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.

Putting the public (back) into public health: leadership, evidence and action.

There is a strong evidence-based rationale for community capacity building and community empowerment as part of a strategic response to reduce health inequalities. Within the current UK policy context, there are calls for increased public engagement in prevention and local decision-making in order to give people greater control over the conditions that determine health. With reference to the challenges and opportunities within the English public health system, this essay seeks to open debate about what is required to mainstream community-centred approaches and ensure that the public is central to public health. The essay sets out the case for a reorientation of public health practice in order to build impactful action with communities at scale leading to a reduction in the health gap. National frameworks that support local practice are described. Four areas of challenge that could potentially drive an implementation gap are discussed: (i) achieving integration and scale, (ii) effective community mobilization, (iii) evidencing impact and (iv) achieving a shift in power. The essay concludes with a call to action for developing a contemporary public health practice that is rooted in communities and offers local leadership to strengthen local assets, increase community control and reduce health inequalities.

The effect of cell death in the initiation of lupus nephritis.

Cell death and the release of chromatin have been demonstrated to activate the immune system producing autoantibodies against nuclear antigens in patients with systemic lupus erythematosus (SLE). Apoptosis, necrosis, necroptosis, secondary necrosis, autophagy and the clearance of dying cells by phagocytosis are processes believed to have a role in tolerance avoidance, activation of autoimmune lymphocytes and tissue damage by effector cells. The released chromatin not only activates the immune system; it also acts as antigen for the autoantibodies produced, including anti-dsDNA antibodies. The subsequent immune complex formed is deposited within the basement membranes and the mesangial matrix of glomeruli. This may be considered as an initiating event in lupus nephritis. The origin of the released chromatin is still debated, and the possible mechanisms and cell sources are discussed in this study.

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.

Risky sexual behaviour in context: qualitative results from an investigation into risk factors for seroconversion among gay men who test for HIV.

OBJECTIVES: The INSIGHT case-control study confirmed that HIV serodiscordant unprotected anal intercourse (SdUAI) remains the primary risk factor for HIV infection in gay men in England. This paper uses qualitative follow-up data to examine the contexts of SdUAI and other risk factors among the case-control study participants. METHODS: In-depth interviews were conducted with 26 recent HIV seroconverters and 22 non-converters. Purposive selection was used to provide diversity in demographics and sexual behaviour and to facilitate exploration of risk factors identified in the case-control study. RESULTS: Condoms were perceived as barriers to intimacy, trust and spontaneity. The potential consequences of the loss of these were traded off against the consequences of HIV infection. Previous negative HIV tests and the adoption of risk reduction strategies diminished the perceived threat of HIV infection, supporting beliefs that HIV was something that happened to others. Depression and low self-esteem, often combined with use of alcohol or other drugs, led to further risk taking and loss of control over risk reduction strategies. CONCLUSIONS: A range of psychosocial reasons led some men to engage in UAI with serodiscordant or unknown partners, despite high levels of risk awareness. Men in their mid-life, those in serodiscordant relationships and men that had experienced bereavement or other significant, negative, life events revealed factors related to these circumstances that contributed to increases in risky UAI. A diverse portfolio of interventions is required to build confidence and control over safer sex practices that are responsive to gay men's wider emotional needs.

Factors associated with HIV seroconversion in gay men in England at the start of the 21st century.

OBJECTIVES: To detect and quantify current risk factors for HIV seroconversion among gay men seeking repeat tests at sexual health clinics. DESIGN: Unmatched case control study conducted in London, Brighton and Manchester, UK. METHODS: 75 cases (recent HIV positive test following a negative test within the past 2 years) and 157 controls (recent HIV negative test following a previous negative test within the past 2 years) completed a computer-assisted self interview focused on sexual behaviour and lifestyle between HIV tests. RESULTS: Cases and controls were similar in socio-demographics, years since commencing sex with men, lifetime number of HIV tests, reasons for seeking their previous HIV tests and the interval between last HIV tests (mean = 10.5 months). Risk factors between tests included unprotected receptive anal intercourse (URAI) with partners not believed to be HIV negative (adjusted odds ratio (AOR) and 95% confidence interval 4.1, 1.8 to 9.3), where increased risk was associated with concomitant use of nitrite inhalants, receiving ejaculate and increasing numbers of partners. Independent risk was also detected for unprotected insertive anal intercourse (UIAI) with more than one man (AOR 2.7, 1.3 to 5.5) and use of nitrite inhalants (AOR 2.4, 1.1 to 5.2). CONCLUSIONS: HIV serodiscordant unprotected anal intercourse remains the primary context for HIV transmission among gay men, with increased risk associated with being the receptive partner, receiving ejaculate and use of nitrite inhalants. Although the HIV transmission risk of URAI is widely acknowledged, this study highlights the risk of UIAI and that nitrite inhalants may be an important facilitator of transmission when HIV exposure occurs.

Nucleosomes possess a high affinity for glomerular laminin and collagen IV and bind nephritogenic antibodies in murine lupus-like nephritis.

AIM: Lupus nephritis is closely associated with in vivo autoantibody-binding to glomerular membrane-associated electron-dense structures (EDS). The biochemical nature and cellular origin of EDS are controversial, and definitive characterisation needs to be performed. METHODS: By using the terminal transferase biotin-dUTP nick end-labelling (TUNEL) assay at the electron microscopic level, we have traced extracellular chromatin within the glomerular basement membranes of nephritic (NZBxNZW)F1 mice. The TUNEL assay was subsequently used in combination with standard immune electron microscopy (IEM). To analyse why chromatin particles associate with membranes, we determined the affinity of nucleosomes and DNA for glomerular laminin, collagen IV and the mesangial matrix proteoglycan perlecan by surface plasmon resonance. RESULTS: This intra-assay colocalisation TUNEL IEM demonstrated that autoantibodies fully colocalised with extracellular TUNEL-positive chromatin observed as EDS in glomerular membranes, similar to results obtained by the same technique applied to human lupus nephritis. Most importantly, these data validate the murine variant of lupus nephritis as a model to study origin of extracellular chromatin as a key element in human lupus nephritis. Kinetic analyses demonstrated that nucleosomes had a high affinity for collagen IV and laminin, but not for perlecan. CONCLUSION: Collectively, these results provide firm evidence that dominant target structures for nephritogenic autoantibodies are constituted by TUNEL-positive chromatin associated with glomerular capillary and mesangial matrix membranes at high affinity.

Sex partner acquisition while overseas: results from a British national probability survey.

BACKGROUND: Over the past 20 years, there has been a huge increase in the number of overseas trips made by UK residents. Although a number of studies have examined the frequency of overseas partner acquisition, they have used convenience samples and thus are not generalisable to the British general population. METHODS: A national probability sample survey was carried out in 1999-2001 of 12,110 men and women aged 16-44 years resident in Britain. Sociodemographic, health-related, travel, sexual behaviour and attitudinal data were collected by computer-assisted interviewing. The main outcomes were the proportion of British residents who reported new sexual partners overseas in the past 5 years, the country of origin of these new sex partners, and the association between reporting a new partner while overseas with a range of demographic, behavioural and attitudinal variables. RESULTS: 13.9% of men and 7.1% of women reported having new sexual partner(s) while overseas in the past 5 years. Among respondents who were aged 16-24 and never married, the proportions were significantly higher (23.0% of men and 17.0% of women). Half of those with new sex partners overseas reported their partner's origin as the UK, and over a third as another European country. In addition to age and marital status, reporting new partners overseas was associated with a higher number of partners, paying for sex (among men), reporting a diagnosis of sexually transmitted infection, and HIV testing. Adjustment for sociodemographic factors attenuated the magnitude of, but did not remove, these associations. CONCLUSIONS: A substantial minority of young, unmarried people form new sexual partnerships abroad, but these are typically with residents from the UK or other European countries. Those who have new partners abroad are likely to have higher-risk sexual lifestyles more generally, and to be at higher risk of sexually transmitted infections. Greater attention should be paid to sexual health promotion for travellers abroad, especially young travellers, emphasising the risks of new sexual relationships with compatriots as well as those from other countries in terms of STI/HIV acquisition and onwards transmission.

Sexual behaviour and HIV infection in black-Africans in England: results from the Mayisha II survey of sexual attitudes and lifestyles.

OBJECTIVES: To estimate HIV prevalence and the distribution of high risk sexual behaviours, sexual health service use, and HIV testing among black Africans aged 16 years or over in England. To determine demographic, behavioural and service use factors associated with HIV prevalence. METHODS: A cross-sectional community-based survey (Mayisha II) in London, Luton and the West Midlands. A short (24-item) anonymous self-completion questionnaire with linked voluntary anonymous oral fluid sampling, using an Orasure device for HIV testing. RESULTS: A total of 1359 eligible black African men (51.9%) and women (48.1%) were recruited, of whom 74% (1006) provided a sufficient oral fluid sample for HIV testing. 42.9% of men and 50.9% of women reported ever having had an HIV test. Overall, 14.0% (141, 95% CI 11.9 to 16.3) of respondents tested HIV positive (13.1% of men and 15.0% of women); 9.2% (93) had undiagnosed HIV infection, while 4.8% (48) had a diagnosed HIV infection. HIV prevalence was significantly higher in men: born in East Africa; who had had a previous STI diagnosis; or who were recruited in bars and clubs; and in women: born in East or Southern Africa; aged 25 years and over; who had had two new sexual partners in the past 12 months; or who had had a previous STI diagnosis. CONCLUSIONS: Despite about half the sample having had an HIV test at some time in the past, 9.2% of respondents had an undiagnosed HIV infection. This study supports current policy efforts to further promote HIV testing and serostatus awareness.

Sexual health services for South Asians in London, UK: a case-control study.

National guidance on sexual health in England recommends service development to meet the specific needs of ethnic minority populations. Our aim was to evaluate mode of referral, number of sexually transmitted infections (STIs) diagnosed, and the offering and uptake of HIV testing in patients of South Asian ethnicity. A retrospective case-control study was undertaken in two London genito-urinary (GU) medicine clinics. There were 250 case-control pairs with approximately equal numbers of men and women. South Asians were less likely to have an STI (Odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45, 0.97) or to report risk factors for HIV (OR 0.45, 95% CI 0.28, 0.71). Offering and uptake of HIV antibody testing were high in both South Asian and non-South Asian groups (OR 0.62, 95% CI 0.27, 1.51). South Asians were significantly more likely than controls to have been referred by other medical services rather than self-referred (OR 2.00, 95% CI 1.32, 3.01), which is in keeping with poorer access to GU medicine services in London.

Men who have sex with men who are born abroad and diagnosed with HIV in England and Wales: an epidemiological perspective.

Relatively little is known about the sexual health needs of men who have sex with men (MSM) born abroad who reside in the UK. We describe here the epidemiology of HIV among MSM born outside the UK and diagnosed with HIV in England and Wales. Reports of HIV diagnoses in England and Wales received at the Health Protection Agency Centre for Infections were analysed. Between 2000 and 2003, 6386 MSM were diagnosed with HIV in England and Wales. Country of birth was recorded for 3571 (56%). Of those with country of birth reported, 2598 (73%) were born in the UK and 973 (27%) abroad. Of those born abroad (973), 424 (44%) were born in Europe, 141 (15%) in Africa, 104 (11%) in South/Central America and the remainder in other regions. Where reported (949), 69% of MSM born abroad were White, 12% other/mixed, 9% Black Caribbean and 7% Black African. Probable country of infection was reported for 612 MSM born abroad: 52% were infected in the UK, 43% in their region of birth and 5% in another region. Men born abroad represent a significant proportion of HIV diagnoses among MSM in England and Wales. More than half probably acquired their HIV infection in the UK, strengthening the call for targeted HIV prevention and sexual health promotion among MSM who are not born in England and Wales.

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.

HIV transmission risk among sub-Saharan Africans in London travelling to their countries of origin.

Migrant black African communities bear the brunt of heterosexual HIV/AIDS epidemic in the UK. This study confirms the close links that exist between UK resident black Africans and their countries of origin. A total of 43% of men and 46% of women visited their home countries within the last five years. While there, men were more likely than women to have acquired a new sexual partner. Previous diagnosis with a sexually transmitted disease, and the use of condoms at last intercourse were independently associated with this practice. This represents a potential risk of HIV transmission, and highlights an area for targeted health promotion within these communities.

An evaluation of partner notification for HIV infection in genitourinary medicine clinics in England.

OBJECTIVE: To evaluate the feasibility and effectiveness of a standardized HIV partner notification programme within genitourinary medicine clinics in England. DESIGN: A prospective survey of HIV partner notification activity over a 12-month period. SETTING: Nineteen genitourinary medicine clinics in England. PATIENTS AND PARTICIPANTS: A total of 501 eligible HIV-positive patients (either newly diagnosed or with whom partner notification had not been undertaken previously) seen during the study period. MAIN OUTCOME MEASURES: The numbers of partners named by patients, and the number of contacts notified, counselled and HIV-tested. RESULTS: Information on overall partner notification activity was obtained by reviewing available medical records of 471 patients; 353 (75%) had discussed partner notification with a health-care worker during the study period and 197 (42%) had undertaken partner notification. Detailed information on outcomes was obtained for only 70 patients who named 158 contacts as being at risk of acquiring HIV. Although 71 (45%) contacts were eventually notified, only 28 were subsequently seen in participating clinics. Almost all contacts (n = 27) requested HIV counselling and testing, and five were diagnosed HIV-positive. Patient referral was the most popular notification method chosen. CONCLUSIONS: This study illustrates some of the practical difficulties that limit HIV partner notification within genitourinary medicine clinics. These include health-care workers' misgivings about undertaking partner notification, insufficient locating information to identify contacts, and migration of newly diagnosed patients, which prevents continuity and completion of notification. Nevertheless, HIV partner notification uncovered previously undiagnosed HIV infections. Further work needs to be undertaken in staff training and policy implementation if higher rates of partner notification and outcome measurements are to be achieved.

Effect of computer-assisted self-interviews on reporting of sexual HIV risk behaviours in a general population sample: a methodological experiment.

OBJECTIVES: To develop methods to maximize the accuracy of reporting HIV risk behaviours in a general population survey. We assessed the feasibility of using a computer-assisted self-completion interview (CASI) in comparison with pen-and-paper self-completion interview (PAPI). DESIGN: A probability sample survey of residents aged 16-44 years in Britain, with alternate assignment of addresses to interview by CASI (462) or PAPI (439). METHODS: Personal interviews exploring demographic and sexual behaviour variables. Principal outcome measures were the impact of CASI in relation to PAPI on data quality and rates of reporting a range of behaviours. RESULTS: A total of 901 interviews were completed; 829 individuals were eligible for and accepted the self-completion module. Internal consistency of data items was greater with CASI than PAPI and item non-response was lower. Overall, there was no significant difference in rates of reporting between CASI and PAPI. The main effect for CASI compared with PAPI in a generalized estimating equation (GEE) analysis was an OR (95% CI) of 1.04 (0.92-1.17). Variables were also examined individually, including homosexual partnership (adjusted OR 1.26 95%, CI 0.69-2.29), payment for sex (adjusted OR 0.68 95% CI 0.29-1.59), masturbation (adjusted OR 0.89 95% CI 0.66 1.22) and five or more partners in the past 5 years (OR 0.85 95% CI 0.61 -1.19). CONCLUSION: We found no evidence of a consistent effect of CASI on rates of reporting sexual HIV risk behaviours in this sample. CASI resulted in improvement in internal consistency and a reduction in missed questions.

Effects of increased dietary calcium intake upon the calcium and bone mineral status of lactating adolescent and adult women.

We studied the effectiveness of an increased calcium (Ca) diet in preventing bone mineral loss in lactating adolescent mothers. Three groups of lactating women were studied: 15 control adolescents consuming their usual Ca diet (900 mg/d), 21 experimental adolescents consuming a high-Ca diet (greater than 1600 mg/d), and 12 adults. At 2 and 16 wk postpartum, serum calcium, phosphate, magnesium, albumin, alkaline phosphatase, vitamin D, parathyroid hormone (PTH), and calcitonin (CT) were determined. Bone mineral analyses were performed by photon absorptiometry. By 16 wk the control adolescent group had a 10% decrease in bone mineral content (BMC) and increased PTH and CT. The experimental adolescent and adult groups had no significant change in BMC during the study. There was a positive correlation (r = 0.45, p less than 0.01) between dietary Ca intake and BMC in all adolescents. Data suggest that bone loss during lactation in adolescents may be prevented with adequate dietary Ca intakes.

Weight gain in adolescents during pregnancy: rate related to birth-weight outcome.

This study of 459 subjects from prenatal clinics for teenagers at three universities across the United States, addresses questions about gestational weight gain in adolescents raised by the 1990 Institute of Medicine Report. Rate and pattern of gain, independent of pregravid weight, are based on serial measures of mothers with favorable and unfavorable outcomes. Rate of gain (determined by using regression statistics) from weeks 15 to 40 was 0.588, 0.510, and 0.488 kg/wk for mothers of term infants weighing 3000-4000 g, term infants weighing < 3000 g, and preterm infants, respectively. The significantly lower percentage of infants weighing 3000-4000 g vs < 3000 g needing intensive care at birth (6% vs 15%, respectively, P < 0.05) further indicates the superior outcome among mothers with higher rates of gain. Rate of gain of mothers of infants weighing 3000-4000 g (favorable outcome) equaled the highest amount provisionally recommended, suggesting that restricting natural gain of adolescents to recommended rates may result in smaller than optimal infants.