Steven G. Badman

Field Evaluation of Xpert HPV Point-of-Care Test for Detection of Human Papillomavirus Infection by Use of Self-Collected Vaginal and Clinician-Collected Cervical Specimens

ABSTRACT The World Health Organization has recommended that testing for high-risk human papillomavirus (HPV) (hrHPV) infection be incorporated into cervical screening programs in all settings worldwide. In many high-burden, low-income countries, it will not be feasible to achieve high cervical screening coverage using hrHPV assays that require clinician-collected samples. We conducted the first evaluation of self-collected vaginal specimens compared with clinician-collected cervical specimens for the detection of hrHPV infection using the Xpert HPV test. Women aged 30 to 54 years attending two well-woman clinics in Papua New Guinea were invited to participate and provided self-collected vaginal and clinician-collected cervical cytobrush specimens. Both specimen types were tested at the point of care by using the Xpert HPV test. Women were given their cervical test result the same day. Those with a positive hrHPV test and positive examination upon visual inspection of the cervix with acetic acid were offered same-day cervical cryotherapy. A total of 1,005 women were enrolled, with 124 (12.3%; 95% confidence interval [CI], 10.3%, 14.4%) being positive for any hrHPV infection. There was a 99.4% overall percent agreement (OPA) between vaginal and cervical tests for HPV-16 (95% CI, 98.9%, 99.9%), a 98.5% OPA for HPV-18/45 (95% CI, 97.7%, 99.3%), a 94.4% OPA for other hrHPV infections (95% CI, 92.9%, 95.9%), and a 93.4% OPA for all hrHPV types combined (95% CI, 91.8%, 95.0%). Self-collected vaginal specimens had excellent agreement with clinician-collected cervical specimens for the detection of hrHPV infection using the Xpert HPV test. This approach provides for the first time an opportunity to incorporate point-of-care hrHPV testing into clinical cervical screening algorithms in high-burden, low-income settings.

Point-of-Care Testing for Chlamydia and Gonorrhoea: Implications for Clinical Practice

Objectives Point-of-care (POC) testing for chlamydia (CT) and gonorrhoea (NG) offers a new approach to the diagnosis and management of these sexually transmitted infections (STIs) in remote Australian communities and other similar settings. Diagnosis of STIs in remote communities is typically symptom driven, and for those who are asymptomatic, treatment is generally delayed until specimens can be transported to the reference laboratory, results returned and the patient recalled. The objective of this study was to explore the clinical implications of using CT/NG POC tests in routine clinical care in remote settings. Methods In-depth qualitative interviews were conducted with a purposively selected group of 18 key informants with a range of sexual health and laboratory expertise. Results Participants highlighted the potential impact POC testing would have on different stages of the current STI management pathway in remote Aboriginal communities and how the pathway would change. They identified implications for offering a POC test, specimen collection, conducting the POC test, syndromic management of STIs, pelvic inflammatory disease diagnosis and management, interpretation and delivery of POC results, provision of treatment, contact tracing, management of client flow and wait time, and re-testing at 3 months after infection. Conclusions The introduction of POC testing to improve STI service delivery requires careful consideration of both its advantages and limitations. The findings of this study will inform protocols for the implementation of CT/NG POC testing, and also STI testing and management guidelines.

Field evaluation of the CRT and ACON chlamydia point-of-care tests in a tropical, low-resource setting

Objective To evaluate the clinical performance of two chlamydia point-of-care (POC) tests compared with a gold standard nucleic acid amplification testing (NAAT). Methods Tests evaluated were the Chlamydia Rapid Test (CRT), Diagnostics for the Real World and the ACON Chlamydia Rapid Test Device, ACON Laboratories (ACON). Overall 226 men and 225 women in Port Vila, Vanuatu, participated in this prospective study in 2010. NAAT and POC testing was performed on samples of male urine and female vaginal swabs for 156 men and 223 women (CRT), and 133 men and 75 women (ACON). Results The sensitivity and specificity of the CRT in men were 41.4% (95% CI 23.5% to 61.1%) and 89.0% (95% CI 82.2% to 93.8%), respectively, and in women 74.2% (95% CI 61.5% to 84.5%) and 95.7% (95% CI 91.3% to 98.2%), respectively; for ACON, they were 43.8% (95% CI 19.8% to 70.1%) and 98.3% (95% CI 93.9% to 99.8%) in men, and in women 66.7% (95% CI 22.3% to 95.7%) and 91.3% (95% CI 82.0% to 96.7%), respectively. Both tests were (absolutely) insensitive at organism loads less than 1000 (log=3) per mL or per swab; the CRT sensitivity was significantly lower at loads less than, compared with those greater than, 100 000 (log=5) per mL or per swab. Conclusions The performance of both CRT and ACON is well below the levels stated by the manufacturers. The evaluated tests are unlikely to be helpful in clinical settings due to the high proportion of false-negatives that will go untreated and false-positives that will result in overtreatment and potential adverse social consequences.

A field evaluation of a new molecular-based point-of-care test for chlamydia and gonorrhoea in remote Aboriginal health services in Australia

UNLABELLED Background Point-of-care (POC) tests could be important public health tools in settings with treatment delays and high rates of sexually transmissible infections (STIs). Use is limited due to suboptimal performance. The performance and ease-of-use of a new molecular-based POC test for simultaneous detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) was assessed, alongside two single-organism immunochromatographic tests (ICT). METHODS The evaluation occurred between May 2012 and March 2013 during community STI screens in two remote Aboriginal health services. Urine was tested with the GeneXpert(®)CT/NG and if sufficient volume, also with Diaquick CT and Gonorrhoea Card. The gold standard comparison was laboratory nucleic acid amplification testing (NAAT). Operational characteristics were also assessed. RESULTS Among 198 samples, GeneXpert CT sensitivity and specificity was 100% [95% confidence intervals (CI): 75.9-100] and 99.5% (95% CI: 96.5-100), and NG was 100% (95% CI: 96.5-100) and 100% (95% CI: 97.5-100), respectively. Among a sample subset, Diaquick CT (n=104) sensitivity and specificity was 27.3% (95% CI: 7.3-60.7) and 66.7% (95% CI: 12.5-98.2), and Gonorrhoea Card (n=29), was 66.7% (95% CI: 12.5-98.2) and 76.9% (95% CI: 56.0-90.2), respectively. GeneXpert required 1mL of urine, four steps, 1min specimen preparation and 90min to result. ICTs required 15mL of urine, eight steps, 18min preparation and 10-15min to result. CONCLUSION The accuracy and operational benefits of GeneXpert CT/NG make it very suitable in these settings where delays to treatment are encountered.

I Do Feel Like a Scientist at Times: A Qualitative Study of the Acceptability of Molecular Point-Of-Care Testing for Chlamydia and Gonorrhoea to Primary Care Professionals in a Remote High STI Burden Setting.

Background Point-of-care tests for chlamydia (CT) and gonorrhoea (NG) could increase the uptake and timeliness of testing and treatment, contribute to improved disease control and reduce reproductive morbidity. The GeneXpert (Xpert CT/NG assay), suited to use at the point-of-care, is being used in the TTANGO randomised controlled trial (RCT) in 12 remote Australian health services with a high burden of sexually transmissible infections (STIs). This represents the first ever routine use of a molecular point-of-care diagnostic for STIs in primary care. The purpose of this study was to explore the acceptability of the GeneXpert to primary care staff in remote Australia. Methods In-depth qualitative interviews were conducted with 16 staff (registered or enrolled nurses and Aboriginal Health Workers/Practitioners) trained and experienced with GeneXpert testing. Interviews were digitally-recorded and transcribed verbatim prior to content analysis. Results Most participants displayed positive attitudes, indicating the test was both easy to use and useful in their clinical context. Participants indicated that point-of-care testing had improved management of STIs, resulting in more timely and targeted treatment, earlier commencement of partner notification, and reduced follow up efforts associated with client recall. Staff expressed confidence in point-of-care test results and treating patients on this basis, and reported greater job satisfaction. While point-of-care testing did not negatively impact on client flow, several found the manual documentation processes time consuming, suggesting that improved electronic connectivity and test result transfer between the GeneXpert and patient management systems could overcome this. Managing positive test results in a shorter time frame was challenging for some but most found it satisfying to complete episodes of care more quickly. Conclusions In the context of a RCT, health professionals working in remote primary care in Australia found the GeneXpert highly acceptable. These findings have implications for use in other primary care settings around the world.

A preliminary evaluation of a new GeneXpert (Gx) molecular point-of-care test for the detection of Trichomonas vaginalis

Objectives Global concerns regarding the prevalence, asymptomatic nature and burden of disease associated with Trichomonas vaginalis (TV) continue. The lack of a portable molecular point-of-care assay to detect this infectious disease has meant that many remote or low-resource settings still need to rely on delayed results from central laboratories and/or syndromic management as treatment strategies. We evaluated the new GeneXpert (Gx) TV nucleic acid amplification test (NAAT) compared with an in-house laboratory NAAT to determine whether it would be suitable for use at the point of care. Methods In a state-based laboratory and using their in-house NAAT, we selected the first 60 urine samples that were positive and the first 60 that were negative (n=120) in the study period for Gx TV testing in order to reduce collection delays and avoid the freezing of samples. Results Positive percentage agreement between the Gx TV and NAAT was 95.0% (95% CI 86.1% to 99.0%), negative percentage agreement was 100.0% (95% CI 93.5% to 100.0%) and overall percentage agreement was 97.4% (95% CI 92.5% to 99.5%). Three discordant results were detected with each being close to the cycle threshold of detection using the in-house NAAT assay. Conclusions Findings suggest the Gx TV assay is easy to use and has suitable overall agreement for sexually transmissible infection (STI) testing at the point of care. It may be used in combination with the Gx CT/NG assay to test for all three STIs simultaneously using this portable and modular-based NAAT platform.

Public health implications of molecular point-of-care testing for chlamydia and gonorrhoea in remote primary care services in Australia: a qualitative study

Objectives With accurate molecular tests now available for diagnosis of chlamydia and gonorrhoea (Chlamydia trachomatis (CT)/Neisseria gonorrhoeae (NG)) at the point-of-care (POC), we aimed to explore the public health implications (benefits and barriers) of their integration into remote primary care in Australia. Methods Qualitative interviews were conducted with a purposively selected group of 18 key informants reflecting sexual health, primary care, remote Aboriginal health and laboratory expertise. Results Participants believed that POC testing may decrease community prevalence of sexually transmitted infections (STIs), and associated morbidity by reducing the time to treatment and infectious period and expediting partner notification. Also, POC testing could improve acceptability of STI testing, increase testing coverage and result in more targeted prescribing, thereby minimising the risk of antibiotic resistance. Conversely, some felt the immediacy of diagnosis could deter certain young people from being tested. Participants also noted that POC testing may reduce the completeness of communicable disease surveillance data given the current dependence on reporting from pathology laboratories. Others expressed concern about the need to maintain and improve the flow of NG antibiotic sensitivity data, already compromised by the shift to nucleic acid-based testing. This is particularly relevant to remote areas where culture viability is problematic. Conclusions Results indicate a high level of support from clinicians and public health practitioners for wider access to CT/NG POC tests citing potential benefits, including earlier, more accurate treatment decisions and reductions in ongoing transmission. However, the data also highlight the need for new systems to avoid adverse impact on disease surveillance. Trial registration number Australian and New Zealand Clinical Trials Registry: ACTRN12613000808741.

O22.6 Field Evaluation of Three Point-Of-Care Tests For Chlamydia and Gonorrhoea in Remote Health Services in Australia

Introduction Control of sexually transmissible infections (STIs) can be compromised by delays in time to diagnosis and treatment. Point-of-care (POC) tests can provide results at time of consultation. We conducted field evaluations of three POC tests (one new molecular-based and two best-performing immunochromatographic tests [ICT] identified from preliminary laboratory evaluations) for diagnosis of gonorrhoea (NG) and chlamydia (CT) at selected remote health services in Australia to identify the most suitable device for a larger randomised trial. Methods Urine specimens collected from patients attending health services for routine STI screening were aliquotted and tested onsite with: GeneXpert® CT/NG (simultaneous detection of CT and NG), Diaquick CT (CT only), and Gonorrhea Card (NG only). We compared results to routine laboratory reference results (commercial nucleic-acid amplification test) and calculated sensitivity (Sn) and specificity (Sp) by standard methods. We assessed selected operational characteristics. Results For GenXpert (n = 99): Sn and Sp for CT were: 100% (95% confidence interval [CI]: 56.1–100) and 98.9% (CI: 93.1–99.9); for NG: 100% (CI: 56.1–100) and 100% (CI: 95.0–100). For Diaquick (n = 50), Sn and Sp were: 42.9% (CI: 11.8–79.8) and 97.7% (CI: 86.2–99.9). For Gonorrhea Card (n = 15), Sn and Sp were: 66.7% (CI: 12.5–98.2) and 75.0% (CI: 42.8–93.3). Urine volume required: GeneXpert = 1ml; both ICTs = 15ml. Mean preparation time: GeneXpert = 1 minute and ICTs = 18 minutes. Time to result: GeneXpert = 88 minutes, Diaquick = 10 minutes and Gonorrhea Card = 15 minutes. Results from additional evaluation sites occurring in early 2013 will also be presented. Conclusions The GeneXpert is highly accurate for detection of CT and NG from urine in these field settings. Similar performance has been reported from the laboratory. Despite longer time to results than traditional ICTs, the exceptional accuracy and operational benefits makes the GeneXpert device appealing for use where delays to treatment are frequent. This device will be further evaluated in a cluster-randomised controlled trial (TTANGO) to commence mid-2013.

Molecular test for chlamydia and gonorrhoea used at point of care in remote primary healthcare settings: a diagnostic test evaluation

Objectives A new molecular test for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) (GeneXpert CT/NG) has been demonstrated to be as accurate as conventional nucleic acid amplification tests (NAAT), but performance has not been evaluated in routine primary care, performed at the point of care by clinicians. We aimed to examine its diagnostic performance when used by clinicians in remote community health services in Australia with high prevalences of CT and NG infection. The trial was registered with the Australian and New Zealand Clinical Trials Registry (#12613000808741) Methods At 12 health services, training was provided to 99 clinicians in the use of the GeneXpert CT/NG assay who tested specimens from all patients undergoing STI screening. Specimens were also sent in parallel for conventional laboratory-based NAATs and the concordance of results was evaluated. Results Clinicians conducted 2486 tests: CT concordance was 99.4% (95% CI 99.1 to 99.7) with a positive concordance of 98.6% (95% CI 95.9 to 99.7) and negative concordance of 99.5% (95% CI 99.1 to 99.8); NG concordance was 99.9% (95% CI 99.7 to 100.0) with a positive concordance of 100.0% (95% CI 97.5 to 100.0) and negative concordance of 99.9% (95% CI 99.7 to 100.0). Conclusions In this first study reporting routine point-of-care use of GeneXpert CT/NG by primary care clinicians, we found excellent concordance with conventional NAATs. The use of the GeneXpert CT/NG at the point of care could potentially transform management and control of these infections in many endemic settings, including low/middle-income countries.

Molecular point-of-care testing for chlamydia and gonorrhoea in Indigenous Australians attending remote primary health services (TTANGO): a cluster-randomised, controlled, crossover trial

BACKGROUND Timely diagnosis and treatment of sexually transmissible infections will prevent morbidity and onward transmission. We aimed to assess the efficacy of a point-of-care molecular test for Chlamydia trachomatis and Neisseria gonorrhoeae infections at the cluster level to improve infection management among Indigenous Australian communities with high prevalence of sexually transmissible infections. METHODS In this cluster-randomised crossover study, we recruited primary health services in Western Australia, Far North Queensland, and South Australia that provide care to Indigenous people in regional or remote locations. The services were eligible if they did 150 or more tests for C trachomatis or N gonorrhoeae infection per year among individuals aged 16-29 years, and if C trachomatis or N gonorrhoeae positivity was 10% or higher. Services were randomly assigned (1:1) by use of a random-number generator, stratified by geographical region, to either standard care conditions with routine laboratory-based sexually transmissible infection testing for 12 months followed by 12 months of intervention with molecular point-of-care testing, or the reverse sequence. The primary outcome was the proportion of people (aged 16-29 years) found to have C trachomatis or N gonorrhoeae who had a positive result at retesting 3 weeks to 3 months after treatment, and a secondary outcome was treatment within 7 days, both in those aged 16-29 years and at the cluster level. We did these analyses using data from all participants who had a positive result at testing, by point-of-care of laboratory testing (ie, the intention-to-treat population). The trial is registered with Australian and New Zealand Clinical Trials Registry (ACTRN12613000808741). FINDINGS Between June 1, 2013, and Feb 29, 2016, 12 health services were enrolled and randomly assigned to standard care followed by intervention (six) and the reverse sequence (six). After randomisation, one health service that was initially assigned to standard care was excluded because it no longer met the inclusion criteria. 455 individuals tested positive for C trachomatis or N gonorrhoeae infection in the intervention group, and 405 tested positive in the standard care group. In the intervention group, 12 (19%) of 63 individuals retested had a positive test result, compared with nine (13%) of 67 with positive retests in the standard care group (relative ratio [RR] 1·42, 95% CI 0·64-3·13; p=0·405), and 347 (76%) were treated within 7 days in the intervention group, compared with 191 (47%) in the standard care group (RR 1·66, 1·41-1·93; p<0·0001). INTERPRETATION Retesting rates were too low to draw conclusions on the effect of the intervention on repeat infections. Further research will be needed to determine whether point-of-care tests have an effect on reinfection rates, and the sustainability of using this technology. However, our findings show that time to treatment of C trachomatis or N gonorrhoeae infections in primary care clinics in remote areas in Australia with a high prevalence of sexually transmissible infections could be substantially reduced by the use of molecular point-of-care tests. FUNDING The National Health and Medical Research Council, Australia.