among high-risk individuals is very low in some countries [8,9]. Two strong cohort studies of MSM in the United States found that only 4% of the participants reported PrEP use [8,9]. Meanwhile, previous studies have indicated that poor adherence to daily PrEP often leads to a dramatic compromising of its HIV prevention e cacy [10]. Furthermore, while some people with high risk behaviors in China have heard of PrEP, many may be uncertain about the e cacy of PrEP due to accessibility issues and insu cient knowledge, and thus do not intend to use it [11]. Individuals who engage in relatively high-risk behaviors are more likely to use PrEP [12]. However, a previous study has also demonstrated that some high-risk individuals are not willing to use PrEP [13]. It is hence important to explore the barriers to PrEP intention among these individuals. Meanwhile, to increase uptake and adherence, additional alternatives, including injectable and implanted PrEP, have been under investigation in recent years [14,15]. Such alternatives include longacting injectable drugs and sustained release implanted drugs [16,17].
MSM and medical care workers are often concerned with the relationship between high risk sexual behaviors and PrEP use [18,19]. In addition to barriers such as insu cient knowledge, lack of prescribing providers, and concerns about side effects, HIV-related stigma is still experienced by potential and current PrEP users. For example, since antiretrovirals are also used to treat HIV-infected people, PrEP users often have concerns that others may think that they are HIV positive or engage in socially stigmatized behaviors such as injection drug use, unprotected sex and multiple sex partners [20,21]. They may also be concerned that others think they have an HIV-infected partner, which continues to be stigmatized by society [22,23]. In addition, if assessing the risk of acquiring HIV is an indicator of prescribing PrEP by medical care workers, stigmatization might be perceived by those desiring PrEP medicine at clinics. This is because those who are suggested to use PrEP by medical care workers are believed to have a greater risk of acquiring HIV infection. In other words, those who are suggested to use PrEP might be judged by others as being overtly promiscuous.
At present, Truvada is applying to the Chinese FDA to classify the drug as an HIV prevention tool. Once approved, PrEP programming and scale-up will likely be one of China's HIV prevention priorities. Therefore, in order to inform future PrEP prevention efforts, it is critical to identify factors associated with PrEP intention among Chinese MSM. The objective of this study is to identify the barriers and facilitators of PrEP intention among MSM in China.

Participants and procedures
From August to October 2018, study participants were recruited in Nanjing to complete a survey about PrEP use intention and related information. Prior to conducting the cross-sectional survey, a focus group of 15 MSM was conducted where we used an interview guide exploring PrEP knowledge, barriers and facilitators of using PrEP, sexual behavior and sexual risk. Findings from the focus group were used to develop and re ne the survey measures.
We utilized a multifaceted sampling approach to recruit participants. This involved online advertising, social media, referrals from community-based organizations and clinics, and recruiting the peers of eligible participants who completed the survey. 300 individuals completed an on-line anonymous questionnaire survey. To meet the eligibility criteria, participants needed to be: 1) male sex at birth; 2) 18 years old or older; 3) sexually active with other men in the past year; 4) HIV-negative or unknown. An informed consent was displayed if the participants met the eligibility screening questions. Participants received a 50RMB pre-paid cellphone card for completing the survey. The study was approved by the Institutional Review Boards of Chinese Center for Disease Control and Prevention in Beijing.

Measures Background characteristics
Participants were asked about their socio-demographic characteristics including age, educational background, marital status, employment, income, and sexual orientation. The time of their latest HIV test was also asked.
Awareness, knowledge, accessibility and intention to use PrEP Participants were explained the de nition of PrEP in the informed consent. They were asked whether they intended to use PrEP daily or before/after having sex to prevent HIV. Four questions assessed PrEP awareness and knowledge. These questions asked participants if they had heard of PrEP, what the percentage of PrEP e cacy was, whether PrEP could prevent HIV if taken as prescribed, and whether PrEP could cause serious side effects. Another three questions assessed concerns of accessibility: I don't know where to get PrEP drugs, I don't know whether the doctors will prescribe PrEP drugs if I go to the clinic, and whether PrEP could be scaled up in China. Questions regarding intentions to use injectable and implanted PrEP instead of oral PrEP, and the reasons for using injectable and implanted PrEP were also asked. With exceptions for the questions on PrEP e cacy and the reasons for using injectable or implanted PrEP, all response options were either Yes or No.

Sexual behaviors in the last 6 months
We asked participants about their sexual behavior in their past 6 months. Questions included number of male partners, number of positive male partners, number of times having condomless receptive anal intercourse (CRAI) with partners of any HIV status, number of times having condomless insertive anal intercourse (CIAI) with positive partners, and whether they used amphetamines and poppers. With considerations of age, we used the 7-item screening index with a cutoff (if score is 10 or greater, prescribe PrEP or offer other intensive HIV prevention services; If score is 9 or less, provide standard HIV prevention services developed in previous studies to prioritize individuals for intensive HIV prevention efforts, including PrEP [13]. Furthermore, participants were asked about their condom use with regular male sex partners, casual male sex partners, commercial male sex partners and female sex partners. Response options for these questions were always, frequently, occasionally and never use condom.

External HIV stigma
Public stigma is the attitudes and reactions that the general population has towards people who have a particular or undesirable attribute, such as homosexuality or HIV infection [24]. In this study, public HIV stigma was measured by the 7-item subscale from the Chinese version of HIV and homosexuality-related stigma scales [25].

Perceptions on barriers and facilitators of using PrEP
Participants were also asked about their reasons for not using PrEP, motivations to use PrEP accessibility and affordability issues, opinions on promoting PrEP in China and willingness to use PrEP in the next 6 months.

Data Analysis
Descriptive statistics, including numbers and percentages, were calculated for all variables. Bivariate generalized linear modeling with a binary logistic distribution was conducted to examine background variables related to PrEP intention. Background variables that were signi cant at the bivariate level (p <0.05) were adjusted in further multivariate analysis for factors related to PrEP intention. Results were reported as odds ratios (OR) and adjusted odds ratios (aOR).

Results
Background characteristics Table 1 presents the background characteristics of the sample. A total of 300 individuals participated in the questionnaire survey. 55.67% of the sample were between the ages of 18-28, 70.67% completed some college or higher, 90.00% were single, 79.33% had a full-time job, 52.67% had a monthly income over 5000RMB ($745), 77.67% self-identi ed as gay, 81.67% had been HIV tested in the past 6 months. Sexual behaviors in the last 6 months    Experience of PrEP use and perceptions on barriers and facilitators of using PrEP  The motivations for using PrEP included 'with HIV positive partner' (25.56%), 'with HIV status unknown partner' (77.13%), 'fond of the partner' (29.15%) and 'frequent sex behavior' (47.98%). 87.00% of participants would like to use condoms while using PrEP to ensure safety. The most preferable way of getting PrEP is from 'CDC' (48.46%), followed by 'online shopping' (28.63%), 'hospital' (10.13%), 'community' (8.37%) and 'pharmacy' (4.41%). In total, 85.02% of the participants' affordable price is less than 500 Yuan/month. Regarding using generic PrEP drugs, 49.78% stated this was unacceptable and 42.29% would use generics with a lower price if these drugs were provided by a quali ed pharmacy in China.
The willingness to take PrEP increased to 82.33% and 91.00% if the price is affordable and if the indication of PrEP got approval, compared to the 75.34% willingness without any prerequisite.

Discussion
Improving uptake of oral PrEP as a prevention measure for individuals at high risk of HIV has been challenging since it was rst approved in 2012 in the US and other countries. While daily dosing of PrEP could result in signi cant reduction in HIV incidence and has been widely promoted in developed countries [4], uptake of PrEP has been low despite increasing awareness [27]. In our study, nearly half of the participants never heard of PrEP as one of the approaches to prevent HIV. This estimate is much higher than that in the US where just 20% of MSM had never heard of PrEP [28]. In addition, compare to a 19.1% willingness to use oral PrEP in a study of MSM in Shanghai [29], acceptability of PrEP was much higher in our study. However, the real-world effectiveness of oral PrEP would be determined by pill-taking behavior of the population at high risk for HIV. Although intention to use PrEP has increased, it may not necessarily translate to actual PrEP uptake. In another word, self-reported intentions and actual behaviors can be more or less disconnected in various circumstances [22]. For example, in the clinical trial study in Shanghai, actual uptake was only 2.5% compared to 19.1% of participants who said they were willing to use oral PrEP [29]. Therefore, effective strategies to increase PrEP use should underscore the feasibility of promoting PrEP, including improving awareness of PrEP related knowledge, coverage of medical insurance or adjust the market pricing of PrEP to make it affordable to people who are really in need, and even the characteristics of the PrEP pills (color, size etc.) [30].
PrEP has been suggested as the most cost-effective and promising way to decrease HIV incidence among at-risk MSM in previous modeling studies [31]. The Clinical Screening Index had been developed to be used to prioritize individuals for PrEP use and used by US CDC [19]. It was found that individuals who had engaged in high risk behavior were more likely to nd PrEP acceptable than those who had not [32]. Furthermore, willingness to use PrEP was also associated with perceived risk of acquiring HIV [33]. However, in a trial of PrEP use in the US, it was found that MSM with actual high risk behaviors reported low risk perception and declined to use PrEP [34]. Similarly in our study, while the percentage of participants with multiple male partners, inconsistant condom use and sexual risk index scores more than 10 were nearly 50%, high risk score was not signi cantly associated with PrEP intention. Therefore, to identify the gap between perceived high risk and actual high risk behaviors among MSM would be bene cial to future PrEP implementation. For example, regular targeted HIV and sex education, in combination with accessible PrEP counseling and support could be an effective strategy. Finally, a modi ed screening index of PrEP use speci c to the MSM populations in China may also be needed to accurately identify individuals at high risk for HIV.
Similar to previous ndings among MSM in the US and other countries, beliefs of e cacy was associated with the intention of PrEP use [32,35]. To maximize acceptability of PrEP, awareness, correct knowledge and information on PrEP are critical to improving willingness of PrEP use among MSM. Su cient information distribution and marketing of PrEP from various sources such as CDC, HIV clinics, community organizations and social media has the potential to increase PrEP uptake once PrEP is approved in China.
From this study, nearly 85% of the participants can afford the price no more than 500 yuan a month and 70% can accept the generic drugs with lower price from various sources. Meanwhile, insu cient message, lack of relevant experience by doctors, the privacy concerns and coverage of medical insurance are major barriers of promoting PrEP in China. Consequently, to develop PrEP use manuals suitable for doctors and potential PrEP users, to set up an e cient drug supply system and to carry out appropriate media publicity measures would be bene cial in promoting PrEP among MSM population, and thus make the prevention roles of PrEP truly effective in preventing HIV.
Concerns of side effects have been identi ed as one of the major reasons of not willing to use oral PrEP among study participants, this was consistent with previous studies among Chinese MSM [36,37] and MSM in other countries [38]. While there are some side effects when rst starting the medication, such as nausea and frequent vomiting, they usually abate after two months into the regimen [4,39]. However, kidney function decline and bone mineral density decrease were also reported among long-term PrEP users in clinical trials [40,41]. In addition, traditional Chinese beliefs that medicine is somewhat toxic, would also be a barrier for MSM to take medicine before illness occurs. As a part of China's national HIV/AIDS prevention strategy, PrEP is expected to be scaled up in the coming years. Therefore, in addition to disseminate correct knowledge on the e cacy of PrEP, accurate drug safety information of potential short-term and long-term side effects as well as bene ts of using PrEP, which may outweigh side effects, may improve uptake and adherence in the future.
77% of the participants intended to try injectable or implanted PrEP compare to oral PrEP, which suggests us the necessity of studying or introducing some additional alternatives for PrEP, such as injectable PrEP with a cycle of 2-3 months or long-acting sustained release implanted PrEP, in order to increase PrEP adherence and meet the different needs for MSM to uptake PrEP [14,15]. Concerns that doctor may not prescribe PrEP have been identi ed as one of the major reasons of willing to try injectable or implanted PrEP among study MSM. Since there are prejudice and discrimination against MSM or people living with HIV/AIDS, MSM would not disclose their sexual orientation to physicians due to privacy or discrimination concerns in the course of seeking medical treatment, which will seriously affect the promotion of oral PrEP. Accordingly, apart from the developing new regimen of injectable or implanted PrEP, a more supportive social environment needs to be created to promote the use of PrEP among the target population.

Conclusion
Given the low awareness of PrEP-related information in China, a comprehensive package in delivering PrEP, including regular HIV and PrEP education, and further development of feasible intervention strategies targeting high risk individuals and communities would bene t the scale up of oral PrEP.
Furthermore, injectable or implanted PrEP should be investigated as additional alternatives to improve uptake and adherence of PrEP. These ndings also highlight the importance of a more supportive social environment for MSM when implementing PrEP programs that are approved by China's FDA.

Declarations
Ethical Approval and consent to participate The study protocol was reviewed and approved by the Institutional Review Boards of Chinese Center for Disease Control and Prevention in Beijing, and informed consent signed by the investigator after the participant's verbal consent was obtained from all individual participants included in the study.
Consent for publication Not applicable.