Efficacy dilution in randomized placebo-controlled vaginal microbicide trials

<p>Abstract</p> <p>Background</p> <p>To date different vaginal gel microbicides have been evaluated in phase 2b/3 trials, but none have demonstrated effectiveness for preventing HIV infection. Failure to demonstrate effectiveness however does not necessarily indicate that a product is truly inefficacious, as several sources of efficacy dilution may compromise our ability to identify products that may have been truly efficacious.</p> <p>Methods</p> <p>For four individual sources of dilution, we describe the dilution mechanisms and quantify the expected effectiveness. An overall expected effectiveness that combines all sources of dilution in a trial is derived as well.</p> <p>Results</p> <p>Under conditions that have been observed in recent microbicide trials, the overall expected effectiveness assuming an active gel with true efficacy of 50% and 75% are in the range of [16%; 33%] and [28%; 50%], respectively, when considering the four major sources of dilution. In contrast the diluting effect due to adherence alone (assuming an adherence of 80%) leads to higher expected effectiveness, 40% and 60% assuming an active gel with true efficacy of 50% and 75%, respectively. Individual sources of dilution may demonstrate a small effect when evaluated independently, but the overall dilution effect in a trial with several sources of dilution can be quite substantial.</p> <p>Conclusion</p> <p>Currently planned phase 2b/3 microbicide trials of new candidate vaginal microbicides are not immune from these shortcomings. A good understanding of dilution effects is necessary to properly interpret microbicide trial results and to identify products worthy of further development and evaluation. Greater attention should be devoted to reducing and assessing the impact of efficacy dilution and to carefully selecting the effect size in the design of future trials.</p

Psychosocial work factors and social inequalities in psychological distress: a population-based study.

BACKGROUND: Mental health problems (MHP) are the leading cause of disability worldwide. The inverse association between socioeconomic position (SEP) and MHP has been well documented. There is prospective evidence that factors from the work environment, including adverse psychosocial work factors, could contribute to the development of MHP including psychological distress. However, the contribution of psychosocial work factors to social inequalities in MHP remains unclear. This study evaluates the contribution of psychosocial work factors from two highly supported models, the Demand-Control-Support (DCS) and the Effort-Reward Imbalance (ERI) models to SEP inequalities of psychological distress in men and women from a population-based sample of Quebec workers. METHODS: Data were collected during a survey on working conditions, health and safety at work. SEP was evaluated using education, occupation and household income. Psychosocial work factors and psychological distress were assessed using validated instruments. Mean differences (MD) in the score of psychological distress were estimated separately for men and women. RESULTS: Low education level and low household income were associated with psychological distress among men (MD, 0.56 (95% CI 0.06; 1.05) and 1.26 (95% CI 0.79; 1.73) respectively). In men, the contribution of psychosocial work factors from the DCS and the ERI models to the association between household income and psychological distress ranged from 9% to 24%. No clear inequalities were observed among women. CONCLUSIONS: These results suggest that psychosocial work factors from the DCS and the ERI models contribute to explain a part of social inequalities in psychological distress among men. Psychosocial factors at work are frequent and modifiable. The present study supports the relevance of targeting these factors for the primary prevention of MHP and for health policies aiming to reduce social inequalities in mental health

Vitamin D in the prevention of exacerbations of asthma in preschoolers (DIVA): Protocol for a multicentre randomised placebo-controlled triple-blind trial

Introduction Preschoolers have the highest rate of emergency visits and hospitalisations for asthma exacerbations of all age groups, with most triggered by upper respiratory tract infections (URTIs) and occurring in the fall or winter. Vitamin D insufficiency is highly prevalent in Canadian preschoolers with recurrent asthma exacerbations, particularly in winter. It is associated with more URTIs and, in patients with asthma, more oral corticosteroid (OCS) use. Although evidence suggests that vitamin D supplements significantly decrease URTIs and asthma exacerbations requiring OCS, there is insufficient data in preschoolers. This study aims to determine the impact of vitamin D 3 supplementation on exacerbations requiring OCS, in preschoolers with recurrent URTI-induced asthma exacerbations. Methods and analysis This is a phase III, randomised, triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D 3 supplementation in children aged 1-5 years, with asthma triggered by URTIs and a recent history of frequent URTIs and OCS use. Children (n=865) will be recruited in the fall and early winter and followed for 7 months. They will be randomised to either the (1) intervention: two oral boluses of 100 000 international unit (IU) vitamin D 3 (3.5 months apart) with 400 IU vitamin D 3 daily; or (2) control: identical placebo boluses with daily placebo. The primary outcome is the number of exacerbations requiring OCS per child, documented by medical and pharmacy records. Secondary outcomes include number of laboratory-confirmed viral URTIs, exacerbation duration and severity, parent functional status, healthcare use, treatment deintensification, cost and safety. Ethics and dissemination This study has received ethical approval from all sites. Results will be disseminated via international conferences and manuscripts targeting paediatricians and respirologists, and to families of asthmatic children via our Quebec parents-partners outreach programme. If proven effective, findings may markedly influence the management of URTI-induced asthma in high-morbidity preschoolers and could be directly implemented into practice with an update to clinical guidelines. Trial registration number NCT03365687

The role of sexually transmitted infections in male circumcision effectiveness against HIV – insights from clinical trial simulation

BACKGROUND: A landmark randomised trial of male circumcision (MC) in Orange Farm, South Africa recently showed a large and significant reduction in risk of HIV infection, reporting MC effectiveness of 61% (95% CI: 34%–77%). Additionally, two further randomised trials of MC in Kisumu, Kenya and Rakai, Uganda were recently stopped early to report 53% and 48% effectiveness, respectively. Since MC may protect against both HIV and certain sexually transmitted infections (STI), which are themselves cofactors of HIV infection, an important question is the extent to which this estimated effectiveness against HIV is mediated by the protective effect of circumcision against STI. The answer lies in the trial data if the appropriate statistical analyses can be identified to estimate the separate efficacies against HIV and STI, which combine to determine overall effectiveness. OBJECTIVES AND METHODS: Focusing on the MC trial in Kisumu, we used a stochastic prevention trial simulator (1) to determine whether statistical analyses can validly estimate efficacy, (2) to determine whether MC efficacy against STI alone can produce large effectiveness against HIV and (3) to estimate the fraction of all HIV infections prevented that are attributable to efficacy against STI when both efficacies combine. RESULTS: Valid estimation of separate efficacies against HIV and STI as well as MC effectiveness is feasible with available STI and HIV trial data, under Kisumu trial conditions. Under our parameter assumptions, high overall effectiveness of MC against HIV was observed only with a high MC efficacy against HIV and was not possible on the basis of MC efficacy against STI alone. The fraction of all HIV infections prevented which were attributable to MC efficacy against STI was small, except when efficacy of MC specifically against HIV was very low. In the three MC trials which reported between 48% and 61% effectiveness (combining STI and HIV efficacies), the fraction of HIV infections prevented in circumcised males which were attributable to STI was unlikely to be more than 10% to 20%. CONCLUSION: Estimation of efficacy, attributable fraction and effectiveness leads to improved understanding of trial results, gives trial results greater external validity and is essential to determine the broader public health impact of circumcision to men and women

Tenofovir-based preexposure prophylaxis for HIV infection among African women.

CAPRISA, 2015.Abstract available in pdf

No increase in HIV incidence in a cohort of men who have sex with men in Montréal: too early to conclude?

Made available in DSpace on 2010-08-23T16:58:37Z (GMT). No. of bitstreams: 3 Bastos_No increase in HIV incidence in a cohort_2002-----.pdf: 43914 bytes, checksum: 20c44c2971fe016c1e2426cef85faa58 (MD5) license.txt: 1842 bytes, checksum: a1519072ae4ff7b177d7989d4044ac48 (MD5) Bastos_No increase in HIV incidence in a cohort_2002-----.pdf.txt: 7776 bytes, checksum: 9d3d5766834975c1d13817a154f6098c (MD5) Previous issue date: 2002Made available in DSpace on 2010-11-04T14:19:37Z (GMT). No. of bitstreams: 3 Bastos_No increase in HIV incidence in a cohort_2002-----.pdf.txt: 7776 bytes, checksum: 9d3d5766834975c1d13817a154f6098c (MD5) license.txt: 1842 bytes, checksum: a1519072ae4ff7b177d7989d4044ac48 (MD5) Bastos_No increase in HIV incidence in a cohort_2002-----.pdf: 43914 bytes, checksum: 20c44c2971fe016c1e2426cef85faa58 (MD5) Previous issue date: 2002Center for Disease Control. Division of STD and Prevention. Atlanta, GA, USA.Oswaldo Cruz Foundation. Centre for Scientific and Technological Information. Rio de Janeiro, RJ, Brazil.Fred Hutchinston Cancer Institute. SHARP. Seattle, WA, USA

Changes in the transmission dynamics of the HIV epidemic after the wide-scale use of antiretroviral therapy could explain increases in sexually transmitted infections: results from mathematical models

Made available in DSpace on 2010-08-23T16:58:32Z (GMT). No. of bitstreams: 3 license.txt: 1841 bytes, checksum: f16166aab4aff880e915c4a4a93989aa (MD5) Bastos_Changes in the transmission dynamics_2004.pdf: 1639966 bytes, checksum: 31fffa63fcf01041340b8300fb09db8f (MD5) Bastos_Changes in the transmission dynamics_2004.pdf.txt: 68739 bytes, checksum: ed8f05f6c3414d9cd56fd19af9883f64 (MD5) Previous issue date: 2004Made available in DSpace on 2010-11-04T14:19:58Z (GMT). No. of bitstreams: 3 Bastos_Changes in the transmission dynamics_2004.pdf.txt: 68739 bytes, checksum: ed8f05f6c3414d9cd56fd19af9883f64 (MD5) Bastos_Changes in the transmission dynamics_2004.pdf: 1639966 bytes, checksum: 31fffa63fcf01041340b8300fb09db8f (MD5) license.txt: 1841 bytes, checksum: f16166aab4aff880e915c4a4a93989aa (MD5) Previous issue date: 2004MCB acknowledges ATPM for financial support. KD thanks FCAR and WT for financial support. FIB is supported by Fiocruz PAPES grant 250.250.122.Imperial College. Faculty of Medicine. Department of Infectious Disease Epidemiology. London, UK.Fundação Oswaldo Cruz. Centro Informação Científica e Tecnológica. Departamento de Informações para a Saúde. Rio de Janeiro, RJ, Brasil.Imperial College. Faculty of Medicine. Department of Infectious Disease Epidemiology. London, UK.Fred Hutchinson Cancer Research Centre. HPTN/SCHARP. Seattle, DC, Washington, USA.Background: Recent increases in bacterial sexually transmitted infections (STI) and risk behavior have coincided with the introduction of antiretroviral therapy (ART) in homosexual communities of industrialized countries. The reasons for these increases are not fully understood. Goal: The goal of this study was to understand the various effects of ART on risk behaviors and STI. Objective: The objective of this study was to assess the independent impact of the change in the transmission dynamics of HIV/AIDS as a result of the wide-scale use of ART on a bacterial STI. Study Design: We developed a mathematical model of bacterial STI and treated/untreated HIV/AIDS infection for an open homosexual population. At the individual level, we assume that susceptible and healthy HIV-positive individuals do not increase their risk behavior as a result of ART over time. However, individuals with AIDS, who are successfully treated with ART, can resume sexual activity. The impact of the wide-scale use of ART on risky behavior, STI, and HIV/AIDS was evaluated over a wide range of assumptions on treatment use, ART efficacy, and population characteristics. Results: Over 10 years, 0% to 55% new bacterial STI could be attributed to the wide-scale use of ART as a result of more modest increases (0–25%) in risky sex occurring at the population level rather than at the individual level. These increases have a negative impact on HIV if coverage is too low. Increasing treatment coverage helps to prevent more HIV infections despite larger increases in risky sex and STI that is predicted to ensue. Conclusion: Taking the differential impact of wide-scale use of ART into account helps to interpret recent behavioral and STI trends. Our results have implications for prevention strategies and for the formulation of public health policies. A better understanding of the differential impact of ART on sexual network over time is required

Work absence after breast cancer diagnosis: a population-based study

BACKGROUND: Absence from work after breast cancer diagnosis may be part of the burden of disease for women with cancer, but little research has addressed this. We examined work absences of 4 weeks or more among women who had had breast cancer during the 3 years after diagnosis and compared their absences with those of women who had never had cancer. METHODS: Our 2 target study groups were women in Quebec 18–59 years of age who were working when they first received therapy for breast cancer between November 1996 and August 1997 and similarly aged women randomly selected from provincial health care files who had never had cancer and were working at the time of diagnosis in women who had cancer. We interviewed 646 women who had had breast cancer (73% of those eligible) and 890 women in the comparison group (51% of those eligible) by telephone 3 years after first diagnosis. RESULTS: One year after diagnosis, 85% (459/541) of breast cancer survivors who remained free of disease during the 3-year study period were absent from work for 4 weeks or more compared with 18% (156/881) of healthy women (geometric mean total duration 5.6 v. 1.7 months, p < 0.001). By the third year, disease-free women were not absent more than women in the comparison group; however, more women who had experienced any new cancer event continued to be absent from work and to be absent from work for longer periods of time. Receiving adjuvant chemotherapy prolonged absence duration (9.5 v. 5.4 months among women not receiving chemotherapy). Compared with survivors belonging to a union, those who did not belong to a union (multivariate relative risk [RR] 7.54, 95% confidence interval [CI] 3.02–18.83) and those who were self-employed (RR 13.95, 95% CI 5.53–35.21) were more likely to report no work absence. INTERPRETATION: Most of the women with breast cancer took time off work (almost 6 months on average) after receiving the diagnosis. Three years after diagnosis, breast cancer survivors who remained disease-free — a large proportion of women with nonmetastatic breast cancer — were not absent from work more often or for longer periods of time than other working women