Delivering advanced therapies: the big pharma approach.

After two decades of focused development and some recent clinical successes, cell and gene therapy (CGT) is emerging as a promising approach to personalized medicines. Genetically engineered cells as a medical modality are poised to stand alongside or in combination with small molecule and biopharmaceutical approaches to bring new therapies to patients globally. Big pharma can have a vital role in industrializing CGT by focusing on diseases with high unmet medical need and compelling genetic evidence. Pharma should invest in manufacturing and supply chain solutions that deliver reproducible, high-quality therapies at a commercially viable cost. Owing to the fast pace of innovation in this field proactive engagement with regulators is critical. It is also vital to understand the needs of patients all along the patient care pathway and to establish product pricing that is accepted by prescribers, payers and patients.

Prospective parallel randomized trial of the MultiCyte™ ThinPrep(®) imaging system: the Scottish experience.

BACKGROUND: Computer-assisted screening of cervical liquid-based cytology (LBC) preparations using the ThinPrep® Imaging System (TIS) has shown improved qualitative and quantitative gains. The use of Multicyte™ has not been described in a well-established national screening programme with a low incidence of high-grade dyskaryosis. OBJECTIVES: To assess the impact of computer-assisted screening within the Scottish Cervical Screening Programme (SCSP). METHODS: Two groups of three laboratories, each sharing a ThinPrep® Imager, screened 79 366 slides randomized to test and 90 551 to control arms by laboratory accession. Screeners were not blinded. Standard laboratory reporting profiles of the SCSP, sensitivity, specificity and false-negative rates of all grades of LBC abnormalities with respect to final cytology reports, predictive value for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) on histology; and screening rates were compared for both arms. RESULTS: Inadequate and negative reporting rates were significantly lower and low-grade reporting rates significantly higher in the imager arm. Imager-assisted screening showed significantly better specificity than manual screening with respect to the final cytology result. There was no evidence of a significant difference in the detection of CIN2+ or CIN3 +. Positive, abnormal and total predictive values (high-grade, low-grade and all abnormal cytology found to be CIN2+, respectively) were similar in both arms. Productivity was significantly higher in the imager arm. CONCLUSION: Computer-assisted screening in a well established screening programme showed significantly improved productivity without loss of quality. These findings should inform future policy for cervical screening programmes.

Developmental outcome post allogenic bone marrow transplant for Niemann Pick Type C2.

Niemann Pick Type C2 (NPC2) is a rare autosomal recessive disease caused by mutations in the NPC2 gene (OMIM 601015). Clinically, NPC2 presents in most cases in the neonatal period with inflammatory lung disease, which may lead to death in the first year. If patients survive the neonatal period, they may develop a severe neurological disease. Here we present the developmental and neurological follow up at 5 years of age of a child with NPC2 successfully treated with allogenic bone marrow transplantation (BMT) at the age of 16 months. A homozygous p.E20X sequence variation previously associated with a severe phenotype was identified. In contrast to the previously reported patients with the same mutations, our patient has no respiratory compromise and has made some developmental progress (especially gross motor), though is significantly delayed (particularly in speech and language). Haematopoietic stem cell transplantation (HSCT) could be considered for patients with this mutation as long as performed early in the course of the disease.

Dietary modifications in patients receiving miglustat.

Weight loss and gastrointestinal disturbances are often seen during miglustat therapy for lysosomal storage diseases. A retrospective analysis of data from a mixed group of patients treated with miglustat at two UK centres was performed to evaluate the effect of two different dietary interventions on body weight and gastrointestinal tolerability during the initial 6 months of miglustat therapy. Neurological outcomes in these patients are not discussed herein. Data were analysed from a total of 29 patients with varied neurolipidoses (21 children/adolescents; 8 adults). Negative mean changes in body weight were seen in children/adolescents on an unmodified diet (-8.1%), and in adults (-4.1%) and children/adolescents (-5.2%) on a low-lactose diet. Patients on the low-disaccharide diet showed a positive mean change in body weight (+2.0%), although there was high variability in this group. Non-parametric sub-analysis of median body-weight change in children/adolescents also showed high variability both within and between diet groups, with no statistically significant difference between the effects of different diets on body weight (p = 0.062). The low-lactose diet reduced gastrointestinal disturbances; single small doses of loperamide were required in some patients. Patients on the low-disaccharide diet showed the lowest frequency of gastrointestinal effects. In conclusion, simple dietary modifications allowed the maintenance of body-weight gain in line with normal growth potential during miglustat therapy in young patients with lysosomal storage diseases, and reduced gastrointestinal disturbances.

Distribution of HPV types associated with cervical cancers in Scotland and implications for the impact of HPV vaccines.

BACKGROUND/METHODS: This study evaluated human papillomavirus (HPV) type prevalence in 370 Scottish invasive cervical cancers (ICCs) using HPV genotyping and HPV mRNA detection. RESULTS: HPV 16 and/or 18 was detected in 72% of cancers overall and in 82% of HPV-positive cancers. HPV 45 and 16 were the most frequently transcribed types. CONCLUSION: A significant reduction in ICC in Scotland should be achieved through the HPV immunisation programme.

Attitudes towards new HIV biomedical prevention technologies among a cohort of HIV-negative gay men in Sydney, Australia.

OBJECTIVES: The aim of the study was to explore the awareness of rectal microbicides, the use of pre-exposure prophylaxis (PREP) and the willingness to participate in biomedical HIV prevention trials in a cohort of HIV-negative gay men. METHODS: In a community-based cohort study, HIV-negative homosexually active men in Sydney, Australia were questioned about awareness of rectal microbicides, use of PREP, and willingness to participate in trials of such products. Predictors of awareness and willingness to participate were analysed by logistic regression. Use of PREP was examined prospectively. RESULTS: Overall, 14% had heard of rectal microbicides. Older (P=0.05) and university-educated men (P=0.001) were more likely to have knowledge of rectal microbicides. Almost one-quarter (24%) of men reported that they were likely/very likely to participate in rectal microbicide trials. Among those men with definite opinions on participation, awareness of rectal microbicides was significantly associated with unwillingness to participate [odds ratio (OR) 0.78, 95% confidence interval (CI) 0.65-0.93, P=0.007]. Willingness to participate in trials using antiretroviral drugs (ARVs) to prevent HIV infection was reported by 43% of men, and was higher among those who reported unprotected anal intercourse (UAI) with HIV-positive partners (OR 1.88, 95% CI 0.99-3.56). There was no evidence of current PREP use. CONCLUSIONS: This study demonstrates that Australian gay men have had little experience with PREP use and rectal microbicides. About half would be willing to consider participation in trials using ARVs to prevent HIV infection. Extensive community education and consultation would be required before PREP or rectal microbicides could be trialled in populations of gay Australian men.

Current issues in care and support for HIV-positive gay men in Sydney.

We explored current access to care among HIV-positive people in Australia. In 2006, 270 HIV-positive gay men from a community-based Positive Health cohort in Sydney were asked about their health (including medical and social) service needs and, subsequently, about difficulty in accessing services. We report the prevalence of specific needs, barriers and associated factors. Participants most commonly used general practitioners (64%) for HIV management and needed at least one HIV-related medical service (usually several: doctors experienced in HIV management, dentists and hospital pharmacies). Most participants were able to access them. Barriers in accessing services were related to their convenience rather than lack or quality. Cost emerged as a substantial barrier to dental care and psychological counselling (91% and 48% respectively of those in need). Need for an HIV-related social service was reported by 46% of respondents. Difficulties in accessing these related to poor services and staff attitudes. Income was associated with limited access to multiple services. In Australia, HIV-related medical service needs outweigh those for social services. Complex health services remain essential to HIV-positive people, but some services are currently not meeting their needs. To remain adequate, services need to understand and constantly adapt to the changing needs of HIV-positive people.

Sexually transmitted infection risk exposure among black and minority ethnic youth in northwest London: findings from a study translating a sexually transmitted infection risk-reduction intervention to the UK setting.

OBJECTIVES: Young black women are disproportionately affected by sexually transmitted infections (STI) in the UK, but effective interventions to address this are lacking. The Young Brent Project explored the nature and context of sexual risk-taking in young people to inform the translation of an effective clinic-based STI reduction intervention (Project SAFE) from the USA to the UK. METHODS: One-to-one in-depth interviews (n = 37) and group discussions (n = 10) were conducted among men and women aged 15-27 years from different ethnic backgrounds recruited from youth and genitourinary medicine clinic settings in Brent, London. The interviews explored the context within which STI-related risks were assessed, experienced and avoided, the skills needed to recognise risk and the barriers to behaviour change. RESULTS: Concurrent sexual partnerships, mismatched perceptions and expectations, and barriers to condom use contributed to STI risk exposure and difficulties in implementing risk-reduction strategies. Women attempted to achieve monogamy, but experienced complex and fluid sexual relationships. Low risk awareness, flawed partner risk assessments, negative perceptions of condoms and lack of control hindered condom use. Whereas men made conscious decisions, women experienced persuasion, deceit and difficulty in requesting condom use, particularly with older partners. CONCLUSIONS: Knowledge of STI and condom use skills is not enough to equip young people with the means to reduce STI risk. Interventions with young women need to place greater emphasis on: entering and maintaining healthy relationships; awareness of risks attached to different forms of concurrency and how concurrency arises; skills to redress power imbalances and building self-esteem.

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.

Improvements in sexual health testing among gay men in Sydney, Australia, 2003-2007.

In order to be effective, sexually transmitted infection (STI) testing should be comprehensive based on the clients' sexuality and risk practices. Using data from the Sydney Gay Community Periodic Survey, we explored trends in and factors associated with STI testing among gay men during 2003-2007. Among men who were not HIV-positive, 68% were tested for HIV in 2007. HIV testing was more common than STI testing and remained stable during 2003-2007. Use of swabs and urine samples increased significantly (P-trend<0.001 for each). However, until 2007, 33% of men were not tested. Sexual behaviours (higher number of partners, having casual partners and engaging in unprotected anal intercourse with them) were associated with STI testing. HIV-negative men were tested for STI less often than HIV-positive men (prevalence ratio=0.56; 95% CI: 0.47-0.68). STI testing among HIV-negative men has improved significantly but remains inadequate for STI control and HIV prevention. It should not be assumed that appropriate and comprehensive STI screening is always provided to clients.

Prevalence, incidence and risk factors for pharyngeal chlamydia in the community based Health in Men (HIM) cohort of homosexual men in Sydney, Australia.

OBJECTIVES: To determine the prevalence, incidence and risk factors for pharyngeal Chlamydia trachomatis in the community based Health in Men (HIM) cohort of HIV negative homosexual men in Sydney, Australia. METHODS: From January 2003, all HIM participants were offered annual screening for pharyngeal chlamydia using BD ProbeTec nucleic acid amplification testing (NAAT). Detailed sexual behavioural data were collected every 6 months, and risk factors for infection and hazard ratios were calculated using Cox regression. RESULTS: Among 1427 participants enrolled, the prevalence of pharyngeal chlamydia on initial testing was 1.06% and the incidence rate was 0.58 per 100 person-years. More than 50% of all infections were identified on baseline testing and 68% of men with pharyngeal infection had no evidence of concurrent anogenital chlamydia. There was no association of pharyngeal chlamydia with sore throat. Infection was significantly associated with increasing frequency of receptive penile-oral sex with ejaculation with casual partners (p = 0.009), although approximately half of infections occurred in participants not reporting this risk behaviour. Neither kissing nor oro-anal practices were associated with infection. CONCLUSION: The incidence of pharyngeal chlamydia infection in the HIM study was relatively low; however, the relatively high prevalence on baseline testing compared to incidence suggests a long duration of infection. Occasional screening for pharyngeal chlamydia in homosexual men who frequently practise receptive oral sex with ejaculation may be warranted.

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.

HIV voluntary counselling and testing for African communities in London: learning from experiences in Kenya.

OBJECTIVES: To explore the feasibility and acceptability of translating a successful voluntary counselling and testing (VCT) service model from Kenya to African communities in London. METHODS: Qualitative study with focus group discussions and a structured workshop with key informants. Five focus group discussions were conducted in London with 42 participants from 14 African countries between August 2006 and January 2007. A workshop was held with 28 key informants. Transcripts from the group discussions and workshop were analysed for recurrent themes. RESULTS: Participants indicated that a community-based HIV VCT service would be acceptable to African communities in London, but also identified barriers to uptake: HIV-related stigma, concerns about confidentiality, and doubts about the ability of community-based services to maintain professional standards of care. Workshop participants highlighted three key requirements to ensure feasibility: (a) efficient referrals to sexual health services for the newly diagnosed; (b) a locally appropriate testing algorithm and quality assurance scheme; (c) a training programme for VCT counsellors. CONCLUSIONS: Offering community-based VCT with rapid HIV tests appears feasible within a UK context and acceptable to African communities in London, provided that clients' confidentiality is ensured and appropriate support is given to the newly diagnosed. However, the persistence of concerns related to HIV-related stigma among African communities suggests that routine opt-out testing in healthcare settings may also constitute an effective approach to reducing the proportion of late diagnoses in this group. HIV service models and programmes from Africa constitute a valuable knowledge base for innovative interventions in other settings, including developed countries.

The natural history of Niemann-Pick disease type C in the UK.

Niemann-Pick disease type C (NPC) is an autosomal recessive, neurovisceral lipid storage disorder. Mutations in two genes (NPC1 and NPC2) produce indistinguishable clinical phenotypes by biochemical mechanisms that have not yet been entirely clarified. The wide spectrum of clinical presentations of NPC includes hepatic and pulmonary disease as well as a range of neuropsychiatric disorders. Late-onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied in adult neurology clinics. The clinical presentation and follow-up of 94 patients with NPC is described, 58 of whom were still alive at the time this report was prepared. The age at diagnosis ranged from the prenatal period (with hydrops fetalis) up to 51 years. This review of NPC patients in the UK confirms the phenotypic variability of this inherited lipid storage disorder reported elsewhere. Although a non-neuronopathic variant has been described, most patients in this series who survived childhood inevitably suffered neurological and in some cases neuropsychiatric deterioration. While symptomatic treatment, such as anticholinergic and antiepileptic drugs, can alleviate some aspects of the disease, there is a clear need to develop a specific treatment for this progressively debilitating neurodegenerative disorder.

Why the(y) wait? Key informant understandings of factors contributing to late presentation and poor utilization of HIV health and social care services by African migrants in Britain.

The majority of new HIV diagnoses in the UK occur in people with heterosexually acquired HIV infection, the majority of whom are migrant Africans. In the UK HIV positive Africans access HIV services at a later stage of disease than non-Africans (Burns et al., 2001; Sinka et al., 2003). Employing purposive sampling techniques, semi-structured interviews were conducted with key informants to identify the key issues affecting utilization of HIV services for Africans in Britain. Considerable agreement about the major issues influencing uptake of HIV services existed amongst the key informants. Respondents felt there was high HIV awareness but this did not translate into perception of individual risk. Home country experience and community mobilization was highly influential on HIV awareness, appreciation of risk, and attitudes to health services. Institutional barriers to care exist; these include lack of cultural understanding, lack of open access or community clinics, failure to integrate care with support organizations, and the inability of many General Practitioners to address HIV effectively. Community involvement should include input to ensure there is: better cultural understanding within the health care system; normalization of the HIV testing process; and a clear message on the effectiveness of therapy.

Who uses condoms with whom? Evidence from national probability sample surveys.

OBJECTIVES: To explore the changing pattern of condom use from 1990 to 2000; to identify sociodemographic and behavioural factors associated with condom use; and reasons for condom use in 2000. METHODS: Large probability sample surveys administered among those resident in Britain aged 16-44 (n = 13 765 in 1990, n = 11 161 in 2000). Face to face interviews with self completion components collected sociodemographic, behavioural, and attitudinal data. RESULTS: Condom use in the past year among sexually active 16-24 year old men increased from 61.0% in 1990 to 82.1% in 2000 (p<0.0001), and from 42.0% to 63.2% (p<0.0001) among women of the same age, with smaller increases among older age groups. Among individuals reporting at least two partners in the previous 4 week period, approximately two thirds reported inconsistent or no condom use (63.1% (95% CI 55.9% to 69.8%) of the men and 68.5% (95% CI 57.6% to 77.7%) of the women). CONCLUSIONS: Rates of condom use increased substantially between 1990 and 2000, particularly among young people. However, inconsistent condom use by individuals with high rates of partner acquisition may contribute significantly to the recent resurgence in STIs. This group is an important target for intensive and specific sexual health interventions.

Behavioural predictors of subsequent hepatitis C diagnosis in a UK clinic sample of HIV positive men who have sex with men.

OBJECTIVE: To explore the associations between self reported high risk sexual behaviours and subsequent diagnosis with hepatitis C virus (HCV) infection. METHODS: The Sex, Health and Anti-Retrovirals Project (SHARP) was a cross sectional study of sexual behaviour in HIV positive, men who have sex with men (MSM) attending a London outpatient clinic. From July 1999 to August 2000 participants completed a computer assisted self interview questionnaire (CASI) on recent sexual behaviour, recreational drug use, and detailed reporting of the last two sexual episodes involving different partners. Results were combined with routine clinic data and subsequent testing for HCV up to 21 April 2005. A new HCV diagnosis was defined as anti-HCV antibody seroconversion or positive HCV RNA following a previous negative. Incident rate ratios (IRR) were calculated using Poisson regression in Stata (version 9). Men contributed time at risk from interview until either their diagnosis or their last negative test result. RESULTS: Of the 422 men who completed questionnaires, 308 (73%) had sufficient clinical and HCV testing data available for analysis. Incident HCV infection was identified in 11 men. Unprotected anal intercourse, more than 30 sex partners in the past year, higher numbers of new anal sex partners, rimming (oro-anal sex), fisting, use of sex toys, and intranasal recreational drug use were associated with HCV. In multivariate analysis only fisting remained associated with HCV (adjusted IRR 6.27, p = 0.005). CONCLUSIONS: In this study of HIV positive MSM, fisting is strongly associated with HCV infection. Where individuals report high risk sexual behaviours, clinicians should offer appropriate testing for HCV infection.

Refocusing health promotion for syphilis prevention: results of a case-control study of men who have sex with men on England's south coast.

BACKGROUND: Prevention interventions have had little impact on syphilis outbreaks among men who have sex with men (MSM) and diagnosis rates continue to rise rapidly. Detailed studies of the determinants of syphilis transmission are needed to inform new prevention interventions. OBJECTIVE: To investigate factors associated with recent syphilis diagnosis and recommend strategies for improved prevention interventions. METHODS: A case-control study of MSM attending genitourinary medicine (GUM) and HIV outpatient clinics. Cases were MSM testing positive for early syphilis, based on either laboratory or microscopy results, with those testing negative being controls. All participants completed the same anonymous questionnaire covering demographics, lifestyle, sexual behaviour, and sexual partnerships. RESULTS: 50 cases and 108 controls returned questionnaires. Syphilis diagnosis was significantly associated with sexually transmitted infection history, recent recreational drug use, receptive anal sex practices, but not insertive ones, higher numbers of oral sex partners, but not specific oral sex practices. Overall, there were no differences between HIV positive and HIV negative/untested men in reporting of sexual behaviours or partnership combinations. The use of public sex settings (backrooms, saunas, "cruising grounds," etc) was reported by 68% of all participants and not significantly associated with syphilis diagnosis. CONCLUSIONS: Many key behavioural and partnership risk factors for syphilis are also risk behaviours for HIV transmission and point to the need for integrated strategies that tackle the two infections together. Simplified procedures for syphilis screening should be available in GUM clinical settings, along with targeted community outreach prevention interventions.

Community based syphilis screening: feasibility, acceptability, and effectiveness in case finding.

OBJECTIVES: To investigate the feasibility and acceptability of implementing community based syphilis screening using different sample collection techniques, and its effectiveness in screening at-risk populations and identifying new syphilis cases. METHODS: Two phases of syphilis screening were conducted in venues frequented by men who have sex with men (MSM). Phase 1 used venepuncture and phase 2 a validated saliva test. Evaluation used quantitative data from testers, venues and the local genitourinary medicine (GUM) clinic, and qualitative data from venue and programme staff. RESULTS: 1090 MSM were tested over 7 weeks. 62% of testers had not attended a GUM clinic in the past year. 64% of testers reported > or = 2 sexual contacts in the past 90 days and 11% reported > or = 10. Similar diagnosis rates were recorded for phase 1 (1.4%) and phase 2 (1.8%). There was greater uptake of testing with the saliva test in saunas during phase 2. CONCLUSIONS: Syphilis screening in gay venues is feasible and acceptable to at-risk MSM, and reaches a group not routinely accessing GUM services. The low case detection for syphilis suggest this approach, while unlikely to contain outbreaks, may be more useful if combined with screening for other sexually transmitted infections and effective health promotion strategies.