Ann K Sullivan

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

Summary 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.

Missed opportunities for earlier HIV diagnosis within primary and secondary healthcare settings in the UK

Objective: To identify opportunities for earlier HIV diagnosis within primary and secondary care settings in the UK in Africans with newly diagnosed HIV infection. Methods: A survey of newly diagnosed HIV-positive Africans attending 15 HIV treatment centres across London was conducted between April 2004 and February 2006. The survey consisted of a confidential self-completed questionnaire linked to clinician-completed clinical records. Results: A total of 263 questionnaires were completed, representing an uptake rate of 79.5% of patients approached and 49.8% (131/263) of participants presented with advanced HIV disease (CD4 cell count < 200 cells/μl at diagnosis). In the year prior to HIV diagnosis 76.4% (181/237) had seen their GP, 38.3% (98/256) had attended outpatient services, and 15.2% (39/257) inpatient services, representing missed opportunities for earlier HIV diagnosis. Of those attending GP services the issue of HIV and/or HIV testing was raised for 17.6% (31/176) and 37.1% (78/210) had a previous negative HIV test, 32.5% of these within the UK. Medical attention was sought for wide ranging reasons, often not obviously connected to underlying HIV status. Despite the population predominantly coming from countries of high HIV prevalence personal appreciation of risk was comparatively low and knowledge of benefits of testing lacking. Conclusion: Africans are accessing health services but clinicians are failing to use these opportunities effectively for preventive and diagnostic purposes with regards to HIV infection. Comparatively low appreciation of personal risk and lack of perceived ill health within this community means clinicians need to be more proactive in addressing HIV.

Texting decreases the time to treatment for genital Chlamydia trachomatis infection.

Objective: To assess the effectiveness of a text message result service within an inner London sexual health clinic. Method: Demographic data, diagnoses, and time to diagnosis and treatment were collected over a 6 month period for patients receiving text messages and a matched standard recall group. Data on messages sent, staff time, and cost in relation to result provision were collected. Results: Over a 6 month period 952 text messages were sent. In the final month of analysis, 33.9% of all clinic results were provided by text, resulting in a saving of 46 hours of staff time per month. 49 messages requested that the patient return for treatment, 28 of these patients had untreated genital Chlamydia trachomatis (CT) infection. The mean number of days (SD) to diagnosis was significantly shorter in the text message group (TG) v the standard recall group (SG) (7.9 (3.6) v 11.2 (4.7), p <0.001). The median time to treatment was 8.5 days (range 4–27 days) for the TG group v 15.0 (range 7–35) for SG, p  =  0.005. Conclusion: Patients with genital CT infection are diagnosed and receive treatment sooner since the introduction of a text message result service. The introduction of this service has resulted in a significant saving in staff time.

Feasibility and Effectiveness of Indicator Condition-Guided Testing for HIV: Results from HIDES I (HIV Indicator Diseases across Europe Study)

Improved methods for targeting HIV testing among patients most likely to be infected are required; HIDES I aimed to define the methodology of a European wide study of HIV prevalence in individuals presenting with one of eight indicator conditions/diseases (ID); sexually transmitted infection, lymphoma, cervical or anal cancer/dysplasia, herpes zoster, hepatitis B/C, mononucleosis-like illness, unexplained leukocytopenia/thrombocytopenia and seborrheic dermatitis/exanthema, and to identify those with an HIV prevalence of >0.1%, a level determined to be cost effective. A staff questionnaire was performed. From October 2009– February 2011, individuals, not known to be HIV positive, presenting with one of the ID were offered an HIV test; additional information was collected on previous HIV testing behaviour and recent medical history. A total of 3588 individuals from 16 centres were included. Sixty-six tested positive for HIV, giving an HIV prevalence of 1.8% [95% CI: 1.42–2.34]; all eight ID exceeded 0.1% prevalence. Of those testing HIV positive, 83% were male, 58% identified as MSM and 9% were injecting drug users. Twenty percent reported previously having potentially HIV-related symptoms and 52% had previously tested HIV negative (median time since last test: 1.58 years); which together with the median CD4 count at diagnosis (400 cell/uL) adds weight to this strategy being effective in diagnosing HIV at an earlier stage. A positive test was more likely for non-white individuals, MSM, injecting drug users and those testing in non-Northern regions. HIDES I describes an effective strategy to detect undiagnosed HIV infection. All eight ID fulfilled the >0.1% criterion for cost effectiveness. All individuals presenting to any health care setting with one of these ID should be strongly recommended an HIV test. A strategy is being developed in collaboration with ECDC and WHO Europe to guide the implementation of this novel public health initiative across Europe.

Coronary artery disease occurring with protease inhibitor therapy

Protease inhibitors are increasingly recognized as causing significant metabolic abnormalities including hypertriglyceridaemia, hypercholesterolaemia, insulin resistance, diabetes, and lipodystrophy. Considerable concern has been generated by recent reports of premature coronary artery disease occurring in HIV-1 infected patients on protease inhibitor containing regimens.

Recurrent Helicobacter cinaedi cellulitis and bacteraemia in a patient with HIV infection

A 44-year-old HIV antibody positive homosexual man with a CD4 count of 264/mm3 and no AIDS de® ning diagnosis presented with a 2 week history of fevers and general lethargy, and a 5 day history of a painful, hot, red right ankle and calf. He experienced some mild abdominal discomfort but no other gastrointestinal symptoms. A diagnosis of bacterial cellulitis was made and he was treated with intravenous ̄ ucloxacillin 500 mg qds. Blood cultures taken at the time of presentation grew a Gram-negative rod from the aerobic bottle which failed to grow on subculture. His cellulitis settled and he was discharged. He returned 2 days later with a recurrence of his symptoms and was treated with intravenous benzylpenicillin 600 mg qds and ̄ ucloxacillin 500 mg qds with good clinical response. He was once more discharged on oral therapy, amoxycillin 500 mg tds and ̄ ucloxacillin 500 mg qds. Five days later he re-presented whilst on this therapy with a further recurrence. He was treated with intravenous cefuroxime 750 mg tds and ̄ ucloxacillin 500 mg qds with initial response, but again he relapsed 2 days after discharge. Blood cultures on this occasion grew H. cinaedi in both aerobic and anaerobic bottles. His therapy was changed to oral azithromycin 500 mg bd and intravenous ̄ ucloxacillin 1 g qds. He re-presented on a fourth occasion, 7 days later whilst still compliant with his therapy, systemically unwell with rigors and sweats together with his cellulitis. His therapy was changed to intravenous cipro ̄ oxacin 200 mg bd and cefuroxime 750 mg bd for 7 days and was continued orally for 4 weeks (cefuroxime 500 mg bd and cipro ̄ oxacin 750 mg bd). The symptoms and signs of his recurrent cellulitis were similar for each episode; however, apart from his initial presentation, he did not experience further abdominal symptoms. Three months later he remains well with no recurrences and on no antibiotic therapy. In culturing the organism, our laboratory employed the Bac T-Alert blood culture system, which identi® es positive samples by the amount of dissolved carbon dioxide. The specimens were then subcultured onto blood and chocolate agar under microaerophillic conditions at 37°C. The resulting curved, Gram-negative, oxidase positive bacillus was sent to a reference laboratory for further identi® cation. Antibiotic sensitivity was not assessed in our laboratory.

Auditing HIV Testing Rates across Europe: Results from the HIDES 2 Study.

European guidelines recommend the routine offer of an HIV test in patients with a number of AIDS-defining and non-AIDS conditions believed to share an association with HIV; so called indicator conditions (IC). Adherence with this guidance across Europe is not known. We audited HIV testing behaviour in patients accessing care for a number of ICs. Participating centres reviewed the case notes of either 100 patients or of all consecutive patients in one year, presenting for each of the following ICs: tuberculosis, non-Hodgkins lymphoma, anal and cervical cancer, hepatitis B and C and oesophageal candidiasis. Observed HIV-positive rates were applied by region and IC to estimate the number of HIV diagnoses potentially missed. Outcomes examined were: HIV test rate (% of total patients with IC), HIV test accepted (% of tests performed/% of tests offered) and new HIV diagnosis rate (%). There were 49 audits from 23 centres, representing 7037 patients. The median test rate across audits was 72% (IQR 32–97), lowest in Northern Europe (median 44%, IQR 22–68%) and highest in Eastern Europe (median 99%, IQR 86–100). Uptake of testing was close to 100% in all regions. The median HIV+ rate was 0.9% (IQR 0.0–4.9), with 29 audits (60.4%) having an HIV+ rate >0.1%. After adjustment, there were no differences between regions of Europe in the proportion with >0.1% testing positive (global p = 0.14). A total of 113 patients tested HIV+. Applying the observed rates of testing HIV+ within individual ICs and regions to all persons presenting with an IC suggested that 105 diagnoses were potentially missed. Testing rates in well-established HIV ICs remained low across Europe, despite high prevalence rates, reflecting missed opportunities for earlier HIV diagnosis and care. Significant numbers may have had an opportunity for HIV diagnosis if all persons included in IC audits had been tested.

Risk factors for rectal lymphogranuloma venereum in gay men: results of a multicentre case-control study in the UK

Objective To identify risk factors for rectal lymphogranuloma venereum (rLGV) in men who have sex with men (MSM). Design A case-control study at 6 UK hospitals compared MSM with rLGV (cases) with rLGV-negative controls: MSM without potential rLGV symptoms (CGa) and separately, MSM with such symptoms (CGs). Methods Between 2008 and 2010, there were 90 rLGV cases, 74 CGa and 69 CGs recruited. Lifestyles and sexual behaviours in the previous 3 months were reported using internet-based computer-assisted self-interviews. Logistic regression was used to investigate factors associated with rLGV. Results Cases were significantly more likely to be HIV-positive (89%) compared with CGa (46%) and CGs (64%). Independent behavioural risks for rLGV were: unprotected receptive anal intercourse (adjusted OR (AOR)10.7, 95% CI 3.5 to 32.8), fisting another (AOR=6.7, CI 1.8 to 25.3), sex under the influence of gamma-hydroxybutyrate (AOR=3.1, CI 1.3 to 7.4) and anonymous sexual contacts (AOR=2.7, CI 1.2 to 6.3), compared with CGa; unprotected insertive anal intercourse (AOR=4.7, CI 2.0 to 10.9) and rectal douching (AOR=2.9 CI 1.3 to 6.6), compared with CGs. An incubation period from exposure to symptoms of 30 days was indicated. Conclusions Unprotected receptive anal intercourse is a key risk factor for rectal LGV with the likelihood that rectal-to-rectal transmission is facilitated where insertive anal sex also occurs. The association between HIV and rLGV appears linked to HIV-positive men seeking unprotected sex with others with the same HIV status, sexual and drug interests. Such men should be targeted for frequent STI screening and interventions to minimise associated risks.

Exploring staff attitudes to routine HIV testing in non-traditional settings: a qualitative study in four healthcare facilities

Objectives To explore staff attitudes towards and experiences of the implementation of routine HIV testing in four healthcare settings in areas of high diagnosed HIV prevalence. Methods As part of the HINTS (HIV Testing in Non-traditional Settings) Study, routine offer of an HIV test to all 16–65-year-old patients was conducted for 3 months in an emergency department, an acute admissions unit, a dermatology outpatients department and a primary care practice. The authors conducted focus groups with staff at these sites before and after the implementation of testing. Transcriptions of focus groups were subject to thematic analysis. Results Four major themes were identified: the stigma of HIV and exceptionalisation of HIV testing as a condition; the use of routine testing compared with a targeted strategy as a means of improving the acceptability of testing; the need for an additional skill set to conduct HIV testing; and the existence within these particular settings of operational barriers to the implementation of HIV testing. Specifically, the time taken to conduct testing and management of results were seen by staff as barriers. There was a clear change in staff perception before and after implementation of testing as staff became aware of the high level of patient acceptability. Conclusions The routine offer of HIV testing in general medical services is feasible, but implementation requires training and support for staff, which may be best provided by the local sexual health service.

Time to use text reminders in genitourinary medicine clinics.

Faced with a national 48-hour waiting time target and high non-attendance rates for booked appointments, our sexual health service sought patient preferences for appointment reminders. Questionnaires were distributed to 350 consecutive genitourinary medicine clinic attendees. Eighty-eight percent of respondents approved of appointment reminders, with text messaging being the preferred option. Automated voicemail reminders to mobile phones were acceptable to 84%. Patients would generally choose a voicemail reminder to their mobile phone as opposed to home or work phone, and this preference was more pronounced in younger patients (P = 0.03). The majority of patients considered reminders two or three days in advance sufficient notice, with 98% owning a mobile phone. Text or voicemail reminders may significantly reduce non-attendance rates and their associated costs, improve accessibility and reduce waiting times.