Roy Robertson

A Genetic Analysis of Hepatitis C Virus Transmission between Injection Drug Users

Hepatitis C virus (HCV) genotype 1a and 3a partial NS5B gene segment sequences obtained from 154 HCV-infected injection drug users were studied to determine the extent to which HCV transmission occurs between injection drug user communities in London, Edinburgh, Glasgow (United Kingdom), Marseilles (France), and Melbourne. Phylogenetic relationships between sequences were analyzed by conventional methods and by a recently developed method that numerically scores the extent of sequence segregation between groups through calculation of association indices. The association indices revealed that none of the cities sampled support an HCV population that is completely isolated from that circulating in the other cities. Sequences from Melbourne were most isolated, whereas those from London were most dispersed. This suggests that HCV transmission between these cities occurs, with London playing a pivotal role. The degree of city-specific segregation of HCV subtype 1a sequences was linearly related to that of subtype 3a, indicating that these subtypes have spread through similar transmission networks.

Transmission of HIV to heterosexual partners of infected men and women.

Future heterosexual spread of HIV will in part depend on the efficiency of transmission from men to women and from women to men. We studied seventy-eight female sexual partners of men infected with HIV and 18 male sexual partners of infected women. Participants were interviewed concerning sexual practices, use of contraception and other risk factors for HIV infection. Fifteen out of 78 (19.2%) female partners and one out of eighteen (5.5%) male partners were seropositive for HIV antibody. All couples had practised vaginal intercourse. Seropositive female partners did not differ significantly from seronegative partners with regard to length of relationship, number of acts of vaginal intercourse, other sexual practices, stage of clinical disease in the index case, or numbers of other sexual partners in the last five years. In two women, seroconversion was documented after one act of unprotected sexual intercourse. The majority of infected female partners (eight out of 15) had sexual relationships with men who were asymptomatic and did not practice anal intercourse. Biological factors such as variability in infectivity of the index case and susceptibility of the contact, as well as behavioural variables may be important in determining transmission.

Predisposition to accelerated Alzheimer-related changes in the brains of human immunodeficiency virus negative opiate abusers

Cognitive impairment is a recognized effect of drug misuse, including the use of opiates. The pathological basis for this is unknown but the temporal and frontal cortices have been implicated. We have shown previously that deposits of hyperphosphorylated tau in drug user brains exceed those seen in age-matched controls. The present quantitative study of hyperphosphorylated tau and beta amyloid in drug user brains allows comparison with the related pathology in Alzheimers disease. Brains were obtained from the Edinburgh Medical Research Council Brain Banks, comprising 39 human immunodeficiency virus negative drug users, five subjects with Alzheimers disease and 37 age-matched, cognitively normal controls, all legally and ethically approved for research. Hyperphosphorylated tau positive (AT8, AT100) neuropil threads were significantly increased in the frontal and temporal cortex, and in the locus coeruleus, of drug users aged > 30 years (all P = 0.04). Under the age of 30 years, drug users showed a similar increase in neuropil threads compared with controls, but this reached significance only in the frontal cortex (P = 0.03). Immunopositivity for both three- and four-repeat tau was present in drug user brains. There was a direct relationship between the numbers of neuropil threads and of neurofibrillary tangles: neurofibrillary tangles were sparse in brains that had neuropil thread counts below 200 cm(2). Hyperphosphorylated tau positive neuropil threads increased at a faster rate in drug users than in controls and the levels of the phosphorylating enzyme, GSK-3, was raised in drug user brains. Beta amyloid (AB4, AB42 and 4G8) was raised in drug user brains (mainly as shadow plaques) but not significantly different from controls and there was no correlation between high beta amyloid and hyperphosphorylated tau in individual cases. Hyperphosphorylated tau levels correlated significantly (P = 0.038) with microglial activation in drug users but not in controls. The levels of hyperphosphorylated tau in drug users fell far short of those seen in Alzheimers disease but overlapped with those in elderly controls. We conclude that drug users show early Alzheimers disease-related brain pathology that may be the basis for cognitive impairment and that neuroinflammation is an early accompanying feature. This provides an opportunity to study the pathogenesis of tau pathology in the human brain.

HIV and drug misuse in the Edinburgh cohort

Summary: The Edinburgh cohort of intravenous drug users (IVDUs) became infected with HIV between 1983 and 1984. Before the era of effective therapy, many of these infected IVDUs displayed cognitive impairments on progressing to AIDS and were found to have HIV encephalitis (HIVE). Full autopsies were conducted on these patients, providing an opportunity to study the intersecting pathology of pure HIVE and drug use. High proviral load in the brain correlated well with the presence of giant cells and HIV p24 positivity. In presymptomatic HIV infection, IVDUs were found to have a lymphocytic infiltrate in the central nervous system (CNS). Apart from the expected microglial activation in the presence of HIV infection of the CNS, drug use in its own right was found to be associated with microglial activation. Examination of HIV‐negative IVDUs revealed a number of neuropathologic features, including microglial activation, which may underpin HIV‐related pathology in the CNS. HIV isolated from different regions of the brain was exclusively of R5‐tropic type throughout the course of infection. Detailed studies of p17gag and V3 sequences suggest that viral sequestration occurs in the CNS before the onset of AIDS and that increasing diversity of HIV variants within the brain is associated with increasing severity of HIVE. Because brain isolates have proved to be different from those in lymphoid tissue (and blood), it is likely that selective neuroadaptive pressures operate before HIVE supervenes. Drug abuse may be synergistic in this process through activation of microglia, breakdown of the blood‐brain barrier, and direct neurotoxicity. Collections of clinically well‐characterized HIV‐infected tissues such as those in the Edinburgh Brain Bank are a vital resource to support ongoing studies of viral pathogenesis in the CNS and interactions with drug abuse.

From evidence to policy: The Scottish national naloxone programme

Drug-related death (DRD) is a major public health problem globally, with rates in Scotland higher than any other UK region and among the highest in Europe. One of the most important public health interventions to emerge aimed at tackling rising DRD rates is the distribution of naloxone, the opioid antagonist, for peer administration. The Scottish Government established a national naloxone programme in 2010 aimed at reducing the increasing levels of DRD. The national coverage of the programme is unique by comparison and is an important development in substance misuse public health. This review aims to describe the journey to this landmark public health programme, detailing the research, advocacy and policy contributions that facilitated its creation. The use of naloxone in other countries will also be described, discussing the barriers in place to adopting similar national programmes elsewhere.

Cannabis, tobacco smoking, and lung function: a cross-sectional observational study in a general practice population

BACKGROUND Health concerns around cannabis use have focused on the potential relationship with psychosis but the effect of cannabis smoking on respiratory health has received less attention. AIM To investigate the association between tobacco-only smoking compared with tobacco plus cannabis smoking and adverse outcomes in respiratory health and lung function. DESIGN AND SETTING The design was cross-sectional with two groups recruited: cigarette smokers with tobacco pack-years; cannabis smokers with cannabis joint-years. Recruitment occurred in a general practice in Scotland with 12 500 patients. METHOD Exposures measured were tobacco smoking (pack-years) and cannabis smoking (joint-years). Cannabis type (resin, herbal, or both) was recorded by self-report. Respiratory symptoms were recorded using NHANES and MRC questionnaires. Lung function was measured by spirometry (FEV1/FVC ratio). RESULTS Participants consisted of 500 individuals (242 males). Mean age of tobacco-only smokers was 45 years; median tobacco exposure was 25 pack-years. Mean age of cannabis and tobacco smokers was 37 years; median tobacco exposure was 19 pack-years, rising to 22.5 when tobacco smoked with cannabis. Although tobacco and cannabis use were associated with increased reporting of respiratory symptoms, this was higher among those who also smoked cannabis. Both tobacco and cannabis users had evidence of impaired lung function but, in fully adjusted analyses, each additional joint-year of cannabis use was associated with a 0.3% (95% confidence interval = 0.0 to 0.5) increase in prevalence of chronic obstructive pulmonary disease. CONCLUSION In adults who predominantly smoked resin cannabis mixed with tobacco, additional adverse effects were observed on respiratory health relating to cannabis use.

Factors affecting repeated cessations of injecting drug use and relapses during the entire injecting career among the Edinburgh Addiction Cohort.

Highlights • We examine the pattern of ceasing and relapsing during the entire injecting career.• Opiate substitution treatment (OST) was associated with reduced time to cessation.• OST was associated with lower risk of relapse, but not statistically significant.• Women and older people who inject drugs (PWID) were less likely to relapse (had lower hazard of relapse).• With each relapse, time to next cessation event is shortened.

What Happens When GPs Proactively Prescribe NRT Patches in a Disadvantaged Community

Background and Aims: The high prevalence of smoking in disadvantaged communities gives serious cause for concern in terms of adverse effects on health and social outcomes. In Scotland, smoking—related lung cancer rates are particularly high and compare less favourably with the rest of the UK and Europe. GPs are increasingly being recognised as having an important role in smoking cessation and are allowed to prescribe NRT to those on a low income. This study aimed to follow up a group patients from a disadvantaged area who had been prescribed nicotine patches by their GP. Methods: An initial self-complete questionnaire gathered details on age, sex, motivation, marital status, employment history, contact with other smokers, concern about weight gain, and nicotine dependence. (Nicotine dependence was assessed by using the Tagerstrom Test). Follow up was carried out at three months after commencing NRT prescription. Data was also gathered from patient case notes as to whether the participant had a smoking-related diagnosis, periods of depression, drug and/or alcohol problems. Outcome was measured in terms of “smoke the same”, “smoke less” and “stopped”. The statistical methods used for testing each factor against smoking were Spearman rank correlation, chi-squared test for trend and Kruskal-Wallis test. Basic descriptive statistics were used to report general outcomes of the study. Results: The study enrolled 120 patients but 19 were lost to follow up. Out of 101 who used their prescription, 35 were smoking the same, 46 were smoking less and 20 had stopped. The variables most strongly affecting outcome were age, with older smokers having more success (p<0.001), and those who had a diagnosis of depression having a worse outcome in terms of smoking cessation (p<0.05). Conclusion: This studys findings indicate that encouraging GPs to take a proactive approach in prescribing NRT is effective, even in an area of socio-economic deprivation, and particularly with older smokers.

Hepatitis C infection in a cohort of injecting drug users

Objectives: To establish prevalence rates for hepatitis C antibodies in a cohort of injecting drug users and to study factors influencing positivity. To record current injecting practices. To identify the entry of hepatitis C into the cohort. To investigate the association between HCV positivity and PCR status. Design: (i) Questionnaire covering demographic data, injecting behaviour, number of sexual partners, awareness of risk behaviour, awareness of serological status and subsequent behaviour change. (ii) Second questionnaire on recent drug use and injecting practices with a strong focus on frequency of sharing paraphernalia. (iii) PCR testing on HCV positive. (iv) Retrospective testing of subgroup to determine entry of hepatitis C into the cohort. Setting: Recruitment in a large general practice in North West Edinburgh. Participants: The main study group consisted of a large cohort (619) of past or present illegal drug injectors. The first, n=95, received the questionnaire (i). If they had injected in the past month they also completed the second questionnaire (n=26). PCR testing was carried out on a subset of the group of 95, selected because they had had a recent blood test (n=33). A random group of 20 of the main cohort of 619 who had hepatitis C antibody positive tests were selected for retrospective testing. Main outcome measures: Prevalence of HCV antibodies, perceived and actual risk-taking behaviour. Antibody status of randomly selected early stored specimens. HCV PCR status. Results: Positivity was associated with age, year of first use, sharing of injecting paraphernalia, year of most sharing, as well as length of use of injected drugs. Awareness of HCV as a risk was found to be later than either HBV or HIV. No significant difference was found in numbers of sexual partners between those who were HCV positive and negative. Women and younger drug users were found to engage in more sharing of injecting paraphernalia, with women having more sharing partners. The entry of HCV into the cohort predated the early stored blood samples. No correlation was identified between length of drug use and PCR status. Conclusions: HCV is acquired early in drug injecting careers. Whether or not this is changing is unclear but attempts to educate and support need to be directed towards younger drug users and women, who are at risk. Knowledge of risks from sharing injecting paraphernalia is poor. The impact of the hepatitis C epidemic is likely to continue to escalate with cases progressing to advanced clinical stages. PCR tests could be employed to select cases for referral or treatment. The harm reduction message needs to be clarified and re-emphasised.

Targets for Hepatitis C virus test uptake and case-finding among injecting drug users: in prisons and general practice

We re-analyse data on new diagnoses of Hepatitis C virus (HCV) for injectors in prison or attending general practices which were relied on for the cost-effectiveness of HCV testing in injectors. We use these revised estimates to suggest readily achievable targets in Scottish general practices on HCV diagnoses for injectors born in 1956–1975. Using audit data from general practices around Edinburgh, we confirm that, with effort, the suggested targets are achievable. On re-analysis, we found that over 20% of HCV-undiagnosed injectors in English prisons accepted HCV testing, and half the injectors aged 30–54 years who attended a Glasgow general practice. On the basis of 30% HCV test uptake and 80% of ever-injectors having self-identified, a target of 2500 HCV diagnoses within a year in known ever-injectors born in 1956–1975 attending Scottish general practices is feasible. Its target of five new HCV diagnoses was achieved during an HCV testing intervention by Muirhouse Practice, Edinburgh. During a 2-year audit period, 86 other general practices around Edinburgh providing enhanced services for drug users increased HCV test uptake by known ever-injectors from 43% (314/727) to 62% (655/1062) in the 1956–1975 birth-cohort. Their new HCV diagnoses in ever-injectors were 171 over two years against a target of 166 within 1 year.