- Email: [email protected]
Dual Intervention to Increase Chlamydia Retesting
Dual Intervention to Increase Chlamydia Retesting A Randomized Controlled Trial in Three Populations Kirsty S. Smith, MPH, Jane S. Hocking, PhD, Marcus Y. Chen, PhD, Christopher K. Fairley, PhD, Anna M. McNulty, MMed (Sexual Health), Phillip Read, MPH, Catriona S. Bradshaw, PhD, Sepehr N. Tabrizi, PhD, Handan Wand, PhD, Marion Saville, MBChB, William Rawlinson, PhD, Suzanne M. Garland, MD, Basil Donovan, MD, John M. Kaldor, PhD, Rebecca J. Guy, PhD This activity is available for CME credit. See page A3 for information.
Introduction: Chlamydia retesting 3 months after treatment is recommended to detect reinfections, but retesting rates are typically low. The purpose of this study is to determine if the addition of a postal home collection kit to a short message service (SMS) reminder at 3 months increases the percentage of patients retested for chlamydia at 1–4 months, compared to SMS alone. Design: In this unblinded randomized controlled trial, participants were randomized 1:1 to intervention (home arm) or control (clinic arm) status. Setting/participants: Participants included 200 each of women, heterosexual men, and men who have sex with men diagnosed and treated for chlamydia at sexual health services. Intervention: Three months after chlamydia diagnosis, home arm participants received an SMS reminder and postal home collection kit (women, vaginal swab; heterosexual men, Copan UriSwab; men who have sex with men, UriSwab and rectal swab). Main outcome measures: The main outcome measures were the percentage of participants retested at 1–4 months after chlamydia diagnosis and the percentage in each arm with repeat positive tests, by risk group and overall, analyzed by intention to treat. Data were collected from 2011 to 2013 and analyzed in 2014. Results: The percentage retested within 1–4 months of chlamydia diagnosis was significantly higher in home versus clinic arm participants among women (64% [66/103] vs 39% [38/97], po0.001); heterosexual men (56% [57/101] vs 34% [34/99], p¼0.002); men who have sex with men (62% [61/98] vs 44% [45/102], p¼0.010); and overall (61% [184/302] vs 39% [117/298], po0.001). The percentage in the home versus clinic arm with repeat positive tests was significantly higher among men who have sex with men (16% [16/98] vs 5% [5/102], p¼0.021) and overall (10% [31/302] vs 4% [12/298], p¼0.006). Conclusions: The addition of a postal home collection kit to routine SMS reminders resulted in substantial improvements in chlamydia retesting rates in all three risk groups and detection of more repeat positive tests, compared with SMS alone. Extending the intervention to other primary care settings with low retesting rates should be considered. (Am J Prev Med 2015;49(1):1–11) Crown Copyright & 2015 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
From the Kirby Institute (Smith, Read, Wand, Donovan, Kaldor, Guy), School of Public Health and Community Medicine (McNulty), University of New South Wales; Sydney Sexual Health Centre (McNulty, Donovan), Sydney; Kirketon Road Centre (Read), Kings Cross; Virology Division (Rawlinson), SEALS Microbiology, Prince of Wales Hospital, Randwick, New South Wales; Melbourne School of Population and Global Health
(Hocking, Chen, Bradshaw), Department of Obstetrics and Gynaecology (Tabrizi, Garland), University of Melbourne; Melbourne Sexual Health Centre (Chen, Fairley, Bradshaw); VCS Pathology (Saville), Carlton; Central Clinical School (Fairley, Bradshaw), Monash University; Department of Microbiology (Tabrizi, Garland), Department of Microbiology and Infectious Diseases (Tabrizi, Garland), Royal Women’s Hospital; and
Crown Copyright & 2015 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
Am J Prev Med 2015;49(1):1–11
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Smith et al / Am J Prev Med 2015;49(1):1–11
Introduction
C
hlamydia trachomatis is the most frequently reported sexually transmissible infection (STI) in most developed countries and notification rates are increasing steadily each year.1–3 The greatest infection burden is among young people aged 15–29 years, with population-based prevalence estimates ranging from 3% to 6%.4–6 High chlamydia prevalence estimates have also been reported in men who have sex with men (MSM), ranging from 5% to 9% for rectal infections and 3% to 6% for urethral infections.7–10 Repeat chlamydial infections are also common in these populations. A systematic review in 200911 of chlamydia repeat infection following treatment found that the overall median proportion of women with repeat positive tests in cohorts with active follow-up was 13%, and a prospective cohort study in Australia in 201212 demonstrated that 18% of young women had a repeat infection at 3 months after treatment. From routine retesting data, repeat infections also appear high in MSM.13 Repeat chlamydial infections increase the risk of chlamydia-related sequelae such as pelvic inflammatory disease and infertility when compared to initial infection,14 and in MSM, repeat infections are associated with an increased risk of HIV transmission.15 Most repeat positive tests are due to reinfection from the same partner (indicating ineffective partner management); infection from a new partner; or less commonly treatment failure.16–18 Although clinical guidelines in a number of countries recommend retesting 3 months after treatment for chlamydia to detect reinfections,19–23 retesting rates are low, especially among men.24–26 From the patient perspective, a key barrier to retesting is the time and effort involved in going back to the clinic.27 In addition, given that chlamydia infection is asymptomatic in more than 80% of cases,28 patients who are asymptomatic or do not see themselves as being at high risk may be less likely to initiate retesting. A recent meta-analysis29 demonstrated that phone calls, letters, postcard reminders, and home collection kits resulted in modest increases in chlamydia retesting. As the majority of Australians have a mobile phone30 and messages are inexpensive, immediate, and can be automated,31 using short message service (SMS) to remind people to return for retesting is a potentially effective strategy. Subsequent to the meta-analysis, an evaluation of the operational use of SMS reminders at Sydney Sexual Health Centre showed moderately increased retesting (footnote continued) Murdoch Children’s Research Institute (Tabrizi, Garland), Parkville, Victoria, Australia Address correspondence to: Kirsty S. Smith, MPH, Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, New South Wales
rates at 1–4 months after chlamydia infection (from 21% to 30%)32; however, more effective interventions are needed if higher rates of retesting are to be achieved. To our knowlege, no previous intervention has combined home collection strategies with SMS reminders to maximize the efficiency of an intervention to increase STI retesting. This RCT evaluates the effectiveness of combining postal home collection kits with SMS reminders on chlamydia retesting and repeat infections in MSM, women, and heterosexual men, compared with routine SMS reminders only.
Methods Trial Design In this unblinded RCT, individuals were randomized in a 1:1 ratio to either an SMS reminder and postal home collection kit (intervention: home arm) or an SMS reminder and clinic testing (control: clinic arm). Participants in the home arm had the option to return to the clinic for retesting if they preferred.
Setting and Participants The trial was conducted between 2011 and 2014 in two public clinics in Australia (Melbourne and Sydney Sexual Health Centres). Participants included three risk groups: heterosexual men (reported sexual contact only with female partner(s) in the last 12 months); MSM (reported sexual contact with male partner (s) in the last 12 months); and women (predominantly women who have sex with men). To be eligible, participants had to be aged Z16 years; have a diagnosis by nucleic acid amplification tests (NAATs) of chlamydial infection (genital infection in heterosexual men and women, and urethral or rectal infection in MSM); and reside in the jurisdiction serviced by the clinic for the next 6 months. They were also required to have a mobile phone. Patients were excluded if they were unwilling or unable to comply with all the requirements of the protocol; they could not speak English; or were HIV positive or a current sex worker, as patients in these categories are recommended to have regular STI testing. The trial was advertised by postcards left in the waiting room or provided to patients at the time of chlamydia testing or treatment. All positive chlamydia results were reviewed by study nurses based at each of the clinics. At both clinics, it is routine practice for patients reporting anal or urogenital signs or symptoms of chlamydia to be treated empirically and partner notification and treatment to be initiated by the clinician. The nurse contacted all potentially eligible patients by telephone and informed them of their chlamydia diagnosis, and for those not already treated, recommended they come to the clinic for treatment. During the call, the nurse gave patients a brief overview of the study, checked their eligibility, and if eligible, asked for their permission to pass on their contact details to a member of the research team. If the 2052. E-mail: [email protected]. 0749-3797/$36.00 http://dx.doi.org/10.1016/j.amepre.2015.01.014
www.ajpmonline.org
Smith et al / Am J Prev Med 2015;49(1):1–11 patient agreed, a member of the research team contacted the patient to explain the trial requirements and undertake a verbal consent process. As part of the verbal consent process, participants were informed that they would receive a AU$40 (US$35, GB£22) voucher for completing a survey at 4.5 months after enrollment. Computer-generated randomization codes, stratified by risk group, were produced by a statistician and sealed in opaque envelopes by a research assistant not associated with the trial. Once consent was given, the research team member selected the next randomization envelope according to the risk group of the patient and informed the patient which group they had been assigned to— the home or clinic group. The statistician analyzing the RCT data was blinded to the study group.
Intervention For participants in the intervention arm, 3 months after chlamydia diagnosis, an SMS was sent by the research team to let the patient know their retest was due and a kit would soon be mailed to them. The home collection kit contained the collection device(s) (women, self-collected vaginal swab; heterosexual men, UriSWAB for urine collection [Copan Diagnostics, Murrieta, CA]; MSM, UriSwab and rectal swab) plus illustrated collection instructions; a laboratory request form; and a prepaid envelope. The swabs and request form were pre-labeled with identifying information. The collection kit was mailed to the patient in an unmarked package by the research team at 3 months. Patients were instructed in a cover letter to collect their specimen(s), package them according to the provided instructions, and mail them to the laboratory in the prepaid envelope. For participants in the control arm, 3 months after chlamydia diagnosis, patients were sent an SMS by the clinic to remind them to return to the clinic for retesting. This is routine practice at the two participating clinics. At one clinic, an opt-out system was used where the SMS was automatically generated on receipt of a positive result, and at the other, the automated SMS system was activated via the electronic patient management system by the attending clinician. Specimens collected at the clinics were tested by the usual pathology provider according to their standard protocol. The method of chlamydia testing varied according to the pathology provider. At one laboratory, testing was performed using Cobas 4800 duplex realtime polymerase chain reaction (PCR) for C. trachomatis and Neisseria gonorrhoeae (Roche Diagnostics, Mannheim, Germany); at the other laboratory, the BDProbeTec ET C. trachomatis and N. gonorrhoeae Amplified DNA Assay (BD Biosciences, Sparks, MD) was used. All specimens collected at home were sent by mail to VCS Pathology. Samples were tested using the Artus C. trachomatis Plus RG PCR kit (Qiagen, Hilden, Germany), an in vitro nucleic acid amplification test for the detection of C. trachomatis DNA. All three assays have sensitivities and specificities for chlamydia in swab and urine samples 490% and 95%, respectively,33–35 and studies have demonstrated the adequacy of the UriSwab, self-collected vaginal and rectal swabs for detection of chlamydia,36–38 and the robustness of swabs sent by mail.39 Results of home tests were reported back to and managed by the referring clinics in the usual manner. Results were given to patients according to the clinic’s protocol for managing test results. Treatment for positive chlamydia cases was a 1-gram single dose of azithromycin according to the routine practice.21 July 2015
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Measures The primary outcome was the percentage of patients who retested 1–4 months after chlamydia diagnosis. The secondary outcome was the percentage of repeat positive tests, defined in two ways: (1) the percentage of study arm participants who retested positive between 1 and 4 months and (2) the percentage of retesters who retested positive between 1 and 4 months. The following variables were extracted from the patient management system at baseline consultation: date of birth, residential postcode, country of birth, new or existing client, condom use (consistent, inconsistent, or never), number and gender of sexual partners in the last 3 months, previous chlamydia diagnoses (ever), date of the last chlamydia diagnosis, anal and urogenital symptoms, site and type of collected specimens, chlamydia treatment, and chlamydia results.
Survey Participants in both arms of the study were asked to complete a quantitative survey online. An SMS request was sent to participants at 4.5 months (after ascertainment of the primary outcome) and a reminder was sent at 5 months if the survey was not completed. The SMS contained a link to the study website and the participant’s unique study code. For this paper, the only survey data that are included are the number of days between home collection and mailing specimen(s) to the laboratory and if the participant retested at a clinic other than a study clinic. If participants reported testing elsewhere, they were mailed a consent form to obtain their permission to access the results of their tests. The consent form was then mailed to the doctor at the clinic.
Statistical Analysis Analyses were undertaken in 2014 using Stata, version 12.1. The percentage of patients who returned for retesting in each arm (home and clinic); percentage of retesters by risk group (women, heterosexual men, MSM), age group (o25 years, Z25 years), and symptoms at baseline (yes, no); and the percentage of patients who retested positive between 1 and 4 months of a chlamydia diagnosis in each arm and by risk group were assessed with intention-totreat analysis. The per-protocol analyses included (1) among the home testing arm, the percentage who retested at home compared with the clinic and the median time to retest among those who tested at home versus the clinic; and (2) Kaplan–Meier survival analysis to compare the time to retest between study arms and by risk group during the study period. Chlamydia retesting within 1–4 months after a chlamydia diagnosis was calculated as a second test occurring within 1–4 months of an initial positive test. A repeat infection included a positive result from any anatomic site. The effects of the intervention were measured by comparing the percentage who retested; the percentage with a repeat infection in all study arm participants; and the percentage with a repeat positive test in those retested and between the two groups (home versus clinic) using the chi-square test. Kaplan–Meier survival analysis was performed using a Kaplan–Meier plot and the logrank test.
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Smith et al / Am J Prev Med 2015;49(1):1–11
Sample Size
Results
The sample size was based on a chlamydia retesting rate of 40% in the clinic group based on findings from previous studies.31,40 The analysis was intended to assess the primary outcome in the three risk groups (200 women, 200 heterosexual men, and 200 MSM) and overall. A sample size of 194 in each risk group was needed to achieve at least 80% statistical power to detect an overall 20% difference (60% compared to 40%) in retesting between home and clinic groups. The 194 was rounded to 200 and summed to give an overall sample size of 600. A total sample size of 600 would achieve at least 80% statistical power to detect an overall 12% difference (52% compared to 40%) between the home and clinic group for all three risk groups combined. This study was approved by the Alfred Health Human Research Ethics Committee (HREC); South Eastern Sydney and Illawarra Area Health Service HREC; and the University of New South Wales HREC. All participants provided informed consent.
Between July 2011 and September 2012, 1,896 chlamydia-positive patients were assessed for eligibility (748 women, 529 heterosexual men, and 619 MSM). The reasons for ineligibility and exclusion varied by risk group (Figure 1). In total, 200 women, 200 heterosexual men, and 200 MSM were recruited and randomized. Of these, 302 were allocated to the intervention (home) arm and 298 to the control (clinic) arm, with approximately equal numbers of participants from each risk group allocated to each arm (Figure 1). The median age of participants was 26 years (interquartile range [IQR], 23–31 years); the majority resided in metropolitan areas (97%); and about half were born in Australia (48%). Most participants reported using
Figure 1. CONSORT diagram of participants’ flow through the trial. www.ajpmonline.org
Smith et al / Am J Prev Med 2015;49(1):1–11
condoms inconsistently or never in the last 3 months (84%); about half (51%) had two to five sexual partners in the last 3 months; 46% reported anal or urogenital symptoms at their baseline consultation; and 12% had a previous chlamydia diagnosis. The characteristics of each risk group are described in Table 1 and were comparable between the study arms. The percentage who retested within 1–4 months of chlamydia diagnosis was significantly higher among participants randomized to the home arm compared to the clinic arm in all risk groups: 64% (66/103) vs 39% (38/97) in women (absolute difference in the percentage retested of 25%, 95% CI¼12%, 38%, po0.001); 56% (57/101) vs 34% (34/99) in heterosexual men (absolute difference in the percentage retested of 22%, 95% CI¼9%, 36%, p¼0.002); and 62% (61/98) vs 44% (45/102) in MSM (absolute difference in the percentage retested of 18%, 95% CI¼5%, 32%, p¼0.010). Overall, the percentage was 61% (184/302) vs 39% (117/298) (absolute difference in the percentage retested of 22%, 95% CI¼14%, 30%, po0.001) (Table 2). Three home kits were returned to sender. For each of these, the participant was contacted by SMS and the kit was resent. Of the 301 participants who retested between 1 and 4 months, three (1%) tested outside the study sites but were verified by contacting the sites and included in the primary analysis. In women and MSM, the difference in the percentage retested within 1–4 months in the home versus the clinic arm was greater for those aged Z25 years compared to those aged o25 years. In heterosexual men, the opposite pattern was observed, with the difference greater in younger men aged o25 years compared to those aged Z25 years. The difference in retesting between the two arms appeared greater in those with symptoms at baseline compared with those without symptoms (Table 2). Among all study arm participants, the positivity in the home collection arm compared with the clinic arm was significantly higher among MSM (16% [16/98] vs 5% [5/102], p¼0.021) and overall (10% [31/302] vs 4% [12/298], p¼0.006), but there was no significant difference in women (8% [8/103] vs 2% [2/97], p¼0.107) and heterosexual men (7% [7/101] vs 5% [5/99], p¼0.768) (Table 2). Among those who retested at 1–4 months, the positivity at retest in the home collection arm compared with the clinic arm was significantly higher in MSM (26% [16/61] vs 11% [5/45], p¼0.048), but there was no significant differences in women (12% [8/66] vs 5% [2/38], p¼0.253); heterosexual men (12% [7/57] vs 15% [5/34], p¼0.575); or overall (17% [31/184] vs 10% [12/117], p¼0.128) (Table 2). Half (21/43) of the repeat positive tests were among MSM, and most were from rectal swabs. Among MSM in July 2015
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the home arm, 16 had repeat positive tests (rectal swabs, 13; UriSwabs, 2; both, 1). Among MSM in the clinic arm, five had repeat positive tests (rectal swabs, 4; UriSwabs, 1). The median time to retest for the clinic arm was 3.1 (2.1–3.4) months and for the home arm was 3.3 (3.1–3.5) months (p¼0.791). The Kaplan–Meier survival curve showed very little difference in time to retest between the two arms until about 3 months, when the two curves diverged considerably (po0.01) (Figure 2). Time to retest between the two arms was significantly different within each risk group (po0.01 for women and heterosexual men; p¼0.03 for MSM). Among participants in the home arm who retested at 1–4 months, 27% (50/184) chose to retest at the clinic (28% [14/50] of women, 32% [16/50] of heterosexual men, and 40% [20/50] of MSM), with a median time to retest of 2.4 months compared to 3.4 months among those who retested using the postal home collection kit (po0.001). For those who self-collected using the home collection kit, the median time between specimen collection and mailing specimens to the laboratory was 1 day. Among participants in the home arm who chose to retest at the clinic, the positivity at retest was 32% overall (16/50), compared with 11% (15/134) in the home arm who retested using the postal home collection kit (p¼0.001). According to risk group, the differences were as follows: 14% (2/14) vs 12% (6/52) for women (p¼0.674); 44% (7/16) vs 0% (0/41) for heterosexual men (po0.001); and 35% (7/20) vs 22% (9/41) for MSM (p¼0.277).
Discussion In this RCT, SMS reminders combined with home collection resulted in significantly higher rates of retesting and significantly more repeat positive tests compared with SMS reminders and retesting at the clinic. The intervention increased retesting rates in all three risk groups, with the greatest effect in women and MSM aged Z25 years and heterosexual men aged o25 years. The Kaplan–Meier survival curve showed very little difference in time to retest between the two arms until the intervention at 3 months, after which the curves diverged. Retesting is vital to identifying and treating any repeat infections that may have arisen owing to inadequate partner management or treatment failure. The timing of when to do a retest is difficult—if done too early, there is the risk of a false positive diagnosis due to the detection of remnant, non-viable chlamydial infection, which has been found to persist for up to 8 weeks following treatment.41 To minimize this risk of false positivity,
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Table 1. Baseline Characteristics of Stratified Risk Groups by Intervention Group Women
Heterosexual men
MSM
Overall
Clinic
Home
Clinic
Home
Clinic
Home
Clinic
Home
All
97
103
99
101
102
98
298
302
600
24 (21–27)
25 (21–27)
29 (24–31)
29 (24–31)
32 (25–37)
32 (25–36)
26 (23–31)
27 (23–31)
26 (23–31)
o25
56 (57.7)
54 (52.4)
33 (33.3)
30 (29.7)
24 (25.5)
21 (21.4)
113 (37.9)
105 (34.8)
218 (36.3)
Z25
41 (42.3)
49 (47.6)
66 (66.7)
71 (70.3)
78 (76.5)
77 (78.6)
185 (62.1)
197 (65.2)
382 (63.7)
90 (92.8)
101 (98.1)
96 (97.0)
99 (98.0)
99 (97.1)
95 (96.9)
285 (95.6)
295 (97.7)
580 (96.7)
7 (7.2)
2 (1.9)
3 (3.0)
2 (2.0)
3 (2.9)
3 (3.1)
13 (4.4)
7 (2.3)
20 (3.3)
51 (53.7)
58 (58.0)
37 (38.9)
41 (41.0)
52 (51.0)
45 (47.9)
140 (47.9)
144 (49.0)
284 (48.4)
8 (8.4)
10 (10.0)
11 (11.6)
13 (13.0)
9 (8.8)
17 (18.1)
28 (9.6)
40 (13.6)
68 (11.6)
Europe
25 (26.3)
21 (21.0)
35 (36.8)
32 (32.0)
25 (24.5)
23 (24.5)
85 (29.1)
76 (25.8)
161 (27.5)
Other
11 (11.6)
11 (11.0)
12 (12.6)
14 (14.0)
16 (15.7)
9 (9.6)
39 (13.4)
34 (11.6)
73 (12.5)
New
63 (65.0)
69 (67.0)
55 (55.6)
54 (53.5)
40 (39.2)
36 (36.7)
158 (53.0)
159 (52.6)
317 (52.8)
Existing
34 (35.1)
34 (33.0)
44 (44.4)
47 (46.5)
62 (60.8)
62 (63.3)
140 (47.0)
143 (47.4)
283 (47.2)
Yes
4 (4.1)
13 (12.6)
11 (11.1)
11 (10.9)
18 (17.7)
15 (15.3)
33 (11.1)
39 (12.9)
72 (12.0)
No
93 (95.9)
90 (87.4)
88 (88.9)
90 (89.1)
84 (82.4)
83 (84.7)
265 (88.9)
263 (87.1)
528 (88.0)
84 (91.3)
84 (92.3)
77 (84.6)
76 (82.6)
72 (79.1)
69 (74.2)
233 (85.0)
229 (83.0)
462 (84.0)
8 (8.7)
7 (7.7)
14 (15.4)
16 (17.4)
19 (20.9)
24 (25.8)
41 (15.0)
47 (17.0)
88 (16.0)
Number Age, median (IQR) Age group (years)
Area of residence
Non-metropolitan Country of birth Australia Asia
Client status
Previous chlamydia diagnosis (ever)
Condom use last 3 months Inconsistent (never/sometimes)
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Consistent (always)
Number of sexual partners last 3 months 0
3 (3.1)
8 (7.8)
6 (6.1)
6 (5.9)
5 (4.9)
8 (8.2)
14 (4.7)
22 (7.3)
36 (6.0)
1
35 (36.1)
25 (24.5)
20 (20.2)
22 (21.8)
27 (26.5)
30 (30.6)
82 (27.5)
77 (25.6)
159 (26.5)
(continued on next page)
Smith et al / Am J Prev Med 2015;49(1):1–11
Metropolitan
Smith et al / Am J Prev Med 2015;49(1):1–11
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July 2015
325 (54.2) 55 (56.7) No
Note: Values are n (%). Baseline data was extracted from the clinic’s patient management system. Data for some variables were not available for all participants. a Anal and /or urogenital symptoms. HM, heterosexual men; IQR, interquartile range; MSM, men who have sex with men; STI, sexually transmitted infection; W, women.
167 (55.3) 158 (53.0) 45 (45.9) 49 (48.0) 58 (57.4) 54 (54.6)
140 (47.0) 53 (54.1) 53 (52.0) 43 (42.6) 45 (45.5) 39 (37.9) 42 (43.3) Yes
STI symptoms at baseline
64 (62.1)
275 (45.8) 135 (44.7)
101 (16.9) 49 (16.3) 52 (17.5) 21 (21.4) 19 (18.6) 13 (12.9) 21 (21.2) 12 (12.4) a
45
15 (14.7)
303 (50.6) 153 (50.8) 150 (50.3) 39 (39.8) 51 (50.0) 60 (59.4) 52 (52.5) 54 (52.9) 47 (48.5)
Clinic
2–5
Home Clinic Home
Heterosexual men Women
Table 1. Baseline Characteristics of Stratified Risk Groups by Intervention Group (continued)
Clinic
MSM
Home
Clinic
Overall
Home
All
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Australian guidelines recommend a retest at 3 months after treatment rather than a test of cure at 4–6 weeks. The percentage who retested in this trial was comparable between the two study groups up to the point of the intervention at 3 months, and then retesting rates increased dramatically among those who had access to home collection kits. The effect of increased retesting was greater among young heterosexual men compared to older men. As young heterosexual men have been found to have low rates of retesting,25 this could be a particularly useful strategy for this group. Compared with other studies that have evaluated single interventions (reminders or home collection)31,32,42–45 higher rates of retesting were achieved by combining the two strategies of SMS and home collection. Two previous RCTs also combined interventions: incentives plus SMS reminders46 and home collection plus phone reminders27; however, the overall retesting rate in these studies were much lower because of some inadequacies of one of the chosen intervention strategies. In the study of Xu and colleagues,27 only a subset of women were reached by reminder calls despite multiple attempts. In the study of Downing et al.,46 a high proportion of SMS messages were undelivered, particularly to Aboriginal and Torres Strait Islander patients, owing to deactivation as a result of non-payment, failing to recharge phones, and phones being reported lost or stolen.46 This suggests that this strategy may not be ideal for all population groups. This study also highlights the importance of providing patients with choices. Over a quarter of home arm participants retested early at the clinic, and among heterosexual men there was a higher positivity compared to those who used the postal home collection system, suggesting they were at high risk or had symptoms and opted to be seen sooner rather than waiting 3 months for the kit to be posted. As it is appropriate for these patients to revisit the clinic promptly for assessment, rather than waiting to be recalled, this option should be incorporated into any retesting intervention. Other studies in the U.S. have also highlighted the importance of providing retesting options, with one study finding that when given a choice, 70% of youth opted to retest at the clinic rather than mailing a specimen for testing.47 Another study found that although the majority of young women were mailed their home collection kit, 9% opted to pick it up from the clinic.43 As seen in other studies, a high percentage (14%) of repeat infections was detected at 1–4 months. However, unlike the majority of previous retesting interventions,27,43–45,48 more repeat infections were detected in the intervention arm compared with the control arm, and repeat positivity was significantly higher among MSM.
Smith et al / Am J Prev Med 2015;49(1):1–11
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Table 2. Proportion Retested for Chlamydia and Repeat Positivity at 1–4 Months by Risk Group
Baseline characteristics
Clinic group
Home group
Overall
Absolute difference in the percentage retestedclinic arm versus home arm, % (95% CI)
p-valuea
o0.001
Retest at 1–4 months (retests/participants), n (%) Women
38/97 (39.2)
66/103 (64.1)
104/200 (52.0)
24.9 (11.5, 38.3)
Heterosexual men
34/99 (34.3)
57/101 (56.4)
91/200 (45.5)
22.1 (8.6, 35.5)
0.002
45/102 (44.1)
61/98 (62.2)
106/200 (53.0)
18.1 (4.5, 31.7)
0.010
117/298 (39.3)
184/302 (60.9)
301/600 (50.2)
21.6 (13.9, 29.5)
o0.001
o25
23/56 (41.1)
31/54 (57.4)
54/110 (49.1)
16.3 (–2.1, 34.8)
0.087
Z25
15/41 (36.6)
35/49 (71.4)
50/90 (55.6)
34.8 (15.4, 54.3)
0.001
o25
9/33 (27.3)
18/30 (60.0)
27/63 (42.9)
32.7 (9.5, 55.9)
0.009
Z25
25/66 (37.9)
39/71 (54.9)
64/137 (46.7)
17.0 (0.6, 33.5)
0.046
o25
10/24 (41.7)
11/21 (52.4)
21/45 (46.7)
10.7 (–18.4, 39.8)
0.472
Z25
35/78 (44.9)
50/77 (64.9)
85/155 (54.8)
20.0 (4.7, 35.4)
0.012
o25
42/113 (37.2)
60/105 (57.1)
102/218 (46.8)
20.0 (7.0, 33.0)
0.003
Z25
75/185 (40.5)
124/197 (62.9)
199/382 (52.1)
22.4 (12.6, 32.2)
o0.001
Yes
49/140 (35.0)
85/135 (63.0)
134/275 (48.7)
28.0 (16.6, 39.3)
o0.001
No
68/158 (43.0)
99/167 (59.3)
167/325 (51.4)
16.2 (5.5, 27.0)
MSM All Women
Heterosexual men
MSM
All
Symptoms at baseline
0.003
Repeat positivity at 1–4 months (positive tests/study arm), n (%) Women
2/97 (2.1)
8/103 (7.8)
10/200 (5.0)
0.107
Heterosexual men
5/99 (5.0)
7/101 (6.9)
12/200 (6.0)
0.768
5/102 (4.9)
16/98 (16.3)
21/200 (10.5)
0.021
12/298 (4.0)
31/302 (10.3)
43/600 (7.2)
0.006
10/104 (9.6)
0.253
MSM All
Repeat positivity at 1–4 months (positive tests/repeat tests), n (%) Women
2/38 (5.3)
8/66 (12.1)
Heterosexual men
5/34 (14.7)
7/57 (12.3)
12/91 (13.2)
0.575
MSM
5/45 (11.1)
16/61 (26.2)
21/106 (19.8)
0.048
12/117 (10.3)
31/184 (16.8)
43/301 (14.3)
0.128
All
Note: Intention-to-treat analysis. Boldface indicates statistical significance (po0.05). a 2 χ or Fisher’s exact test was used when appropriate. MSM, men who have sex with men.
This is most likely to be due to self-selection, that is, patients who perceived they were at higher risk of reinfection, and particularly those with the easier option to self-collect at home, were more likely to retest. Other
home collection kit programs have also demonstrated a high yield of chlamydia infection due to self-selection.49 Future programs could contact patients by SMS at 3 months, and if they have not already returned to the www.ajpmonline.org
Smith et al / Am J Prev Med 2015;49(1):1–11
9
returned to sender, this is not expected to have influenced the findings. Another potential limitation is that the time to retest was calculated from the date of diagnosis rather than the date of treatment. If treatment was delayed and retesting occurred within 3–4 weeks post-treatment, there is the possibility that false positive results may have occurred because of detection of non-viable chlamydial infection.41 However, there is no reason to believe this would be different between study arms. It is also possible that some repeat positive tests may have included treatment failures, although the proportion would be limited and equal Figure 2. Kaplan–Meier curve comparing time to retest between the home and between arms.16,51 Sexual behavior clinic groups (per-protocol analysis). data and genotyping/multilocus sequence typing will be used to clinic, they could be sent a home collection kit. differentiate between chlamydia reinfection, persistent Other considerations for future programs include infection, and treatment failure, which will be the systems to check the accuracy of contact details and subject of a future analysis, along with acceptability opt-out systems for SMS reminders. Also, retesting and cost. strategies for MSM should incorporate testing for other STIs such as HIV and syphilis. The home collection strategy could also be used in populationConclusions based home testing programs. As recently demonstrated This evaluation demonstrates that in the sexual health by van Liere and colleagues,50 home collection comclinic setting, postal home collection kits in combination bined with clinic-based screening has the potential to with SMS reminders is a very effective strategy for increase the coverage of chlamydia screening in the increasing retesting rates and detecting additional repeat population. infections, compared with SMS reminders alone. Consideration of other primary care settings where this strategy may also be effective should be given.
Limitations
This study has some limitations to consider. The trial may have appealed to a more motivated group of patients who were more likely to retest irrespective of the intervention, and resulted in an overestimation of retesting in both arms. However, as the percentage that retested in the clinic arm was comparable with operational research from one of the participating clinics,32 this is unlikely. Patients were also not blinded to their study arm allocation, which may have had a differential impact on the likelihood of them retesting; however, there is no way to assess this. Also, it is possible that retesting in the home arm may have been underestimated if some kits had not been delivered to the participant because of change of address, but as addresses were checked and only three kits were July 2015
We thank all the participants of the study and the clinical staff of Melbourne and Sydney Sexual Health Centres—especially the study nurses: Karen Worthington and Samantha Blake; Rose Chevkenova-Mohamed, Muhammad Shahid Jamil, Larissa Lewis, and Natasha Karunaratne, Kirby Institute; and Vickie Knight and Simon Wright, Sydney Sexual Health Centre. The study was funded by National Health and Medical Research Council of Australia program grant number 568971. This study was approved by the Alfred Health Human Research Ethics Committee (HREC) on February 3, 2011; South Eastern Sydney and Illawarra Area Health Service HREC on June 7, 2011; and the University of New South Wales HREC on June 14, 2011.
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Smith et al / Am J Prev Med 2015;49(1):1–11
The trial was registered with the Australian and New Zealand Clinical Trials Registry on September 9, 2011: ACTRN 12611000968976. No financial disclosures were reported by the authors of this paper.
16.
17.
18.
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syphilis in men who have sex with men. PLoS One. 2013;8(4): e61972. http://dx.doi.org/10.1371/journal.pone.0061972. Cook RL, Ostergaard L, Hillier SL, et al. Home screening for sexually transmitted diseases in high-risk young women: randomised controlled trial. Sex Transm Infect. 2007;83(4):286–291. http://dx.doi.org/ 10.1136/sti.2006.023762. Paneth-Pollak R, Klingler EJ, Blank S, Schillinger JA. The elephant never forgets; piloting a chlamydia and gonorrhea retesting reminder postcard in an STD clinic setting. Sex Transm Dis. 2010;37(6):365–368. Kohn R, Reynolds A, Snell A, et al. New reminder system does not improve chlamydia re-screening rate. Paper presented at: National STD Prevention Conference; 2010 Mar 8–10; Atlanta, GA, 2010. Downing SG, Cashman C, McNamee H, Penney D, Russell DB, Hellard ME. Increasing chlamydia test of re-infection rates using SMS reminders and incentives. Sex Transm Infect. 2013;89(1): 16–19. http://dx.doi.org/10.1136/sextrans-2011-050454. Sparks R, Helmers JR, Handsfield HH, et al. Rescreening for gonorrhea and chlamydial infection through the mail: a randomized trial. Sex Transm Dis. 2004;31(2):113–116. http://dx.doi.org/10.1097/01.OLQ. 0000109512.95959.ED. Gotz HM, Wolfers ME, Luijendijk A, van den Broek IV. Retesting for genital Chlamydia trachomatis among visitors of a sexually transmitted infections clinic: randomized intervention trial of home- versus clinicbased recall. BMC Infect Dis. 2013;13(1):239. http://dx.doi.org/10. 1186/1471-2334-13-239. Jamil MS, Hocking JS, Bauer HM, et al. Home-based chlamydia and gonorrhoea screening: a systematic review of strategies and outcomes. BMC Public Health. 2013;13(1):189. http://dx.doi.org/10.1186/14712458-13-189. van Liere GAFS, Dukers-Muijrers NHTM, van Bergen JEAM, Götz HM, Stals F, Hoebe CJPA. The added value of chlamydia screening between 2008-2010 in reaching young people in addition to chlamydia testing in regular care; an observational study. BMC Infectious Diseases. 2014;14(1):612. http://dx.doi.org/10.1186/s12879-014-0612-2. Drummond F, Ryder N, Wand H, et al. Is azithromycin adequate treatment for asymptomatic rectal chlamydia? Int J STD AIDS. 2011; 22(8):478–480. http://dx.doi.org/10.1258/ijsa.2011.010490.
Introduction: Chlamydia retesting 3 months after treatment is recommended to detect reinfections, but retesting rates are typically low. The purpose of this study is to determine if the addition of a postal home collection kit to a short message service (SMS) reminder at 3 months increases the percentage of patients retested for chlamydia at 1–4 months, compared to SMS alone. Design: In this unblinded randomized controlled trial, participants were randomized 1:1 to intervention (home arm) or control (clinic arm) status. Setting/participants: Participants included 200 each of women, heterosexual men, and men who have sex with men diagnosed and treated for chlamydia at sexual health services. Intervention: Three months after chlamydia diagnosis, home arm participants received an SMS reminder and postal home collection kit (women, vaginal swab; heterosexual men, Copan UriSwab; men who have sex with men, UriSwab and rectal swab). Main outcome measures: The main outcome measures were the percentage of participants retested at 1–4 months after chlamydia diagnosis and the percentage in each arm with repeat positive tests, by risk group and overall, analyzed by intention to treat. Data were collected from 2011 to 2013 and analyzed in 2014. Results: The percentage retested within 1–4 months of chlamydia diagnosis was significantly higher in home versus clinic arm participants among women (64% [66/103] vs 39% [38/97], po0.001); heterosexual men (56% [57/101] vs 34% [34/99], p¼0.002); men who have sex with men (62% [61/98] vs 44% [45/102], p¼0.010); and overall (61% [184/302] vs 39% [117/298], po0.001). The percentage in the home versus clinic arm with repeat positive tests was significantly higher among men who have sex with men (16% [16/98] vs 5% [5/102], p¼0.021) and overall (10% [31/302] vs 4% [12/298], p¼0.006). Conclusions: The addition of a postal home collection kit to routine SMS reminders resulted in substantial improvements in chlamydia retesting rates in all three risk groups and detection of more repeat positive tests, compared with SMS alone. Extending the intervention to other primary care settings with low retesting rates should be considered. (Am J Prev Med 2015;49(1):1–11) Crown Copyright & 2015 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
From the Kirby Institute (Smith, Read, Wand, Donovan, Kaldor, Guy), School of Public Health and Community Medicine (McNulty), University of New South Wales; Sydney Sexual Health Centre (McNulty, Donovan), Sydney; Kirketon Road Centre (Read), Kings Cross; Virology Division (Rawlinson), SEALS Microbiology, Prince of Wales Hospital, Randwick, New South Wales; Melbourne School of Population and Global Health
(Hocking, Chen, Bradshaw), Department of Obstetrics and Gynaecology (Tabrizi, Garland), University of Melbourne; Melbourne Sexual Health Centre (Chen, Fairley, Bradshaw); VCS Pathology (Saville), Carlton; Central Clinical School (Fairley, Bradshaw), Monash University; Department of Microbiology (Tabrizi, Garland), Department of Microbiology and Infectious Diseases (Tabrizi, Garland), Royal Women’s Hospital; and
Crown Copyright & 2015 Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine.
Am J Prev Med 2015;49(1):1–11
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Smith et al / Am J Prev Med 2015;49(1):1–11
Introduction
C
hlamydia trachomatis is the most frequently reported sexually transmissible infection (STI) in most developed countries and notification rates are increasing steadily each year.1–3 The greatest infection burden is among young people aged 15–29 years, with population-based prevalence estimates ranging from 3% to 6%.4–6 High chlamydia prevalence estimates have also been reported in men who have sex with men (MSM), ranging from 5% to 9% for rectal infections and 3% to 6% for urethral infections.7–10 Repeat chlamydial infections are also common in these populations. A systematic review in 200911 of chlamydia repeat infection following treatment found that the overall median proportion of women with repeat positive tests in cohorts with active follow-up was 13%, and a prospective cohort study in Australia in 201212 demonstrated that 18% of young women had a repeat infection at 3 months after treatment. From routine retesting data, repeat infections also appear high in MSM.13 Repeat chlamydial infections increase the risk of chlamydia-related sequelae such as pelvic inflammatory disease and infertility when compared to initial infection,14 and in MSM, repeat infections are associated with an increased risk of HIV transmission.15 Most repeat positive tests are due to reinfection from the same partner (indicating ineffective partner management); infection from a new partner; or less commonly treatment failure.16–18 Although clinical guidelines in a number of countries recommend retesting 3 months after treatment for chlamydia to detect reinfections,19–23 retesting rates are low, especially among men.24–26 From the patient perspective, a key barrier to retesting is the time and effort involved in going back to the clinic.27 In addition, given that chlamydia infection is asymptomatic in more than 80% of cases,28 patients who are asymptomatic or do not see themselves as being at high risk may be less likely to initiate retesting. A recent meta-analysis29 demonstrated that phone calls, letters, postcard reminders, and home collection kits resulted in modest increases in chlamydia retesting. As the majority of Australians have a mobile phone30 and messages are inexpensive, immediate, and can be automated,31 using short message service (SMS) to remind people to return for retesting is a potentially effective strategy. Subsequent to the meta-analysis, an evaluation of the operational use of SMS reminders at Sydney Sexual Health Centre showed moderately increased retesting (footnote continued) Murdoch Children’s Research Institute (Tabrizi, Garland), Parkville, Victoria, Australia Address correspondence to: Kirsty S. Smith, MPH, Kirby Institute, UNSW Australia, Wallace Wurth Building, Sydney, New South Wales
rates at 1–4 months after chlamydia infection (from 21% to 30%)32; however, more effective interventions are needed if higher rates of retesting are to be achieved. To our knowlege, no previous intervention has combined home collection strategies with SMS reminders to maximize the efficiency of an intervention to increase STI retesting. This RCT evaluates the effectiveness of combining postal home collection kits with SMS reminders on chlamydia retesting and repeat infections in MSM, women, and heterosexual men, compared with routine SMS reminders only.
Methods Trial Design In this unblinded RCT, individuals were randomized in a 1:1 ratio to either an SMS reminder and postal home collection kit (intervention: home arm) or an SMS reminder and clinic testing (control: clinic arm). Participants in the home arm had the option to return to the clinic for retesting if they preferred.
Setting and Participants The trial was conducted between 2011 and 2014 in two public clinics in Australia (Melbourne and Sydney Sexual Health Centres). Participants included three risk groups: heterosexual men (reported sexual contact only with female partner(s) in the last 12 months); MSM (reported sexual contact with male partner (s) in the last 12 months); and women (predominantly women who have sex with men). To be eligible, participants had to be aged Z16 years; have a diagnosis by nucleic acid amplification tests (NAATs) of chlamydial infection (genital infection in heterosexual men and women, and urethral or rectal infection in MSM); and reside in the jurisdiction serviced by the clinic for the next 6 months. They were also required to have a mobile phone. Patients were excluded if they were unwilling or unable to comply with all the requirements of the protocol; they could not speak English; or were HIV positive or a current sex worker, as patients in these categories are recommended to have regular STI testing. The trial was advertised by postcards left in the waiting room or provided to patients at the time of chlamydia testing or treatment. All positive chlamydia results were reviewed by study nurses based at each of the clinics. At both clinics, it is routine practice for patients reporting anal or urogenital signs or symptoms of chlamydia to be treated empirically and partner notification and treatment to be initiated by the clinician. The nurse contacted all potentially eligible patients by telephone and informed them of their chlamydia diagnosis, and for those not already treated, recommended they come to the clinic for treatment. During the call, the nurse gave patients a brief overview of the study, checked their eligibility, and if eligible, asked for their permission to pass on their contact details to a member of the research team. If the 2052. E-mail: [email protected]. 0749-3797/$36.00 http://dx.doi.org/10.1016/j.amepre.2015.01.014
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Smith et al / Am J Prev Med 2015;49(1):1–11 patient agreed, a member of the research team contacted the patient to explain the trial requirements and undertake a verbal consent process. As part of the verbal consent process, participants were informed that they would receive a AU$40 (US$35, GB£22) voucher for completing a survey at 4.5 months after enrollment. Computer-generated randomization codes, stratified by risk group, were produced by a statistician and sealed in opaque envelopes by a research assistant not associated with the trial. Once consent was given, the research team member selected the next randomization envelope according to the risk group of the patient and informed the patient which group they had been assigned to— the home or clinic group. The statistician analyzing the RCT data was blinded to the study group.
Intervention For participants in the intervention arm, 3 months after chlamydia diagnosis, an SMS was sent by the research team to let the patient know their retest was due and a kit would soon be mailed to them. The home collection kit contained the collection device(s) (women, self-collected vaginal swab; heterosexual men, UriSWAB for urine collection [Copan Diagnostics, Murrieta, CA]; MSM, UriSwab and rectal swab) plus illustrated collection instructions; a laboratory request form; and a prepaid envelope. The swabs and request form were pre-labeled with identifying information. The collection kit was mailed to the patient in an unmarked package by the research team at 3 months. Patients were instructed in a cover letter to collect their specimen(s), package them according to the provided instructions, and mail them to the laboratory in the prepaid envelope. For participants in the control arm, 3 months after chlamydia diagnosis, patients were sent an SMS by the clinic to remind them to return to the clinic for retesting. This is routine practice at the two participating clinics. At one clinic, an opt-out system was used where the SMS was automatically generated on receipt of a positive result, and at the other, the automated SMS system was activated via the electronic patient management system by the attending clinician. Specimens collected at the clinics were tested by the usual pathology provider according to their standard protocol. The method of chlamydia testing varied according to the pathology provider. At one laboratory, testing was performed using Cobas 4800 duplex realtime polymerase chain reaction (PCR) for C. trachomatis and Neisseria gonorrhoeae (Roche Diagnostics, Mannheim, Germany); at the other laboratory, the BDProbeTec ET C. trachomatis and N. gonorrhoeae Amplified DNA Assay (BD Biosciences, Sparks, MD) was used. All specimens collected at home were sent by mail to VCS Pathology. Samples were tested using the Artus C. trachomatis Plus RG PCR kit (Qiagen, Hilden, Germany), an in vitro nucleic acid amplification test for the detection of C. trachomatis DNA. All three assays have sensitivities and specificities for chlamydia in swab and urine samples 490% and 95%, respectively,33–35 and studies have demonstrated the adequacy of the UriSwab, self-collected vaginal and rectal swabs for detection of chlamydia,36–38 and the robustness of swabs sent by mail.39 Results of home tests were reported back to and managed by the referring clinics in the usual manner. Results were given to patients according to the clinic’s protocol for managing test results. Treatment for positive chlamydia cases was a 1-gram single dose of azithromycin according to the routine practice.21 July 2015
3
Measures The primary outcome was the percentage of patients who retested 1–4 months after chlamydia diagnosis. The secondary outcome was the percentage of repeat positive tests, defined in two ways: (1) the percentage of study arm participants who retested positive between 1 and 4 months and (2) the percentage of retesters who retested positive between 1 and 4 months. The following variables were extracted from the patient management system at baseline consultation: date of birth, residential postcode, country of birth, new or existing client, condom use (consistent, inconsistent, or never), number and gender of sexual partners in the last 3 months, previous chlamydia diagnoses (ever), date of the last chlamydia diagnosis, anal and urogenital symptoms, site and type of collected specimens, chlamydia treatment, and chlamydia results.
Survey Participants in both arms of the study were asked to complete a quantitative survey online. An SMS request was sent to participants at 4.5 months (after ascertainment of the primary outcome) and a reminder was sent at 5 months if the survey was not completed. The SMS contained a link to the study website and the participant’s unique study code. For this paper, the only survey data that are included are the number of days between home collection and mailing specimen(s) to the laboratory and if the participant retested at a clinic other than a study clinic. If participants reported testing elsewhere, they were mailed a consent form to obtain their permission to access the results of their tests. The consent form was then mailed to the doctor at the clinic.
Statistical Analysis Analyses were undertaken in 2014 using Stata, version 12.1. The percentage of patients who returned for retesting in each arm (home and clinic); percentage of retesters by risk group (women, heterosexual men, MSM), age group (o25 years, Z25 years), and symptoms at baseline (yes, no); and the percentage of patients who retested positive between 1 and 4 months of a chlamydia diagnosis in each arm and by risk group were assessed with intention-totreat analysis. The per-protocol analyses included (1) among the home testing arm, the percentage who retested at home compared with the clinic and the median time to retest among those who tested at home versus the clinic; and (2) Kaplan–Meier survival analysis to compare the time to retest between study arms and by risk group during the study period. Chlamydia retesting within 1–4 months after a chlamydia diagnosis was calculated as a second test occurring within 1–4 months of an initial positive test. A repeat infection included a positive result from any anatomic site. The effects of the intervention were measured by comparing the percentage who retested; the percentage with a repeat infection in all study arm participants; and the percentage with a repeat positive test in those retested and between the two groups (home versus clinic) using the chi-square test. Kaplan–Meier survival analysis was performed using a Kaplan–Meier plot and the logrank test.
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Sample Size
Results
The sample size was based on a chlamydia retesting rate of 40% in the clinic group based on findings from previous studies.31,40 The analysis was intended to assess the primary outcome in the three risk groups (200 women, 200 heterosexual men, and 200 MSM) and overall. A sample size of 194 in each risk group was needed to achieve at least 80% statistical power to detect an overall 20% difference (60% compared to 40%) in retesting between home and clinic groups. The 194 was rounded to 200 and summed to give an overall sample size of 600. A total sample size of 600 would achieve at least 80% statistical power to detect an overall 12% difference (52% compared to 40%) between the home and clinic group for all three risk groups combined. This study was approved by the Alfred Health Human Research Ethics Committee (HREC); South Eastern Sydney and Illawarra Area Health Service HREC; and the University of New South Wales HREC. All participants provided informed consent.
Between July 2011 and September 2012, 1,896 chlamydia-positive patients were assessed for eligibility (748 women, 529 heterosexual men, and 619 MSM). The reasons for ineligibility and exclusion varied by risk group (Figure 1). In total, 200 women, 200 heterosexual men, and 200 MSM were recruited and randomized. Of these, 302 were allocated to the intervention (home) arm and 298 to the control (clinic) arm, with approximately equal numbers of participants from each risk group allocated to each arm (Figure 1). The median age of participants was 26 years (interquartile range [IQR], 23–31 years); the majority resided in metropolitan areas (97%); and about half were born in Australia (48%). Most participants reported using
Figure 1. CONSORT diagram of participants’ flow through the trial. www.ajpmonline.org
Smith et al / Am J Prev Med 2015;49(1):1–11
condoms inconsistently or never in the last 3 months (84%); about half (51%) had two to five sexual partners in the last 3 months; 46% reported anal or urogenital symptoms at their baseline consultation; and 12% had a previous chlamydia diagnosis. The characteristics of each risk group are described in Table 1 and were comparable between the study arms. The percentage who retested within 1–4 months of chlamydia diagnosis was significantly higher among participants randomized to the home arm compared to the clinic arm in all risk groups: 64% (66/103) vs 39% (38/97) in women (absolute difference in the percentage retested of 25%, 95% CI¼12%, 38%, po0.001); 56% (57/101) vs 34% (34/99) in heterosexual men (absolute difference in the percentage retested of 22%, 95% CI¼9%, 36%, p¼0.002); and 62% (61/98) vs 44% (45/102) in MSM (absolute difference in the percentage retested of 18%, 95% CI¼5%, 32%, p¼0.010). Overall, the percentage was 61% (184/302) vs 39% (117/298) (absolute difference in the percentage retested of 22%, 95% CI¼14%, 30%, po0.001) (Table 2). Three home kits were returned to sender. For each of these, the participant was contacted by SMS and the kit was resent. Of the 301 participants who retested between 1 and 4 months, three (1%) tested outside the study sites but were verified by contacting the sites and included in the primary analysis. In women and MSM, the difference in the percentage retested within 1–4 months in the home versus the clinic arm was greater for those aged Z25 years compared to those aged o25 years. In heterosexual men, the opposite pattern was observed, with the difference greater in younger men aged o25 years compared to those aged Z25 years. The difference in retesting between the two arms appeared greater in those with symptoms at baseline compared with those without symptoms (Table 2). Among all study arm participants, the positivity in the home collection arm compared with the clinic arm was significantly higher among MSM (16% [16/98] vs 5% [5/102], p¼0.021) and overall (10% [31/302] vs 4% [12/298], p¼0.006), but there was no significant difference in women (8% [8/103] vs 2% [2/97], p¼0.107) and heterosexual men (7% [7/101] vs 5% [5/99], p¼0.768) (Table 2). Among those who retested at 1–4 months, the positivity at retest in the home collection arm compared with the clinic arm was significantly higher in MSM (26% [16/61] vs 11% [5/45], p¼0.048), but there was no significant differences in women (12% [8/66] vs 5% [2/38], p¼0.253); heterosexual men (12% [7/57] vs 15% [5/34], p¼0.575); or overall (17% [31/184] vs 10% [12/117], p¼0.128) (Table 2). Half (21/43) of the repeat positive tests were among MSM, and most were from rectal swabs. Among MSM in July 2015
5
the home arm, 16 had repeat positive tests (rectal swabs, 13; UriSwabs, 2; both, 1). Among MSM in the clinic arm, five had repeat positive tests (rectal swabs, 4; UriSwabs, 1). The median time to retest for the clinic arm was 3.1 (2.1–3.4) months and for the home arm was 3.3 (3.1–3.5) months (p¼0.791). The Kaplan–Meier survival curve showed very little difference in time to retest between the two arms until about 3 months, when the two curves diverged considerably (po0.01) (Figure 2). Time to retest between the two arms was significantly different within each risk group (po0.01 for women and heterosexual men; p¼0.03 for MSM). Among participants in the home arm who retested at 1–4 months, 27% (50/184) chose to retest at the clinic (28% [14/50] of women, 32% [16/50] of heterosexual men, and 40% [20/50] of MSM), with a median time to retest of 2.4 months compared to 3.4 months among those who retested using the postal home collection kit (po0.001). For those who self-collected using the home collection kit, the median time between specimen collection and mailing specimens to the laboratory was 1 day. Among participants in the home arm who chose to retest at the clinic, the positivity at retest was 32% overall (16/50), compared with 11% (15/134) in the home arm who retested using the postal home collection kit (p¼0.001). According to risk group, the differences were as follows: 14% (2/14) vs 12% (6/52) for women (p¼0.674); 44% (7/16) vs 0% (0/41) for heterosexual men (po0.001); and 35% (7/20) vs 22% (9/41) for MSM (p¼0.277).
Discussion In this RCT, SMS reminders combined with home collection resulted in significantly higher rates of retesting and significantly more repeat positive tests compared with SMS reminders and retesting at the clinic. The intervention increased retesting rates in all three risk groups, with the greatest effect in women and MSM aged Z25 years and heterosexual men aged o25 years. The Kaplan–Meier survival curve showed very little difference in time to retest between the two arms until the intervention at 3 months, after which the curves diverged. Retesting is vital to identifying and treating any repeat infections that may have arisen owing to inadequate partner management or treatment failure. The timing of when to do a retest is difficult—if done too early, there is the risk of a false positive diagnosis due to the detection of remnant, non-viable chlamydial infection, which has been found to persist for up to 8 weeks following treatment.41 To minimize this risk of false positivity,
6
Table 1. Baseline Characteristics of Stratified Risk Groups by Intervention Group Women
Heterosexual men
MSM
Overall
Clinic
Home
Clinic
Home
Clinic
Home
Clinic
Home
All
97
103
99
101
102
98
298
302
600
24 (21–27)
25 (21–27)
29 (24–31)
29 (24–31)
32 (25–37)
32 (25–36)
26 (23–31)
27 (23–31)
26 (23–31)
o25
56 (57.7)
54 (52.4)
33 (33.3)
30 (29.7)
24 (25.5)
21 (21.4)
113 (37.9)
105 (34.8)
218 (36.3)
Z25
41 (42.3)
49 (47.6)
66 (66.7)
71 (70.3)
78 (76.5)
77 (78.6)
185 (62.1)
197 (65.2)
382 (63.7)
90 (92.8)
101 (98.1)
96 (97.0)
99 (98.0)
99 (97.1)
95 (96.9)
285 (95.6)
295 (97.7)
580 (96.7)
7 (7.2)
2 (1.9)
3 (3.0)
2 (2.0)
3 (2.9)
3 (3.1)
13 (4.4)
7 (2.3)
20 (3.3)
51 (53.7)
58 (58.0)
37 (38.9)
41 (41.0)
52 (51.0)
45 (47.9)
140 (47.9)
144 (49.0)
284 (48.4)
8 (8.4)
10 (10.0)
11 (11.6)
13 (13.0)
9 (8.8)
17 (18.1)
28 (9.6)
40 (13.6)
68 (11.6)
Europe
25 (26.3)
21 (21.0)
35 (36.8)
32 (32.0)
25 (24.5)
23 (24.5)
85 (29.1)
76 (25.8)
161 (27.5)
Other
11 (11.6)
11 (11.0)
12 (12.6)
14 (14.0)
16 (15.7)
9 (9.6)
39 (13.4)
34 (11.6)
73 (12.5)
New
63 (65.0)
69 (67.0)
55 (55.6)
54 (53.5)
40 (39.2)
36 (36.7)
158 (53.0)
159 (52.6)
317 (52.8)
Existing
34 (35.1)
34 (33.0)
44 (44.4)
47 (46.5)
62 (60.8)
62 (63.3)
140 (47.0)
143 (47.4)
283 (47.2)
Yes
4 (4.1)
13 (12.6)
11 (11.1)
11 (10.9)
18 (17.7)
15 (15.3)
33 (11.1)
39 (12.9)
72 (12.0)
No
93 (95.9)
90 (87.4)
88 (88.9)
90 (89.1)
84 (82.4)
83 (84.7)
265 (88.9)
263 (87.1)
528 (88.0)
84 (91.3)
84 (92.3)
77 (84.6)
76 (82.6)
72 (79.1)
69 (74.2)
233 (85.0)
229 (83.0)
462 (84.0)
8 (8.7)
7 (7.7)
14 (15.4)
16 (17.4)
19 (20.9)
24 (25.8)
41 (15.0)
47 (17.0)
88 (16.0)
Number Age, median (IQR) Age group (years)
Area of residence
Non-metropolitan Country of birth Australia Asia
Client status
Previous chlamydia diagnosis (ever)
Condom use last 3 months Inconsistent (never/sometimes)
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Consistent (always)
Number of sexual partners last 3 months 0
3 (3.1)
8 (7.8)
6 (6.1)
6 (5.9)
5 (4.9)
8 (8.2)
14 (4.7)
22 (7.3)
36 (6.0)
1
35 (36.1)
25 (24.5)
20 (20.2)
22 (21.8)
27 (26.5)
30 (30.6)
82 (27.5)
77 (25.6)
159 (26.5)
(continued on next page)
Smith et al / Am J Prev Med 2015;49(1):1–11
Metropolitan
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7
July 2015
325 (54.2) 55 (56.7) No
Note: Values are n (%). Baseline data was extracted from the clinic’s patient management system. Data for some variables were not available for all participants. a Anal and /or urogenital symptoms. HM, heterosexual men; IQR, interquartile range; MSM, men who have sex with men; STI, sexually transmitted infection; W, women.
167 (55.3) 158 (53.0) 45 (45.9) 49 (48.0) 58 (57.4) 54 (54.6)
140 (47.0) 53 (54.1) 53 (52.0) 43 (42.6) 45 (45.5) 39 (37.9) 42 (43.3) Yes
STI symptoms at baseline
64 (62.1)
275 (45.8) 135 (44.7)
101 (16.9) 49 (16.3) 52 (17.5) 21 (21.4) 19 (18.6) 13 (12.9) 21 (21.2) 12 (12.4) a
45
15 (14.7)
303 (50.6) 153 (50.8) 150 (50.3) 39 (39.8) 51 (50.0) 60 (59.4) 52 (52.5) 54 (52.9) 47 (48.5)
Clinic
2–5
Home Clinic Home
Heterosexual men Women
Table 1. Baseline Characteristics of Stratified Risk Groups by Intervention Group (continued)
Clinic
MSM
Home
Clinic
Overall
Home
All
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Australian guidelines recommend a retest at 3 months after treatment rather than a test of cure at 4–6 weeks. The percentage who retested in this trial was comparable between the two study groups up to the point of the intervention at 3 months, and then retesting rates increased dramatically among those who had access to home collection kits. The effect of increased retesting was greater among young heterosexual men compared to older men. As young heterosexual men have been found to have low rates of retesting,25 this could be a particularly useful strategy for this group. Compared with other studies that have evaluated single interventions (reminders or home collection)31,32,42–45 higher rates of retesting were achieved by combining the two strategies of SMS and home collection. Two previous RCTs also combined interventions: incentives plus SMS reminders46 and home collection plus phone reminders27; however, the overall retesting rate in these studies were much lower because of some inadequacies of one of the chosen intervention strategies. In the study of Xu and colleagues,27 only a subset of women were reached by reminder calls despite multiple attempts. In the study of Downing et al.,46 a high proportion of SMS messages were undelivered, particularly to Aboriginal and Torres Strait Islander patients, owing to deactivation as a result of non-payment, failing to recharge phones, and phones being reported lost or stolen.46 This suggests that this strategy may not be ideal for all population groups. This study also highlights the importance of providing patients with choices. Over a quarter of home arm participants retested early at the clinic, and among heterosexual men there was a higher positivity compared to those who used the postal home collection system, suggesting they were at high risk or had symptoms and opted to be seen sooner rather than waiting 3 months for the kit to be posted. As it is appropriate for these patients to revisit the clinic promptly for assessment, rather than waiting to be recalled, this option should be incorporated into any retesting intervention. Other studies in the U.S. have also highlighted the importance of providing retesting options, with one study finding that when given a choice, 70% of youth opted to retest at the clinic rather than mailing a specimen for testing.47 Another study found that although the majority of young women were mailed their home collection kit, 9% opted to pick it up from the clinic.43 As seen in other studies, a high percentage (14%) of repeat infections was detected at 1–4 months. However, unlike the majority of previous retesting interventions,27,43–45,48 more repeat infections were detected in the intervention arm compared with the control arm, and repeat positivity was significantly higher among MSM.
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Table 2. Proportion Retested for Chlamydia and Repeat Positivity at 1–4 Months by Risk Group
Baseline characteristics
Clinic group
Home group
Overall
Absolute difference in the percentage retestedclinic arm versus home arm, % (95% CI)
p-valuea
o0.001
Retest at 1–4 months (retests/participants), n (%) Women
38/97 (39.2)
66/103 (64.1)
104/200 (52.0)
24.9 (11.5, 38.3)
Heterosexual men
34/99 (34.3)
57/101 (56.4)
91/200 (45.5)
22.1 (8.6, 35.5)
0.002
45/102 (44.1)
61/98 (62.2)
106/200 (53.0)
18.1 (4.5, 31.7)
0.010
117/298 (39.3)
184/302 (60.9)
301/600 (50.2)
21.6 (13.9, 29.5)
o0.001
o25
23/56 (41.1)
31/54 (57.4)
54/110 (49.1)
16.3 (–2.1, 34.8)
0.087
Z25
15/41 (36.6)
35/49 (71.4)
50/90 (55.6)
34.8 (15.4, 54.3)
0.001
o25
9/33 (27.3)
18/30 (60.0)
27/63 (42.9)
32.7 (9.5, 55.9)
0.009
Z25
25/66 (37.9)
39/71 (54.9)
64/137 (46.7)
17.0 (0.6, 33.5)
0.046
o25
10/24 (41.7)
11/21 (52.4)
21/45 (46.7)
10.7 (–18.4, 39.8)
0.472
Z25
35/78 (44.9)
50/77 (64.9)
85/155 (54.8)
20.0 (4.7, 35.4)
0.012
o25
42/113 (37.2)
60/105 (57.1)
102/218 (46.8)
20.0 (7.0, 33.0)
0.003
Z25
75/185 (40.5)
124/197 (62.9)
199/382 (52.1)
22.4 (12.6, 32.2)
o0.001
Yes
49/140 (35.0)
85/135 (63.0)
134/275 (48.7)
28.0 (16.6, 39.3)
o0.001
No
68/158 (43.0)
99/167 (59.3)
167/325 (51.4)
16.2 (5.5, 27.0)
MSM All Women
Heterosexual men
MSM
All
Symptoms at baseline
0.003
Repeat positivity at 1–4 months (positive tests/study arm), n (%) Women
2/97 (2.1)
8/103 (7.8)
10/200 (5.0)
0.107
Heterosexual men
5/99 (5.0)
7/101 (6.9)
12/200 (6.0)
0.768
5/102 (4.9)
16/98 (16.3)
21/200 (10.5)
0.021
12/298 (4.0)
31/302 (10.3)
43/600 (7.2)
0.006
10/104 (9.6)
0.253
MSM All
Repeat positivity at 1–4 months (positive tests/repeat tests), n (%) Women
2/38 (5.3)
8/66 (12.1)
Heterosexual men
5/34 (14.7)
7/57 (12.3)
12/91 (13.2)
0.575
MSM
5/45 (11.1)
16/61 (26.2)
21/106 (19.8)
0.048
12/117 (10.3)
31/184 (16.8)
43/301 (14.3)
0.128
All
Note: Intention-to-treat analysis. Boldface indicates statistical significance (po0.05). a 2 χ or Fisher’s exact test was used when appropriate. MSM, men who have sex with men.
This is most likely to be due to self-selection, that is, patients who perceived they were at higher risk of reinfection, and particularly those with the easier option to self-collect at home, were more likely to retest. Other
home collection kit programs have also demonstrated a high yield of chlamydia infection due to self-selection.49 Future programs could contact patients by SMS at 3 months, and if they have not already returned to the www.ajpmonline.org
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9
returned to sender, this is not expected to have influenced the findings. Another potential limitation is that the time to retest was calculated from the date of diagnosis rather than the date of treatment. If treatment was delayed and retesting occurred within 3–4 weeks post-treatment, there is the possibility that false positive results may have occurred because of detection of non-viable chlamydial infection.41 However, there is no reason to believe this would be different between study arms. It is also possible that some repeat positive tests may have included treatment failures, although the proportion would be limited and equal Figure 2. Kaplan–Meier curve comparing time to retest between the home and between arms.16,51 Sexual behavior clinic groups (per-protocol analysis). data and genotyping/multilocus sequence typing will be used to clinic, they could be sent a home collection kit. differentiate between chlamydia reinfection, persistent Other considerations for future programs include infection, and treatment failure, which will be the systems to check the accuracy of contact details and subject of a future analysis, along with acceptability opt-out systems for SMS reminders. Also, retesting and cost. strategies for MSM should incorporate testing for other STIs such as HIV and syphilis. The home collection strategy could also be used in populationConclusions based home testing programs. As recently demonstrated This evaluation demonstrates that in the sexual health by van Liere and colleagues,50 home collection comclinic setting, postal home collection kits in combination bined with clinic-based screening has the potential to with SMS reminders is a very effective strategy for increase the coverage of chlamydia screening in the increasing retesting rates and detecting additional repeat population. infections, compared with SMS reminders alone. Consideration of other primary care settings where this strategy may also be effective should be given.
Limitations
This study has some limitations to consider. The trial may have appealed to a more motivated group of patients who were more likely to retest irrespective of the intervention, and resulted in an overestimation of retesting in both arms. However, as the percentage that retested in the clinic arm was comparable with operational research from one of the participating clinics,32 this is unlikely. Patients were also not blinded to their study arm allocation, which may have had a differential impact on the likelihood of them retesting; however, there is no way to assess this. Also, it is possible that retesting in the home arm may have been underestimated if some kits had not been delivered to the participant because of change of address, but as addresses were checked and only three kits were July 2015
We thank all the participants of the study and the clinical staff of Melbourne and Sydney Sexual Health Centres—especially the study nurses: Karen Worthington and Samantha Blake; Rose Chevkenova-Mohamed, Muhammad Shahid Jamil, Larissa Lewis, and Natasha Karunaratne, Kirby Institute; and Vickie Knight and Simon Wright, Sydney Sexual Health Centre. The study was funded by National Health and Medical Research Council of Australia program grant number 568971. This study was approved by the Alfred Health Human Research Ethics Committee (HREC) on February 3, 2011; South Eastern Sydney and Illawarra Area Health Service HREC on June 7, 2011; and the University of New South Wales HREC on June 14, 2011.
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The trial was registered with the Australian and New Zealand Clinical Trials Registry on September 9, 2011: ACTRN 12611000968976. No financial disclosures were reported by the authors of this paper.
16.
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