Polydrug use is associated with new HIV infections among men who have sex with men in China: a multicenter cross-sectional survey

Background: Recreational drug use is popular among men who have sex with men (MSM), while there is limited information about polydrug use and its consequent impact on sexual health and human immunodeciency virus (HIV) acquisition. Methods: Mixed methods were used to recruit MSM from seven cities in China between 2012 and 2013. Participants were divided into four subgroups based on the number of recreational drugs (RDs) used in the past 6 months. “Polydrug use” was dened as simultaneous use of ≥ 2 types of RDs. Information on demographics and HIV high-risk behaviors (HIV-HRBs) was collected, and blood samples were tested for recent HIV infection by the BED capture enzyme immunoassay. Results: A total of 4,496 Chinese MSM participated, of which 28.4% used RDs, and 5% were polydrug users. Polydrug users commonly took poppers with one or more types of other RDs (e.g. methamphetamine). Polydrug users were likely to be aged 26–30 years, have low educational attainment, be internal migrants, have a high monthly income, use versatile positions during anal intercourse, and have inadequate knowledge about prevention of HIV infection. As the number of RDs used in the past 6 months increased, the prevalence of HIV-HRBs increased ( P <0.05 for all). The odds of recent HIV infection were higher among those who used one type (aOR = 2.2, 95%CI: 1.5–3.0) or two types of RDs (2.3, 1.0–5.2) in the past 6 months compared with those who did not use RDs. Conclusion: The level and pattern of polydrug use among Chinese MSM were different from high-income countries. Polydrug use had a dose-effect relationship with HIV-HRBs. Polydrug users who have higher levels of RDs use are more likely to engage in various sexual risks, thus may be associated with new HIV infections.


Introduction
Men who have sex with men (MSM) experience a disproportionately high burden of human immunode ciency virus (HIV) infection [1]. Use of recreational drugs (RDs) among this population is regarded as a serious public health concern in China and overseas [2][3][4]. Such as ecstasy and methamphetamine, RDs are stimulants synthesized by chemistry, which are different from traditional drugs such as heroin and opium. Most of RDs have a hallucinogenic effect and make it very easy for users to form psychological dependence. RDs are di cult to quit, and excessive ingestion would lead to severe consequences such as sudden death. Therefore, RDs are expressly prohibited by Chinese laws [5].
At the end of the twentieth century, RD use was widespread among MSM in high-income countries [6]. Currently, this phenomenon is expanding to MSM communities in China and other middle-low income countries [3,[7][8][9]. RDs can enhance sexual function [10], increase sexual pleasure [11], and decrease pain during anal intercourse [12]. However, RD use has been reported to correlate with high-risk sexual behaviors and an increased chance of HIV infection [11][12][13].
In this context, "polydrug use" refers to use of multiple RDs simultaneously or during the same period to achieve a particular effect. Polydrug use has attracted worldwide attention concerning the prevention of HIV infection. Polydrug use can lead to a greater risk of transmission of HIV or other sexually transmitted infections than the use of a single RD [14]. Polydrug use alters the mental state and decreases cognitive inhibition [15]. This action can lead to an increased prevalence of condomless sex (CLS), CLS with HIVpositive partners, group sex, and the number of sexual partners among MSM [16,17]. Compared with using a single RD, any combination of psychoactive drugs (e.g., methamphetamine, ecstasy) and physiologically actives substances (e.g., poppers, erectile-dysfunction agents) can increase the risk of HIV acquisition dramatically [18].
Despite the severity of this problem, most of the research on polydrug use has been in high-income countries [2,17] which, because of political, legal, and cultural differences, may not apply to middle-low income countries [8,19]. Also, the HIV incidence among MSM is higher in middle-low income countries than in high-income countries [20], which suggests a need for studying the effects of polydrug use upon recent HIV infection in middle-low income countries.
China is the largest middle-low income country in the world. The HIV prevalence among China MSM shows an increasing trend and reached ~ 6.9% in 2019 [1,21]. By the end of 2017, there were 2.6 million drug addicts nationwide [22]. The rate of RD use among China MSM ranged from 24.1 to 77.1% [23][24][25]. Thus, it is imperative to understand the relationship between polydrug use and recent HIV infection among Chinese MSM to develop "tailored" interventions that control RD abuse speci cally in the hope of mitigating the HIV epidemic. The present study aims to provide researchers and practitioners with information about patterns of polydrug use among Chinese MSM, as well as the impact of polydrug use on HIV high-risk behaviors and HIV acquisition.

Study participants and questionnaire
In order to better understand the HIV epidemic among Chinese MSM, a multicenter cross-sectional survey was conducted among Chinese MSM in seven large cities in China (Shenyang, Ji'nan, Zhengzhou, Shanghai, Nanjing, Changsha, and Kunming) from June 2012 to June 2013. The cruising areas and service points for MSM were used as the sampling sites. Site-speci c sampling periods were determined based on attendance and hours of operation. Participants were recruited by multiple approaches: advertisements on gay websites, collaborating with local MSM community-based organizations, peer referrals, and venues such as gay bars and bathrooms visited by MSM. To be eligible for this study, participants should be physically male aged 16 years or older, self-reported anal/oral sex experiences within the last year, and able to provide informed consent.
Eligible participants completed an anonymous structured questionnaire concerning sociodemographics, recent sexual behaviors, and other HIV related risk factors. (1) demographics: age, residence, city, education, occupation, marital status, monthly income (USD), predominant sex position in anal intercourse (AI); (2) recent sexual behaviors or HIV risk factors: age of sexual debut with males, main venue of seeking male sexual partners in the past 6 months, group sex in the past 6 months, number of male sexual partners in the past 6 months, commercial sex in the past 6 months, mucosally-traumatic sex in the past 6 months, condom break during AI in the past 6 months, STI-related symptoms in the past year, non-Chinese male sexual partners in the past 6 months. Participants were asked about their use (nonmedical or recreational) of seven commonly used RDs in parties or during sexual contact in the past 6 months: poppers, ecstasy, methamphetamine, amphetamine, codeine, tramadol, and ketamine. Thus, participants were grouped based on the number of drugs used in the past 6 months (i.e., no drug, single drug, two types of drugs, and ≥3 types of drugs). "Polydrug use" was de ned as using ≥2 types of drugs simultaneously in the past 6 months.

Laboratory testing
Samples of venous blood were collected from participants to diagnose HIV-1 antibody. HIV-1 antibody was tested using enzyme-linked immunosorbent assay [ELISA] (bioMerieux, Durham, NC, USA), and HIVseropositive specimens were con rmed by western blotting [WB] (HIV Blot 2.2 WBTM, Genelabs Diagnostics, Singapore). The antibody test for HIV was conducted in respective provincial HIV laboratories of CDC to which the seven study sites were a liated. These WB-positive samples were tested by the immunoglobulin G (IgG)-capture BED-enzyme immunoassay [BED-CEIA] (Calypte Biomedical Corporation, Rockville, MD, USA) at the key laboratory in Shenyang. Based on the measurement of HIV-1speci c IgG to total IgG after seroconversion, BED-CEIA was able to distinguish between recent and established HIV-1 infections [26,27]. To test cross-sectional specimens, we followed the algorithm shown in Figure 1. The calibrator (CAL) and control (including high-positive control, low-positive control, and negative control) specimens were tested in triplicate on every plate, and median values were used to calculate the normalized OD (ODn; ODn=specimen OD/calibrator OD). Specimens with initial ODn>1.2 were classi ed as established infection. Specimens with initial ODn≤1.2 were repeated tested in triplicate to con rm their ODn values by using the median values of the triplicate values. During the retesting, if median ODn values were <0.8, the specimens were considered to be recently infected [28].

Statistical analyses
The chi-square test was used to determine the signi cance of differences in social demographics of the different subgroups. The Cochran-Armitage trend test was used to analyze the association between different subgroups and social demographics. We calculated the prevalence of nine de ned HIV high-risk behaviors in each subgroup. We estimated the ratio of the prevalence of unadjusted HIV high-risk behaviors through the chi-square test, and adjusted this prevalence ratio for social demographics through multivariate logistic regression analysis. An alpha of 0.05 was considered signi cant. The HIV incidence was estimated using a formula to adjust sensitivity/speci city, and the time window to de ne recent HIV infection was 168 days. The formula and parameters were recommended by the Chinese Centers for Disease Control and Prevention [29]. Then, we used multivariable logistic regression to determine the adjusted odds ratios (AORs) and respective 95% con dence intervals (CIs) of the different subgroups. We adjusted for social demographics using recent or established HIV infection, as de ned by the BED-CEIA, as the outcome. Statistical analyses were carried out using SAS 9.2 (SAS Institute, Cary, NC, USA) and STATA 13.0 (Stata Corporation, College Station, TX, USA).

Characteristics of polydrug users
MSM aged 26-30 years had the highest prevalence of RD use in the past 6 months in 1DUs and 2DUs. Also, the proportion of MSM aged 26-30 years increased as the number of RDs used in the past 6 months increased (P < 0.001 for trend) ( Table 1).
For all the other social demographics examined, participants who were internal migrants, had a monthly income ≥600 USD, used versatile positions during anal intercourse, and who had inadequate positive HIV-prevention attitude had the highest prevalence of all types of RD use in the past 6 months. Also, the proportions of these demographics increased signi cantly as the number of RDs used in the past 6 months increased (P < 0.05 for trend). Although participants with the educational attainment of junior school or below had the lowest prevalence for the use of one type of RD in the past 6 months, the prevalence of use of two or more types of RDs in the past 6 months was signi cantly higher ( Table 1).

Characteristics of HIV high-risk behaviors
For almost all the HIV high-risk behaviors examined (e.g., seeking male sexual partners through the Internet in the past 6 months, having group sex in the past 6 months), the prevalence of HIV high-risk behavior was higher among those who used RDs in the past 6 months compared with those who did not. There was a signi cant association between HIV high-risk behavior and RD subgroup (P<0.05 for all). In general, the prevalence of HIV high-risk behaviors increased as the number of RDs used in the past 6 months increased ( Table 2).

Association between RD use and HIV infection
After adjustment for social demographics, 1DUs had higher odds of established HIV infection (AOR = 2.1, 95%CI: 1.5-2.8) and higher odds of recent HIV infection (AOR = 2.2, 95%CI: 1.5-3.0) compared with those who did not use RDs. 2DUs also had higher odds of recent HIV infection (AOR = 2.3, 95%CI: 1.0-5.2) compared with those who did not use RDs. In contrast, 2DUs and 3DUs did not have signi cantly higher odds of established HIV infection compared with those who did not use RDs (Table 3b).

Discussion
We examined the patterns of use of different RD types among Chinese MSM and the impact of such RD use on HIV high-risk behaviors and HIV acquisition. We found that the prevalence of polydrug use among Chinese MSM (5.0%) was lower than the reported prevalence of polydrug use among MSM in western high-income countries(~11.8%) [2]. Chinese MSM who used multiple RDs frequently used poppers along with one or more types of other RDs. As the number of RDs used in the past 6 months increased, the prevalence of various HIV high-risk behaviors also increased. In addition, the odds of recent HIV infection were higher among those who used RDs in the past 6 months compared with those who did not. These data suggested that polydrug users who had higher levels of RD use were more likely to engage in substantially more risky sexual behaviors, and may be associated with a higher risk of HIV acquisition.
Our study has an increased understanding of the characteristics of polydrug use in an MSM population in a middle-low income country and its relationship with HIV infection. Previous studies have shown a correlation between RD use and HIV high-risk behaviors among MSM [6,30]. Our study con rmed those results and showed that the increase in the number of RDs used for recreation was associated with an increase in the prevalence of HIV high-risk behaviors. A similar nding has been documented among HIVpositive MSM in the UK [16], but this relationship has not been examined in a middle-low income country. In contrast with patterns of polydrug use among MSM in high-income countries [16,17,31], Chinese MSM frequently use poppers. We found that 90% of MSM used poppers, and those who used multiple RDs frequently used poppers along with one or more types of other RDs (i.e., methamphetamine, ecstasy, codeine, or ketamine). Poppers are physiologically active substances that facilitate and enhance anal intercourse [2,12]. They do not affect the mental function or decision-making directly [32]. However, when poppers were used with other psychoactive drugs [2] such as methamphetamine, ecstasy, or ketamine, the prevalence of HIV high-risk behaviors increased signi cantly ( Table 2). Most psychoactive drugs are stimulants and, thus, can alter the mental state [15], cause loss of muscle control [15], enhance sexual desires/sexual functions, and affect risk perception and decision-making [10,11]. If psychoactive drugs are used with poppers (which relax the anal-sphincter muscles and reduce pain) simultaneously, MSM can experience more serious sexual disinhibition and, thus, anal intercourse may be more robust or last for longer, leading to an increased risk of HIV infection [32]. This pattern of polydrug use is popular among Chinese MSM but was associated with more HIV high-risk behaviors in our study. Scholars have also found that using poppers with methamphetamine or amphetamine is associated with more unprotected sex acts [33] and, hence, is linked to higher risks of HIV seroconversion [34,35].
The proportion of HIV high-risk behaviors increased as the number of RD used growth in the past 6 months among participants. However, the possible relationship between HIV high-risk behaviors, the number of RDs used, and HIV infections was not clear. However, when we subdivided diagnosed HIV infections into recent and established HIV infections based on the BED-CEIA, we found a signi cant relationship between recent HIV infection and one type of RD used or two types of RD used compared with no RD used in the past 6 months. While we did not nd a signi cant relationship between recent HIV infection and 3DUs compared with those who did not use RDs, this nding could have been due to our small sample size, which would have led to low statistical power to detect the differences in our AOR estimates. In contrast, we found a signi cant relationship only between established HIV infection and one type of RD used in the past 6 months compared with no RD used. This result suggests that RDs used in the past 6 months were associated with recent HIV infection. This may have been because those polydrug users who are less risk-averse would have greater levels of RD use and to be more likely to engage in more sexually risky behaviors and, thus, may be associated with new HIV infections.[41, 42] Several longitudinal studies have found similar associations between polydrug use and recent HIV seroconversion [18,36]. Newly infected individuals have a high level of viral load in plasma and few pronounced symptoms and, thus, are highly infectious, but detection of such people is di cult [37,38]. In addition, MSM in this HIV seroconversion period have been found to participate frequently in HIV high-risk behaviors [38]. Thus, polydrug users will take more sexual risks and, thus, may be associated with new HIV infections and an increased risk of secondary HIV transmission.
Although the collected prevalence of polydrug use among Chinese MSM in our study was lower than the prevalence among MSM reported in high-income countries (5.0% vs. ~11.8%) [2], the actual prevalence of polydrug use of Chinese MSM may have been underestimated due to two main reasons. First, most RDs are illegal in China, so participants may have been afraid of the repercussions of answering honestly about their use of multiple RDs (though participants were asked through an anonymous survey to minimize this bias in social acceptance). Second, we investigated only the seven most commonly used RDs among Chinese MSM. There are many products used by MSM in which the presence of drugs is not clear, so that MSM may have underestimated their RD use unknowingly. Thus, the estimated HIV incidence among polydrug users may also be underestimated because of this bias. We elucidated the characteristics and possible mechanisms of HIV transmission among Chinese MSM who use RDs. We undertook this study in the hope of developing targeted interventions to address the HIV epidemic. We found that participants aged 26-30 years had a higher prevalence of overall RD use in the past 6 months (39.0%) and polydrug use in the past 6 months (7.2%) compared with any other age group examined. The number of identi ed HIV/AIDS cases among MSM aged 26-30 years in China increased rapidly from 2007 to 2015 [39]. Mao and colleagues found a high HIV incidence (~9 infections per 100 PY) among Chinese MSM aged 26-30 years [40]. RD use is associated with behaviors that increase the risk of HIV, so tailored methods reducing RD use must be implemented among Chinese MSM 26-30 years to reduce the risk of HIV acquisition. In addition, we found an association between a decrease proportion in adequate positive attitude towards prevention of HIV infection and an increase in the number of RDs used in the past 6 months, suggesting that strategies focused on increasing positive attitude towards prevention of HIV infection should be targeted at polydrug users. Finally, many Chinese MSM in our study used poppers, which may have been due to the ease of buying this drug (they are not illegal in China) [19]. Thus, the Chinese government should restrict the sale of poppers to reduce RD use to diminish the effect of RD use on HIV transmission. Several intervention measures targeting this group should be considered to control the HIV epidemic: (1) Enhance publicizing the severe irreversible damage to the human body caused by RDs; (2) Emphasize that the use of RDs is a severe illegal behavior to make MSM feel guilty about RDs use; (3) Promote the entertainment venues recti cation; (4) Lead MSM to healthy entertainment methods instead of relying on RDs to vent their inner emptiness, depression and pressure.
Our study had limitations that the proportion of participants who self-reported using multiple types of RDs was only 5%. The low number of polydrug users may have led to the inconsistencies found in the dose-effect relationship between HIV high-risk behaviors and drug subgroups; calculation of the incidence and prevalence of HIV infection by RD subgroups; the association between HIV infection and RD subgroups. We speculate that a bias against social acceptance and misclassi cation because of unknown use of RDs may have limited our ability to develop statistically signi cant results and reduced the observed effect of polydrug use upon HIV infection.

Conclusions
Chinese MSM who used multiple RDs frequently used poppers along with one or more types of other RDs. The proportion of HIV high-risk behaviors increased as the number of RD used growth in the past 6 months. Using one or two types of RDs was associated with increased odds of recent HIV infection compared with MSM who did not use RDs. So polydrug use may be more likely to be associated with new HIV infections. Strategies focusing on decreasing RD use among Chinese MSM and increased governmental control of RDs could reduce drug use and, thus, mitigate the HIV epidemic in China.

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