Summary Background Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir–emtricitabine reduces the risk of HIV infection. However, this ...benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. Methods PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov ( NCT02065986 ). Findings We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64–96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3–11·3). 13 men (90% CI 9–23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. Interpretation In this high incidence population, daily tenofovir–emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. Funding MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.
Summary Background Mathematical models are widely used to simulate the effects of interventions to control HIV and to project future epidemiological trends and resource needs. We aimed to validate ...past model projections against data from a large household survey done in South Africa in 2012. Methods We compared ten model projections of HIV prevalence, HIV incidence, and antiretroviral therapy (ART) coverage for South Africa with estimates from national household survey data from 2012. Model projections for 2012 were made before the publication of the 2012 household survey. We compared adult (age 15–49 years) HIV prevalence in 2012, the change in prevalence between 2008 and 2012, and prevalence, incidence, and ART coverage by sex and by age groups between model projections and the 2012 household survey. Findings All models projected lower prevalence estimates for 2012 than the survey estimate (18·8%), with eight models' central projections being below the survey 95% CI (17·5–20·3). Eight models projected that HIV prevalence would remain unchanged (n=5) or decline (n=3) between 2008 and 2012, whereas prevalence estimates from the household surveys increased from 16·9% in 2008 to 18·8% in 2012 (difference 1·9, 95% CI −0·1 to 3·9). Model projections accurately predicted the 1·6 percentage point prevalence decline (95% CI −0·3 to 3·5) in young adults aged 15–24 years, and the 2·2 percentage point (0·5 to 3·9) increase in those aged 50 years and older. Models accurately represented the number of adults on ART in 2012; six of ten models were within the survey 95% CI of 1·54–2·12 million. However, the differential ART coverage between women and men was not fully captured; all model projections of the sex ratio of women to men on ART were lower than the survey estimate of 2·22 (95% CI 1·73–2·71). Interpretation Projections for overall declines in HIV epidemics during the ART era might have been optimistic. Future treatment and HIV prevention needs might be greater than previously forecasted. Additional data about service provision for HIV care could help inform more accurate projections. Funding Bill & Melinda Gates Foundation.
Recreational drug use in men who have sex with men (MSM) is of concern because it might be linked to the transmission of HIV and other sexually transmitted infections. Evidence about drug use in ...HIV-diagnosed MSM in the UK is limited by representativeness of the study populations. We describe patterns of drug use and associations with sexual behaviours in HIV-diagnosed MSM in the UK.
We used data from the cross-sectional ASTRA study, which recruited participants aged 18 years or older with HIV from eight HIV outpatient clinics in the UK between Feb 1, 2011, and Dec 31, 2012. We examined data for MSM, assessing the prevalence of recreational drug use and polydrug use in the previous 3 months and associations with sociodemographic and HIV-related factors. We examined the association of polydrug use with measures of condomless sex in the previous 3 months and with other sexual behaviours.
Our analysis included data for 2248 MSM: 2136 (95%) were gay, 1973 (89%) were white, 1904 (85%) were on antiretroviral treatment (ART), and 1682 (76%) had a viral load of 50 copies per mL or lower. 1138 (51%) used recreational drugs in the previous 3 months; 608 (27%) used nitrites, 477 (21%) used cannabis, 460 (21%) used erectile dysfunction drugs, 453 (20%) used cocaine, 280 (13%) used ketamine, 258 (12%) used 3,4-methylenedioxy-N-methylamphetamine (MDMA), 221 (10%) used gamma-hydroxybutyrate or gamma-butyrolactone, 175 (8%) used methamphetamine, and 162 (7%) used mephedrone. In the 1138 individuals who used drugs, 529 (47%) used three or more drugs and 241 (21%) used five or more. Prevalence of injection drug use was 3% (n=68). Drug use was independently associated with younger age (p<0·0001), not being religious (p=0·001), having an HIV-positive stable partner (p=0·0008), HIV-serostatus disclosure (p=0·009), smoking (p<0·0001), evidence of harmful alcohol drinking (p=0·0001), and ART non-adherence (p<0·0001). Increasing polydrug use was associated with increasing prevalence of condomless sex (prevalence range from no drug use to use of five or more drugs was 24% to 78%), condomless sex with HIV-seroconcordant partners (17% to 69%), condomless sex with HIV-serodiscordant partners (10% to 25%), and higher-HIV-risk condomless sex after taking viral load into account (4% to 16%; p≤0·005 for all). Associations were similar after adjustment for sociodemographic and HIV-related factors. Methamphetamine was more strongly associated with higher-HIV-risk condomless sex than were other commonly used drugs.
Polydrug use is prevalent in HIV-diagnosed MSM and is strongly associated with condomless sex. Specialist support services for MSM with HIV who use recreational drugs might be beneficial in the reduction of harm and prevention of ongoing transmission of HIV and other sexually transmitted infections.
National Institute for Health Research.
Summary Background Sexual behaviour and relationships are key components of wellbeing and are affected by social norms, attitudes, and health. We present data on sexual behaviours and attitudes in ...Britain (England, Scotland, and Wales) from the three National Surveys of Sexual Attitudes and Lifestyles (Natsal). Methods We used a multistage, clustered, and stratified probability sample design. Within each of the 1727 sampled postcode sectors for Natsal-3, 30 or 36 addresses were randomly selected and then assigned to interviewers. To oversample individuals aged 16–34 years, we randomly allocated addresses to either the core sample (in which individuals aged 16–74 years were eligible) or the boost sample (in which only individuals aged 16–34 years were eligible). Interviewers visited all sampled addresses between Sept 6, 2010, and Aug 31, 2012, and randomly selected one eligible individual from each household to be invited to participate. Participants completed the survey in their own homes through computer-assisted face-to-face interviews and self-interview. We analysed data from this survey, weighted to account for unequal selection probabilities and non-response to correct for differences in sex, age group, and region according to 2011 Census figures. We then compared data from participants aged 16–44 years from Natsal-1 (1990–91), Natsal-2 (1999–2001), and Natsal-3. Findings Interviews were completed with 15 162 participants (6293 men, 8869 women) from 26 274 eligible addresses (57·7%). 82·1% (95% CI 81·0–83·1%) of men and 77·7% (76·7–78·7%) of women reported at least one sexual partner of the opposite sex in the past year. The proportion generally decreased with age, as did the range of sexual practices with partners of the opposite sex, especially in women. The increased sexual activity and diversity reported in Natsal-2 in individuals aged 16–44 years when compared with Natsal-1 has generally been sustained in Natsal-3, but in men has generally not risen further. However, in women, the number of male sexual partners over the lifetime (age-adjusted odds ratio 1·18, 95% CI 1·08–1·28), proportion reporting ever having had a sexual experience with genital contact with another woman (1·69, 1·43–2·00), and proportion reporting at least one female sexual partner in the past 5 years (2·00, 1·59–2·51) increased in Natsal-3 compared with Natsal-2. While reported number of occasions of heterosexual intercourse in the past 4 weeks had reduced since Natsal-2, we recorded an expansion of heterosexual repertoires—particularly in oral and anal sex—over time. Acceptance of same-sex partnerships and intolerance of non-exclusivity in marriage increased in men and women in Natsal-3. Interpretation Sexual lifestyles in Britain have changed substantially in the past 60 years, with changes in behaviour seeming greater in women than men. The continuation of sexual activity into later life—albeit reduced in range and frequency—emphasises that attention to sexual health and wellbeing is needed throughout the life course. Funding Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health.
Summary Background Despite its importance to sexual health and wellbeing, sexual function is given little attention in sexual health policy. Population-based studies are needed to understand sexual ...function across the life course. Methods We undertook a probability sample survey (the third National Survey of Sexual Attitudes and Lifestyles Natsal-3) of 15 162 individuals aged 16–74 years who lived in Britain (England, Scotland, and Wales). Interviews were done between Sept 6, 2010, and Aug 31, 2012. We assessed the distribution of sexual function by use of a novel validated measure (the Natsal-SF), which assessed problems with individual sexual response, sexual function in a relationship context, and self-appraisal of sex life (17 items; 16 items per gender). We assess factors associated with low sexual function (defined as the lowest quintile of distribution of Natsal-SF scores) and the distribution of components of the measure. Participants reporting one or more sexual partner in the past year were given a score on the Natsal-SF (11 690 participants). 4122 of these participants were not in a relationship for all of the past year and we employed the full information maximum likelihood method to handle missing data on four relationship items. Findings We obtained data for 4913 men and 6777 women for the Natsal-SF. For men and women, low sexual function was associated with increased age, and, after age-adjustment, with depression (adjusted odds ratio 3·70 95% CI 2·90–4·72 for men and 4·11 3·36–5·04 for women) and self-reported poor health status (2·63 1·73–3·98 and 2·41 1·72–3·39). Low sexual function was also associated with experiencing the end of a relationship (1·52 1·18–1·95 and 1·77 1·44–2·17), inability to talk easily about sex with a partner (2·36 1·94–2·88 and 2·82 2·28–3·48), and not being happy in the relationship (2·89 2·32–3·61 and 4·10 3·39–4·97). Associations were also noted with engaging in fewer than four sex acts in the past 4 weeks (3·13 2·58–3·79 and 3·38 2·80–4·09), having had same sex partners (2·28 1·56–3·35 and 1·60 1·16–2·20), paying for sex (in men only; 2·62 1·46–4·71), and higher numbers of lifetime sexual partners (in women only; 2·12 1·68–2·67 for ten or more partners). Low sexual function was also associated with negative sexual health outcomes such as experience of non-volitional sex (1·98 1·14–3·43 and 2·18 1·79–2·66) and STI diagnosis (1·50 1·06–2·11 and 1·83 1·35–2·47). Among individuals reporting sex in the past year, problems with sexual response were common (41·6% of men and 51·2% of women reported one or more problem) but self-reported distress about sex lives was much less common (9·9% and 10·9%). For individuals in a sexual relationship for the past year, 23·4% of men and 27·4% of women reported an imbalance in level of interest in sex between partners, and 18·0% of men and 17·1% of women said that their partner had had sexual difficulties. Most participants who did not have sex in the past year were not dissatisfied, distressed, or avoiding sex because of sexual difficulties. Interpretation Wide variability exists in the distribution of sexual function scores. Low sexual function is associated with negative sexual health outcomes, supporting calls for a greater emphasis on sexual function in sexual health policy and interventions. Funding Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health.
Summary Background Invasive community-onset staphylococcal disease has emerged worldwide associated with Panton-Valentine leucocidin (PVL) toxin. Whether PVL is pathogenic or an epidemiological ...marker is unclear. We investigate the role of PVL in disease, colonisation, and clinical outcome. Methods We searched Medline and Embase for original research reporting the prevalence of PVL genes among Staphylococcus aureus pneumonia, bacteraemia, musculoskeletal infection, skin and soft-tissue infection, or colonisation published before Oct 1, 2011. We calculated odds ratios (ORs) to compare patients with PVL-positive colonisation and each infection relative to the odds of PVL-positive skin and soft-tissue infection. We did meta-analyses to estimate odds of infection or colonisation with a PVL-positive strain with fixed-effects or random-effects models, depending on the results of tests for heterogeneity. Results Of 509 articles identified by our search strategy, 76 studies from 31 countries met our inclusion criteria. PVL strains are strongly associated with skin and soft-tissue infections, but are comparatively rare in pneumonia (OR 0·37, 95% CI 0·22–0·63), musculoskeletal infections (0·44, 0·19–0·99), bacteraemias (0·10, 0·06–0·18), and colonising strains (0·07, 0·01–0·31). PVL-positive skin and soft-tissue infections are more likely to be treated surgically than are PVL-negative infections, and children with PVL-positive musculoskeletal disease might have increased morbidity. For other forms of disease we identified no evidence that PVL affects outcome. Interpretation PVL genes are consistently associated with skin and soft-tissue infections and are comparatively rare in invasive disease. This finding challenges the view that PVL mainly causes invasive disease with poor prognosis. Population-based studies are needed to define the role of PVL in mild, moderate, and severe disease and to inform control strategies. Funding None.
Summary Background Population-based estimates of prevalence, risk distribution, and intervention uptake inform delivery of control programmes for sexually transmitted infections (STIs). We undertook ...the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) after implementation of national sexual health strategies, and describe the epidemiology of four STIs in Britain (England, Scotland, and Wales) and the uptake of interventions. Methods Between Sept 6, 2010 and Aug 31, 2012, we did a probability sample survey of 15 162 women and men aged 16–74 years in Britain. Participants were interviewed with computer-assisted face-to-face and self-completion questionnaires. Urine from a sample of participants aged 16–44 years who reported at least one sexual partner over the lifetime was tested for the presence of Chlamydia trachomatis , type-specific human papillomavirus (HPV), Neisseria gonorrhoeae , and HIV antibody. We describe age-specific and sex-specific prevalences of infection and intervention uptake, in relation to demographic and behavioural factors, and explore changes since Natsal-1 (1990–91) and Natsal-2 (1999–2001). Findings Of 8047 eligible participants invited to provide a urine sample, 4828 (60%) agreed. We excluded 278 samples, leaving 4550 (94%) participants with STI test results. Chlamydia prevalence was 1·5% (95% CI 1·1–2·0) in women and 1·1% (0·7–1·6) in men. Prevalences in individuals aged 16–24 years were 3·1% (2·2–4·3) in women and 2·3% (1·5–3·4) in men. Area-level deprivation and higher numbers of partners, especially without use of condoms, were risk factors. However, 60·4% (45·5–73·7) of chlamydia in women and 43·3% (25·9–62·5) in men was in individuals who had had one partner in the past year. Among sexually active 16–24-year-olds, 54·2% (51·4–56·9) of women and 34·6% (31·8–37·4) of men reported testing for chlamydia in the past year, with testing higher in those with more partners. High-risk HPV was detected in 15·9% (14·4–17·5) of women, similar to in Natsal-2. Coverage of HPV catch-up vaccination was 61·5% (58·2–64·7). Prevalence of HPV types 16 and 18 in women aged 18–20 years was lower in Natsal-3 than Natsal-2 (5·8% 3·9–8·6 vs 11·3% 6·8–18·2; age-adjusted odds ratio 0·44 0·21–0·94). Gonorrhoea (<0·1% prevalence in women and men) and HIV (0·1% prevalence in women and 0·2% in men) were uncommon and restricted to participants with recognised high-risk factors. Since Natsal-2, substantial increases were noted in attendance at sexual health clinics (from 6·7% to 21·4% in women and from 7·7% to 19·6% in men) and HIV testing (from 8·7% to 27·6% in women and from 9·2% to 16·9% in men) in the past 5 years. Interpretation STIs were distributed heterogeneously, requiring general and infection-specific interventions. Increases in testing and attendance at sexual health clinics, especially in people at highest risk, are encouraging. However, STIs persist both in individuals accessing and those not accessing services. Our findings provide empirical evidence to inform future sexual health interventions and services. Funding Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health.
Summary Background Unplanned pregnancy is a key public health indicator. We describe the prevalence of unplanned pregnancy, and associated factors, in a general population sample in Britain (England, ...Scotland, and Wales). Method We did a probability sample survey, the third National Survey of Sexual Attitudes and Lifestyles (Natsal-3), of 15 162 men and women aged 16–74 years in Britain, including 5686 women of child-bearing age (16–44 years) who were included in the pregnancy analysis, between Sept 6, 2010, and Aug 31, 2012. We describe the planning status of pregnancies with known outcomes in the past year, and report the annual population prevalence of unplanned pregnancy, using a validated, multicriteria, multi-outcome measure (the London Measure of Unplanned Pregnancy). We set the findings in the context of secular trends in reproductive health-related events, and patterns across the life course. Findings 9·7% of women aged 16–44 years had pregnancies with known outcome in the year before interview, of which 16·2% (95% CI 13·1–19·9) scored as unplanned, 29·0% (25·2–33·2) as ambivalent, and 54·8% (50·3–59·2) as planned, giving an annual prevalence estimate for unplanned pregnancy of 1·5% (1·2–1·9). Pregnancies in women aged 16–19 years were most commonly unplanned (45·2% 30·8–60·5). However, most unplanned pregnancies were in women aged 20–34 years (62·4% 50·2–73·2). Factors strongly associated with unplanned pregnancy were first sexual intercourse before 16 years of age (age-adjusted odds ratio 2·85 95% CI 1·77–4·57, current smoking (2·47 1·46–4·18), recent use of drugs other than cannabis (3·41 1·64–7·11), and lower educational attainment. Unplanned pregnancy was also associated with lack of sexual competence at first sexual intercourse (1·90 1·14–3·08), reporting higher frequency of sex (2·11 1·25–3·57 for five or more times in the past 4 weeks), receiving sex education mainly from a non-school-based source (1·84 1·12–3·00), and current depression (1·96 1·10–3·47). Interpretation The increasing intervals between first sexual intercourse, cohabitation, and childbearing means that, on average, women in Britain spend about 30 years of their life needing to avert an unplanned pregnancy. Our data offer scope for primary prevention aimed at reducing the rate of unplanned conceptions, and secondary prevention aimed at modification of health behaviours and health disorders in unplanned pregnancy that might be harmful for mother and child. Funding Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and the Department of Health.
Summary Background We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral ...sclerosis (ALS) and frontotemporal dementia (FTD). Methods We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion. Findings In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years. Interpretation A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases. Funding Full funding sources listed at end of paper (see Acknowledgments).
Summary Background Physical and mental health could greatly affect sexual activity and fulfilment, but the nature of associations at a population level is poorly understood. We used data from the ...third National Survey of Sexual Attitudes and Lifestyles (Natsal-3) to explore associations between health and sexual lifestyles in Britain (England, Scotland, and Wales). Methods Men and women aged 16–74 years who were resident in households in Britain were interviewed between Sept 6, 2010, and Aug 31, 2012. Participants completed the survey in their own homes through computer-assisted face-to-face interviews and self-interview. We analysed data for self-reported health status, chronic conditions, and sexual lifestyles, weighted to account for unequal selection probabilities and non-response to correct for differences in sex, age group, and region according to 2011 Census figures. Findings Interviews were done with 15 162 participants (6293 men, 8869 women). The proportion reporting recent sexual activity (one or more occasion of vaginal, oral, or anal sex with a partner of the opposite sex, or oral or anal sex or genital contact with a partner of the same sex in the past 4 weeks) decreased with age after the age of 45 years in men and after the age of 35 years in women, while the proportion in poorer health categories increased with age. Recent sexual activity was less common in participants reporting bad or very bad health than in those reporting very good health (men: 35·7% 95% CI 28·6–43·5 vs 74·8% 72·7–76·7; women: 34·0% 28·6–39·9 vs 67·4% 65·4–69·3), and this association remained after adjusting for age and relationship status (men: adjusted odds ratio AOR 0·29 95% CI 0·19–0·44; women: 0·43 0·31–0·61). Sexual satisfaction generally decreased with age, and was significantly lower in those reporting bad or very bad health than in those reporting very good health (men: 45·4% 38·4–52·7 vs 69·5% 67·3–71·6, AOR 0·51 0·36–0·72; women: 48·6% 42·9–54·3 vs 65·6% 63·6–67·4, AOR 0·69 0·53–0·91). In both sexes, reduced sexual activity and reduced satisfaction were associated with limiting disability and depressive symptoms, and reduced sexual activity was associated with chronic airways disease and difficulty walking up the stairs because of a health problem. 16·6% (95% CI 15·4–17·7) of men and 17·2% (16·3–18·2) of women reported that their health had affected their sex life in the past year, increasing to about 60% in those reporting bad or very bad health. 23·5% (20·3–26·9) of men and 18·4% (16·0–20·9) of women who reported that their health affected their sex life reported that they had sought clinical help (>80% from general practitioners; <10% from specialist services). Interpretation Poor health is independently associated with decreased sexual activity and satisfaction at all ages in Britain. Many people in poor health report an effect on their sex life, but few seek clinical help. Sexual lifestyle advice should be a component of holistic health care for patients with chronic ill health. Funding Grants from the UK Medical Research Council and the Wellcome Trust, with support from the Economic and Social Research Council and Department of Health.
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