Increasing awareness of HIV pre‐exposure prophylaxis (PrEP) and willingness to use HIV PrEP among men who have sex with men: a systematic review and meta‐analysis of global data

1Condomless sexual behaviour between men is a well‐recognized route of HIV transmission. In 2019, marginalized populations, such as men who have sex with men (MSM), transgender women (TG) and their corresponding sexual partners, accounted for 62% of new HIV infections globally.

2Several randomized clinical trials have shown that tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) and FTC/tenofovir alafenamide used as pre‐exposure prophylaxis (PrEP) significantly decreased the likelihood of HIV infection among MSM, TG and other high incidence groups. World Health Organization (WHO) has first recommended that, in addition to HIV testing, condom use, screening and treatment of sexually transmitted infections (STIs), policy makers should also routinely incorporate PrEP into prevention programs. In 2015, WHO formally recommended providing PrEP to MSM. Four years later, 44 countries and regions had approved the use of PrEP for HIV prevention. To achieve its promise, PrEP must be both acceptable to users, available and implemented in practice.

3Providing effective PrEP services for high incidence groups is a critical measure to reduce new HIV infections. Many researchers, health providers, policy makers and community leaders/members are committed to enhancing awareness of PrEP and willingness to engage in PrEP among high incidence groups. A previous meta‐analysis has found low proportions of MSM were aware of PrEP and willing to use PrEP in low‐ and middle‐income countries (LMICs). Another meta‐analysis summarized the acceptability of PrEP among MSM on the global scale, including articles which were published before July 2016. However, to our knowledge, there are few large‐sample systematic reviews addressing both the awareness of PrEP and willingness to use PrEP among MSM on the global scale, and few studies have analysed global trends in the awareness of PrEP and willingness to use PrEP over time. More knowledge about the integration of awareness and willingness can be useful for future HIV prevention in high incidence groups.

4We conducted this systematic review and meta‐analysis to summarize the global research on the awareness of PrEP, the willingness to use PrEP among MSM and their integration in the literature. In addition, we sought to analyse the temporal trends in awareness of PrEP and willingness to use PrEP and examine the factors associated with willingness to use PrEP among MSM.

5This meta‐analysis was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta‐Analyses (PRISMA) guidelines. The PRISMA checklist is appended as File S1.

6Web of Science, Embase, PubMed and Cochrane Library were searched to identify literature on awareness of PrEP and willingness to use HIV PrEP among MSM. A combination of relevant keywords and medical subject heading (MeSH) terms were adopted to conduct the literature search using Boolean operators, truncations and synonym extensions, as appropriate. Detailed search strings used in each database are shown in File S2.

7The inclusion criteria were as follows: (1) cross‐sectional studies, cohort studies, case control study, qualitative studies and mixed method studies; (2) studies reporting data generated from HIV‐negative MSM (including gay, bisexual, male sex workers and TG); for studies reporting data separately for MSM and other populations, such as heterosexual male or female sex workers, only data related to MSM were considered and extracted; (3) studies reporting awareness or willingness to use PrEP; and (4) studies that were peer‐reviewed before 31 August 2021.

8The exclusion criteria were as follows: (1) non‐original research, secondary reports, commentaries, editorials, reviews and duplicates; (2) studies focusing on other populations (e.g. women, heterosexual couples or primary care providers) rather than MSM; (3) studies reporting no results for a segregated subgroup of MSM or TG; (4) studies reporting no findings related to PrEP; (5) studies reporting results that cannot be used to calculate the proportion of MSM aware of and willing to use PrEP; and (6) studies focusing on other outcomes.

9Two review team members independently screened references in two stages. In the first stage, two reviewers screened the titles and abstracts to exclude unrelated studies. They further assessed full‐text papers for eligibility in the second stage. A flowchart illustrated the literature selection procedure (Figure 1). All references retrieved according to selection criteria were classified as eligible or ineligible at each stage. A third reviewer resolved discrepancies in the literature inclusion between the two reviewers. Three review team members discussed together to reach a consensus.

10Data extracted independently by two reviewers from the aforementioned two stages were imported into Microsoft Excel Software. The following data were entered into a standardized form: authors, year of publication, research year, country or region of study, study design, sample size, study population characteristics (MSM/TG, primary sex role and high incidence groups), recruitment settings, types of PrEP, policy support, proportion of MSM aware of and MSM willing to use PrEP, and factors associated with willingness to use PrEP. The data were exported into Excel, and then the third reviewer compared the two independent data forms. Three researchers discussed any disagreements until a consensus was reached.

11The quality of eligible quantitative studies and mixed methods studies was evaluated by using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool (http://www.ephpp.ca/tools.html). Study quality was considered strong if none of the six component ratings was weak. Study quality was considered moderate if one component rating was weak and was considered weak if two or more component ratings were weak. To assess the quality of qualitative studies, we used the Qualitative Research Checklist from the Critical Appraisal Skills Program (CASP). Based on the total score of the 10 items, we ranked studies as weak (<5), moderate (5–7) or strong (≥8).

12Due to different study designs of included studies, we assumed a high potential for heterogeneity between included studies, and thus a random effect meta‐analysis was performed to pool the proportion of awareness of PrEP and willingness to use PrEP. Cochran's Q and I 2 statistic were used to assess the heterogeneity among included studies. For the Q statistic, a p‐value of greater than 0.10 suggested no significant heterogeneity. I 2 statistics of 25%, 50% and 75% were classified as low, moderate and high, respectively. To explore the potential source of heterogeneity, subgroup analyses were carried out according to the main relevant variables, such as age, sample size, country/regions, year of study, year of publication, study population, primary sex role, high incidence groups, recruitment settings, types of PrEP and policy support. Publication bias was assessed through funnel plots with Begg's test. Trend analyses were conducted to determine the variation in awareness of PrEP and willingness to use PrEP. Locally estimated scatterplot smoothing (LOESS) regression and linear regression were applied to fit the trend for the proportion of MSM aware of PrEP. The sample size of every data point was used as the weight of the two models. Regarding willingness, we applied grid search using the Akaike information criterion (AIC) to obtain the optimal breakout point for the segmented linear model. The odds ratio (OR) and the corresponding 95% confidence interval (CI) of factors associated with willingness to use PrEP were pooled to summarize the facilitators and barriers. Dose–response meta‐analysis (DRMA) was used to pool the association between factors that contained at least three levels of categories and willingness to use PrEP. The level of education was transformed into years of education, and annual income was converted into monthly income ($) for analysis. The two‐stage DRMA proposed by Berlin et al. was conducted by modelling factors with restricted cubic splines (RCS) of three knots at the 10%, 50% and 90% percentiles of the distribution to estimate the potential trend between factors and ORs related to PrEP willingness. The command “Wald test” in R was used to test whether the slopes of the RCS model for each dose level had a significant difference. If the slopes of each dose level had a significant difference, the dose–response curve had non‐linearity. All analyses were performed by R (version 4.0.3).

13We initially retrieved 8556 articles. Based on the inclusion criteria, we included 156 articles involving 228,403 MSM, among which 145 data points were related to awareness of PrEP and 165 data points were related to willingness to use PrEP (Figure 1). Articles included in this study were published between 2009 and August 2021 with a median sample size of 644 (interquartile range: 222, 866) ranging from 20 to 39,670. One hundred and forty‐two study populations included MSM, 10 articles exclusively included TG and four articles included MSM and TG. A total of 130 cross‐sectional articles, 11 cohort articles, nine mixed method articles and six qualitative articles were included, among which 87 articles were conducted in high‐income countries (HIC), 67 articles were conducted in LMIC and one study was conducted across 145 countries and two studies were conducted in both LMIC and HIC. The participants' characteristics, and the facilitators and barriers associated with the willingness to use PrEP are presented in Table A1. Study characteristics are given in Appendix A.

14High heterogeneity (awareness: p<0.001, I 2 = 99.9%; willingness: p<0.001, I 2 = 99.7%) was presented among the included studies. Awareness of PrEP ranged from 0% to 96.7%, with a pooled estimate of 50.0 (95% CI: 44.8–55.2). Willingness to use PrEP ranged from 5.7% to 100%, and the pooled estimate was 58.6% (95% CI: 54.8–62.4). Among 119 data points simultaneously reporting willingness and awareness, the willingness was higher than awareness at 70 data points, whereas willingness was lower than awareness at 49 data points, which are presented in Figure B1. Studies reporting both awareness of PrEP and willingness to use PrEP are presented in Appendix B. Subgroup analysis for awareness (Table 1) indicated that awareness before 2015 was lower than that after 2014 (p = 0.0003). Awareness in studies published before 2018 was lower than that in studies published after 2017 (p = 0.0004). A significant difference was presented between HIC and LMIC (p<0.0001). Countries or regions that had approved TDF/FTC for HIV prevention showed higher PrEP awareness than those without drug approval (p<0.0001). Awareness varied among different WHO regions (p<0.0001), among which Europe had the highest awareness and South East Asia had the lowest awareness. In addition, awareness varied among different PrEP types (p<0.0001). MSM had the highest awareness of daily oral PrEP, followed by on‐demand PrEP and long‐acting injectable (LAI)‐PrEP. Regarding the subgroup analysis for willingness (Table 2), the results showed that MSM in LMIC were more willing to use PrEP than those in HIC (p = 0.0296). MSM in high incidence groups were more willing to use PrEP (p = 0.0027).

15The funnel plots (Figure B2 Funnel plots for publication bias of awareness of PrEP and willingness to use PrEP in Appendix B) were roughly symmetrical. No significant publication bias was observed for PrEP awareness (p = 0.1945) or willingness (p = 0.41301) according to Begg's test.

16The trend in PrEP awareness increased from 2007 to 2019, with a slope of 0.040260 (p<0.0001). The minimum AIC was found when the piecewise linear model had one turning point in 2014 (Figure B3 AIC results in two piecewise linear regression models in Appendix B). The trend in willingness decreased from 2007 to 2014 (slope = –0.036476, p = 0.00390) but increased after 2014 (slope = 0.0418, p = 0.03895) (Figure 2).

17Among 156 studies, 73 studies provided a specific OR for factors associated with willingness to use PrEP. The main factors are illustrated in Figure 3, with the larger size of the dot referring to being more frequently reported in the literature. The main facilitators of willingness to use PrEP were PrEP awareness, recent condomless sexual behaviours, STI/HIV test history, STI/HIV positivity, perceived high risk of HIV infection, PrEP use and post exposure prophylaxis (PEP) use. MSM who would like to recommend friends to use PrEP were more willing to use PrEP. The main barriers were doubts about the efficacy of PrEP, worries about the side effects of PrEP and heterosexual orientation (Table A2 Factors associated with willingness to use PrEP among MSM in Appendix A).

18The DRMA results revealed that the fitting of the RCS model was statistically significant for willingness to use PrEP based on the number of sexual partners (p<0.0001) and years of education (p<0.0001) but not significant based on age (p = 0.2023) or monthly income (p = 0.0629). The Wald test results of the number of sexual partners (p<0.0001) and years of education (p<0.0001) demonstrated nonlinearity. The RCS results are illustrated in Figure 4, indicating that MSM were more willing to use PrEP when they had more sexual partners but less willing to use PrEP when they had more years of education.

19The quality assessment results of quantitative and qualitative studies are presented in Tables A3 and A4 in Appendix A, respectively. Of the 150 quantitative studies included, 142 studies were classified as weak and eight were classified as moderate according to the EPHPP tool. Most of the included studies were cross‐sectional, and the study design was not described as randomized or blinded, which affected the global rating results. Six qualitative studies were of moderate and robust quality according to the CASP tool.

20To the best of our knowledge, this meta‐analysis is the first to summarize trends in PrEP awareness, willingness to use PrEP, their correlation and the correlates of willingness to use PrEP among MSM based on global data. Our results showed that the proportion of MSM willing to use PrEP among global MSM was moderate, while the awareness of PrEP was low. Subgroup analyses showed that the awareness of PrEP varied among countries based on economic status and WHO regions, type of PrEP (formulation and route of administration), policies, publications and years in which research was conducted. PrEP willingness differed among countries with different economic status and study populations. The proportion of MSM aware of PrEP rose from 2007 to 2019, while the piecewise linear model showed that willingness to use PrEP decreased from 2007 to 2014 and then increased after 2014. No significant publication bias was found for PrEP awareness or willingness.

21In 2012, WHO recommended PrEP for men and TG who have sex with men, and the U.S. Food and Drug Administration approved the use of PrEP in the same year. Before 2015, PrEP was not available in many countries and unaccounted differences in study populations related to availability over time may contribute to the decreasing trend in willingness to use PrEP between 2007 and 2014. Later, in 2015, WHO extended its recommendation to all “people at substantial risk of HIV infection” as a part of combination HIV prevention approaches, which may be the reason why the proportion of MSM willing to use PrEP increased after this time period. Accordingly, clinical practitioners could advise those key populations about PrEP, or prescribe PrEP according to these guidelines, thereby increasing the provision of information on PrEP to MSM and the rollout of PrEP, also in turn, likely increasing the trend in PrEP awareness and the willingness to use PrEP. Correspondingly, awareness was higher in countries that approved the use of PrEP for prevention than in countries that had not yet approved it. As we have shown, increased awareness of PrEP was associated with higher willingness to use PrEP, underscoring the benefits for policy makers to scale up the use of PrEP because of the increasing awareness of PrEP and willingness to use PrEP.

22Individuals from HIC and countries that had approved PrEP reported higher PrEP awareness. Regulatory approval and implementation of PrEP in LMIC has been slow, which likely explains the low awareness in those settings. Healthcare services and comprehensive PrEP education were also more available in HIC, which could be associated with a higher awareness of PrEP than in LMIC. Although a previous meta‐analysis of 23 studies from LMIC conducted in 2017 found that PrEP awareness and willingness to use PrEP among MSM was 29.7% (95% CI: 16.9–44.3) and 64.4% (95% CI: 53.3–74.8), respectively, another meta‐analysis conducted in 2018 found that the overall acceptability of PrEP was 57.8%, and there was no difference between LMIC and HIC. Consistent with the previous meta‐analysis conducted in 2018, our study showed that willingness to use PrEP was more common than awareness among MSM. Although the willingness to use PrEP was comparable among different populations used to calculate the proportion of willingness in these studies, individuals showed higher willingness to use PrEP after they were informed about PrEP, which was supported by previous studies. However, willingness or intention are not necessarily the same with subsequent action, which could be affected by other various factors, such as behavioural skills. Further real‐time studies are needed to summarize the proportion of actual PrEP use among MSM, correlating with awareness and intent.

23Awareness of PrEP varied among different WHO regions, which might reflect different economic status and health policies. The lowest awareness was in South East Asia in the current study, where MSM had relatively higher burden of HIV highlighting the necessity and urgency to bring PrEP to scale as an essential component of comprehensive prevention strategies. In addition, PrEP awareness campaigns should be expanded by the government and community partners to frame PrEP prevention messages appropriately based on accurate information and in easy‐to‐understand formats and ways.

24Individuals in both HIC and LMIC reported a higher willingness to use PrEP after adopting their PrEP guidelines. However, the pooled estimate on the willingness of individuals in LMIC was higher than that of HIC. In a meta‐analysis study by Peng et al. in 2018, they reported a similar, albeit non‐significant, result. In HIC, people paid more attention to privacy because PrEP drugs were also used for HIV treatment, and high incidence populations preferred not to use PrEP due to stigma.

25Our study showed that willingness to use PrEP was higher among MSM in high incidence groups who were at risk of HIV than those not at risk of HIV, while the awareness of PrEP was comparable between the two groups. The higher willingness among groups at risk of HIV could be attributed to their perceived high risk of HIV infection. Therefore, more efforts should be made to improve the awareness of PrEP, especially for MSM belonging to high HIV incidence groups who meet WHO criteria for PrEP use.

26Our study identified several factors that could influence the willingness to use PrEP. Knowledge of PrEP has been found to be important in affecting willingness to use PrEP. MSM with prior knowledge of PrEP were more likely to accept PrEP and less worried about its efficacy. Individuals with a higher education level were not necessarily more likely to use PrEP, but were more likely to use condoms during intercourse and expressed a higher degree of condom use self‐efficacy. Individuals who preferred using condoms for protection against HIV and always used condoms were less willing to use PrEP. Another previous study also suggested that MSM with higher condom use self‐efficacy had decreased odds of entering PrEP contemplation. In addition, individuals with a higher education level were more concerned about long‐term side effects or toxicity of PrEP according to one previous study, which may result in the lower willingness to use PrEP. Accordingly, robust awareness of PrEP, including its efficacy and side effects, helps to promote the willingness to take PrEP. These studies suggest that provision of comprehensive and accurate information about PrEP to MSM is essential for the future rollout of PrEP and to help to allay their concerns.

27Our study also noted that MSM with condomless sexual behaviours or perceived high risk of HIV infection were more willing to use PrEP. Beyond that, MSM who had a history of an STI test and used PEP were more likely to accept it, likely reflecting their perception that they were at high risk of HIV infection and, therefore, more aware of HIV prevention approaches. Multiple sexual partners similarly determined willingness to use PrEP. Furthermore, focusing on social networks of those who are likely to recommend PrEP to their friends is suggested as another effective strategy to promote PrEP uptake, as well as using peer educators to promote PrEP.

28Some limitations in our study should be noted. First, substantial heterogeneity of study populations was observed in our systematic review. We conducted subgroup analyses to explore this finding. Age, sample size, publication year, research year, country, policy and study population were considered, but substantial heterogeneity remained in subgroups. Second, only a small number of studies were included in some subgroup analyses, such as awareness of different modalities of PrEP, which will warrant further investigation when more data become available since the type of PrEP may influence willingness to use it. Finally, most of the included studies were weak in quality assessment, which may weaken the strength of conclusions in the absence of higher quality research.

29Our review demonstrated that the awareness of PrEP was a determinant of the willingness to use PrEP. The proportion of MSM willing to use PrEP was moderate, while the proportion of MSM aware of PrEP was low on the world scale. Both the awareness of PrEP and the willingness to use PrEP have increased in recent years, which indicated the positive effects of the introduction or scaling up of PrEP usage. With an increasing number of countries providing access to PrEP, improving awareness of PrEP through increasing access, expansion of health education for PrEP, enhancing risk perceptions of HIV infection and carrying out peer education could have positive effects on willingness to use PrEP among MSM.

30The authors declare that they have no competing interests.

31HJ designed the research study. ZS, QG, YD and JS contributed to acquisition of data. ZS and QC analysed and interpreted the data. ZS, QG and YD drafted the manuscript. HJ, HZ, BA, PL and YY revised the manuscript critically for important intellectual content. All the authors reviewed and approved the manuscript.