Understanding and modifying Fabry disease: Rationale and design of a pivotal Phase 3 study and results from a patient-reported outcome validation study.

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).

Identifying early pulmonary arterial hypertension biomarkers in systemic sclerosis: machine learning on proteomics from the DETECT cohort.

Pulmonary arterial hypertension (PAH) is a devastating complication of systemic sclerosis (SSc). Screening for PAH in SSc has increased detection, allowed early treatment for PAH and improved patient outcomes. Blood-based biomarkers that reliably identify SSc patients at risk of PAH, or with early disease, would significantly improve screening, potentially leading to improved survival, and provide novel mechanistic insights into early disease. The main objective of this study was to identify a proteomic biomarker signature that could discriminate SSc patients with and without PAH using a machine learning approach and to validate the findings in an external cohort.Serum samples from patients with SSc and PAH (n=77) and SSc without pulmonary hypertension (non-PH) (n=80) were randomly selected from the clinical DETECT study and underwent proteomic screening using the Myriad RBM Discovery platform consisting of 313 proteins. Samples from an independent validation SSc cohort (PAH n=22 and non-PH n=22) were obtained from the University of Sheffield (Sheffield, UK).Random forest analysis identified a novel panel of eight proteins, comprising collagen IV, endostatin, insulin-like growth factor binding protein (IGFBP)-2, IGFBP-7, matrix metallopeptidase-2, neuropilin-1, N-terminal pro-brain natriuretic peptide and RAGE (receptor for advanced glycation end products), that discriminated PAH from non-PH in SSc patients in the DETECT Discovery Cohort (average area under the receiver operating characteristic curve 0.741, 65.1% sensitivity/69.0% specificity), which was reproduced in the Sheffield Confirmatory Cohort (81.1% accuracy, 77.3% sensitivity/86.5% specificity).This novel eight-protein biomarker panel has the potential to improve early detection of PAH in SSc patients and may provide novel insights into the pathogenesis of PAH in the context of SSc.

First use of cenerimod, a selective S1P1 receptor modulator, for the treatment of SLE: a double-blind, randomised, placebo-controlled, proof-of-concept study.

OBJECTIVE: To investigate the pharmacodynamics, pharmacokinetics and safety of cenerimod-a potent, oral, selective sphingosine 1-phosphate 1 receptor modulator-in patients with SLE. METHODS: This multicentre, double-blind, placebo-controlled study was conducted in two parts. In part A, patients with SLE were randomised 1:1:1:1 to receive oral cenerimod 0.5, 1 or 2 mg, or placebo once daily for 12 weeks. Following an interim safety review of part A, additional patients were randomised 3:1 for part B and received cenerimod 4 mg or placebo once daily for 12 weeks. Endpoints included changes in total lymphocyte count, SLE Disease Activity Index-2000 (SLEDAI-2K) score (modified (mSLEDAI-2K) to exclude leucopenia), biomarker anti-double-stranded DNA (anti-dsDNA) antibodies, pharmacokinetic assessments and treatment-emergent adverse events (TEAEs). RESULTS: Part A included 49 patients (1:1:1:1 receiving cenerimod 0.5, 1 or 2 mg, or placebo) and part B included 18 patients (13 cenerimod; 5 placebo). Cenerimod caused a statistically significant dose-dependent reduction in total lymphocyte count from baseline to end of treatment (EOT). Compared with placebo at EOT, cenerimod 4 mg had an estimated treatment effect on change from baseline in mSLEDAI-2K score of -2.420 (p=0.0306), and on anti-dsDNA antibodies of -64.55 U/mL (p=0.0082), suggesting clinical and biological improvement in these exploratory efficacy analyses. Trough plasma concentrations were dose proportional and reached steady-state conditions after 4 weeks of once daily dosing. All groups reported similar, non-dose-related frequencies of TEAEs (cenerimod 0.5 mg: 41.7%; 1 mg: 41.7%; 2 mg: 46.2%; 4 mg: 38.5% and placebo: 58.8%). A small, dose-related, non-clinically relevant decrease in heart rate was only observed in the first 6 hours after initiation. CONCLUSIONS: With an acceptable safety profile, the efficacy findings suggest that cenerimod has the potential to treat patients with SLE. Further investigation in larger patient populations with longer treatment duration is warranted.

MMP-7 is a predictive biomarker of disease progression in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease with poor prognosis, which is characterised by destruction of normal lung architecture and excessive deposition of lung extracellular matrix. The heterogeneity of disease progression in patients with IPF poses significant obstacles to patient care and prevents efficient development of novel therapeutic interventions. Blood biomarkers, reflecting pathobiological processes in the lung, could provide objective evidence of the underlying disease. Longitudinally collected serum samples from the Bosentan Use in Interstitial Lung Disease (BUILD)-3 trial were used to measure four biomarkers (metalloproteinase-7 (MMP-7), Fas death receptor ligand, osteopontin and procollagen type I C-peptide), to assess their potential prognostic capabilities and to follow changes during disease progression in patients with IPF. In baseline BUILD-3 samples, only MMP-7 showed clearly elevated protein levels compared with samples from healthy controls, and further investigations demonstrated that MMP-7 levels also increased over time. Baseline levels of MMP-7 were able to predict patients who had higher risk of worsening and, notably, baseline levels of MMP-7 could predict changes in FVC as early as month 4. MMP-7 shows potential to be a reliable predictor of lung function decline and disease progression.

A bosentan pharmacokinetic study to investigate dosing regimens in paediatric patients with pulmonary arterial hypertension: FUTURE-3.

AIM: The aim of the present study was to investigate whether increasing the bosentan dosing frequency from 2 mg kg-1 twice daily (b.i.d.) to 2 mg kg-1 three times daily (t.i.d.) in children with pulmonary arterial hypertension (PAH) (from ≥3 months to <12 years of age) would increase exposure. METHODS: An open-label, prospective, randomized, multicentre, multiple-dose, phase III study was conducted. Patients (n = 64) were randomized 1:1 to receive oral doses of bosentan of 2 mg kg-1 b.i.d. or t.i.d. The main pharmacokinetic endpoint was the daily exposure to bosentan over 24 h corrected to the 2 mg kg-1 dose (AUC0-24C ). The maximum plasma concentration corrected to the 2 mg kg-1 dose (CmaxC ), the time to reach the maximum plasma concentration (tmax ) and safety endpoints were also assessed. RESULTS: The geometric mean [95% confidence interval (CI)] for AUC0-24C was 8535 h.ng ml-1 (6936, 10 504) and 7275 h.ng ml-1 (5468, 9679) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.85 (0.61, 1.20)]. The geometric mean (95% CI) for CmaxC was 743 ng ml-1 (573, 963) and 528 ng ml-1 (386, 722) for 2 mg kg-1 b.i.d. and t.i.d., respectively [geometric mean ratio (95% CI) 0.71 (0.48, 1.05)]. The median (range) for tmax was 3.0 h (0.0-7.5) and 3.0 h (1.0-8.0) for 2 mg kg-1 b.i.d. and t.i.d., respectively. The proportions of patients who experienced ≥1 adverse event were similar in the b.i.d. (66.7%) and t.i.d. (67.7%) groups. CONCLUSIONS: There appeared to be no clinically relevant difference in exposure to bosentan, or in safety, when increasing the frequency of bosentan dosing from b.i.d. to t.i.d. Therefore, the present study provides no indication that the dosing recommendation should be changed, and 2 mg kg-1 b.i.d. remains the recommended dosing regimen for bosentan in paediatric PAH patients.

Bosentan as Adjunctive Therapy for Persistent Pulmonary Hypertension of the Newborn: Results of the Randomized Multicenter Placebo-Controlled Exploratory Trial.

OBJECTIVE: To evaluate the efficacy, safety, and pharmacokinetics of the endothelin receptor antagonist bosentan as adjunctive therapy for neonates with persistent pulmonary hypertension of the newborn (PPHN). STUDY DESIGN: This was a phase 3, multicenter, randomized, placebo-controlled exploratory trial (FUTURE-4). Eligible patients were >34 weeks gestation, <7 days old, receiving inhaled nitric oxide (iNO) treatment (≥4 hours), and had persistent respiratory failure (oxygenation index [OI] ≥12). After 2:1 randomization, bosentan 2 mg/kg or placebo was given by nasogastric tube twice daily for ≥48 hours and up to 1 day after iNO weaning. RESULTS: Twenty-one neonates received a study drug (13 bosentan, 8 placebo). Compared with the placebo group, the group treated with bosentan had a higher median baseline OI and greater need for vasoactive agents. One treatment failure (need for extracorporeal membrane oxygenation) occurred in the group treated with bosentan. The time to weaning from iNO or mechanical ventilation was not different between the groups. Bosentan was well tolerated and did not adversely affect systemic blood pressure or hepatic transaminase levels. Anemia and edema were more frequent in patients receiving bosentan. Blood concentrations of bosentan were low and variable on day 1, and achieved steady state on day 5. CONCLUSION: Adjunctive bosentan was well tolerated, but did not improve oxygenation or other outcomes in our patients with PPHN. This effect may be related to delayed absorption of bosentan on treatment initiation in critically ill neonates or to more severe illness of the neonates who received bosentan. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01389856.

Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry.

OBJECTIVES: Digital ulcers (DUs) occur in up to half of patients with systemic sclerosis (SSc) and may lead to infection, gangrene and amputation with functional disability and reduced quality of life. This study has elucidated the burden of SSc-associated DUs through identification of four patient categories based on the pattern of DU recurrence over a 2-year observation period. METHODS: Patients with SSc-associated DUs enrolled in the Digital Ulcers Outcome Registry between 1 April 2008 and 19 November 2013, and with ≥2 years of observation and ≥3 follow-up visits during the observation period were analysed. Incident DU-associated complications were recorded during follow-up. Work and daily activity impairment were measured using a functional assessment questionnaire completed by patients after the observation period. Potential factors that could predict incident complications were identified in patients with chronic DUs. RESULTS: From 1459 patients, four DU occurrence categories were identified: 33.2% no-DU; 9.4% episodic; 46.2% recurrent; 11.2% chronic. During the observation period, patients from the chronic category had the highest rate of incident complications, highest work impairment and greatest need for help compared with the other categories. Independent factors associated with incident complications included gastrointestinal manifestations (OR 3.73, p=0.03) and previous soft tissue infection (OR 5.86, p=0.01). CONCLUSIONS: This proposed novel categorisation of patients with SSc-associated DUs based on the occurrence of DUs over time may help to identify patients in the clinic with a heavier DU burden who could benefit from more complex management to improve their functioning and quality of life.

Factors influencing long-term outcomes in relapsing-remitting multiple sclerosis: PRISMS-15.

AIM: An exploratory study of the relationship between cumulative exposure to subcutaneous (sc) interferon (IFN) ß-1a treatment and other possible prognostic factors with long-term clinical outcomes in relapsing-remitting multiple sclerosis (RRMS). METHODS: Patients in the original PRISMS study were invited to a single follow-up visit 15 years after initial randomisation (PRISMS-15). Outcomes over 15 years were compared in the lowest and highest quartile of the cumulative sc IFN ß-1a dose groups, and according to total time receiving sc IFN ß-1a as a continuous variable per 5 years of treatment. Potential prognostic factors for outcomes were analysed. RESULTS: Of 560 patients randomised in PRISMS, 291 returned for PRISMS-15 and 290 (51.8%) were analysed. Higher cumulative dose exposure and longer treatment time appeared to be associated with better outcomes on: annualised relapse rate, number of relapses, time to Expanded Disability Status Scale (EDSS) progression, change in EDSS, proportions of patients with EDSS ≥ 4 or ≥ 6, ≤ 5 relapses and EDSS <4 or <6, and time to conversion to secondary-progressive MS (SPMS). Higher dose exposure was associated with lower proportions of patients with EDSS progression and conversion to SPMS, and longer time on treatment with lower risk of first relapse. Change in EDSS from baseline to 24 months was a strong predictor of evaluated clinical outcomes over 15 years. CONCLUSIONS: These findings suggest that higher cumulative exposure to sc IFN ß-1a may be associated with better clinical outcomes, and early change in EDSS score may have prognostic value, over many years, in RRMS.

Stable or improved neurological manifestations during miglustat therapy in patients from the international disease registry for Niemann-Pick disease type C: an observational cohort study.

BACKGROUND: Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat. METHODS: The NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as 'improved/stable' if ≥3/4 domain scores were lower/unchanged, and as 'progressed' if <3 scores were lower/unchanged between enrolment and last follow-up visit. RESULTS: In total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data. CONCLUSIONS: Disability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years.

Impact of exposure to interferon beta-1a on outcomes in patients with relapsing-remitting multiple sclerosis: exploratory analyses from the PRISMS long-term follow-up study.

OBJECTIVE: To explore the effects of exposure to subcutaneous (sc) interferon (IFN) beta-1a on efficacy in patients with relapsing-remitting multiple sclerosis (RRMS) enrolled in the PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study. METHODS: Patients with RRMS received IFN beta-1a, 44 or 22 µg sc three times weekly (tiw), or placebo, for 2 years, at which point placebo recipients were re-randomized to IFN beta-1a, 44 or 22 µg sc tiw, for a further 2-4 years. Long-term follow-up visits occurred 7-8 years after enrolment and allowed participation of patients who had previously discontinued treatment. Post hoc descriptive analyses were conducted within the lower (MIN) and upper (MAX) quartiles of patients divided according to cumulative dose of IFN beta-1a and cumulative time on treatment. Outcomes were explored in patients initially randomized to IFN beta-1a, 44 µg sc tiw, who had received continuous or noncontinuous therapy during the study. RESULTS: For both cumulative dose and time analyses, the MIN and MAX groups comprised 96 and 95 patients, respectively. The continuous and noncontinuous groups included 45 and 91 patients, respectively. The MAX DOSE and MAX TIME groups had lower annualized relapse rates, lower rates of conversion to secondary progressive MS, lower percentages of patients with Expanded Disability Status Scale progression, higher percentages of relapse-free patients, and less T2 burden of disease than the MIN groups. The continuous therapy group had a lower annualized relapse rate and lower percentages of patients with Expanded Disability Status Scale progression or conversion to secondary progressive MS than the noncontinuous therapy group. CONCLUSIONS: The findings of these post hoc analyses suggest that high exposure to sc IFN beta-1a may be associated with better clinical outcomes than low exposure, and also highlight the importance of maximizing adherence. Additional prospective investigation is warranted to evaluate further the effects of treatment exposure on outcomes and to determine the benefits of interventions to improve adherence.

Magnetic resonance active lesions as individual-level surrogate for relapses in multiple sclerosis.

BACKGROUND: Use of quantitative magnetic resonance imaging (MRI) metrics as surrogates for clinical outcomes in multiple sclerosis (MS) trials is controversial. OBJECTIVES: We sought to validate, at the individual-patient level, the number of MRI active lesions, as a surrogate marker for relapses in MS. METHODS: Individual-patient data from two large, placebo-controlled clinical trials of subcutaneous interferon ß-1a in patients with relapsing-remitting or secondary progressive (SP) MS were analysed separately and as pooled data. The four Prentice criteria were applied to assess surrogacy for the number of new T2 MRI lesions. The predictive value of short-term treatment effects on this MRI marker for longer-term clinical relapses was also assessed. RESULTS: All Prentice criteria were satisfied. The number of new T2 MRI lesions correlated with the number of relapses over the follow-up period. The proportion of treatment effect on relapses accounted for by the effect of treatment on new T2 MRI lesions over 2 years was 53% in patients with relapsing-remitting MS, 67% in patients with secondary progressive MS, and 62% in pooled data. In the pooled data, treatment effects on new lesions over 1 year mediated a good proportion (70%) of effects on relapses over the subsequent year. CONCLUSIONS: This study provides evidence that new T2 MRI lesion count is a surrogate for relapses in patients with MS treated with interferon or drugs with a similar mechanism of action. Short-term treatment effects on this MRI measure can predict longer-term effects on relapses.

Patient-rated suitability of a novel electronic device for self-injection of subcutaneous interferon beta-1a in relapsing multiple sclerosis: an international, single-arm, multicentre, Phase IIIb study.

BACKGROUND: Multiple sclerosis (MS) currently requires long-term treatment with disease-modifying drugs, administered parenterally up to once daily. The need for regular self-injection can be a barrier to treatment for many patients. Autoinjectors can help patients overcome problems or concerns with self-injection and could, therefore, improve treatment adherence. This study was performed to assess the suitability of a new electronic device for the subcutaneous (sc) administration of interferon (IFN) beta-1a, 44 mcg three times weekly, for relapsing MS. METHODS: In this Phase IIIb, multicentre, single-arm study, patients with relapsing MS who had been consistently self-injecting sc IFN beta-1a using an autoinjector for at least 6 weeks were taught to use the new device and self-administered treatment for 12 weeks thereafter. Patient-rated suitability of the device was assessed at the end of Week 12 using the Patient User Trial Questionnaire. Patient satisfaction with, and evaluation of, the injection process was assessed using the MS Treatment Concern Questionnaire. Trainers evaluated the device using the Trainer User Trial Questionnaire. RESULTS: At Week 12, 71.6% (73/102) of patients considered the device 'very suitable' or 'suitable' for self-injection; 92.2% (94/102) reported some degree of suitability and only 7.8% (8/102) found the device 'not at all suitable'. At Weeks 4, 8 and 12, most patients reported that injection preparation and clean-up, performing injections and ease of device use in the previous 4 weeks compared favourably with, or was equivalent to, their previous experience of self-injection. Injection-related pain, injection reactions and 'flu-like' symptoms remained stable over the 12 weeks. Each device feature was rated 'very useful' or 'useful' by at least 80% of patients. All trainers and 95.2% (99/104) of patients found device functions 'very easy' or 'easy' to use. Overall convenience was considered the most important benefit of the device. CONCLUSIONS: Most patients considered the new electronic injection device suitable for the sc injection of IFN beta-1a. They found the device easy to use with useful features, and reported benefits such as overall convenience. The device may, therefore, increase treatment adherence in patients with MS, particularly those with injection-related issues. TRIAL REGISTRATION: NCT00735007.

Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women.

OBJECTIVE: To evaluate interrelationships between bacterial vaginosis (BV), vaginal yeast, vaginal practices (cleansing and drying/tightening), mucosal inflammation, and HIV acquisition. METHODS: A multicenter, prospective, observational cohort study was conducted, enrolling 4531 HIV-negative women aged 18 to 35 years attending family planning clinics in Zimbabwe and Uganda. Participants were tested for HIV and reproductive tract infections and were interviewed about vaginal practices every 3 months for 15 to 24 months. BV was measured by Gram stain Nugent scoring, vaginal yeast by wet mount, and mucosal inflammation by white blood cells on Gram stain. RESULTS: HIV incidence was 4.12 and 1.53 per 100 woman-years of follow-up in Zimbabwe and Uganda, respectively (a total of 213 incident infections). Women with BV or vaginal yeast were more likely to acquire HIV, especially if the condition was present at the same visit as the new HIV infection and the visit preceding it (hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.68 to 3.72 and HR = 2.97, 95% CI: 1.67 to 5.28 for BV and yeast, respectively). These relationships did not seem to be mediated by mucosal inflammation. Vaginal drying/tightening was associated with HIV acquisition in univariate (HR = 1.49, 95% CI: 1.03 to 2.15) but not multivariate models. Vaginal cleansing was not associated with HIV acquisition. CONCLUSIONS: BV and yeast may contribute more to the HIV epidemic than previously thought.

Hormonal contraception and the risk of HIV acquisition.

BACKGROUND: Combined oral contraceptives (COC) and depot-medroxyprogesterone acetate (DMPA) are among the most widely used family planning methods; their effect on HIV acquisition is not known. OBJECTIVE: To evaluate the effect of COC and DMPA on HIV acquisition and any modifying effects of other sexually transmitted infections. METHODS: This multicenter prospective cohort study enroled 6109 HIV-uninfected women, aged 18-35 years, from family planning clinics in Uganda, Zimbabwe and Thailand. Participants received HIV testing quarterly for 15-24 months. The risk of HIV acquisition with different contraceptive methods was assessed (excluding Thailand, where there were few HIV cases). RESULTS: HIV infection occurred in 213 African participants (2.8/100 woman-years). Use of neither COC [hazard ratio (HR), 0.99; 95% confidence interval (CI), 0.69-1.42] nor DMPA (HR, 1.25; 95% CI, 0.89-1.78) was associated with risk of HIV acquisition overall, including among participants with cervical or vaginal infections. While absolute risk of HIV acquisition was higher among participants who were seropositive for herpes simplex virus 2 (HSV-2) than in those seronegative at enrolment, among the HSV-2-seronegative participants, both COC (HR, 2.85; 95% CI, 1.39-5.82) and DMPA (HR, 3.97; 95% CI, 1.98-8.00) users had an increased risk of HIV acquisition compared with the non-hormonal group. CONCLUSIONS: No association was found between hormonal contraceptive use and HIV acquisition overall. This is reassuring for women needing effective contraception in settings of high HIV prevalence. However, hormonal contraceptive users who were HSV-2 seronegative had an increased risk of HIV acquisition. Additional research is needed to confirm and explain this finding.

Sexual risk behaviors and implications for secondary HIV transmission during and after HIV seroconversion.

OBJECTIVES: To determine the potential for secondary HIV transmission among newly HIV-infected men who have sex with men (MSM) during their HIV antibody seroconversion period, and for the 12 months after seroconversion. DESIGN: A cohort study. METHODS: Risk assessment questionnaires administered before receipt of the first positive HIV antibody result, plasma and seminal viral load measurements, and risk assessments one month and quarterly after receipt of the first HIV-positive test, and generalized estimating equation modelling techniques to analyse behavioral trends. RESULTS: Of 66 seroconverters, more than half reported unprotected anal intercourse (UAI) with HIV-negative or unknown-serostatus partners during seroconversion, with 27% reporting insertive UAI with an HIV-negative partner. The initial median plasma viral load was 4.6 log/ml, the median seminal viral load was 2.7 log/ml, suggesting a high level of infectiousness. Compared with risk behavior during seroconversion, UAI with HIV-negative or unknown-serostatus partners was reduced after the receipt of positive antibody results; however, a substantial proportion of participants reported high-risk behaviors for transmission for 12 months of follow-up. After learning of their HIV infection, recent seroconverters did not reduce the risk of secondary transmission by engaging in proportionally more high-risk practices with HIV-infected partners (compared with HIV-negative or unknown-serostatus partners), or engaging in proportionally more receptive compared with insertive UAI. CONCLUSION: Substantial potential exists for secondary HIV transmission during and for one year after HIV seroconversion. Receipt of an HIV-positive test is associated with a significant reduction in risk behavior, reinforcing the need to identify and counsel recently HIV-infected MSM.

Correlates of suicide attempts in an open cohort of young men who have sex with men.

OBJECTIVE: To investigate baseline correlates of attempted suicide in a large cohort of young gay and bisexual men. METHODS: Participants completed annual questionnaires asking demographic information, sexual behaviours, history of forced and paid sex, comfort with sexual orientation, use of illicit drugs, and validated measures of depression, social support, alcohol dependency, self-esteem and suicide ideation and attempts. Contingency table analysis and step-wise logistic regression were used to identify potential predictors of self-reported suicide attempts. RESULTS: Of 345 gay and bisexual men eligible for this cross-sectional analysis, 150 (43.5%) reported that they had ever considered suicide and 67 (19.4%) that they had attempted suicide at least once. After adjustment for multiple explanatory variables, the use of nitrite inhalants (poppers) (AOR = 2.37; 95% CI 1.30, 4.33), social support scores below the 75th percentile of all scores (AOR = 2.19; 95% CI 1.18, 4.09) and low or moderate self-esteem (AOR = 3.73; 95% CI 2.03, 6.86) were independently associated with elevated risk of attempted suicide. CONCLUSION: Our data indicate that men in this analysis who ideate or attempt suicide earlier in life are more likely to report lower social support and self-esteem, and high popper use.