Expanding syphilis test uptake using rapid dual self-testing for syphilis and HIV among men who have sex with men in China: A multiarm randomized controlled trial.

BACKGROUND: Low syphilis testing uptake is a major public health issue among men who have sex with men (MSM) in many low- and middle-income countries. Syphilis self-testing (SST) may complement and extend facility-based testing. We aimed to evaluate the effectiveness and costs of providing SST on increasing syphilis testing uptake among MSM in China. METHODS AND
FINDINGS: An open-label, parallel 3-arm randomized controlled trial (RCT) was conducted between January 7, 2020 and July 17, 2020. Men who were at least 18 years of age, had condomless anal sex with men in the past year, reported not testing for syphilis in the last 6 months, and had a stable residence with mailing addresses were recruited from 124 cities in 26 Chinese provinces. Using block randomization with blocks of size 12, enrolled participants were randomly assigned (1:1:1) into 3 arms: standard of care arm, standard SST arm, and lottery incentivized SST arm (1 in 10 chance to win US$15 if they had a syphilis test). The primary outcome was the proportion of participants who tested for syphilis during the trial period and confirmed with photo verification and between arm comparisons were estimated with risk differences (RDs). Analyses were performed on a modified intention-to-treat basis: Participants were included in the complete case analysis if they had initiated at least 1 follow-up survey. The Syphilis/HIV Duo rapid test kit was used. A total of 451 men were enrolled. In total, 136 (90·7%, 136/150) in the standard of care arm, 142 (94·0%, 142/151) in the standard of SST arm, and 137 (91·3%, 137/150) in the lottery incentivized SST arm were included in the final analysis. The proportion of men who had at least 1 syphilis test during the trial period was 63.4% (95% confidence interval [CI]: 55.5% to 71.3%, p = 0.001) in the standard SST arm, 65.7% (95% CI: 57.7% to 73.6%, p = 0.0002) in the lottery incentivized SST arm, and 14.7% (95% CI: 8.8% to 20.7%, p < 0.001) in the standard of care arm. The estimated RD between the standard SST and standard of care arm was 48.7% (95% CI: 37.8% to 58.4%, p < 0.001). The majority (78.5%, 95% CI: 72.7% to 84.4%, p < 0.001) of syphilis self-testers reported never testing for syphilis. The cost per person tested was US$26.55 for standard SST, US$28.09 for the lottery incentivized SST, and US$66.19 for the standard of care. No study-related adverse events were reported during the study duration. Limitation was that the impact of the Coronavirus Disease 2019 (COVID-19) restrictions may have accentuated demand for decentralized testing.
CONCLUSIONS: Compared to standard of care, providing SST significantly increased the proportion of MSM testing for syphilis in China and was cheaper (per person tested). TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900022409.

Introduction

There were an estimated 6.3 million new cases of syphilis globally in 2016 [1]. Countries have noted syphilis increasing particularly among men who have sex with men (MSM) [2]. This higher risk may be related to structural factors such as denser sexual networks and stigma leading to poorer access to health services and individual factors such as condomless sex with multiple partners [3,4]. In China, syphilis incidence has increased from 1.0 to 32.2 per 100,000 between 1995 and 2016 [5]. Regular syphilis testing is a key strategy for syphilis control [6,7]. Earlier diagnosis and treatment prevents morbidity, mortality, and onward transmission [7]. In most countries, syphilis testing occurs in health facilities [8], but existing facility-based syphilis testing and management resources and services are inadequate to curb the spread of syphilis. Studies suggest that only 30% of MSM in China have ever received a syphilis test [9]. Anticipated stigma associated with syphilis, lack of sexual behavior disclosure to health professionals [8], and the Coronavirus Disease 2019 (COVID-19) restrictions make facility testing more difficult. Syphilis self-testing (SST) may be an effective method to address these barriers by complementing and extending facility-based testing [9].

There are efforts to decentralize syphilis testing, including venue-based testing, self-sampling (sending a specimen to a laboratory), and self-testing [9,10]. SST is a process whereby an individual collects their own specimen, performs the test, and interprets the result themselves [4]. An immunochromatographic test uses blood to detect treponemal antibodies using a rapid test [11], similar to blood-based HIV self-testing. Evidence from a large body of blood-based HIV self-testing programs worldwide demonstrates the feasibility, acceptability, and efficacy of decentralized sexually transmitted infections (STIs) testing and increasing testing uptake among MSM [12]. A cross-sectional study of 699 MSM from 21 provinces in China found 48% of MSM who had tested for syphilis used self-testing [4]. This study also reported that 52% of MSM reported that SST was their first syphilis test. Thus, decentralizing syphilis testing by providing more options for home-testing can open up new possibilities to deliver syphilis testing to those in greatest need. However, the policy context for SST and HIV self-testing is different. Although 59 countries have policies supporting the use of HIV self-testing among key populations [13], none have guidelines supporting SST.

In recent years, there is growing interest in using social innovation methods to solve complex problems [14]. For example, crowdsourcing (where a group of individuals solve a problem and solutions are shared with the public) [15] could be combined with the insight that financial incentives could enhance healthy behaviors [16]. There is evidence that financial incentives may improve uptake of HIV/STI testing [17]. We previously reported that MSM living in China—particularly those at higher risk for syphilis—reported that they were more likely to test for syphilis if a lottery-based incentive was available [18]. A lottery-based incentive is a form of financial incentive whereby an individual who receives a syphilis test is enrolled in a chance to win a monetary reward. We conducted a crowdsourcing call with MSM in China to design a lottery-based incentive to examine if the addition of this would further enhance the appeal of SST. The combination of the implementation of SST with lottery-based financial incentives has not been explored.

This study aimed to evaluate the effectiveness and cost of providing SST on increasing syphilis testing uptake among MSM in China compared with standard of care. The primary null hypothesis was no difference between standard SST and the standard of care among MSM in China. Our secondary objective was to examine the difference between lottery incentivized SST and standard SST. Before implementing this trial, we assessed the acceptability, benefits, and harms associated with SST [4], examined participants’ ability to follow test instructions and interpret results [19], and evaluated the study design, recruitment process, and materials [19].

Methods

Study design and participants

The full study protocol has been published elsewhere (S1 Study Protocol) [19]. This is an open-label, parallel 3-arm randomized controlled trial (RCT) with individuals randomized in a 1:1:1 ratio to 3 study arms: control arm (standard of care); standard SST arm; and lottery incentivized SST arm. Control arm participants received information on self-referral pathways for free facility-based syphilis testing. Both self-testing arms were offered access to dual syphilis/HIV self-test kits for free at monthly intervals via mail.

Recruitment took place from January 7, 2020 to January 17, 2020. Participants in each arm were followed every 3 months for 6 months. The trial follow-up and data collection were completed on July 17, 2020. The follow-up was conducted during the COVID-19 pandemic when facility-based syphilis testing was still available with a series of risk assessment procedures before patients could enter health facilities.

The study was approved by the ethics review committee of the Southern Medical University Dermatology Hospital (GDDHLS-20181206). We reported our studies according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (S1 CONSORT Checklist), and the CONSERVE 2021 statement (S1 CONSERVE Checklists). The trial was registered with the Chinese Clinical Trial Registry, number ChiCTR1900022409.

Syphilis self-testing kit

The practice of HIV self-testing among MSM living in China is acceptable, feasible, and safe [20,21]. SST kits can be accessed on e-commerce platforms or through existing HIV self-testing programs in China [4]. There are 10 brands of SST kits available on the 2 largest e-commerce platforms in China. All the kits use blood to detect treponemal-specific antibodies with a colloidal gold method, which cannot distinguish between current and past infection. In this trial, we used the syphilis and HIV combo rapid test kit because of its excellent test characteristics (sensitivity of 99.7% and specificity of 99.7%) and the World Health Organization (WHO) prequalification [22]. The Syphilis/HIV Duo test is a solid phase immunochromatographic assay for the qualitative detection of antibodies to all isotypes (immunoglobulin G [IgG], immunoglobulin M [IgM], and immunoglobulin A [IgA]) specific to HIV-1/2 and/or Treponema pallidum (TP) simultaneously in human serum, plasma, or whole blood. The procedure of blood-based SST is similar to the procedure for blood-based HIV self-testing. All the kits were certified by the China Food and Drug Administration (CFDA) with excellent sensitivity and specificity [4]. The cost per test kit ranges from US$2.5 to US$15.

Procedures

Fig 1 shows the key concepts of the interventions for each study arm.

Fig 1

Key concepts of the 3 study arms: standard of care, SST, and lottery incentivized self-testing.

SST, syphilis self-testing.

Recruitment

We recruited participants from a large MSM-oriented mobile social app—Blued (Danlan, Beijing, China) [23]. Blued is China’s most popular social networking mobile application among MSM. By February 2018, Blued had 40 million registered users globally, with 70% in Mainland China [24]. An invitation to join the study was posted on Blued’s portal website and startup screen and was also sent via other social media portals (WeChat, a popular Chinese messaging app; Weibo, a microblogging platform; and QQ, a messaging platform). Individuals who clicked the advertisement were directed to a survey website hosted by Sojump (Changsha Haoxing Information Technology, China) to give consent and complete eligibility screening. Participants were eligible if they were born biologically male, aged 18 years or older, had condomless anal sex with other men in the past 12 months, reported not testing for syphilis in the last 6 months, planned to live in China for the next 6 months, and had a stable residence where they could securely receive a postal package. Participants were excluded if they participated in another research program related to HIV/STIs during the study period or could not provide consent.

Eligible participants completed a baseline survey and were required to provide contact information including a cell phone number or a WeChat account to receive text messages, a shipping address for participants who applied for kits, and a preferred name, which were all stored in a password-protected file that a designated research assistant could only access. All participants provided online informed consent before the baseline survey by clicking on a “button” indicating that the participant has read the consent form and agrees to participate. We enrolled participants from 124 cities in 26 Chinese provinces (S1 Table). Participants were provided with US$3 for their time completing the baseline survey.

Randomization and allocation

Men who completed the baseline survey and provided contact information were directed to contact a research assistant responsible for allocating participants into one of the 3 study arms. Participants were randomly assigned (1:1:1) to one of the 3 study arms using block randomization with a block size of 12. Computer-generated randomization codes were produced by a biostatistician using SAS version 9.4 (SAS Institute, Cary, North Carolina, United States of America) who was not involved in participant enrollment. An independent research assistant who was not involved in the trial sealed the study allocation in numbered opaque envelopes. The study design required participants and recruitment staff to be aware of the study arm allocation; however, they did not know the arm assigned until an envelope was opened after informed consent and enrollment.

Intervention

Men in the standard of care arm were provided with an educational message including the risk of acquiring syphilis, the importance of screening for syphilis, a link to resources to locate local STIs or HIV voluntary counseling and testing (VCT) clinics, and encouragement to screen for syphilis testing at their local VCT clinics every 3 months. VCT clinics in China provide both HIV and syphilis testing free of charge. The educational message was sent by SMS or WeChat quarterly: at enrollment, 3 months, and 6 months.

In addition to the message for men in the standard of care arm, men in the standard SST arm were also provided with SST services whereby men could order a maximum of one SST package for free per month through WeChat during the study period. The SST package was sent to men by postal mail (express delivery), which arrived at the intended destination within an average of 2.5 days. The package included the manufacturer-supplied step-by-step instructions, a web link to an instructional video, and a result report card (S1 Text, S1, S2 and S3 Figs). The result report cards allowed participants to upload a photo of their test results to a verification platform by scanning a barcode on the card that was uniquely linked to the study participant.

Men in the lottery incentivized SST arm were provided with the standard SST arm intervention. In addition, men who conducted the SST or facility-based testing during the trial and uploaded photo verification of the results were offered an opportunity to participate in a lottery draw. The lottery draw provided a 10% chance of winning US$15 in cash. Each man could participate in the lottery draw up to 2 times per month during the trial if they uploaded both self-testing and facility-based testing results. An open crowdsourcing contest determined the procedure of the lottery draw and the images that would be shown to men in the lottery incentivized SST arm. The crowdsourcing contest resulted in 14 lottery schemes from which the winning entries were then used to develop the lottery draw program in this trial. A total of 20 volunteer MSM voted on the amount of prize money and the probability of winning in the lottery draw.

Data collection

In all 3 study arms, men were encouraged to upload syphilis testing record and results. Confirmed SST was determined by photo verification of the used test kit. Facility-based syphilis testing and results were determined by photo verification of the test report. A research assistant conducted the verification process by checking the photos uploaded in the verification platform or WeChat. Men in all 3 arms who uploaded photo verification were provided with US$1.

All participants completed a baseline questionnaire at enrollment, which included sociodemographic characteristics, sexual behaviors, past HIV/syphilis testing and treatment, and attitude toward SST. During follow-up, we invited all participants to complete a brief online questionnaire at 3 and 6 months that collected information on the number, time, location, reasons for, and results of syphilis tests (including self-tests) and other STI tests at clinics and community sites, and sexual risk behaviors in the past 3 months. Participants in the 2 self-testing arms were also asked to report the number of self-tests that were used for personal testing, to test a partner, or given to someone else. Participants were provided with US$5 for their time for completing each follow-up survey.

Follow-up support

A syphilis counselor was available for support through WeChat and telephone from 8:00 AM to 5:30 PM, Monday through Friday. Support included giving pretest counseling, instructing how to use the self-test kit, helping to interpret results, and providing advice for reactive test results. Participants were advised to inform the counselor immediately if they had a reactive self-test result. Any participant with a reactive self-test result was referred for confirmatory laboratory testing and clinical examination at the designated clinics or hospitals. A research assistant undertook further follow-up to obtain confirmatory testing results and treatment information for men diagnosed with syphilis. A log of each enquiry was recorded.

Outcomes

The primary outcome was the proportion of participants tested for syphilis either at a clinic or via self-test during the whole 6-month study period, excluding confirmatory tests after a reactive self-test between the intervention groups and the control group. This was assessed in all participants using photo verification. Secondary outcomes included syphilis testing frequency during the trial, number of newly identified syphilis infections during the trial, the linkage to syphilis clinical care after self-testing during the trial, the proportion of HIV and other STIs (chlamydia, gonorrhea, human papillomavirus, and herpes simplex virus) tests during the trial, risky sexual behaviors in the last 3 months (such as number of sex partners, anal group sex, substance use before or during sex, and condomless anal sex). The secondary outcomes were assessed based on self-reported data from each follow-up survey. We also reported the total and incremental unit costs for each arm. The costs collected were from a healthcare provider perspective. Details of the economic evaluation are summarized in S1 Appendix (p. 11–20).

Statistical analysis

General analysis

We used descriptive analyses to report the demographic and behavioral characteristics of participants in each study arm. All inferential tests were 2-sided with a type 1 error level of 0.05. Data analysis was conducted as modified intention to treat: Participants were included in the complete case analysis if they had initiated at least 1 follow-up survey. Risk differences (RDs) and corresponding 95% confidence intervals (CIs) were expressed as percentages. All analyses were conducted using SAS version 9.4 (SAS Institute).

Analysis of primary outcome

The primary outcome of test uptake was evaluated as a difference in the probability of syphilis testing during the trial between the 2 groups. For binomial proportions presented in the abstract, since the sample size was sufficient and there were no extreme proportions (close to 0 or 1), p-values and 95% CIs were obtained via a Wald test. However, due to small or zero cell counts and proportions, RDs were presented with p-values generated from Barnard unconditional exact test and 95% CIs from the Chan and Zhang method (which is based on a score statistic) [25]. We also conducted sensitivity analyses on uptake of syphilis testing using nonresponder imputation (NRI) to impute the worst- and best-case scenarios and multiple imputation (MI) by fully conditional specification (FCS) with logistic regression. For NRI, the sensitivity analyses involved replacing missing values with the worst value (not tested for syphilis) and best value (tested for syphilis) in the observed data. We assumed for the best value that all the men with missing follow-up data who applied for the SST kits received syphilis testing during the trial. For MI, Rubin’s rule [26] was used to compute pooled estimates for the RDs and standard errors. The number of imputations was selected based on relative efficiency such that FMI/m≈0.01, where FMI is the maximum fraction of missing information (computed as in [27]) and m is the number of imputations. The FMI ranged from 0.02 to 0.21, so m = 20 was chosen for the number of imputations. Compared to those who completed at least 1 follow-up survey, participants lost-to-follow-up differed on 3 demographic variables included in the imputation model (S2 Table): annual income, disclosure as MSM to family, friends, or healthcare professionals, and ever tested for HIV.

Analysis of secondary outcome

The secondary outcome of male sex partners in the past 3 months was reported as the mean number of partners in each arm. For the mean differences between groups, p-values and 95% CIs were computed using a Satterthwaite approximation (assuming unequal variances between the groups). Other secondary outcomes, including the proportion of HIV and other STIs and risky sexual behaviors in the last 3 months, were evaluated using the same methods described for the primary outcome.

Economic evaluation

We used a microcosting approach to estimate the financial cost from a health provider perspective. Costs were collected alongside the trial and categorized as either fixed or variable. For fixed costs (i.e., independent of the number of tests conducted), we estimated the cost of capital (building rent), personnel support, and office equipment (Table A in S1 Appendix). For the lottery incentivized self-testing arm, we included the cost of developing the lottery strategy from a crowdsourcing activity—this was annualized over an expected useful life of 5 years, using a discount rate of 3%. For variable costs (i.e., dependent on the number of tests conducted), we estimated the cost of supplies used for syphilis testing. All costs were reported in 2020 USD based on the exchange rates using OANDA currency conversions (1 USD = 6.96 yuan). We analyzed the cost in Microsoft Excel 2019 (Microsoft, USA). Using parameters from Table A in S1 Appendix, which were informed by the trial, we created a decision tree model using TreeAge Pro 2020 (TreeAge Software, Inc., Williamstown, MA) to explore the cost-effectiveness of the 3 arms (Fig A in S1 Appendix).

Results

Overall, the survey link was clicked 54,082 times; 52,089 withdrew before reading the consent form, and 2,713 were screened for study eligibility (Fig 2). In total, 2,124 men were ineligible because they reported no condomless anal sex with men in the last year (n = 1,362), had tested for syphilis in the last 6 months (n = 600), were younger than 18 years old (n = 82), currently had syphilis (n = 55), or were not born biologically male (n = 25). An additional 138 men were excluded for not signing the consent form (n = 38) or not providing contact information (n = 100).

Fig 2

CONSORT flowchart. CONSORT, Consolidated Standards of Reporting Trials; SST, syphilis self-testing.

A total of 451 men were enrolled and randomly assigned to one of the study arms: 150 men in the standard of care arm, 151 men in the standard SST arm, and 150 men in the lottery incentivized SST arm. During the trial, 111 (73.5%) men in the standard SST arm and 117 (78.0%) men in the lottery incentivized SST arm applied for the SST kits at least once. All the applicants received the mailed SST kits. Eight men asked for help on the use of SST or interpretation of the outcome of SST during the trial. During the study, 136 (90.7%) in the standard of care arm, 142 (94.0%) in the standard of SST arm, and 137 (91.3%) in the lottery incentivized SST arm initiated at least 1 follow-up survey and were included in the final analysis (Fig 2). Among them, 48.2% (200/415) of participants uploaded a photo of their test results, and 93.5% (187/200) of those photos matched the self-reported results. Characteristics of participants lost to follow-up (36 men) differed in disclosure of sexual orientation and annual income from those who completed at least 1 follow-up survey (415 men) during the trial period (S2 Table).

Demographic characteristics were similar across the 3 arms (Table 1). Most participants were 30 years of age or younger (79.4%, 358/451), never married (87.1%, 393/451), had at least a college degree (70.3%, 317/451), and had an annual income of US$9,500 or below (69.3%, 312/451). Around half (50.3%, 227/451) reported ever disclosing their sexual orientation. About two-thirds of men (69.2%, 312/451) reported that they had multiple sexual partners in the past 3 months, and 376 (83.4%) men reported having had condomless anal sex in the past 3 months. In total, 309 (68.5%) men had ever tested for HIV, while 91 (20.2%) had ever tested for syphilis. Only 36 (8%) men had ever used syphilis self-test (Table 1).

Table 1

Baseline social demographic and behavioral characteristics of MSM in China.

	Total (N = 451)	SOC (N = 150)	Standard SST (N = 151)	Lottery incentivized SST (N = 150)
Age (years)
≤30	358/451 (79.4)	115/150 (76.7)	126/151 (83.4)	117/150 (78.0)
>30	93/451 (20.6)	35/150 (23.3)	25/151 (16.6)	33/150 (22.0)
Mean (SD)	25.6 (6.3)	25.6 (6.5)	25.6 (6.4)	25.7 (6.2)
Marital status
Never married	393/451 (87.1)	128/150 (85.3)	134/151 (88.7)	131/150 (87.3)
Ever married	58/451 (12.9)	22/150 (14.7)	17/151 (11.3)	19/150 (12.7)
Annual income (US$)
<3,000	85/451 (18.9)	32/150 (21.3)	23/151 (15.2)	30/150 (20.0)
3,000 to 6,000	85/451 (18.9)	25/150 (16.7)	31/151 (20.5)	29/150 (19.3)
6,001 to 9,500	142/451 (31.5)	47/150 (31.3)	47/151 (31.1)	48/150 (32.0)
9,501 to 12,500	78/451 (17.3)	26/150 (17.3)	28/151 (18.5)	24/150 (16.0)
≥12,501	61/451 (13.5)	20/150 (13.3)	22/151 (14.6)	19/150 (12.7)
Highest education
High school or below	134/451 (29.7)	39/150 (26.0)	48/151 (31.8)	47/150 (31.3)
College or beyond	317/451 (70.3)	111/150 (74.0)	103/151 (68.2)	103/150 (68.7)
Disclosure as MSM to family, friends, or healthcare professionals
Never	224/451 (49.7)	84/150 (56.0)	64/151 (42.4)	76/150 (50.7)
Ever	227/451 (50.3)	66/150 (44.0)	87/151 (57.6)	74/150 (49.3)
Number of male sex partners in the past 3 months
0 to 1	139/451 (30.8)	40/150 (26.7)	48/151 (31.8)	51/150 (34.0)
Multiple	312/451 (69.2)	110/150 (73.3)	103/151 (68.2)	99/150 (66.0)
Mean (SD)	2.8 (2.3)	2.9 (2.3)	2.8 (2.4)	2.5 (2.0)
Anal sex without the use of condom in the past 3 months
No	75/451 (16.6)	27/150 (18.0)	27/151 (17.9)	21/150 (14.0)
Yes	376/451 (83.4)	123/150 (82.0)	124/151 (82.1)	129/150 (86.0)
Ever tested for HIV
No	142/451 (31.5)	55/150 (36.7)	37/151 (24.5)	50/150 (33.3)
Yes	309/451 (68.5)	95/150 (63.3)	114/151 (75.5)	100/150 (66.7)
Ever tested for syphilis
No	360/451 (79.8)	124/150 (82.7)	117/151 (77.5)	119/150 (79.3)
Yes	91/451 (20.2)	26/150 (17.3)	34/151 (22.5)	31/150 (20.7)
Ever used a syphilis self-test
No	415/451 (92.0)	141/150 (94.0)	139/151 (92.1)	135/150 (90.0)
Yes	36/451 (8.0)	9/150 (6.0)	12/151 (7.9)	15/150 (10.0)

Data are n/N (%) unless otherwise indicated.

MSM, men who have sex with men; SOC, standard of care; SST, syphilis self-testing.

Overall, 90 (63.4%) of 142 men in the standard SST arm underwent at least 1 syphilis test during the trial period compared to 90 (65.7%) of 137 men in the lottery incentivized SST arm and 20 (14.7%) of 136 men in the standard of care arm (Table 2). The proportion of individuals who underwent syphilis testing during the trial period was higher in the standard SST arm compared to standard of care (RD: 48.7%, 95% CI: 37.8% to 58.4%, p < 0.001) and in the lottery incentivized SST arm compared to standard of care (RD: 51.0%, 95% CI: 40.2% to 60.6%, p < 0.001). Compared to the standard SST arm, there was no observed difference in the proportion of individuals testing for syphilis in the lottery incentivized SST arm during the first 3 months (RD: −0.3%, 95% CI: −12.2% to 11.8%, p = 1.00). However, there was an observed difference between the standard SST and lottery incentivized SST arm during the second 3 months of follow up (RD: 18.1%, 95% CI: 3.8% to 29.9%, p = 0.003) (Table 2). Sensitivity analyses for the primary outcome returned similar results (S3 Table).

Table 2

Uptake of syphilis testing among participants who initiated at least 1 follow-up survey.

	SOC	Standard SST	Lottery incentivized SST	Standard SST versus SOC		Lottery incentivized SST versus SOC		Lottery incentivized SST versus standard SST
	n/N (%)	n/N (%)	n/N (%)	RD (95% CI)	p-Value	RD (95% CI)	p-Value	RD (95% CI)	p-Value
Proportion of participants who tested for syphilis (primary outcome)
Month 0 to 3	7/131 (5.3)	74/137 (54.0)	72/134 (53.7)	48.7 (38.9, 57.8)	<0.0001	48.4 (38.3, 57.6)	<0.0001	−0.3 (−12.2, 11.8)	1.00
Month 4 to 6	14/129 (10.9)	51/139 (36.7)	69/126 (54.8)	25.8 (15.6, 35.7)	<0.0001	43.9 (33.2, 54.0)	<0.0001	18.1 (3.8, 29.9)	0.003
Overall	20/136 (14.7)	90/142 (63.4)	90/137 (65.7)	48.7 (37.8, 58.4)	<0.0001	51.0 (40.2, 60.6)	<0.0001	2.3 (−9.0, 13.6)	0.77
Participants by the total of syphilis testing during the trial (secondary outcome)
0	116/136 (85.3)	52/142 (36.6)	47/137 (34.3)	−48.7 (−58.4, −37.8)	<0.0001	−51.0 (−60.6, −40.2)	<0.0001	−2.3 (−13.6, 9.0)	0.77
1	16/136 (11.8)	50/142 (35.2)	31/137 (22.6)	23.5 (12.9, 33.2)	<0.0001	10.9 (1.75, 20.0)	0.02	−12.6 (−23.1, −1.6)	0.02
2	3/136 (2.2)	25/142 (17.6)	29/137 (21.2)	15.4 (8.6, 22.9)	<0.0001	19.0 (11.6, 26.9)	<0.0001	3.6 (−5.9. 13.2)	0.53
3	1/136 (0.7)	8/142 (5.6)	20/137 (14.6)	4.9 (0.7, 10.2)	0.02	13.9 (8.0, 21.0)	<0.0001	9.0 (1.7, 16.8)	0.01
4	0/136 (0.0)	6/142 (4.2)	8/137 (5.8)	4.2 (1.1, 9.0)	0.02	5.8 (2.3, 11.2)	0.004	1.6 (−4.0, 7.6)	0.56
>4	0/136 (0.0)	1/142 (0.7)	2/137 (1.5)	0.7 (−2.2, 3.9)	0.52	1.5 (−1.4, 5.3)	0.21	0.8 (−2.6, 4.7)	0.60
Participants who tested more than 1 time during the trial (secondary outcome)
>1	4/136 (3.0)	40/142 (28.2)	59/137 (43.1)	25.2 (17.2, 33.7)	<0.0001	40.1 (31.2, 49.2)	<0.0001	14.9 (2.4, 26.0)	0.01

RD = risk (probability) difference expressed as a percentage.

CI, confidence interval; RD, risk difference; SOC, standard of care; SST, syphilis self-testing.

The proportion of men who tested for syphilis more than once during the trial was higher in the standard SST arm compared to standard of care (RD: 25.2%, 95% CI: 17.2% to 33.7%, p < 0.001) and in the lottery incentivized SST arm compared to standard of care (RD: 40.1%, 95% CI:% 31.2 to 49.2%, p < 0.001). Additionally, this proportion was higher in the lottery incentivized SST arm than standard SST (RD: 14.9%, 95% CI: 2.4% to 26.0%, p = 0.01) (Table 2).

Table 3 summarized the economic evaluation: The cost per person tested was US$66.19 for standard of care, US$26.55 for SST, and US$28.09 for lottery incentivized SST. The incremental cost per person tested for SST compared to standard of care was US$17.55 per person tested and for lottery incentivized SST compared to SST was US$35.55 per person tested. Fig B in S1 Appendix demonstrated that the incremental cost per person tested comparing SST with standard of care would decrease the most with lower (variable and fixed) costs for SST and higher fixed costs of standard of care. Fig C in S1 Appendix showed that the standard of care option was most likely to be cost-effective when the willingness to pay was less than US$17 per case tested, and SST was most likely to be cost-effective between a willingness to pay of US$17 and US$36 per case tested. These findings highlight the benefits of SST from a cost-effectiveness standpoint. The complete economic evaluation was provided in the S1 Appendix.

Table 3

Incremental cost per additional person tested and per additional case detected of syphilis testing strategies among MSM in China.

	Unit cost	Effectiveness	Cost-effectiveness ratio
Proportion of men tested
SOC	US$5.60	0.0846
SST	US$12.12	0.4565	US$17.55 per additional man tested
Lottery	US$15.45	0.5500	US$35.55 per additional man tested
Case positivity
SOC	US$5.60	0.0039
SST	US$12.12	0.0254	US$303.27 per additional case detected
Lottery	US$15.45	0.0308	US$614.56 per additional case detected

Lottery, lottery incentivized syphilis self-testing; MSM, men who have sex with men; SOC, standard of care; SST, syphilis self-testing.

Of the 200 participants tested for syphilis, 191 (95.5%) men were SST, and 150 (78.5%) men reported that the self-test was their first ever syphilis test. A total of 14 (7.0%, 14/200) men were found to be infected with syphilis, 5 of whom (35.7%, 5/14) were newly identified through this study (1 was in the standard of care arm, 2 in the standard SST arm, and 2 in the lottery incentivized arm), and all 5 reported receiving further confirmatory testing and treatment (S4 Table). Additionally, among those who self-tested for syphilis, 18 (9.4%, 18/191) men were found to be infected with HIV, and 8 men (44.4%, 8/18) were newly identified through this study. The proportion of men who conducted syphilis testing by different testing mode (self-testing versus facility-based testing) are summarized in S5 Table.

Among the men who had syphilis testing during the trial, the proportion of individuals testing for other STIs during the trial in the standard SST arm was significantly lower than in the standard of care arm (RD: −24.4%, 95% CI: −48.5% to −0.9%, p = 0.02) (Table 4).

Table 4

HIV/STI testing and sexual behaviors self-reported by men who had syphilis testing during the trial and initiated at least 1 follow-up survey.

SOC group	Standard SST group	Lottery incentivized SST group	Standard SST versus SOC		Lottery incentivized SST versus SOC		Lottery incentivized SST versus standard SST
Mean (SD)	Mean (SD)	Mean (SD)	MD (95% CI)a	p-Value	MD (95% CI)	p-Value	MD (95% CI)	p-Value
Number of male sex partners in the past 3 months
Month 0 to 3	2.0 (1.0)	2.2 (1.7)	2.3 (1.9)	0.2 (−0.8, 1.1)	0.67	0.3 (−0.6, 1.3)	0.45	0.2 (−0.4, 0.8)	0.60
Month 4 to 6	1.6 (1.0)	2.1 (1.7)	2.0 (1.6)	0.4 (−0.3, 1.1)	0.26	0.3 (−0.4, 1.0)	0.33	−0.1 (−0.7, 0.5)	0.78
	n/N (%)	n/N (%)	n/N (%)	RD (95% CI)	p-Value	RD (95% CI)	p-Value	RD (95% CI)	p-Value
Male sex partners without condoms in the past 3 months
Month 0 to 3	2/7 (28.6)	22/66 (33.3)	26/68 (38.2)	4.8 (−37.1, 32.4)	0.98	9.7 (−32.8, 37.4)	0.81	4.9 (−11.7, 21.2)	0.60
Month 4 to 6	5/13 (38.5)	20/45 (44.4)	24/62 (38.7)	6.0 (−26.2, 34.1)	0.82	0.3 (−31.5, 26.8)	1.00	−5.7 (−24.8, 13.5)	0.61
Anal group sex in the past 3 months
Month 0 to 3	2/7 (28.6)	5/74 (6.8)	6/72 (8.3)	−21.8 (−63.1, 3.2)	0.08	−20.2 (−61.3, 5.1)	0.10	1.6 (−7.9, 11.4)	0.77
Month 4 to 6	1/14 (7.1)	5/51 (9.8)	9/69 (13.0)	2.7 (−24.9, 17.1)	0.84	5.9 (−22.1, 19.1)	0.70	3.2 (−9.8, 15.2)	0.61
Ever used substances before or during sex in the past 3 months
Month 0 to 3	3/7 (42.9)	31/74 (41.9)	40/72 (55.6)	−1.0 (−39.6, 32.7)	0.99	12.7 (−26.3, 46.2)	0.66	13.7 (−3.0, 29.7)	0.11
Month 4 to 6	5/14 (35.7)	18/51 (35.3)	33/69 (47.8)	−0.4 (−31.0, 25.9)	1.00	12.1 (−19.0, 37.4)	0.47	12.5 (−5.8, 29.9)	0.17
Tested for HIV
Month 0 to 3	7/7 (100.0)	60/74 (81.8)	55/72 (76.4)	−18.9 (−31.3, 25.5)	0.26	−23.6 (−36.6, 20.4)	0.17	−4.7 (−18.3, 8.8)	0.53
Month 4 to 6	14/14 (100.0)	48/51 (94.1)	62/69 (89.9)	−5.9 (−17.1, 18.6)	0.46	−10.1 (−20.6, 15.8)	0.24	−4.3 (−14.9, 7.5)	0.56
Overall	19/20 (95.0)	83/90 (92.2)	80/90 (88.9)	−2.8 (−12.4, 18.3)	0.82	−6.1 (−16.5, 14.7)	0.50	−3.3 (−12.9, 5.7)	0.53
Tested for other STIs b
Month 0 to 3	1/7 (14.3)	6/74 (8.1)	6/72 (8.3)	−6.2 (−49.1, 11.2)	0.79	−6.0 (−49.2, 11.5)	0.86	0.2 (−9.7, 10.1)	1.00
Month 4 to 6	4/14 (28.6)	3/51 (5.9)	9/69 (13.0)	−22.7 (−51.7, −0.6)	0.02	−15.5 (−44.8, 6.6)	0.15	7.2 (−4.7, 18.4)	0.22
Overall	8/20 (40.0)	14/90 (15.6)	20/90 (22.2)	−24.4 (−48.5, −0.9)	0.02	−17.8 (−42.5, 5.5)	0.10	6.7 (−5.2, 18.4)	0.28

MD = mean difference. RD = risk (probability) difference expressed as a percentage.

aDue to rounding error, mean differences may differ by one decimal place from differences obtained by subtracting means listed in table.

bOther STIs included gonorrhea, chlamydia, human papillomavirus, and herpes simplex virus.

CI, confidence interval; SOC, standard of care; SST, syphilis self-testing; STI, sexually transmitted infection.

Discussion

Our RCT found that promoting SST among MSM substantially increased syphilis test uptake compared with the standard of care. We also explored any further benefits from adding a financial incentive, but we observed that the additional benefits from lottery incentivized SST were marginal. To our knowledge, this study is the first RCT to evaluate the effectiveness and cost of SST and extends the limited literature on SST among MSM [4,19,28]. SST could complement other efforts to decentralize syphilis testing such as syphilis self-collection and venue-based testing [9].

Our study showed that the SST strategy could increase syphilis testing uptake among MSM. This finding is consistent with the results of our pilot RCT [19] and a number of studies on HIV self-testing among MSM [3,29]. This effect of SST might be related to the increasing availability of online SST kits, and the growing acceptability of self-testing due to widespread public health and community-based organization programs to promote HIV self-testing. Additionally, we found that the majority (78.5%) of syphilis self-testers reported that the self-test was their first ever syphilis test. This suggests that SST could help increase first-time testing among individuals who do not seek testing in a facility-based setting. Better understanding first-time testers within sexual networks is critical for the control of syphilis [30]. Our study observed that those tested for syphilis/HIV in the intervention arms were less likely to be tested for other STIs. However, the benefits of improving the uptake of HIV and syphilis testing might outweigh the cost of not screening for other STIs in asymptomatic persons [31]. Further research is warranted to evaluate the impact of a likely reduction in testing for other STIs if HIV/SST is scaled up.

We found that SST is cheaper per person tested compared to facility-based testing. While numerous economic research exists for HIV-self testing [32,33], little is known about the costs associated with implementing SST. We only found one current estimate of the unit cost for syphilis management in China of US$124 (USD, 2011) [34]. Therefore, our economic evaluation data are important for decision-makers to efficiently and fairly allocate limited resources. We likely underestimated the value of screening because we did not include the benefit of averting ongoing syphilis transmissions. Another study has highlighted the value of frequent syphilis testing reducing onward transmission of syphilis [7]. Our study found a higher proportion of men in the intervention arms who tested for syphilis more than once during the trial period. Together, this further reinforces the economic value of investing in syphilis screening programs that encourages regular syphilis testing among those at risk.

Our study findings may be generalizable to the many other settings where MSM seek online public health information that can be accessed without providing identifying information [35,36]. Online platforms represent a major opportunity for reaching marginalized MSM and designing pragmatic interventions [37]. Online platforms can reach MSM in remote rural areas, MSM who do not tell doctors about their same-sex behaviors (an especially important consideration in low- and middle-income countries with severe stigma), and other vulnerable subsets of MSM. At the same time, the approach used in this study requires an online connection, willingness to use an online platform for requesting testing, and a postal service to mail the kits. Our empirical generalizability research found that MSM population characteristics from an online MSM trial were comparable to data from a national, cross-sectional sample of MSM [38].

We used rapid dual self-testing for syphilis and HIV in this study, given the syndemic of syphilis and HIV among MSM globally [38]. HIV self-testing has already created extensive infrastructure and public health pathways, including online testing programs, verification methods, integration of public health and community-based organization programs, and communication materials [20,21]. Previous studies have shown the feasibility and necessity of integrating SST into HIV self-testing services [4,21]. WHO also recommended using dual rapid tests for HIV and syphilis as the initial screening test in antenatal care [39]. Our study suggests that integrating HIV and SST could contribute to public health interventions focused on HIV and syphilis among MSM [40].

This study has implications for research and implementation. First, syphilis is a major public health problem, but is often overlooked and underfunded, especially in low- and middle-income countries. Our study expands the evidence base for self-care interventions and would provide valuable data for self-care programs and research. Increasing syphilis and HIV self-testing through self-care interventions may help address the syndemic of syphilis and HIV among MSM globally [38]. These self-testing programs could also be further expanded to include self-care interventions for other STIs (e.g., chlamydia self-collection and gonorrhea self-collection) [41]. Second, SST could expand syphilis testing among MSM. The ongoing COVID-19 pandemic restrictions on facility-based testing highlight the importance and potential of promoting SST. Third, from a financial perspective, SST can reduce costs compared with facility-based testing, enabling savings in syphilis testing programs to be reinvested in delivery of syphilis or other STI related services. This cost reduction is particularly relevant to many low- and middle-income countries with limited funding for non-HIV STI prevention services. Fourth, research on linkage to clinical services is essential to ensure the full benefit of self-testing approaches.

Several important limitations merit discussion. First, the impact of COVID-19 restrictions during the study period may have accentuated the demand for decentralized testing, as access to facility-based testing likely decreased. An online survey conducted among MSM across 31 provinces in China estimated that there was a 59% (95% CI: 58 to 60%) decrease in the number of MSM undergoing facility-based HIV testing in the first quarter of 2020 compared to the first quarter of 2019 [41]. A sensitivity analysis conducted by the coauthor AMW on the uptake of syphilis testing in the standard of care arm (see Methods) revealed no evidence of a difference (RD: −3.6%; 95% CI: −12.6% to 5.4%) between the original and the imputed dataset involving a 22% increase in testing uptake (S4 Table). Given the ongoing impacts of the COVID-19 pandemic on health facilities and preferences for self-testing, our study demonstrates how self-testing can meet the demand for syphilis testing among MSM through decentralized testing models. Second, while we present the first economic evaluation of SST using data from this RCT, future studies to evaluate the costs of scaling up this model and the long-term impact on syphilis epidemiology is warranted to confirm the value of SST. Third, although we used an objective measure for our primary outcome (photo verification), there is potential to underestimate the number of people testing for syphilis if they did not upload their syphilis test result. Fourth, we have data from treponemal test results because these test kits are commercially available, accurate, and field tested. The addition of nontreponemal tests [42] will be important for differentiating previous and new infections. Fifth, we used dual self-testing for syphilis and HIV in this study, which might raise the concern that the increase in the proportion of testing uptake is due to participants interested in the HIV testing. In this study, we identified 18 men living with HIV, and 8 men were newly identified through participation in this study. We conducted a sensitivity analysis by removing the 18 men from the study and found little change to the original outcomes (results not shown). Sixth, there might be a risk of inadvertent disclosure of requesting a syphilis test.

In conclusion, this RCT demonstrates the effectiveness of SST to substantially increase syphilis test uptake among MSM in China. Further evaluation of SST is warranted to confirm its role in controlling syphilis in other contexts.

CONSORT 2010 checklist of information to include when reporting a randomized trial.* CONSORT, Consolidated Standards of Reporting Trials.

(DOCX)

Click here for additional data file.

Use CONSERVE–CONSORT for completed trial reports and CONSERVE-SPIRIT for trial protocols.

CONSORT, Consolidated Standards of Reporting Trials.

(DOCX)

Click here for additional data file.

Promoting routine syphilis screening among MSM in China: study protocol for a RCT of SST and lottery incentive.

MSM, men who have sex with men; RCT, randomized controlled trial; SST, syphilis self-testing.

(DOCX)

Click here for additional data file.

Complete economic evaluation.

Table A: Cost items included. Table B: Unit costs of SOC, SST, and lottery incentivized SST. Fig A: Decision tree model. Fig B: Tornado plot of the incremental cost per person tested for SST compared to SOC. Fig C: Cost-effectiveness acceptability curve for cost per person tested. Fig D: Tornado plot of incremental cost per person tested for lottery incentivized SST compared to SST. Fig E: Tornado plot of incremental cost per person diagnosed for SST compared to SOC. Fig F: Tornado plot of incremental cost per person diagnosed for lottery incentivized SST compared to SST. Fig G: Cost-effectiveness acceptability curve for cost per person diagnosed. SOC, standard of care; SST, syphilis self-testing.

(DOC)

Click here for additional data file.

Web link to an instructional video for the SST package.

(DOCX)

Click here for additional data file.

Manufacturer-supplied step-by-step instructions for the SST package.

(TIF)

Click here for additional data file.

Result report card for the standard SST arm. SST, syphilis self-testing.

(TIF)

Click here for additional data file.

Result report card for the lottery incentivized self-testing arm.

(TIF)

Click here for additional data file.

Participants’ geographic distribution.

(DOCX)

Click here for additional data file.

Baseline characteristics of study participants stratified by loss to follow-up in the SST RCT in China in 2020.

RCT, randomized controlled trial; SST, syphilis self-testing.

(DOCX)

Click here for additional data file.

Sensitivity analysis on the uptake of syphilis testing among all participants.

(DOCX)

Click here for additional data file.

Newly identified syphilis infections and linkage to care among men who had syphilis testing during the trial.

(DOCX)

Click here for additional data file.

Syphilis testing by mode: self-test, facility-based test, or both.

(DOCX)

Click here for additional data file.

29 Jun 2021

Dear Dr Wang,

Thank you for submitting your manuscript entitled "Expanding syphilis test uptake using rapid dual self-testing for syphilis and HIV among men who have sex with men: a multi-arm randomized controlled trial in China" for consideration by PLOS Medicine.

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13 Oct 2021

Dear Dr. Wang,

Thank you very much for submitting your manuscript "Expanding syphilis test uptake using rapid dual self-testing  for syphilis and HIV  among men who have sex with men: a multi-arm randomized controlled trial  in China" (PMEDICINE-D-21-02784R1) for consideration at PLOS Medicine.

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Comments from the Academic Editor:

Please pay special attention to reviewer concerns regarding: 1) the “dual intervention and 2) drop-out rates and availability of generic information on those who did not proceed with the rest of the study.

The authors could address the first point (about dual HIV/syphilis testing) as a limitation to the study and just comment on its possible implications. The second point (very high rate of self-exclusion) is more problematic, as it does call into question the generalizability of the results. This needs to be addressed in the analysis.

Three other comments from the Academic editor:

1. There is no discussion at all of the confidentiality/unintentional disclosure risk of requesting a syphilis test. I assume that there must be some stigma associated with STIs. It would improve the paper to learn something about this.

2. Related to point 1, there is no mention of the yield (% positive) for any of the arms. It's reasonable to guess that those actively seeking a test are at higher risk than those not. This could differ by arm; in any case it almost surely differs among those volunteering to participate and those not. The yield also affects the cost-effectiveness. This needs to be discussed, if not incorporated into the analysis.

3. The cost analysis did not capture the "full economic cost" as stated. It captured the financial cost to the provider. This is fine in terms of methods but a full economic evaluation should not be claimed. Including the cost of developing the lottery is odd, as this appears to be a research-specific cost that would not be incurred if the intervention were to be adopted for routine use. I would take that out.

Comments from the reviewers:

Reviewer #1: Thanks for the opportunity to review your manuscript. My role is a statistical reviewer so my comments focus on the study design, analysis and data presented. I have put general comments first, and followed these with queries specific to a section of the manuscript.

The study is a 3-arm parallel RCT that compares three strategies (usual care, self-testing, and self-testing with a 'lottery' incentive) in improving rates of syphilis testing in MSM in China. The study showed much higher rates of testing where self-resting was offered, and higher rates again with incentives at the final follow-up.

Was a statistical analysis plan prepared for the trial before data were unblinded to the investigators? What led to the changes in the statistical analysis specified in the protocol (a GEE model)?

In the protocol, it was specified that if outcome measures were missing for 11-<20% of the participants, a sensitivity analysis with multiple imputation would be used. It looks based on Figure 2 that this is the case for the 6 months follow-up outcome. What was the results of this? For 3 months follow-up it is very close to 11% missing data - it would strengthen the reporting of the study if an appropriate MI procedure was completed with 3-month follow-up data as well.

One thing to clarify - how would patients in standard care arm be able to provide a photo verification of testing? Are patients routinely given results via email/message or are they given at in-person appointments? Could this change the ascertainment of outcomes in this usual care group?

Was there any generic information captured before consent about who did not proceed with the rest of the study? The drop-out rate at this point is fairly high and I was interested in the reasons why so many people dropped out at this point.

P2, Abstract, Results. It's unclear at first glance what the '48.7%' refers to - maybe rephrasing as 'absolute difference in proportions' would be clearer? In tables, it's referred to as risk difference which would also work.

P5, Recruitment. Just to clarify - this was advertised on Blued, but users could share the link via other social media?

P9, Sample Size. Setting the number of participants based on >99% looks a bit odd - was the sample size for the study fixed and then the power calculated after this had been decided? I don't have any objections to the sample size here, 120 per arm is not an outrageous number and the study arms are unlikely to have any detrimental effect on participants, it's just unusual to plan a sample size with power >0.9. The sample size information presented here is different to that in the protocol - what was the reason for the update?

P9, General Analysis. 'modified intention to treat' is a variable term that I think is almost meaningless. It would be better to be straightforward and say exactly what the assumptions were, e.g. analysed as randomised to the extent we had at least one available visit, with list-wise deletion

P10, Analysis of Primary Outcome. Usually I would say Clopper-Pearson has undesirable qualities (i.e. conservative relative to more modern estimators) but with the sample size, and high prevalence of the outcomes it is safely applied here.

P11. What about the comparison of SST vs SST + incentives at 3 months?

Table S2. This is a useful table - clearly the participants lost to follow-up were different on some of the key variables. When looking at the sensitivity analysis with imputation there are some good auxiliary variables that could be included based on this table.

Table S4. This wasn't specified in the protocol - when was this sensitivity test planned? This type of imputation (similar to NRI) is an ok sensitivity test but the sensitivity test in the protocol (with MI) is more likely to give realistic results (assuming MAR).

Reviewer #2: The manuscript by Wang et al assesses the acceptability of self-testing for syphilis and HIV using a rapid test in a multi-arm randomized trial involving men who have sex with men in China. When compared to standard laboratory-based testing of specimens collected during a health visit, the option self-testing at home increased the proportion of participants tested from 14.7% to over 63%.

Specific comment

Figure 2. The box listing those exclusion states that '55 were currently living with syphilis.' This gives the impression that syphilis is like HIV regarding the lack of curable treatments. Consider using the same statement in the text (page 11 stating that 55 currently had syphilis).

Reviewer #3: This RCT study aimed to examine whether providing syphilis self-testing kits would increase the proportion of syphilis uptake among MSM in China. The results of this study are significant and had good implications for public health improvement. This manuscript is well written.

However, the main concern is that the self-testing kits is dual syphilis/HIV self-testing kits, thus we do not know whether the increase of the proportion of the kits uptake is due to participants'interest in HIV testing or syphilis testing. The intervention is kind of a "dual intervention", while the authors only focused on part of the intervention and its result, which is not appropriate.

Here are other comments need to be addressed:

1.In China, actually there is no free HIV and syphilis self-testing kits available. Thus, the SST arm provided free kits is a big offer for MSM, and could be recommended for public health policy makers, but why the authors design an SST +incentive arms? Since it needs more budget for government, and the implication is kind of far from the reality.

2.The conclusion stated that :"…..particularly among men who had never tested for syphilis. I am thinking whether this conclusion is appropriate or not, since the enrollment is not stratified by non-testers or former testers.

3.The big difference between the two intervention groups with the standard of care group partly due to the social isolation during the COVID-19 outbreak during Jan to May 2020. Most of the places strongly recommended people to stay home, and some of the VCTs are closed, for example, those run by gay-friendly CBOs. Thus the last sentence on page 4 stated that facility-based testing is still available is not always the truth, since the participants were from 124 cities, and the lockdown measures might not be the same.

4.Another concern is that, 54082 participants clicked the flyer link, and 52089 withdrew before consent, which means that most of the participants were not interested in this program. Thus the external validity of the study intervention need to be considered.

5.Among the 2124 men who are interested in this study, 1362 reported no condomless anal sex during the previous year, which is much different from the general MSM population.

6. On page 5, the cost of the kit has a range, which means on market the kit has range of cost, or in this study? Typically the cost of the kit in this study should be same.

7.What do you mean by "online informed consent"? do they provided written informed consent?

8.How many of kits has been delivered to the participants per month (and in total)? And how much proportion of those kits were tested for themselves, and how much for partners or others?

Any attachments provided with reviews can be seen via the following link:

[LINK]

27 Oct 2021

Submitted filename: Response to Editor and Reviewer-25Oct2021.docx

Click here for additional data file.

22 Dec 2021

Dear Dr. Wang,

Thank you very much for re-submitting your manuscript "Expanding syphilis test uptake using rapid dual self-testing  for syphilis and HIV  among men who have sex with men: a multi-arm randomized controlled trial  in China" (PMEDICINE-D-21-02784R2) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by two reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Dec 22 2021 11:59PM.

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1) With regard to data access, do you have contact information (web or email address) for a local authority in China that can grant permission?

2) Please add line numbers in the next revision

3) Author summary

a) Under “Why was this study done?”, 2nd line should read “….expand syphilis testing”

b) adapting the author summary to present the findings in a narrative way rather than repeating all the numbers already in the abstract.

4) In the abstract and main text, please rephrase “win $15 if they tested for syphilis” to “…win $15 if they had a syphilis test or similar…”

5) Please add p values (including “p<0.001”) after the CIs

6) Please do not report P<0.0001; report as P < 0.001.

Comments from the Academic Editor:

I continue to have doubts about generalizability. I would like to see a paragraph in the discussion that addresses the generalizability of results to the entire potentially eligible population and makes clear that the sampling strategy, very large number of self-excluders, potential for disclosure, etc. all limit the applicability of results to a subset of the MSM population who are willing to be identified as wanting a syphilis/HIV test. As it stands, there is an implication that the findings would be relevant for the entire population, which is not correct.

Comments from Reviewers:

Reviewer #1: Thanks for the revised manuscript and response to my original queries. Overall, the updates address almost of my original queries (see below for a change with the missing data sensitivity analyses).

The extra information about recruitment (from the splash screen of the app) explains the drop-out rate. From my involvement with other work with similar approaches to recruitment via an app (although with a different target population) there was low 'click-through' rate to consent to recruitment. There probably isn't an easy way around this, the views of the subject-matter reviewers familiar with the population are important here in establishing if generalisability is likely to be an issue.

The sensitivity analyses around the missing data are reassuring. For the MI sensitivity analysis some additional detail is needed in the methods (e.g. number of imputations, rationale for the number of imputations chose, what variables were used in the imputation model). Table S4 (or another table) should include a repeat of the main analysis with the imputed datasets. Given the summary data it's very unlikely the conclusions would be different from the main analysis but it should still be included.

Reviewer #3:

Most of the comments have been addressed. However, there are a couple concerns for authors' consideration.

1. In the abstract: The conclusion of "Compared to standard-of-care, providing SST significantly increased the proportion of MSM testing for syphilis in China and was cheaper (per person tested)."---- Since the "SST is short for "syphilis self testing", then I think "providing SST" should be specified as "providing SST plus HIV self-testing dual kits", since the study is not examining the effectiveness of providing single SST kits.

And the same problem during the Author Summary and other parts of the main text.

2. On page 16: "Previous studies have shown the feasibility and necessity of integrating syphilis selftesting into HIV self-testing services.4,24 WHO also recommended using dual rapid tests for HIV and syphilis as the initial screening test in antenatal care." --------With this information already in the literature, the authors should justify the significance of this study, since WHO has recommended and China also conducted in reality (many CDC and Community-based organizations used duo testing kits in daily practice).

3. What so called the "online informed consent" is more like an information notification rather than informed consent. Usually IRB requires written or oral IC.

4. The inclusion criteria for having condomless anal sex is previous 12 months, but having no syphilis test is previous 6 months. Why the time point selection is different? What is the rational? [as stated by authors, in literature, usually they evaluated condomless sex in recent 6 months, 3 months and the last time]

Any attachments provided with reviews can be seen via the following link:

[LINK]

28 Dec 2021

Submitted filename: Response to Editor and Reviewer-29Dec2021.docx

Click here for additional data file.

20 Jan 2022

Dear Dr. Wang,

Thank you very much for re-submitting your manuscript "Expanding syphilis test uptake using rapid dual self-testing  for syphilis and HIV  among men who have sex with men: a multi-arm randomized controlled trial  in China" (PMEDICINE-D-21-02784R3) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

***Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.***

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript.

Please note, when your manuscript is accepted, an uncorrected proof of your manuscript will be published online ahead of the final version, unless you've already opted out via the online submission form. If, for any reason, you do not want an earlier version of your manuscript published online or are unsure if you have already indicated as such, please let the journal staff know immediately at plosmedicine@plos.org.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Jan 27 2022 11:59PM.

Sincerely,

Beryne Odeny,

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

1) Title: Please remove “in China” from the subtitle and place it right before the colon. It should read “Expanding syphilis test uptake using rapid dual self-testing for syphilis and HIV among men who have sex with men in China: a multi-arm randomized controlled trial”

2) Abstract: Please remove the following sentence from the end of the Methods and Findings section: “The trial is registered with the Chinese Clinical Trial Registry, number ChiCTR1900022409. The study design and results were reported according to CONSORT 2010 guidelines.”

3) Please replace “Chinese MSM” with "MSM in China."

4) Please ensure that journal name abbreviations consistently match those found in the National Center for Biotechnology Information (NCBI) databases. https://journals.plos.org/plosmedicine/s/submission-guidelines#loc-references. For example, PLOS Medicine should be PLOS Med.

Any attachments provided with reviews can be seen via the following link:

[LINK]

21 Jan 2022

Submitted filename: Response to Editor and Reviewer-22Jan2022.docx

Click here for additional data file.

25 Jan 2022

Dear Dr Wang,

On behalf of my colleagues and the Academic Editor, Dr. Sydney Rosen, I am pleased to inform you that we have agreed to publish your manuscript "Expanding syphilis test uptake using rapid dual self-testing  for syphilis and HIV  among men who have sex with men in China: a multi-arm randomized controlled trial" (PMEDICINE-D-21-02784R4) in PLOS Medicine.

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To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Thank you again for submitting to PLOS Medicine. We look forward to publishing your paper.

Sincerely,

Beryne Odeny

PLOS Medicine