Background Canadian clinical guidelines recommend at least annual and quarterly sexually transmitted infection (STI) testing among sexually active men who have sex with men (MSM), including those on HIV PrEP or in HIV care. We built consensus around interventions to improve local STI testing services for MSM using a web-based ‘e-Delphi’ process. Methods We recruited Experts for a Community Panel (MSM who sought/underwent STI testing in the preceding 18 months, conducted 09/2019–11/2019) and a Provider Panel (offered STI testing to MSM in the past 12 months, conducted 02/2020–05/2020). Experts prioritized 6–8 potential interventions, generated from a literature review, on a 7-point Likert scale of ‘Definitely not a priority’ to ‘Definitely a priority’ over 3 survey rounds. Consensus was defined as ≥60% within a ±1 response point. Summaries of panel responses were given in successive rounds. We report the percentage of ‘a priority’ at the final round of survey. Results Among Community Experts, 43/51 (84%) completed all rounds; 19% HIV-positive, 37% HIV-negative on PrEP, 42% HIV-negative not on PrEP. We reached consensus on 6 interventions – Client Reminders (95%), Express testing (88%), Routine testing (84%), Online booking app (84%), Online testing (77%) and Nurse-led testing (72%). Experts favoured interventions that were convenient while also maintaining a relationship with their provider. Among Provider Experts, 37/48 (77%) completed all rounds; 59% were physicians. Consensus was reached on the aforementioned interventions (range 68%-100%) but not reached for Provider Alerts (19%) and Provider Audit and Feedback (16%). Express, Online and Nurse-led testing were prioritized by >95% of Experts because of streamlined processes and decreased need to see a provider. Conclusions Both panels were enthusiastic about innovations that make STI testing more efficient. However, Community Experts preferred convenient interventions that involved their provider while Provider Experts favoured interventions that prioritized patient independence and reduced patient-provider time.

Background: Infections with human papillomaviruses (HPV) may enter into a latent state in epithelial basal cells, and eventually become reactivated following loss of immune control. It is unclear what proportion of incident detections of HPV are due to reactivation of previous latent infections versus new transmissions. Methods: The HITCH cohort study prospectively followed young newly formed heterosexual partners recruited between 2005-2011 in Montreal, Canada. We calculated the fraction of incident HPV detections non-attributable to sexual transmission risk factors with a Bayesian Markov state transition model. Results are the median (2.5-95.5th percentiles) of the estimated posterior distribution. Findings: 544 type-specific incident HPV detection events occurred in 849 participants; 32.5% of all incident HPV detections occurred in participants whose HITCH partners were negative for that HPV type and who did not report having sex with anyone else over follow-up. We estimate that 42.7% (38.4-47.2%) of all incident HPV detections in this population might be attributable to reactivation of latent infections, not transmission. Interpretation: A positive HPV test result in many cases may be a reactivated past infection, rather than a new infection from recent sexual behaviors or partner infidelity. The potential for reactivation of latent infections in previously HPV-negative women should be considered in the context of cervical cancer screening.

OBJECTIVES:The aim of this study was to assess the adequacy of immunological recovery and virological suppression in response to antiretroviral therapy (ART) in the growing population of older people living with HIV (PLWH), as treatment regimens become more effective and tolerable.METHODS:An interprovincial Canadian cohort of treatment-naïve PLWH who initiated ART after 1 January 2000 was used and age assessed in decades. Longitudinal absolute CD4 count response to treatment was modelled using generalized estimating equations. Cumulative incidence functions and proportional hazards models with a competing risk of death were used to estimate time to: (1) CD4 ≥ 200 cells/µL, (2) CD4 ≥ 500 cells/µL, (3) virological suppression (≤ 50 copies/mL), and (4) virological failure (> 200 copies/mL).RESULTS:In all, 12 489 individuals starting ART between 2000 and 2016 with one or more post-treatment CD4 count or viral load were included in the analysis. Age > 60 years was associated with lower absolute CD4 recovery (adjusted β = -31 cells/µL) compared with age ≤ 30 years when pre-treatment CD4 count and other covariates were accounted for. Older age groups were less likely to achieve a CD4 ≥ 500 cells/µL, with the greatest effect in the > 60 group [adjusted hazard ratio (aHR) = 0.69, 95% confidence interval (CI): 0.57-0.84 vs. age ≤ 30). Older age groups were more likely to achieve viral suppression (age > 60, aHR = 1.20, 95% CI: 1.05-1.37) and less likely to have virological failure (age > 60, aHR = 0.46, 95% CI: 0.3-0.71) compared with those aged ≤ 30 years.CONCLUSIONS:Older adults have robust virological responses to ART; however, individuals over the age 60 are more likely to experience blunted CD4 recovery.

Introduction Human papillomavirus (HPV) is a causal agent of malignancies including cervical, vulvar, vaginal, penile, anal and oropharyngeal cancer, as well as benign conditions such as anogenital warts. HPV vaccination protects individuals against infections with the target HPV types and their clinical outcomes. However, little is known about the protection an immunised individual confers to their sexual partner or its impact on HPV transmission dynamics. In this context, the Transmission Reduction and Prevention with HPV vaccination (TRAP-HPV) study was designed to determine the efficacy of an HPV vaccine in reducing transmission of genital and oral HPV infection in sexual partners of vaccinated individuals.Methods and analysis The TRAP-HPV study is an ongoing randomised controlled trial among heterosexual couples living in Montreal, Canada. Sexually active couples, aged between 18 and 45 years, who have been in a relationship no longer than 6 months are considered eligible. Participants are independently randomised to receive either the intervention HPV vaccine, Gardasil 9, or a placebo hepatitis A vaccine, Avaxim, creating four vaccination groups among couples: intervention–intervention, intervention–placebo, placebo–intervention and the placebo–placebo. Participants provide genital (vaginal/penile) and oral samples at baseline and five follow-up visits over a 1-year duration. Linear Array HPV genotyping is used to detect 36 HPV types. Cox proportional hazard regression models will be used to estimate the effect of vaccination on HPV transmission.Ethics and dissemination The TRAP-HPV study received ethical approval by institutional review boards McGill University, Concordia University and Centre Hospitalier de l’Université de Montréal. Before enrolment, all participants provide informed written consent. Results will be published in peer-reviewed journals and presented at national and international conferences. The generated empirical evidence could be used in mathematical models of vaccination to inform policymakers in Canada and elsewhere.Trial registration number NCT01824537.

Selection as a consequence of volunteer participation in, and loss to follow-up from, cohort studies may bias estimates of mortality and other health outcomes. To quantify this potential, we estimated mortality and health service use among people living with HIV (PLWH) who were lost to cohort follow-up (LTCFU) from a volunteer clinical HIV-infected cohort, and compared these to mortality and health service use in active cohort participants and non-cohort-participants living with HIV in Ontario, Canada.We analysed population-based provincial health databases from 1995 to 2014, identifying PLWH ≥ 18 years old; these included data from participants in the Ontario HIV Treatment Network Cohort Study (OCS), a volunteer, multi-site clinical HIV-infected cohort. We calculated all-cause mortality, hospitalization and emergency department (ED) visit rates per 100 person-years (PY) and estimated hazard ratios (HRs) of mortality, adjusting for age, sex, income, rurality, and immigration status.Among 23 043 PLWH, 5568 were OCS participants. Compared with nonparticipants, participants were younger and less likely to be female, to be an immigrant and to reside in a major urban centre, and had lower comorbidity. Mortality among active participants, participants LTCFU and nonparticipants was 2.52, 3.30 and 2.20 per 100 PY, respectively. After adjustment for covariates, mortality risk was elevated among participants LTCFU compared with active participants (HR 2.26; 95% confidence interval 1.91, 2.68). Age-adjusted hospitalization rates and ED visit rates were highest among participants LTCFU.Mortality risk and use of health care resources were lower among active cohort participants. Our findings may inform health outcome estimates based on volunteer cohorts, as well as quantitative bias adjustment to correct for such biases.

OBJECTIVES:We sought to compare all-cause mortality of people living with HIV and accessing care in Canada and the UK.METHODS:Individuals from the Canadian Observational Cohort (CANOC) collaboration and UK Collaborative HIV Cohort (UK CHIC) study who were aged ≥ 18 years, had initiated antiretroviral therapy (ART) for the first time between 2000 and 2012 and who had acquired HIV through sexual transmission were included in the analysis. Cox regression was used to investigate the difference in mortality risk between the two cohort collaborations, accounting for loss to follow-up as a competing risk.RESULTS:A total of 19 960 participants were included in the analysis (CANOC, 4137; UK CHIC, 15 823). CANOC participants were more likely to be older [median age 39 years (interquartile range (IQR): 33, 46 years) vs. 36 years (IQR: 31, 43 years) for UK CHIC participants], to be male (86 vs. 73%, respectively), and to report men who have sex with men (MSM) sexual transmission risk (72 vs. 56%, respectively) (all P < 0.001). Overall, 762 deaths occurred during 98 798 person-years (PY) of follow-up, giving a crude mortality rate of 7.7 per 1000 PY [95% confidence interval (CI): 7.1, 8.3 per 1000 PY]. The crude mortality rates were 8.6 (95% CI: 7.4, 10.0) and 7.5 (95% CI: 6.9, 8.1) per 1000 PY among CANOC and UK CHIC study participants, respectively. No statistically significant difference in mortality risk was observed between the cohort collaborations in Cox regression accounting for loss to follow-up as a competing risk (adjusted hazard ratio 0.86; 95% CI: 0.72-1.03).CONCLUSIONS:Despite differences in national HIV care provision and treatment guidelines, mortality risk did not differ between CANOC and UK CHIC study participants who acquired HIV through sexual transmission.

ObjectivesSustained optimal use of combination antiretroviral therapy (cART) has been shown to decrease morbidity, mortality and HIV transmission. However, incomplete adherence and treatment interruption (TI) remain challenges to the full realization of the promise of cART. We estimated trends and predictors of treatment interruption and resumption among individuals in the Canadian Observational Cohort (CANOC) collaboration.MethodscART-naive individuals 18 years of age who initiated cART between 2000 and 2011 were included in the study. We defined TIs as 90 consecutive days off cART. We used descriptive analyses to study TI trends over time and Cox regression to identify factors predicting time to first TI and time to treatment resumption after a first TI.ResultsA total of 7633 participants were eligible for inclusion in the study, of whom 1860 (24.5%) experienced a TI. The prevalence of TI in the first calendar year of cART decreased by half over the study period. Our analyses highlighted a higher risk of TI among women [adjusted hazard ratio (aHR) 1.59; 95% confidence interval (CI) 1.33-1.92], younger individuals (aHR 1.27; 95% CI 1.15-1.37 per decade increase), earlier treatment initiators (CD4 count 350 vs. <200 cells/L: aHR 1.46; 95% CI 1.17-1.81), Aboriginal participants (aHR 1.67; 95% CI 1.27-2.20), injecting drug users (aHR 1.43; 95% CI 1.09-1.89) and users of zidovudine vs. tenofovir in the initial cART regimen (aHR 2.47; 95% CI 1.92-3.20). Conversely, factors predicting treatment resumption were male sex, older age, and a CD4 cell count <200 cells/L at cART initiation.ConclusionsDespite significant improvements in cART since its advent, our results demonstrate that TIs remain relatively prevalent. Strategies to support continuous HIV treatment are needed to maximize the benefits of cART.

Although combination antiretroviral therapy (cART) can restore CD4 T‐cell numbers in HIV infection, alterations in T‐cell regulation and homeostasis persist. We assessed the incidence and predictors of reversing these alterations with cART.

Glycogen storage diseases (GSDs) are autosomal recessive metabolic disorders resulting in storage of abnormal amounts and/or forms of glycogen. Von Gierke disease is a GSD caused by defective liver and kidney glucose-6-phosphatase activity and is named after the pathologist who first described excess glycogen storage in the liver. The disease-causing mutation(s) can be either in the gene coding for the liver glucose-6-phosphatase enzyme (G6PC) or in the gene coding for the endoplasmic reticulum substrate and/or product transport proteins of the glucose-6-phosphatase system. The two common forms of GSD1 are termed GSD1a and GSD1b, and are caused by deficiency in G6PC and the glucose-6-phosphate transporter (G6PT1), respectively. The disease is currently managed by nocturnal nasogastric infusion of glucose and/or cornstarch mixed into drinks during the day, but compliance is often low. Recent advances in the use of gene therapy in animal models of the disease provide hope for this approach in the treatment of human patients in the future.

The purpose of this study was to define plasma catecholamine responses as part of the counterregulatory hormonal reaction to hypoglycemia in infants after a regular 3- to 4-h feed was omitted. Hormone levels were assessed once, at the end of the fast or at hypoglycemia. The 121 infants were subdivided into three groups for analysis: normoglycemia (n = 94, 78%); transient hypoglycemia (n = 11, 9%); or severe and persistent hypoglycemia (n = 16, 13%). The severe and persistent hypoglycemic group had significantly higher levels of cortisol and epinephrine than the normoglycemic group. Norepinephrine and glucagon levels did not differ between the groups. Human GH levels were higher in the transiently hypoglycemic group but not in the severe and persistent hypoglycemic group. Prefeed blood lactate levels differed significantly among the groups and were highest in the severe and persistent groups. Multiple regression analysis showed that cortisol levels were significantly higher in infants who had severe and persistent hypoglycemia. The counterregulatory hormonal response in infants to severe and persistent hypoglycemia was limited to elevations in only cortisol and epinephrine levels but did not involve glucagon or human GH. This limited hormonal response may also contribute to the frequent occurrence of hypoglycemia in these infants.

Background Since 2000, new syphilis cases increased ten-fold in Canada, particularly among men who have sex with men (MSM) co-infected with HIV. We calculated the prevalence and incidence of syphilis in a large cohort of HIV-positive MSM. Methods We analysed data from 2,903 MSM followed from 2000 to 2009 in the OHTN Cohort Study, an ongoing cohort of persons in HIV care in Ontario, Canada. Syphilis serology was obtained via record linkage with the provincial public health laboratories. We classified reactive rapid plasma reagin results as acute (≥ 16:1) or non-acute (≤ 8:1) and calculated the lifetime and annual prevalence of syphilis and incidence of new syphilis diagnoses and re-diagnoses. Risk factors were identified using Poisson regressions and are reported as rate ratios (RR) with 95% confidence intervals (CI). Results We linked 7,036 syphilis results from 2,422 men (83.4%). Lifetime prevalence was 23.4% (95% CI 21.7, 25.2) by 2009. The annual prevalence of acute syphilis increased from 0.1% (95% CI 0.002, 0.5) in 2000 to 3.8% (95% CI 3.0, 4.6) in 2009. Among 1505 men with a negative specimen, incidence of first syphilis infection was 2.7/100PY (95% CI 2.3, 3.1), with higher rates in men who were aged < 30 years (RR = 2.8, 95% CI 1.4–5.5), ART-naïve (RR = 1.7, 95% CI 1.2–2.5), and had high viral load (> 100,000 copies/mL cf undetectable: RR = 1.8, 95% CI 1.1–3.0). Incidence rose over time, peaking in 2009 at 3.97/100PY (95% CI 3.0, 5.2). Among 591 men with past infection, the rate of re-diagnosis was 4.8 per 100PY (95% CI 3.7, 5.5), with 35% experiencing multiple re-diagnoses. Conclusion Syphilis incidence among HIV-positive MSM was over 300 times greater than in the general male population. Temporal and regional trends mimicked provincial surveillance reports and remain extremely high despite public health education and testing campaigns. Re-diagnosis was common, suggesting treatment failure or re-infection. Novel syphilis control efforts are urgently needed.

Background There is evidence of sexual HCV transmission among HIV-positive MSM from the UK and Europe. We estimated HCV seroincidence and its risk factors in a North American population of HIV-positive MSM with no known history of injection drug use. Methods We analysed data from the OHTN Cohort Study, an ongoing cohort of persons in HIV care in Ontario, Canada. Data were obtained from medical charts, interviews, and record linkage with the provincial public health laboratories. We restricted the analysis to 1,534 MSM who: (1) did not report injection drug use; (2) were under follow-up in 2000–2010; and (3) had 2+ HCV antibody tests, of which the first was negative. Person-time commenced at the later of the HCV-negative result or HIV diagnosis and ended at the first HCV+ or last date of follow-up (median 6.1 person-years (PY) of follow-up; sum 9,987PY). Results We observed 51 HCV seroconversions, for an overall incidence of 0.51 per 100PY (CI: 0.39–0.67). Annual incidence varied from 0.16 to 0.89 per 100 PY, with no statistical evidence of a temporal trend. Seroconversion was statistically-significantly associated with acute syphilis infection in the previous 6 months (adjusted hazard ratio = 4.9, CI 1.2–21) and there was a marginally statistically-significant association for men who had not yet initiated antiretroviral treatment (adjusted hazard ratio = 1.9, CI 0.91–4.0). There were no statistically significant effects of age, ethnicity, region, CD4+ cell count or viral load. Conclusion Sexual behaviour was unmeasured and we cannot exclude the possibility of HCV acquisition via unreported injection drug use. Nevertheless, the strong association with recent syphilis suggests that at least some cases were due to sexual transmission. Future research is needed to establish whether syphilis is a marker for high-risk behaviour or may potentiate sexual HCV transmission among persons with HIV.

Background Understanding patterns of human papillomavirus (HPV) infection in partnerships is essential in exploring transmission of HPV in sexual networks. Risk factors for HPV infection have yet to be explored at the dyad level. We studied features that predict presence of HPV in a new sexual partnership. Methods We analysed data from the HITCH Cohort Study of recently-formed couples. Women aged 18–24 attending university/college in Montreal, Canada and their male partners were recruited in 2006–10. Self-collected vaginal swabs and clinician-obtained swabs from the penis and scrotum were tested for DNA of 36 HPV types. We analysed baseline data from 479 couples. HPV in a partnership was defined as the presence of 1 or more HPV types in either or both partners. We used Poisson regression to calculate prevalence ratios with 95% confidence intervals for candidate risk factors. Results Most women were unvaccinated (88%). 67% of partnerships harboured HPV. For 49% both partners were HPV+. Detection was associated with the combined total of the male’s and female’s lifetime partners; from 27.5% among couples who jointly had no more than 4 partners to 94.2% among couples with > 20. Couples reporting concurrent partners were 2.8 times (95% CI 1.7–4.5) more likely to have HPV compared to those with a 12-month gap since the last extra-dyadic partner but this effect disappeared after adjustment for number of partners. Couples who always or frequently used condoms with their previous partner(s) were 29% (95% CI 9–45%) less likely to have HPV after accounting for number of partners and gap length/concurrency. Conclusions Number of extra-dyadic partners (past or concurrent) predicts the likelihood of HPV in a partnership. Condoms may have some impact on limiting spread of HPV, although protection was incomplete. Epidemiologic monitoring of HPV in sexual networks is needed, particularly in populations with suboptimal HPV vaccine coverage.

G6PC3 is a widely expressed isoform of glucose-6-phosphatase, found in many foetal and adult tissues. Mutations in this gene cause developmental abnormalities and severe neutropenia due to abolition of glucose recycling between the cytoplasm and endoplasmic reticulum. Low G6PC3 expression as a result of promoter polymorphisms or dysregulation could produce similar outcomes. Here we investigated the regulation of human G6PC3 promoter activity. HeLa and H4IIE cells were transiently transfected with G6PC3 promoter coupled to the firefly luciferase gene, and promoter activity was measured by dual luciferase assay. Activity was highest in a 453 bp segment of the G6PC3 promoter, from -455 to -3 relative to the transcriptional start site. This promoter was unresponsive to glucostatic hormones. Its activity increased significantly between 1 and 5.5 mM glucose, and was not elevated further by glucose concentrations up to 25 mM. Pyruvate increased its activity, but β-hydroxybutyrate and sodium acetate did not. Promoter activity was reduced by inhibitors of hexokinase, glyceraldehyde phosphate dehydrogenase and the oxidative branch of the pentose phosphate pathway, but not by a transketolase inhibitor. Deletion of two adjacent Enhancer-boxes (-274 to -279 and -299 to -304) reduced promoter activity and abolished the glucose effect, suggesting they could function as a glucose response element. Deletion of an additional downstream 140 bp (-140 to -306) restored activity, but not the glucose response, suggesting the presence of repressor elements in this region. 5-Aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR) reduced promoter activity, showing dependence on AMP-kinase. Regulation of the G6PC3 promoter is thus radically different to that of the hepatic isoform, G6PC. It is sensitive to carbohydrate, but not to fatty acid metabolites, and at much lower physiological concentrations. Based on these findings, we speculate that reduced G6PC3 expression could occur during hypoglycemic episodes in vivo, which are common in utero and in the postnatal period. If such episodes lower G6PC3 expression they could place the foetus or infant at risk of impaired immune function and development, and this possibility requires further examination both in vitro and in vivo.

Background There have been few studies of the sexual transmission of human papillomavirus (HPV) between partners. Our objective was to estimate transmission rates among persons with documented sexual exposure to an infected partner and longitudinal follow-up. Methods We analysed data from the HITCH Cohort Study, a study of recently-formed couples. Women aged 18–24 attending a university or junior college in Montreal, Canada and their male partners were eligible. Self-collected vaginal swabs and clinician-obtained swabs of epithelial cells from the penis and scrotum were tested for DNA of 36 HPV types. We analysed follow-up data at visit 2 from 179 couples who were discordant for one or more HPV types at enrolment. We defined the index partner as that which was infected with a type(s) not found in the other partner, and a transmission event as subsequent detection of that HPV type in the non-index partner. Transmission rates are expressed as the number of transmissions per 100 person-months (PM), with 95% CI estimated using Poisson regression. Results Transmission was observed in 73 partnerships. There was little difference between the male-to-female (3.5 per 100PM, 95% CI 2.7 to 4.5) and the female-to-male transmission rate (4.0 per 100PM, 95% CI 3.0 to 5.5). These rates are consistent with a per-partnership transmission probability of 0.20 (95% CI 0.16 to 0.24) over 6 months. Transmission rates did not differ with the lifetime number of partners reported by the non-index partner at enrolment or with the circumcision status of the male partner. Rates were highest when the index partner was still positive for that type at follow-up; rates of male-to-female transmission quadrupled and female-to-male transmission tripled (5.2 and 6.2 per 100PM, respectively), compared to when the index partner was negative at follow-up (1.2 and 1.8 per 100PM, respectively, p<0.05). Conclusions Transmission rates based on follow-up of discordant partners are probably underestimates of the true rate due to clearance in index partner and the depletion of susceptibles. Our results contribute to a small but growing evidence base regarding the natural history of HPV transmission and the probability of transmission. These estimates may be of utility to improve forecasting estimates from mathematical modelling efforts to project the public health impact and cost-effectiveness of HPV vaccination.

Background Human placenta may be capable of glucose release due to the presence of Glucose-6-Phosphatase (G6Pase). This release may be from placental glycogen. The authors hypothesised that there would be differences in G6Pase activity and glycogen content in normal pregnancy and small for gestational age (SGA) pregnancies. Methods 48 subjects were recruited to the Appropriate for gestational Age (AGA) group and 48 subjects to the SGA group. SGA was defined as an ultrasound measurement of abdominal circumference 95th centile) and Group 2 (N=19) with Normal Doppler (ND). The placentas were collected postdelivery and analysed for G6Pase activity and glycogen content. Results There was no significant difference in G6Pase activity in the AGA group and SGA group (9.42±2.79 vs 9.1±2.68) mg/min, (p=0.675) and between the SGA ND and SG AD (8.9±2.66 vs 9.6±2.7) mg/min, (p=0.435). Glycogen content in the AGA group was significantly lower compared to the SGA group (3.87 (2.89–5.35) vs 6.2 (4.4–10.35), p=0.001) per mg protein but no significant difference in the glycogen content in SGA ND compared to SGA AD (p=0.242). Conclusion G6Pase activity is similar in AGA and SGA pregnancies. SGA placentas contain more glycogen than AGA subjects which is not explained by G6Pase activity. SGA ND and AD pregnancies display no differences in G6Pase activity and glycogen content.