Awareness and Willingness to Use Pre-Exposure Prophylaxis (Prep) Amongst Men Who Have Sex with Men (MSM) in China: A Mini-Review

The purpose of this review is to research the awareness of and willingness to use pre-exposure prophylaxis (PrEP) to protect themselves from HIV infection amongst MSM in China. In addition, we explored the potential impact factors and evaluated the need and user preferences related to access and utilization ofPrEP in China. PUBMED, EMBASE, and CNKI were accessed to search for the relevant articles published before August 2019. The studies included in this review were conducted in 9 cities in China. The awareness of PrEPuse was from 11.2% (Zhou et al., 2012) to 52.7%(Peng et al., 2019). The lowest willingness to use PrEP was 19.1% (Ding et al., 2016), the highest is 91.9% (Wei et al., 2011) provided the drug is safe, effective and free. Assuming HIV prevention medicines are effective and safe, the willingness to use PrEP was in the range of 63%-89.8%. Factors associated with willingness to use PrEPinclude the factors of drug products (e.g., perceived safety, efficacy, price and dosing schedule, etc.); sociodemographic characteristics (e.g., age, education, income, sex identity and sex role, etc.); behavioral factors (e.g., drug use, condom use, STI history and sex partner, etc.), and the awareness and knowledge of HIV treatment and prevention. Results indicate that as more MSM in China are becoming aware of PrEP, the willingness to use PrEP is higher than 63% if the medicine is safe and effective. Future research is needed to solicit effective education and intervention programs to support the access and use of PrEP.


Introduction
In 2018, 1.7 million people became newly infected with HIV, 37.9 million people were living with HIV, the risk of acquiring HIV is22 times higher among men who have sex with men [1]. Global HIV epidemic among men who have sex with men (MSM) remained uncontrolled [2].  [3]. A meta-analysis reported a pooled incidence of HIV incidence among Chinese MSM is 5.61/100 person-years, with an increasing trend over time [4].

Epidemic in China
Unprotected anal intercourse is common and puts MSM in China at high risks of acquiring and transmitting HIV [5]. In Sichuan province, the average survival time of HIV/AIDS cases was 11.51 years during 1991-2017 [6]. From 2010 to 2015, HIV antibody positive rate amongst MSMat sentinel surveillance sites increased from 5.73% to 7.98% [9].
MSM had quickly become a high-risk population for HIV infection and the growing epidemic amongst MSM is one of the new challenges regarding HIV prevention/treatment in China.

Pre-Exposure Prophylaxis (PrEP)
Antiretroviral agents remain the cornerstone of HIV treatment and prevention [10]. HIV pre-exposure prophylaxis (PrEP) typically refers to the use of antiviral drugs as a strategy to prevent the acquisition of HIV amongst HIV-uninfected people [11,12]. Randomized placebo-controlled trials [13], as well as the PROUD study [14], have shown that daily oral PrEP reduces the risk of HIV infection when medications are taken as indicated. PrEP has been shown to be effective and acceptable amongst MSM in multiple clinical trials [15,16]. WHO recommends PrEP to be used as part of a package of prevention interventions that also include male and female condoms, voluntary medical male circumcision, prevention of mother-to-child HIV transmission (PMTCT) and harm reduction strategies such as the provision of sterile injecting equipment and opiate substitution therapy for people who inject drugs [11]. PrEP is not only highly effective within the MSM subject population at the individual level, but it is also effective on population-level, for example, intensive promotion of PrEP within the MSM population in Australia has reduced the overall incidence in this population [17]. HIV/AIDS strategy emphasizes the importance of bringing prevention to the most at-risk populations. While, PrEP may be particularly challenging among key populations such as MSM in low-and middle-income countries where healthcare infrastructure and socio-cultural contexts are extremely different from that in developed countries [18].
As of March 2018, PrEP has been approved in more than 50 countries globally [19]. Despite the effectiveness of PrEP, it has not been adopted in many countries including China.  [21]. To achieve HIV elimination in the next 10, 15 and 20 years in China, the required PrEP coverage rates would be 65%, 32% and 19%, respectively, if 100% PrEP compliance [22]. It is necessary to strengthen the comprehensive intervention in MSM, including improving PrEP adherence.
One study identified moderate acceptability (57.8%) of PrEP in MSM worldwide, showed efficacy, perception of HIV risk and experienced stigma determine its acceptance [23]. However, very few surveys exploring PrEP use amongst MSM population have been published and there are not any guidelines or medicines approved for PrEP in China. The goal of this review is to understand the awareness of and willingness to use PrEP amongst Chinese MSM. In addition, for those showing a willingness to use PrEP, we examined the factors involved in that decision, including the user preferences to access and utilize PrEP.
The data may help to better understand the motivations and willingness to use PrEP beyond clinical trials amongst MSM.

Materials and Methods
Both PUBMED and EMBASE were used to research the relevant articles using the keywords "PrEPor pre-exposure prophylaxis", "MSM or men who have sex with men" and "China or Chinese", and searched CNKI (National Knowledge Infrastructure) to identify the relevant Chinese-language articles using the keywords "暴露前 (Bao Lu Qian) or PrEP" and "男男 (Nan Nan) or MSM" on human subjects published from 2008 to February 2018. Two reviewers (Y. R. and J. P.) independently extracted and tabulated all data. Discrepancies were resolved by discussion and agreement.

Summary of included studies
This review involved a total of 98 identified publications and 27 articles were excluded due to duplication. Additional exclusions (n = 58) were due to a variety of reasons, including (i) review articles, (ii) not focused on the Chinese mainland, (iii) articles focussed on other outcomes or (iv) non-peer reviewed articles, (v) in-depth interview which has small sample size. Two more Chinese language articles were added additionally. 13 studies only explored oral PrEP, "PrEP" in the articles regards to "oral PrEP", while 2studies explored both oral and long-acting injectable (LAI) PrEP.   very willing (definitely willing)". In addition, one study evaluated willingness by four-level scales (very unwilling, unwilling, willing and very willing). Those who "somewhat (probably)" and "very (definitely)" willing on the five-level scale were grouped "willing" on a four-level scale for analysis purpose. In the Peng et al. study [25], willingness to use oral PrEP, LAI PrEP is 60.1% and 60.8% respectively. In general, the willingness to use PrEP is greater than 63% if the medicine is safe and effective. In contrast, an on-line study that recruited subjects throughout China [33] showed a lower willingness to use PrEP 6 (32.1%). Moreover, combining the "daily" use and "on-demand" use of PrEP, the willingness to use was 61% in Shenyang [30]. In general, there does not appear to be a significant difference in willingness to use PrEP by regions or years.

Impact factors on the willingness of using PrEP
Based on included studies, I summarized 4 kinds of of factors which are potentially associated with willingness to use  (Table.2). Included studies were variety in regions, years, enrolled population, the documented impact factors were lack of standard wordings, showed different meanings in different studies, they may bring big bias when doing analysis.
These factors may play an important role in the prevention of HIV among MSM, we list the information here without analysis to provide references for future study.  In addition, compared to always using condoms, MSM who reported never using condoms with their regular sexual partners were more likely to explain their willingness to use PrEP in terms of "problems using condoms" (

Discussion
At the community-level in China, many do not know that HIV is a manageable disease, and there is a severe lack of awareness and correct knowledge of the benefits of ART [39], even among MSM living with HIV [40,41]. Despite PrEPbeing initially low amongst MSM in China, once they become aware of PrEP, many MSM is willing to use it. Even though the willingness to use PrEP is relatively high, the actual reported use is low (<1%~3.1%) [32, 38,42]. Perception of low HIV risk, mistrust of the national PrEP program, and concerns of side effects, lack of main sexual partner's support, difficulties in adhering to the daily oral PrEP regimen, and the inconvenient schedules in securing the medicine were the major reasons for not wanting to use or quitting the use of PrEP [43]. On the other hands, the effectiveness of oral HIV preexposure prophylaxis (PrEP) strongly depends on maintaining adherence [44]. One study showed the median adherence rate of daily oral PrEPin clinical trials was 64.29%, the main objective factor in non-adherence was forgetting to take the medicine [45], LAI PrEP may improve PrEP ad-herence to some extent and may further reduce the incidence of HIV. Qu, et al. [46]. explored the impact factors to the low-level PrEP self-efficacy (Self-efficacy, as the determinant of individual behavior, is also the center of individual factors that often influences the choice and continuation of individual behavior [47] in China, age and anxiety score were negatively related to PrEP self-efficacy, AIDS-related knowledge and PrEP-related motivation were activities related to PrEP self-efficacy. One more potential reason may be a lack of community's attention or availability One study [27] showed that the top 2 reasons for willingness to use PrEP are "efficacy to sexual health" and "problems using condoms" and the top 3 reasons for unwillingness to use PrEP are "concern about side effects, long dose schedule", "confidence in protecting themselves" and "cost and atigma". Our find- Therefore, online educational efforts can greatly facilitate PrEP uptake among young Chinese MSM [50]. For MSM with higher education, PrEP seems to be another reliable method for them to protect themselves. PrEP would need to be integrated into existing prevention strategies, however, rather than replacing them [51]. Additionally, in order to encourage the use of PrEP, an accessible price is necessary to consider because of the cost may be a big burden for those with lower income. Negotiating with the industry and striving for subsidies from the government to make reimbursement and insurance cover medicine is a positive method to control the price. As the data reported here is limited, future studies among Chinese may be conducted more thoroughly.

An interesting point in our study is the association of between
MSMEs behaviors and willingness to use PrEP. While a study in Hongkong [52] showed that there were no significant associations between risky behaviors (eg.the practice of condomless sex) and PrEP acceptance which is different from mainland China.
In mainland China, recreational drug use has increased considerably amongst MSM and became a high-risk factor for HIV infection [53]. As reported by Lauby, et al. [55] and Tweed, et al. [56], recreational drug use is related to an increase in unprotected sex and HIV risk. Even though drug use did not seem to have a significant influence on the willingness to use PrEP in our review, once drug users realized they are in high HIV risk, prevention methods including PrEP may become popular among the population, further study on this factor is needed. Current literature has also identified barrier of condom use, STI history, multiple sex partner and stable sex partner as potential factors for willingness to use PrEP.It's likely that these with stronger self-perceptions of risk are more willing to explore additional protection methods, including PrEP. Condom use greatly decreases the risk of gonorrhea, chlamydia, HIV/AIDS, as well as to a lesser extent to protect against syphilis [57]. MSM who use condoms regularly regard themselves as already protected against the acquisition of HIV. Of concern, however, one study in India [58] found that availability of PrEP could reduce the use of condoms, one study showed STI is on the rise in PrEP Users [59]. Mansegh et al. [60] concluded that as PrEP becomes more available among MSM, HIV prevention programs can be enhanced in a way that reinforces condom use and helps men perceive PrEP as a supplementary biomedical intervention. For HIV and STI prevention, we should clarify if and how condoms should be used in combination with PrEP. Ongoing screening and timely treatment of STIs is both a part of broader PrEP intervention and a potential method for decreasing STI burden in the face of decreasing condom use [61]. As China begins to thinking about usingPrEP targeting MSM at high risk for HIV, it will be increasingly important to evaluate ways in which we can use PrEP programs to engage MSM in sexual health and comprehensive STI prevention programs that do not solely focus on condom use [62]. For sex partner, a study in Malaysia showed that having 2 or more male anal sex partners in the past 6 months (aOR=1.98, 95% CI: 1.29-3.05) were independently associated with greater willingness to use PrEP [63]. This is expected as other studies have shown that STI incidence increases with multiple sex partners [64]. In contrast, MSM who have stable sex partner also have a higher willingness to use PrEP in one of the six publications which analyzed this factor. One possible explanation may be that partner in such a stable same-sex relationship may have sex without a condom, but may also not be clear as to the HIV infection status of their partner. One study indicated that people were less likely to inform their main partner when they had unprotected sexual intercourses with casual partners [65]. It is reasonable for someone who has both stable and casual partners, PrEP is an attractive option for self-protection and for protection of the partner. Also, Hu, et al. suggested that integrated delivery of sexual partners' PrEP and early ART could nearly eliminate HIV transmission and reduce costs [66].
As highlighted by the WHO guidelinec [67] there are some other potential issues among potential PrEP users, such as not taking up HIV testing regularly, not seeking medical consultation before they decide to start or discontinue using PrEP which should be monitored and prevented to ensure the effectiveness of PrEP and safety of PrEP users. While willingness is not always a good indicator of future use, this helps to identify cultural values and beliefs, and concerns that need to be addressed to adequately counsel HIV high-risk individuals who would benefit from PrEP use [70].
This review contributes to knowledge around the awareness and willingness to use PrEP in China, by reporting factors that impact willingness such as product information, sociodemography, knowledge, awareness, and behavior.
In China, the awareness of PrEP is low, ranging from 11.2% to 34.2% based on these 11 studies, and one in-depth personal interview [71] even showed that no one had heard PrEPamongst the 31 subjects. In contrast, amongst those aware, the willingness to use PrEP is higher than 63% if the medicine is presumed safe and effective. Our review also found that several factors could potentially prevent or facilitate participants' willingness to use PrEP. Drug use, unprotected (condomless) anal intercourse, STI history, and multiple sex partner are a potential predictor to a willingness to use PrEP in our study which is consistent with the target situation of PrEP. But few studies have investigated the potential use PrEP in China and the small number of studies included in our review is the biggest limitation. 36. Jackson T, Huang A, Chen H, Gao X, Zhong X, Zhang Y