Increased integrated testing for HIV, hepatitis C and sexually transmitted infections in health care facilities: results from the INTEGRATE Joint Action pilots in Lithuania, Romania and Spain.

BACKGROUND: Indicator condition guided HIV testing is a proven effective strategy for increasing HIV diagnosis in health care facilities. As part of the INTEGRATE Joint Action, we conducted four pilot studies, aiming to increase integrated testing for HIV/HCV/HBV and sexually transmitted infections, by introducing and expanding existing indicator condition guided HIV testing methods. METHODS: Pilot interventions included combined HIV/HCV testing in a dermatovenerology clinic and a clinic for addictive disorders in Lithuania; Increasing HIV testing rates in a tuberculosis clinic in Romania by introducing a patient information leaflet and offering testing for HIV/HCV/sexually transmitted infections to chemsex-users in Barcelona. Methods for implementing indicator condition guided HIV testing were adapted to include integrated testing. Testing data were collected retrospectively and prospectively. Staff were trained in all settings, Plan-do-study-act cycles frequently performed and barriers to implementation reported. RESULTS: In established indicator conditions, HIV absolute testing rates increased from 10.6 to 71% in the dermatovenerology clinic over an 18 months period. HIV testing rates improved from 67.4% at baseline to 94% in the tuberculosis clinic. HCV testing was added to all individuals in the dermatovenerology clinic, eight patients of 1701 tested positive (0.47%). HBV testing was added to individuals with sexually transmitted infections with a 0.44% positivity rate (2/452 tested positive). The Indicator condition guided HIV testing strategy was expanded to offer HIV/HCV testing to people with alcohol dependency and chemsex-users. 52% of chemsex-users tested positive for ≥ 1 sexually transmitted infection and among people with alcohol dependency 0.3 and 3.7% tested positive for HIV and HCV respectively. CONCLUSIONS: The four pilot studies successfully increased integrated testing in health care settings, by introducing testing for HBV/HCV and sexually transmitted infections along with HIV testing for established indicator conditions and expanding the strategy to include new indicators; alcohol dependency and chemsex. HCV testing of individuals with alcohol abuse showed high positivity rates and calls for further implementation studies. Methods used for implementing indicator condition guided HIV Testing have proven transferable to implementation of integrated testing.

Outcomes with durvalumab by tumour PD-L1 expression in unresectable, stage III non-small-cell lung cancer in the PACIFIC trial.

BACKGROUND: In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression. PATIENTS AND METHODS: Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians). RESULTS: In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups. CONCLUSIONS: PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.

HIV testing strategies outside of health care settings in the European Union (EU)/European Economic Area (EEA): a systematic review to inform European Centre for Disease Prevention and Control guidance.

OBJECTIVES: In recent years, new technologies and new approaches to scale up HIV testing have emerged. The objective of this paper was to synthesize the body of recent evidence on strategies aimed at increasing the uptake and coverage of HIV testing outside of health care settings in the European Union (EU)/European Economic Area (EEA). METHODS: Systematic searches to identify studies describing effective HIV testing interventions and barriers to testing were run in five databases (2010-2017) with no language restrictions; the grey literature was searched for similar unpublished studies (2014-2017). Study selection, data extraction and critical appraisal were performed by two independent reviewers following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Eighty studies on HIV testing in non-health care settings were identified, the majority set in Northern Europe. Testing was implemented in 65 studies, with men who have sex with men the risk group most often targeted. Testing coverage and positivity/reactivity rates varied widely by setting and population group. However, testing in community and outreach settings was effective at reaching people who had never previously been tested and acceptability of HIV testing, particularly rapid testing, outside of health care settings was found to be high. Other interventions aimed to increase HIV testing identified were: campaigns (n = 8), communication technologies (n = 2), education (n = 3) and community networking (n = 1). CONCLUSIONS: This review has identified several strategies with potential to achieve high HIV testing coverage outside of health care settings. However, the geographical spread of studies was limited, and few intervention studies reported before and after data, making it difficult to evaluate the impact of interventions on test coverage.

The EuroSIDA study: 25 years of scientific achievements.

The EuroSIDA study was initiated in 1994 and follows adult people living with HIV (PLHIV) in 100 collaborating clinics across 35 countries covering all European regions, Israel and Argentina. The study aims to study the long-term virological, immunological and clinical outcomes of PLHIV and to monitor temporal changes and regional differences in outcomes across Europe. Annually collected data include basic demographic characteristics, information on AIDS- and non-AIDS-related clinical events, and details about antiretroviral therapy (ART), hepatitis C treatment and other medications, in addition to a range of laboratory values. The summer 2016 data set held data from a total of 23 071 individuals contributing 174 481 person-years of follow-up, while EuroSIDA's unique plasma repository held over 160 000 samples. Over the past 25 years, close to 300 articles have been published in peer-reviewed journals (h-index 52), covering a range of scientific focus areas, including monitoring of clinical and virological outcomes, ART uptake, efficacy and adverse events, the influence of hepatitis virus coinfection, variation in the quality of HIV care and management across settings and regions, and biomarker research. Recognizing that there remain unresolved issues in the clinical care and management of PLHIV in Europe, EuroSIDA was one of the cohorts to found The International Cohort Consortium of Infectious Disease (RESPOND) cohort consortium on infectious diseases in 2017. In celebration of the EuroSIDA study's 25th anniversary, this article aims to summarize key scientific findings and outline current and future scientific focus areas.

HIV testing strategies employed in health care settings in the European Union/European Economic Area (EU/EEA): evidence from a systematic review.

OBJECTIVES: Despite the availability of HIV testing guidelines to facilitate prompt diagnosis, late HIV diagnosis remains high across Europe. The study synthesizes recent evidence on HIV testing strategies adopted in health care settings in the European Union/European Economic Area (EU/EEA). METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed and systematic searches were run in five databases (2010-2017) to identify studies describing HIV testing interventions in health care settings in the EU/EEA. The grey literature was searched for unpublished studies (2014-2017). Two reviewers independently performed study selection, data extraction and critical appraisal. RESULTS: One hundred and thirty intervention and/or feasibility studies on HIV testing in health care settings were identified. Interventions included testing provision (n = 94), campaigns (n = 14) and education and training for staff and patients (n = 20). HIV test coverage achieved through testing provision varied: 2.9-94% in primary care compared to 3.9-66% in emergency departments. HIV test positivity was lower in emergency departments (0-1.3%) and antenatal services (0-0.05%) than in other hospital departments (e.g. inpatients: 0-5.3%). Indicator condition testing programmes increased HIV test coverage from 3.9-72% before to 12-85% after their implementation, with most studies reporting a 10-20% increase. There were 51 feasibility and/or acceptability studies that demonstrated that HIV testing interventions were generally acceptable to patients and providers in health care settings (e.g. general practitioner testing acceptable: 77-93%). CONCLUSIONS: This review has identified several strategies that could be adopted to achieve high HIV testing coverage across a variety of health care settings and populations in the EU/EEA. Very few studies compared the intervention under investigation to a baseline, but, where this was assessed, data suggested increases in testing.

The HepHIV 2017 Conference in Malta: joining forces for the earlier diagnosis of HIV and viral hepatitis.

OBJECTIVES: The objective of the article is to provide an overview of the results of the HepHIV 2017 Conference organized by the HIV in Europe initiative under the Maltese EU Presidency in January 2017. METHODS: A thourough review of all conference presentations (oral and poster presentations) was performed to retrieve the key outcomes of the conference. RESULTS: The key result from the conference was a call to action summarising key priorities in HIV and viral hepatitis testing and linkage to care. This included improving monitoring of viral hepatitis and HIV, mixing testing strategies and ensuring policy support. The important contribution and outcomes of EU funded projects OptTEST and EuroHIVEdat was highlighted. CONCLUSION: An integrated approach to earlier testing and linkage to care across diseases is needed in Europe and the HepHIV conferences create an important forum to reach this aim.

Comprehensive genomic profiling of salivary mucoepidermoid carcinomas reveals frequent BAP1, PIK3CA, and other actionable genomic alterations.

Background: We sought to identify genomic alterations (GAs) in salivary mucoepidermoid carcinomas. Patients and methods: DNA was extracted from 48 mucoepidermoid carcinomas. Comprehensive genomic profiling (CGP) including the calculation to tumor mutational burden (TMB) was performed on hybridization-captured adaptor ligation-based libraries of 315 cancer-related genes plus introns from 28 genes frequently rearranged for cancer and evaluated for all classes of GAs. Results: A total of 183 GAs were found in 80 unique genes. High-grade tumors had more GAs (mean 5 ± 3.8) compared with low (2.3 ± 1.4) or intermediate (2.6 ± 1.5) (P = 0.019). TP53 GAs were seen in all tumor grades (41.7%) but were most common in high-grade malignancies (56%) (P = 0.047). CDKN2A GAs were seen in 41.6% of tumors. PI3K/mTOR pathway activation, including PI3KCA mutations, were more common in high grade (52%) than in low- and intermediate-grade tumors (4.3%) (P = 0.007). BAP1 GAs were observed in 20.8% of tumors and BRCA1/2 GAs present in 10.5% of specimens. ERBB2 amplifications were seen in only 8.3% of tumors. The TMB for this patient group was relatively low with only 5 (10%) of cases having greater than 10 mutations/megabase of sequenced DNA. Conclusion: CGP of salivary mucoepidermoid carcinomas revealed diverse GAs that may lead to customized treatment options for patients with these rare tumors.

Measuring Diacylglycerol Kinase-θ Activity and Binding.

This section provides detailed protocols for the analysis of a mammalian diacylglycerol kinase, DGKθ, including an activity assay, a kinetic analysis, preparation of small unilamellar vesicles, and a vesicle pulldown assay. The goal of this section is to provide an overview of the unique challenges inherent in the study of an interfacial enzyme such as DGKθ and to outline methods useful for analysis. We include a short tutorial on selecting lipids for forming the interface since this is critical for a successful in vitro assay, and lipids are important regulators of this enzyme. The general principles can be applied to the study of other interfacial enzymes.

Evaluation of HIV testing recommendations in specialty guidelines for the management of HIV indicator conditions.

OBJECTIVES: European guidelines recommend HIV testing for individuals presenting with indicator conditions (ICs) including AIDS-defining conditions (ADCs). The extent to which non-HIV specialty guidelines recommend HIV testing in ICs and ADCs is unknown. Our aim was to pilot a methodology in the UK to review specialty guidelines and ascertain if HIV was discussed and testing recommended. METHODS: UK and European HIV testing guidelines were reviewed to produce a list of 25 ADCs and 49 ICs. UK guidelines for these conditions were identified from searches of the websites of specialist societies, the National Institute of Clinical Excellence (NICE) website, the NICE Clinical Knowledge Summaries (CKS) website, the Scottish Intercollegiate Guidance Network (SIGN) website and the British Medical Journal Best Practice database and from Google searches. RESULTS: We identified guidelines for 12 of 25 ADCs (48%) and 36 of 49 (73%) ICs. In total, 78 guidelines were reviewed (range 0-13 per condition). HIV testing was recommended in six of 17 ADC guidelines (35%) and 24 of 61 IC guidelines (39%). At least one guideline recommended HIV testing for six of 25 ADCs (24%) and 16 of 49 ICs (33%). There was no association between recommendation to test and publication year (P = 0.62). CONCLUSIONS: The majority of guidelines for ICs do not recommend testing. Clinicians managing ICs may be unaware of recommendations produced by HIV societies or the prevalence of undiagnosed HIV infection among these patients. We are piloting methods to engage with guideline development groups to ensure that patients diagnosed with ICs/ADCs are tested for HIV. We then plan to apply our methodology in other European settings as part of the Optimising Testing and Linkage to Care for HIV across Europe (OptTEST) project.

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.

The lag time in initiating clinical testing of new drugs in combination with radiation therapy, a significant barrier to progress?

BACKGROUND: The clinical development of new drugs with radiation appears to be limited. We hypothesised that phase I clinical trials with radiation therapy (RT) are initiated too late into a new drug's lifetime, impeding the ability to complete RT-drug development programmes before patent expiration. METHODS: We identified novel drug-radiation phase I combination trials performed between 1980 and 2012 within the PubMed and ClinicalTrials.gov databases. Data gathered for each drug included: date the initial phase I trial with/without RT was opened/published, date of the published positive phase III trials, and patent expiration dates. Lag time was defined as the interval between opening of the phase I trial without RT and the opening of the phase I with RT. Linear regression was used to model how the lag time has changed over time. RESULTS: The median lag time was 6 years. The initial phase I trial with RT was typically published 2 years after the first published positive phase III trial and 11 years before patent expiration. Using a best-fit linear model, lag time decreased from 10 years for phase I trials published in 1990 to 5 years in 2005 (slope significantly non-zero, P<0.001). CONCLUSIONS: Clinical drug development with RT commences late in the life cycle of anti-cancer agents. Taking into account the additional time required for late-phase clinical trials, the delay in initiating clinical testing of drug-RT combinations discourages drug companies from further pursuing RT-based development. Encouragingly, lag time appears to be decreasing. Further reduction in lag time may accelerate RT-based drug development, potentially improving patient outcomes.

Conclusions from the HIV in Europe Copenhagen 2012 Conference and ways forward: working together for optimal HIV testing and earlier care.

The objective of this article is to set the scene for this supplement by presenting and discussing the overall outcomes of the HIV in Europe Copenhagen 2012 Conference and how the HIV in Europe initiative intends to further address challenges and themes raised during the conference.

Comparison of two HIV testing strategies in primary care centres: indicator-condition-guided testing vs. testing of those with non-indicator conditions.

OBJECTIVES: The aim of the study was to compare prospectively indicator-condition (IC)-guided testing versus testing of those with non-indicator conditions (NICs) in four primary care centres (PCCs) in Barcelona, Spain. METHODS: From October 2009 to February 2011, patients aged from 18 to 65 years old who attended a PCC for a new herpes zoster infection, seborrhoeic eczema, mononucleosis syndrome or leucopenia/thrombopenia were included in the IC group, and one in every 10 randomly selected patients consulting for other reasons were included in the NIC group. A proportion of patients in each group were offered an HIV test; those who agreed to be tested were given a rapid finger-stick HIV test (€6 per test). Epidemiological and clinical data were collected and analysed. RESULTS: During the study period, 775 patients attended with one of the four selected ICs, while 66,043 patients presented with an NIC. HIV screening was offered to 89 patients with ICs (offer rate 11.5%), of whom 85 agreed to and completed testing (94.4 and 100% acceptance and completion rates, respectively). In the NIC group, an HIV test was offered to 344 persons (offer rate 5.2%), of whom 313 accepted (90.9%) and 304 completed (97.1%) testing. HIV tests were positive in four persons [prevalence 4.7%; 95% confidence interval (CI) 1.3-11.6%] in the IC group and in one person in the NIC group (prevalence 0.3%; 95% CI 0.01-1.82%; P < 0.009). If every eligible person had taken an HIV test, we would have spent €4650 in the IC group and €396,258 in the NIC group, and an estimated 36 (95% CI 25-49) and 198 persons (95% CI 171-227), respectively, would have been diagnosed with HIV infection. The estimated cost per new HIV diagnosis would have been €129 (95% CI €107-153) in the IC group and €2001 (95% CI €1913-2088) in the NIC group. CONCLUSIONS: Although the number of patients included in the study was small and the results should be treated with caution, IC-guided HIV testing, based on four selected ICs, in PCCs seems to be a more feasible and less expensive strategy to improve diagnosis of HIV infection in Spain than a nontargeted HIV testing strategy.

The case for indicator condition-guided HIV screening.

One-half of the estimated 2.5 million people who now live with HIV in the World Health Organization (WHO) European Region are still diagnosed late. A central question is which clinical scenarios should trigger an HIV test recommendation in order to avoid late presentation. Drawing on the work of the HIV Indicator Diseases across Europe Study (HIDES), new guidance brings together in one place a list of the conditions that should result in an HIV screening recommendation.

Overcoming obstacles to late presentation for HIV infection in Europe.

OBJECTIVE: The central goal of the HIV in Europe Initiative is to promote testing and treatment throughout Europe and Central Asia in order to decrease the number of people living with HIV presenting late for care. This article summarizes the results from the HIV in Europe 2009 Conference and the early results of the projects set up by the initiative, and discusses their implications for the future. METHODS: In November 2009, 100 key stakeholders from 25 countries met in Stockholm at the HIV in Europe Conference. The focus was to address five key issues that contribute to the barriers to testing identified in 2007 at an innovative HIV conference. The conference discussed barriers to testing and other reasons for late presentation and outlined concrete recommendations to address the problem. RESULTS: An early result of the initiative has been stimulation of the process of reaching a consensus definition of what is meant by a 'late presenter', with this definition to be implemented at the European level. Steps are being taken to advocate for appropriate health policies and surveillance data related to HIV throughout Europe. Also, the initiative has set up projects related to the barriers to testing, i.e. criminalization law, stigmatization and lack of offering of testing for people presenting with certain indicator diseases. CONCLUSIONS: The final results of ongoing projects will be published and widely disseminated in 2010 and beyond. The HIV in Europe Initiative will continue to reinforce collaboration, advocacy and networking activities in the field throughout Europe.

Late presentation of HIV infection: a consensus definition.

OBJECTIVES: Across Europe, almost a third of individuals infected with HIV do not enter health care until late in the course of their infection. Surveillance to identify the extent to which late presentation occurs remains inadequate across Europe and is further complicated by the lack of a common clinical definition of late presentation. The objective of this article is to present a consensus definition of late presentation of HIV infection. METHODS: Over the past year, two initiatives have moved towards a harmonized definition. In spring 2009, they joined efforts to identify a common definition of what is meant by a 'late-presenting' patient. RESULTS: Two definitions were agreed upon, as follows. Late presentation: persons presenting for care with a CD4 count below 350 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. Presentation with advanced HIV disease: persons presenting for care with a CD4 count below 200 cells/µL or presenting with an AIDS-defining event, regardless of the CD4 cell count. CONCLUSION: The European Late Presenter Consensus working group believe it would be beneficial if all national health agencies, institutions, and researchers were able to implement this definition (either on its own or alongside their own preferred definition) when reporting surveillance or research data relating to late presentation of HIV infection.

Treatment of locally advanced non-small cell lung cancer in the elderly.

PURPOSE OF REVIEW: Non-small cell lung cancer (NSCLC) may be considered typical of advanced age. Most cases of NSCLC are diagnosed in the advanced or locally advanced stage. It has been shown that combined chemo-radiotherapy is more efficient than either chemotherapy alone or radiation alone, for the therapeutic management of localized unresectable NSCLC. However, chemo-radiotherapy, even if given with sequential approach, in clinical practice can be contraindicated in elderly patients. In fact, this patient population often present at diagnosis with cardiovascular and/or pulmonary comorbidities that increase the risk of severe side effects from chemo-radiotherapy. The present review aims at focusing the currently available evidences on the treatment of elderly patients affected by locally advanced NSCLC and at giving future perspectives on this topic. RECENT FINDINGS: Very few specific prospective data are available on the treatment of locally advanced NSCLC in the elderly. Some phase II studies suggest that low-dose chemotherapy given concurrently with radiotherapy could be safely administered to this patient population. Retrospective analyses on full-dose sequential and concurrent chemo-radiation are to be considered globally ambiguous and at risk of selection bias. SUMMARY: Only specifically designed prospective studies will elucidate the real role and feasibility of combined chemo-radiotherapy in the treatment of locally advanced NSCLC in the elderly. Future perspectives on this topic include the evaluation of alternative schedules of chemo-radiotherapy, innovative radiation techniques more suitable to elderly patients, and the introduction of new, well-tolerated, molecularly targeted agents combined with standard treatments.

Nuclear production and metabolism of diacylglycerol.

The story of nuclear diacyglycerol is proving to be a complex one. Sub-pools of nuclear diglyceride that differ in their metabolism, nuclear localization and temporal regulation have been identified, suggesting potentially diverse signaling functions. One of the great remaining challenges is to assign functional roles to these diverse populations. In the last twenty years great strides have been made toward understanding the character and composition of nuclear DAG. Determining the functions of this nuclear lipid should make the next twenty years interesting indeed.