Pre-exposure prophylaxis uptake for high-risk men who have sex with men in China: a multi-city cross-sectional survey

Background Pre-exposure prophylaxis (PrEP) is a proven biomedical strategy to prevent HIV transmission among men who have sex with men (MSM). Despite oral PrEP is safe and effective in MSM, the use of PrEP has been discouraging, especially in high-risk MSM. And there are no relevant studies showing the use of PrEP in high-risk MSM. The purpose of this study was to get the rate of PrEP use and the factors influencing PrEP use among high-risk MSM. Methods A cross-sectional study was conducted through an electronic questionnaire on the “i guardian Platform”, and “snowballing” method was used to recruit MSM in six cities in China, including Beijing, Shenzhen, Chengdu, Changsha, Jinan and Nanjing in China, from January to April 2021. Univariate and multivariate logistic regression analysis were used to analyze the factors associated with the use of PrEP among high-risk MSM who had heard about PrEP. Results Among the 1865 high-risk MSM who had heard of PrEP, the rates of those who were willing to use PrEP, had knowledge awareness of PrEP, and had used PrEP were 96.7%, 24.7%, and 22.4%, respectively. Multivariate logistic regression analysis of PrEP use in high-risk MSM showed that more PrEP was used by those who were 26 years or older (OR = 1.86, 95%CI 1.17 ~ 2.99), had master degree or above (OR = 2.37, 95% CI 1.21 ~ 4.72), had unstable work (OR = 1.86, 95% CI 1.16 ~ 2.96), had tested five or more HIV times in the past year (OR = 3.09, 95% CI 1.65 ~ 6.04), had consulted PrEP (OR = 22.05, 95% CI 14.87 ~ 33.91) and had PrEP knowledge awareness (OR = 1.90, 95% CI 1.41 ~ 2.55) (P < 0.05). Conclusions The rate of PrEP use in high-risk MSM was relatively low. PrEP was used more by high-risk MSM with unstable jobs, higher education, frequent HIV testing, and PrEP counseling. Public education on PrEP for MSM should continue to be enhanced to help them use PrEP in a timely and accurate manner.


Introduction
By the end of 2020, there were 1.053 million people living with human immunodeficiency virus (HIV) in China, and the cumulative number of reported deaths was 351,000 [1]. Data extracted from 355 studies in China estimated the overall prevalence of HIV among men who have sex with men (MSM) from 2001 to 2018 was 5.7% [95% confidence interval (CI): 5.4% ~ 6.1%] [2]. MSM are a high-risk group for HIV infection and a growing public health challenge in China.
Pre-exposure prophylaxis (PrEP), a preventive measure to prevent HIV infection by taking antiviral drugs in people who are not yet infected but are at risk of infection, is one of the most important preventive measures for HIV [3]. World Health Organization (WHO) [4] recommends oral PrEP as an additional prevention strategy for key populations (including MSM), who are at high risk of HIV infection in 2012. In 2016, the Chinese Center for Disease Control and Prevention (CDC) released the Guidelines for HIV Prevention Interventions in High-Risk Populations, which for the first time clarified the applicable population, medication regimen and follow-up for PrEP in MSM [5]. Expert Consensus on PrEP for HIV prevention in China was published in 2020 [6]. In the same year, Truvada (oral PrEP medicine) was approved by the National Medical Products Administration of China in August in China [7]. Despite several policies emphasizing the importance of implementing PrEP among MSM in China, there are still no separate PrEP guidelines for MSM to directly refer to.
Despite oral PrEP is safe and effective in MSM, the use of PrEP has been discouraging, especially in MSM [8][9][10]. The U.S. National AIDS Strategy (2021) reported that 13.2% of MSM used PrEP in 2017, which was far from the goal that 50% of PrEP-eligible MSM should use PrEP [11]. In the Italian snowball survey, only 7.5% of MSM had used PrEP [12]. A cross-sectional survey in China based on online questionnaires showed that 4.3% of MSM had used PrEP [13]. Therefore, the rate of PrEP uptake in MSM is low and there are no relevant studies showing the use of PrEP in high-risk MSM. In addition, barriers to PrEP among gay, bisexual, and other MSM have received substantial research attention, but less is known about what factors may be affecting PrEP use among high-risk MSM [14]. Therefore, a cross-sectional study was designed to obtain information on the use of PrEP in high-risk MSM and the factors influencing PrEP use, in order to provide a theoretical basis for future PrEP guidelines in China.

Study design
A cross-sectional survey was conducted from January 2021 to April 2021 in six cities in China, including Beijing, Shenzhen, Chengdu, Changsha, Jinan and Nanjing. These six cities had high rates of new HIV infections in China (above 3/100 person-years) [15]. Given the strong influence of social organizations for MSM among gay in China, this study relied on them to distribute an electronic questionnaire to eligible MSM and then recruited more participants through the snowballing method [16].The inclusion criteria for participants were as follows. (1) completed informed consent; (2) male 18 years of age or older; (3) had sex with men; and (4) HIV negative or unclear.

Procedures
First, the questionnaire was designed based on the literature review at home and abroad and consultation of experts.
Second, a pre-survey was conducted in February 2021 on the "i Guardian" Platform. Relying on the People's Health Publishing House, the "i Guardian" platform is dedicated to building an authoritative information dissemination platform, including the service of conducting online questionnaires. Ten MSM completed the survey and the questionnaire was revised based on their feedback.
Third, from January to February 2021, researchers contacted MSM social organizations in six cities that had worked with us on multiple HIV-related projects and had good project implementation experience. Each MSM social organization in the six cities chose one or two people to conduct the survey, and then the researchers taught them how to conduct this study and helped them understand each question.
Fourth, the study launched from March 1 to April 30, 2021. The person in charge of the investigation sent the QR code of the questionnaire to the participants who came to the MSM social organization for consultation. After participants filled out the questionnaire anonymously on the "i Guardian" platform, they could share the QR code with qualified male companions around them via webpage, WeChat, QQ and other forms. Sample size was estimated by cross-sectional survey formula (N = Z 2 1-a/2 P(1-P)/d 2 ). Based on the PrEP utilization rate of 13.2% [17], 2526 people were needed. Considering the invalid response and other factors, the sample size was designed to be 2600.
Finally, the researchers checked the questionnaire database to ensure the completeness of the information (the authors were able to identify individual participants in the questionnaire database).

Study variables
The questionnaire included demographic characteristics (age, ethnicity, domicile, education, etc.); basic knowledge of PrEP, willingness and use of PrEP; and sexual behavior (number of sexual partners, condom use, history of STDs, frequency of HIV testing, etc.). The primary outcome of this study was the rate of PrEP use among high-risk MSM. The secondary outcome of this study was the factors influencing the use of PrEP in highrisk MSM. Relevant definitions involving the outcome were shown below.
PrEP use was measured with a question, "Have you used PrEP?". Answering "Yes" indicated that the participant had used PrEP.
The willingness to use PrEP was measured with a question, "Do you want to use PrEP if you are about to have a high-risk HIV behavior?". Answering "Yes" indicated that the participant had the willingness to use PrEP.
PrEP knowledge awareness was defined by four questions [18], including (1) "What do you think is the function of HIV pre-exposure prophylaxis?"; (2) "Who do you think needs HIV pre-exposure prophylaxis?"; (3) "Do you know how to take pre-exposure prophylaxis?"; (4) "Do you think it is necessary to use condoms when having sex while taking pre-exposure prophylaxis?" The correct answers to the four questions were "HIV prevention", "at risk for HIV infection", "take daily" and "take two days before and after high-risk sex", and "Yes". Correct responses to all four questions would be recorded as PrEP knowledge awareness.
The definition of high-risk MSM included seven questions [19][20][21][22]. (1) Number of male sexual partners in the past six months was 10 or more; (2) Never used condoms when having sex with a male in the past six months; (3) Had commercial sex with MSM in the past six months. (4) Had male-to-male group sex frequently in the past 6 months (sex with 2 or more men at the same time); (5) Male sexual partner was HIV positive and had not received ART in the past 6 months; (6) Used drugs in the past 6 months (rush, methamphetamine, cocaine, ketamine, MDMA, etc.); (7) Having been diagnosed with an STD in the past 6 months. Meeting any of these conditions was considered as high risk MSM.

Statistical analysis
This study focused on the use of PrEP by high-risk MSM who had heard of PrEP. MSM who had not heard of PrEP were not required to answer PrEP-related questions, so only those who had heard of PrEP were selected for subsequent statistical analysis. First, descriptive analysis (counts, percentages) was performed to describe demographic characteristics, awareness and use of PrEP, and sexual behavior among high-risk MSM. Then, factors influencing the use of PrEP among high-risk MSM who had heard of PrEP were analyzed by univariate and multivariate logistic regression. All statistical tests were analyzed with R 4.1.0, and P-value < 0.05 was considered statistically significant.

Results
A total of 6147 questionnaires were collected. According to the inclusion criteria, invalid questionnaires were deleted, leaving 6035 valid questionnaires. The number of qualified questionnaires in the six cities of Beijing, Shenzhen, Chengdu, Changsha, Jinan and Nanjing were 2256, 809, 813, 408, 863 and 886, respectively. 4443 questionnaires were from WeChat, and the rest were filled in through other ways.

High-risk MSM
Among 3882 (64.3%, 3882/6035) MSM had sex with men in the past six months, 6.2% (243) had more than 10 male sexual partners, 7.4% (287) never used condoms when having sex with a male, 7.4% (288) had commercial sex with MSM, 1.3% (48) had male-to-male group sex frequently, 1% (39) of the most recent male sexual partner was HIV positive and had not received ART, 45.3% (1760) took drugs, and 7.6% (292) had been diagnosed with STD (Table 1). According to the definition of high-risk MSM, there were 2188 high-risk MSM in this study. Then, only 1865 high-risk MSM had heard of PrEP.

Characteristics of high-risk MSM
Among high-risk MSM who had heard of PrEP, median age was 32.2 years. 93.6% (1745/1865) of high-risk MSM who had heard of PrEP were Han nationality, 54.8% (1022) were domiciled in the city or province other than the one they lived in, 76.2% (1421) had a diploma degree or above, 75.8% (1413) were unmarried, 77.2% (1439/1865) had stable jobs, 62.2% (1160) had an average monthly income above 5000 RMB, 328(17.6) were bisexual, and 9.6% (180) had never been tested for HIV in the past year (Table 2).

Discussion
Although PrEP is an important measure to HIV prevention in high-risk MSM, the rate of PrEP use was low (22.4%). Because there were no studies in the literature on the use of PrEP in high-risk MSM, PrEP use was relatively high in high-risk MSM compared to MSM. For example, the rate (22.4%) was higher than a crosssectional survey of PrEP use among MSM in 34 cities in China (1.2% had used PrEP) [23] and a cohort study implemented in Harbin, China (0.7% of MSM used PrEP at baseline survey) [24]. This was because high-risk MSM were more sexually active and had a greater need for PrEP and therefore used more of it. In addition, high-risk MSM had higher knowledge of the role, suitable crowd, dosing regimen of PrEP than non-high-risk MSM, and PrEP knowledge was a factor promoting PrEP use among high-risk MSM, considering that PrEP use also be higher among high-risk MSM due to better knowledge of PrEP. But, the rate of PrEP use among High-risk MSM (22.4%) was lower than a cross-sectional analysis of MSM who had problematic sexual behavior within the United Kingdom (34%) [25] and a descriptive analysis of MSM in the   increase the knowledge and use of PrEP among high-risk MSM to meet their high willingness. Factors influencing PrEP use among high-risk MSM included age, education, job, number of HIV tests in the past year, knowledge awareness of PrEP, and whether or not consulted PrEP. The results showed that high-risk MSM with unstable jobs and higher education were more likely to use PrEP, which was consistent with the results of Siyan Yi et al. [27]. Since MSM with higher education might have easier access to health-related information [28]. Besides, the results of Guan Y [23] showed that subjective barriers to using PrEP included unemployment and objective barriers included high costs. In response to the unemployment issue, this study complemented that high-risk MSM without regular jobs used more PrEP than MSM with regular jobs, considering that MSM with unstable jobs had more frequent high-risk sexual behaviors. In addition, in order to deal with the issue of high costs being an objective barrier to the use of PrEP, this study had made a different finding. This study found that monthly income was not an influence on PrEP use in high-risk MSM, which was inconsistent with the study by Brooks, R. A. et al. [29]. The current price of PrEP drugs in China fluctuated greatly. Users only needed to take 4 pills in a course of PrEP for an average of 25-43 yuan (RMB). The low price made more MSM willing to use it. The THRIVE program provided PrEP to higher proportions of PrEP-eligible persons than current national estimates, however PrEP use disparities persist, suggesting a need to increase PrEP coverage [30]. It is suggested that improving the coverage of PrEP is one of the key issues to solve the differences in the use of PrEP. However, online services for selling PrEP drugs have flourished in China, with multiple online purchasing platforms available to purchase PrEP, further helping to increase PrEP accessibility and expand coverage.
A systematic review of 23 studies showed that younger MSM were more likely to take PrEP [31], in contrast to the results of Yu Liu et al. [32] and our findings. Older high-risk MSM had more exposure to PrEP and might have better knowledge about PrEP. Combined with the results of the multivariate logistic regression analysis, knowledge awareness promoted PrEP use in high-risk MSM, so that older MSM had more use of PrEP. In addition, participants who had consulted PrEP were more likely to use PrEP. MSM who have consulted PrEP would know more information about PrEP, on the other hand, it might also be due to the fact that MSM who had consulted PrEP had a higher willingness to use PrEP. The accompanying measures and one-on-one counseling by a trained counselor could increase the effectiveness of this PrEP program [33]. Therefore, valid and accurate information from PrEP counselors is needed.
The results showed that as the number of HIV tests increased, more high-risk MSM used PrEP, consistent with the findings of the other two studies [34,35]. Because patients seeking PrEP were screened for HIV before starting therapy as well as every 3 months after beginning treatment with PrEP [36]. In addition, highrisk MSM had more frequent high-risk sexual behavior, and going for frequent HIV testing reflected both the importance they placed on their health and the fear of HIV infection. Early testing can reduce complications of HIV infection and reduce the risk of transmission. It is estimated that 40% of new infections of HIV are transmitted by those who are not aware of their HIV diagnosis [37]. The day of HIV testing was the critical moment for people with high HIV exposure risk to start PrEP [38]. It was suggested that advertising PrEP during HIV testing or HIV self-testing was a very good way to increase the use of PrEP. MSM who do not test frequently for HIV are less likely to be aware of PrEP, test for sexually transmitted infections, or use condoms [32]. 6.3% of high-risk MSM thought that condom use was not required for sex while taking PrEP, consistent with the findings of Braksmajer. A. and Ahouada. C. [18,39]. Although the percentage was relatively small, this issue should not be ignored. After all, PrEP is not absolutely 100% effective in HIV prevention. Furthermore, in Brazil, MSM reported that learning about PrEP online positively influenced their willingness to use it [40]. And a web-based survey in Latin America, willingness to use PrEP was found to be high and directly related to PrEP awareness [41]. The results of these two studies suggested that MSM had higher acceptability when PrEP was promoted on the Web, so PrEP promotion can be enhanced on the Web, with particular emphasis on condom use when promoting PrEP.
In this study, MSM were recruited through an MSM social organization in an online "snowballing" way where participants anonymously completed questionnaires and shared it with their eligible male peers. This "snowballing" method has the disadvantage of not being able to track the entire process, such as not knowing how many times it has been rolled, how many people were contacted each time and how many people responded, and only knowing the total number of questionnaires at the end. This shortage does not affect the quality of the questionnaire. Besides, through this online questionnaire sharing, MSM who were more interested in the topic would choose to answer. In addition, MSM had recalling bias when completing the questionnaire, but the researchers limited the questions to a certain period of time, such as "in the past six months" to reduce bias.

Conclusion
In conclusion, the rate of PrEP use in high-risk MSM was relatively low. And high-risk MSM showed high willingness to use PrEP, low knowledge awareness, and low usage. Therefore, government and health authorities should continue to strengthen MSM awareness of PrEP and condoms. How to reduce the gap between high willingness and low usage is the next step to be studied. PrEP was more used by high-risk MSM with unstable jobs, higher education, frequent HIV testing, and PrEP counseling. However, it is also worth considering whether these variables have a direct effect on PrEP use, or an indirect effect on PrEP use through knowledge of PrEP or other factors.