The ECHELON-2 Trial: 5-year results of a randomized, phase III study of brentuximab vedotin with chemotherapy for CD30-positive peripheral T-cell lymphoma.

BACKGROUND: For patients with peripheral T-cell lymphoma (PTCL), outcomes using frontline treatment with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP-like therapy are typically poor. The ECHELON-2 study demonstrated that brentuximab vedotin plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) exhibited statistically superior progression-free survival (PFS) per independent central review and improvements in overall survival versus CHOP for the frontline treatment of patients with systemic anaplastic large cell lymphoma or other CD30-positive PTCL. PATIENTS AND METHODS: ECHELON-2 is a double-blind, double-dummy, randomized, placebo-controlled, active-comparator phase III study. We present an exploratory update of the ECHELON-2 study, including an analysis of 5-year PFS per investigator in the intent-to-treat analysis group. RESULTS: A total of 452 patients were randomized (1 : 1) to six or eight cycles of A+CHP (N = 226) or CHOP (N = 226). At median follow-up of 47.6 months, 5-year PFS rates were 51.4% [95% confidence interval (CI): 42.8% to 59.4%] with A+CHP versus 43.0% (95% CI: 35.8% to 50.0%) with CHOP (hazard ratio = 0.70; 95% CI: 0.53-0.91), and 5-year overall survival (OS) rates were 70.1% (95% CI: 63.3% to 75.9%) with A+CHP versus 61.0% (95% CI: 54.0% to 67.3%) with CHOP (hazard ratio = 0.72; 95% CI: 0.53-0.99). Both PFS and OS were generally consistent across key subgroups. Peripheral neuropathy was resolved or improved in 72% (84/117) of patients in the A+CHP arm and 78% (97/124) in the CHOP arm. Among patients who relapsed and subsequently received brentuximab vedotin, the objective response rate was 59% with brentuximab vedotin retreatment after A+CHP and 50% with subsequent brentuximab vedotin after CHOP. CONCLUSIONS: In this 5-year update of ECHELON-2, frontline treatment of patients with PTCL with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, with a manageable safety profile, including continued resolution or improvement of peripheral neuropathy.

Oligoclonal bands in multiple sclerosis reactive against two herpesviruses and association with magnetic resonance imaging findings.

BACKGROUND: Two human herpesviruses, human herpesvirus 6 (HHV-6), and Epstein-Barr virus (EBV), have been repeatedly linked to multiple sclerosis (MS). OBJECTIVE: The aim of this study was to investigate HHV-6 and EBV reactive oligoclonal bands (OCBs), and viral DNA in the intrathecal compartment in MS. METHODS: The reactivity of OCBs in cerebrospinal fluid (CSF) for EBV and HHV-6 antigens and stability of virus reactive OCBs over time were studied in a well-characterized MS patient cohort. Associations between virus reactive OCBs and viral DNA in CSF (and any clinical and/or radiological findings) were investigated. RESULTS: Of patients with MS, 38% had OCBs reactive to either one of the viruses studied, compared to none in the patients with other inflammatory neurological diseases (p=0.005). The banding pattern of virus reactive OCBs remained the same over time. Furthermore, MS patients with viral DNA in CSF had more contrast enhancing lesions (CELs). CONCLUSION: The stable presence of herpesvirus reactive OCBs in CSF further strengthens the association of MS with these viruses. The finding that herpesviruses might be linked to the appearance of active lesions warrants investigation of new therapeutic strategies to treat these viruses in MS.

The state of hepatitis B and C in the Mediterranean and Balkan countries: report from a summit conference.

The burden of disease due to chronic viral hepatitis constitutes a global threat. In many Balkan and Mediterranean countries, the disease burden due to viral hepatitis remains largely unrecognized, including in high-risk groups and migrants, because of a lack of reliable epidemiological data, suggesting the need for better and targeted surveillance for public health gains. In many countries, the burden of chronic liver disease due to hepatitis B and C is increasing due to ageing of unvaccinated populations and migration, and a probable increase in drug injecting. Targeted vaccination strategies for hepatitis B virus (HBV) among risk groups and harm reduction interventions at adequate scale and coverage for injecting drug users are needed. Transmission of HBV and hepatitis C virus (HCV) in healthcare settings and a higher prevalence of HBV and HCV among recipients of blood and blood products in the Balkan and North African countries highlight the need to implement and monitor universal precautions in these settings and use voluntary, nonremunerated, repeat donors. Progress in drug discovery has improved outcomes of treatment for both HBV and HCV, although access is limited by the high costs of these drugs and resources available for health care. Egypt, with the highest burden of hepatitis C in the world, provides treatment through its National Control Strategy. Addressing the burden of viral hepatitis in the Balkan and Mediterranean regions will require national commitments in the form of strategic plans, financial and human resources, normative guidance and technical support from regional agencies and research.

Circulating chromatin-anti-chromatin antibody complexes bind with high affinity to dermo-epidermal structures in murine and human lupus nephritis.

Murine and human lupus nephritis are characterized by glomerular deposits of electron-dense structures (EDS). Dominant components of EDS are chromatin fragments and IgG antibodies. Whether glomerular EDS predispose for similar deposits in skin is unknown. We analysed (i) whether dermo-epidermal immune complex deposits have similar molecular composition as glomerular deposits, (ii) whether chromatin fragments bind dermo-epidermal structures, and (iii) whether deposits in nephritic glomeruli predispose for accumulation of similar deposits in skin. Paired skin and kidney biopsies from nephritic (NZBxNZW)F1 and MRL-lpr/lpr mice and from five patients with lupus nephritis were analysed by immunofluorescence, immune electron microscopy (IEM) and co-localization TUNEL IEM. Affinity of chromatin fragments for membrane structures was determined by surface plasmon resonance. Results demonstrated (i) presence of EDS containing chromatin fragments and IgG in both organs in nephritic patients, (ii) chromatin fragments possessed high affinity for dermo-epidermal laminins and collagens, (iii) glomerular immune complex deposits did not predict similar interstitial deposits in skin, although such complexes were present in capillary lumina in glomeruli and skin of all nephritic individuals. Thus, chromatin-IgG complexes accounting for lupus nephritis seem to reach skin through circulation, but other undetermined factors are required for these complexes to deposit within skin membranes.

HIV in gay and bisexual men in the United Kingdom: 25 years of public health surveillance.

It is more than 25 years since the first case of AIDS was reported in the United Kingdom. In December 1981 a gay man was referred to a London hospital with opportunistic infections indicative of immunosuppression. National surveillance began the following year, in September 1982, with the notification of deaths and clinical reports of AIDS and Kaposi's sarcoma plus laboratory reports of opportunistic infections. Since then epidemiological surveillance systems have evolved, adapting to, and taking advantage of advances in treatments and laboratory techniques. The introduction of the HIV antibody test in 1984 led to the reporting of HIV-positive tests by laboratories and the establishment of an unlinked anonymous survey in 1990 measuring undiagnosed HIV infection among gay men attending sexual health clinics. The widespread use of highly active antiretroviral therapies (HAART) since 1996 has averted many deaths among HIV-positive gay men and has also resulted in a large reduction in AIDS cases. This led to a need for an enumeration of gay men with HIV accessing NHS treatment and care services (1995 onwards), more clinical information on HIV diagnoses for epidemiological surveillance (2000 onwards) and the routine monitoring of drug resistance (2001 onwards). Twenty-five years after the first case of AIDS was reported, gay and bisexual men remain the group at greatest risk of acquiring HIV in the United Kingdom. Latest estimates suggest that in 2004, 26 500 gay and bisexual men were living with HIV in the United Kingdom, a quarter of whom were undiagnosed. In this review, we examine how national surveillance systems have evolved over the past 25 years in response to the changing epidemiology of HIV/AIDS among gay and bisexual men in the United Kingdom as well as advances in laboratory techniques and medical treatments. We also reflect on how they will need to continue evolving to effectively inform health policy in the future.

A comparison of the population diagnosed with chlamydia in primary care with that diagnosed in sexual health clinics: implications for a national screening programme.

OBJECTIVES: To compare demographic, behavioural and HIV testing characteristics of individuals diagnosed with chlamydia infection in primary care with those in genitourinary medicine clinics, in the absence of a screening programme. The aim was to explore the current and potential contribution of primary care to the control of chlamydia. STUDY DESIGN AND METHODS: We analysed data on individuals who reported one or more chlamydia diagnoses in the past 5 years in a large probability sample survey of the resident, UK general population aged 16-44 years. Estimates were weighted and odds ratios calculated. RESULTS: Women diagnosed in primary care reported fewer sexual partners, and were less likely to have had an HIV test in the past 5 years than their counterparts diagnosed in genitourinary medicine clinics. Age, ethnicity, social class, educational attainment and urbanization of area of residence did not differ between the two groups. Too few men were diagnosed in primary care to allow for such a comparison. CONCLUSIONS: Primary care already diagnoses a large number of women with chlamydia infection, who may perceive themselves as low risk through age or sexual behaviour, yet are likely to comprise a substantial proportion of all infections. Few men are diagnosed in primary care. These groups need to be strategically targeted in the context of a future chlamydia screening programme, which will focus on the screening of younger women at high risk, and in which the role of primary care is still in development.

Monitoring the effectiveness of HIV and STI prevention initiatives in England, Wales, and Northern Ireland: where are we now?

Primary and secondary prevention are essential components of the response to HIV and sexually transmitted infections (STIs). We present findings from nationally implemented HIV/STI prevention interventions. In 2003, of those attending STI clinics at least 64% of men who have sex with men (MSM) and 55% of heterosexuals accepted a confidential HIV test; 88% of all HIV infections in women giving birth in England were diagnosed before delivery; 85% of MSM eligible for hepatitis B vaccination received a first dose of vaccine at their first STI clinic attendance; 74% of STI clinic attendees for emergency appointments, and 20% of those for routine appointments were seen within 48 hours of initiating an appointment; the National Chlamydia Screening Programme in England found a positivity of 10% and 13% among young asymptomatic women and men, respectively. Prevention initiatives have seen recent successes in limiting further HIV/STI transmission. However, more work is required if current levels of transmission are to be reduced.

Screening, diagnosis and management of early syphilis in genitourinary medicine clinics in the UK.

New diagnoses of syphilis in the UK increased eight-fold between 1997 and 2002. This study, conducted in 2002, demonstrated that 31% of clinics were not confident of their expertise to obtain an adequate specimen for dark ground microscopy (DGM), and 35% were not confident of their expertise to detect treponemes on DGM. In all, 64% of clinics had observed adherence problems in HIV-positive patients treated with parenteral regimens, as against 42% with oral regimens. Also, 51% of clinics waited more than a week for the results of initial serological tests for syphilis, and 88% of clinics waited more than a week for confirmatory test results. Other concerns include the failure to perform syphilis serology consistently whenever HIV-positive patients were at risk, and the widespread use of doxycycline as a therapy for syphilis in HIV-positive patients despite concerns that this is not known to be fully treponemicidal in cerebrospinal fluid.

Using chlamydia positivity to estimate prevalence: evidence from the Chlamydia Screening Pilot in England.

Studies have suggested that positivity can be used to estimate the prevalence of Chlamydia trachomatis in large-scale chlamydia screening programmes. A recent pilot of opportunistic screening in England estimated that the prevalence among 16-24-year-old women in Portsmouth and Wirral was 9.8% and 11.2%, respectively. This study assessed the continued validity of positivity as an approximate for prevalence. We re-analysed data from the Chlamydia Screening Pilot to estimate positivity,calculated as total positive tests divided by total tests, and compared these estimates with the previously reported prevalence, measured as the number of women testing positive divided by the total number of women screened. Overall positivity was 9.4% in Portsmouth and 11.0% in the Wirral; these estimates were not statistically different from prevalence, regardless of health-care setting, age group or symptoms. We conclude that positivity can be used as a proxy for prevalence.

Establishing the National Chlamydia Screening Programme in England: results from the first full year of screening.

BACKGROUND: The phased implementation of the National Chlamydia Screening Programme (NCSP) began in September 2002. The NCSP offers opportunistic screening for chlamydia to women and men under 25 years of age attending clinical and non-clinical screening venues using non-invasive urine or vulvo-vaginal swab samples tested via nucleic acid amplification. This review describes the implementation of the NCSP, reports positivity rates for the first year, and explores risk factors for genital chlamydial infection. METHODS: Cross sectional study of the first year's screening data from the NCSP. A standardised core dataset for each screening test was collected from 302 screening venues, excluding genitourinary medicine (GUM) clinics, across 10 phase 1 programme areas. We estimated chlamydia positivity by demographic and behavioural characteristics, and investigated factors associated with infection through univariate and multivariate analyses. RESULTS: Chlamydia positivity among people under 25 years of age screened in non-GUM settings was 10.1% (1538/15 241) in women and 13.3% (156/1172) in men. Risk factors varied by sex: for women-age 16-19, non-white ethnicity, and sexual behaviours were associated with infection; for men-only age 20-24 and non-white ethnicity were associated with infection. DISCUSSION: In the first phase of the NCSP, 16 413 opportunistic screens among young adults under 25 years of age were performed at non-GUM settings and testing volume increased over time. Rates of disease were similar to those found during the English screening pilot and were comparable to the first year of widespread screening in Sweden and the United States. The screening programme in England will continue to expand as further phases are included, with national coverage anticipated by 2008.

Modelling the healthcare costs of an opportunistic chlamydia screening programme.

OBJECTIVES: To estimate the average cost per screening offer, cost per testing episode and cost per chlamydia positive episode for an opportunistic chlamydia screening programme (including partner management), and to explore the uncertainty of parameter assumptions, based on the costs to the healthcare system. METHODS: A decision tree was constructed and parameterised using empirical data from a chlamydia screening pilot study and other sources. The model was run using baseline data from the pilot, and univariate and multivariate sensitivity analyses were conducted. RESULTS: The total estimated cost for offering screening over 12 months to 33,215 females aged 16-24 was 493,412 pounds . The average cost (with partner management) was 14.88 pounds per screening offer (90% credibility interval (CI) 10.34 to 18.56), 21.83 pounds per testing episode (90% CI 18.16 to 24.20), and 38.36 pounds per positive episode (90% CI 33.97 to 42.25). The proportion of individuals accepting screening, the clinician (general practitioner/nurse) time and their relative involvement in discussing screening, the test cost, the time to notify patients of their results, and the receptionist time recruiting patients had the greatest impact on the outcomes in both the univariate and multivariate sensitivity analyses. CONCLUSIONS: Results from this costing study may be used to inform resource allocation for current and future chlamydia screening programme implementation.

Surveillance systems for STIs in the European Union: facing a changing epidemiology.

OBJECTIVES: To characterise the nature, content, and performance characteristics of existing national STI surveillance systems in the European Union (EU) and Norway, to facilitate collection of comparable surveillance data. METHODS: Cross sectional survey using a structured questionnaire. RESULTS: Case reporting from clinicians and/or laboratories is the mainstay of EU surveillance systems for bacterial STIs. Coverage of case reporting varies from less than 10% to over 75%, and lack of and/or heterogeneity in case definitions affect the relative specificity and sensitivity of reporting systems. Considerable variations also exist in STI care sites; the populations who use these services; and in partner notification practices, STI screening practices, and STI laboratory diagnostic tests employed, affecting the representativeness of reported data and the sensitivity of surveillance systems for detecting the true number of STI cases. CONCLUSIONS: The heterogeneity of current surveillance systems complicates direct comparison of STI incidence rates across Europe. Introduction of standardised case definitions for reporting, and increased coverage of mandatory reporting systems where necessary, are needed. Definition of standardised minimum datasets and use of sentinel and enhanced surveillance systems to supplement universal case/laboratory notification data, could improve our understanding of the distribution and determinants of STIs across Europe, and aid in the design of effective public health responses. In the context of the changing epidemiology of STIs, systems for detection and monitoring of localised outbreaks of acute bacterial STIs (syphilis and antimicrobial resistant gonorrhoea), as well as prevalence monitoring systems for frequently asymptomatic STIs (chlamydial infection and viral STIs), are also necessary.

Provision of chlamydia testing in a nationwide service offering termination of pregnancy: with data capture to monitor prevalence of infection.

OBJECTIVES: To establish a methodology by which all women attending for termination of pregnancy (TOP) at British Pregnancy Advisory Service (BPAS) branches may be approached to participate in Chlamydia trachomatis screening. To examine the feasibility of monitoring C trachomatis prevalence and the impact of charging for screening on the uptake rate in this population. METHODS: Patients attending for TOP at participating BPAS branches were offered a test for chlamydia infection and asked to complete a questionnaire. Urine samples from participants were tested using a nucleic acid amplification test (NAAT). RESULTS: 1001 women provided a urine sample, a 77% response rate among those participating in the study. Factors significantly associated with taking up chlamydia screening included symptoms, previous TOP, parity, and no previous chlamydial test. Overall prevalence of genital chlamydial infection was 7.5%, with highest age specific prevalences occurring among attendees aged 20-24 years (11.5%) and under 20 years (10.8%). In univariate analysis, chlamydia positivity was significantly associated with respondent age and previous diagnosis with chlamydia. Only 35% of women who had the screening test would have done so had they been asked to pay the pound 20 clinical, administrative, and laboratory costs of the examination. CONCLUSIONS: We have demonstrated the feasibility of routine chlamydia screening and the potential for prospective prevalence monitoring across the nationwide BPAS service. In most cases the chlamydia result was available within the clinical contact period for the TOP. Charging patients directly for the test could reduce uptake of chlamydia screening to levels unsatisfactory for both the public health and prevalence monitoring purposes.

Phase specific strategies for the prevention, control, and elimination of sexually transmitted diseases: background country profile, England and Wales.

The development of non-invasive tests for evidence of current or past infection offers new prospects for carrying out population studies of sexually transmitted infection (STI) epidemiology, and for improved understanding of the behavioural and biological determinants of STI transmission. In turn this may guide screening, treatment, and behavioural interventions. The evidence base for many interventions is sparse and randomised trials of interventions are in their early days. Increasingly, linked behavioural and biological outcomes will be required to measure effectiveness. Integrated efforts are needed at a national level to achieve greater coordination between STD, HIV, and contraception services, school education, and broader public education and programmes.

Recent trends in Chlamydia trachomatis in the United Kingdom and the potential for national screening.

A pilot study has been carried up in the United Kingdom to assess the feasibility of a national screening programme of genital chlamydial infections. The preliminary results show a high acceptance rate (70% of the candidates) and a significant coverage of the target population (40% over a six months period). Several other studies are ongoing in order to specify the more appropriate screening processes and partner notification strategies, as well as the cost effectiveness of a national programme.

Assessing the impact of national anti-HIV sexual health campaigns: trends in the transmission of HIV and other sexually transmitted infections in England.

OBJECTIVE: To assess the impact of the sexual component of AIDS and HIV campaigns on transmission of HIV and other sexually transmitted infections (STIs). DESIGN: Comparison of time series data. SETTING: England, 1971-1999. OUTCOME MEASURES: HIV transmission and diagnoses among men who have sex with men (MSMs), rates of attendances and specific STI diagnoses (per 100 000 total population) at genitourinary medicine (GUM) clinics. RESULTS: Awareness of AIDS and campaigns in 1983-4 among homosexual men coincided with substantial declines in transmission of HIV and diagnoses of syphilis among MSMs. During general population campaigns in 1986-7 new GUM clinic attendances requiring treatment fell by 117/10(5) in men and 42/10(5) in women. Rates for gonorrhoea fell by 81/10(5) and 43/10(5) and genital herpes by 6/10(5) and 4/10(5), respectively. Previous rises in genital wart rates were interrupted, while rates of attendances not requiring treatment (the "worried well") increased by 47/10(5) and 58/10(5) for men and women, respectively. Since 1987 diagnoses of HIV among MSMs have not declined, averaging 1300-1400 annually. Following a period of unchanging rates there have been substantial increases in GUM attendances requiring treatment, notably for gonorrhoea, syphilis, and viral STIs since 1995. CONCLUSIONS: Self help initiatives and awareness among homosexual men in 1983-4 contributed significantly to a fall in HIV transmission among MSMs, and the general campaigns of 1986-7 were associated with similar effects on all STI transmission. Both effects seem to have occurred through changing sexual behaviour, and probably contributed to the UK's low national HIV prevalence. Bacterial STI incidence has increased significantly since 1995 and there is no evidence that recent prevention initiatives have reduced HIV transmission among MSMs, hence sexual health initiatives need to be comprehensively reinvigorated in England.