Test of cure study: a feasibility study to estimate the time to test of cure (TOC) for Neisseria gonorrhoeae and Chlamydia trachomatis infections.

OBJECTIVES: Test of cure (TOC) for Neisseria gonorrhoeae (NG) and Chlamydia trachomatis (CT) infection is an important tool in the public health management of STIs. However, there are limited data about the optimal time to perform TOC using nucleic acid amplification tests (NAATs) for NG and CT infections. A study was performed to assess the feasibility of a larger study to determine the optimal time to TOC using NAATS. METHODS: The Sexually Transmitted Bacteria Reference Unit at Public Health England undertook testing of gonococcal and chlamydial nucleic acids within neat urine stored in different conditions over 25 days to provide evidence of the stability of the nucleic acid prior to recruitment. Individuals diagnosed with uncomplicated NG or CT infection were recruited from three sexual health clinics. Individuals were asked to return nine self-taken samples from the site of infection over a course of 35 days. Survival analyses of time to first negative NAAT result for NG and CT infection and univariate regression analysis of factors that affect time to clearance were undertaken. RESULTS: At room temperature, chlamydial DNA in urine is stable for up to 3 weeks and gonococcal DNA for up to 11 days. We analysed data for 147 infections (81 NG and 66 CT). The median time to clearance of infection was 4 days (IQR 2-10 days) for NG infection and 10 days (IQR 7-14 days) for CT infection. Vaginal CT infections took longer to clear (p=0.031). NG infection in men who have sex with men took longer to clear (p=0.052). CONCLUSION: Chlamydial and gonococcal nucleic acids are stable in urine before addition of preservatives, longer than recommended by the manufacturer. The TOC results suggest that it may be possible to undertake TOC for NG and CT infections earlier than current guidelines suggest and that anatomical site of infection may affect time to clearance of infection.

Detection of the United States Neisseria meningitidis urethritis clade in the United Kingdom, August and December 2019 - emergence of multiple antibiotic resistance calls for vigilance.

Since 2015 in the United States (US), the US Neisseria meningitidis urethritis clade (US_NmUC) has caused a large multistate outbreak of urethritis among heterosexual males. Its 'parent' strain caused numerous outbreaks of invasive meningococcal disease among men who have sex with men in Europe and North America. We highlight the arrival and dissemination of US_NmUC in the United Kingdom and the emergence of multiple antibiotic resistance. Surveillance systems should be developed that include anogenital meningococci.

The Context of Sexual Risk Behaviour Among Men Who Have Sex with Men Seeking PrEP, and the Impact of PrEP on Sexual Behaviour.

There are still important gaps in our understanding of how people will incorporate PrEP into their existing HIV prevention strategies. In this paper, we explore how PrEP use impacted existing sexual risk behaviours and risk reduction strategies using qualitative data from the PROUD study. From February 2014 to January 2016, we conducted 41 in-depth interviews with gay, bisexual and other men who have sex with men (GBMSM) enrolled in the PROUD PrEP study at sexual health clinics in England. The interviews were conducted in English and were audio-recorded. The recordings were transcribed, coded and analysed using framework analysis. In the interviews, we explored participants' sexual behaviour before joining the study and among those using or who had used PrEP, changes to sexual behaviour after starting PrEP. Participants described the risk behaviour and management strategies before using PrEP, which included irregular condom use, sero-sorting, and strategic positioning. Participants described their sexual risk taking before initiating PrEP in the context of the sexualised use of drugs, geographical spaces linked with higher risk sexual norms, and digitised sexual networking, as well as problematic psychological factors that exacerbated risk taking. The findings highlight that in the main, individuals who were already having frequent condomless sex, added PrEP to the existing range of risk management strategies, influencing the boundaries of the 'rules' for some but not all. While approximately half the participants reduced other risk reduction strategies after starting PrEP, the other half did not alter their behaviours. PrEP provided an additional HIV prevention option to a cohort of GBMSM at high risk of HIV due to inconsistent use of other prevention options. In summary, PrEP provides a critical and necessary additional HIV prevention option that individuals can add to existing strategies in order to enhance protection, at least from HIV. As a daily pill, PrEP offers protection in the context of the sex cultures associated with sexualised drug use, digitised sexual applications and shifting social norms around sexual fulfilment and risk taking. PrEP can offer short or longer-term options for individuals as their sexual desires change over their life course offering protection from HIV during periods of heightened risk. PrEP should not be perceived or positioned in opposition to the existing HIV prevention toolkit, but rather as additive and as a tool that can and is having a substantial impact on HIV.

Acceptability of an open-label wait-listed trial design: Experiences from the PROUD PrEP study.

BACKGROUND: PROUD participants were randomly assigned to receive pre-exposure prophylaxis (PrEP) immediately or after a deferred period of one-year. We report on the acceptability of this open-label wait-listed trial design. METHODS: Participants completed an acceptability questionnaire, which included categorical study acceptability data and free-text data on most and least liked aspects of the study. We also conducted in-depth interviews (IDI) with a purposely selected sub-sample of participants. RESULTS: Acceptability questionnaires were completed by 76% (415/544) of participants. After controlling for age, immediate-group participants were almost twice as likely as deferred-group participants to complete the questionnaire (AOR:1.86;95%CI:1.24,2.81). In quantitative data, the majority of participants in both groups found the wait-listed design acceptable when measured by satisfaction of joining the study, intention to remain in the study, and interest in joining a subsequent study. However, three-quarters thought that the chance of being in the deferred-group might put other volunteers off joining the study. In free-text responses, data collection tools were the most frequently reported least liked aspect of the study. A fifth of deferred participants reported 'being deferred' as the thing they least liked about the study. However, more deferred participants disliked the data collection tools than the fact that they had to wait a year to access PrEP. Participants in the IDIs had a good understanding of the rationale for the open-label wait-listed study design. Most accepted the design but acknowledged they were, or would have been, disappointed to be randomised to the deferred group. Five of the 25 participants interviewed reported some objection to the wait-listed design. CONCLUSION: The quantitative and qualitative findings suggest that in an environment where PrEP was not available, the rationale for the wait-listed trial design was well understood and generally acceptable to most participants in this study.

Randomized controlled trial of the tolerability and completion of maraviroc compared with Kaletra® in combination with Truvada® for HIV post-exposure prophylaxis (MiPEP Trial).

Objectives: Post-exposure prophylaxis (PEP) for HIV is often poorly tolerated and not completed. Alternative PEP regimens may improve adherence and completion, aiding HIV prevention. We conducted a randomized controlled trial of a maraviroc-based PEP regimen compared with a standard-of-care regimen using ritonavir-boosted lopinavir. Methods: Patients meeting criteria for PEP were randomized to tenofovir disoproxil/emtricitabine (200/245 mg) once daily plus ritonavir-boosted lopinavir (Kaletra ® 400/100 mg) or maraviroc 300 mg twice daily. The composite primary endpoint was completion of 28 days of the allocated PEP regimen without grade 3 or 4 clinical or laboratory adverse events (AEs) related to the PEP medication. Results: Two hundred and thirteen individuals were randomized (107 to maraviroc; 106 to Kaletra ® arm). Follow-up rates were high in both groups. There was no difference in the primary endpoint; 70 (71%) in the maraviroc and 64 (65%) in the Kaletra ® arm ( P = 0.36) completed PEP without grade 3 or 4 AEs. Discontinuation of PEP was the same (18%) in both groups. There were no grade 3 or 4 clinical AEs in either arm, but more grade 1 or 2 clinical AEs in the Kaletra ® arm (91% versus 70%; P < 0.001). Antidiarrhoeal medication use was higher in the Kaletra ® arm (67% versus 25%; P < 0.001). There were no HIV seroconversions in the study period. Conclusions: The completion rate in the absence of grade 3 or 4 AEs was similar with both regimens. Maraviroc-based PEP was better tolerated, supporting its use as an option for non-occupational PEP.

Efficacy and safety of emtricitabine/tenofovir alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial.

BACKGROUND: FTC/TAF was shown to be noninferior to FTC/TDF with advantages in markers of renal and bone safety. OBJECTIVE: To evaluate the efficacy and safety of switching to FTC/TAF from FTC/TDF by third agent (boosted protease inhibitor [PI] vs. unboosted third agent). METHODS: We conducted a 48-week subgroup analysis based on third agent from a randomized, double blind study in virologically suppressed adults on a FTC/TDF-containing regimen who switched to FTC/TAF vs. continued FTC/TDF while remaining on the same third agent. RESULTS: We randomized (1:1) 663 participants to either switch to FTC/TAF (N = 333) or continue FTC/TDF (N = 330), each with baseline third agent stratifying by class of third agent in the prior treatment regimen (boosted PI 46%, unboosted third agent 54%). At week 48, significant differences in renal biomarkers and bone mineral density were observed favoring FTC/TAF over FTC/TDF (p < 0.05 for all), with similar improvements in the FTC/TAF arm in those who received boosted PI vs. unboosted third agents. At week 48, virologic success rates were similar between treatment groups for those who received a boosted PI (FTC/TAF 92%, FTC/TDF 93%) and for those who received an unboosted third agent (97% vs. 93%). CONCLUSIONS: In virologically suppressed patients switching to FTC/TAF from FTC/TDF, high rates of virologic suppression were maintained, while renal and bone safety parameters improved, regardless of whether participants were receiving a boosted PI or an unboosted third agent. FTC/TAF offers safety advantages over FTC/TDF and can be an important option as an NRTI backbone given with a variety of third agents.

An analysis of baseline data from the PROUD study: an open-label randomised trial of pre-exposure prophylaxis.

BACKGROUND: Pre-exposure prophylaxis (PrEP) has proven biological efficacy to reduce the sexual acquisition of the human immunodeficiency virus (HIV). The PROUD study found that PrEP conferred higher protection than in placebo-controlled trials, reducing HIV incidence by 86 % in a population with seven-fold higher HIV incidence than expected. We present the baseline characteristics of the PROUD study population and place the findings in the context of national sexual health clinic data. METHODS: The PROUD study was designed to explore the real-world effectiveness of PrEP (tenofovir-emtricitabine) by randomising HIV-negative gay and other men who have sex with men (GMSM) to receive open-label PrEP immediately or after a deferral period of 12 months. At enrolment, participants self-completed two baseline questionnaires collecting information on demographics, sexual behaviour and lifestyle in the last 30 and 90 days. These data were compared to data from HIV-negative GMSM attending sexual health clinics in 2013, collated by Public Health England using the genitourinary medicine clinic activity database (GUMCAD). RESULTS: The median age of participants was 35 (IQR: 29-43). Typically participants were white (81 %), educated at a university level (61 %) and in full-time employment (72 %). Of all participants, 217 (40 %) were born outside the UK. A sexually transmitted infection (STI) was reported to have been diagnosed in the previous 12 months in 330/515 (64 %) and 473/544 (87 %) participants reported ever having being diagnosed with an STI. At enrolment, 47/280 (17 %) participants were diagnosed with an STI. Participants reported a median (IQR) of 10 (5-20) partners in the last 90 days, a median (IQR) of 2 (1-5) were condomless sex acts where the participant was receptive and 2 (1-6) were condomless where the participant was insertive. Post-exposure prophylaxis had been prescribed to 184 (34 %) participants in the past 12 months. The number of STI diagnoses was high compared to those reported in GUMCAD attendees. CONCLUSIONS: The PROUD study population are at substantially higher risk of acquiring HIV infection sexually than the overall population of GMSM attending sexual health clinics in England. These findings contribute to explaining the extraordinary HIV incidence rate during follow-up and demonstrate that, despite broad eligibility criteria, the population interested in PrEP was highly selective. TRIAL REGISTRATION: Current Controlled Trials ISRCTN94465371 . Date of registration: 28 February 2013.

Pre-exposure prophylaxis to prevent the acquisition of HIV-1 infection (PROUD): effectiveness results from the pilot phase of a pragmatic open-label randomised trial.

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

Narratives of HIV: measuring understanding of HIV and the law in HIV-positive patients.

OBJECTIVE: This study aimed to identify the understanding of people living with HIV and AIDS (PLWHA) regarding the application of the law around transmission of HIV in England and Wales. DESIGN: A questionnaire was designed to prompt participants attending a large HIV department to discuss their understanding of the law with reference to HIV transmission. The design focused on qualitative analysis as there were insufficient data available to inform a metric reflecting quantitative data on PLWHA's understanding of the legal implications of transmission. METHODS: The data were collected from PLWHA attending their HIV outpatient appointment to ensure relevance of population to the analysis. The answers were analysed using grounded theory and thematic analysis to identify key themes and theories for further testing. RESULTS: Analysis demonstrated that understanding of legal obligations and outcomes of prosecutions was poor and patchy, with behavioural restrictions often overstated. There was a strong theme of ownership of responsibility amongst PLWHA, and of reference to principles of morality beyond legal restrictions. CONCLUSIONS: PLWHA remain at risk of prosecution through poor understanding of the law. Clinical services and advocacy agencies should strive to increase understanding in order to enable PLWHA to comprehend the law and negotiate it successfully. This information should be shared as a process, not an isolated event.

Should we screen heterosexuals for extra-genital chlamydial and gonococcal infections?

Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) are two of the most prevalent bacterial sexually transmitted infections in the UK. Although the high burden of extra-genital infections with GC and CT in men who have sex with men has been well established, a significant number of extra-genital site infections with CT and GC could similarly be present in heterosexual women. For this reason we started to routinely offer extra-genital site testing for GC and CT in all patients attending our sexual health clinic who reported having had receptive anal sex and/or giving oral sex. This followed a review of current evidence by the clinical team and a change in local testing policy. This study not only confirmed a large reservoir of extra-genital infection amongst men who have sex with men, but also demonstrates that a comparable reservoir of extra-genital infection is present amongst heterosexual women. Our study adds to the mounting evidence that extra-genital site testing in heterosexual women should occur when oral or anal sexual activity is reported.

Risk factors for chlamydial infection in chlamydia contacts: a questionnaire-based study.

BACKGROUND AND METHODOLOGY: Treatment of individuals with chlamydial infection and their sexual partners is an important aspect of reproductive health care. Partners of infected individuals are currently offered 'epidemiological treatment', which means that they are offered antibiotic treatment at their first visit without waiting for the result of their chlamydia test. We carried out a study to identify the risk factors for chlamydial infection in partners of infected individuals. Individuals attending a genitourinary clinic as chlamydia contacts were identified and asked to complete a questionnaire about their relationship with the index case and their prior sexual history. The result of their chlamydia test was then analysed against those variables. RESULTS: A total of 115 chlamydia contacts were analysed in this study; 60 (52%) were found to be positive for chlamydial infection. In a multivariate analysis, young age, more than one episode of sexual intercourse with the infected partner and a greater total number of sexual partners were associated with a positive chlamydia result. A prediction model for chlamydial infection using these risk factors had a discriminatory ability quantified by an area under the curve (AUC) of 0.76 (95% CI 0.66-0.85). DISCUSSION AND CONCLUSIONS: The risk factors identified can be used when discussing epidemiological treatment with individuals who attend sexual health services as chlamydia contacts, or to target clinic resources to a higher-risk group. Larger studies will be necessary to assess the benefits and risks of changing to a policy of offering epidemiologic treatment to 'high-risk' contacts only, identified using a predictive model such as the one described here.

Cervical surveillance in HIV-positive women: a genitourinary medicine clinic experience.

BACKGROUND: The prevalence of cervical intraepithelial neoplasia (CIN) is increased in HIV infection. The UK National Health Service Cervical Screening Programme (NHSCSP) guidelines therefore provide specific recommendations for HIV-positive women. An audit of cervical surveillance in HIV-positive women who attend the genitourinary medicine (GUM) department at the Leicester Royal Infirmary, Leicester, UK was conducted. The objectives were to assess adherence to UK and local screening guidelines, prevalence of cervical pathology and appropriate referral for colposcopy. METHODS: A retrospective case note review of 130 HIV-infected women attending the GUM department between January 2000 and December 2005 was undertaken. RESULTS: Results showed that 76.2% of patients had cervical cytology within a year of HIV diagnosis and 42.4% of patients had abnormal cytology. All patients with dyskaryosis were referred for colposcopy according to local and national guidelines. Cytology results were consistent with histological findings and the prevalence of CIN was 15.2%. CD4 counts at presentation were significantly lower in those with dyskaryosis compared with those without dyskaryosis (p = 0.038). Twenty-two patients were lost to follow-up after initial cytology. DISCUSSION AND CONCLUSIONS: A designated health advisor in the GUM department co-ordinates cervical surveillance in HIV-positive women. This, together with an increasingly integrated service with family planning services, may contribute to relatively successful surveillance. Overall, patients are carefully monitored to ensure that surveillance is adequate. Extra vigilance is, however, required and further cost-effective measures in future may include more active involvement of general practitioners.