HIV pre-exposure prophylaxis and its implementation in the PrEP Impact Trial in England: a pragmatic health technology assessment.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is highly effective in preventing HIV acquisition. To enable routine commissioning of PrEP in England, we aimed to establish population need, duration of need, PrEP uptake, and duration of use in attendees of sexual health services (SHS) in England. METHODS: The Impact Trial was a prospective, open-label, single-arm, multicentre trial conducted at 157 SHS across England between Oct 13, 2017, and July 12, 2020. Clinicians assessed HIV-negative attendees for their risk of HIV acquisition to identify those who were eligible to participate and receive either daily or event-based oral PrEP (tenofovir disoproxil maleate with emtricitabine), as appropriate. Eligible participants were aged 16 years or older, considered HIV-negative on the day of enrolment, and willing to adhere to the trial procedures. Non-trial attendees are mutually exclusive of trial participants and included SHS attendees who were not recruited to the Impact Trial at any point. They include HIV-negative individuals aged 16 years or older who attended a participating SHS at least once after recruitment at that SHS had begun and before Feb 29, 2020. The main outcomes assessed were PrEP need, uptake, and use, and HIV and sexually transmitted infection (STI) incidence. Data are presented up to Feb 29, 2020, before the introduction of COVID-19 control measures. The study is registered with ClinicalTrials.gov, NCT03253757. FINDINGS: In this analysis, we include 21 356 of 24 268 participants enrolled before Feb 29, 2020. 20 403 participants (95·5%) were men who have sex with men (MSM). Uptake of PrEP among SHS attendees clinically assessed and coded as eligible was 21 292 (57·1%) of 37 289. 18 400 trial participants had at least one post-enrolment visit and a median of 361 days of follow-up (IQR 143-638); 14 039 (75·9%) of these had enough PrEP prescribed to provide protection for 75% of their follow-up time. Among MSM, HIV incidence was 0·13 (95% CI 0·08-0·19) per 100 person-years in trial participants (27 seroconversions) and 0·95 (95% CI 0·88-1·03) per 100 person-years in non-trial attendees (587 seroconversions; proportionate reduction of 86·8%, 95% CI 80·2-91·6). 18 607 bacterial STIs were recorded (incidence 68·1 per 100 person-years in trial participants who were MSM). 4343 (24·4%) MSM participants were diagnosed with two or more STIs, accounting for 14 800 (79·5%) of all 18 607 diagnoses. INTERPRETATION: PrEP need was higher than initially estimated by an expert stakeholder group. The high proportion of follow-up time protected by PrEP suggests that the need for protection persisted throughout trial participation for most participants. HIV incidence among MSM trial participants was low. The large unmet need for PrEP suggests that greater provision is required to maximise the potential of a national programme. The high incidence of bacterial STIs among participants, concentrated within a subgroup of PrEP users, presents an opportunity for tailored STI control measures. FUNDING: NHS England.

Infection risk in sexual contacts of syphilis: A systematic review and meta-analysis.

OBJECTIVES: Current guidelines recommend offering epidemiological treatment to asymptomatic contacts of early syphilis. This is on the expectation that up to 60% of sexual contacts of patients with syphilis will be infected. However, the evidence for this figure is sparse. We performed a systematic review and meta-analysis, to estimate the proportion of sexual contacts of syphilis that are infected with syphilis. METHODS: Two electronic databases (Medline and Embase) were reviewed in March 2021, to identify studies that reported rates of infection in sexual contacts of syphilis. RESULTS: Of 3,051 Embase and 1,828 Medline articles identified, 32 were included in the meta-analysis. In total 36,397 contacts were tested. The proportion of contacts infected varied across the studies, ranging from 10.7% to 97.5%, resulting in considerable heterogeneity (I2=98.5%). Pooling the studies gave an estimated proportion of infected contacts of 32.6% (95% confidence interval: 26.2% - 39.7%). CONCLUSIONS: The risk of infection in sexual contacts of syphilis reported in the literature is highly variable, with a pooled estimate of 32.6%. This will help guide decisions regarding epidemiological treatment of sexual contacts of patients with syphilis. These decisions are increasingly important in this era of antibiotic resistance, with increasing emphasis being placed on antimicrobial stewardship.

Correlation between Cepheid GeneXpert and Abbott M2000 assays for HIV viral load measurements.

Measurement of HIV viral load (VL) is the best indicator of success of antiretroviral therapy. We investigated the correlation between results by the Cepheid GeneXpert and a standard of care VL assay (Abbott M2000). This was a prospective study of people living with HIV who attended the department for routine VL measurement with the Abbott M2000. Consenting patients agreed to provide one extra blood sample for VL measurement with the Cepheid GeneXpert assay. One hundred patients consented to participate in the study. There were 18 patients with VL ≥ 40 copies/mL and 75 patients with VL < 40 copies on both assays. The two assays had 93% agreement, with a kappa of 0.79 (p < 0.001). Treating VL as a continuous variable found measurements to be significantly higher on the Cepheid GeneXpert assay than the Abbott (p = 0.002). Analysis of samples with VL ≥ 40 copies/mL on either assay (n = 25) found the mean difference between the two assays to be 0.31 log10 copies/mL (95% limits of agreement: -0.63, 1.25). Whilst the measurements on the two assays are relatively highly correlated, there is a clear bias, with the Cepheid GeneXpert tending to give higher VL values.

COVID-19: to be or not to be; that is the diagnostic question.

Since the first cases in December 2019, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread across the globe, resulting in the COVID-19 pandemic. Early clinical experiences have demonstrated the wide spectrum of SARS-CoV-2 presentations, including various reports of atypical presentations of COVID-19 and possible mimic conditions.This article summarises the current evidence surrounding atypical presentations of COVID-19 including neurological, cardiovascular, gastrointestinal, otorhinolaryngology and geriatric features. A case from our hospital of pneumocystis pneumonia initially suspected to be COVID-19 forms the basis for a discussion surrounding mimic conditions of COVID-19. The dual-process model of clinical reasoning is used to analyse the thought processes used to make a diagnosis of COVID-19, including consideration of the variety of differential diagnoses.While SARS-CoV-2 is likely to remain on the differential diagnostic list for a plethora of presentations for the foreseeable future, clinicians should be cautious of ignoring other potential diagnoses due to availability bias. An awareness of atypical presentations allows SARS-CoV-2 to be a differential so that it can be appropriately investigated. A knowledge of infectious mimics prevents COVID-19 from overshadowing other diagnoses, hence preventing delayed diagnosis or even misdiagnosis and consequent adverse outcomes for patients.

Observational study of factors associated with return of home sampling kits for sexually transmitted infections requested online in the UK.

OBJECTIVES: To investigate factors associated with the return of home sampling kits for sexually transmitted infections (STIs). SETTING: Online STI testing service offered to the residents of Birmingham and Solihull. PARTICIPANTS: All patients requesting STI home sampling kits via the Umbrella sexual health service website between 15 July 2016 and 14 December 2016. INTERVENTIONS: Associations between data collected at online registration and the rate of return of STI home sampling kits within 30 days of request was assessed. RESULTS: A total of 5310 kits were requested, of which 3099 (58.4%) were returned to the medical microbiology laboratory. On multivariable analysis, women and men who have sex with men were similarly likely to return their sampling kits (adjusted OR (ORadj) 1.06, 95% CI 0.86 to 1.30), while heterosexual men were significantly less likely to return their sampling kits (ORadj 0.63, 95% CI 0.55 to 0.72, p<0.001 vs women). Patients reporting symptoms were also less likely to return kits (ORadj 0.77, 95% CI 0.67 to 0.89, p=0.001 vs asymptomatic patients). Kits that were delivered to the patient's home, rather than to a clinic or pharmacy (p<0.001), and those requested from less economically deprived neighbourhoods (p=0.029) were significantly more likely to be returned. CONCLUSION: STI self-sampling testing kits delivered to patients' homes are most likely to be returned. Heterosexual men and those from more economically deprived areas are the less likely groups to return the kits. Further research on the barriers to return self-sampling STI testing kits of these subgroups of patients is warranted. TRIAL REGISTRATION NUMBER: Registered with R&D department at University Hospitals Birmingham; CARMS-13551.

Lenalidomide as a treatment for relapsed AL amyloidosis in an HIV-positive patient.

We present a case of an HIV-positive man with systemic immunoglobulin light chain (AL) amyloid with cardiac involvement. At relapse, he was treated with lenalidomide and dexamethasone having previously developed autonomic neuropathy with bortezomib-based chemotherapy. The patient achieved a serological complete response with symptomatic improvement. After 11 cycles, lenalidomide was discontinued due to extensive ischaemia of the gastrointestinal tract. The patient remains symptomatically stable with normal levels of serum-free light chains 11 months after the treatment was discontinued. Lenalidomide can be a good treatment option for AL amyloidosis in HIV-infected patients on antiretroviral therapy.

Emerging sexually transmitted viral infections: 1. Review of Ebola virus disease.

This is the first in a series of articles reviewing four viral infections, Ebola virus, Zika virus, human T-cell lymphotropic virus, type 1 and hepatitis C virus, with an emphasis on recent advances in our understanding of their sexual transmission. With current day speed and ease of travel it is important for staff in sexual healthcare services to know and understand these infections when patients present to them and also to be able to advise those travelling to endemic regions. Following the recent resurgence in West Africa, this first article looks at Ebola virus disease (EVD). EVD has a high mortality rate and, of note, has been detected in the semen of those who have cleared the virus from their blood and have clinically recovered from the disease. As the result of emerging data, the WHO now recommends safe sex practices for all male survivors of EVD for 12 months after the onset of the disease or after having had two consecutive negative tests of semen specimens for the virus. This review provides an up-to-date summary of what is currently known about EVD and its implications for sexual health practice.

An observational study on the incidence of tuberculosis among a cohort of HIV infected adults in a setting with low prevalence of tuberculosis.

BACKGROUND: Tuberculosis (TB) remains a main cause of morbidity and mortality among individuals infected with HIV. We investigated the incidence of TB among a cohort of HIV infected patients attending a setting with low TB burden where screening for latent TB infection is not routinely carried out. METHODS: an observational cohort study on HIV-infected adults attending the HIV clinic at Queen Elizabeth Hospital Birmingham, UK between 1 January 2011 and 30 September 2015. Patients with culture-proven TB after HIV diagnosis, or those treated for clinical diagnosis of the infection, were classified as having "active TB". RESULTS: 1824 patients were included in the study (5347 patient years of follow up), of whom 21 patients developed TB (16 microbiology confirmed). Of the 666 new HIV diagnoses, six patients developed TB within one month, giving a TB prevalence at the time of HIV diagnosis of 0.9%. The total TB incidence for the remaining 1818 patients was 2.81 cases per 1000 patient years (95% CI: 1.63-4.53). TB incidence was significantly more common among patients with CD4 ≤ 200 cells/mm3 compared to those with CD4 > 500 cells/mm3 (28.2 vs. 1.22 per 1000 patient years, p < 0.001), and in patients with VL ≥ 40 copies/mL compared to <40 copies/mL (8.30 vs. 1.42, p < 0.001). CONCLUSION: In settings with low TB prevalence, early start of combined antiretroviral therapy and intensified TB case finding protocols may significantly reduce the incidence of TB.

Brief Report: Immunization of HIV-Infected Adults in the UK With Haemophilus influenzae b/Meningococcal C Glycoconjugate and Pneumococcal Polysaccharide Vaccines.

U.K. guidelines for vaccinating HIV-infected adults against bacteria are based on limited data. We compared antibody responses between 211 HIV-infected and 73 HIV-uninfected adults vaccinated with pneumococcal polysaccharide vaccine (PPV) and Haemophilus influenzae b/meningococcal C polysaccharide-tetanus toxoid glycoconjugate vaccine (Hib/MenC-TT). IgG responses to Hib/MenC-TT were not significantly different. PPV induced median IgGs >1.3 µg/mL for 10/12 serotypes among HIV-uninfected participants and 5/12 in HIV-infected participants. HIV-uninfected adults had higher post-vaccination IgGs than HIV-infected adults for 4/12 serotypes (P < 0.001). Responses did not associate with CD4 count or viral suppression. In a U.K. HIV-infected population, Hib/MenC-TT induced similar responses to HIV-uninfected adults, whereas PPV induced poor responses.

The Significance of Isolated Reactive Treponemal Enzyme Immunoassay in the Diagnosis of Early Syphilis.

BACKGROUND: The Treponemal test algorithm for syphilis screening is widely used. A diagnostic challenge between identifying early syphilis versus a false positive signal occurs in cases where the treponemal enzyme immunoassay (EIA) is reactive and confirmatory T. pallidum particle agglutination assay is negative. We investigated the diagnostic outcome of isolated reactive EIA in patients attending a sexual health clinic. METHODS: Results of syphilis serology tests carried out at Birmingham Whittall Street Clinic between August 10, 2010, and November 31, 2014, were reviewed. Cases with isolated EIA were routinely invited for repeat syphilis serology. Outcomes of patients with isolated EIA were reviewed and the proportion with confirmed positive syphilis serology on their repeat test identified. The number of isolated EIA cases needed to retest to identify 1 case of early syphilis was calculated. RESULTS: A total of 121,724 syphilis screening tests were performed. Among the 1561 individual patients with reactive EIA sera, 316 (20% of total reactive tests) had isolated reactive EIA. Repeat syphilis serology results of 163 patients were reviewed; 106 patients remained with isolated reactive EIA, 50 had negative EIA test and 7 (4.3%) had confirmed reactive EIA. Of the 7 patients, 2 had evidence of early syphilis infection. The number of isolated EIA needed to retest to identify 1 case of early syphilis was 81.5 (95% confidence interval, 22.9-671.4). CONCLUSIONS: Routine recall of patients with isolated EIA sera is not warranted. Risk of acquisition or presence of early syphilis should be assessed independently and irrespective of a negative syphilis screening test or isolated EIA.

Clinical challenges of thyroid eye disease in HIV-positive patients on highly active antiretroviral therapy.

BACKGROUND: Graves' disease (GD) as an immune reconstitution inflammatory syndrome during highly active antiretroviral therapy (HAART) for HIV has previously been reported. However, clinical challenges associated with HIV in the context of thyroid eye disease (TED) are not as well-characterized. OBJECTIVE: To determine the frequency of coexisting HIV and TED, describe TED presentation and course in the context of HIV, and evaluate management difficulties as well as potential solutions. METHODS: Cross-sectional study of all patients with coexisting GD and HIV at University Hospitals Birmingham (2003-2014). Retrospective case note review to identify TED with particular reference to HAART regimen, CD4+ T-cell count, HIV viral load, and TED activity and severity. RESULTS: Of 783 subjects with GD and 1186 with HIV, 11 were identified with both GD and HIV. Of these, three had clinical features of TED; each was of Afro-Caribbean origin, was in their fourth decade, and initially presented with undetectable CD4 T cells and high HIV viral loads. All went on to develop GD >3 years after commencing HAART, with normal CD4 count and undetectable viral load at the time of GD diagnosis. The full spectrum of TED was represented, with two subjects requiring orbital decompression surgery. DISCUSSION: TED in the context of HIV is uncommon. Many challenges exist in such patients, particularly HAART drug interactions with antithyroid and immunosuppressant medications. To better understand TED in HIV and to counsel patients with this copathology most effectively, future multicenter surveillance is required.

Lowering the limit: reducing the CD4 T-cell threshold for ophthalmic screening in patients with HIV in an ethnically diverse UK population.

BACKGROUND: Before highly active antiretroviral therapy, cytomegalovirus (CMV) retinitis was a major threat to vision in individuals with HIV. We investigate whether ophthalmic screening of asymptomatic HIV patients still has value in the highly active antiretroviral therapy era and consider CD4 thresholds in line with the world literature and UK experience. METHODS: A retrospective chart review was conducted of all patients seen by the HIV Ophthalmic Service of a UK university hospital both before (2007-2008) and after (2011-2012) introduction of a threshold of CD4 lower than 100 cells/mm(3). Data collected included CMV and HIV RNA load, CD4 cell counts and CD4 percentage, CMV-immunoglobulin G status, ocular symptoms, and evidence of HIV-related ocular disease. RESULTS: In total, 54 patients were referred to the HIV ophthalmic service. Three patients failed to attend, resulting in complete data for 51 patients (n=24 for 2007-2008; n=27 for 2011-2012). Seven patients had ophthalmic manifestations of their HIV; these cases had lower CD4 counts than those with normal examinations (median [interquartile range], 9 [7-80] versus 175 [44-394]; P=0.0039; Mann-Whitney test). Six cases had HIV retinopathy without sight loss; one case had sight-threatening CMV retinitis associated with a CD4 count of 6 cells/mm(3). CONCLUSION: Before 2008, our practice was to screen all asymptomatic patients with CD4 counts lower than 200 cells/mm(3). Screening asymptomatic patients with CD4 counts below 100 cells/mm(3) was not associated with any missed or late-presenting cases of CMV retinitis in our HIV population.

Intracerebral and spinal cord syphilitic gummata in an HIV-negative man: a case report.

We present a case of an HIV-negative individual who presented with worsening central and peripheral neurological symptoms and signs. Clinical, serological, histopathological, and radiological features were in keeping with concurrent cerebral and spinal cord syphilitic gummata, a tertiary manifestation of syphilis. Clinical improvement occurred after treatment of neurosyphilis.

Assessing the predictive value of HIV indicator conditions in general practice: a case-control study using the THIN database.

BACKGROUND: UK HIV guidelines identify 37 clinical indicator conditions for adult HIV infection that should prompt an HIV test. However, few data currently exist to show their predictive value in identifying undiagnosed HIV. AIM: To identify symptoms and clinical diagnoses associated with HIV infection and assess their relative importance in identifying HIV cases, using data from The Health Improvement Network (THIN) general practice database. DESIGN AND SETTING: A case-control study in primary care. METHOD: Cases (HIV-positive patients) were matched to controls (not known to have HIV). Data from 939 cases and 2576 controls were included (n = 3515). Statistical analysis assessed the incidence of the 37 clinical conditions in cases and controls, and their predictive value in indicating HIV infection, and derived odds ratios (ORs) for each indicator condition. RESULTS: Twelve indicator conditions were significantly associated with HIV infection; 74.2% of HIV cases (n = 697) presented with none of the HIV indicator conditions prior to diagnosis. The conditions most strongly associated with HIV infection were bacterial pneumonia (OR = 47.7; 95% confidence interval [CI] = 5.6 to 404.2) and oral candidiasis (OR = 29.4; 95% CI = 6.9 to 125.5). The signs and symptoms most associated with HIV were weight loss (OR = 13.4; 95% CI = 5.0 to 36.0), pyrexia of unknown origin (OR = 7.2; 95% CI = 2.8 to 18.7), and diarrhoea (one or two consultations). CONCLUSION: This is the first study to quantify the predictive value of clinical diagnoses related to HIV infection in primary care. In identifying the conditions most strongly associated with HIV, this study could aid GPs in offering targeted HIV testing to those at highest risk.

The significance of low-level plasma HIV viral load on COBAS TaqMan HIV-1 assays for patients with undetectable plasma viral load on COBAS Amplicor monitor version 1.5.

BACKGROUND: COBAS TaqMan assay is a new HIV assay for measuring plasma viral load (VL). A significant number of patients with undetectable plasma VL on Amplicor assay were reported to have detectable VL with TaqMan in the study centre. PURPOSE: The aim of the present study was to investigate the significance of detectable VL counts with TaqMan assay amongst patients who have had undetectable plasma VL with COBAS Amplicor assay. METHOD: Observational study on patients who have had undetectable (40 copies/mL) in 113 (14%) patients on 126 episodes using TaqMan assay. VL was less than 500 copies/mL in 90% of those episodes. All episodes ended with VL <40 copies/mL after a median of 117 (94-143) days without change in HAART regimes. The duration of those episodes was longer than 150 days in 75% of cases. No new mutation was detected amongst specimens with detectable VL. CONCLUSION: Short-term detectable VL may be common with using TaqMan assay. This phenomenon did not result in new mutations or failure of HAART in study patients in the short term.

Plasma lopinavir trough levels in a group of pregnant women on lopinavir, ritonavir, zidovudine, and lamivudine.

During pregnancy, the absorption of antiretroviral drugs may not be optimal, therefore a prospective study was conducted to investigate the plasma levels of lopinavir in 26 HIV-infected pregnant women. Plasma lopinavir levels were examined in specimens obtained 12 h post-dose. The lopinavir level was found to be subtherapeutic in four women (15.4%); one patient who discontinued treatment and three (13.6%) with therapeutic levels of lopinavir had detectable HIV viral loads at the time of therapeutic drug monitoring.

A review on infection with human immunodeficiency virus.

Management of infection with human immunodeficiency virus (HIV) improved dramatically during the 1990s. The advent of high-performance quantitative HIV assays and highly active antiretroviral therapy were the two most important developments in HIV medicine. As a result, HIV mortality and morbidity have reduced significantly, although a proportion of HIV-infected patients are still diagnosed late. Management of HIV during pregnancy has also improved so that vertical transmission is now limited to less than 2% of all cases. Knowledge of the different stages of HIV infection enables optimal timing of start of antiretroviral therapy. Routine offering of HIV testing might also reduce the number of patients diagnosed with immunodeficiency. Better knowledge of the life cycle of HIV has made it possible to design new classes of antiretroviral drugs. The new drugs, however, pose new challenges as they might have long-term side effects. In addition, their interactions with other antiretroviral drugs might not be favourable.

A review on infection with Chlamydia trachomatis.

Infection with Chlamydia trachomatis accounts for the most common bacterial sexually transmitted infection in the UK. Men between 20 and 24 years and women between 16 and 19 years have the highest prevalence of chlamydial infection. Because the majority of women with chlamydial infection are asymptomatic, a proportion remains untreated and eventually develops pelvic inflammatory disease (PID). PID can result in ectopic pregnancy, infertility and chronic pelvic pain. Screening for chlamydial infection might reduce the incidence of complications of PID. The advent of nucleic acid amplification tests and single-dose therapy for chlamydial infection has made home testing and easy treatment possible.