Benoît Mâsse

Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women.

Objectives:To establish the highest practical dose and frequency (HPDF) of 0.3% or 1% tenofovir vaginal gel applied once or twice daily by sexually abstinent HIV-uninfected women, and to evaluate the safety, tolerability and systemic pharmacokinetics of the HPDF in abstinent and sexually active HIV-negative and HIV-infected women. Methods:Eighty-four women, enrolled in sequential cohorts, used the study product for 14 consecutive intermenstrual days. Safety laboratory assessments and pelvic examinations were carried out during five study visits, with colposcopy at enrollment and on day 14. Samples for pharmacokinetics were collected before and after the initial tenofovir gel use and at day 13. Results:The 1% tenofovir gel used twice daily was as well tolerated as other regimens used by the 48 HIV-negative sexually abstinent women, establishing the HPDF. Although 92% of the women reported at least one adverse event, the majority were mild (87%) and involved the genitourinary tract (70%). One possibly product-related severe adverse event involving lower abdominal cramping was reported by a sexually abstinent woman who used 0.3% gel twice daily. Serum tenofovir levels were low but detectable in 14 of the 25 women. No new HIV RNA resistance mutations were detected after 2 weeks of tenofovir gel in the 24 HIV-infected participants. No significant systemic toxicity was detected. Conclusion:A 2-week course of 1% tenofovir vaginal gel used twice daily was well tolerated in sexually abstinent and sexually active HIV-negative and HIV-positive women. Systemic tenofovir absorption occurred. Expanded safety and effectiveness testing is warranted.

Effects of Job Strain on Blood Pressure: A Prospective Study of Male and Female White-Collar Workers

OBJECTIVES We evaluated whether cumulative exposure to job strain increases blood pressure. METHODS A prospective study of 8395 white-collar workers was initiated during 1991 to 1993. At follow-up, 7.5 years later, 84% of the participants were reassessed to estimate cumulative exposure to job strain. RESULTS Compared with men who had never been exposed, men with cumulative exposure and those who became exposed during follow-up showed significant systolic blood pressure increments of 1.8 mm Hg (95% confidence interval [CI]=0.1, 3.5) and 1.5 mm Hg (95% CI=0.2, 2.8), respectively, and relative risks of blood pressure increases in the highest quintile group of 1.33 (95% CI = 1.01, 1.76) and 1.40 (95% CI = 1.14, 1.73). Effect magnitudes were smaller among women. Effects tended to be more pronounced among men and women with low levels of social support at work. CONCLUSIONS Among these white-collar workers, exposure to cumulative job strain had a modest but significant effect on systolic blood pressure among men. The risk was of comparable magnitude to that observed for age and sedentary behavior. Men and women with low levels of social support at work appeared to be at higher risk for increases in blood pressure.

Wage Losses in the Year After Breast Cancer: Extent and Determinants Among Canadian Women

BACKGROUND Wage losses after breast cancer may result in considerable financial burden. Their assessment is made more urgent because more women now participate in the workforce and because breast cancer is managed using multiple treatment modalities that could lead to long work absences. We evaluated wage losses, their determinants, and the associations between wage losses and changes for the worse in the familys financial situation among Canadian women over the first 12 months after diagnosis of early breast cancer. METHODS We conducted a prospective cohort study among women with breast cancer from eight hospitals throughout the province of Quebec. Information that permitted the calculation of wage losses and information on potential determinants of wage losses were collected by three pretested telephone interviews conducted over the year following the start of treatment. Information on medical characteristics was obtained from medical records. The main outcome was the proportion of annual wages lost because of breast cancer. Multivariable analysis of variance using the general linear model was used to identify personal, medical, and employment characteristics associated with the proportion of wages lost. All statistical tests were two-sided. RESULTS Among 962 eligible breast cancer patients, 800 completed all three interviews. Of these, 459 had a paying job during the month before diagnosis. On average, these working women lost 27% of their projected usual annual wages (median = 19%) after compensation received had been taken into account. Multivariable analysis showed that a higher percentage of lost wages was statistically significantly associated with a lower level of education (P(trend) = .0018), living 50 km or more from the hospital where surgery was performed (P = .070), lower social support (P = .012), having invasive disease (P = .086), receipt of chemotherapy (P < .001), self-employment (P < .001), shorter tenure in the job (P(trend) < .001), and part-time work (P < .001). CONCLUSION Wage losses and their effects on financial situation constitute an important adverse consequence of breast cancer in Canada.

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.

Safety and acceptability of cellulose sulfate as a vaginal microbicide in HIV-infected women.

Objectives:Few studies of topical microbicides have assessed their safety in HIV-infected women. We conducted this study to evaluate the safety and acceptability of 6% cellulose sulfate (CS) gel as a vaginal microbicide in sexually abstinent and active HIV-infected women. Methods:Fifty-nine HIV-infected women were enrolled in a randomized double-blind placebo-controlled study comparing 6% CS to placebo gel used for 14 days. Sexually abstinent women applied gel once or twice daily and sexually active women used gel once daily. Results:CS gel was safe with no reported severe or life-threatening adverse events (AE). Thirty-nine (66%) of the participants experienced urogenital AE judged as probably or possibly related to gel. The majority (51%) of these participants reported only mild events. Fewer women (62%) who used CS experienced urogenital AE than those assigned to placebo gel (70%) (P = 0.59). Eleven (19%) women experienced intermenstrual bleeding judged to be probably or possibly related to gel use (four in the CS and seven in the placebo gel group). There was no increase in AE by frequency of gel use or sexual activity with the exception of abdominal/pelvic pain which was noted more frequently with twice daily use among sexually abstinent women. Women and men found the gel highly acceptable. Conclusions:This Phase I study demonstrated that CS vaginal gel was safe, well tolerated and acceptable by HIV-infected women and their male partners. Thus, further development of CS is warranted as a potential method to prevent HIV transmission and acquisition.

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.

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.

Etiology of urethral discharge in West Africa: the role of Mycoplasma genitalium and Trichomonas vaginalis

OBJECTIVE To determine the etiological role of pathogens other than Neisseria gonorrhoeae and Chlamydia trachomatis in urethral discharge in West African men. METHODS Urethral swabs were obtained from 659 male patients presenting with urethral discharge in 72 primary health care facilities in seven West African countries, and in 339 controls presenting for complaints unrelated to the genitourinary tract. Polymerase chain reaction analysis was used to detect the presence of N. gonorrhoeae, C. trachomatis, Trichomonas vaginalis, Mycoplasma genitalium, and Ureaplasma urealyticum. FINDINGS N. gonorrhoeae, T. vaginalis, C. trachomatis, and M. genitalium--but not U. urealyticum--were found more frequently in men with urethral discharge than in asymptomatic controls, being present in 61.9%, 13.8%, 13.4% and 10.0%, respectively, of cases of urethral discharge. Multiple infections were common. Among patients with gonococcal infection, T. vaginalis was as frequent a coinfection as C. trachomatis. M. genitalium, T. vaginalis, and C. trachomatis caused a similar clinical syndrome to that associated with gonococcal infection, but with a less severe urethral discharge. CONCLUSIONS M. genitalium and T. vaginalis are important etiological agents of urethral discharge in West Africa. The frequent occurrence of multiple infections with any combination of four pathogens strongly supports the syndromic approach. The optimal use of metronidazole in flowcharts for the syndromic management of urethral discharge needs to be explored in therapeutic trials.

Efficacy dilution in randomized placebo-controlled vaginal microbicide trials.

BackgroundTo 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.MethodsFor 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.ResultsUnder 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.ConclusionCurrently 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.

Association of hepatitis B virus infection with other sexually transmitted infections in homosexual men

OBJECTIVES This study determined the prevalence and factors associated with hepatitis B virus (HBV) infection among men who have sex with men. METHODS At the baseline visit of an HIV study among men who have sex with men, we asked about HBV vaccination status and tested for HBV markers. RESULTS Of 625 subjects, 48% had received at least 1 dose of HBV vaccine. Of 328 unvaccinated men, 41% had 1 or more HBV markers. HBV prevalence increased markedly with age and was associated with many sexual and drug-related behaviors. In a multivariate model, 7 variables were independently associated with HBV infection: ulcerative sexually transmitted diseases (odds ratio [OR] = 10.1; 95% confidence interval [CI] = 2.6, 54); injection drug use (OR = 5.2; 95% CI = 1.2, 26); gonorrhea or chlamydia (OR = 4.0; 95% CI = 1.9, 8.9); sexual partner with HIV/AIDS (OR = 3.6; 95% CI = 1.8, 7.1); 50 or more casual partners (OR = 3.4; 95% CI = 1.6, 7.1); received money for sex (OR = 3.0; 95% CI = 1.2, 7.8); and 20 or more regular partners (OR = 2.5; 95% CI = 1.1, 6.1). CONCLUSIONS In Montreal, men who have sex with men are at risk for HBV infection, but a substantial proportion remain unvaccinated; new strategies are required to improve coverage. Men who have sex with men and who have a sexually transmitted infection, especially a genito-ulcerative infection, appear to be at particularly high risk for HBV infection.

Risk factors associated with HIV infection among young gay and bisexual men in Canada

Objective: To assess risk factors associated with HIV prevalence and incidence among gay and bisexual men in two prospective Canadian cohorts. Methods: The Vanguard Project and the Omega Cohort are prospective cohort studies of gay and bisexual men ongoing in Vancouver and Montreal, respectively. For this analysis, baseline sociodemographic characteristics, sexual behavior, and substance use data from these two cohorts were combined. Assessment of risk factors for HIV seroprevalence and seroconversion were carried out using univariate and multivariate analysis. Results: This analysis was based on 1373 gay and bisexual men aged 16 to 30 years. Men who were HIV‐seropositive at baseline (n = 48) were more likely to report living in unstable housing, to have had less than a high school education, and to have been unemployed than those who were HIV‐negative (n = 1325). HIV‐positive men were also more likely to report having engaged in sexual risk behavior, including having had consensual sex at a younger age, having had at least 6 partners during the previous year, ever having been involved in the sex trade, and having engaged in unprotected receptive anal intercourse. With respect to substance use, HIV‐positive men were more likely to report the use of crack, cocaine, heroin, and marijuana and to use injection drugs. Similarly, men who seroconverted during the course of the studies (n = 26) were more likely to report having less than a high school education and having lived in unstable housing at baseline. Compared with HIV‐negative men, men who seroconverted were more likely to report ever having been involved in the sex trade and engaging in unprotected receptive anal intercourse. Reports of cocaine use and injection drug use were also significantly higher for men who seroconverted compared with HIV‐negative men. Conclusions: Our data indicate that HIV‐positive gay and bisexual men are more likely to be living in unstable conditions and to report more risky sexual and substance use behaviors than HIV‐negative men.